Category Archives: Gene Medicine

DALLASMay 28, 2021A study of gene activity in the brains hippocampus, led by UT Southwestern researchers, has identified marked differences between the regions anterior and posterior portions. The findings, published today in Neuron, could shed light on a variety of brain disorders that involve the hippocampus and may eventually help lead to new, targeted treatments.

Genevieve Konopka, Ph.D.

These new data reveal molecular-level differences that allow us to view the anterior and posterior hippocampus in a whole new way, says study leader Genevieve Konopka, Ph.D., associate professor of neuroscience at UTSW.

She and study co-leader Bradley C. Lega, M.D., associate professor of neurological surgery, neurology, and psychiatry, explain that the human hippocampus is typically considered a uniform structure with key roles in memory, spatial navigation, and regulation of emotions. However, some research has suggested that the two ends of the hippocampus the anterior, which points downward toward the face, and the posterior, which points upward toward the back of the head take on different jobs.

Bradley C. Lega, M.D.

Scientists have speculated that the anterior hippocampus might be more important for emotion and mood, while the posterior hippocampus might be more important for cognition. However, says Konopka, a Jon Heighten Scholar in Autism Research, researchers had yet to explore whether differences in gene activity exist between these two halves.

For the study, Konopka and Lega, both members of the Peter ODonnell Jr. Brain Institute, and their colleagues isolated samples of both the anterior and posterior hippocampus from five patients who had the structure removed to treat epilepsy. Seizures often originate from the hippocampus, explains Lega, who performed the surgeries. Although brain abnormalities trigger these seizures, microscopic analysis suggested that the tissues used in this study were anatomically normal.

Marked differences in gene activity were identified in the anterior portion of the hippocampus, which points downward toward the face, and the posterior, which points upward toward the back of the head. Credit: Melissa Logies

After removal, the samples underwent single nuclei RNA sequencing (snRNA-seq), which assesses gene activity in individual cells. Although snRNA-seq showed mostly the same types of neurons and support cells reside in both sections of the hippocampus, activity of specific genes in excitatory neurons those that stimulate other neurons to fire varied significantly between the anterior and the posterior portions of the hippocampus. When the researchers compared this set of genes to a list of genes associated with psychiatric and neurological disorders, they found significant matches. Genes associated with mood disorders, such as major depressive disorder or bipolar disorder, tended to be more active in the anterior hippocampus; conversely, genes associated with cognitive disorders, such as autism spectrum disorder, tended to be more active in the posterior hippocampus.

Lega notes that the more researchers are able to appreciate these differences, the better theyll be able to understand disorders in which the hippocampus is involved.

The idea that the anterior and posterior hippocampus represent two distinct functional structures is not completely new, but its been underappreciated in clinical medicine, he says. When trying to understand disease processes, we have to keep that in mind.

Other UTSW researchers who contributed to this study include Fatma Ayhan, Ashwinikumar Kulkarni, Stefano Berto, Karthigayini Sivaprakasam, and Connor Douglas.

This work was funded by grants from the National Institutes of Health (NIH grants NS106447, T32DA007290, T32HL139438, NS107357), a University of Texas BRAIN Initiative seed grant (366582), the Chilton Foundation, the National Center for Advancing Translational Sciences of the NIH (under Center for Translational Medicine award UL1TR001105), the Chan Zuckerberg Initiative (an advised fund of the Silicon Valley Community Foundation, HCA-A-1704-01747), and the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition (scholar award 220020467).

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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Same Difference: Two halves of the hippocampus have different gene activity - UT Southwestern

A massive genome-wide association study (GWAS) of genetic and health records of 1.2 million people from four separate data banks has identified 178 gene variants linked to major depression, a disorder that will affect one of every five people during their lifetimes.

The results of the study, led by the U.S. Department of Veterans Affairs (V.A.) researchers at Yale University School of Medicine and University of California-San Diego (UCSD), may one day help identify people most at risk of depression and related psychiatric disorders and help doctors prescribe drugs best suited to treat the disorder.

The study was published May 27 in the journal Nature Neuroscience.

For the study, the research team analyzed medical records and genomes collected from more than 300,000 participants in the V.A.s Million Veteran Program (MVP), one of the largest and most diverse databanks of genetic and medical information in the world.

These new data were combined in a meta-analysis with genetic and health records from the UK Biobank, FinnGen (a Finland-based biobank), and results from the consumer genetics company 23andMe. This part of the study included 1.2 million participants. The researchers crosschecked their findings from that analysis with an entirely separate sample of 1.3 million volunteers from 23andMe customers.

When the two sets of data from the different sources were compared, genetic variants linked to depression replicated with statistical significance for most of the markers tested.

Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.

Daniel Levey

What is most heartening is we could replicate our findings in independent data sets, said Daniel Levey, an associate research scientist in the Yale Department of Psychiatry and co-lead author. Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.

Like many mental health disorders, depression is genetically complex and is characterized by combinations of many different genetic variants, the researchers say.

Thats why we werent surprised by how many variants we found, said Joel Gelernter, the Foundations Fund Professor of Psychiatry at Yale, professor of genetics and of neuroscience, and co-senior author of the study. And we dont know how many more there are left to discover hundreds? Maybe even thousands?

The size of the new GWAS study will help clinicians to develop polygenic risk scores to pinpoint those most at risk of developing major depression and other related psychiatric disorders such as anxiety or post-traumatic stress disorder, the authors say.

The study also provides deep insights into the underlying biology of genetic disorders. For instance, one gene variant implicated in depression, NEGR1, is a neural growth regulator active in the hypothalamus, an area of the brain previously linked to depression. That confirms research done by the late Yale neuroscientist Ronald Duman on the role of neurotrophic factors in depression, Levey said.

Its really striking when completely different kinds of research converge on similar biology, and thats whats happening here, he said.

Insights into the functions of the variants can also help identify many drugs that hold promise in the treatment of depression, the researchers say. For instance, the drug riluzole, which is approved for the treatment of amyotrophic lateral sclerosis (ALS), modulates glutamate transmission in brain. Several gene variants linked by the new study to depression affect the glutamate system, which is actively being studied for depression treatments.

One of the real goals of the research is bringing forward new ways to treat people suffering from depression, added co-senior author Dr. Murray Stein, staff psychiatrist at the V.A. San Diego Healthcare System and Distinguished Professor of Psychiatry and Public Health at UCSD.

Research was primarily funded by the U.S. Department of Veterans Affairs, including the Million Veteran Program and the Cooperative Studies Program. Levey also received support from a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation.

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Roots of major depression revealed in all its genetic complexity - Yale News

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD patients are at higher risk of developing Non-alcoholic steatohepatitis (NASH), which causes severe and chronic liver inflammation, fibrosis and liver damage. A patient with NASH is believed to be at high risk for developing a form of liver cancer called hepatocellular carcinoma (HCC).

Apart from lifestyle interventions, there are currently no approved treatments for NASH. A liver transplant is sometimes the only remedy.

While risk factors for NASH (obesity, type-2 diabetes and gene mutations like PNPLA3) and HCC (Hepatitis B and C infections, alcohol overconsumption and cirrhosis) are well known, the precise mechanism of how simple fatty liver progresses to chronic inflammation, liver fibrosis, NASH and HCC is not known.

Debanjan Dhar, PhD, is co-senior author of the study and assistant professor in the Department of Medicine, Division of Gastroenterology at UC San Diego School of Medicine.

