Category Archives: Transhuman News

Finding vaccines or drugs against COVID-19 is certainly one of the main current objectives of medical research centers worldwide. At Childrens National Medical Center, researchers are deploying technology tools from Amazon Web Services Inc. to combine hundreds of data sets to identify genes that might be targeted to treat many diseases, including COVID-19.

We know that there are a lot of drugs that target different genes,and we are particularly interested in, for example, can we repurpose some of these drugs to treatdifferent types of viruses, including COVID-19? said Wei Li (pictured), principal investigator at the Center for Genetic Medicine Research & Center for Cancer and Immunology Research at Childrens National Medical Center.

Li spoke with Stu Miniman, host of theCUBE, SiliconANGLE Medias livestreaming studio, during the AWS Public Sector Summit event. They discussed how the genome project can help combat COVID-19, as well as the role of AWS technology tools in scientific research. (* Disclosure below.)

The Childrens National Medical Center has been using computational biology and gene editing approaches to understand humangenome and disease, and it is particularly interested in a gene-editingtechnology called CRISPR screening, according to Li, who has a research background in computer science.

This is a fascinating technology because it tells you whether one of the 20,000human genes are connected with some certain disease phenotype in one single experiment, he said. We are tryingto, for example, perform machine-learning and data-mining approaches to find new clues of human diseasefrom the original mix and screening big data.

CRISPR screening and other similar screening methods have been widely used in recent years by several research laboratories to study virus infections, such as those related to HIV, Ebola, influenza and now coronavirus, according to Li. Then, the team at the Childrens National Medical Center had an idea: to connect all the sets of screening data related to these viruses to try to extract new information that cannot be identified in a single study.

Can we identify new patterns or new human genes that are commonly responsible for many different virus types? Or can we find some genes that work only from some certain type of viruses? he asked.

Researchers use AWS technology to process and analyze huge amount of data sets, in addition to creating an integrated database in the cloud, so that research results can be freely accessed around the world. It is estimated that AWS technology can reduce the time to process screening data from months to days, according to Li.

Two major benefits are expected from the outcome of this research project.

The first thing is that we hope to find some genes thatcan be potentially drug targets. So, if there are existing drugs that target the genes, then that would be perfect, because we dont need to do anything about this, he explained. And,in the end, we hope that these drugs can have the broad antiviral activity; that means that these drugs can be potentially used to treat COVID-19 and in the future if theres a new virus coming out.

Watch the complete video interview below, and be sure to check out more of SiliconANGLEs and theCUBEs coverage of the AWS Public Sector Summit event. (* Disclosure: TheCUBE is a paid media partner for the AWS Public Sector Summit Online event. Neither Amazon Web Services Inc., the sponsor for theCUBEs event coverage, nor other sponsors have editorial control over content on theCUBE or SiliconANGLE.)

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Children's National Medical Center and AWS partner for genome project targeting COVID-19 - SiliconANGLE

DURHAM, N.C. (WTVD) Duke University School of Medicine researchers have helped discover a new coronavirus gene mutation that helps the virus spread faster.

Dr. David Montefiori is a professor of surgery who also serves as Director of the Laboratory for AIDS Vaccine Research and Development. He explained that the gene mutation causes a new strain of coronavirus.

Were looking at the genetic sequence of the virus. And in particular, were looking at the sequence of the spike protein. This is a protein thats on the surface of a virus, that the virus uses to attach to a cell and to get into a cell, Dr. Montefiori said.

Scientists around the world study sequences taken from people infected with viruses. They then deposit the sequences into a central database originally designed to help researchers study the flu.

Once those sequences are deposited into the database, scientists have access to those sequences to analyze them. And my colleague at Los Alamos National Laboratory Dr. Bette Korber, who is an expert at analyzing sequences, and we have been collaborating together for many years on HIV, she immediately started analyzing the spike sequences in that database that were coming in from around the world, Dr. Montefiori said. And we were both interested in whether or not mutations might arise that showed evidence of spreading in the human population that many people would show evidence of being infected with a virus that carries a mutation in it.

He explained how the mutation spread quickly.

(Dr. Korber) noticed this mutation that we call D614G in the spike protein that was found in about six people in very early March. So it became a mutation of interest because of showing some evidence of spreading, suggesting that it might have a fitness advantage. And within weeks, it was found in more and more people, Dr. Montefiori said. As more and more sequences came into the database, more and more of those sequences had this mutation. And it just kept spreading. By the end of April, it was now the dominant strain of the virus globally.

