Category Archives: Molecular Genetics

Armed with a 100-page packet of data, Dr. Patrick Moore helped evaluate the safety and efficacy of Pfizers COVID-19 vaccine for the United States in just four days.

But even though the U.S. Food and Drug Administrations approval of this vaccine wasnt normal, Moore said he wants all Americans to know the Pfizer vaccine is an important step in ending the pandemic and keeping Americans safe.

Were in an emergency, obviously. We have to have some way of stopping this epidemic its completely disrupted our entire social and economic fabric, Moore, a distinguished professor of microbiology and molecular genetics at UPMC, said. Were facing enormous risk from COVID-19, and we feel very confident that theres very low risk for the vaccine.

Moore serves on the FDAs Vaccines and Related Biological Products Committee, which reviewed data regarding Pfizers COVID-19 vaccine in December. The FDA approved the Pfizer-BioNTech vaccine on Dec. 11 for emergency use authorization.

Moore said the FDA invited him to analyze preliminary data from Pfizer about the safety and efficacy of its COVID-19 vaccine alongside 20 other scientists. He said the committee gives advice to the FDA regarding the release of pharmaceuticals.

We give [the FDA] a better sense of whether we agree with releasing it under the circumstances that theyve posed or not, Moore said. Its a committee that, every year, has to also give advice on the components on the influenza vaccine.

Moore speculated that he was selected for the committee due to his experience in cancer neurology and chronic disease biology, as well as handling epidemics. As an epidemic intelligence service officer for the Centers for Disease Control and Prevention, he said he worked in Chad and Ethiopia to control meningitis epidemics in Africa.

Moore said all the scientists serving on the committee must be mature, since their job is to look objectively at this data in a critical way. Besides the panels own critique, the committee comments from the public that were previously submitted to the FDA.

There are legitimate concerns that people may have, Moore said. We should bring [them] up with the company as best we can, even if we, personally, do not think those concerns are terribly important.

Moore said having the publics trust in the safety of the vaccine is crucial to get a nationwide vaccine rollout going.

A reasonable person will want to know, and should know, that people who dont have a conflict of interest are evaluating this, and its based on data, not opinions, Moore said.

Dr. Shou-Jiang Gao has worked with Moore for many years, initially as a postdoctoral researcher in Moores lab at Columbia University. Now Moores boss, Gao, a professor in the department of microbiology and molecular genetics, said they focus on cancer viruses. Moore, along with his wife, Dr. Yuan Chang, a distinguished professor in the department of pathology at Pitt, discovered two of the seven human cancer viruses one in 1994 and another in 2008.

Gao said Moore is one of the brightest scientists Ive ever known and that the scientific review he was a part of was critical.

Scientific review is critical and a topic of public concern in terms of efficacy and safety, Gao said. I think the panel, which included him, did a fantastic job and evaluated all the data to give the best recommendation.

Moores former colleague Dr. Lee Harrison, a professor of medicine and epidemiology in the department of medicine at Pitt and chair of the Allegheny County Board of Health, also spoke highly of Moore. He said they traveled together for the CDC, where they intercepted airplanes carrying passengers from Saudi Arabia who may have contracted meningitis.

We traveled to New York City to intercept Saudia 747s at the tarmac of JFK Airport because there was a big meningitis outbreak going on in Mecca during the Hajj, Harrison said. We intercepted before they got to the gate and did a study of how to prevent meningococcal infection in people coming off the airplane.

While potential COVID-19 vaccines were being discussed months before any approval, Gao said the decision to approve the vaccine must have been a difficult one.

The majority of these vaccine trials only have two-month data available right now, Gao said. They have to make the best scientific judgment they can.

With the vaccine approved, Americans are eager to get vaccinated. But vaccine rollouts have been slower than anticipated, according to Moore. According to the Associated Press, Pennsylvania is tied for 39th among the 50 states in terms of the percentage of the population that has received at least one dose of a vaccine, as of Feb. 3. Only 10.6% of Pennsylvanians have received at least one dose of a vaccine as of Sunday, according to The New York Times.

Countrywide, [the vaccine distribution] has been miserable.You knew there was a vaccine being evaluated, I certainly knew there was a vaccine being evaluated, Moore said. Everyone in the public health community should have had clear marching orders from Washington to the states to the counties to the providers.

Moore said there are a lot of hurdles with distributing this vaccine, including the necessity for two doses and identifying patients who are at a higher risk to line them up in an orderly way early on.

Harrison agreed that the vaccine rollout was less than ideal. He said a prevalent issue was having more demand than supply.

Theres a big demand, and then not as much supply. The logistics of getting people immunized is proving more difficult than was anticipated, and its really tough for people to figure out when its their turn, Harrison said. Its this patchwork system that is still really suboptimal, to say the least. Hopefully thats going to get better and better, because were not going to get out of this until we get a minimum of 70% of the population immunized.

Despite the challenges, Moore is optimistic that President Joe Bidens administration may be able to get the vaccine rollout back on track.

Im so happy because now it seems that, at least in Washington, there is an organized attempt at distributing the vaccine in a way that will truly get out to the entire population, Moore said. I have hope that its being taken quite seriously, now that weve lost two to three months during the transition to get to this point.

Regardless of politics, Gao said he urges everyone to get the vaccine if they have the opportunity.

They should be vaccinated not just for themselves, but also for whoever they encounter as a citizen, Gao said. You could still produce virus to spread to other people, and for those not vaccinated, they may still be at risk.

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Pitt doctor helped review, approve Pfizer COVID-19 vaccine - University of Pittsburgh The Pitt News

SALT LAKE CITY, Feb. 18, 2021 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (NASDAQ: MYGN), a leader in genetic testing and precision medicine, today announced several new technology and healthcare leaders who recently joined the company as well as key promotions to drive critical business functions, transformation and growth initiatives.

With the addition of new leaders from other industry leading enterprises, we continue to augment our strong bench of talent across a range of functions that will accelerate the execution of our strategy with disciplined process management and proven expertise, said Paul J. Diaz, president and CEO of Myriad Genetics. We are pleased to welcome new teammates who share the passion for our mission to improve health and wellbeing for all as we continue to recruit and promote top talent from outside and inside our company.

The following Myriad Genetics leaders are assuming broader roles:

Kevin R. Haas is promoted to Chief Technology Officer, reporting directly to Diaz, responsible for engineering, data and analytics, genetic laboratory software, and improving the customer experience through tech-enabled, customer-centric commercial capabilities. Since joining Myriad in 2013, Haas has served in senior level leadership roles across research and development, bioinformatics, engineering and technology.

Faith Zaslavsky is promoted to president of Myriad Oncology which offers genetic testing for patients who have cancer and companion diagnostic tests that work with corresponding drugs. Since 2019, Zaslavsky has served as general manager of this business unit, overseeing products including Myriad myRisk Hereditary Cancer, myChoice CDx companion diagnostic, and EndoPredict breast cancer tests. Over her 21-year career at Myriad, Zaslavsky has held progressively responsible sales, strategic account management and leadership roles.

New leaders recently joining Myriad include:

Maggie Ancona, senior vice president, Enterprise Transformation and Program Management Office. She reports directly to Diaz, managing a broad range of enterprise-wide transformation initiatives and workstreams with a focus on operational excellence. Ancona previously led Global Transformation and Program Management at Hewlett Packard (HP) and Dell Technologies where she oversaw business transformation strategy, executed large-scale programs and cost management efforts, while retooling digital infrastructure for the future.

David Hammer, senior vice president, Revenue Cycle Management, has overall accountability for the process, including functions that contribute to the capture, management, and collection of diagnostic-service revenue and related areas designed to improve the customer experience. He previously held senior revenue cycle management roles at RGP Healthcare, MedAssets, and Accenture. Hammer also serves on the Board of Advisors of the University of Florida's College of Public Health and Health Professions.