A recent study led by researchers at University of California San Diego School of Medicine found in a mouse model that when fed a Western diet rich in calories, fat and cholesterol, the mice progressively became obese, diabetic and developed NASH, which progressed to HCC, chronic kidney and cardiovascular disease.

The findings, published in the May 31, 2021 online edition of Cellular and Molecular Gastroenterology and Hepatology, showed that by simply changing the Western diet in a mouse model to a normal chow diet, where calories are derived from proteins and carbohydrates rather than fats, with no cholesterol, NASH and liver fibrosis were improved; and cancer progression and mortality prevented.

While the mice that continued on a Western diet developed HCC and had an increased risk of death, 100 percent of the mice that stopped the diet survived the length of the study without developing HCC, said Debanjan Dhar, PhD, co-senior author of the study and assistant professor in the Department of Medicine, Division of Gastroenterology at UC San Diego School of Medicine.

David Brenner, MD, is co-senior author and vice chancellor of UC San Diego Health Sciences.

This indicates that NASH and HCC may be a preventable disease and that diet plays a crucial role in the disease outcome.

In mice no longer fed the Western diet, researchers also found a decrease in liver fat and improvement in glucose tolerance an indicator of diabetes and several genes and cytokines that were affected in NASH returned to normal levels and function. In addition, Dhar and his team found key changes in the gut microbiome that modulate liver disease progression.

Although NASH is a liver disease, our results show its development and progression is orchestrated by multiple organs.

A surprising finding, said the researchers, was that when they switched the Western diet of the mice with NASH to normal chow, the effect was more pronounced on the liver rather than on whole body weight.

This could mean that slight changes in the liver might have profound effects on the disease outcome, said David Brenner, MD, co-senior author and vice chancellor of UC San Diego Health Sciences.

Researchers also compared mouse model findings to human patient datasets, indicating that gene expression changes in mouse livers were similar to human counterparts.

Our animal model provides an important pre-clinical testing platform to study the safety and efficacy of drugs that are currently being developed, as well as to test the repurposing of other drugs that are already FDA approved for other diseases, said Dhar.

Co-authors include: Souradipta Ganguly, Linshan Shang, Ruoyu Wang, Yanhan Wang, Bernd Schnabl, Rob Knight, Sara Brin Rosenthal, Gibraan Rahman, Anthony Diomino, Tatiana Kisseleva, Mojgan Hosseini and Mojgan Hosseini, all with UC San Diego; German Aleman Muench and Pejman Soorosh with Janssen Research and Development; and Hyeok Choon Kwon with National Medical Center, South Korea.

The research was funded, in part, by the National Institutes of Health (Grants DK120515, KL2TR001444 and 5P50AA011999), an ALF Liver Scholar award, the Southern California Research Center for ALPD and Cirrhosis.

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Diet Plays Critical Role in NASH Progressing to Liver Cancer in Mouse Model - UC San Diego Health

PARIS--(BUSINESS WIRE)--Regulatory News:

GenSight Biologics (Paris:SIGHT) (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced that it will host a Key Opinion Leader (KOL) call on June 4, 2021 from 8:00 am to 9:00 am EDT. The webinar will feature presentations by KOLs Jos-Alain Sahel, MD (University of Pittsburgh School of Medicine) and Botond Roska, MD, PhD (Institute of Molecular and Clinical Ophthalmology Basel), who will discuss the Nature Medicine Case Report of partial recovery of visual function in a blind patient with late-stage retinitis pigmentosa (RP)., The subject is a participant in the ongoing PIONEER Phase I/II clinical trial of GenSight Biologics GS030 optogenetic therapy. Following the formal presentations, Drs. Sahel and Roska will be available to answer questions.

In addition, GenSight's management team will discuss highlights from the Nature Medicine Case Report and provide an update on their pipeline candidate, GS030. Administered via intravitreal injection, GS030 uses an optimized viral vector (GS030-DP) to express the light-sensitive opsin ChrimsonR in retinal ganglion cells and proprietary light-stimulating goggles (GS030-MD) to project the right wavelength and intensity of light onto the treated retina.

The webinar will be webcast live at https://bit.ly/3uzvG1j. You will need to register in advance to get access to the webinar. For those unable to attend the live broadcast, a recording will be accessible using the same link.

The Nature Medicine Case Report can be found at https://www.nature.com/articles/s41591-021-01351-4. A video of the patient performing the tests, which was submitted as supplementary material to the publication, can be viewed at http://www.gensight-biologics.com.

About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. Using its gene therapy-based approach, GenSight Biologics product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery. Developed as a treatment for Leber Hereditary Optic Neuropathy (LHON), GenSight Biologics lead product candidate, LUMEVOQ (GS010; lenadogene nolparvovec), is currently in the review phase of its registration process in Europe, and in Phase III to move forward to a BLA filing in the U.S.

About GS030

GS030 leverages GenSight Biololgics optogenetics technology platform, a novel approach to restore vision in blind patients using a combination of ocular gene therapy and tailored light-activation of treated retinal cells. The gene therapy, which is delivered via a single intravitreal injection, introduces a gene encoding for a light-sensitive protein (ChrimsonR-tdT) into retinal ganglion cells, making them responsive to light and bypassing photoreceptors killed off by diseases such as retinitis pigmentosa (RP). Because ChrimsonR-tdT is activated by high intensities of amber light, a wearable medical device is needed to stimulate the treated retina. The optronic light-stimulating goggles (GS030-MD) encode the visual scene in real-time and project a light beam with a specific wavelength and intensity onto the treated retina. Treatment with GS030 requires patients to wear the external wearable device in order to enable restoration of their visual function. With the support of the Institut de la Vision in Paris and the team of Dr. Botond Roska at the Friedrich Miescher Institute in Basel, GenSight is investigating GS030 as therapy to restore vision in patients suffering from late-stage RP. GenSights optogenetics approach is independent of the specific genetic mutations causing blindness and has potential applications in other diseases of the retina in which photoreceptors degenerate, like dry age-related macular degeneration (dry-AMD). GS030 has been granted Orphan Drug Designation in the United States and Europe.

About Optogenetics

Optogenetics is a biological technique that involves the transfer of a gene encoding for a light sensitive protein to cause neuronal cells to respond to light stimulation. As a neuromodulation method, it can be used to modify or control the activities of individual neurons in living tissue and even in-vivo, with a very high spatial and temporal resolution. Optogenetics combines (1) the use of gene therapy methods to transfer a gene into target neurons with (2) the use of optics and electronics (optronics) to deliver the light to the transduced cells. Optogenetics holds clinical promise in the field of vision impairment or degenerative neurological disorders.

About Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a family of orphan genetic diseases caused by multiple mutations in numerous genes involved in the visual cycle. Over 100 genetic defects have been implicated. RP patients generally begin experiencing vision loss in their young adult years, with progression to blindness by age 40. RP is the most widespread hereditary cause of blindness in developed nations, with a prevalence of about 1.5 million people throughout the world. In Europe and the United States, about 350,000 to 400,000 patients suffer from RP, and every year between 15,000 and 20,000 new patients with RP lose sight. There is currently no curative treatment for RP.