Researchers dont believe the strain is more deadly than the original coronavirus strain, they are still concerned.

It appears to spread faster. And thats probably why the virus liked the mutation, and why its so dominant because it provided an advantage to the virus to spread easier. And thats what a virus wants to do to survive. It wants to be able to transmit, Dr. Montefiori said.

Dr. Montefiori did not believe this mutation is the cause for the US having so many more cases, hospitalizations and deaths than any other country.

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Duke researchers help discover new strain of coronavirus that spreads faster because of gene mutation - WGHP FOX 8 Greensboro

Chong-Hou Lok, Dong Zhu, Jia Wang, Yu-Tang Ren, Xuan Jiang, Shu-Jun Li, Xiu-Ying Zhao

Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, Peoples Republic of China

Correspondence : Xiu-Ying ZhaoBeijing Tsinghua Changgung Hospital,School of Clinical Medicine, Tsinghua University, Beijing 10220, Peoples Republic of ChinaEmail zxya00340@btch.edu.cn

Introduction: Understanding drug resistance is important in drug selection for Helicobacter pylori (H. pylori) eradication, and drug resistance data are lacking in Beijing.Purpose: This cross-sectional study aimed to isolate H. pylori from patients with gastroduodenal diseases and to analyze drug resistance to clarithromycin (CLA) and levofloxacin (LEV), which are used frequently in China.Patients and Methods: One hundred and seventy-six patients with gastroduodenal diseases undergoing gastroduodenoscopy were selected by convenient sampling. Gastric mucosa samples were cultured and sub-cultured using a new medium broth. Active H. pylori strains were confirmed by microscopy observation as Gram-negative curved bacilli with positive test results for urease, oxidase, and catalase, and H. pylori 16S rRNA amplification by polymerase chain reaction (PCR). CLA and LEV resistance was identified by minimum inhibitory concentration (MIC) tests and sequencing of 23S rRNA, gyrA, and gyrB genes.Results: From the 176 clinical samples, 112 (112/176, 63.6%) were confirmed with H. pylori infection and 65 (65/176, 36.9%) active H. pylori strains were obtained and further confirmed by MIC assay. Overall, the rates of CLA-resistant and LEV-resistant mutations in the 112 samples were 50.9% and 33.0%, respectively. Mutation related to CLA resistance was A2143G in the 23S rRNA gene and mutations associated with LEV resistance were N87K, D91G, and D91Y in the gyrA gene. Of 112 samples, 22 (19.6%) presented dual resistance to CLA and LEV. Resistance of the H. pylori strains to CLA (r=0.846, P< 0.001) and LEV (r=0.936, P< 0.001) had a strong correlation in phenotypic and genotypic level.Conclusion: The results indicated that resistance of CLA and LEV is severe among patients with gastroduodenitis. A good consistency could be found as to drug resistance between genotypic or phenotypic assay, suggested extending the detection of H. pylori drug resistance from the MIC method to a genotypic assay.

Keywords: Helicobacter pylori, clarithromycin, levofloxacin, antibiotic resistance

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Phenotype and Molecular Detection of Clarithromycin and Levofloxacin R | IDR - Dove Medical Press

TOKYO & MUNICH--(BUSINESS WIRE)--Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced that the European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for trastuzumab deruxtecan, a HER2 directed antibody drug conjugate (ADC), for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens. Trastuzumab deruxtecan was granted accelerated assessment by the EMAs Committee for Medicinal Products for Human Use (CHMP).

Validation confirms that the application is complete and commences the scientific review process by the EMAs CHMP. Accelerated assessment is granted by the CHMP to products expected to be of major interest for public health and therapeutic innovation and can significantly reduce the review timelines.

The accelerated assessment highlights the significant unmet need for patients with HER2 positive metastatic breast cancer that trastuzumab deruxtecan aims at addressing, said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. Trastuzumab deruxtecan is already available for patients in the U.S. and Japan, and we look forward to working with the EMA to bring this important new medicine to patients in the EU as quickly as possible.