Chris Williamson, senior vice president, Information Systems and Security. Williamson previously led all facets of information technology, infrastructure, business intelligence and operations for Data2Logistics, a leading data-driven freight, audit and payment services company. A retired Naval Officer, Williamson served in the White House (executive office of the President) for the Technology Assessment Center and Information Technology Working Group.

Edward Gala, senior vice president, Enterprise Marketing Communications, responsible for strategic public relations, employee and executive communications, and overall brand marketing. Gala previously held global marketing and communications leadership positions at Xerox and Philips where he played a key role in brand transformation and positioning, business-to-business and consumer marketing across corporate, business, market and product groups.

Karen Renner, vice president, Digital Marketing, responsible for digital infrastructure, patient lead nurturing, conversion and support for products including Myriads myRisk Hereditary Cancer test and related digital initiatives across Womens Health and Oncology. Karen previously served as the global digital and eBusiness leader at Nestle Purina and brings prior digital agency experience with leading consumer product accounts at VMLY&R.

Jackie Zou, vice president, Business Development, responsible for supporting new growth opportunities, including the development and execution of transactions such as divestitures, potential mergers and acquisitions (M&A), and new partnerships. Zou held senior roles in strategy and finance, at Western Digital Corporation (WD), a global data technology, storage and digital content company, where she planned and executed merger, acquisition and divestiture transactions, joint venture initiatives, strategic partnerships and business development. Zou previously worked at Symantec, ZS Associates and Goldman Sachs.

Justin Hunter, vice president, Corporate Legal Affairs, responsible for providing legal counsel and support for corporate governance, SEC reporting, M&A, and related matters. Hunter previously served as senior legal counsel for Parsley Energy where he was responsible for SEC reporting and compliance, acquisitions and divestitures, and corporate governance. Previously he worked at Vinson & Elkins LLP and as a law clerk to Vice Chancellor Noble on the Delaware Court of Chancery.

Top Place to WorkMyriad Genetics recently was named among the Top Places to Work in Energages Top Workplaces USA list for 2021. The company ranked number one in the Health Industry category and earned additional awards in Cultural Excellence and Innovation & Leadership. Myriad employs more than 2,800 people across the United States and in several countries around the globe. To learn more about career opportunities at Myriad, visit our website.

About Myriad GeneticsMyriad Genetics Inc., is a leading genetic testing and precision medicine company dedicated to transforming patient lives worldwide. Myriad discovers and commercializes genetic tests that determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across medical specialties where critical genetic insights can significantly improve patient care and lower healthcare costs.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor StatementThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to driving key business functions, transformation and growth initiatives and accelerating the execution of Myriads strategy with disciplined process management and proven expertise; and the Companys strategic directives under the caption "About Myriad Genetics." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties associated with COVID-19, including its possible effects on our operations and the demand for our products and services; our ability to efficiently and flexibly manage our business amid uncertainties related to COVID-19; the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions in Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading "Risk Factors" contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2020, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

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Technology and Health Leaders Join Myriad Genetics, Advance in Senior Roles to Drive Key Enterprise Functions, Transformation and Growth Initiatives -...

The Institute for Molecular Medicine Finland (FIMM) is an international research institute focusing on human genomics and personalised medicine at the University of Helsinki. In the beginning of 2017 FIMM joined the University of Helsinkis new life science research centre, Helsinki Institute of Life Science HiLIFE, as an operational unit. FIMM integrates molecular medicine research, technology centre and biobanking infrastructures under one roof, promoting translational research in grand challenge projects, specifically, the impact of genome information from the Finnish population in personalised health and medicine, individualised cancer medicine, and digital molecular medicine. FIMM is part of the Nordic EMBL Partnership for Molecular Medicine, composed of the European Molecular Biology Laboratory (EMBL) and the centres for molecular medicine in Norway, Sweden and Denmark, and the EU-LIFE Community.

The INTERVENE consortium (https://www.interveneproject.eu/) is a 5-year 10 million EU funded project that aims to develop and test next generation tools for disease prevention, diagnosis and personalized treatment utilizing the first US-European pool of genomic and health data and integrating longitudinal and disease-relevant -omics data into genetic risk scores. The consortium includes 18 partners from 11 countries which are closely collaborating together.

The coordinating center at Institute for Molecular Medicine Finland, University of Helsinki is recruiting two fellow positions (post-doc level or higher), that will work in close collaboration with Prof. Samuli Ripatti and Dr. Andrea Ganna. One fellow will be working on the breast cancer clinical pilot, coordinating the multinational study on translating the genetic information to treatment and screening and the other will work on development and application of next generation risk prediction tools.

Professor Samuli Ripatti is a vice-director at FIMM, Professor of Biometry at Faculty of Medicine and a director of Academy of Finlands Center of Excellence in Complex Disease Genetics. His research group has broad collaboration with international research groups to study genetic variation and its connection to lipids, metabolites and other risk factors for cardiometabolic diseases and common cancers. Professor Ripattis group also builds statistical and computational models for complex disease risk estimation. Ripatti has played key roles in major Finnish sequencing efforts. He is the PI of the GeneRISK Study, pioneering studies utilizing personal genetic risk information and returning it to the participants with couching to lower the risk.

Dr. Andrea Ganna (https://www.dsgelab.org/) is an EMBL-group leader at FIMM and an instructor at Harvard Medical School and Massachusetts General Hospital. His research vision is to integrate genetic data and information from electronic health record/national health registries to enhance early detection of common diseases and public health interventions. Dr. Ganna has been recently awarded with an ERC starting grant to study the application of artificial intelligence methods for prediction of cardiovascular diseases.

Qualification and requirements: We are looking for two future research leaders to work in a highly stimulating international environment with an unprecedented amount of health and genetic information from up to 1.7 million individuals.

The first INTERVENE fellow, who will work on the breast cancer clinical pilot, will have clinical or genetic background with statistics/data science/epidemiological skill set and interest in developing tools to help clinicians and clinical geneticist in making genetically informed decisions in their choices for treatment and cancer screening.

The second INTERVENE fellow, who will work on the development of risk prediction tools, will develop and pilot cutting edge approaches for the next generation of genetic tools for disease prevention, diagnosis, and personalized treatment. The candidates should have a background in statistics, machine learning or related data science. The ideal candidate should have experience in developing or applying cutting-edge methods for genetic prediction based on results from genome-wide association studies and sequencing data.

The candidates should hold a Ph.D. or are about to finish the doctorate studies in the field of genetics, statistics, mathematics, computational sciences, (genetic) epidemiology or clinical medicine. The ideal candidate shows scientific independence, has publishing experience, and an aptitude towards developing novel techniques. Together with the PI, he/she is jointly responsible for coordinating projects and supervising PhD students.

Contract & salary:

The job is for a fixed-term of 2-3 years with a possibility of extension. The salary of the position is determined in accordance with the salary system of Finnish universities, and depends on the candidates qualifications. The University of Helsinki offers comprehensive services to its employees, including occupational health care and health insurance, sports facilities, and opportunities for professional development. A trial period of 6 months will be applied.

How to apply:

The application should include cover letter, CV, list of publications, contact information for referees. Documents should be submitted as a single PDF file.

To apply, please submit the application through the University of Helsinki electronic recruitment system by clicking on the "Apply for job" link below. Internal applicants (i.e., current employees of the University of Helsinki) please submit your applications through the SAP HR portal. Please apply no later than March 15, 2021.

For further information about the position, please contact the recruiting PIs: Prof. Samuli Ripatti samuli.ripatti@helsinki.fi); Dr. Andrea Ganna (aganna@broadinstitute.org)

If you need support with the recruitment system, please contact recruitment@helsinki.fi.