About the PIONEER Phase I/II trial

PIONEER is a first-in-man, multi-center, open label dose-escalation study to evaluate the safety and tolerability of GS030 in 12-18 subjects with late-stage retinitis pigmentosa. GS030 combines a gene therapy (GS030-DP) administered via a single intravitreal injection with a wearable optronic visual stimulation device (GS030-MD). Eligible patients in the first three cohorts are those affected by end-stage non-syndromic RP with no light perception (NLP) or light perception (LP) levels of visual acuity. The extension cohort will include patients with hand motion (HM) and counting fingers (CF) levels of visual acuity.

As per protocol, three cohorts with three subjects each will be administered an increasing dose of GS030-DP via a single intravitreal injection in their worse-seeing eye. An extension cohort will receive the highest tolerated dose. The DSMB will review the safety data of all treated subjects in each cohort and will make recommendations before a new cohort receives the next dose. The primary outcome analyses will be on the safety and tolerability at one year post-injection. PIONEER is being conducted in three centers in the United Kingdom, France and the United States.

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GenSight Biologics to Host a Key Opinion Leader Webinar on the Nature Medicine Case Report: Visual Recovery after GS030 Optogenetic Treatment -...

Key Highlights:

MELBOURNE, Australia, June 01, 2021 (GLOBE NEWSWIRE) -- Genetic Technologies Limited (ASX: GTG; NASDAQ: GENE, Company, GTG), a diversified Genomics and AI-driven preventative health business, is pleased to announce the official launch of its COVID-19 Serious Disease Risk Test (COVID-19 Risk Test) in the US through its partnership with Infinity BiologiX LLC (IBX). IBX will produce, distribute, and sell GENEs test across its established network, https://ibx.bio/services/covid-19-severity-test/

Designed to predict disease severity using genetic and clinical information the test provides a risk score to help individuals aged 18 years and over to understand their personal risk of contracting a serious case of COVID-19. In addition, employers, governments, and other public health entities may use the data to make informed decisions about disease risk, treatment options, and vaccination priorities. This will assist in guiding proactive steps to minimize disease exposure and manage the pandemic in the weeks and months ahead.

This is a fantastic milestone for our team, commented Simon Morriss, CEO of Genetic Technologies. Our COVID-19 Risk Test is a crucial product that will provide individuals with the ability to understand their personal risk associated with contracting a serious case of this disease. Alongside existing treatment options and vaccines, we believe this test will enable more insightful decisions for states, workplaces and individuals on pathways forward in managing this pandemic.

IBX is a market-disrupting central laboratory supporting academia, government, and industry. IBX provides global sample collection, processing, storage, and analytical services integrated with scientific and technical support in both the research and clinical arenas. As a leader in biomaterials, IBX provides support to the development of diagnostics, therapeutics, and research in the genomics, precision, and regenerative medicine arenas.

Extensive experience with large-scale COVID testing and sample processing made IBX a clear choice for this endeavor. Through its labs in New Jersey and Minnesota and with partner organizations around the US, the company is able to process over 100,000 risk tests per day.

IBX launched its COVID-19 saliva-test in May 2020, after receiving FDA Emergency Use Authorization. It was the first test to utilize saliva as the primary biomaterial for SARS-CoV-2, and IBX subsequently became the first company to offer an at-home collection with this approach.

Developed by GENE, the COVID-19 risk test will be distributed and sold in the US by IBX, released under GENEs powered by GeneType brand, and is applicable to men and women ages 18 and up. IBX will determine sales and end consumer pricing structure for the risk test and will produce, distribute, and market it in the US.

About Genetic Technologies Limited Genetic Technologies Limited (ASX: GTG; Nasdaq: GENE) is an Australian based diversified molecular diagnostics company. GENE offers cancer predictive testing and assessment tools to help physicians proactively manage patient health. The companys lead products, GeneType for Breast Cancer for non-hereditary breast cancer and GeneType for Colorectal Cancer, are clinically validated risk assessment tests and are first in class. Genetic Technologies is developing a pipeline of risk assessment products based on a world leading technology platform created over the past 10 years.

For more information, please visit http://www.genetype.com

About Infinity BiologiX LLC: Infinity BiologiX (IBX) is a market-disrupting central laboratory supporting academia, government, and industry. IBX provides global sample collection, processing, storage, and analytical services integrated with scientific and technical support in both the research and clinical arenas. As a leader in biomaterials, IBX provides support to the development of diagnostics, therapeutics, and research in the genomics, precision, and regenerative medicine arenas. IBX previously operated as RUCDR Infinite Biologics before spinning off from Rutgers University-New Brunswick in August 2020.

For more information, visit http://www.ibx.bio

Forward-Looking Statements

This press release may contain forward-looking statements about the Company's expectations, beliefs or intentions regarding, among other things, statements regarding the expected use of proceeds. In addition, from time to time, the Company or its representatives have made or may make forward-looking statements, orally or in writing. Forward-looking statements can be identified by the use of forward-looking words such as "believe," "expect," "intend," "plan," "may," "should" or "anticipate" or their negatives or other variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical or current matters. These forward-looking statements may be included in, but are not limited to, various filings made by the Company with the U.S. Securities and Exchange Commission, press releases or oral statements made by or with the approval of one of the Company's authorized executive officers. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to risks and uncertainties that could cause the Company's actual results to differ materially from any future results expressed or implied by the forward-looking statements. Many factors could cause the Company's actual activities or results to differ materially from the activities and results anticipated in such forward-looking statements as detailed in the Company's filings with the Securities and Exchange Commission and in its periodic filings in Australia and the risks and risk factors included therein. In addition, the Company operates in an industry sector where securities values are highly volatile and may be influenced by economic and other factors beyond its control. The Company does not undertake any obligation to publicly update these forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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Genetic Technologies' COVID-19 Risk Test Now Available in US through Partnership with Infinity BiologiX - GlobeNewswire

HOUSTON and SAN DIEGO, June 1, 2021 /PRNewswire/ -- Neurophth Biotechnology Ltd., a fully-integrated genetic medicines company developing AAV-mediated gene therapies for the treatment of ocular diseases, and Hopstem Biotechnology, the leading human induced pluripotent stem cell (hiPSC) and neural differentiation technology platform company, today announced a strategic partnership aiming to provide human iPSC-derived cell therapy for ocular diseases.

The partnership leverages Neurophth's experience in global gene/cell therapy drugs development and understanding of ophthalmic diseases to complement Hopstem's expertise in GMP manufacturing and quality assurance of iPSC-derived clinical cell products to provide next-generation ocular treatments. Under the terms of agreement, Hopstem Biotechnology will receive upfront and milestone payments for the development of candidate cell product for agreed retinal degenerative disorder. Neurophth will have the option to license the candidate product and will be responsible for development and commercialization of the licensed product. In addition, Neurophth agreed to license Hopstem's iPSC reprogramming patent and GMP iPSC line with additional payments to Hopstem at different product development stages. According to the agreement, Hopstem will also share part of the product sales.

"This collaboration exemplifies Neurophth's long-term commitment to advancing the field of ophthalmic treatment as we continue to expand and progress our innovative pipeline of ocular candidates," said Bin Li, M.D., Ph.D., Founder and Chairman of Neurophth Therapeutics. "Combining the methods of stem cell technology, induced pluripotent stem cells is a promising technology that can offer an extraordinary potential for regenerative therapy, disease modeling and drug screening."