The MAA is based on the positive results from the pivotal phase 2 DESTINY-Breast01 trial of trastuzumab deruxtecan monotherapy in patients with HER2 positive metastatic breast cancer who had received two or more prior anti-HER2 regimens. The results of the DESTINY-Breast01 trial are published in The New England Journal of Medicine.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including gastric, breast and lung cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.1

About HER2 Positive Breast Cancer

Approximately one in five breast cancers are HER2 positive.2,3 Despite recent improvements and approvals of new medicines, there remain significant clinical needs for patients with HER2 positive metastatic breast cancer.4,5 This disease remains incurable with patients eventually progressing after available treatment.5

About Trastuzumab Deruxtecan

Trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (payload) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyos proprietary DXd ADC technology, trastuzumab deruxtecan is comprised of a HER2 monoclonal antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

Trastuzumab deruxtecan (5.4 mg/kg) is approved in the U.S. and Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Trastuzumab deruxtecan has not been approved in the EU, or countries outside of Japan and the U.S., for any indication. It is an investigational agent globally for various indications.

About the Trastuzumab Deruxtecan Clinical Development Program

A comprehensive development program for trastuzumab deruxtecan is underway globally with six pivotal trials evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy across multiple HER2 cancers including breast, gastric, and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

In May 2020, trastuzumab deruxtecan received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with HER2 positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab, and Orphan Drug Designation for gastric cancer, including gastroesophageal junction cancer. In March 2018, trastuzumab deruxtecan received a SAKIGAKE designation for potential use in the same HER2positive patient population and a supplemental New Drug Application was submitted to the Japan Ministry of Health, Labour and Welfare (MHLW) for approval in April 2020.

In May 2020, trastuzumab deruxtecan also received Breakthrough Therapy Designation for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About the Collaboration between Daiichi Sankyo and AstraZeneca

In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize trastuzumab deruxtecan worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for the manufacturing and supply.

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical therapies to improve standards of care and address diversified, unmet medical needs of people globally by leveraging our world-class science and technology. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 15,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for cardiovascular diseases, under the Groups 2025 Vision to become a Global Pharma Innovator with Competitive Advantage in Oncology, Daiichi Sankyo is primarily focused on providing novel therapies in oncology, as well as other research areas centered around rare diseases and immune disorders. For more information, please visit: http://www.daiichisankyo.com

References :

1Iqbal N, et al. Mol Biol Int. 2014; 2014: 852748

2Tandon A, et al. J Clin Oncol. 1989;7(8):1120-8.

3Sledge G, et al. J Clin Oncol. 2014;32(19):1979-1986.

4de Melo Gagliato D, et al. Oncotarget. 2016;7(39):64431-46.

5National Comprehensive Cancer Network (NCCN). NCCN Guidelines. Breast Cancer. Accessed June 2020.

Visit link:
EMA Validates and Grants Accelerated Assessment for Trastuzumab Deruxtecan for the Treatment of HER2 Positive Metastatic Breast Cancer - Business Wire

My husband, Matteo Adinolfi, who has died aged 91 from Covid-19, was an internationally esteemed immunologist focusing on prenatal diagnosis of gene disorders, and a talented amateur artist.

Matteo was born in Eritrea. His parents, Attilio Adinolfi and his wife, Maria (nee Sellitti) had moved there from Italy, to escape fascism. In 1943, on a visit back to Naples, the family was trapped by the advancing war and unable to return to Africa.

Attilio joined the navy; Matteo and his mother and two sisters survived the bombardments by fleeing from one hill to another, foraging for food and finding shelter where they could. At the end of the war, Matteo was emaciated and extremely ill with gastroenteritis.

After he recovered, his experience motivated him to study medicine in Naples in 1954. He then worked at the University of Naples until 1962. Once, while sharing a pizza with an American geneticist visiting Naples, he heard about a new electrophoretic starch gel the visitor had invented for identification of plasma proteins he wrote the formula on a paper napkin. Matteos curiosity led him to prepare the gel and test the blood of a lamprey eel from the laboratory aquarium. To his surprise, the lamprey haemoglobin closely resembled a single strand of four-chain human haemoglobin. The paper, published in Nature (1955), received international attention and got him known as the famous lamprey Adinolfi.

In 1962 he moved to London and joined the experimental haemotology research unit at the Wright Fleming Institute, at the same time practising at St Marys hospital. He was awarded his PhD in immunology at the University of London in 1966 and became a senior lecturer at the paediatric research unit at Guys hospital and medical school. Over the next 30 years, he worked as a consultant, teacher and researcher in London at Guys and at University College hospital and in Lambeth, Southwark and Lewisham Area Health Authority. He was appointed professor of developmental immunology at the University of London in 1983. In 1994 he was elected an honorary fellow of the Royal Society of Medicine. The same year he went to the Galton Institute; he retired in 2004, aged 76.

