PITTSBURGH, Oct. 13, 2020 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (NASDAQ: NBSE) (NeuBase or the Company), a biotechnology company accelerating the genetic revolution using a new class of synthetic medicines, announced the addition of Peter Nielsen, Ph.D. to its scientific advisory board. Dr. Nielsen, the primary inventor of peptide nucleic acid (PNA) technology, brings extensive experience in genetic medicine to NeuBase as the Company optimizes its PATrOL therapies and moves them towards the clinic.

We are honored to welcome Dr. Nielsen, a transformational leader in the field of genetics and genomic technologies, to the NeuBase scientific advisory board. His unique perspective gained over his distinctive career will undoubtedly provide valuable insight and complement our team of renowned experts, said Dietrich A. Stephan, Ph.D., chief executive officer of NeuBase. We believe that our new class of synthetic medicines, which relies on the elegant scaffold chemistry invented by Dr. Nielsen, has the potential to change the treatment landscape for many diseases, both common and rare. We look forward to leveraging his unparalleled knowledge as we continue to advance our PATrOL platform under the guidance of our outstanding group of scientific advisors.

Dr. Nielsen added, NeuBases PNA technology is among the first to be advanced through development for therapeutic applications, and I am thrilled to be part of the revolution the Company is leading. I look forward to working with the team and lending my guidance as NeuBase progresses its first-in-class medicines.

Dr. Peter Nielsen is a leading expert in gene targeting, RNA interference and chemical replication and translation and was one of the inventors of PNAs in 1991. He is currently a professor at the University of Copenhagen where his lab focuses on PNAs in regard to drug discovery, gene targeting, antisense principles, cellular and in vivo delivery and administration of biopharmaceuticals. He is the co-author of more than 400 scientific papers and reviews as well as over 20 patents and patent applications, and he serves on the advisory board of four scientific journals.In addition to his esteemed academic career, Dr. Nielsen is the co-founder of two biotech companies in Denmark and is a member of EMBO and the Danish Academy of Technical Sciences. He received his Ph.D. in 1980 from University of Copenhagen.

About NeuBase Therapeutics, Inc.NeuBase is accelerating the genetic revolution using a new class of synthetic medicines. NeuBases designer PATrOL therapies are centered around its proprietary drug scaffold to address genetic diseases at the source by combining the highly targeted approach of traditional genetic therapies with the broad organ distribution capabilities of small molecules. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as "will," "would," "anticipate," "expect," "believe," "designed," "plan," or "intend," the negative of these terms, and similar references to future periods. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission, may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Company's current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Company's plans to develop and commercialize its product candidates; the timing of initiation of the Company's planned clinical trials; the timing of the availability of data from the Company's clinical trials; the timing of any planned investigational new drug application or new drug application; the Company's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Company's product candidates; the Company's commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Company's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the U.S. Securities and Exchange Commission. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

NeuBase Investor Contact:Dan FerryManaging DirectorLifeSci Advisors, LLCDaniel@lifesciadvisors.comOP: (617) 430-7576

NeuBase Media Contact:Cait Williamson, Ph.D.LifeSci Communicationscait@lifescicomms.comOP: (646) 751-4366

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NeuBase Therapeutics Announces Addition of Peter Nielsen, Ph.D., Inventor of Peptide Nucleic Acid Technology, to Scientific Advisory Board - BioSpace

Culture-adapted AAV2 is a viral vector which is used to deliver gene therapy to the liver. However, clinical trials targeting diseases of the liver have had an 'unexpectedly low success rate' using the vector, according to researchers: who have now found that naturally occurring AAVs may be more effective.

The prototypical AAV2 discovered more than 50 years ago provides the serotype on which the field of AAV vectorology and gene therapy is based. The researchers from Australias Childrens Medical Research Institute (CMRI) say the discovery 'will shake the foundations of the field of AAV-based gene therapeutics and will mark the beginning of a new era not only for biomedical research, but most importantly, for millions of patients affected by genetic disorders'.

One area of interest in gene therapy is using AAVs to target the liver, which is involved in genetic disorders such as haemophilia and various enzyme deficiencies.

AAV2 is a viral vector used to deliver gene therapy to the liver, carrying therapeutic DNA to target cells in the body. It binds to a receptor on the target cell. However, the researchers found that while AAV2 binds to the attachment receptors - heparan sulfate proteoglycans (HSPCs) - it does so too tightly.

This means that the vector can get trapped on other cells in the body and not the target liver cells. This reduces the number of vectors that deliver their therapeutic cargo to the liver, diminishing therapeutic efficacy.

The teams of Dr Leszek Lisowski, Head of the Translational Vectorology Research Unit, and Prof Ian Alexander, Head of the Gene Therapy Research Unit, then turned to naturally occurring vectors isolated from liver samples. They found that these which use an as of yet unknown receptor are much more successful at delivering therapies to the liver.

CMRI researchers are now able to make vectors in the lab that use this better receptor, instead of HSPGs, potentially making the next generation of gene therapy targeting the liver 'vastly more successful'.

Theorizing that manufacturing methods could be playing a role, the researcherscompared traditional AAV vectors grown in culture with naturally occurring vectors that they isolated from liver samples. They observed that the cultured vectors rapidly mutated as they replicated in the lab: with these changes making the vectors bind more tightly to molecules called HSPGs on the surface of liver cells, but also impeding their ability to infect humanized liver cells in mice.

In contrast, the naturally occurring vectors infected liver cells more efficiently and bound less tightly to HSPGs, although these effects disappeared when the scientists grew the natural vectors in culture over time.

This really challenges a basic concept in our field that binding strongly to HSPG was essential for AAVs' entry into human cells and suggests that vectors targeting the other receptor used by natural AAVs, of human liver origin, are likely to be more effective for clinical gene therapy applications, said Dr Lisowski. The prototypical AAV2, discovered over 50yrs ago, is the serotype on which the entire field of AAV vectorology and gene therapy is based.

Our study sheds new light and challenges our previous understanding and corrects misconceptions about how the vector binds to the cells.

Researchers at the CMRI can now start to improve on the use of vectors to help children with liver conditions. A better vector can increase safety and improve efficiency, while the increased therapeutic efficacy will mean lower doses are needed and thus reduce the cost of treatment.

The insights on adeno-associated virus receptor binding can potentially be extended to other tissues beyond the liver, add researchers. This makes this a very impactful study which will change the trajectory of AAV-based gene therapies.

Adeno-associated viruses (AAVs) were discovered in the 1960s. The vectorization of AAV2, a human isolate, in 1984 set in motion the development the use of the viral vector in gene therapy.

The liver is a key target for developing more efficient AAV vector delivery, given its direct involvement in a number of genetic and acquired diseases.

Source: Science Translational Medicine, September 9, 2020.DOI: 10.1126/scitranslmed.aba3312

Title: Restoring the natural tropism of AAV2 vectors for human liver

Authors: M. Cabanes-Creus; C.V. Hallwirth; A. Westhaus; B.H. Ng; S.H.Y. Liao; E. Zhu; R.G. Navarro; G. Baltazar; M. Drouyer; S. Scott; G.J. Logan; S.L. Ginn; I.E. Alexander; L. Lisowski at University of Sydney in Westmead, NSW, Australia; C.V. Hallwirth; S. Scott; G.J. Logan; S.L. Ginn; I.E. Alexander at Sydney Children's Hospitals Network in Westmead, NSW, Australia; A. Westhaus; G. Santilli; A.J. Thrasher at University College London in London, UK.

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Researchers explore naturally occurring viral vectors: 'Our study will change the trajectory of AAV-based gene therapies' - BioPharma-Reporter.com

AUSTIN, Texas--(BUSINESS WIRE)--Genprex, Inc. (Genprex or the Company) (NASDAQ: GNPX), a clinical-stage gene therapy company developing potentially life-changing technologies for patients with cancer and diabetes, today announced that it will be presenting at the Alliance for Regenerative Medicines (ARM) virtual Cell and Gene Meeting on the Mesa, taking place October 12-16, 2020. Michael Redman, Executive Vice President and Chief Operating Officer of Genprex, will lead the companys presentation.

The 2020 Cell and Gene Meeting on the Mesa will be delivered in a virtual format over the course of five days where attendees will be able to watch company presentations on-demand, in addition to two live-streaming panels each day. The Cell and Gene Meeting on the Mesa is the sectors foremost annual conference, bringing together senior executives and top decision-makers in the industry to advance cutting-edge research into cures. Tackling the commercialization hurdles facing the cell and gene therapy sector today, this meeting covers a wide range of topics from clinical trial design to alternative payment models to scale-up and supply chain platforms for advanced therapies.

For more information on the conference, or to register, please visit https://www.meetingonthemesa.com.

About Genprex, Inc.

Genprex, Inc. is a clinical-stage gene therapy company developing potentially life-changing technologies for patients with cancer and diabetes. Genprexs technologies are designed to administer disease-fighting genes to provide new treatment options for large patient populations with cancer and diabetes who currently have limited treatment options. Genprex works with world-class institutions and collaborators to develop drug candidates to further its pipeline of gene therapies in order to provide novel treatment approaches. The Companys lead product candidate, GPX-001 (quaratusugene ozeplasmid), is being evaluated as a treatment for non-small cell lung cancer (NSCLC). GPX-001 has a multimodal mechanism of action that has been shown to interrupt cell signaling pathways that cause replication and proliferation of cancer cells; re-establish pathways for apoptosis, or programmed cell death, in cancer cells; and modulate the immune response against cancer cells. GPX-001 has also been shown to block mechanisms that create drug resistance. In January 2020, the U.S. Food and Drug Administration granted Fast Track Designation for GPX-001 for NSCLC in combination therapy with osimertinib (AstraZenecas Tagrisso) for patients with EFGR mutations whose tumors progressed after treatment with osimertinib alone. For more information, please visit the Companys web site at http://www.genprex.com or follow Genprex on Twitter, Facebook and LinkedIn.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the effect of Genprexs product candidates, alone and in combination with other therapies, on cancer and diabetes, regarding potential, current and planned clinical trials, regarding the Companys future growth and financial status and regarding our commercial partnerships and intellectual property licenses. Risks that contribute to the uncertain nature of the forward-looking statements include the presence and level of the effect of our product candidates, alone and in combination with other therapies, on cancer; the timing and success of our clinical trials and planned clinical trials of GPX-001, alone and in combination with targeted therapies and/or immunotherapies, and whether our other potential product candidates, including GPX-002, our gene therapy in diabetes, advance into clinical trials; the success of our strategic partnerships, including those relating to manufacturing of our product candidates; the timing and success at all of obtaining FDA approval of GPX-001 and our other potential product candidates including whether we receive fast track or similar regulatory designations; costs associated with developing our product candidates and whether patents will ever be issued under patent applications that are the subject of our license agreements. These and other risks and uncertainties are described more fully under the caption Risk Factors and elsewhere in our filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

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Genprex to Present at the Alliance for Regenerative Medicine's Virtual Cell and Gene Meeting on the Mesa - Business Wire

Helixmith said Wednesday that it has submitted a phase 3-3 extension study protocol of its gene therapy Engensis (VM202) for diabetic peripheral neuropathy (DPN), to the U.S. Food and Drug Administration.

The company set a one-year follow-up period to confirm the pain reduction and safety of VM202 in treating DPN. DPN is one of the most common complications of diabetic diseases. About 30 million Americans have diabetes, and 28.5 percent of them develop DPN. Among the DPN patients, 40 to 50 percent experience painful symptoms.

The study's primary endpoint is the average pain reduction effect measured and recorded in the pain diary over the last week of the sixth month from the first injection.

The study will be carried out with patients who had not taken Gabapentinoids, such as Pregabalin and Gabapentine, in 15 research laboratories across the U.S., including Northwestern University in Chicago.

"Existing painkillers for DPN patients are not a fundamental treatment for the disease as they only relieved pain while often accompanying serious side effects and high addiction," Helixmith CEO Kim Sun-young said. "We will try our best for the success of phase 3-3 clinical trials as well as the ongoing phase 3-2 study."

FDA recognized the clinical results of Engennsis and designated it as an advanced regenerative medicine advanced therapy (RMAT) in 2018, the company said. RMAT is a new system designed to speed up the development and approval of innovative regenerative therapies. It gives special privileges of the U.S. fast track and priority or accelerated screening.

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Helixmith eyeing P3-3 clinical trials of gene therapy Engensis - Korea Biomedical Review

Sept. 18, 2020 10:45 UTC

KENILWORTH, N.J.--(BUSINESS WIRE)-- AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive five-year follow-up data from the Phase 3 SOLO-1 trial which demonstrated a long-term progression-free survival (PFS) benefit of LYNPARZA versus placebo as a first-line maintenance treatment in patients with newly diagnosed, advanced BRCA-mutated (BRCAm) ovarian cancer who were in complete or partial response to platinum-based chemotherapy.

Ovarian cancer is the eighth most common cause of cancer death in women worldwide and in 2018 there were nearly 300,000 new patients diagnosed and around 185,000 deaths globally. Approximately 22% of patients with ovarian cancer have a BRCA1/2 mutation.

Five-year follow-up data from the Phase 3 SOLO-1 trial showed LYNPARZA reduced the risk of disease progression or death by 67% (HR 0.33 [95% CI 0.250.43]), and improved median PFS to 56 months vs. 13.8 months for placebo. At five years, 48.3% of patients treated with LYNPARZA remained free from disease progression vs. 20.5% on placebo. The median duration of treatment with LYNPARZA was 24.6 months vs. 13.9 months with placebo. Median follow-up in the LYNPARZA arm was 4.8 years and 5 years for placebo.

The safety profile of LYNPARZA was consistent with previous observations in SOLO-1. The most common adverse reactions (ARs) 20% were nausea (77%), fatigue/asthenia (63%), vomiting (40%), anemia (39%) and diarrhea (34%). Grade 3 or greater ARs were reported in 40% of patients in the LYNPARZA arm with the most common being anemia (22%) and neutropenia (9%). ARs led to a dose interruption with LYNPARZA in 58% of patients and a dose reduction in 29% of patients. Twelve percent of patients on LYNPARZA discontinued treatment due to an AR.

Dr. Susana Banerjee, one of the investigators from the SOLO-1 trial and consultant medical oncologist at The Royal Marsden NHS Foundation Trust and reader at the Institute of Cancer Research, said, For patients with newly diagnosed BRCA-mutated advanced ovarian cancer, the benefit derived from two years of maintenance treatment with LYNPARZA continued long after treatment ended. At five years, almost half of these women had not progressed and were still living with stable disease. These results represent a significant step forward in the treatment of BRCA-mutated advanced ovarian cancer.

Dr. Jos Baselga, executive vice president, oncology R&D, AstraZeneca, said, Once a patients ovarian cancer recurs, it has historically been incurable. Even at an advanced stage, we have shown that maintenance treatment with LYNPARZA can help patients achieve sustained remission. Todays results further underline the critical importance of identifying a patients biomarker status at the time of diagnosis to be able to offer a maintenance treatment that may help delay disease progression for these patients.

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, This is the first trial of a PARP inhibitor to read out a five-year follow-up and showed LYNPARZA improved progression-free survival to over four and half years versus 13.8 months with placebo following response to first-line platinum-based chemotherapy. This latest data represents a major and significant milestone in a disease which has historically had such a poor prognosis.