"We are very excited by this partnership with Neurophth. The human induced pluripotent stem cell (hiPSC) line we developed is made by transforming the skin of a healthy donor into stem cells that are capable of multiplying and becoming any type of cell in the human body, meeting GMP requirements. Thanks to our iPSC-derived clinical cell product manufactory and quality platform developed since 2019, we are able to speed up ocular cell product development with Neurophth, the leading ocular therapy company in the field. Together, our aim is to offer safe and effective regenerative medicine with hiPSC-derived cellsfor reversing the progression of ocular diseases and restoring vision for patients," Jing Fan, Ph.D., Founder and CEO of Hopstem Biotechnology.

"iPSCs holds the promise for treatment of retinal degenerative disorders where AAV-mediated gene therapy is unreachable," said Alvin Luk, Ph.D., M.B.A., CEO at Neurophth. "Hopstem is one of the most respected pioneers in the field of iPSC translational medicine. We are confident that their technology and expertise, combined with Neurophth's deep knowledge in ophthalmology and drug development, has the potential to unlock future generations of gene/cell therapy treatments for patients."

About Neurophth

Neurophth is China's first gene therapy company for ophthalmic diseases. Headquartered in Wuhan with subsidiaries in Shanghai, Suzhou, and US, Neurophth, a fully integrated company, is striving to discover and develop gene therapies for patients suffering from blindness and other eye diseases globally. Our validated AAV platform which has been published in Nature - Scientific Reports, Ophthalmology, and EBioMedicine, has successfully delivered proof-of-concept data with investigational gene therapies in the retina. Our most advanced investigational candidate, NR082 (NFS-01 project, rAAV2-ND4), in development for the treatment ofND4-mediated Leber hereditary optic neuropathy (LHON), has granted orphan designation by theU.S FDA and its IND has also been approved by China NMPA. The pipeline also includesND1-mediated LHON, autosomal dominant optic atrophy, optic neuroprotection (e.g., glaucoma), vascular retinopathy (e.g., diabetic macular edema and wet age-related macular degeneration), and five other preclinical candidates. Neurophth has initiated the scaling up in-house manufacturing process in single-use technologies to support future commercial demand at the Suzhou facility. To learn more about us and our growing pipeline, please visitwww.neurophth.com.

About Hopstem

Hopstem Biotechnology is one of the first few iPSC cell therapy companies in China. The company was founded in January 2017 in Hangzhou (China) and Baltimore (US) by neuroscientists and stem-cell biologists from Johns Hopkins University. Hopstem has established a world-leading neural differentiation platform as well as patented iPSC reprogramming method and high standard GMP manufactory and quality system. The mission of Hopstem is to apply these cutting-edge technologies to develop innovative cell therapies for CNS and other disorders. Our leading clinical product, hNPC01, is a human forebrain neural progenitor cell product for stroke and traumatic brain injuries, etc. Preliminary studies in rat and monkey pMCAO stroke models have suggested that majority of those transplanted hNPCs differentiated into functional neural cells and formed significant new connections with the rat neurons in distal regions. To learn more about us, please visit http://www.hopstem.com.

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SOURCE Neurophth Therapeutics, Inc.

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Neurophth Therapeutics and Hopstem Biotechnology Announce Strategic Partnership to Develop Human Induced Pluripotent Stem Cell-Derived Therapies for...

On May 17, NHGRI announced plans to appoint Vence Bonham Jr., J.D. as acting deputy director. Vence, who joined NHGRI in 2003, is currently senior advisor to the NHGRI director on genomics and health disparities as well as head of the Health Disparities Unit in NHGRIs Social and Behavioral Research Branch. His appointment as acting deputy director will expand on his current roles, in which he has made major contributions to the Institutes research on diversity, inclusion, and health equity. In this new role, Vence will assume a more elevated position at the Institute, helping the NHGRI leadership advance NHGRIs mission and priorities.

The NHGRI deputy director position has been vacant since Mark Guyer, Ph.D., retired in 2014. The upcoming appointment of Vence as the NHGRI acting deputy director reflects the Institutes desire to have a leader at the highest possible level to guide programmatic activities to advance work related to diversity, inclusion, and health equity at the national level, but also lead NIH and NHGRIs efforts to address anti-racism and social justice. These are significant priority areas for NHGRI, and Vences leadership will be invaluable.

One of Vences first responsibilities as acting deputy director will be to create a new Office of Workforce Diversity and Health Equity within the NHGRI Office of the Director. The new office will work towards NHGRIs goals Vence will work closely with other NHGRI leaders to develop the offices mission and vision, establish a staffing plan, and lead efforts to recruit its first director.

Vence is familiar with NHGRIs long-standing leadership on issues related to diversity in genomics. Most recently, he led the NHGRI Genomic Workforce Diversity Working Group that established an action agenda for enhancing the diversity of the genomics workforce, which was published earlier this year. Vence and NHGRIs Director, Dr. Eric Green, also co-authored a commentary in the American Journal of Human Genetics, which described the imperative to enhance the diversity of the genomics workforce for achieving the promise of genomics. In his new role, Vence will focus on implementing this action agenda and will continue to be one of three NHGRI leaders serving on key NIH-wide committees as part of the NIH UNITE Initiative, which aims to end structural racism in biomedical research.

Vence also has a long history of starting successful initiatives at NHGRI. He established the Education and Community Involvement Branch and served as its inaugural chief. The branch thrived under his leadership, including the creation of the Smithsonian-NHGRI exhibition, Genome: Unlocking Lifes Code.

His research program focuses primarily on the social implications of new scientific knowledge, particularly in communities of color. He and his group study how genomics influences the use of the constructs of race and ethnicity in biomedical research and clinical care, as well as how genomics worsens or improves health inequities. They also study sickle cell disease, a condition that is affected by emerging curative genomic technologies and that faces significant health disparities both in the US and worldwide.

Vences appointment as the NHGRI acting deputy director is anticipated to begin in early summer.

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Vence Bonham to be appointed acting NHGRI deputy director - National Human Genome Research Institute

Many of us are familiar with Parkinsons disease, but the term parkinsonism may not be as familiar.

Parkinsonism is a term for a group of neurological conditions that cause difficulty with movement. Some of the defining symptoms of parkinsonism include:

Parkinsons disease is the most common type of parkinsonism. It makes up about 80 percent of parkinsonism cases.

Other types of parkinsonism are collectively known as atypical parkinsonian disorders or Parkinson-plus syndromes. There are many types of parkinsonism that closely mimic symptoms of Parkinsons, and diagnosis can be difficult.

In this article, we look at the different types of parkinsonism and break down the symptoms and treatment of each.

Parkinsons disease is one of many types of parkinsonism. Its caused by a loss of cells in the part of your brain that produces the neurotransmitter dopamine.

Parkinsons disease and the different types of parkinsonism progress in different ways. Some may progress more rapidly than Parkinsons disease. Others, like secondary parkinsonism, may be reversible.

The conditions also respond differently to treatments. For instance, someone who has a type of parkinsonism may not respond to the drug levodopa, which is commonly used for Parkinsons disease.

It can be hard to tell the difference between types of parkinsonism. Heres a look at some of the identified categories of parkinsonism with their typical symptoms and treatments.

Atypical parkinsonism refers to any type of parkinsonism that isnt Parkinsons disease.

Types of atypical parkinsonism include:

Multiple system atrophy is a rare and progressive disease thats characterized by abnormal deposits of protein in the nervous system. The cause is unknown, and it affects about 15,000 to 50,000 Americans.