Besides the lamprey haemoglobin work in Naples, in recent years at Guys hospital, Matteo and international colleagues developed laser microscopy in prenatal diagnoses of chromosome disorders and single-cell gene defects.

Matteo published hundreds of scientific papers, contributed chapters to many books and organised courses in many countries.

AMaking art was another of his passions. A prolific artist, he was proficient with collage, sculpture, drawing and printmaking. He and others founded the popular 407 Art Club at Guys hospital. He and I met at an etching class at the City Literary Institute in 1978, lived together from then, and married in 1985.

Matteo is survived by me and by his children, Carlo, Nora and Marina, from his first marriage, to Annetta De Giorgio, which ended in divorce. His second wife, Camille (nee Guthrie), died in 1975.

Link:
Matteo Adinolfi obituary | From the Guardian - The Guardian

Daix (France), July 6, 2020 Inventiva (Euronext: IVA) ("Inventiva" or the "Company"), a clinical-stage biopharmaceutical company developing oral small molecule therapies for the treatment of non-alcoholic steatohepatitis (NASH), mucopolysaccharidoses (MPS) and other diseases with significant unmet medical need, today announced the decision by the investigator to reduce the number of patients to be enrolled in the investigator-initiated Phase II clinical trial of lanifibranor in patients with TD2M and NAFLD being conducted by Prof. Cusi at the University of Florida.

This trial aims to evaluate the metabolic effects of lanifibranor and its potential efficacy on liver triglycerides inT2DM patients with NAFLD and provide additional clinical data supporting lanifibranors potential for the treatment of NASH.

Originally, the trial was expected to enroll 64 patients to be treated with a single daily dose of lanifibranor (800 mg/day) or placebo for a 24-week period and 10 subjects in a healthy, non-obese control group. However, given the observed effects of lanifibranor in reducing steatosis during the Phase IIb NATIVE clinical trial evaluating lanifibranor for the treatment of NASH, the investigator Prof. Cusi has decided to reduce the number of patients to be evaluated to 34 patients from 64 originally, while maintaining the same statistical powering in the trial.

At present, this investigator-initiated trial has recruited 23 patients, 15 of which have completed the 24-week period of treatment. Results from this trial are currently expected in 2021. However, due to the COVID-19 pandemic, the recruitment and screening of new patients has been suspended at the University of Florida, where the trial is being conducted, and the results could therefore be delayed.

The table below sets forth data from the Phase IIb NATIVE clinical trial with respect to the pre-specified analysis of changes in CRN steatosis score in the subset of T2DM patients, as compared to the overall population of patients treated in the trial. These data contributed to the investigators decision to reduce target enrollment in the ongoing investigator-initiated NAFLD trial.

* Statistically significant in accordance to the statistical analysis plan (SAP)

Prof. Ken Cusi, M.D., F.A.C.P., F.A.C.E., Professor of Medicine, Chief, Division of Endocrinology, Diabetes and Metabolism, University of Florida, said: The results recently shown by lanifibranor in NASH patients with respect to its ability to reduce steatosis and significantly improve insulin sensitivity and glycemic control are higher than I expected and support lanifibranors potential for the treatment of patients with NASH. I now look forward to advancing this trial and developing data to support the hypothesis that lanifibranor can have a significant impact on hepatic triglycerides in patients with type 2 diabetes and NAFLD.

Pierre Broqua, CSO and cofounder of Inventiva, stated: We are very pleased with this decision following the positive results of lanifibranor during the Phase IIb clinical trial in NASH. Type 2 diabetes patients with NASH are generally exposed to an increased risk of poor clinical outcomes and are therefore in a critical need for an efficacious NASH treatment. We were thus particularly pleased to see significant improvements in CRN steatosis scores in patients with type 2 diabetes in the NATIVE trial and look forward to data from Prof. Cusis trial, which could further support lanifibranors potential in this population.

About lanifibranor

Lanifibranor, Inventivas lead product candidate, is an orally-available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferatoractivated receptor (PPAR) isoforms, which are wellcharacterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a wellbalanced activation of PPAR and PPAR, and a partial activation of PPAR. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only panPPAR agonist in clinical development. Inventiva believes that lanifibranors moderate and balanced panPPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and preclinical studies to date.