Helsinki Institute of Life Science

Helsinki Institute of Life Science (HiLIFE) is a new institute established in 2017 that supports high quality life science research across the University campuses and faculties. HiLIFE builds on existing strengths and new recruits and partnerships to create an attractive international environment for researchers to solve grand challenges in health, food, and environment. HiLIFE coordinates research infrastructures in life sciences and provides research-based interdisciplinary training.

University of Helsinki

The University of Helsinki (UH), founded in 1640, is a vibrant scientific community of 40,000 students and researchers. It is one of the leading multidisciplinary research universities and ranks among the top 100 international universities in the world. It is currently investing heavily in life sciences research. UH offers comprehensive services to its employees, including occupational health care and health insurance, sports facilities, and opportunities for professional development.

Due date

15.03.2021 23:59 EET

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INTERVENE Fellow in Statistical/ Medical Human Genetics job with UNIVERSITY OF HELSINKI | 246627 - Times Higher Education (THE)

According to the State of Oklahomas vaccine rollout plan, college professors and faculty are listed as a lower priority than pre-k through twelfth grade teachers, despite college faculty and staff being collectively older and at a higher risk of exposure due to mandatory in-person learning at colleges like Oklahoma State.

Pre-k through twelfth grade teachers and support staff will be eligible to receive the vaccine in phase two of the State of Oklahomas vaccine rollout plan. Unless university staff and faculty are over the age of 65 or an adult with a compromised immune system, they will not be eligible until phase three.

Jennifer Rudd, a veterinarian on faculty at the College of Veterinary Medicine, says there are factors making university classrooms safer than pre-k through twelfth grade classrooms.

Our students have strict guidelines for masking, distancing, and can better learn virtually than younger kids can, Rudd said. "We also have university support to enforce these guidelines and we meet with students for smaller time frames than my sons kindergarten class would meet.

Additionally, Dr. Rudd said younger people are more likely to have asymptomatic infections so more kids are likely to show up at school with COVID-19. Knowing this, Rudd said she supports prioritizing pre-k through twelfth grade teachers and support staff.

There are 24,649 students at OSU and some professors teach in person while wearing masks and practicing social distancing. Dr. Clint Jones, a regents professor and Sitlington professor of infectious diseases, said he taught an in-person class last semester and is impressed by how aware students are about upholding safety guidelines.

Even though Jones said in his experience students are responsible and should not be expected to only go to class and stay in their rooms. He said the possibility of transmitting the virus is still an issue because of what happens outside of the classroom.

Like it or not, a lot of college kids are going to go to bars, and lets face it, after two or three beers youre probably not thinking about wearing a mask, Jones said.

Jones said he does not understand why university faculty and staff could not be in the same phase as pre-k through twelfth grade teachers and support staff because the risk involved with teaching in person is still present.

While there is still risk involved with holding in-person class, Barry Fuxa, public relations and communications specialist for Stillwater Public Schools, said considering the current supply chain, he understands prioritizing groups.

Like Rudd, Fuxa said it is easier for university staff and faculty to practice social distancing because it's easier to distance themselves from students and hold classes online than it is for pre-k through twelfth grade teachers.

Some educators are ready to get the vaccine. Tera Mitchell, a kindergarten teacher at Westwood Elementary school, said at first, she was uncertain about getting the vaccine because of how fast it was developed. However, after her mom died due to COVID-19 she said will most certainly be getting the vaccine.

I feel it is remarkable that scientists and medical professionals have been able to develop a vaccine in less than two years for distribution to the public, Mitchell said. While I wish that it is something that could be administered rapidly, I have to trust the process and continue doing my part to keep vulnerable populations safe.

There many factors why vaccinations get administered to certain populations before others. Dr. Marianna Patrauchan, a professor in the department of microbiology and molecular genetics, said the distribution of the vaccine is more complex.

Patrauchan said vaccine distribution is largely based on who is the most vulnerable or at risk. However, when distinguishing between campus faculty and staff and pre-k through twelfth grade teachers and staff, it becomes tougher. Not only because there are still things unknown about the virus, and it is difficult to find easily accessible information about how many vaccines have been distributed in a specific area.

news.ed@ocolly.com

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Phased and confused: OSU professors react to being in Phase III of COVID vaccine - Daily O'Collegian

Fuelled by a changing climate, plant pathogens encounter increasingly favourable conditions to spread and wreak havoc on global crop yields. But could artificial intelligence help predict the spread of disease, buying farmers valuable time to take preventative measures?

As part of an effort that took top honours and a $20,000 prize in the recent ProjectX global undergraduate research competition, a team of University of Toronto students proposed the use of a new machine learning architecture to forecast infections of black Sigatoka, a fungal disease that blackens bananas from the inside out.

ProjectX,the brainchild of the U of T Artificial Intelligence student group, challenged teams of undergraduate students from universities around the world to use machine learning to address the impacts of climate change. The competition, which concluded in December, was divided into three categories: infectious disease; weather and natural disaster prediction; and emissions and energy efficiency.

Left to righ (top row):Ziyad Edher, Yuchen Wang, Sornnujah Kathirgamanathan, (bottom row) Matthieu Chan Chee, Minh Duc Hoang andShion Fujimori.

ProjectX organizers maintained a strict firewall between themselves and U of T student competitors to ensure fairness in the competition.

The team from U of T that emerged victorious in the infectious disease category included computer science studentsYuchen Wang,Matthieu Chan Chee,Ziyad Edher,Minh Duc HoangandShion Fujimori; as well asSornnujah Kathirgamanathan, a molecular genetics and microbiology student in the Temerty Faculty of Medicine.

Operating remotely from Toronto, Vancouver, Japan, and Vietnam, the team members focusedon devising a neural network to forecast the infection risk of black Sigatoka.The fungal disease can have devastating consequences for farmers, decreasing yields and driving up costs. The Food and Agriculture Organization of the United Nations reported that, between 2007 and 2009, St. Vincent and the Grenadines faced a 90 per centdecline in banana crop production due to the disease.

For more information: utoronto.ca

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Prize-winning team uses AI to beat banana blight - FreshPlaza.com

Introduction

Lung cancer is one of the leading causes of cancer-related death globally.1 Although there are different types of lung cancer, non-small cell lung cancer (NSCLC) represents 85% of all primary lung tumors. NSCLC is a grim disease that is aggravated by the fact that patients normally either receive their diagnosis at advanced stages or present with recurrent disease after initial locoregional treatment.2 Over the last few decades, conventional chemotherapy, mainly platinum-based chemotherapy, used to be the only therapeutic option for those not eligible for radical intent treatment: a treatment with limited efficacy and very few long-term survivors (5-year overall survival less than 15%). Furthermore, these patients often lacked therapeutic options beyond first-line treatment.3

More recently, though, immune checkpoint molecules involved in tumor immune evasion were identified and immune checkpoint inhibitors (ICIs) were introduced in antitumor immunotherapy. This new therapeutic approach targets an inhibitory receptor, the programmed cell death-1 (PD-1) receptor, to assist the immune system in identifying and neutralizing malignant cells. However, tumor cells may evade the host immunosurveillance by expressing the programmed death-1-ligand 1 (PD-L1) as an adaptive, resistant mechanism to suppress this inhibitory receptor.4 Thus, because PD-L1 up-regulation by tumor cells can protect them from antitumor immune response, the blockade of PD-L1/PD-1 interactions has been recently selected for antitumor immune therapy.5 Agents targeting the PD-1/PD-L1 signaling pathway have shown promising responses in different types of cancer, including NSCLC. These results point to PD-L1 protein expression as a potential predictive marker for a successful blockade of PD-L1/PD-1 interactions.6 However, several challenges remain in producing robust evidence to support the use of this biomarker.