The initial symptoms are similar to those of Parkinsons disease, but they tend to progress more quickly. They include:

Theres currently no treatment for multiple system atrophy thats known to delay the progression of the disease. Treatment involves targeting individual symptoms.

Progressive supranuclear palsy is a disorder caused by damage to parts of the brain controlling the cranial nerves. Symptoms vary between people, but the first sign is often loss of balance while walking. This condition also progresses faster than Parkinsons disease.

Other signs include:

Theres no effective treatment for progressive supranuclear palsy, and it usually doesnt respond to medication. Treatment revolves around targeting individual symptoms.

Corticobasal syndrome is a progressive neurological disorder that leads to the deterioration of certain areas of your brain. The initial sign is often trouble moving one limb. Eventually, this movement difficulty spreads to all limbs.

The onset of this syndrome is usually between ages 50 to 70. It affects roughly 5 in 100,000 people.

Symptoms vary greatly but may include:

No treatment has been found to slow the progression of corticobasal syndrome. Parkinsons drugs are generally ineffective but may help manage stiffness in some people.

Dementia with Lewy bodies is a disease that leads to deposits of alpha-synuclein proteins in the brain. These proteins are also called Lewy bodies.

Abnormal build-up of these chemicals can cause movement, behavior, mood, and cognitive changes.

More than 1 million people in the United States have Lewy body dementia. It most often occurs in adults over 50 and can progress for 2 to 20 years from its onset to death.

Movement symptoms include:

Cognitive symptoms can include:

Secondary parkinsonism is when a medical condition or medication leads to symptoms that resemble Parkinsons. The most common cause of secondary parkinsonism is a side effect of medications, also known as pseudoparkinsonism.

Some drugs can interfere with dopamine transmission in your brain and cause symptoms resembling Parkinsons.

Drugs that are known to induce parkinsonism include:

Treatment usually involves lowering the dose or ceasing use of the offending medication.

A number of underlying conditions can potentially lead to brain damage that causes parkinsonism. Some conditions include:

Treatment for parkinsonism caused by an underlying condition involves targeting the root cause and treating the symptoms.

Its thought that multiple small strokes in the part of your brain that controls movement can lead to a condition called vascular parkinsonism. Vascular parkinsonism is characterized by parkinsonism symptoms primarily in the lower limbs and an unsteady gait in the absence of tremors.

Symptoms include:

Vascular parkinsonism is typically poorly responsive to the medication levodopa. Treatment primarily focuses on treating symptoms. Physical therapy and lifestyle changes to improve cardiovascular health are often recommended.

Infantile parkinsonism-dystonia is a rare disorder thats also known as dopamine transporter deficiency syndrome. It causes a progressive decline in involuntary muscle contractions and other symptoms that resemble those of Parkinsons disease. It usually begins in infants.

Theres no cure for infantile parkinsonism-dystonia, and its caused by a mutation of the gene SLC6A3.

Symptoms of infantile parkinsonism-dystonia include:

Other symptoms can be present, like:

Treatment involves targeting individual symptoms to increase quality of life. Medications to control involuntary muscular contractions and physical therapy are also commonly used.

Juvenile parkinsonism develops before the age of 21. Juvenile parkinsonism that responds to the medication levodopa is most often caused by mutations in the genes PARK-Parkin, PARK-PINK1, or PARK-DJ1.

The symptoms of juvenile parkinsonism are the same as late-onset parkinsonism, but the onset is at a younger age.

The medication levodopa is the most common treatment. But other supportive therapies may also be used, like botulinum toxin for treating involuntary spasms, as well as deep brain stimulation and physical therapy.

No single test can diagnose parkinsonism disorders. Doctors use a combination of tests to rule out other possible conditions and make a diagnosis based on your symptoms and medical history.

For many types of parkinsonism, the exact cause isnt known. Genetic and environmental factors are both believed to play a role.

Parkinsons disease has been linked to exposure to pesticides and herbicides, as well as living close to industrial plants. Some genes are also associated with an elevated risk of developing Parkinsons.

Conditions that cause brain damage, like traumatic injuries, tumors, and exposure to certain toxins, are also potentially contributing factors to the development of parkinsonism.

The outlook of parkinsonism is highly variable depending on factors like the age of onset, the underlying cause, and your overall health. For example, late-onset Parkinsons disease tends to progress faster and cause earlier cognitive dysfunction than early-onset Parkinsons.

Parkinsonisms are progressive conditions that get worse over time. Initiating treatment shortly after symptoms begin can help increase life expectancy and improve quality of life.

For Parkinsons, the primary treatment is the medication levodopa. Treatment varies for other types of parkinsonism, but primarily involves managing symptoms.

Read this article:
Parkinsonism: Types, Causes, and More - Healthline

1Department of Orthopedics, The 923rd Hospital of the Joint Logistics Support Force of the Peoples Liberation Army, Nanning, Peoples Republic of China; 2Department of Orthopedics, Peoples Hospital of Guilin, Guilin, Guangxi, 541001, Peoples Republic of China; 3Department of Orthopedics, Fifth Clinical Medical College, Guilin Medical University, Guilin, Guangxi, 541001, Peoples Republic of China; 4Department of Orthopedics, The Tenth Peoples Hospital of Nanning, Nanning, Guangxi, 530105, Peoples Republic of China

Correspondence: Bo LvPeoples Hospital of Guilin, 12 Wenming Road, Guilin, Guangxi, 541001, Peoples Republic of ChinaTel +867738997962Email [emailprotected]

Purpose: Osteosarcoma is the most common malignant bone cancer affecting adolescents and young adults. This study aimed to screen potential diagnostic and therapeutic markers for osteosarcoma.Methods: Differential expression analysis between osteosarcoma and control was performed in GSE99671, the differentially expressed genes (DEGs) were subjected to co-expression analysis. Enrichment analysis was employed to identify the biological functions and KEGG signaling pathways of module genes. In addition, a differential analysis was also performed between recurrent and non-recurrent osteosarcoma samples in GSE39055, and enrichment analysis was performed for DEGs. Further, KaplanMeier curve analysis was performed on the module genes, and receiver operating characteristic (ROC) curve was drawn. Comparison of the module with the highest correlation to osteosarcoma identified key genes. Cox regression model was utilized to identify the predictive ability of key genes for the prognosis of osteosarcoma.Results: A total of 13 co-expression modules were identified from 4871 DEGs of GSE99671, module 1 had the highest positive correlation with osteosarcoma. Module genes were mainly enriched in autophagy and macrophage migration functions. A total of 1126 DEGs were obtained from GSE39055, significantly involved in neutrophil mediated immunity. Screening of genes with area under the ROC curve (AUC) values greater than 0.73 in both GSE99671 and GSE39055 identified 5 key genes when compared with genes from module 1. The nomogram results showed that ATF5, CHCHD8, ENOPH1, and LOC286367 might predict 5-year or 8-year survival time of osteosarcoma patients. The Cox model results confirmed that the signals of ATF5, CHCHD8, and LOC286367 were robust, and it may be used in the diagnosis, treatment, and prognosis of osteosarcoma.Conclusion: We found that ATF5, CHCHD8, and LOC286367 can effectively identify osteosarcoma tumorigenesis and even recurrence status. This is helpful for early diagnosis and treatment, improving the clinical treatment of patients with osteosarcoma.