About the study of lanifibranor in type 2 diabetes (T2DM) patients with non-alcoholic fatty liver disease (NAFLD)

The trial being conducted by Prof. Kenneth Cusi, Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida, Gainesville, is expected to enroll 34 patients treated for a 24-week period with a single daily dose of lanifibranor (800 mg/day) or placebo and 10 subjects in a healthy, non-obese control group. The studys overall objective is to measure the metabolic effects of lanifibranor and its potential efficacy on liver triglycerides in T2DM patients with NAFLD. The primary endpoint is the change in liver triglycerides as assessed by proton magnetic resonance spectroscopy. Secondary endpoints include changes in liver fibrosis, evidence of metabolic improvements in insulin resistance, de novo lipogenesis, free fatty acids and lipids, as well as safety. Results from this trial are currently expected in 2021. However, due to the COVID-19 pandemic, the recruitment and screening of new patients has been suspended at the University of Florida, where the trial is being conducted, and the results could therefore be delayed.

About Inventiva

Inventiva is a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of NASH, MPS and other diseases with significant unmet medical need.

Leveraging its expertise and experience in the domain of compounds targeting nuclear receptors, transcription factors and epigenetic modulation, Inventiva is currently advancing two clinical candidates, as well as a deep pipeline of earlier stage programs.

Lanifibranor, its lead product candidate, is being developed for the treatment of patients with NASH, a common and progressive chronic liver disease for which there are currently no approved therapies. Inventiva recently announced positive topline data from its Phase IIb clinical trial evaluating lanifibranor for the treatment of patients with NASH.

Inventiva is also developing odiparcil, a second clinical stage asset, for the treatment of patients with subtypes of MPS, a group of rare genetic disorders. A Phase I/II clinical trial in children with MPS VI is currently under preparation following the release of positive results of the Phase IIa clinical trial in adult MPS VI patients at the end of 2019.

In parallel, Inventiva is in the process of selecting an oncology development candidate for its Hippo signalling pathway program. Furthermore, the Company has established a strategic collaboration with AbbVie in the area of autoimmune diseases. AbbVie has started the clinical development of ABBV157, a drug candidate for the treatment of moderate to severe psoriasis resulting from its collaboration with Inventiva. This collaboration enables Inventiva to receive milestone payments upon the achievement of pre-clinical, clinical, regulatory and commercial milestones, in addition to royalties on any approved products resulting from the collaboration.

The Company has a scientific team of approximately 70 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, as well as in clinical development. It also owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a whollyowned research and development facility.

Inventiva is a public company listed on compartment C of the regulated market of Euronext Paris (Euronext: IVA ISIN: FR0013233012). http://www.inventivapharma.com

Contacts

InventivaFrdric CrenChairman & CEOinfo@inventivapharma.com+33 3 80 44 75 00

Brunswick GroupYannick Tetzlaff / Tristan Roquet Montegon /Aude LepreuxMedia relationsinventiva@brunswickgroup.com+33 1 53 96 83 83

Westwicke, an ICR CompanyPatricia L. BankInvestor relationspatti.bank@westwicke.com +1415513 1284

Important Notice

This press release contains forward-looking statements, forecasts and estimates with respect to Inventivas clinical trials, clinical trial data releases, clinical development plans and anticipated future activities of Inventiva. Certain of these statements, forecasts and estimates can be recognized by the use of words such as, without limitation, believes, anticipates, expects, intends, plans, seeks, estimates, may, will and continue and similar expressions. Such statements are not historical facts but rather are statements of future expectations and other forward-looking statements that are based on management's beliefs. These statements reflect such views and assumptions prevailing as of the date of the statements and involve known and unknown risks and uncertainties that could cause future results, performance or future events to differ materially from those expressed or implied in such statements. Actual events are difficult to predict and may depend upon factors that are beyond Inventiva's control. There can be no guarantees with respect to pipeline product candidates that the clinical trial results will be available on their anticipated timeline, that future clinical trials will be initiated as anticipated, or that candidates will receive the necessary regulatory approvals. Therefore, actual results may turn out to be materially different from the anticipated future results, performance or achievements expressed or implied by such statements, forecasts and estimates. Given these uncertainties, no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts and estimates. Furthermore, forward-looking statements, forecasts and estimates only speak as of the date of this press release. Readers are cautioned not to place undue reliance on any of these forward-looking statements.