In this context, some studies with NSCLC patients have demonstrated that those with more than 50% PD-L1 positive tumor cells are non-responders to anti-PD-1/PD-L1 treatment. In contrast, others have shown that patients whose tumors do not express PD-L1 are good responders.79 To explain the controversies that affect PD-L1 expression, some studies have considered that the heterogeneity between axis expression and response to PD-1/PD-L1 treatment in NSCLC depends on other factors, such as more precise methods to investigate immune evasion mechanisms and the immune microenvironment, as well as greater knowledge on the immune checkpoint genomic profile and the genetic variants of the PD-L1 gene.1013

Some genetic variants have been shown to affect normal gene activation and transcriptional initiation, and hence influence the amount of mRNA and encoded protein in the cell.14 Non-coding variants also presumably affect genetic regulatory elements, since a majority of driver variants in cancer genomes occur in non-coding regions.15,16

Thus, several studies have investigated the association between PD-1 and PD-L1 genetic variants and the risk of various cancers, but their findings have yet failed to completely elucidate this question.17 A previous study suggested that PD-L1 polymorphism may predict chemotherapy response and survival rates in advanced-stage NSCLC patients after first-line paclitaxel-cisplatin.18 More recently, PD-L1 copy number variations, point mutations, and 3-UTR disruptions have been highlighted as genetic mechanisms of PD-L1 deregulation.19 Furthermore, previous research on Brazilian patients suggested that their ethnic background could account for their distinct cancers molecular profile, perhaps due to their characteristic genetic admixture, inherited from European, African, and Native American ancestors.2022

We hypothesize that PD-L1 non-coding genetic variants modulate the function of this immune checkpoint in NSCLC. To explore this issue, we investigated fifteen PD-L1 non-coding genetic variants using next-generation sequencing (NGS) in a Brazilian cohort, aiming to uncover the effect of their ethnic admixture on NSCLC. We also combined our analyses with an in-silico approach to predict the impact of these genetic variants on the disease. We evaluated the associations between PD-L1 protein expression level and clinicopathological characteristics, including the prognosis of NSCLC patients undergoing surgical resection, glimpsing the impact of genetic variants on post progression survival (PPS) and overall survival (OS). Herein, in this context, we intend to expand the existing literature on PD-L1 gene alterations at the genetic level and their impact on NSCLC in patients from different ethnicities, thus increasing the knowledge about the molecular basis of immunotherapy biomarkers.

In this retrospective multi-center study, we obtained archival formalin-fixed paraffin-embedded histologic tumor sections from 70 patients diagnosed with NSCLC (33 adenocarcinomas [ADC], 24 squamous cell carcinoma [SqCC] and 13 large cell carcinoma [LCC]) who underwent surgical resection between January 1, 1995, and December 31, 2015. Patients had been treated at the Hospital das Clnicas of the University of So Paulo Medical School (HC-FMUSP), at the Heart Institute of the University of So Paulo (INCOR), at the Cancer Institute of So Paulo (ICESP), and at the A.C. Camargo Cancer Center in So Paulo, Brazil.

All samples were histologically reviewed by lung pathologists who selected samples with at least 30% of lung cancer cells before nucleic acid extraction. The samples were classified using the 2017 International Association for the Study of Lung Cancer (IASLC) classification system.23 The clinicopathological features of patients were obtained from the medical records. The study was approved in accordance with the ethical standards of the responsible committee on human experimentation local (Research Ethics Committee of University of So Paulo Medical School - CAAE: 79769017.1.0000.5440; opinion number: 2.673.320) and with the 1964 Helsinki declaration. A waiver of the requirement for informed consent was obtained from committee, and to identity of the subjects under this retrospective analysis was omitted and anonymized.

We performed a Multiplex immunofluorescence (mIF) staining using methods that had been previously described and validated.24,25 Four-micrometer-thick consecutive TMA sections were stained using an automated staining system (BOND-RX; Leica Biosystems, Buffalo Grove, IL) to characterize PD-L1 (clone E1L3N, dilution 1:100; Cell Signaling Technology, Danvers, MA). The PD-L1 marker was stained with its respective fluorophore from the Opal 7 kit (catalogue #NEL797001KT; Akoya Biosciences/PerkinElmer, Waltham, MA). A complete validation using immunofluorescence (IF) allowed us to obtain a uniform, specific, and appropriate signal across all the channel; ie, a well-balanced staining pattern for the multiplex staining.24,25 We also defined and optimized the correct fluorophore signals between 10 and 30 counts of intensity to maintain good balance and similar thresholds of intensity across all antibodies. In parallel, to detect possible variations in staining and optimize the separation of the signal, positive and negative (autofluorescence) controls were included during the staining process to ensure that all the antibodies performed well together. Autofluorescence controls with an expected spectral resolution of 488nm were able to accurately remove the autofluorescence from all the label signals during the analysis. The stained slides were then scanned using a multispectral microscope, the Vectra Polaris 3.0 imaging system (Akoya Biosciences/PerkinElmer, Waltham, MA), under fluorescence conditions.

Multispectral images of tumor sections from each core were analyzed with inForm 2.2.1 (Akoya Biosciences/PerkinElmer, Waltham, MA) software Individual cells, which were defined by nuclei staining and identified by the InForm cell segmentation tool, were subjected to a phenotyping pattern-recognition learning algorithm to characterize co-localization of the various cell populations using panel labeling.26 The panel labeling was as follows: Malignant cells (MCs), with the AE1/AE3+ marker, including those with and without PD-L1 expression (AE1/AE3+ PD-L1+ and AE1/AE3+ PD-L1-, respectively). The individual cell phenotype report produced by the InForm software was processed using Excel 2010 (Microsoft. Houston, TX), and a final summary of the data, which contained the median of each individual phenotype (given as number of cells/mm2) and the percentage of macrophages and MCs expressing PD-L1, was created for statistical analysis. If the percentage of MCs or macrophages expressing PD-L1was greater than the median value, the PD-L1 expression was considered positive. If the percentage of macrophages or MCs expressing PD-L1 was lower than or equal to the median, the PD-L1 expression was considered negative.

Genomic DNA (gDNA) was extracted from frozen NSCLC tissue using the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturers recommendations. DNA concentration was measured using the Qubit 3.0 Fluorometer (Invitrogen, Life Technologies, CA, USA). DNA integrity was assessed using the Bioanalyzer 2100 system (Agilent Technologies, CA, USA).

We performed a PD-L1 (CD274) full gene screening by deep targeted sequencing using the TruSeq Custom Amplicon Panel v1.5 kit (TSCAP, Illumina, SanDiego, CA) and the MiSeq platform (Illumina, SanDiego, CA). The DNA libraries were performed according to the manufacturers instructions and consisted of 150 bp paired-end reads (300 cycles).

We performed an NGS data analysis on the Molecular Genetics and Bioinformatics Laboratory of the Experimental Research Unit (UNIPEX) at the Medical School of So Paulo State University (FMB-UNESP). Sequencing quality was assessed by FastQC. Reads were aligned to the human genome (hg19, GRCh37) with BWA software, and SAM tools converted the alignment results to BAM format.27 Next, the mapped reads underwent variant calling for SNP with GATK command line tools, including HaplotypeCaller, SelectVariants, and VariantFiltration programs with default parameters. After the calling step, the variants were annotated using the VEP28 software. Coverage depth was a priori set at 100. Variants had to have >10 reads of position depth (PD) and/or >6 reads of allele depth (AD) and/or an AD/PD ratio of >0.05 and/or a population frequency higher than 1% (popfreq_all >0.01) were included in the study. Finally, variants were compared using ABraOM, a web-based public database of Brazilian genomic variants.29

Several tools were used to predict potential functional effects of SNPs on non-coding binding sites, such as splice sites and binding sites for transcription factors, exonic splicing enhancers (ESEs), and microRNA (miRNA). The impact of each genetic variant was assessed using VarSome30 an integrated search engine that allows access to several databases, forecasting tools, and publications on a single website. Variant pathogenicity was reported using an automatic variant classifier that evaluates each submitted variant according to guideline of the American College of Medical Genetics and Genomics (ACMG) and classifies it as either pathogenic, likely pathogenic, likely benign, benign or uncertain significance. Varsome predicts the pathogenicity of each variant through a DANN31 score, a methodology for scoring deleterious annotations of genetic variants using neural networks that results in a number ranging from 0 to 1. Higher DANN scores represent greater variant deleteriousness.31

Next, we applied the Genomic Evolutionary Rate Profiling (GERP)32,33 conservation score. This score is used to calculate the reduction of substitutions in a multi-species sequence alignment when compared to a neutral expectation. GERP scores >5.5 are strongly associated with a purifying selection. Mutations that occur at highly conserved sites in many species are assumed as harmful and therefore contribute to the genetic load within a species.