Summary of efficacy results

Progression-Free Survival

(Primary Endpoint)

Recurrence-Free Survival*

(Post Hoc Analysis)

LYNPARZA

N=260

Placebo

N=131

LYNPARZA

N=189

Placebo

N=101

Events, n (%)

118 (45)

100 (76)

79 (42)

74 (73)

Median, m

56.0

13.8

NR

15.3

HR (95% CI)

0.33 (0.250.43)

0.37 (0.270.52)

Patients progression or recurrence free at timepoint, % (Kaplan-Meier estimates)

These analyses are descriptive only; the SOLO-1 trial was not powered to assess a

statistical difference between treatment groups at these time points

1y

87.7 (N=212)

51.4 (N=65)

91.0 (N=159)

58.0 (N=56)

2y

73.6 (N=173)

34.6 (N=41)

77.2 (N=132)

39.0 (N=35)

3y

60.1 (N=129)

26.9 (N=30)

64.0 (N=99)

28.9 (N=25)

4y

52.3 (N=101)

21.5 (N=23)

55.2 (N=75)

23.0 (N=19)

5y

48.3 (N=58)

20.5 (N=16)

51.9 (N=42)

21.8 (N=12)

*Defined post hoc as time from randomization to disease recurrence or death. Patients had complete response at baseline based on electronic case report form data. CI, confidence interval; HR, hazard ratio; NR, not reached

The results were presented on Friday, Sept. 18, 2020, at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 (Abstract #811MO).

The Phase 3 SOLO-1 trial met the primary endpoint of PFS in June 2018, which formed the basis of approvals in the U.S., the EU, Japan, China and several other countries.

About SOLO-1

SOLO-1 was a Phase 3, randomized, double-blinded, placebo-controlled, multi-center trial to evaluate the efficacy and safety of LYNPARZA tablets (300 mg twice daily) as a maintenance monotherapy compared with placebo in newly diagnosed patients with BRCAm advanced ovarian cancer following response to first-line platinum-based chemotherapy. The trial randomized 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy.

Patients were randomized (2:1) to receive LYNPARZA or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigators discretion. The primary endpoint was investigator-assessed PFS and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival. The primary analysis results were presented at the 2018 ESMO Congress and published in The New England Journal of Medicine.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

ADVERSE REACTIONSFirst-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in 25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONSFirst-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in 10% of patients treated with LYNPARZA/bevacizumab compared to a 5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in 25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%).

ADVERSE REACTIONSMaintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in 25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONSAdvanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in 20% of patients in clinical trials of

LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in 25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONSgBRCAm, HER2-negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in 20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

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LYNPARZA (olaparib) Improved Median Progression-Free Survival to Over Four and a Half Years Compared to 13.8 Months with Placebo for Patients with...

Fabrication and endothelialization of spiral tubes in PDMS and collagen gels

We exploited subtractive molding techniques to fabricate spiral tubes in both polydimethylsiloxane (PDMS) and collagen hydrogels and tested the fabrication limit and fidelity. In PDMS, stainless steel springs of various dimensions were molded in liquid-phase PDMS (10:1, base:curing agent) and manually removed after cross-linking. Robust perfusable spiral tubes with constant curvature were generated in PDMS with a diameter larger than 200 m and a pitch greater than 1 mm per turn. The fabrication of smaller spiral tubes in PDMS is less consistent because of the distortion of the channel structure during spring removal. In collagen hydrogels (6 to 7.5 mg/ml), an automatic two-axis motion system was designed to retract the spring from the hydrogel after thermal gelation. Automatic retraction was critical to minimize distortion of the spiral pattern and maximize continuity of the luminal geometry in three dimensions in soft matrices (see Materials and Methods) (Fig. 1A). Spiral tubes of a wide range of wire diameter (dw = 120 to 400 m), spiral diameter (ds = 1 to 3 mm), and pitch (p 400 m) were formed in collagen hydrogels, corresponding to curvature in the range of 0.43 to 1.05 mm1 and torsion in the range of 0.32 to 0.72 mm1 (fig. S1A). Fluorescent beads were perfused to visualize the 3D structure of the spiral lumen [Fig. 1B (a); fig. S1, A and B; and movie S1], where loops of the spiral tubes were periodically spaced with distinct boundaries. Using off-the-shelf springs, we were able to achieve spacing between loops ( = p dw) as small as 210 m. We further modified the spiral mold by adding a cylinder in the center of the spring to generate a second independently perfusable lumen in the hydrogel structure [Fig. 1B (b)]. We fabricated constructs with a central tube concentrically wrapped with a spiral tube and separated by a wall as thin as 200 m.

(A) Schematic of spiral vessel fabrication strategy. Top: A hydrogel is cross-linked around an off-the-shelf spring (a), the pattern is retracted from the gel via a two-axis motion system (b), and vessels were seeded with cells by perfusion (c). Bottom: An independent rod was introduced at the center of the spring to form an additional lumen for independent access and cell seeding. (B) (a) Maximum intensity projection (MIP) of a confocal z-stack of a spiral vessel in collagen perfused with fluorescent beads. (b) Optical section of a collagen spiral vessel (magenta) with an independently perfused center channel (green). Scale bars, 500 m. (C to E) MIP of side (C) and top (D) views of an endothelialized spiral vessel in PDMS and top view of endothelialized collagen vessel (E). Scale bars, 750, 600, and 150 m. (F) Integrated fabrication of spiral vessel (z directional flow) and planar microvessel (x and y directional flow) showing MIP of side and top views with magnified views of regions near (a) and distant from the connection of spiral to planar microvessels (b and c). Magenta, CD31; green, von Willebrand factor; blue, nuclei. Scale bars, 200 m and 50 m (inset). (G) Engineered vascularized tumor model with ECs from the spiral vessel sprouting toward avascular tumor cells embedded in the center lumen of the spiral. Green, CD31; red, KG1a cancer cells; blue, nuclei. Scale bars, 200 m (left) and 100 m (right). (H) Vascularized cardiac chamber model. Green, CD31; red, cTnT; blue, nuclei. Scale bars, 500 m.

Next, we perfused human umbilical vein ECs (HUVECs) into the spiral tubes in either PDMS or collagen to allow cell attachment followed by culture under flow. Both materials supported the growth of a robust endothelium under steady flow for at least 1 week (Q = 1 l/min; Fig. 1, C to E). PDMS spiral vessels with a lumen diameter of less than 200 m often had sparse coverage of ECs on the vessel surface after seeding and were not used in experimental conditions. Collagen spiral vessels better supported endothelialization, and HUVECs were seeded and cultured under similar flow conditions for spiral vessels as small as 180 m with high reproducibility (fig. S1C). ECs in PDMS vessels (lumen diameter > 200 m) and all sized collagen vessels had robust junctions at cell-cell contacts and localized expression of CD31 to the plasma membrane (Fig. 1, C to E). Together, we successfully generated spiral microvessels with constant curvature and torsion at high fidelity and reproducibility and with robust endothelialization and perfusion.

The fabrication process for spiral vessels has the flexibility to integrate with existing vascularization approaches to further enhance tissue perfusion. By incorporating ECs into the bulk matrix, the endothelium in spiral tubes was readily anastomosed with self-assembled vessel networks and increased vascular density (fig. S1D). When combined with lithography and injection molding techniques (31), we successfully connected a spiral vessel with a microfabricated rectilinear vessel so that the spiral outflow was connected to the perfusion of microvessels in an orthogonal direction to the spiral. This integration allows the rotation of the spiral flow direction into another plane and mimics the architecture of the spiral artery to vascular bed connection found in vivo (Fig. 1F). We observed a continuous endothelium in the spiral microvessel connection [Fig. 1F (a)]. ECs in the planar microvessels near the spiral vessel outflow showed greater alignment with the direction of flow, likely due to higher flow stresses [Fig. 1F (a); average angle, 13.5 10.2] compared to cells in regions distant from the spiral microvessel interface [Fig. 1F (b and c); average angle, 39.3 23.7 and 58.13 29.25, respectively]. These findings illustrate the potential of spiral vessels as a new strategy for rapidly generating long and high surface area vascular structures that may enhance tissue vascularization.

Using the concentric spiral platform in collagen gel, we further demonstrated the potential of spiral vessels in supporting 3D tissue function. By dispensing tumor cells (KG1a, a leukemia cell line; Materials and Methods) in a collagen gel (6 mg/ml) into the spatially defined center cylinder (1.3 mm diameter), we formed an artificial tumor surrounded by spiral vessels and monitored the sprouting of vessels from the spiral. This cell-remodelable system mimics the physiological origins of some tumors, where malignancies begin as an avascular cellular mass surrounded by host vasculature that it must recruit for expansion (32). When cultured under flow (Q = 1 l/min) in normal growth medium, spiral vessels (dw = 400 m, ds = 3.0 mm, and p = 1 mm) maintained patency throughout 7 days of culture and sprouted consistently by day 7, but not at day 3 (N = 4 for each time point) (Fig. 1G). These sprouts extended exclusively toward the tumor, with sprouts reaching as far as 220 m from the vessel wall by day 7. No sprouts were observed when there were no tumor cells in the center.

We also created a thick cardiac chamber supported by a spiral vessel using the same concentric model (1.3-mm-diameter by 6-mm-long chamber surrounded by spiral vessel). GCaMP3-transduced human embryonic stem cellderived cardiomyocytes (hESC-CMs) and stromal cells (HS27a) were added into the bulk collagen matrix (33) and ECs (HUVECs) into both the bulk matrix and the spiral lumen, while the center of the tissue was kept open (Fig. 1H). By day 12 of culture, organized calcium waves were observed and appeared to propagate in three dimensions along the spiral vessel wall (movie S2). The conduction velocity in engineered cardiac tissues was 2.7 0.97 cm/s, as determined by analysis of the GCaMP3 signal (fig. S2). These proof-of-concept examples show that the spiral vessel platform can be used to support 3D vascularization and perfusion in large tissues, to study the vascular-tissue interaction in a spatially and temporally controlled manner, and to model complex tissue functions.

We next examined the flow characteristics in these spiral microvessels and compared them with straight vessels of the same caliber. We visualized the flow characteristics by perfusing fluorescent bead solutions in two parallel streams through straight and spiral PDMS vessels of the same diameter and length (dvessel = 400 m, dspiral = 3 mm, pspiral = 1 mm, spiral = 0.46 mm1, spiral = 0.31 mm1, and L = 6.5 cm) at three steady flow conditions (Q = 1, 50, and 100 l/min, corresponding to Re = 0.01, 0.76, and 1.52, respectively). The 3D flow images were taken under confocal fluorescence microscopy at set distances (Lv = 5, 30, and 55 mm in straight vessels, or loops 3/4, 3 3/4, and 6 3/4 in spiral vessels) from the vessel inlet. Straight tubes displayed a classical parallel flow profile where the two streams of beads traveled to the outlet and maintained their position over the whole vessel length at both flow rates (Fig. 2, A and C). In spiral tubes, the two bead streams remained distinct and parallel at low flow (Q = 1 l/min) but rotated over the vessel length without obvious mixing in the bulk [Fig. 2B (a to c)]. The orientation of the two parallel streams inverted after approximately four loops from the inlet [Fig. 2B (b)] and completed a full rotation at approximately loop 7 [Fig. 2B (c)]. At a higher flow rate (Q = 50 l/min) in the same spiral geometry (De = 2.77), the two bead streams developed obvious bulk mixing with the leading edge of flow rotating 270 after three loops [Fig. 2B (e)] and completed another full rotation by loop 7 [Fig. 2B (f)]. At even higher flow (Q = 100 l/min), a stronger mixing effect was observed in the same spiral geometry [Fig. 2B (g to i)], whereas the two streams remained parallel and unmixed in straight vessels under the same flow conditions.

(A and B) Confocal cross sections of perfusion of two parallel streams of red and blue beads into a straight PDMS vessel (A) at a flow rate of Q = 50 l/min and a spiral PDMS vessel (B) at three flow rates (Q = 1, 50, and 100 l/min) at three distances from the vessel inlet (Lv,a 5 mm, Lv,b 30 mm, and Lv,c 55 mm), corresponding to the 3/4, 3 3/4, and 6 3/4 spiral loops (LL = linear length, Lv = vessel length, dv = vessel diameter, p = pitch). (C and D) Computational fluid dynamics plots of straight (C) and spiral (D) vessels at Q = 50 l/min for (a) streamlines (color expressed with primary velocity magnitude), (b) primary velocity magnitude, (c) secondary flow velocity orthogonal to cross-sectional plane, and (d) shear rate at the cross-sectional views.

Using numerical simulation with COMSOL, we confirmed these flow characteristics: (i) Idealized parallel streamlines were present in fully developed flow in straight vessels [Fig. 2C (a)]; (ii) parallel streamlines in spiral vessels slightly rotate along circumferential direction at low flow (Q = 1 l/min; fig. S3A); and (iii) streamline rotation was enhanced in spiral vessels and developed twists at higher flow [Q = 50 l/min; Fig. 2D (a)] and had clear twists at Q = 100 l/min (fig. S3B). The spiral geometry did not induce a significant change in the primary flow compared to straight vessels but did lead to the emergence of secondary flows with a peak magnitude of around 1% of the primary flow velocity [Q = 50 l/min; Fig. 2, C (b and c) and D (b and c)]. This also led to the development of a shear stress gradient in 3D space and a change in the wall shear stress (WSS), with a maximum (10% increase over the straight tube) on the surface of the inner curvature and minimum on the outer bend, unlike in a straight tube where the WSS was constant across the lumen cross section with zero gradients [Fig. 2, C (d) and D (d)]. These data demonstrated that spiral vessels induced bulk flow mixing and heterogeneous hemodynamic forces on the endothelium lining the wall due to 3D curvature and torsion.

To understand how the distinct hemodynamic features of flow in spiral vessels affected ECs, we cultured cells in both geometries under flow. In straight and spiral vessels, ECs formed robust junctions and a stable endothelium in low (Q = 1 l/min and WSS = 0.1 dyne/cm2 in straight vessels) and high (Q = 50 l/min and WSS = 4.6 dynes/cm2 in straight vessels) flow conditions. The increased flow appeared to change the EC morphology and enhance EC alignment in the direction of flow (Fig. 3A). Under low flow conditions (Q = 1 l/min; Fig. 3B), fewer Ki67+ proliferating cells were observed in spiral vessels than in straight vessels. When exposed to higher flow, however, more proliferating cells were observed in the spiral geometry than the straight geometry, suggesting distinct roles for geometry and flow on the ECs. Previous literature has highlighted that very low laminar flows activate ECs, whereas high laminar flow enhances EC quiescence (11). Our data were consistent with this in straight vessels with significantly reduced cell proliferation at higher flow. In spiral vessels, however, the flow rotation in low flow may alter transport and promote quiescence at low flow. Given that the magnitude of flow forces is very low in the low flow conditions, it is also likely that differences in substrate curvature between straight and spiral geometries contribute to these observed differences (34).