Please refer to the Universal Registration Document filed with the Autorit des Marchs Financiers on June 19, 2020 under n D.20-0551 for additional information in relation to such factors, risks and uncertainties.

Except as required by law, Inventiva has no intention and is under no obligation to update or review the forward-looking statements referred to above. Consequently, Inventiva accepts no liability for any consequences arising from the use of any of the above statements.

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Inventiva announces the decision by the investigator to reduce the number of patients in the ongoing Phase II trial evaluating lanifibranor in type 2...

CHAPTER TWELVE

GRAND CANYON SUITE

Kemo Sabe, how many outlaws are left? Tonto asked the Ranger during a lull in the melee.

The Masked man, standing high in Silvers stirrups surveyed the battleground quickly, his dark piercing eyes catching all the important details in their scan of the cacophony.

He turned and looked towards Tonto.

About twenty or twenty five Tonto, now we outnumber them! he said enthusiastically.

Just as quickly as the battle waned, it resumed as the remaining outlaws charged once more.

Bracing themselves for the brutal onslaught, the tired ranchers formed a defensive wall. The Lone Ranger, Tonto, Monte Hale, Rex Allen, Gabby Hayes, the Harts, Tex Ritter and crew, Tim McCoy and his outriders; all lined up, their pistols still hot and smoking as they stood tall and defiant to face the bloodthirsty outlaws final surge!

The outlaws, battered, bruised and wounded stared ahead at the growing line of vengeful determined ranchers.

Fear grew within their villainous breasts as man by man, they looked to the man beside them. Left, then right, each man assessed his sideman and finally, faced front again.

By now the moon was almost mid sky, and the shadows of the ranchers were eerie dancers on the uneven beat up ground. Slowly, gun barrel reflections of white light met each outlaws gaze as they surveyed the wide line of vengeance before them.

More men joined in the ever widening swath of ranchers . Bob Nolan, Pat Brady, Dusty Rogers, and Sunset Carson had galloped up and merged with the ranchers.

The masked outlaw leader, waiting in line with the outlaws, waved the desperate men forward. Over poorly lit ground, they walked slowly at first, guns raised in preparation for a final shoot out! The masked leader walked one step behind, examining all he could see.

The Lone Ranger yelled out.

Forward men!

Like two columns of marching Roman centurions, the desperate groups moved towards a certain collision with destiny. A charged silence filled the air between the two approaching masses of men. The ground, trampled and torn, bore signs of recent violence, and the anger in the air screamed the promise of more!

Fear showed in every outlaws numbers as the ranchers neared. The masked leader, still walking a step behind, sensing certain defeat, yelled

CHARGE!!!

The outlaws, waiting for the sign to attack, ran forward desperately. Guns held high, each outlaw fired his brace of ammunition. Reloading, they fired again, and again.

The ranchers led by the Ranger and Roy, met the villainous onslaught with courage born of confidence. The outlaw bullets did little harm to the revenge driven cattlemen. A few fell back with slight wounds, then recovering from the hot stings, rejoined their comrades.

GETEM BOYS! the Ranger shouted as he lifted his pistol, and fired, and fired.

Roy Rogers, beside the Ranger, charged into the mass of fighting men, pistols held high and blazing. All around him, rancher fought outlaw, and with one sure result; death or capture for the evil doer!

The masked leader, fighting for his life with a rancher spotted Roy out of the corner of his eye. he feigned left, then punched right felling the exhausted rancher. Roy, seeing the man fall, plunged towards the mysterious leader.

Rogers! Come get me he taunted.

Roy reached the hooded man, and leaping upon the outlaw leader, pulled him to the ground.

The leader, somewhat hampered by his disguise, rolled Roy off into the moist hardback.

Give yourself up! Roy shouted.

Roy stood up, and slipped.

The masked leader, sensing that defeat was close at hand, jumped up and mounted his horse in desperation. Taking a quick look around the melee, he reined his horse around, back again and then fled!

Come back, you coward! Roy shouted.

The masked leader kicked at the lunging cowboy. Missing Roy by a couple of inches, he spurred his horse onward.

Roy Rogers, ducking to avert the outlaw leaders silver tipped boot, fell onto the trampled ground again.