Finally, we used two tools, SNPinfo (FuncPred)34 and RegulomeDB,35 to track SNPs according to their functions. SNPinfo is a web server that helps researchers investigate SNPs in studies of genetic association and provide different pipelines for SNP selection, whereas RegulomeDB is an online composite database and prediction tool to annotate and prioritize potential regulatory variants from the human genome.35 RegulomeDB divides the variants into six categories: category 1 variants are likely to affect binding and are linked to the expression of a gene target, category 2 variants are likely to affect binding, category 3 variants are less likely to affect binding, and category 4, 5, and 6 variants have minimal binding evidence.35

The allelic and genotypic frequencies of the PD-L1 polymorphisms found in NSCLC were calculated by Hardy Weinberg equilibrium ([1 _ (hC 2H)]/2N, where h stands for a heterozygous genotype, H for homozygous genotype and N for the number of samples). Associations between polymorphisms, PD-L1 protein expression, and the clinicopathological parameters of NSCLC patients were investigated by Chi-square test. The prognostic value of each polymorphism was assessed by a survival analysis using the KaplanMeier method with the Log rank test for statistical significance. In addition, Coxs proportional hazards regression models were used in a multivariate analysis to test the association between SNPs and PPS and OS. PPS was considered as the period from tumor progression until death or last follow-up. OS was defined as the time from curative surgery to death or last date known to be alive. The statistical software program IBM SPSS (version 22; Armonk, NY, USA) performed all analyses. Differences were considered statistically significant at P<0.05.

Of the 70 patients included in the study, 33 presented with ADC (47.1%), 24 with SqCC (34.3%), and 13 with LCC (18.6%). The clinical characteristics by histologic types are summarized in Table 1. While SqCC cases were more frequent in males (81.8%), ADC cases were equally distributed between genders, and LCC cases were close to equal distribution (male 55.6%, female 44.4%). All histological types were more frequent in patients aged 63 years or younger. 8 patients reported a history of tobacco smoking in the ADC group (72.7%) and in the SqCC group (88.9%), versus 3 patients in the LCC group (50.0%). All the histological subtypes included advanced stages of disease (9 cases in ADC, 6 cases in SqCC, and 4 cases in LCC). Most of the patients had not received either chemotherapy (12 cases to ADC, 8 cases to SqCC, and 6 cases to LCC) or radiation therapy (18 cases to ADC, 10 cases to SqCC, and LCC) as adjuvant treatment. Malignant cells expressed PD-L1 above the median in 7 LCC cases (70.0%), the most relevant expression compared to the other two histological subtypes. The median follow-up was 66 (12144) months. None of the analysis revealed significant differences between histological types (P>0.05).

Table 1 Demographic and Clinicopathological Characteristics of 70 NSCLC Patients

All NSCLC patients who underwent surgical resection were successfully genotyped for fifteen PD-L1 SNPs: rs76805387T>C, rs4742098A>G, rs47946526A>G, rs10217310G>T, rs7864231G>A, rs41280725C>T, rs573692330A>G, rs1011769981G>A, rs41280723T>C, rs138135676T>C, rs4143815G>C, rs2297136G>A, rs148242519G>A, rs41303227C>T, and rs7041009G>A. Supplementary Table 1 shows the SNP identification numbers, allele and genotype frequencies, and P-value for HWE. Of the 15 SNPs studied, 11 were found to be monomorphic, whereas 4 SNPs, namely rs4742098, rs4143815, rs2297136, and rs7041009, were polymorphic in NSCLC. Monomorphic SNPs were excluded from further analysis. All the polymorphic SNPs were found to be in equilibrium (P>0.05) for HWE. The allele frequency of our cohort was compared to different populations in the 1000 Genomes Project (Supplementary Table 2).

We performed stratified analyses on the associations between clinical characteristics and the four PD-L1 polymorphisms with different genotypic distributions. Table 2 shows each SNP genotype frequency and their associated clinicopathological characteristics. Three of the four PD-L1 gene polymorphisms (rs4742098, rs4143815, and rs7041009) were significantly associated with relapse (P=0.01; P=0.05; P=0.02, respectively). For the rs4742098 variant, carriers of the G allele (AG or GG genotypes) were less likely to relapse (P=0.01). Similarly, for rs4143815, carriers of the alternative C allele (CG or CC genotypes) were also less likely to relapse (P=0.05). In rs7041009, however, carriers of the alternative allele A (AG or GG genotypes) were more likely to relapse (P=0.02). Moreover, GG genotype (reference) of rs7041009 showed a significant correlation with age, being more prevalent among younger patients (16 patients, or 69.6%), and status, being more prevalent among patients who were alive (11 patients, or 84.6%), compared to carriers of the A allele (P=0.02 and P<0.01, respectively). No statistical significance was observed in the association between rs2297136 genotypes and clinicopathological variants.

Table 2 Clinicopathological Characteristics of 70 NSCLC Patients Stratified by the PD-L1 Polymorphisms rs4742098, rs4143815, rs2297136 and rs7041009

The correlation between PD-L1 protein expression and PD-L1 gene polymorphisms are shown in Table 2. There were no statistically significant associations between PD-L1 protein expression in malignant cells and PD-L1 gene polymorphisms. In our cohort, the four PD-L1 gene polymorphisms were in non-coding regions and, apparently, cause no interference in PD-L1 protein expression in NSCLC malignant cells. However, when we correlated PD-L1 protein expression with histological subtype, we observed that the expression in malignant cells was above the median in 70% of patients with LLC, in contrast with 45.8% and 47.4% of patients with ADC and SqCC, respectively.

Our first statistical test examined the individual effect of patients characteristics to estimate statistical differences in survival using the KaplanMeier method (Table 3). Patients younger than 63 years showed increased OS, 111.62 vs 66.54 months in older patients (P=0.05). Choice of treatment was also an independent factor in diagnosis, with patients who did not receive radiotherapy presenting a better survival rate when compared with those who were treated with radiotherapy, 94.43 vs 12.00 months, respectively (P<0.01). Patients who presented disease recurrence had lower survival rates and poorer prognostic when compared with those who did not relapse, 48.23 vs 123.10 months, respectively (P<0.01).

Table 3 A Survival Analysis Conducted by the KaplanMeier Method Showing the Difference in the Means of the Log Rank Test According to the Optimal Upper and Lower Binary Cut-off Limits of Different Variables

Moreover, differences in the genotypes of PD-L1 polymorphisms seemed to also impact the prognosis of NSCLC patients. PD-L1 rs7041009, for instance, led to a statistically significant difference in OS (Figure 1), with carriers of the A allele of rs7041009 having lower OS than carriers of the GG genotype (reference), 59.00 vs 116.93 months, respectively (P<0.01).