Keywords: osteosarcoma, predictive biomarkers, recurrence, weighted co-expressed network analysis

Osteosarcoma is the most common primary bone malignancy, mainly affecting children and young adults.1 Osteosarcoma consists of malignant osteoblasts producing immature bone and bone tissue.2 Although standard treatment with surgical resection and adjuvant chemotherapy has significantly improved the 5-year survival rate of osteosarcoma patients to approximately 6070%, no significant progress has been made in improving the survival rate of patients with recurrence or metastasis over the past 30 years.3,4 The lack of understanding of the molecular mechanisms underlying the occurrence and recurrence of osteosarcoma has severely hampered improved patient survival. When diagnosed, 40% of metastases occur in patients with advanced osteosarcoma.5 Therefore, elucidating the functions of osteosarcoma-related genes and exploring the possible pathological mechanisms of osteosarcoma initiation, development and recurrence are crucial for the future detection and treatment of osteosarcoma.

Depending on the histological morphology, three main categories can be distinguished: high-grade, which includes most subtypes, and intermediate and low-grade, which include periosteal and periosteal.6 Conventional osteosarcoma refers to high-grade tumors with intramedullary growth and is the most common type, accounting for 85% of all osteosarcoma cases during childhood and adolescence.7 The osteosarcoma tumor microenvironment is composed of osteosarcoma cells, osteocytes, stromal cells, vascular cells, immune cells, and the extracellular matrix (ECM).8 This creates a complex environment for tumor growth. More immune infiltration is found in osteosarcoma tumors to promote a local immune tolerant environment.9 Given the close connection between bone tissue and the immune system, it has been speculated that osteosarcoma may use similar mechanisms to evade immune recognition.10

With the development of molecular biology technology, tumor gene therapy for osteosarcoma has potential clinical applications.11,12 Accumulating evidence indicates that the occurrence, development and prognosis of osteosarcoma are closely related to molecular mechanisms.13,14 Through high-throughput sequencing, gene expression in osteosarcoma can be compared to normal samples, leading to an initial selection of potential targets for anticancer therapy.15 This also includes some common long non-coding RNAs (lncRNAs).16

This study aimed to discover the occurrence- or recurrence-related potential markers according to the osteosarcoma-related gene expression profiles in Gene Expression Omnibus (GEO) database. Multiple differentially expressed genes (DEGs) were screened using the weighted gene co-expression network analysis (WGCNA) algorithm. The main signaling pathways of osteosarcoma were analyzed by Gene Ontology (GO), function and Kyoto Encyclopedia of genes (KEGG) pathways. Subsequently, KaplanMeier and Cox models were utilized to screen the key genes related to the prognosis of osteosarcoma. The findings may provide new biomarkers and therapeutic target molecules for the occurrence and recurrence of osteosarcoma.

Osteosarcoma data were collected from the gene expression omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo) databases. GSE99671 included mRNA expression profiling of fresh-frozen bone samples from 18 tumoral samples and 18 non-tumoral paired samples by high throughput sequencing.17,18 The raw data were standardized and normalized through R package DEseq2;19 then, the gene expression profile was provided in Table S1. GSE39055 included mRNA expression profiling of formalin-fixed, paraffin-embedded (FFPE) samples from 37 unique diagnostic biopsy specimens of osteosarcoma with (n=18) or non-recurrence (n=19) by array.20 Expression data were processed using the R package lumi21 and provided in Table S2. All data were obtained from an open-access database, thus, acquiring ethical approval was not necessary.

Next, the DEseq2 package was used to identify differentially expressed genes (DEGs) in osteosarcoma (n = 18) and healthy controls (n = 18) in GSE99671 data. The limma package22 was used to screen DEGs between the recurrent osteosarcoma and non-recurrent osteosarcoma in GSE39055 data. P < 0.05 was set as the screening condition. The expression of DEGs was visualized with volcano plots.

The coexpression network for DEGs in GSE99671 was performed using Weighted correlation network analysis (WGCNA) by WGCNA R package.23 The samples were used to construct scale-free topology networks, and all gene adjacencies were calculated to make a topological overlap matrix (TOM). The soft-thresholding power was chosen and used as the correlation coefficient threshold. Then, a minimum number of genes in the modules were built. The expression pattern of eigengene in each module is condensed into module eigengene (ME). Genes in MEs were considered had similar expression patterns. The moduletrail relationships were demonstrated using Pearson correlation analysis.

The biological process (BP) in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for module genes or DEGs in GSE39055 were performed using R software package clusterProfiler.24 Gene set variation analysis (GSVA) was carried out using the GSVA package.25 For each sample, a score for the enrichment of a set of genes using gene expression profile was obtained. A P value < 0.05 was considered statistical significance. The R package clusterProfiler was used to obtain the background set for gene set enrichment analysis (GSEA). GSEA runs in Java environment and conducted between osteosarcoma and control samples.

KaplanMeier (K-M) survival analysis with the R package survival was applied to identify overall survival (OS) associated genes among the module genes. Prognostic relevant genes among the key genes were determined using Cox regression analysis in a survival package based on gene expression values and survival status data. P < 0.05 was considered to be a statistically significant difference. Based on the correlation coefficients of the risk model, a formula for calculating the prognostic risk score for each patient was established. According to the median value of the risk score, patients were divided into high- and low-risk groups.

To evaluate whether the identified survival-related genes have significant diagnostic value for osteosarcoma or recurrent osteosarcoma, we performed ROC analysis using the R software package pROC.26 The area under the ROC curve (AUC) was calculated for each gene. The diagnostic accuracy of key biomarkers was evaluated using AUC values. Here, this gene can distinguish osteosarcoma from healthy individuals or recurrent osteosarcoma from non-recurrent osteosarcoma when the AUC value is greater than 0.6.

The marker gene expression information for immune cell types was obtained by Bindea et al.27 The infiltration scores of immune cells were calculated using ssGSEA in GSVA R software package. Correlations between immune cells and key genes were calculated using Pearson correlation. P value <0.05 was considered significant.

The flowchart of this study is shown in Figure 1. To identify differences in gene expression between osteosarcoma and controls, we performed a differential analysis of the osteosarcoma and control groups in GSE99671. Using threshold screening, we obtained 4871 differentially expressed genes (DEGs) between osteosarcoma and controls (Figure 2A). The co-expression behaviors of these genes were identified by performing WGCNA on the DEGs. To ensure that the coexpression network could obey the scale-free criterion, we selected = 9 as a soft-thresholding (Figure 2B). We identified a total of 13 coexpression modules (Figure 2C). Pearson correlation analysis showed that MEturquoise (M1) had the highest positive correlation with osteosarcoma (Figure 2D).

Figure 1 The flowchart of this study. The GSE99671 data and GSE39055 data were used to identify potential biomarkers related to the occurrence and recurrence of osteosarcoma. The module genes identified in GSE99671 were used to evaluate their prognostic and diagnostic value in GSE39055. Further screening of key genes may be a target for diagnosis and treatment of osteosarcoma.

Abbreviations: WGCNA, weighted gene co-expression network analysis; GSEA, gene set enrichment analysis; ROC, receiver operating characteristic curve; AUC, area under the ROC curve.

Figure 2 Coexpression modules of differentially expressed genes. (A) The differentially expressed genes between osteosarcoma and controls in GSE99671. (B) The scale-free fit index and the mean connectivity for various soft-thresholding powers. (C) Common genes were identified for thirteen coexpression modules by WGCNA. (D) Correlations between modules and clinical trait were analyzed by Pearson correlation.