The masked leader galloped desperately away from the battle scene. One thought filled his mind-ESCAPE!! Pushing his mount mercilessly, he looked back and saw Roy rising from the ground dazed somewhat. Turning frontwards, he leaned down and fled for his life!

Roy Rogers, getting up from the ground looked up to see through blurry eyes. Shaking his head to clear the cobwebs, he called out.

Here Trigger and he whistled.

Trigger, not far away, galloped enthusiastically towards Roy. Roy, running alongside Trigger, mounted him mid gallop. He quickly reined Trigger around toward the fleeing outlaw leader.

Come on boy, hes got a big lead on us! Roy shouted to Trigger.

Trigger accelerated strongly, the cool night air rushing across his face and bruising his lungs. Dust flew as his hooves beat out a tune that could only be called JUSTICE!

Roy urged Trigger on, as the outlaw ahead pushed his mount brutally. the distance between them was steadily decreasing. One hundred, ninety, eight yards and closer.

A shot from the outlaw puffed back and went wide. A second came a little closer. Roy pulled his silver handled pistol out and took careful bead, then fired once.

By now, Roy and Trigger had closed the gap down to twenty yards.

Roy pushed Trigger onward, with the outlaw this close nothing could stop them. Triggers golden mane, waving in the rushing wind shimmered ghostly in the moonlight. Like a pair of rushing gladiators smelling victory, Roy and Trigger were transformed into avenging angels.

The outlaw leader, now scant yards away, looked back with fear in his eyes. His horse, stopped short as Trigger and Roy outran the pair briefly. Turning quickly, Roy and Trigger met the outlaw pairs attack head on.

Trigger reared up in response to the chestnuts menacing hooves. Roy, balancing on Triggers back, tensed in preparation for the final battle. Trigger struck out with his left hoof, the chestnut reeled back. Striking out in retaliation, the chestnut nicked Triggers shoulder drawing blood with a sharp shoe. Trigger, lashed out with both hooves, the other horse recoiled in fear and stepped back and down again. Trigger landed on his front hooves and attacked again and again.

Silhouetted in the moonlight, the mounted riders looked like ghosts dueling eternally over some long forgotten disagreement. Triggers mane, adopting the shimmery translucence of the silvery light, whirled as if tethered to an invisible line. Roys figure, against the moon, loomed mightily over the masked leaders as the horses, tired by their exertion, planted themselves firmly on the ground. The chestnut, beaten by Triggers pummeling hooves, succumbed to the golden stallion.

Roy, sensing victory for Trigger, urged him closer to the outlaw pair. Leaping from his saddle, Roy landed on the frantic outlaw leader and pulled him to the ground.

Roy, atop the masked leader, punched once, twice. The masked evildoer, arched his back and sent Roy flying through the air.

Blood dripping out of the leaders mask minimized his vision. His fear of dying drove him on! The leader ran and jumped on Roy dazing him temporarily.

Taking his pistol out of his holster he grabbed the barrel end and swung towards Roy.

Ducking to avoid the heavy pistol end, Roy swung out with his right fist. Connecting with the outlaws blood drenched chin solidly, Roy felt a snap.

The leaders head jerked back and his body followed. The masked outlaw rolled off Roy onto the ground, his pistol falling harmlessly to the side.

Roy sat up and knelt beside the stunned outlaw. He wiped his mouth with his gloved hand.

Finding his hat in the dirt, Roy picked it up and knocked the dust off. Placing it on his head, he turned and looked at the outlaw.

In the moonlight his menace was diminished, thickening blood shone black in the silvery glow. Roy stood up and rolled the masked leader over. He reached down and pulled the mask off.

The moonlight fell upon the face of Sheriff Bill Stockton!

Roy whistled.

So, our suspicions were right he said.

Roy walked over to Trigger, took his lasso off and tied Bill up. Wrapping the outlaw sheriff tightly, Roy threw him onto his tired chestnut. Whinnying in protest, the horse struggled with the dead weigh of the sheriff/outlaw leader.

Come on boy. Well go slow Roy said soothingly.

Breathing the cool prairie air, Roy whistled a nameless tune. Trigger, nodding in response, sauntered over beside where Roy was standing. Roy placed his left foot in the stirrup, grasped the horn, and back, then swung up into the well worn saddle.

Lets go Trigger, take it easy. Weve got ourselves a tag along Roy said as he rubbed the palominos neck.

Trigger whinnied and tossed his head from left to right.