(A) MIP of EC cultured under flow (Q = 50 l/min) for 24 hours. Blue, nuclei; green, CD31; red, Ki67. Scale bar, 50 m. (B) Quantification of the percentage of Ki67-positive nuclei by counting 100+ cells per vessel in N = 3 vessels at two flow conditions (Q = 1 and 50 l/min). Error bars represent 95% confidence interval of the mean. *P < 0.05 using a one-way analysis of variance (ANOVA) with Tukeys pairwise comparisons. (C) PCA of RNA-seq data from cells cultured at static and at two flow conditions in two vessel geometries (N = 3). (D) Venn diagram showing the overlap of genes significantly changed by increasing flow in straight and spiral geometries. (E) Heatmap of log counts per million (CPM) values of known flow-responsive genes. All genes are present in the overlapping region of (D) (green). (F) Heatmaps of the CPM values of significantly regulated transcripts belonging to the nonoverlapping regions of (D). Three hundred fifty-five genes uniquely regulated in straight high versus low (top, yellow) and 1261 genes uniquely regulated in spiral high versus low (bottom, blue). (G) Heatmaps of the CPM values of selected growth factors, transporters, and transcription factors. (H) IPA functional pathways identified by comparing spiral to straight vessels under high flow.

We next examined the transcriptional changes in ECs in these conditions via RNA sequencing (RNA-seq) for ECs cultured under both flow conditions in straight and spiral vessels and under static conditions. Principal components analysis (PCA) of gene expression data showed clustering of individual groups, with the largest variance between static and all flow conditions (Fig. 3C). Activation of classical flow-dependent genes was confirmed in all flow conditions compared to static culture (Fig. 3, D and E). Among these genes, KLF2 and KLF4 appeared to only change with the onset of flow but were not sensitive to a further increase in flow, whereas SMAD6, SMAD7, and NOS3 increased further at higher flow conditions. Among the genes differentially expressed in straight vessels due to the increase of flow, 52% (533 of 1012) overlap with genes differentially expressed in the onset of flow (static versus low flow condition) (fig. S4, A and B). The genes unique to the increase of flow include up-regulation of many genes previously reported to regulate vascular development and flow sensing (35), such as Notch ligands JAG1 and JAG2; Notch target HEY2 and other transcription factors such as SNAI2; transmembrane proteins IL21R and EFNB2; transporter GJA5; peptidases MMP10, MMP1, and MT1F; growth factors and cytokines NOG, DKK2, WNT4, CXCL12, and TGFB1; and other molecules such as VCAN and CYP1B1 (fig. S4C). Gene Ontology (GO)enriched terms for this group of genes showed up-regulation of cellular response to growth factors, vascular development, transmembrane receptor protein tyrosine kinase signaling pathway, blood vessel morphogenesis, cell migration and motility, and others (fig. S4D).

Approximately 66% (722 of 1136) of differentially expressed genes in straight vessels overlap with those in spiral vessels in response to increased flow (Fig. 3D). Almost all overlapping genes are changed in the same direction (99%), suggesting a conserved response to flow in both geometries (fig. S5A). MARC2, PTX3, and STX11 did not follow this trend and were up-regulated in spiral vessels with increased flow but down-regulated in straight vessels. PTX3 has been reported as a biomarker for endothelial dysfunction in preeclampsia, which is a disease caused by spiral artery dysfunction (36). Many genes down-regulated in straight vessels by the increase of flow did not show changes in spiral vessels, such as growth factors CTGF, FGF2, NRG1, and FGF16; transmembrane proteins CAV1, UNC5A, KIT, and SMAD4A; transcription regulators EGR1/2/3, MAF, MYRF, and MZF1; transporters such as LDLR; and cytokines TNFSF18, IL12A, CCL2, CCL16, and CCL28 (fig. S5B). This suggests that the EC response to flow in spiral vessels is a combination of both canonical flow pathways and a distinct response involving a wide range of other transcripts.

Increased flow also led to an additional 1294 genes significantly changed in spiral vessels that were not in straight ones (Fig. 3F). High flow in spiral vessels appeared to activate growth factors such as DKK1, ESM1, BMP2, PDGFA, OSGIN2, and VEGFC; many solute carrier (SLC) and adenosine triphosphate (ATP)binding cassette (ABC) superfamily transporters; transcriptional regulators such as GLI2; cytokine CXCL1; peptidases TLL1, ADAMTS1, ADAMTS9, and TASP1; and kinases PODXL, EPHA5, HK2, PRKCA, CCT2, and MAP2K1 (Fig. 3G and fig. S6A). In addition, high flow in spiral vessels repressed growth factors such as MST, NRG2, GDF3, GAS6, and IGF2; transmembrane receptors CHRNA1, SELP, LRP1, ITGB3, and ROBO3; transporters including MAL2, ATP2A3, RBP1, and APOL1 and several members of SLC and ABC superfamilies; transcriptional regulators such as NOTCH3, CITED4, CAND2, FOXO4, DACH1, and EBF3; cytokines DKK3, CSF1, and FLT3LG; GPCR (G proteincoupled receptor) group SIPR4, OPRL1, and HTR2B; and kinases PDGFRB, CKB, and SBK1 (Fig. 3F and fig. S6A). GO term analysis showed the up-regulation of primarily ribosome biogenesis, which would be critical for cellular growth and proliferation (fig. S6B). These expression profiles show that spiral vessels share a common set of flow-responsive elements with straight vessels but have an additional response that appeared to promote vascular growth.

PCA analysis showed that the separation of straight and spiral geometries was enhanced under higher flow conditions (Fig. 3E). Under low flow conditions (Re << 1; inertia effect is negligible), ECs in the two geometries were largely similar, with only a handful of significantly regulated transcripts (fig. S7A). These included CYTL1, which is known to up-regulate proangiogenic function, but not proinflammatory pathways (37). HES2, a downstream Notch pathway gene, STK32B (serine/threonine kinase 32B), and CCND1, a cell cycle regulation gene, were also up-regulated in low flow spiral vessels. The up-regulation of these genes was further enhanced in high flow conditions. In addition, many genes that regulate vascular development were up-regulated when comparing spiral to straight vessels at high flow, for example, growth factors HGF, DKK1, ESM1, PGF, PDGFA, GDF6, PDGFB, CTGF, VEGFC, BMP2, and PDGFC; peptidases ADAMTS1, ADAMTS9, MME, and CTSS; kinases EPHA5, MPP4, PODXL, SPRY2, CDK7, and MAP2K1; transmembrane receptors KIT, SELE, ULBP2, PLXNA2, and LRP8; transcriptional regulators GLI2 (a hedgehog pathway mediator), ATF3 (required for endothelial regeneration) (38), and FOSL1 (required for vascular formation) (39); and many SLC and ATP family transporters (Fig. 3G). Ingenuity Pathway Analysis (IPA) showed that ECs in spiral vessels have activated upstream regulators including prosurvival factors HGF, PGF, EGF, VEGF, and HIF-1a. Up-regulated functional pathways included vascular development, angiogenesis, vasculogenesis, cell invasion, and cell survival, whereas cell death and necrosis were decreased compared to the straight vessel in high flow conditions (Fig. 3H and fig. S7B). Spiral vessels also showed the activation of antiapoptotic and proliferative pathways marked by cell cycle and mitotic genes. PDGF (platelet-derived growth factor) family members were relatively more abundant, as were molecules associated with IL-8 (interleukin-8) and HGF (hepatocyte growth factor) signaling (fig. S7B).

Together, the bulk RNA-seq showed that spiral vessels maintain a normal flow response to a certain extent, but curvature and torsion modified the response by up-regulating markers for transporters, cycling, and survival and down-regulating markers of cell death. These data suggest that flow in spiral vessels promoted vascular growth or development rather than inducing a common inflammatory response to disturbed flow.

We hypothesized that ECs exposed to flow within spiral vessels experienced a spatial variation in hemodynamic forces not present in straight vessels that would result in a heterogeneous transcriptional response to flow. To understand this heterogeneity at the single-cell level, we sequenced the transcriptomes of more than 2000 individual ECs pooled from three to four devices of each geometry cultured at high flow (Q = 50 l/min). Dimensionality reduction by Uniform Manifold Approximation and Projection (UMAP) and cluster analysis was performed using Monocle (4042). Projection in the top two UMAP dimensions shows overlapping contributions of ECs from spiral and straight vessels that form mostly contiguous clusters with nearly uniform expression of pan-endothelial markers such as CDH5 (VE-cadherin) (Fig. 4, A and B). Expression of classical flow-dependent genes, including KLF4 and NOS3, is distributed throughout the major clusters of ECs in this projection (Fig. 4C). We identified variation in gene expression across the first UMAP dimension driven largely by cell cycle genes that have been shown to be regulated, in part, by flow. Specifically, a large cluster of cells to the right in UMAP space (cluster 3) express genes such as MKI67, consistent with active cell cycle status, whereas cells clustered to the opposite pole (cluster 1) express genes implicated in cell cycle arrest and arterial phenotype shown to be regulated by the Notch pathway downstream of laminar shear stress (including CDKN1C, EFNB2, HEY1, GJA4, and IL33; Fig. 4C) (4345).

(A) UMAP plots of spiral high flow and straight high flow cells, computationally derived clusters (B), and the distribution of endothelial and cell cycling genes across cells (C). (D) UMAP plots of the first and third UMAP dimensions, the corresponding location of clusters in this dimensional space (E) with examples of cluster specific genes (F), as well as a selection of genes identified as significantly differentially expressed (G).

To evaluate heterogeneity in the transcriptional response of ECs resulting from vessel geometry, we next identified differentially expressed genes on the basis of single-cell RNA-seq (scRNA-seq) data of EC from straight versus spiral vessels. Examination of the third UMAP dimension revealed separation in transcriptional space between EC from straight versus spiral vessels, with many of the identified differentially expressed genes polarized in this dimension (Fig. 4, D to F). Among the genes up-regulated in EC from spiral vessels are many that were also identified as differentially expressed in bulk RNA-seq analysis, including ATF3, SPRY2, IL8, JUN, AKAP12, ANGPTL4, FOSL1, ADAMTS1, and ADAMTS9 (Fig. 4G and fig. S8A). Most of these genes are expressed in a common pattern, with increased expression in cells localized in UMAP space to the lower (spiral) portion of cluster 2. This suggests a distinct transcriptional program among the primarily spiral ECs in this region that may correspond with their transcriptional response to specific hemodynamic conditions unique to spiral vessels under high flow. In further support of this hypothesis, analysis of the scRNA-seq data also identified differentially expressed genes not detected in bulk RNA-seq, including DCN, SLC6A9, GEM, NRG1, RSPO3, BAMBI, TGFBI, and PRRX2, that were highly specific to EC from spiral vessels localized in cluster 2 (Fig. 4G and fig. S8B). These data suggest that flow in spiral vessels induced a population of ECs with unique gene expression profiles that are not present in straight vessels, with potential roles in processes such as angiogenesis, vascular growth, and inflammatory and stress responses.

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3D curvature-instructed endothelial flow response and tissue vascularization - Science Advances

Following the death of Chadwick Boseman, who died after being diagnosed with colon cancer four years ago, a doctor is speaking about the importance of screening.

SEATTLE Fans of Chadwick Boseman were shocked to hear the accomplished actor died at the age of 43 after being diagnosed with colon cancer four years ago.

As people continued to grieve Boseman's death over the weekend, a doctor at Swedish Medical Center explained that while the overall rate of colon cancer is decreasing due to improved screening, it is rising in people under the age of 50.

"I've had patients as young as fourteen with colorectal cancer," Dr. Amir Bastawrous said. "That's very rare, but I can tell you in 2020 I've had half a dozen patients under the age of 50 with colorectal cancer. Just me, myself."

Though the stigma behind colon cancer has changed over the years, knowing the risk factors and symptoms is just as important as screening, Dr. Bastawrous said.

"The biggest risk factor would be if you've got a genetic predisposition if you clearly have a gene that predisposes you to colorectal cancer," he said. If that's the case, he recommends people be tested as early as in their 20s. "If you have a first-degree relative that had colon cancer under the age of 50, you'd usually start ten years young than they were when they were diagnosed with colorectal cancer."

Advancements in medicine over the past 20 years have made early detection easier and more important, he said.

"It was still quite, quite difficult to get people to have their screening test even at age fifty, and our rate of screening was in the twenty-five to forty percent range across the country, which is terrible. And now, across the country, there are places that are well over eighty percent screening.

"Here in Washington state we're about sixty-seven percent."

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Know the risk factors, symptoms of colon cancer - KING5.com

Dublin, Aug. 31, 2020 (GLOBE NEWSWIRE) -- The "RNA-interference (RNAi) Market - Growth, Trends, and Forecast (2020 - 2025)" report has been added to ResearchAndMarkets.com's offering.

The RNA-interference (RNAi) market is expected to witness a CAGR of 10.12% during the forecast period. Certain factors that are driving the market growth include the increasing number of applications in molecular diagnostics, particularly in cancer and improving synthetic delivery carriers and chemical modifications to RNA.

Cancer diagnosis and treatment is currently undergoing a shift with the incorporation of RNAi techniques in personalized medicine and molecular diagnostics. The availability of high throughput techniques for the identification of altered cellular molecules and metabolites allows the use of RNAi techniques in various cancer diagnosis and targeting approaches. For diagnostic purposes, small interfering RNAs (siRNA) or microRNAs (miRNA) can be utilized. The commercial availability of siRNAs to silence virtually any gene in the human genome is dramatically accelerating the pace of molecular diagnosis and biomedical research. Thus, increasing the application of RNAi in molecular diagnosis and its viability as a therapeutic technique is expected to drive the growth of the RNAi market during the forecast period.

However, in recent years, there has been a decline in FDA drug approval rates. Getting FDA approval for a new drug has become extremely challenging. It approved less than half the number of new drugs in 2016 (19 so far) when compared to 2015 (45 total) and 2014 (41 total). Hence, despite the large investments, there has been a decline in the number of innovative drugs manufactured. FDA explains manufacturing standards and other complying issues as the major reasons for this declining trend. This can impede the growth of the RNAi therapeutics, especially since the miRNAs and siRNAs fall into the relatively new field of genetic medicine, wherein they may require more intensified clinical trials. The highly extensive clinical trials effectively result in low approval rates of drugs. This would mean that the stringent guidelines will be a major restraint for the growth of the market.

Key Market Trends

Oncology is Expected to Hold Significant Market Share in the Therapeutics Type

According to the World Health Organization, cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer. The number of new cases is expected to rise by about 70% over the next two decades.

Recent advancements, such as the development of small interfering RNA (siRNA) tolerant to nucleases and the development of non-viral vectors, such as cationic liposomes and nanoparticles, can overcome this obstacle and facilitate the clinical use of RNAi-based therapeutics in the treatment of cancer.

Substantial pipeline for cancer therapies by companies and institutes such as Enzon Pharmaceuticals (Santaris Pharma), University of Texas, OncoGenex, Isarna Therapeutics, Astrazeneca (Ionis Pharmaceuticals), and INSYS Therapeutics, Inc. are expected to drive the market. In addition, many companies have invested in R&D for nanocarriers to deliver oligonucleotides for cancer treatment, which is expected to contribute to the oncology verticle.