To identify the biological roles of module genes, we performed enrichment analysis. It was found that module genes were significantly enriched in activated positive regulation of macrophage migration, chaperone mediated autophagy, MHC protein complex assembly biological processes; and inhibited neutrophil aggregation, regulation of vascular permeability, regulation of cell killing in osteosarcoma (Figure 3A). Using KEGG enrichment results, we found that activated HIF-1 signaling pathway, PI3K-Akt signaling pathway, and autophagy animal were significantly enriched by module genes, and inhibited B cell receptor signaling pathway, Rap1 signaling pathway, and ECM receptor interaction were also significantly enriched in osteosarcoma (Figure 3B). GSEA results showed that protein export, RNA polymerase, and proteasome were significantly enriched in osteosarcoma, primary immunodeficiency, PPAR signaling pathway, and neutrophil extracellular trap formation were significantly enriched in control samples (Figure 3C).

Figure 3 Biological functions of module gene enrichment. (A) Module genes significantly enriched for activated and inhibited biological processes. (B) Module genes significantly enriched for activated and inhibited KEGG pathway. (C) The activated and inhibited KEGG pathways in GSEA of module genes involved. P < 0.05 was considered statistically significant.

Abbreviation: GSVA, gene set variation analysis.

To identify molecular alterations associated with osteosarcoma recurrence, we performed a differential analysis of recurrent and non-recurrent osteosarcoma gene expression in GSE39055. A total of 1126 differentially expressed genes were obtained (Figure 4A). In GO enrichment results, the activated neutrophil mediated immunity, skeletal muscle fiber differentiation, response to iron (III) ion and inhibited neutrophil apoptotic process, leukocyte homeostasis, mitochondrial organization were significantly enriched by differentially expressed genes (Figure 4B). KEGG enrichment results identified that the differentially expressed genes were significantly involved in the activated endocrine resistance, oxidative phosphorylation, renin angiotensin system; and inhibited p53 signaling pathway, cell cycle, FOXO signaling pathway in recurrent osteosarcoma (Figure 4C).

Figure 4 The potential molecular changes in osteosarcoma recurrence. (A) Volcano plot of differentially expressed genes between recurrent osteosarcoma and non-recurrent osteosarcoma. Red for activated and green for inhibited. The four genes with the largest fold change of activated or inhibited were labeled. (B) Differentially expressed genes involved in activated and inhibited biological processes quantified by gene set variation analysis (GSVA). The longer the column, the more genes involved in this term. (C) Differentially expressed genes involved in activated and inhibited KEGG pathway quantified by gene set variation analysis (GSVA). The longer the column, the more genes involved in this term.

Abbreviation: BP, biological processes.

From the survival information of 37 osteosarcoma patients obtained from GSE39055, we found that the patients 5-year overall survival (OS) was 35% (Figure 5A). The survival probability increased per year already survival related to the total survival time. To identify key genes involved in the prognosis of osteosarcoma, we performed KM curve analysis of module genes. Among the module genes, we identified 262 genes that significantly affected osteosarcoma survival. By plotting the ROC curves of these survival-related genes, we screened for genes with AUC values greater than 0.73 in both GSE99671 and GSE39055 (Figure 5B). Including AEBP1, ATF5, CHCHD8, DYRK3, ENOPH1, GMIP, LOC286367, PKP4, R3HDM1, TRIM66, and ZMYND17. They were also differentially expressed genes in GSE39055 and thus may predict both osteosarcoma occurrence and recurrence. In addition, five genes (ATF5, CHCHD8, ENOPH1, LOC286367, and R3HDM1) were identified as potentially most strongly associated with osteosarcoma by contrasting with the gene for module 1. They were identified as key genes. Nomograms were constructed using Cox regression analysis results, and differential expression of ATF5, CHCHD8, ENOPH1, and LOC286367 could predict 5 - and 8-year OS of osteosarcoma patients (Figure 5C).

Figure 5 Screening of key genes predicting the occurrence and recurrence of osteosarcoma. (A) KaplanMeier estimates for conditional survival up to 6 years in 37 patients given 05 years survival of osteosarcoma. Each column represents the survival time, and each row represents the percentage reaching the specified survival time. (B) On the left are survival associated genes with AUC values in GSE99671 and GSE39055 and on the right are genes with AUC values greater than 0.73 in both datasets. Red represents up-regulated expression and blue represents down regulated expression. The length of the column represents the mean AUC value. (C) Nomogram for the prediction of overall survival to achieve 5-year or 8-year survival time.

Abbreviation: AUC, area under the ROC curve.

On the other hand, osteosarcoma patients in GSE39055 were divided into high-risk and low-risk groups according to the median risk score which calculated by the Cox model (Figure 6A). The expressions of key genes in the high-risk and low-risk groups were different. Patients with death status were significantly higher in the high-risk group than in the low-risk group. In addition, we calculated the correlation of key genes and immune cells, LOC286367 was positively correlated with most immune cells, other key genes were negatively correlated with more immune cells (Figure 6B). The prediction capability of the key genes was evaluated by calculating the area under the ROC curve (AUC). The AUC values of ATF5, CHCHD8, and LOC286367 for predicting OS were greater than 0.6 in the first, third, and fifth year of osteosarcoma, indicating that they had good performance (Figure 6C). High expression of ATF5, CHCHD8, and LOC286367 was associated with the worst OS in osteosarcoma patients (Figure 6D). ATF5, CHCHD8, and LOC286367 were expressed at significantly higher levels of osteosarcoma compared with the normal group in GSE99671 (Figure 6E).

Figure 6 Diagnostic role of key genes predicting the survival of osteosarcoma. (A) Distribution of risk score, overall survival, and overall survival status and heatmap of the five key genes in the GSE39055. (B) Correlations between immune infiltrating cells and key genes were calculated using Pearson. *P < 0.05, **P < 0.01. (C) Time-dependent ROC curves measuring the predictive value of key genes in GSE39055 for 3-year, 5-year or 10-year survival time. (D) Effect of key genes expression on overall survival by KaplanMeier analysis in 37 patients with osteosarcoma. (E) The expression levels of ATF5, CHCHD8, and LOC286367 in osteosarcoma and normal of GSE99671. ***P < 0.001.

Abbreviation: OS, overall survival.

Osteosarcoma is one of the most common aggressive bone tumors and is currently treated with chemical drugs combined with surgical resection. A major unsolved problem is the poor prognosis characterized by drug resistance, recurrence and metastasis.28 The identification of gene signatures is crucial both for a better understanding of the molecular basis of osteosarcoma progression and for the discovery of novel targets.29 In the present study, we focused on the potential target genes with prognostic value for osteosarcoma. Gene expression profiling of differentially expressed genes detected by GSE99671 in osteosarcoma tissue samples established 13 coexpression modules. Module genes were mainly enriched in immune, inflammatory and metabolic responses. In the gene co-expression network, module 1 was most significantly associated with osteosarcoma, in which genes significantly affecting survival may be potential target genes. Furthermore, combining GSE39055, we identified 5 key genes that may serve as diagnostic markers for the occurrence and recurrence of osteosarcoma. Finally, high expression of ATF5, CHCHD8, and LOC286367 was associated with worse prognosis in osteosarcoma.