Figure 1 KaplanMeier survival curve for PD-L1 rs7041009 G>A. A allele carriers (AG+AA) presented worse prognosis and a lower survival rate when compared to GG genotyped patients (P<0.01).

Next, using a univariate Cox Regression analysis, we were able to associate the following variables with a lower risk of death: the absence of radiotherapy treatment, relapse, and GG genotype of PDL1 rs7041009 (Table 4). However, after feeding these variables into a multivariate analysis, only the absence of radiotherapy treatment and relapse were considered to be independent factors for OS (HR 9.82, P=0.02; HR 6.15, P=0.04, respectively).

Table 4 Variables Associated with Overall Survival (OS) in 70 Patients Diagnosed with NSCLC. Univariate and Multivariate Analyses Employing a Cox Proportional Hazards Model

Then, we introduced the PD-L1 polymorphisms into the Cox model, controlling for radiotherapy treatment and tumor relapse. Of the four SNPs, only rs7041009 was identified as a co-dependent factor associated with radiotherapy and relapse. We thus inferred that patients with NSCLC who carried the A allele (AG/AA) presented a higher risk of relapse in the presence of radiotherapy, resulting in a poorer prognosis and decreased survival rates than patients who carried the rs7041009 GG genotype. In relapsed patients, we observed that the PD-L1 polymorphisms rs7041009 and rs4742098 might have an impact on PPS (Figure 2). Patients with the rs7041009 GG genotype had a higher PPS than those with the alternative A allele of rs7041009 (AG/AA), 110.98 vs 56.18 months, respectively (P<0.01); whereas, patients who carried the reference rs4742098 AA genotype had lower PPS than those who carried the alternative G allele of rs4742098 (AG/GG), 56.00 vs 115.71 months, respectively (P=0.02).

Figure 2 KaplanMeier survival curves estimating post-progression survival (PPS) in NSCLC patients according to PD-L1 polymorphisms. (A) KaplanMeier survival curve for rs7041009 G>A. A allele carriers (AG+AA) presented worse prognosis and a lower PPS rate when compared GG genotyped patients (P<0.01); (B) KaplanMeier survival curve for rs4742098 A>G. G allele carriers (AG+GG) had a higher PPS rate and better prognosis when compared AA genotyped patients (P=0.02).

The in silico analysis predicted the PD-L1 variants rs4742098 (c.*2635A>G), rs4143815 (c.*395G>C), rs2297136 (c.*93G>A), and rs7041009 (c.682+122G>A) to be benign (Table 5). Not only was the DANN score low for all four variants (0.8226, 0.6475, 0.7056, and 0.5428, respectively), but their GERP score was also lower than 5.5 (1.74, 2.38, 4.4, and 1.81, respectively), indicating that these variants are found in non-conserved positions and are unlikely to be harmful.

Table 5 List of the Selected Non-Coding SNP and the Tools Used to Study Them

SNPinfo predicted miRNA-binding function to be affected by two of these variants, namely rs2297136 and rs4143815. Rs2297136 was predicted to affect the binding function of hsa-miR-324-5p and hsa-miR-632, whereas rs4143815 was found to correlate with hsa-miR-1252, hsa-miR-1253, hsa-miR-539, hsa-miR-548, and hsa-miR-570 (Table 6). RegulomeDB was then used to complement the SNP analysis. Three of the four SNPs, rs4742098, rs4143815, and rs2297136, had a RegulomeDB score of 5, whereas rs7041009 had a score of 6, meaning that all four variants show minimal binding evidence (Table 5).

Table 6 List of the 3 UTR SNPs Analyzed in FuncPred and Their miRNA Motif

Lung cancer has a high mortality rate and lacks suitable markers for early diagnosis and prognosis. Thus, it is essential to detect the best potential biomarker out of the several genetic and protein markers. Fortunately for patients, the translational impact of such findings is rapidly increasing, and the stimulation of immune response by ICIs has emerged as a dramatic paradigm shift in the treatment of advanced tumors, mainly NSCLC.19,36 PD1/PDL1 monoclonal antibodies have shown potential efficacy in advanced squamous-cell and non-squamous NSCLC.37,38 However, despite the remarkable success achieved by immunotherapy so far, its effectiveness still seems to vary among cancer patients.19 The expression of PD-L1 on tumor cells remains the only recognized predictive factor for immunotherapy response in NSCLC patients; however, patients without PD-L1 expression on tumor cells may also respond to immunotherapy.3943 Based on these findings, the present study inferred that PD-L1 non-coding genetic variants could help predict the prognosis of patients with NSCLC and impact disease recurrence and OS.

In our cohort of 70 NSCLC specimens, we evaluated PD-L1 protein expression in malignant cells by PD-L1 multiplex immunofluorescence (mIF) assays, using the Cell Signaling E1L3N clone and image analysis, and investigated PD-L1 polymorphisms by NGS sequencing. This method resulted in the detection of high PD-L1 expression in LCC malignant cells when compared to other histological subtypes, suggesting that LCC patients may benefit from ICIs. As described by Shimoji et al,44 PD-L1 expression using the Cell Signaling E1L3N clone was significantly correlated with a consistent vimentin expression, increased Ki-67 labeling index and poor prognosis in ADC but not in SqCC. Other studies have reported that PD-L1 was detected at significantly higher frequencies in SqCC than in ADC of the lung.44,45 Cha et al46 found that PD-L1 expression using the SP142 clone was significantly associated with an ADC solid subtype histology, p53 aberrant expression, and poor prognosis.

We also assessed PD-L1 polymorphisms. Of the fifteen genetic variants genotyped, eleven were monomorphic. The four potential variants (rs4742098, rs4143815, rs2297136, and rs7041009) present in the non-coding region were correlated with the clinicopathological characteristics of the NSCLC patients and were submitted to an in silico analysis investigating their functional role. The MAF of the rs4742098, rs4143815, and rs7041009 polymorphisms was consistent with the genotype frequency among European and Mixed Americans populations present in The 1000 Genomes Project, whereas the G allele in the rs2297136 polymorphism was the main allele in our cohort to show racial differences.

When assessing patient prognosis, three of the four PD-L1 variants rs4742098, rs4143815, and rs7041009 were significantly associated with disease recurrence. Carriers of the G allele (individuals with the AG or GG genotypes) of rs4742098 were less likely to relapse compared to carriers of the homozygous AA genotype. Similar findings were published by Du and colleagues,47 who reported that the AG genotype differed from the AA genotype in terms of risk of NSCLC recurrence. In the case of rs4143815G, patients with the alternative C allele were less likely to relapse in our study, in agreement with Nomizo et als report.48 In their study, the authors even suggested that this polymorphism might be a biomarker for nivolumab efficacy.48 Finally, in our study, for rs7041009G>A, carriers of the alternative G allele were more likely to exhibit relapse. The rs7041009 GG genotype also showed a significant correlation with age, being more present in younger patients, and with status, being more present in patients who are alive, compared to carriers of the A allele. Rs7041009 (c.682+122G>A) is located at position 2377 in intron 4 of the PD-L1 gene. However, little is known about the exact function of this genetic variation, except that it is located near the transcription factor binding site.

Our cohort showed a significant association between these PD-L1 polymorphisms and OS in NSCLC. 18 Patients presenting the GG genotype of rs7041009 benefited from longer OS. In addition, our findings indicated that both the rs7041009G and rs4742098G polymorphisms were significantly related to a longer PPS. The clinical impacts of PD-L1 variants had also been investigated by previous studies. Zhao et al49 suggested that patients with the GG genotype of another PD-L1 polymorphism (rs822336) had worse disease-free survival and OS in a Chinese patient population.