North America Dominates the Market and Expected to do the Same in the Forecast Period

The U.S. has a number of RNAi therapeutics that are in developmental pipelines. A number of biotechnology companies have made considerably high investments for RNAi therapeutic development. Big pharmaceutical developers have entered into collaboration agreements or licensing deals with a number of smaller firms in an attempt to capitalize on the expected growth in revenue that this market can have over the forecast period. For instance, AstraZeneca's agreement with Ionis pharmaceuticals is one of the big deals that are investing heavily into RNA-interference technology

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS4.1 Market Overview4.2 Market Drivers4.2.1 Increasing Number of Applications in Molecular Diagnostics, Particularly in Cancer4.2.2 Improving Synthetic Delivery Carriers and Chemical Modifications to RNA4.3 Market Restraints4.3.1 Stringent FDA Regulations and Changing Reimbursement Environment4.3.2 Unstable Potentially Immunogenic Nature of RNA4.4 Porter's Five Forces Analysis4.4.1 Threat of New Entrants4.4.2 Bargaining Power of Buyers/Consumers4.4.3 Bargaining Power of Suppliers4.4.4 Threat of Substitute Products4.4.5 Intensity of Competitive Rivalry

5 MARKET SEGMENTATION5.1 Application5.2 Geography

6 COMPETITIVE LANDSCAPE6.1 Company Profiles6.1.1 Alnylam Pharmaceuticals6.1.2 Arcturus Therapeutics6.1.3 Arrowhead6.1.4 Dicerna Pharmaceuticals6.1.5 Quark Pharmaceuticals Inc.6.1.6 Ionis Pharmaceuticals Inc.6.1.7 Merck & Co. Inc. (Sigma Aldrich)6.1.8 Silence Therapeutics PLC6.1.9 Qiagen NV6.1.10 Phio Pharmaceuticals Corp.6.1.11 Thermo Fisher Scientific Inc.

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

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World RNAi Market 2020-2025: Oncology is Expected to Hold Significant Market Share in the Therapeutics Type Area - Yahoo Finance

Efforts to use regenerative medicinewhich seeks to address ailments as diverse as birth defects, traumatic injury, aging, degenerative disease, and the disorganized growth of cancerwould be greatly aided by solving one fundamental puzzle: How do cellular collectives orchestrate the building of complex, three-dimensional structures?

While genomes predictably encode the proteins present in cells, a simple molecular parts list does not tell us enough about the anatomical layout or regenerative potential of the body that the cells will work to construct. Genomes are not a blueprint for anatomy, and genome editing is fundamentally limited by the fact that its very hard to infer which genes to tweak, and how, to achieve desired complex anatomical outcomes. Similarly, stem cells generate the building blocks of organs, but the ability to organize specific cell types into a working human hand or eye has been and will be beyond the grasp of direct manipulation for a very long time.

But researchers working in the fields of synthetic morphology and regenerative biophysics are beginning to understand the rules governing the plasticity of organ growth and repair. Rather than micromanaging tasks that are too complex to implement directly at the cellular or molecular level, what if we solved the mystery of how groups of cells cooperate to construct specific multicellular bodies during embryogenesis and regeneration? Perhaps then we could figure out how to motivate cell collectives to build whatever anatomical features we want.

New approaches now allow us to target the processes that implement anatomical decision-making without genetic engineering. In January, using such tools, crafted in my lab at Tufts Universitys Allen Discovery Center and by computer scientists in Josh Bongards lab at the University of Vermont, we were able to create novel living machines, artificial bodies with morphologies and behaviors completely different from the default anatomy of the frog species (Xenopus laevis) whose cells we used. These cells rebooted their multicellularity into a new form, without genomic changes. This represents an extremely exciting sandbox in which bioengineers can play, with the aim of decoding the logic of anatomical and behavioral control, as well as understanding the plasticity of cells and the relationship of genomes to anatomies.

Deciphering how an organism puts itself together is truly an interdisciplinary undertaking.

Deciphering how an organism puts itself together is truly an interdisciplinary undertaking. Resolving the whole picture will involve understanding not only the mechanisms by which cells operate, but also elucidating the computations that cells and groups of cells carry out to orchestrate tissue and organ construction on a whole-body scale. The next generation of advances in this area of research will emerge from the flow of ideas between computer scientists and biologists. Unlocking the full potential of regenerative medicine will require biology to take the journey computer science has already taken, from focusing on the hardwarethe proteins and biochemical pathways that carry out cellular operationsto the physiological software that enables networks of cells to acquire, store, and act on information about organ and indeed whole-body geometry.

In the computer world, this transition from rewiring hardware to reprogramming the information flow by changing the inputs gave rise to the information technology revolution. This shift of perspective could transform biology, allowing scientists to achieve the still-futuristic visions of regenerative medicine. An understanding of how independent, competent agents such as cells cooperate and compete toward robust outcomes, despite noise and changing environmental conditions, would also inform engineering. Swarm robotics, Internet of Things, and even the development of general artificial intelligence will all be enriched by the ability to read out and set the anatomical states toward which cell collectives build, because they share a fundamental underlying problem: how to control the emergent outcomes of systems composed of many interacting units or individuals.

Many types of embryos can regenerate entirely if cut in half, and some species are proficient regenerators as adults. Axolotls (Ambystoma mexicanum) regenerate their limbs, eyes, spinal cords, jaws, and portions of the brain throughout life. Planarian flatworms (class Turbellaria), meanwhile, can regrow absolutely any part of their body; when the animal is cut into pieces, each piece knows exactly whats missing and regenerates to be a perfect, tiny worm.

The remarkable thing is not simply that growth begins after wounding and that various cell types are generated, but that these bodies will grow and remodel until a correct anatomy is complete, and then they stop. How does the system identify the correct target morphology, orchestrate individual cell behaviors to get there, and determine when the job is done? How does it communicate this information to control underlying cell activities?

Several years ago, my lab found that Xenopus tadpoles with their facial organs experimentally mixed up into incorrect positions still have largely normal faces once theyve matured, as the organs move and remodel through unnatural paths. Last year, a colleague at Tufts came to a similar conclusion: the Xenopus genome does not encode a hardwired set of instructions for the movements of different organs during metamorphosis from tadpole to frog, but rather encodes molecular hardware that executes a kind of error minimization loop, comparing the current anatomy to the target frog morphology and working to progressively reduce the difference between them. Once a rough spatial specification of the layout is achieved, that triggers the cessation of further remodeling.

The deep puzzle of how competent agents such as cells work together to pursue goals such as building, remodeling, or repairing a complex organ to a predetermined spec is well illustrated by planaria. Despite having a mechanistic understanding of stem cell specification pathways and axial chemical gradients, scientists really dont know what determines the intricate shape and structure of the flatworms head. It is also unknown how planaria perfectly regenerate the same anatomy, even as their genomes have accrued mutations over eons of somatic inheritance. Because some species of planaria reproduce by fission and regeneration, any mutation that doesnt kill the neoblastthe adult stem cell that gives rise to cells that regenerate new tissueis propagated to the next generation. The worms incredibly messy genome shows evidence of this process, and cells in an individual planarian can have different numbers of chromosomes. Still, fragmented planaria regenerate their body shape with nearly 100 percent anatomical fidelity.

Permanent editingof the encoded target morphology without genomic editing reveals a new kind of epigenetics.

So how do cell groups encode the patterns they build, and how do they know to stop once a target anatomy is achieved? What would happen, for example, if neoblasts from a planarian species with a flat head were transplanted into a worm of a species with a round or triangular head that had the head amputated? Which shape would result from this heterogeneous mixture? To date, none of the high-resolution molecular genetic studies of planaria give any prediction for the results of this experiment, because so far they have all focused on the cellular hardware, not on the logic of the softwareimplemented by chemical, mechanical, and electrical signaling among cellsthat controls large-scale outcomes and enables remodeling to stop when a specific morphology has been achieved.

Understanding how cells and tissues make real-time anatomical decisions is central not only to achieving regenerative outcomes too complex for us to manage directly, but also to solving problems such as cancer. While the view of cancer as a genetic disorder still largely drives clinical approaches, recent literature supports a view of cancer as cells simply not being able to receive the physiological signals that maintain the normally tight controls of anatomical homeostasis. Cut off from these patterning cues, individual cells revert to their ancient unicellular lifestyle and treat the rest of the body as external environment, often to ruinous effect. If we understand the mechanisms that scale single-cell homeostatic setpoints into tissue- and organ-level anatomical goal states and the conditions under which the anatomical error reduction control loop breaks down, we may be able to provide stimuli to gain control of rogue cancer cells without either gene therapy or chemotherapy.

During morphogenesis, cells cooperate to reliably build anatomical structures. Many living systems remodel and regenerate tissues or organs despite considerable damagethat is, they progressively reduce deviations from specific target morphologies, and halt growth and remodeling when those morphologies are achieved. Evolution exploits three modalities to achieve such anatomical homeostasis: biochemical gradients, bioelectric circuits, and biophysical forces. These interact to enable the same large-scale form to arise despite significant perturbations.

N.R. FULLER, SAYO-ART, LLC

BIOCHEMICAL GRADIENTS

The best-known modality concerns diffusible intracellular and extracellular signaling molecules. Gene-regulatory circuits and gradients of biochemicals control cell proliferation, differentiation, and migration.

BIOELECTRIC CIRCUITS

The movement of ions across cell membranes, especially via voltage-gated ion channels and gap junctions, can establish bioelectric circuits that control large-scale resting potential patterns within and among groups of cells. These bioelectric patterns implement long-range coordination, feedback, and memory dynamics across cell fields. They underlie modular morphogenetic decision-making about organ shape and spatial layout by regulating the dynamic redistribution of morphogens and the expression of genes.

BIOMECHANICAL FORCES

Cytoskeletal, adhesion, and motor proteins inside and between cells generate physical forces that in turn control cell behavior. These forces result in large-scale strain fields, which enable cell sheets to move and deform as a coherent unit, and thus execute the folds and bends that shape complex organs.

The software of life, which exploits the laws of physics and computation, is enabled by chemical, mechanical, and electrical signaling across cellular networks. While the chemical and mechanical mechanisms of morphogenesis have long been appreciated by molecular and cell biologists, the role of electrical signaling has largely been overlooked. But the same reprogrammability of neural circuits in the brain that supports learning, memory, and behavioral plasticity applies to all cells, not just neurons. Indeed, bacterial colonies can communicate via ionic currents, with recent research revealing brain-like dynamics in which information is propagated across and stored in a kind of proto-body formed by bacterial biofilms. So it should really come as no surprise that bioelectric signaling is a highly tractable component of morphological outcomes in multicellular organisms.

A few years ago, we studied the electrical dynamics that normally set the size and borders of the nascent Xenopus brain, and built a computer model of this process to shed light on how a range of various brain defects arise from disruptions to this bioelectric signaling. Our model suggested that specific modifications with mRNA or small molecules could restore the endogenous bioelectric patterns back to their correct layout. By using our computational platform to select drugs to open existing ion channels in nascent neural tissue or even a remote body tissue, we were able to prevent and even reverse brain defects caused not only by chemical teratogenscompounds that disrupt embryonic developmentbut by mutations in key neurogenesis genes.

Similarly, we used optogenetics to stimulate electrical activity in various somatic cell types totrigger regeneration of an entire tadpole tailan appendage with spinal cord, muscle, and peripheral innervationand to normalize the behavior of cancer cells in tadpoles strongly expressing human oncogenes such as KRAS mutations. We used a similar approach to trigger posterior regions, such as the gut, to build an entire frog eye. In both the eye and tail cases, the information on how exactly to build these complex structures, and where all the cells should go, did not have to be specified by the experimenter; rather, they arose from the cells themselves. Such findings reveal how ion channel mutations result in numerous human developmental channelopathies, and provide a roadmap for how they may be treated by altering the bioelectric map that tells cells what to build.

We also recently found a striking example of such reprogrammable bioelectrical software in control of regeneration in planaria. In 2011, we discovered that an endogenous electric circuit establishes a pattern of depolarization and hyperpolarization in planarian fragments that regulate the orientation of the anterior-posterior axis to be rebuilt. Last year, we discovered that this circuit controls the gene expressionneeded to build a head or tail within six hours of amputation, and by using molecules that make cell membranes permeable to certain ions to depolarize or hyperpolarize cells, we induced fragments of such worms to give rise to a symmetrical two-headed form, despite their wildtype genomes. Even more shockingly, the worms continued to generate two-headed progeny in additional rounds of cutting with no further manipulation. In further experiments, we demonstrated that briefly reducing gap junction-mediated connectivity between adjacent cells in the bioelectric network that guides regeneration led worms to regenerate head and brain shapes appropriate to other worm species whose lineages split more than 100 million years ago.

My group has developed the use of voltage-sensitive dyes to visualize the bioelectric pattern memory that guides gene expression and cell behavior toward morphogenetic outcomes. Meanwhile, my Allen Center colleagues are using synthetic artificial electric tissues made of human cells and computer models of ion channel activity to understand how electrical dynamics across groups of non-neural cells can set up the voltage patterns that control downstream gene expression, distribution of morphogen molecules, and cell behaviors to orchestrate morphogenesis.

The emerging picture in this field is that anatomical software is highly modulara key property that computer scientists exploit as subroutines and that most likely contributes in large part to biological evolvability and evolutionary plasticity. A simple bioelectric state, whether produced endogenously during development or induced by an experimenter, triggers very complex redistributions of morphogens and gene expression cascades that are needed to build various anatomies. The information stored in the bodys bioelectric circuitscan be permanently rewritten once we understand the dynamics of the biophysical circuits that make the critical morphological decisions. This permanent editing of the encoded target morphology without genomic editing reveals a new kind of epigenetics, information that is stored in a medium other than DNA sequences and chromatin.

Recent work from our group and others has demonstrated that anatomical pattern memories can be rewritten by physiological stimuli and maintained indefinitely without genomic editing. For example, the bioelectric circuit that normally determines head number and location in regenerating planaria can be triggered by brief alterations of ion channel or gap junction activity to alter the animals body plan. Due to the circuits pattern memory, the animals remain in this altered state indefinitely without further stimulation, despite their wildtype genomes. In other words, the pattern to which the cells build after damage can be changed, leading to a target morphology distinct from the genetic default.

N.R. FULLER, SAYO-ART, LLC

First, we soaked a planarian in voltage-sensitive fluorescent dye to observe the bioelectrical pattern across the entire tissue. We then cut the animal to see how this pattern changes in each fragment as it begins to regenerate.

We then applied drugs or used RNA interference to target ion channels or gap junctions in individual cells and thus change the pattern of depolarization/hyperpolarization and cellular connectivity across the whole fragment.

As a result of the disruption of the bodys bioelectric circuits, the planarian regrows with two heads instead of one, or none at all.

When we re-cut the two-headed planarian in plain water, long after the initial drug has left the tissue, the new anatomy persists in subsequent rounds of regeneration.

Cells can clearly build structures that are different from their genomic-default anatomical outcomes. But are cells universal constructors? Could they make anything if only we knew how to motivate them to do it?