Dont worry, well get your cut washed out too. If youre lucky, the vetll have a girl patient there too. Or well get Tonto to fix you up. Roy said to comfort Trigger.

Roy turned Trigger. The chestnut caboose followed and headed off towards Rexs place.

As the masked outlaw leader fled from Roy, the remaining villains were battling viciously. Like trapped wolves they used every weapon at their disposal; teeth, knives, boots, even mud. The sounds of hand to hand combat intermingled with the echoes of gunfire drifted over to the ranch where Mary Sterling waited for the battle to end and peace to begin once more.

Now and then, Gabbys voice could be heard over the lull.

Got ya varmint of Drop it polecat. Ive got you covered.

As the outlaw numbers diminished, strength and resolve of the ranchers increased.

Twisting his head quickly y from side to side and scanning as well as he could in the moonlight, Aces sharp vision caught the lunar sparkle from the masked leaders disguise. Much to his surprise, the leader glanced back, kicked out at a flying Roy Rogers, then turned and galloped off!

Above the din, he yelled to the surviving outlaws.

Men- Scatter!

Each man found his horse, then fled as well as he could. The ranchers, led by the Lone Ranger and Tonto, fell upon the fleeing outlaws.

Quick men! Theyre leaving! he shouted.

Silver responded to the masked mans gentle commands- left here to cut a retreat, right to block an outlaw. Tonto found the fleeing Ace Parker and gave chase. Within a few hundred yards, Tonto and Scout overtook the villainous gunman. The Indian flung Ace to the ground, Aces head ricocheting off a rock. With savage fury Tonto swung once, twice, three, and out Ace Parker went. Collapsing into a heap on the ground and bleeding from half a dozen wounds, he whispered.

You got me Indian. You got me.

All around the melee, whoops of victory filled the air. Triumphant ranchers pulled back fleeing outlaws. Some men gathered the fallen together in a line. The outlaws, some bound, some not, all bore signs of battle weariness. and failure. The grinning ranchers, their faces battered but jubilant, slapped got down to the business of securing the prisoners.

Rex Allen found Koko, and pursued Trig Larson. Trig Larson, too scared and confused to find a horse, bolted desperately. Rex, in a couple of Kokos strides caught up him. He lept upon the fleeing outlaw. They went down. Rex, landing squarely on Trigs back heard a crack. Trig Larson let out a yell of pain.

Ya broke my arm Allen! I give up he howled.

Rex Allen stepped off Larson, and lifted him up by his good arm. A surge of anger came over Rex. He wanted to beat Trig Larson within an inch of his life, but he couldnt. They had won.

Lets go Larson. You walk, I ride Rex said grimly.

Trig Larson, downcast, started back towards Rexs place. Rex, atop Koko, held back tears of gratitude.

Somehow tonight, the deaths of his friends and fellow ranchers had been avenged, and the dead now knew.

One by one, the escaping outlaws found their retreat blocked by the inspired ranchers. The Corrigans, Haydens, Ritters and Pierce Lyden all found their targets and bore down. Some fights were quick, some long, but the prospect of peace drove the ranchers to a feverish pace. In the end, not one outlaw was left standing. Some got killed in the battle, some just got shot escaping.

Rex the Lone Ranger said to the exhausted ranch owner as he sauntered into the corral area, Its all over now.

Rex , took his dirty hat off, and brushed his hand against the crest and sides. He put his hat back on and smiled a tired smile.

Lone Ranger, I hope youre right he said, his hand on the Rangers shoulder.

The Ranger stood atop Silver and yelled.

Men-bring the outlaws here. Well tie them to the fence,

The men grumbled. One man spoke up.

Lets lynchem!

They killed my pa!

They killed my uncle!

The Ranger and Tonto looked around. The men were poised to finish the night with more violence. Rex looked at the pair, concern showing on his face.

Men, we have to hold them for the law. If we dont, were not better than

Roy Rogers came around the corner. Reining Trigger back he dismounted and walked over to where the Ranger, Rex and Tonto stood. The flickering light evidenced Roys battle scars. His dungarees and shirt, were now stained brown and red.

What took so long Roy? Rex asked.

Roy pointed to the chestnut behind Trigger where the masked leader/Bill Stockton lay gagged and unmoving.

He did Roy said smiling. But we took care of the both of them, didnt we Trigger.

Trigger whinnied in response to Roys praise.

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Bing and Ol' Medicine Hat - Todayville.com