Further contribution was provided in that respect by Lee et al50 who demonstrated that rs4143815 and rs2297136 were significantly associated with clinical outcomes after chemotherapy. Of 379 patients with NSCLC treated with first-line paclitaxelcisplatin chemotherapy, those carrying the rs4143815 G allele responded better to chemotherapy and had gains in overall survival. In our study, however, the polymorphism rs2297136 showed no significant association with clinical outcome, a finding that was corroborated by Zhao et al.49 This difference might be explained by the heterogeneity of patients enrolled in each study, and further research is needed to settle this question.

In our study, we were unable to find any statistical significance between the rs4742098, rs4143815, rs2297136, and rs7041009 genotypes and PD-L1 protein expression in malignant cells. However, recent data have helped to shed light on the impact of PD-L1 genetics on PD-L1 expression, though the existing results remain controversial. Recently, Tao and colleagues51 showed that rs4143815 and rs10815225 in the PD-L1 gene contributed to PD-L1 overexpression in gastric cancer. So far, Lee et al18 have conducted the largest study on PD-L1 polymorphisms and PD-L1 expression in NSCLC. The authors showed that rs822336C, rs822337A and rs4143815G were associated with worse OS in NSCLC patients but found no significant correlation between PD-L1 expression and the genotypes of these polymorphisms. Krawczyk et al52 demonstrated that carriers of the rs822335 CC genotype were predisposed to higher expression of the PD-L1 protein in NSCLC tumor cells, whereas rs822336 had no effect on PD-L1 expression in these cells. Their results are consistent with our findings, but future research is needed to clarify remaining confounders.

In our study, using in silico approaches, we report that rs4742098, rs4143815, rs2297136, and rs7041009 can be considered benign variants. However, little is known about the effect that mutations in conserved non-coding regions might have on fitness and how many of them are present in the human genome as deleterious polymorphisms. Moreover, rs2297136 was predicted to affect the miRNA-binding function of hsa-miR-324-5p and hsa-miR-632, whereas the variant rs4143815 was found to correlate with hsa-miR-1252, hsa-miR-1253, hsa-miR-539, hsa-miR-548, and hsa-miR-570. In this context, others have reported that variants in the 3UTR region of the PD-L1 gene can affect the interaction of miRNAs, possibly resulting in PD-L1 underexpression.53 Therefore, additional studies are necessary to validate our findings. However, there are limitations to our analysis. We did not perform a casecontrol approach and our cohort comprises a relatively small sample size. Nonetheless, to our knowledge, our research on the effect of the rs7041009 polymorphism of PD-L1 gene on NSCLC patients is unique.

We believe this study is also the first to evaluate variants in the non-coding region of the PD-L1 in Brazilian patients with NSCLC, since most studies of PD-L1 polymorphisms have been conducted in Asian patients. Thus, we consider this exploratory study as a pioneer in the understanding of PD-L1 polymorphisms in a genetic admixed population.

We appreciate all subjects who participated in this study and the Illumina members for assistance with the initial runs.

This study was supported by the So Paulo Research Foundation, FAPESP (grant numbers 2013/14277-4 and 2018/20403-6).

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

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[Full text] Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Gene | PGPM - Dove Medical Press

TBINGEN, Germany--(BUSINESS WIRE)--February 19, 2021 -- Illumina, Inc. (Nasdaq: ILMN) today announced an agreement with the Institute of Medical Genetics and Applied Genomics at the University Hospital of Tbingen to assess the value of whole-genome sequencing (WGS) as a first-line diagnostic test for patients with genetic diseases and familial cancer syndromes. Illumina will support the new investigator-initiated study, called the Ge-Med Project, with sequencing, analysis and health economic expertise.

The Institute is the first laboratory in Germany accredited to perform clinical WGS. Previously, it used whole exome sequencing for the diagnosis of rare disease conditions which involves sequencing only around 1% of the genome known to contain the coding regions that provide instructions for making proteins.

The move to WGS is based on a two-year feasibility study by the Institute, supported by Illumina, which found that WGS provided improved diagnosis across a range of rare diseases. For example, as many as 75% of genetic eye diseases were accurately diagnosed using WGS, including some forms of disease that could only be identified by sequencing the entire genome. Similar results were found for rare childhood cancers and for conditions that cause developmental delay in children.

In addition to expanding the range of conditions for diagnosis, the new study will examine the ability of WGS to generate scores for the risk of common diseases based on genomic data. Known as a polygenic risk score, this will help identify individuals that may benefit from personalized healthcare management.

We are delighted to be able to study whole genome sequencing as a diagnostic in an expanded range of conditions because we have demonstrated that it changes the management of patients who previously remained unresolved after whole exome and other sequencing approaches, said Tobias Haack, Head of Molecular Diagnostics at the Institute of Medical Genetics and Applied Genomics, University Hospital of Tbingen.

We are proud to support the University Hospital of Tbingen on this important step in their genomic work, said Dr. Phil Febbo, Chief Medical Officer, Illumina. Offering a clear diagnosis as well as disease risk for common conditions will give patients peace of mind and offer actionable steps to improve their overall health.

Professor Olaf Rie said, We know that the exome isnt the whole story when looking for answers to rare diseases and we have proven the value that WGS brings to families who otherwise would wait years for a diagnosis, or may never even receive one. Through the new study, we hope to help Germany lead the way in applying cutting edge genomics to improve healthcare.

About Illumina

Illumina is improving human health by unlocking the power of the genome. Our focus on innovation has established us as the global leader in DNA sequencing and array-based technologies, serving customers in the research, clinical, and applied markets. Our products are used for applications in the life sciences, oncology, reproductive health, agriculture, and other emerging segments. To learn more, visit http://www.illumina.com and connect with us on Twitter, Facebook, LinkedIn, Instagram, and YouTube.

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Illumina and the University Hospital of Tbingen Evaluate Potential of Whole Genome Sequencing to Improve Diagnosis of Full Range of Genetic Diseases -...

SALT LAKE CITY, Feb. 12, 2021 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc.. (NASDAQ: MYGN), a leader in genetic testing and precision medicine, announced today additional data further validating the prognostic power of its Prolaris test and its ability to help accurately predict which men with more aggressive prostate cancer will benefit from intensification of therapy and which patients may safely avoid such treatments. This second validation study was presented during an oral presentation at the American Society of Clinical Oncology Genitourinary Cancer Symposium (ASCO-GU) by Jonathan Tward M.D., Ph.D, associate professor in the Department of Radiation Oncology at the University of Utah.

According to estimates by the American Cancer Society, 248,530 new cases of prostate cancer are expected to be diagnosed this year in the U.S. While early screening tests have helped reduce the mortality rate, they can often result in overdiagnosis and overtreatment of a disease that is clinically insignificant. The Prolaris test can more accurately predict the aggressiveness of the cancer allowing for more precise treatment and avoidance of more intense therapies with a patients parallel morbidities.

There are many viable treatment paths for men with prostate cancer, said Dr. Tward. This new data helps distinguish the most appropriate personalized treatment path for each patient based on how their specific tumor is behaving. For some men, this means being able to avoid overtreating patients with therapies including hormone treatment that can momentously impact their quality of life, while still appropriately treating their prostate cancer.

The new data comes from a second study following previous data, recently published in Clinical Genitourinary Cancer in January 2021, that incorporated men treated surgically or with radiation therapy. This new study combined a Prolaris molecular risk score threshold with a clinical model for predicting a patients benefit from androgen deprivation therapy. Prolaris determined that about one of every two men with unfavorable intermediate-risk and one of every five men with high-risk prostate cancer are below the proposed threshold associated with aggressive disease and can therefore safely be treated with less intense therapy while maintaining the benefits of treatment. Additional key findings revealed that the Prolaris test was an accurate predictor of progression to metastatic disease.

Myriad Genetics was the first company to offer a test that directly measures the molecular biology of an individual patients prostate cancer, said Todd D. Cohen, M.D., vice president of Medical Affairs for Urology at Myriad Genetics. This study by Dr. Tward and his team is another strong validation of the prognostic power of the Prolaris test and our ongoing commitment to providing healthcare professionals with the tools needed to determine the most effective treatments and monitoring strategies for each patient.