The most recent advances in the new field at the intersection of developmental biology and computer science are driven by synthetic living machines known as biobots. Built from multiple interacting cell populations, these engineered machines have applications in disease modeling and drug development, and as sensors that detect and respond to biological signals. We recently tested the plasticity of cells by evolving in silico designs with specific movement and behavior capabilities and used this information to sculpt self-organized growth of aggregated Xenopus skin and muscle cells. In a novel environmentin vitro, as opposed to inside a frog embryoswarms of genetically normal cells were able to reimagine their multicellular form. With minimal sculpting post self-assembly, these cells form Xenobots with structures, movements, and other behaviors quite different from what might be expected if one simply sequenced their genome and identified them as wildtype X. laevis.

These living creations are a powerful platform to assess and model the computations that these cell swarms use to determine what to build. Such insights will help us to understand evolvability of body forms, robustness, and the true relationship between genomes and anatomy, greatly potentiating the impact of genome editing tools and making genomics more predictive for large-scale phenotypes. Moreover, testing regimes of biochemical, biomechanical, and bioelectrical stimuli in these biobots will enable the discovery of optimal stimuli for use in regenerative therapies and bioengineered organ construction. Finally, learning to program highly competent individual builders (cells) toward group-level, goal-driven behaviors (complex anatomies) will significantly advance swarm robotics and help avoid catastrophes of unintended consequences during the inevitable deployment of large numbers of artificial agents with complex behaviors.

Understanding how cells and tissues make real-time anatomical decisions is central to achieving regenerative outcomes too complex for us to manage directly.

The emerging field ofsynthetic morphology emphasizes a conceptual point that has been embraced by computer scientists but thus far resisted by biologists: the hardware-software distinction. In the 1940s, to change a computers behavior, the operator had to literally move wires aroundin other words, she had to directly alter the hardware. The information technology revolution resulted from the realization that certain kinds of hardware are reprogrammable: drastic changes in function could be made at the software level, by changing inputs, not the hardware itself.

In molecular biomedicine, we are still focused largely on manipulating the cellular hardwarethe proteins that each cell can exploit. But evolution has ensured that cellular collectives use this versatile machinery to process information flexibly and implement a wide range of large-scale body shape outcomes. This is biologys software: the memory, plasticity, and reprogrammability of morphogenetic control networks.

The coming decades will be an extremely exciting time for multidisciplinary efforts in developmental physiology, robotics, and basal cognition to understand how individual cells merge together into a collective with global goals not belonging to any individual cell. This will drive the creation of new artificial intelligence platforms based not on copying brain architectures, but on the multiscale problem-solving capacities of cells and tissues. Conversely, the insights of cognitive neurobiology and computer science will give us a completely new window on the information processing and decision-making dynamics in cellular collectives that can very effectively be targeted for transformative regenerative therapies of complex organs.

Michael Levinis the director of the Allen Discovery Center at Tufts University and Associate Faculty at Harvard Universitys Wyss Institute. Email him atmichael.levin@tufts.edu. M.L. thanks Allen Center Deputy DirectorJoshua Finkelsteinfor suggestions on the drafts of this story.

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How Groups of Cells Cooperate to Build Organs and Organisms - The Scientist

For years Ive walked a tightrope with my professional life on one side and personal life on the other. Two very separate existences. Slowly, as Ive become more comfortable sharing my personal story the tightrope has become steadier. I have become more comfortable with the rope and learnt to stop looking down.

Today, after years of balancing (well at least attempting to), the tightrope has disintegrated, and Im still standing, now ready to share my story.

I have been dancing on the personal-work-life tightrope since 2012. The journey began eight years ago when my second daughter was three months old and I started consulting to AIA Australia to help launch Vitality into the Australian market.

Over the next three years, I juggled the darkest times of my personal life while effectively working in a start-up. I was in survival mode, emotionally for myself and literally for my children and I rarely mentioned a word of it to my colleagues.

My husband and I were dealing with our 2.5 year-old, Jaeli, who had developed uncontrolled seizures (in fact hundreds a day), extreme behaviours, autistic features, childhood insomnia, three-hour nightly and daily screaming fits, self-injurious behaviour and cognitive delays.

My second daughter, Dali, born 2 years after Jaeli, had hit all of her milestones at the age of one, beforewe saw it that first sign the subtle eye lid seizures. This time we knew how those subtle eyelid seizures would progress.

We were heartbroken.

In those early years, we were driven by the sense of urgency to get a diagnosis and fix our kids, acutely aware of the neurodevelopmental plasticity window closing further every day.

My survival technique was to compartmentalise.

I was in survival mode at home and work was my escape. An escape from the helplessness I felt watching our beautiful girls suffer, every attempt to help them only making them worse.

I didnt intentionally hide the situation from my colleagues, but I rarely mentioned it. I didnt want to burden others with my pain, I didnt want them to pity me and I definitely didnt want to be treated differently.

Unknowingly, I was protecting my illusion of control.

Our journey took a new direction and energy when we finally received a diagnosis for the girls in 2016. At that time they were four and six years old. We were one of the first in Australia to undergo whole genome sequencing, and after five long years we had a name for our enemy. It was a rare genetic epilepsy called Syngap. At the time, there were less than 100 diagnosed in the world, now, four years later, there are almost 600.

Knowledge is power and armed with a diagnosis, we became empowered to change our daughters destinies. We were buoyed learning that there has never been a better time for science, medical discoveries, precision medicine and gene therapy.

We connected with other families, with researchers and clinicians who gave us hope that precision medicine was a realistic concept for our kids.

Next, we established Syngap Research Fund Australia, co-founded Genetic Epilepsy Team Australia (GETA) and the Syngap Global Network. We advocated for whole genome sequencing, jumped into collating data on the condition which inspired the largest Syngap study, published in the neurology journal in 2019 on which I was a co-author. We lobbied government, leading to a $2m investment in genetic epilepsy research, which kickstarted our Syngap research project in 2018 at the Florey Institute for Neuroscience and Mental Health.

Weve learnt along the way that those who bear the burden of disease have an unrelenting passion like no other which accelerates scientific breakthroughs.

And, Ive slowly learnt, that the two worlds professional and personal that I had deliberately kept apart, could in fact benefit one another. I learnt the tightrope could in fact become a runway.

Professionally, I thrive in a team environment, partly because I own my shortcomings and naturally seek partnerships that combine complementary skillsets and genuinely subscribe to the shared value concept. I like to rely on others and I like to be relied on.

Personally, I am inspired by those I fight shoulder to shoulder with in battle from our Genetic Epilepsy Team Australia group, to the Syngap Global Network team, and my husband who is so driven and optimistic, grateful for that optimism especially when I am not.

Only recently have I realised the same theory of combining complementary skills applies to the two versions of myself the professional version and the rare disease mum version that each contribute to the same person.

Im surprised and grateful that the skills Ive obtained in each of these versions of myself are transferrable. That my persistence, optimism, passion, empathy, tolerance and resilience straddle both sides of that tightrope, ultimately bringing strength and balance to both.

Through this journey, Ive also learnt the power of gratitude. I am grateful for my family, friends, community and personal network that have loved me in my darkest times. And, I am indebted to AIA Australia, and particularly Damien Mu, who have supported me professionally, and who chose to keep my tightrope taut when I felt the need to keep my two roles as employee and rare disease mum balanced, but apart.

Today, after eight years trying to balance the tightrope, I feel empowered by that runway on which I can make a difference in both my professional and personal roles.

This is an edited version of a post that Danielle first published on LinkedIn. Its shared here with permission.

For more information on Syngap Research Australia, click here. Or check them out on Facebook or Twitter.

You can find more information on GETA: Genetic Epilepsy Team Australia here, or on Facebook or Twitter

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I've been walking a work-life tightrope. It's finally disintegrated and I'm ready to share my story - Women's Agenda

A special thank you to Kathleen Dickson and Dr. John Bergeron for pointing out that yes, indeed, there are also many women who have made and continue to make significant contributions to health. We have added their additions below, but this list is by no means complete.

From open heart surgery to child-resistant containers, prestigious awards and bombs (not that kind), Canada has a long history of Canadians whose ideas and inventions have played huge roles in defining this nations healthcare.

DNA and cancer

Nada Jabado at McGill affiliated Childrens Hospital is a pioneer in pediatric cancer and her discovery of the role of what is known as the epigenome that marks the DNA in our genes in cancer. She is a leader in innovation in Health research and recognized for her leadership in the application of discoveries to address brain tumours in children.

Insulin

Perhaps the most famous health innovation to come out of Canada, if such a thing can be measured. The arrival of insulin has saved countless lives since its creation in 1922 when Frederick Banting and Charles Best isolated and extracted insulin from the pancreas of dogs. Their Nobel Prize arrived swiftly thereafter in 1923.

Link:
28 cool health things that started with a Canadian - Regina Leader-Post

In the United States, the average wait time for COVID-19 test results is about four days. Even worse, 10 percent of individuals dont receive lab results for 10 days or more.

Quick reporting of test results helps identify infected individuals so they and anyone they potentially spread the coronavirus to can be isolated, preventing further spread of the virus.

If you have a 14-day lag to knowing if someone is actually sick and contagious, then theyll interact with many, many more people in that period than if you have a one-day or a six-hour or one-hour turnaround, says Omar Abudayyeh, a bioengineer at MIT.

Abudayyeh is among the many researchers and companies racing to develop new and speedier types of diagnostic tests that circumvent clinical labs altogether. Some of these tests complete their analyses in all-in-one machines that are portable enough to be set up in schools, nursing homes and offices. Several companies are developing tests like these that can diagnose COVID-19 in 30 minutes or less, with a level of accuracy comparable to lab tests. Others are harnessing the power of the gene editor CRISPR to deliver rapid results.

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And another type of test, made by Abbott Laboratories and granted emergency use authorization by the U.S. Food and Drug Administration on August 26, works more like a pregnancy test. All it requires is a test card the size of a credit card, a few drops of a reaction solution and a sample from a nasal swab. Within 15 minutes, two lines appear on the card if the sample contains the virus; one line appears if it doesnt.

The current gold standard for accurate COVID-19 testing is PCR, or polymerase chain reaction, which can detect even tiny quantities of the viruss genetic material, RNA (SN: 3/6/20).

The test requires collecting viral RNA directly from the patient, typically gathered using a swab inserted deep into the nasal cavity. At a clinical laboratory, the viruss RNA is converted to DNA and then run through a specialized instrument that heats and cools that DNA to multiply copies of it, making it easier to detect. After repeating the process for around an hour, if DNA shows up, the sample is considered positive for SARS-CoV-2, the virus that causes COVID-19.

Such tests are fairly accurate. They miss some people very early in the infection or because of lab errors, producing false negatives, meaning that the test results indicate someone isnt infected when they really are. False positives when tests wrongly indicate an uninfected person has the virus are rare with this type of technology. So if a PCR test indicates a person is infected, they probably do carry the virus. The main drawback is the speed. It typically takes days to get results back, and backups at labs can drag the process out for a week or two.

Some people find the nasal probe uncomfortable, so other lab tests have been developed that rely on less invasive samples. On August 15, the FDA authorized a saliva-based test, SalivaDirect, for emergency use. This isnt the first test to detect the SARS-CoV-2 virus in saliva, which is easier to collect than samples from nasal passages. But its simplified protocol speeds up sample preparation and bypasses testing supplies that have been in short supply in recent months. SalivaDirect, however, is not a rapid test. It still requires processing by clinical laboratories, which contributes to the wait time between providing a sample and receiving results.

To develop faster tests, companies are taking a variety of approaches. Funding for some of this work comes from the Rapid Acceleration of Diagnostics initiative, or RADx, from the National Institutes of Health, which has invested $248.7 million in seven companies tackling testing challenges.

San Diegobased Mesa Biotech, for instance, received RADx funding to manufacture a PCR test that replaces an entire clinical lab with a handheld dock and a single-use cartridge. The company says the proprietary technology in its Accula test, which has already received FDA emergency use authorization, can provide a COVID-19 diagnosis in just 30 minutes.

Other RADx-funded companies, such as Talis Biomedical, headquartered in Menlo Park, Calif., arent using PCR to amplify SARS-CoV-2 viral material. The Talis One system instead uses LAMP, or loop-mediated isothermal amplification. In a typical LAMP assay, a patients nasal or oral swab sample is mixed with enzymes and specially designed DNA fragments, then heated to 65 Celsius to copy the viral RNA to DNA and produce many more DNA copies. With the Talis test, samples are placed in a cassette, popped into a specialized dock, and analyzed in just 30 minutes.

As opposed to an instrument that cycles between hot and cold, LAMP heats the reaction to one temperature. You could run the reaction in a water bath, says Nathan Tanner, a molecular biologist at New England Biolabs in Ipswich, Mass.

In general, LAMP-based diagnostic tests arent quite as sensitive as ones based on PCR, Tanner says, but could be used to test more people, given their simpler requirements. In one newly described LAMP testing method, a solution changes color in the presence of 100 or more SARS-CoV-2 RNA molecules. The authors, who describe the test August 12 in Science Translational Medicine, propose that the approach, which didnt detect the lowest viral loads, would be suitable for identifying individuals with a moderate to high viral load.

A third RADx-funded test provides results in a mere 15 minutes. Rather than detecting viral RNA, the test, by Quidel, based in San Diego, detects proteins from virus particles. These viral proteins are also antigens, meaning they stimulate immune responses when they invade our bodies. Such antigen tests are similar to ones used in doctors offices and pharmacies to diagnose people with influenza.

Dont confuse antigen tests with an antibody test that detects antibodies a person develops in response to an infection (SN: 4/28/20) Much like a pregnancy test, COVID-19 antigen tests use antibodies to detect the viral proteins and give a yes or no answer, says Kim Hamad-Schifferli, a bioengineer at the University of Massachusetts Boston.

The Quidel Sofia SARS antigen test has been authorized for emergency use. Like the other RADx-funded rapid tests, it uses a dock and single-use cartridges: Instead of making a line on stick the way a pregnancy test does, the dock detects a fluorescent signal if SARS-CoV-2 proteins are present.

Abbott Laboratories test granted emergency use authorization August 26 also is an antigen test and, with its card-based technology, is even simpler. Abbott, based in Abbott Park, Ill., said its test was able to detect 34 of 35 COVID-19-positive patients with symptoms, or 97 percent, in initial studies.

The benefit: An antigen test doesnt require any specialized lab instruments or enzymes. Its all self-contained, Hamad-Schifferli says. Without a step to amplify viral material, however, an antigen test can be less sensitive than PCR or LAMP and result in a higher rate of false-negative results, up to 20 percent per the FDAs emergency use authorization guidelines for antigen tests.

Thats because people may produce widely varying amounts of virus, depending on how long has passed since they became infected. In most people, the coronavirus is most abundant from a couple of days after infection to about nine days into the illness (SN: 3/13/20). After that, the immune system kicks in, preventing viruses from being made. On the other hand, viral RNA can be detectable in some people for more than a month. A negative result from an antigen test has a higher chance of being false comfort, so the FDA says that diagnosis may need to be confirmed with another type of test, like PCR.

Even though antigen tests typically are not as accurate as standard PCR or the new rapid tests, they could play a crucial role helping to end the pandemic if their use becomes widespread. As of now, though, even Abbotts 15-minute test still needs to be ordered by a doctor and performed in a health care setting, so that can provide hurdles to its use. But what if people didnt even have to leave home to get a test?