WGCNA is a systems biology approach that describes correlation patterns between genes in transcriptome samples with soft threshold algorithms.23 The results of GO and KEGG pathway enrichment analysis of the module genes led us to focus on the biological functions of autophagy and macrophage migration, as well as the HIF-1 signaling pathway and PI3K-Akt signaling pathway. Autophagy promotes the proliferation and development of osteosarcoma cells and resists tumor treatment.30 Autophagy may be involved in drug sensitivity or chemoresistance during osteosarcoma treatment.31 Macrophages are an important immune component in the osteosarcoma microenvironment. Macrophages are highly plastic and the inflammatory phenotype (M1) and anti-inflammatory phenotype (M2) may play opposite roles in the progression of osteosarcoma.32 Activation of the HIF-1 signaling pathway promotes osteosarcoma cell growth and is a promising therapeutic target.33 Accumulating evidence suggests that the PI3K/Akt pathway is involved in cancer initiation and progression, such as tumorigenesis, apoptosis inhibition, proliferation and drug resistance.34

To further identify the underlying molecular mechanisms of osteosarcoma recurrence, we performed enrichment analysis of the differentially expressed genes between recurrence and non-recurrence. We found multiple immune related pathways, neutrophil mediated immunity, neutrophil apoptotic process, and leukocyte homeostasis. They may be associated with metastasis and recurrence of osteosarcoma.35 In addition to a large number of aberrant biological functions, FOXO could control the expression of genes involved in cell death and cell cycle arrest, exerting tumor suppressor activity.36 Tumor suppressor p53 tumor cells have been reported to exert anticancer effects by inducing cell cycle arrest and apoptosis.37

Of the 13 coexpression modules we identified, module 1 was found to be strongly associated with osteosarcoma. Among the module genes identified to be significantly associated with OS of osteosarcoma, 11 genes were screened with high specificity and sensitivity as potential molecular markers for predicting the occurrence and recurrence of osteosarcoma. Among them, 5 genes were genes in module 1 and were considered as key genes. In the Cox regression model, high expression of CHCHD8 or ENOPH1 may benefit the prognosis of osteosarcoma patients, and low expression of ATF5 or LOC286367 may prolong patient survival. However, the K-M curve results differed from the Cox analysis results in that patients with low expression of the CHCHD8 gene had better overall survival. The risk assessment model constructed by 5 key genes clearly distinguished the status of osteosarcoma survival and death. Based on the time-dependent ROC curves results, we identified ATF5, CHCHD8, and LOC286367 as potential diagnostic and prognostic biomarkers for clinical outcome prediction. ATF5 is considered an anti-apoptotic factor because it regulates the expression of the anti-apoptotic components BCL2 and MCL1.38 Studies have reported ATF5 to promote tumor growth and survival and have been reported to be associated with recurrence of osteosarcoma.39,40 CHCHD8 has been reported to be associated with drug resistance in gastric cancer, but the association with osteosarcoma has not been reported.41 LOC286367 was reported to be associated with inflammatory response,42,43 the results of our analysis argued that it may be a potential marker for the occurrence and recurrence of osteosarcoma.

However, the present study has certain limitations. The first and most important is the lack of experimental validation. Second, the lack of detailed clinical data, such as chemotherapy regimens and tumor stages, limits in-depth association analyses. Finally, whether the biomarkers we identified can be applied in the clinic also needs a large number of samples to validate, which will be the focus of our future studies.

The present study identified potential diagnostic markers and useful therapeutic targets for osteosarcoma patients, and they may be able to predict patient prognosis. The mechanism of recurrence of osteosarcoma may be associated with neutrophil immunity and cell cycle arrest. In-depth exploration of the potential target genes and molecular deregulation mechanisms to develop corresponding prevention and treatment countermeasures can achieve breakthrough progress in the prognosis of osteosarcoma.

Data were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).

This study was supported by the Scientific Research Project of Guangxi Health Commission (Z20180799).

The authors report no conflicts of interest related to this work.

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Identification of Gene as Predictive Biomarkers for the Occurrence and | IJGM - Dove Medical Press

Cell and gene therapies rapid penetration in clinical trials globally is testimony to the incredible potential these in understanding, treating, and curing diseases. The cell and gene therapy clinical trials market is rapidly evolving, touching numerous frontiers in personalized medicine, especially for chronic diseases. A number of gene therapies approved by the U.S. FDA reinforces the potential. Pharmaceutical companies in clinical trials that test cell and gene therapies have bloomed strikingly, most notably in oncology, eye diseases, and rare hereditary diseases. A partial list of the top diseases that attract massive attention of contract research organizations in cell and gene therapy market are type 1 diabetes, Parkinsons disease, spinal cord injuries, amyotrophic lateral sclerosis, the Alzheimers disease, and osteoarthritis.

The number of cell and gene therapies is seeing marked increase year over year. According to an estimate, there were more than a thousand cell and gene therapy clinical trials by 2019. To complement the trend, investments by pharma companies are also rising by large bounds in those years.

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The study on the cell and gene therapy clinical trials offers deep expounding of current and emerging business strategies, elements of competition, facets of markets attractiveness, and insights into regional growth dynamics across the globe.

Cell And Gene Therapy Clinical Trials Market: Key Trends

Clinical trials pertaining to advanced therapy medicinal product (ATMP) are making consistent increase in some developed nations. A predominant percentage of these in recent years have been viral vector mediated gene therapies. Thus far, some remarkable strides have been witnessed in this direction, enriching the investment scope in the cell and gene therapy market. The effect has been notices in all phases, from Phase I to Phase IV.

A prevalent trend over the past few years is the focus on oncology. Oncology--notably including haematological malignancies and solid tumourshave been at the center of ATMP clinical trials. Metabolic disease trials have also seen a significant increase, cementing revenue growth in the cell and gene therapy market. Advances made in gene therapy trials continue to pave way to new vistas for oncology research, both in vivo and in vitro.

Cell And Gene Therapy Clinical Trials Market: Competitive Dynamics and Key Developments

The profound potential of cell and gene therapies (CGT) notwithstanding, their successful clinical translation is, no doubt, rests on panoply of problems. These also determine the key restraints for the evolution of the cell and gene therapy market. The high degree of personalization that CGT entails, factors affecting their efficacy and safety are difficult to ascertain, if not impossible. For one, obtaining cells from donors is replete with some unique challenges, such as invasiveness of the process to patients. So are the lack of availability of cutting-edge biomarkers and targets anchored on which gene therapies will show their potential. The whole process of delivering CGT in clinical trials is itself associated with some tall challenges for contract research organizations.

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Having put these perspectives, the prospects have limitless potential waiting to be extracted, and researchers are not disheartened by the aforementioned challenges. In oncology alone, a number of new approaches have added liveliness to CGT clinical trials. Biotech companies are testing new waters in allogeneic therapies. T-cell receptor (TCR) are increasingly penetrating safety and feasibility trials, adding momentum to the cell and gene therapy market.

Some of the industry players likely to invade the space of these limitless possibilities are;

Cell And Gene Therapy Clinical Trials Market: Regional Assessment

North America has been at the cynosure of attention for CGT trials. European nations have also been showing substantial potential for generating revenues in the global market. In coming years, Asia Pacific is expected to show high growth potential

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Cell And Gene Therapy Clinical Trials Market in 2021 | Expansive Coverage on the Latest Developments in the Market - BioSpace