Thats what Hamad-Schifferli and her colleagues are working on. The idea is to build a cheaper test that doesnt involve a dedicated instrument just a paper strip and a signal detectable by eye. Such a simple test could be used more widely by people at home. It would be a game changer, she says.

If COVID-19 tests are deployed widely enough, they could serve as a public health measure to identify people with high levels of SARS-CoV-2 and spreading the virus to others, even if theyre not displaying symptoms. Thats because frequent and fast tests can be used to pinpoint outbreaks as they are happening (SN: 7/1/20). If cheap enough, these tests could be used by people daily, catching any missed detections through repeated rounds of testing.

The United States is currently testing nearly 700,000 people a day on average, based on data from August 21 through August 27. Michael Mina, however, wants to see even more tests, like 200 million tests every day in this country. Surveillance provided by such widespread testing will effectively do the same thing as a vaccine in slowing the spread of the coronavirus says Mina, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston.

But for daily, population-wide testing that could alert people when they first start transmitting the coronavirus to be adopted, a test needs to be cheap enough for instance, under a dollar for many people to use them frequently. Abbott said its tests would cost $5. Quidels test cartridges cost $23 apiece and the other RADx-funded rapid tests are likely in a similar price range. Given their higher accuracy, those tests could serve a separate purpose: to conclusively determine if an individual is infected and ensure they receive treatment.

The holy grail of tests may be one that is fast, easy, accurate and inexpensive and that could be used broadly even by people at home. One group of scientists may be among those nearing that goal. The work is led by Abudayyeh, Jonathan Gootenberg and Feng Zhang, all bioengineers at the McGovern Institute for Brain Research at MIT. Zhang is also at the Broad Institute of MIT and Harvard University.

The team developed a test that uses the gene-editing tool CRISPR. All someone has to do is add a sample either from a nasal swab or saliva to a tube with a reaction solution, heat the tube to 60 C for an hour in a pot of water, then add a paper test strip to the tube. If two lines appear, that means SARS-CoV-2 RNA is present.

The readout relies on activity of a CRISPR enzyme, Cas12b. If SARS-CoV-2 RNA is present in the reaction, Cas12b cuts whats called a reporter, a short piece of DNA thats labeled on both ends. The two halves of the reporter then wick up the paper strip to different places and appear as two lines. If viral RNA isnt present, the reporter remains intact and wicks up the strip to one place, showing up as one line.

The new test, STOPCovid, is not yet authorized for clinical use, but based on tests in a small number of patients, it identifies SARS-CoV-2 cases as well as PCR tests, the researchers reported May 8 in a preprint posted at medRxiv.org. It returns results in about an hour and would cost under $10, they say.

Unlike rapid tests relying on docks and cartridges, the STOPCovid test is designed to scale up to millions of tests per week, says Gootenberg. Theres never been a demand for millions or tens of millions of tests per week ever.

Other research groups have also developed similar CRISPR-based COVID-19 tests (SN: 4/17/20).

With the development of so many new technologies to test for the coronavirus, were going to come away from the epidemic with a whole new field of diagnostics, Mina says.

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New coronavirus tests promise to be faster, cheaper and easier - Science News

WALTHAM, Mass., Sept. 18, 2020 (GLOBE NEWSWIRE) -- Oncologie, Inc., a precision medicine company using an innovative RNA-based biomarker platform to predict patient responses for potentially first-in-class targeted oncology therapies, today announced new data and analyses from its lead clinical programs, bavituximab and navicixizumab. On the basis of these positive data, the company also announced its rebranding to OncXerna Therapeutics, Inc., a change that reinforces the companys focus on using its RNA-based approach to guide novel, targeted treatments to specific people with cancer.

With a deep understanding of the tumor microenvironment biology at the RNA-level through our novel biomarker panel, we aim to dramatically improve clinical outcomes by matching patients to therapies with a mechanism of action that targets that specific biology, said Laura Benjamin, Ph.D., President and Chief Executive Officer at OncXerna Therapeutics. Todays results demonstrate a clear ability of our first panel to distinguish responders versus non-responders in our bavituximab and navicixizumab programs, and we are excited to deploy this approach in the next prospectively-defined trials that could support registration.

Interim results from Phase 2 (ONCG100) trial of bavituximab and KEYTRUDA

Trial design and background:

The Phase 2 (ONCG100) trial is a multicenter, open-label, single-arm global trial designed to assess the safety, tolerability, and antitumor activity of the investigational agent bavituximab, a chimeric monoclonal antibody that targets phosphatidylserine, in combination with KEYTRUDA, Mercks anti-PD-1 therapy, in patients with advanced gastric and gastroesophageal cancer who have progressed on or after at least one prior standard therapy. Bavituximab previously demonstrated clinical activity in a post-hoc subset analysis in patients with non-small cell lung cancer (NSCLC) who were given a PD-1 inhibitor following bavituximab treatment, suggesting that a treatment combination of bavituximab and a PD-1 inhibitor could generate similar activity in a prospective clinical trial. In addition to measuring safety and antitumor activity in this trial, OncXerna is deploying its proprietary RNA biomarker platform (TME Panel-1) to identify patients based on their response to treatment and the dominant biology of their tumor microenvironment with the potential to dramatically improve outcomes in the next, prospectively designed trial.

Approximately 80 patients in the U.S., United Kingdom, South Korea and Taiwan are planned for enrollment in two separate groups of patients: Checkpoint inhibitor-nave and checkpoint inhibitor-relapsed. The trial is continuing to enroll both groups with planned updates from all patients during the first half of 2021.

Interim results:

Interim results provided today, from the first 36 patients enrolled and with a post-baseline scan in the checkpoint inhibitor-nave group, include the following:

Next steps:

These data are being presented at the European Society for Molecular Oncology (ESMO) Virtual Congress 2020 taking place September 19-21, 2020.

OncXerna plans to conduct additional clinical trials designed to prospectively enrich for TME Panel-1 biomarker positive patients, as well as to explore additional solid tumor types.

OncXerna biomarker analysis from Phase 1b trial evaluating navicixizumab in ovarian cancer

Previously announced data and background:

OncXernas navicixizumab is a bispecific antibody designed to inhibit both Delta-like ligand 4 (DLL4) in the Notch cancer stem cell pathway as well as vascular endothelial growth factor (VEGF). Interim data from a Phase 1b dose escalation and expansion trial of navicixizumab plus paclitaxel in 44 platinum-resistant ovarian cancer patients who had failed more than two prior therapies and/or received prior Avastin (bevacizumab) therapy were presented virtually at the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting in May 2020. Treatment with navicixizumab and paclitaxel demonstrated an ORR of 43% in all patients, and 64% and 33% in bevacizumab-nave, and bevacizumab pre-treated patients, respectively. Treatment-related adverse events were manageable and included hypertension (58%), headache (29%), fatigue (26%) and pulmonary hypertension (18%).

Updated biomarker analyses and results:

Using its RNA-based biomarker TME Panel-1, OncXerna recently analyzed patient tissue samples obtained from 28 of the 44 patients from the Phase 1b trial. Results from this analysis revealed the following:

Next steps:

As a result of these analyses, OncXerna plans to conduct additional clinical trials designed to prospectively enrich for TME Panel-1 biomarker positive patients with ovarian cancer who are platinum-resistant and Avastin-experienced to support registration, as well as to explore additional solid tumor types.

About Bavituximab

Bavituximab is an investigational antibody that reverses immune suppression by inhibiting phosphatidylserine (PS) signaling and is currently in Phase 2 clinical trials to treat a specific subset of patients with advanced gastric cancer to improve their response to anti-PD-1 treatment. The mechanism of action of bavituximab is to block tumor immune suppression signaling from PS to multiple immune cell receptor families (e.g., TIMs and TAMs). The dominant biology targeted by bavituximab may be relevant for patients with many types of solid tumors whose immune systems are too suppressed to benefit from currently available immune oncology therapies. Our clinical trials currently combine bavituximab with KEYTRUDA to test the hypothesis that relieving immunosuppression can enhance responses to checkpoint inhibitors. Bavituximab is an investigational agent that has not been licensed or approved anywhere globally, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced gastric cancer.

About Navicixizumab

Navicixizumab is an investigational anti-DLL4/VEGF bispecific antibody that has demonstrated antitumor activity in patients who have progressed on Avastin (bevacizumab) in a Phase 1a/b clinical trial. The U.S. Food and Drug Administration granted Fast Track designation to navicixizumab for the treatment of high-grade ovarian, primary peritoneal or fallopian tube cancer in patients who have received at least three prior therapies and/or prior treatment with Avastin. OncXerna is targeting patients whose dominant tumor biology is driven by angiogenesis with a focus beyond VEGF to include broader anti-angiogenic pathways. Navicixizumab is an investigational agent that has not been licensed or approved anywhere globally, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced ovarian cancer.

About OncXerna Therapeutics

OncXerna is aiming to deliver next-generation precision medicine for a larger group of cancer patients by leveraging the companys deep understanding of how to prospectively identify patients based on the dominant, RNA-based biology of their tumor microenvironments. This allows OncXerna to pair those patients with OncXernas clinical-stage therapies and known mechanism of action that directly address these biologies, to dramatically improve patient outcomes. For more information on OncXerna, please visit oncxerna.com/

About OncXernas RNA-based Biomarker Platform

Existing precision medicines target only approximately 10% of cancersthose with gene mutations or oncogenic drivers for a small number of genes. Using its proprietary biomarker platform, OncXerna is leveraging the companys deep understanding of tumor biology at the RNA level to identify the dominant biology underlying a patients cancer. OncXernas first biomarker panel is specific to the tumor microenvironment (TME Panel-1). Initial results from TME Panel-1 reveal 4 different dominant biologies, demonstrating the presence of specific patient subgroups and their predictive value in responding to treatment. OncXerna is further optimizing the biomarker platforms tumor microenvironment panel through multiple research collaborations, including a collaboration with Moffitt Cancer Center.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Investor and Media Contact:

Ashley R. RobinsonLifeSci Partners, LLCarr@lifesciadvisors.com

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Oncologie Announces New Data and Analyses from Clinical Programs and Name Change to OncXerna Therapeutics - BioSpace

BCH-BB694 an experimental gene therapy targeting the BCL11A gene safely increased the levels of fetal hemoglobin and prevented disease-associated complications in six people with severe sickle cell disease (SCD), according to interim data from a Phase 1 clinical trial.

These findings further support the feasibility and therapeutic value of approaches targeting BCL11A,which is involved in the suppression of fetal hemoglobin in adult red blood cells.

Trial findings were reported in the study, Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease, published in The New England Journal of Medicine.

BCH-BB694, developed by a team of researchers at Boston Childrens Hospital led by David Williams, MD, uses a modified and harmless virus to promote the production of fetal hemoglobin in blood precursor cells (hematopoietic stem cells)collected from a patient.

The virus was created in collaboration with Bluebird Bio, and delivers a genetic sequence with the instructions to produce a microRNA that suppresses BCL11As activity in red blood cells.

MicroRNAs are small RNA molecules that target a specific genes messenger RNA the genetic blueprint derived from DNA and used as a template for protein production to prevent generation of that protein.

The modified cells are re-introduced to the patient in the form of astem cell transplant, following myeloablativechemotherapy to kill cells in the bone marrow, thereby lowering the number of blood-forming cells. This way, the stem cell transplant will have a better chances of rebuilding a healthy bone marrow.

Of note, fetal hemoglobin is a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart.By increasing the levels of fetal hemoglobin, BCH-BB694 is expected to lower the frequency of SCD complications, such as vaso-occlusive crises (VOCs) and acute chest syndrome.

Based on positive data from preclinical studies, Williams is sponsoring a two-year, pilot Phase 1 trial (NCT03282656) to evaluate the feasibility, safety, and preliminary effectiveness of a single administration of patients own blood precursor cells modified with BCH-BB694 to people with severe SCD.

Patient recruitment at Boston Childrens Hospital and UCLA Mattel Childrens Hospital in Los Angeles may still be ongoing; more information can be found here. Those who finish two years of follow-up may choose to enter a 13-year long-term follow-up study.

Six of the nine enrolled patients asof October 2020 had at least six months of follow-up data, and were included in the interim analysis. Their age at enrollment ranged from 7 to 25, and they were followed for a median of 18 months (range, seven to 29 months) after treatment.

Results showed that BCH-BB694 treatment was generally safe, with most adverse events being consistent with known effects of myeloablative chemotherapy, and with no reports of severe or life-threatening side effects.

The gene therapy led to a robust and sustained increase in fetal hemoglobin levels, accounting for a median of 30.5% of all hemoglobin levels, and being detected in a median of 70.8% of red blood cells. Mean levels of fetal hemoglobin per red blood cell were also uniformly high.

Based on these laboratory findings, we predict that the patients in this study will have protection from sickling to prevent or significantly ameliorate both acute and chronic complications of sickle cell disease, the researchers wrote.

Notably, all patients remained free from VOCs, acute chest syndrome, and strokes since the treatment was given. Other SCD complications, such as priapism (prolonged, often painful erection), were also reduced.

BCH-BB694s use also prevented a need for blood transfusions in two patients who had been receiving them regularly to avoid a stroke. One patient with a rare blood vessel disorder continued to receive predefined blood transfusions due to a potentially higher risk of stroke, but on a less frequent basis than before treatment.

The initial results of this trial provide validation that BCL11A can be targeted to lead to successful [fetal hemoglobin] induction in humans, the researchers wrote.

Additional follow-up data will help determine BCH-BB69s long-term beneficial effects, they noted.

This type of microRNA-based gene therapy approach has potential implications for other diseases that could benefit from downregulation of gene expression rather than addition of a gene, the team wrote.

The study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

A separate Phase 1/2 trial with a different approach in targeting theBCL11A gene also recently released promising findingsinpeople with severe SCD. The therapy being investigated here,CTX001, uses the CRISPR-Cas9 gene editing tool to inactivateBCL11Ain patients blood cell precursors.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 2

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia.Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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BCH-BB694 Gene Therapy Safely Treating Severe SCD Patients in... - Sickle Cell Anemia News

FINDINGS

Newswise Researchers at the UCLA Jonsson Comprehensive Cancer Center analyzed gene-expression patterns in the most aggressive prostate cancer grade group known as Gleason grade group 5 and found that this grade of cancer can actually be subdivided into four subtypes with distinct differences. The findings may affect how people are treated for the disease.

One subtype, which accounts for about 15% of the grade group 5 cancers, has highly aggressive features and is associated with much worse outcomes than the other subtypes. Another, which makes up about 20% of the tumors, appears to be much less aggressive and may not require intensified and aggressive treatments. Traditionally, all tumors in Gleason grade group 5 have been treated in the same way.

BACKGROUND

Prostate cancer is the leading solid-tumor cancer among men in the United States and a major cause of morbidity globally. While early-stage, localized prostate cancer is curable, current treatments dont always work for everyone. To find out why standard treatment may work for some and not others, the UCLA researchers looked at tumors in the Gleason grade group 5 subset of prostate cancer. These tumors are at the highest risk to fail standard treatment, leading to metastasis and death. The researchers thought that studying the gene expression the unique signature of each cancer cell in these tumors might provide insight into how to make treatments more personalized for each patient.

METHOD

The researchers first analyzed data from more than 2,100 Gleason grade group 5 tumors, looking at how the genetic blueprints differed among the tumors. They identified distinct clusters of subgroups and validated their findings by analyzing an additional cohort of more than 1,900 Gleason grade group 5 prostate cancers.

IMPACT

By using the genetic information from tumors in men with prostate cancer, physicians hope to one day create more personalized treatments based on the actual characteristics of the cancer. This information will help optimize quality of life and avoid overtreating subgroups of men who may not need aggressive treatments.

AUTHORS

The studys lead author is Dr. Amar Kishan, an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and a researcher at the UCLA Jonsson Comprehensive Cancer Center. The co-senior authors are Dr. Joanne Weidhaas, a professor of radiation oncology and director of translational research at the Geffen School of Medicine, and Paul Boutros, a professor of urology and human genetics and director of cancer data science for the Jonsson Cancer Center. Boutrosis also a member of the UCLA Institute of Urologic Oncology and the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA. Other UCLA authors include David Elashoff, Dr. Rob Reiter and Dr. Matthew Rettig.

JOURNAL

Thestudy was publishedin the journal European Urology.

FUNDING

The research was funded in part by an award from the American Society for Radiation Oncology and the Prostate Cancer Foundation, the Radiological Society of North America, and the National Institutes of Health.

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Some types of prostate cancer may not be as aggressive as originally thought - Newswise

Impact of New Tissue Stem Cell Counting Algorithms

BOSTON (PRWEB) September 01, 2020

Stem cell biotechnology company, Asymmetrex, has been counting tissue stem cells like those used for bone marrow and cord blood transplantation therapies for a few years now. Recently, the company announced the issue of patents for its first-in-kind technology both in the U.S. and the U.K. However, until last Friday, August 28, Asymmetrex had not reported in the peer-reviewed academic literature how it achieves this feat that had been pursued by many distinguished labs for more than six decades.

Now in a report published in a special issue of OBM Transplantation, a peer-review journal for transplantation medicine research, Asymmetrex completes its introduction of the new technology to the fields of stem cell science and stem cell medicine. The report is the second invited article published in a special issue focused on the Isolation and Characterization of Adult Therapeutic Cells.

The new report describes Asymmetrexs discovery of mathematical formulas, call algorithms, that can be used to determine the number of stem cells in complex tissue cell preparations, like experimental samples or patient treatments. The stem cell counting algorithms are specific for different types of tissue stem cells. So, the algorithms defined for blood stem cells are distinct from the algorithms for liver stem cells, or lung stem cells. Once an algorithm is defined by the Asymmetrex technology, it can be used repeatedly as a simple, rapid, and inexpensive test to determine the quantity and dosage of its specific tissue stem cell type.

Asymmetrexs founder and director, James L. Sherley, M.D., Ph.D., anticipated the August publication of the new algorithms in a talk given earlier at the 6th Annual Perinatal Stem Cell Society Congress in March of this year. Then and now, he says that he believes, Now that the tissue stem cell counting algorithms are available, everything will change in stem cell science and medicine.

Prior to Asymmetrexs technology, there was no method for counting tissue stem cells in research, medicine, or for any other of their many uses. So, the impact of the stem cell counting algorithms in research and medicine is far-reaching. Such information is a game changer for accelerating progress in stem cell science and stem cell medicine, including improving treatments like gene therapy whose success depends on targeting tissue stem cells. There will also be tremendous gains in cell biomanufacturing, drug development, and environmental toxicology, all whose capabilities are currently limited by the lack of a facile means to quantify tissue stem cells.

To make the new counting technology readily accessible for evaluation by the greater academic, medical, and industrial stem cell communities, Asymmetrex provides free tissue stem cell counting on its company website.

About Asymmetrex

Asymmetrex, LLC is a Massachusetts life sciences company with a focus on developing technologies to advance stem cell medicine. The companys U.S. and U.K. patent portfolio contains biotechnologies that solve the two main technical problems production and quantification that have stood in the way of effective use of human adult tissue stem cells for regenerative medicine and drug development. Asymmetrex markets the first technology for determination of the dose and quality of tissue stem cell preparations (the AlphaSTEM Test) for use in stem cell transplantation therapies and pre-clinical drug evaluations. Asymmetrex is a member company of the Advanced Regenerative Manufacturing Institute BioFabUSA and the Massachusetts Biotechnology Council.

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New Report Begins a New Era of Stem Cell Science and Medicine: Stem Cell Biotechnology Company Asymmetrex Tells How It Counts Therapeutic Tissue Stem...

(CNN) Alzheimers disease and dementia are two diseases that many Americans are all too familiar with, but there is another dementia that plagued the late comedian Robin Williams.

It might be the most common disease youve never heard of, said Dr. James Galvin, a professor of neurology and director of the Lewy Body Dementia Research Center of Excellence at the University of Miamis Miller School of Medicine.

Williams had Lewy body dementia, which his family learned only after his death. Its often misdiagnosed as Alzheimers or Parkinsons disease due to its early similarity to those other neurodegenerative diseases.

That unfortunate misconception is one focus of Robins Wish, a documentary releasing September 1 about the final days of Williams, before he died by suicide in 2014.

Affecting about 1.4 million Americans, Lewy body dementias which include Lewy body dementia and Parkinsons disease dementia are the second most common form of dementia after Alzheimers disease, according to the Lewy Body Dementia Association.

Dementia is a disorder of mental processes characterized by memory disorders, personality changes and impaired reasoning due to brain disease or injury.

Lewy body dementia is associated with an accumulation of a protein called alpha-synuclein that builds up and deposits inside of cells and some classic areas in the brain, said Dr. Ford Vox, medical director of the Disorders of Consciousness Program at the Shepherd Center in Atlanta and a contributor for CNN. Parkinsons disease dementia, the other Lewy body dementia, starts as a movement disorder but progresses to include dementia and mood and behavioral changes.

When working properly, alpha-synuclein which is typically present in the brain and in small amounts in the heart, muscle and other tissues might play a role in regulating neurotransmitters. But when this protein aggregates and forms masses (called Lewy bodies) within the brain, the consequences are severe.

The most common symptoms of LBD include impaired thinking, fluctuations in attention, problems with movement, visual hallucinations, sleep disorders, behavioral and mood issues and changes in bodily functions such as the ability to control urinating.

Over time, people with LBD lose layer upon layer of that life that youve built, said Angela Taylor, the senior director of research and advocacy at the Lewy Body Dementia Association.

Thats what happened to Williams, who had been diagnosed with Parkinsons disease in 2013. It wasnt until his autopsy that his widow, Susan Schneider Williams, learned he actually had LBD. The film highlights how the disease devastated Williams health.

My husband had unknowingly been bottling a deadly disease, Schneider Williams said in the documentarys trailer. Nearly every region of his brain was under attack. He experienced himself disintegrating.

CNN founder Ted Turner is also battling the disease, as he revealed in a 2018 interview.

Experiences of dysfunction and ambiguity are common for many patients and their families. Here is what the disease really is, why its difficult to identify and how it damages peoples lives.

An elusive and insidious disease

The first published cases of Lewy body dementia occurred in the mid-1960s, but it took two decades for the disorder to be recognized by medical researchers.

In the 1980s, as the molecular understanding of Alzheimers improved, it became clear that a bunch of these people didnt seem to fit that (diagnosis), Galvin said.

For example, patients with LBD had visual hallucinations when most Alzheimers patients didnt. They also had more parkinsonism the signs and symptoms of Parkinsons disease, which include slowness, stiffness, tremors and imbalance than Alzheimers patients.

It wasnt until the mid-90s when a large group of people (the Dementia with Lewy Bodies Consortium) got together and coined the phrase dementia with Lewy bodies and started to write diagnostic criteria that could be applied, Galvin added. And that really changed the game because once you have criteria, then people can start to be better classified.

Aside from the association with Lewy bodies those abnormal accumulations of the protein alpha-synuclein in the brain the exact cause of LBD is unknown.

Potential, but rare, genetic factors include higher levels of mutations of certain enzymes and a family gene that might make someone predisposed to the disease.

Sorting through the symptoms

Some patients exhibit movement disorders that doctors first diagnose as Parkinsons disease. If those patients later develop dementia, they would then be diagnosed with Parkinsons disease dementia.

Others may begin with cognitive or memory disorders mistaken for Alzheimers disease. More specific changes in their cognitive function over time can lead to the diagnosis dementia with Lewy bodies.

Rarely will some individuals first show neuropsychiatric symptoms, which can include hallucinations, behavioral problems and difficulty with mental activities. When those appear simultaneously, that can prompt an initial diagnosis of LBD.

To specifically and accurately diagnose a person with LBD, doctors have to ask the right questions about his symptoms, Vox said.

Delusions for Alzheimers patients might occur late in the disease and be ill-formed, appearing as paranoia or mistrust such as thinking a spouse is cheating. For LBD patients, delusions happen earlier and are well-formed misidentifications, such as looking at a loved one and thinking she has been replaced by an identical impostor.

The more detailed the assessment, Galvin said, the easier it is to separate out the conditions.

Because Lewy body proteins cant be tested like Alzheimers proteins can, cases of LBD are often diagnosed during hospitalization for something else, Vox said. Or diagnosis can happen postmortem, when the family requests an autopsy for closure, to gain more context for any doubts or to donate the brain for research, Taylor said.

Transforming mental, cognitive and physical health

The symptoms may first hinder a persons ability to work, Taylor said. Then they can disrupt their ability to drive; manage their affairs and health; be socially active; dress themselves; and shower. A person might also become unable to control involuntary behaviors, Galvin said, resulting in constipation, drooling, low blood pressure or the inability to control urine or bowel movements.

A persons inability to visually perceive the spatial relationships of objects can lead to car accidents or injuries. People with LBD can experience anxiety, depression and REM sleep disorder in which people lose the muscle paralysis that normally occurs during deep stages of sleep and physically (and sometimes violently) act out their dreams. Once a person is finally diagnosed, the life expectancy is about four to five years, Vox said.

Theyre losing the essence of who they are slowly over time, Taylor said. Thats a journey that is a very difficult one.

Research to improve diagnoses and treatments is underway, but there are currently no treatments for Lewy body dementia specifically. Most patients are treated with medications for Alzheimers or Parkinsons disease, since the symptoms of LBD are similar. However, treating the various symptoms of LBD with medications not fine-tuned for the condition can be a real art and quickly fill up a patients medicine cabinet, Vox said.

You have to weigh costs-benefits of treating this versus that, or get double effects of this medication and a little bit of that as well, he said.

Newfound challenges for patients and familiesLewy body dementia can be a harrowing experience for both patients and their families.

Getting a diagnosis can be a matter of months- to yearslong doctor shopping, Galvin said.

Executive dysfunction can lead to behaviors that family members initially perceive as bad judgments. Delusions can make them frustrated and fearful.

As a caregiver, I think one of the challenges is recognizing that we cannot use the same skills and interpersonal dynamics that we came to rely on in our relationship with the person with LBD, Taylor said.

We have to develop new ones because you cannot reason with somebody who is having a hallucination or delusion. Sometimes you have to more step into their reality and empathize (and) learn a new way to offer assistance without them feeling like theyre being treated like a child.

Living with Lewy body disease

Its possible that the same healthy diet, sleep and exercise routines that have been found to mitigate symptoms of Alzheimers and Parkinsons diseases might also help people with LBD.

So exercise is very important in Lewy body dementia, too, Taylor said, because its biologically related to Parkinsons disease and shares a lot of the same symptoms.

For patients and families in need of support and guidance, the Lewy Body Dementia Association is equipped with such resources.

Nobody should face LBD alone, Taylor sasid. Not the person with LBD and not the family caregiver. This disease doesnt make anything really easy in life. And they shouldnt have to go through it without a guide and a support.

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Lewy body dementia: The life-changing disease that devastated Robin Williams - East Idaho News

In the early days of COVID-19, the Alliance for Regenerative Medicine (ARM) was unsure how the pandemic and its accompanying economic downturn would affect the cell and gene therapy space.

It was a really specific time when the world and the markets were clearly reeling from the first appreciation for the seriousness of COVID-19, Janet Lambert, the organizations CEO said.

Now, the numbers are inand theyre better than ever. In the first half of 2020, the regenerative medicine sector raised $10.7 billion, more than the total capital raised in 2019 and a 120% jump over the first half of 2019, ARM found in a new report titled, Innovation in the Time of COVID-19. The proceeds were shared pretty evenly between cell therapy companies ($7.5 billion) and gene and gene-modified cell therapy companies ($7.9 billion), with companies focused on tissue engineering reeling in $84 million.

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RELATED: Biotech IPO bonanza: Legend's $350M offering as Repare, Forma get in on the action

That $10.7 billion was driven by a couple of outsize deals and includes $1.4 billion raised in five IPOs, $1.6 billion in follow-on offerings and $3 billion in venture capital. Chinese CAR-T player Legend Biotech led the pack with its mammoth $487 million Wall Street debut in June, but its peers netted considerable sums too. That same month, gene therapy companies Generation Bio and Akouos raised $230 million and $244 million, respectively. In February, another gene therapy outfit, Passage Bio, raised $284 million and gene-editing biotech Beam Therapeutics bagged $207 million.

On the venture side, Sana Biotechnology scored $700 millionalmost as much as the five next largest private rounds raised by Orca Bio Elevate Bio, Legend, Freeline Therapeutics and Poseida, the report found. Like Legend, Generation Bio and Akouos also completed sizable private rounds the same year they went public.

RELATED: 'The silver lining': Biotech IPOs in the time of coronavirus

All this enthusiasm for this sector right now is evidenced by these really astonishing financing numbers I think the drivers of that enthusiasm remain in place and make me optimistic for the second half of 2020, Lambert said. We continue to see really promising clinical results. We continue to see products making it to market. We continue to see patient, regulator and payer enthusiasm for these products.

Part of that enthusiasm stems from an appreciation for the biotech sector generally, Lambert said.

Attention is being paid to what the biopharma sector can do for us all as we try to weather and get out of the pandemic, she said, echoing the sentiments of venture capitalists whove managed to raise life sciences funds in spite of the pandemic.

The other side of the equation is the nature of biotechbecause the drug development cycle is long, biotech investors arent looking for quarter-to-quarter returns, but at milestone readouts that can come more than a year after IPO, Jordan Saxe, head of healthcare listings at Nasdaq, said in a previous interview.

Biotech is actually fairly well positioned to weather these kinds of events because youre not relying on day-to-day consumer spending. Youre relying on meaningful clinical catalysts at the end of the day to really generate value, and thats still going to be there in this environment, said Jason Pitts, Ph.D., a principal at Sofinnova, in ARMs report.

RELATED: Flagship raises $1.1B to create biotechs for post-pandemic world

All this gas in the tank isnt just bankrolling existing cell and gene therapies, but also driving company formation, Lambert said. For the first time, ARM counts more than 1,000 companies working in the sector, with more than 1,000 clinical trials going on worldwide. More than half of those studies are in phase 2, with just over a third in phase 1 and the remainder in phase 3.

Of those studies, 11 are testing regenerative medicine approaches against COVID-19, with several academic research centers and biopharma companies working on new treatments to treat the disease in the short and long term.

Most of them are using cell therapies to address ARDS, or acute respiratory distress syndrome, which is a consequence of COVID-19, Lambert said. Unlike other prospects in the pipeline, such as antibodies, which could potentially be used to prevent infection as well as treat it, regenerative treatments focus on repairing damage to the lungs or other organs that patients can suffer as part of COVID-19.

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In the face of COVID-19, cell and gene therapy space shows 'remarkable resilience:' report - FierceBiotech

September1,2020|Bio-IT World Conference & Expo Virtual kicks off in a month. The program this year includesthree days full of content, networking, and interaction across 16 tracks, plenary session, workshops, posters, awards,and happy hours.Thevirtual meeting platformoffers integrated tools to stay connected with colleagues,reach out to speakers, ask questions during presentations and live Q&A panels,and tour virtualexhibitbooths.

Andfor the first time ever, many presentations will be availableon demandafter their first showing. Attendees will be able to learn more, ask more questions, and derive more value from the program for weeks and months to come.

We are already busy marking our agendasnotations well be able to transfer to the virtual platform soon. Heres some of what is our on currentlist.The Editors

As usual, the event kicks off withworkshopsdesigned to be instructional, interactive and in-depth. This year topics include data management for biologics, a crash course in AI, data science-informed decisions, data at scale, and more.

The 2020 Bio-IT Worldplenaryprogramis exceptional.SusanGregurick, NIHs Office of Data Science Strategy, and Rebecca Baker, Director, HEAL, will share NIHs strategic vision for data science, and how thethepandemic will shape NIHs future.Tuesday, October 6

Robert Green,Brigham & Womens HospitalandHarvard Medical School will sharefascinating news on his latest sequencing project.AndNatalijaJovanovic, Sanofi Pasteur, will share pharmas view of the AI-enabled future.Thursday, October 8

A panel of experts includingSeth Cooper, Northeastern University; LeeLancashire, Cohen Veterans Bioscience;PietroMichelucci, Human Computation Institute; andJrmeWaldisphl, McGill Universitywill tackle how AI,citizenscience, andhumancomputationare working together with the help of gaming.Wednesday, October 7

And Trends from the TrenchesBio-IT Worldsannual deep dive into IT for life scienceswillcelebrate its 10th year with an all-star panelincluding VivienBonazzi, Deloitte; TimCutts,WellcomeTrust Sanger Institute;KjierstenFagnan, Lawrence Berkeley National Laboratory; MatthewTrunnell, Data Commoner-at-Large; andof courseChrisDagdigian.Thursday, October8

As commercial, governmental, and research organizations continue to move from manual pipelines to automated processing of their vast and growing datasets, they are struggling to find meaning in their repositoriessaysTerrell Russell, Chief Technologist, TheiRODSConsortium at Renaissance Computing Institute (RENCI). With an open, policy-based platform,Russell argues thatmetadata can be elevated beyond assisting in just search and discoverability. Metadata can associate datasets, help build cohorts for analysis, coordinate data movement and scheduling, and drive the very policy that provides the data governance. Data management should be data centric, and metadata driven.Wednesday, October 7

Michael C. Conway, Technical Architect, Office of Data Science, NIH NIEHSoutlinesNIEHSwork to build its own Data Commons to manage todays research data. Managing daily work while observing future trends, incorporating key capabilities, often in a tentative and piecemeal fashion, without losing sight of the big picturethis is the challenge we all face.Wednesday, October 7

Ian D. Harrow,Pistoia Alliancewill report on building a new toolkit to help life science industry implement the FAIR (Findable, Accessible, Interoperable, Reusable) principles for data management and stewardship. It provides practical support by bringing together relevant methods for tools, training and managing change, which are illustrated by use cases mostly from life science industry. These elements are assembled together as one user-friendly and freely accessible website.Wednesday, October 7

In a collection of talks and a panel discussion, a team of Gen3 users and architects present their experiences buildingpatientplatforms with Gen3. Speakers includeRobert Grossman, University of Chicago;Christopher G. Meyer, University of Chicago;Gabriella Miller,Kids First Data Resource Center;Allison Heath, Childrens Hospital of Philadelphia;William VanEtten,BioTeam; andDaniel Huston, Bristol-Myers Squibb Co.For an inside look at the collaboration withBioTeamand Bristol-Myers Squibb to set up a Gen3 data commons seeBuilding A Commons: How Bristol-Myers Squibb AndBioTeamUsed Gen3 To Build A New Data Paradigm.Wednesday, October 7

Luis A. Mendez, Bristol Myers Squibb, willpresent advances in multiparameter flow cytometry analysis using machine learning algorithms. Both t-distributed Stochastic Neighbor Embedding (t-SNE) andFlowSOMalgorithms are very effective in the comprehensive analysis and visualization of multiparameter flow cytometry data, resulting in a deeper understanding of disease biology at the single-cell level.Mendez will describe BMSscloud-based, high-performance compute environmentcoupled with GPU processing, deployed to overcome challenges with executing these CPU/RAM/GPU-intensive algorithms on large datasets.Wednesday, October 7

Rare disease patients suffer too often from long diagnostic delays and misidentified diseases. This creates a significant burden, not just for patients, but for healthcare systems.TomDefay,Alexion,will shareexamplesofcollaborationwith researchers and hospital systems to developnovel approaches for rare disease patient identification using tools like genomics, machine learning, and NLP.Thursday, October 8

Biomedical research over the last decade has become increasingly complex, and different disciplinary expertsare needed tosolve challenging scientific questions. No longer is a single disciplinary perspective enough for truly breakthrough research advances.L. Michelle Bennett, NIH NCI, explores how to build the most impactful interdisciplinary teams and how to keep them working effectively. (For more, see our conversation with Michelle atTraining Scientists For Our Interdisciplinary Future.)Wednesday, October 7

John Quackenbush, Harvard Medical School, will outline how his group uses networks tounderstandgenetic andgenomicdrivers ofdisease.By using innovative computational methods built around network representations of biological interactions, we can gain insight into the disease process, develop predictive biomarkers, and identify possible avenues of therapeutic intervention, he argues.Wednesday, October 7

ImanTavassoly, Icahn School of Medicine at Mount Sinai, will present themTOR system, adatabasehedesigned for exploring biomarkers and systems-level data related tothemTOR pathway in cancer. This database consists of different layers of molecular markers and quantitative parameters assigned to them through a current mathematical modelandis an example of merging systems-level data with mathematical models for precision oncology.Wednesday, October 7

Alexander Sherman, Massachusetts General Hospital, will describe how MGH is pursuingpatient centricity to bring such information together and bridge clinical trials data with RWD, such as data from EHRs, DNA sequences, image banks, biobanks, -omics, etc. We are introducing patient-centric approaches with a unique secure patient identification and aligning incentives for all players in a research continuum, including academia, industry, government, patient advocates, and patients.Wednesday, October 7

Exploratory visualizations generated from clinical trials and real-world data sources provide important insights into safety, efficacy, and biomarker responses to novel and standard-of-care treatments, saysPhilip Ross, Bristol-Myers Squibb.Hell explain how automation of data updates in near-real time increases the impact of this information on decision-makingand can driveclinical andbiomarkerexploration.Wednesday, October 7

Two presentersYan Ge, Director, Data Analytics, Data Science InstituteandErik Koenig, Principle Scientist, Translational Oncology, Head Strategy Innovation Management,both ofTakeda Pharmaceuticalswillpresent how aknowledge-baseanalyticsplatformhasempowereddata-drivendecisionmaking andistransformingtranslationalresearch. TheTakeda R&D Data Hub has been established to maximize the value of data, make them FAIR, increase access for efficient analysis and to drive data-driven decision making. The StrategicTranslational Oncology Research Knowledge-base (STORK) platform is a mission-critical strategic application leveraging both the R&D Data Hub and leading-edge Big Data technologies to harmonize the increasing data density of Immuno-Oncology Research and Development. STORK provides better catalogued and enriched biomarker assays data, allows researchers to intuitively and easily query internal preclinical data, clinical trials data, and external data like full-text literature and clinicaltrials.gov sources using NLP. Furthermore, STORKs self-service visualizations enable more efficient benchmarking, cross comparisons, forward and reverse translational insights to support key decision-making throughout the therapeutic lifecycle.Thursday, October 8

MatthewTrunnell, Data Commoner-at-Large(former Vice President and Chief Data Officer, Fred Hutchinson Cancer Research Center) will present theCascadia Data Discovery Initiative, and its goal to acceleratehealthinnovation andcancerresearch throughcollaboration,datasharing, anddata-drivenresearch.Wednesday, October 7

The future of the intersection of healthcare and the life sciences will be data- and process-focused, not application- or software-focused. Bringing the analytics todata is the challenge from an infrastructure and methods perspective. According to the FDA, Real-World Evidence (RWE) is defined as the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of Real-World Data (RWD): e.g., effectiveness or safety outcomes from an RWD source in randomized clinical trials or in observational studies.Sanjay Joshi, Dell EMC, leadsatopical, honest, and real-world paneltodiscuss the sources of RWD (EHR, Claims & Billing, Registries, Patient Reported Data, etc.) and their process implications for RWE and the future of clinical trials themselves.Wednesday, October 7

Many critical facts required by healthcare AI applications are locked in unstructured free-text data. Recent advances in deep learning have raised the bar on achievable accuracy for tasks, like named entity recognition, entity resolution, de-identification and others, using novel healthcare-specific networks and models.VishakhaSharma, Roche Molecular Systems,will discuss how Roche applies the greatest advances in AI for healthcare to extract clinical facts from pathology reports and radiology.Shewill then detail the design of the deep learning pipelines used to simplify training, optimization, and inference of such domain-specific models at scale.Wednesday, October 7

Researchers use biomarker and outcomes data to model and predict adverse events. However, access restrictions to safeguard patient privacy necessarily slow down the rate of discovery and increase research costs via IRB review.KimberlyRobasky, Renaissance Computing Institute (RENCI),makes an argument forsynthetic data that preserve patient-variable relationships. She willdiscuss current advances made by generative models in this area and the breakthrough AI technologies accelerating those advances.Wednesday, October 7

Digital transformation is still a driving principle in pharma R&D with the ultimate goal being to streamline processes and enable precision medicine.Anastasia Christianson, JanssenPharmaceuticals,willpresentexamples of digital technologies driving transformation and tangible results in R&D.Wednesday, October 7

While the value of FAIR data has been establishedas well as the costs of un-FAIR dataadoption lacks easy routes.Tom Plasterer, AstraZeneca, presents the Pistoia Alliance FAIR data toolkit and Innovative Medicines Initiative (IMI)FAIRplusCookbookwhichoffer frameworks to start. Key decisions on what to name things (e.g., identifiers) and their semantics (e.g., vocabularies) are critical at journey inception. Once established, FAIR knowledge graphs and FAIR analytic services become enterprise data-centric enablers.Wednesday, October 7

In less than a decade, CRISPR has evolved from a bacterial immune system to the foundation of a powerful, flexible genome editing technology that has already transformed biomedical research, spawned a $10-billion biotech industry, and is poised to make major strides in the clinic.Kevin Davies, the founding editor ofBio-IT World, has spent the past few years working closely with the CRISPR community as the Executive Editor ofThe CRISPR Journal. In this talk, he shares highlights of his new book,EDITING HUMANITY,to be released October 6, which explores the genesis of the CRISPR revolution, its impact on the gene therapy field, and the recent scandal involving the birth of CRISPR babies in China.Wednesday, October 7

Lara M.Mangravite, Sage Bionetworks, willdescribe a radically open approach to diversifyingthe AD drug portfolio. Using multi-omicand genetic models of disease built from human brain data, a suite of emerging therapeutic hypotheses are generated that complement the small set already in drug development. To catalyze rapid evaluation of these targets, target enabling packagescontaining computational and experimental resources including prototype drug compoundsare developed and openly distributed for use across the research community.Thursday, October 8

TanyaCashorali, TCB Analytics, leads a panel discussion on how to create an effective data and analytics strategy answering the questions:Whichdataareactionable? What is the end goal? How do you build out an organization? Are you sure you know what problem you are trying to solve? How do you set up an analytics environment?Shes joined by panelistsLauren Young, Beam Therapeutics, andHeather Shapiro, Pear Therapeutics.Wednesday, October 7

The Hutch usesEasyBuildfor building software containers and all software foritscomputer cluster.John Dey, Fred Hutchinson Cancer Research Center,will share more details about thesoftware stackand how the Hutchsharesitswork with the global community of EasyBuild users. Wednesday, October 7

CarolinaNobre, Harvard University, reports on the state of the art in visualizing multivariate networks.Multivariate networks are made up of nodes and their relationships (links), but also data about those nodes and links as attributes. Most real-world networks are associated with several attributes, and many analysis tasks depend on analyzing both, relationships and attributes. Visualization of multivariate networks, however, is challenging, especially when both the topology of the network and the attributes need to be considered concurrently.Nobrewillanalyze current practices and classify techniques along four axes: layouts, view operations, layout operations, and data operations.She willalso provide an analysis of tasks specific to multivariate networks and give recommendations for which technique to use in which scenario. Finally,she willsurvey application areas and evaluation methodologies.Wednesday,October 7

RituKamal, Illumina, will present IlluminasTruSightSoftware Suite, offeringready-made infrastructure to analyze and interpret rare disease variants.Powered by DRAGEN variant-calling, this software platform can evaluate all rare disease variant types within a single interface. Intuitive variant filtering, visualization and curation enable laboratories to perform streamlined interpretation and generate customizable reports.Wednesday, October 7

Biomedical researchers have access to many data sources but finding data with specific characteristics remains a challenge. Datasets have different metadata, format, and structure.TheBroad Instituteenvision a simpler and more comprehensive search capability to allow researchers to find and reuse data across many datasets.KathyReinoldproposesa cross-domain data model built specifically to facilitate search and reuseand will share methods, lessons learned, and status.Wednesday, October 7

KjierstenFagnan, Lawrence Berkeley National Laboratory, will present the National Microbiome Data Collaborative: A FAIRdataresource formicrobiomeresearch. Thismulti-lab collaborative partnership will pilot an integrated, community-centric framework within 27 months to fully leverage existing microbiome data science resources and high-performance computing systems available within the DOE complex for data access, integration, and advanced analyses,Fagnansays. She willcover some of the challenges in microbiome data sciences and howthe partnershipsaim to overcome these by creating a large, open-access repository of FAIR data.Wednesday, October 7

In a pair of talks fromBristol-Myers Squibbspeakers,Ajay ShahandAlbert Wangwill present Sage, a comprehensiveplatform forinnovation withdataand how BMS researchers use Sage to maximize real-world assets. Shah will start by giving an overview of essential components of the platform, such as uniform high-quality data ingestion, data lake enhancement with semantic integration conformance of data, and a reproducible research framework.Wang willhighlight how Sage catalogs, models, integrates, conforms, and presents patient-level metadata across all RWD assets to facilitate downstream cross-dataset analysis within an integrated managed analytics environment. This talk will touch on the business drivers for this initiative, our current progress, as well as some lessons learned.Wednesday, October 7

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A Virtual Feast: A Preview of Bio-IT World 2020 - Bio-IT World

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