In March 2020, the National Comprehensive Cancer Network updated its professional guidelines to include biomarker testing for unfavorable intermediate and high-risk patients with prostate cancer. With the updated guidelines, Prolaris was one of only two prognostic tests to be considered for those expanded indications. Approximately 60% of men with prostate cancer currently have insurance or Medicare access to Prolaris, and Myriad continues to work toward expanding access so that every man who is facing difficult treatment decisions will be able to utilize the full benefits of the test.

About ProlarisProlaris is a genetic test developed by Myriad Genetics that directly measures tumor cell growth. The Prolaris test paired with other clinical and pathologic variables provides the level of aggressiveness of a patients individual prostate cancer and assesses risk of death or the development of metastatic disease from prostate cancer. For more information visit: http://www.prolaris.com.

About Myriad GeneticsMyriad Genetics Inc., is a leading genetic testing and precision medicine company dedicated to transforming patient lives worldwide. Myriad discovers and commercializes genetic tests that determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across medical specialties where critical genetic insights can significantly improve patient care and lower healthcare costs. For more information, visit the Company's website:www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor StatementThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to the validation study presented during at ASCO-GU by Jonathan Tward M.D., Ph.D; expanding access so that every man who is facing difficult treatment decisions will be able to utilize the full benefits of the Prolaris test; and the Companys strategic directives under the caption "About Myriad Genetics." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties associated with COVID-19, including its possible effects on our operations and the demand for our products and services; our ability to efficiently and flexibly manage our business amid uncertainties related to COVID-19; the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions in Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading "Risk Factors" contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2020, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

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New Study from Leading University of Utah Radiation Oncologist Validates Ability of Myriad Genetics' Prolaris test to Guide Treatment for Prostate...

Linda Chalker-Scott

By Brian C. Clark

From sourdough to home-improvement projects, the coronavirus pandemic has inspired a renaissance in quotidian creativity.

Gardening, too, has blossomed in popularity in the past year and thats a good thing, said Linda Chalker-Scott, an urban horticulturist and professor in the Washington State University Department of Horticulture. Gardening, she said, is great for your mental, physical, and spiritual wellbeing.

Chalker-Scotts latest book is a perfect fit for the times.

Gardening with Native Plants of the Pacific Northwest was recently published in a much revised and updated third edition to great acclaim. The lavishly illustrated book won the 2020 Award of Excellence in Gardening and Gardens from the Council on Botanical and Horticultural Libraries, while Chalker-Scott garnered the R.W. Harris Authors Citation Award from the International Society of Arboriculture.

Gardening with Native Plants was originally published in 1986 by the University of Washington Press and authored by longtime UW botanist Arthur Kruckeberg, with a second revised edition in 2006. The third edition, Chalker-Scott said, was a monumental, eight-year project.

An internationally recognized expert on the science of gardening, Chalker-Scott is also a prolific writer. Shes a founding member of the highly regarded Garden Professors blogging team, which answers gardeners questions (and busts gardening myths) with science, and the author of numerous Extension publications covering a wide variety of gardening and plant-health related topics.

Chalker-Scott was tapped by the UW Press editorial team to revise the book for a new edition. Given her expertise, she was the natural choice. I was very flattered. I brought the practical science behind gardening to the new edition, she said, and relied on a team of experts to make the book something totally new.

Chalker-Scott said she knew Art Kruckeberg socially when she was a faculty member at UW in the late 90s and early 00s. He was already retired, she said. The first and second editions of Gardening with Native Plants were always best sellers, but by the time for a third edition, he was in his 90s.

When it was published 35 years ago, Kruckebergs original edition had descriptions and black and white illustrations of some 250 plants. The third edition describes a whopping 900 plants, all with color photos that had to be sourced. To further complicate matters, molecular genetics in the past couple of decades has overturned our understanding of the relatedness of plantschanging the names of entire families of plants, much to the frustration of gardeners and scientists alike, Chalker-Scott writes in the preface.

Richard Olmstead, a UW biologist, wrote the foreword for the new edition and guided the taxonomic revisions, providing both new and old scientific names.

Nearly a thousand color photos were donated for use in the book, a monumental task curated by Sami Gray. Chalker-Scott said she met Gray through the Garden Professors Facebook group, a stroke of serendipitous luck that also resulted in Gray writing descriptions of the new plants. Samis a great writer in her own regard, Chalker-Scott said, who was able to channel Arts voice so closely that you will be hard-pressed to identify which entries are hers and which are Arts. I cant believe how lucky I was to find her.

One thing that has been omitted from the new edition is the location of native plant populations. Harm has been done all over the world by native-plant collectors, Chalker-Scott said. Art would describe locations and how to collect seeds without digging them up, but, she adds, while most collectors are ethical, it only takes a tiny minority to decimate and damage a microenvironment due to encroachment. Besides, native plant nurseries are by definition local, so support them. Theres lots of information on how to propagate native plants in home gardens.

Chalker-Scott said she has always been a gardener but never got into the science of it until she realized how very little scientific information was available. In addition to her many short pieces that explode gardening myths (and which have been collected in two volumes by the UW Press), she is also the author of How Plants Work, a sublimely accessible explanation of plant growth and development, health, and photosynthesis. Her free Extension publication on scientific literacy for citizen scientists is a must read in an era of conspiracy folklore gone wild and is used in courses on the philosophy of science.

When we return to normal, Chalker-Scott said, I hope people dont give up gardening. When youre able to understand the science, you dont get frustrated and you dont waste money.

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Gardening with Native Plants book inspires perennial passions | WSU Insider | Washington State University - WSU News

New pathways in plants and microbes

Plants and microbes have interacted through evolution in ways that shaped diversity and helped plants colonize land. Delaux and Schornack review how insights from a range of plant and algal genomes reveal sustained use through evolution of ancient gene modules as well as emergence of lineage-specific specializations. Mosses, liverworts, and hornworts have layered innovation onto existing pathways to build new microbial interactions. Such innovations may be transferrable to crop plants with an eye toward building a more sustainable agriculture.

Science, this issue p. eaba6605

Microbial interactions have shaped plant diversity in terrestrial ecosystems. By forming mutually beneficial symbioses, microbes helped plants colonize land more than 450 million years ago. In parallel, omnipresent pathogens led to the emergence of innovative defense strategies. The evolution of plant-microbe interactions encompasses ancient conserved gene modules, recurrent concepts, and the fast-paced emergence of lineage-specific innovations. Microbes form communities on the surface or inside plant tissues and organs, and most intimately, microbes live within single plant cells. Intracellular colonization is established and controlled in part by plant genes that underpin general cell processes and defense mechanisms. To benefit from microbes, plants also evolved genetic modules for symbiosis support. These modules have been maintained despite the risk of getting hijacked by pathogens.

The hundreds of land plant and algal genomes that are now available enable genome-wide comparisons of gene families associated with plant immunity and symbiosis. Reconstruction of gene phylogenies and large-scale comparative phylogenomic approaches have revealed an ancient subset of genes coevolving with the widespread arbuscular mycorrhiza symbiosis, the most ancient plant intracellular symbiosis, and with other types of more recently evolved intracellular symbioses in vascular and nonvascular plants. Intercellular symbiotic interactions formed with cyanobacteria or ectomycorrhizal fungi seem to repeatedly evolve through convergent, but not necessarily genetically conserved, mechanisms. Phylogenetic analyses revealed occurrence of candidate disease-resistance genes in green algae, as well as orthologs of flowering plant genes involved in symbiosis signaling and sensing microbial patterns. Yet, more research is needed to understand their functional conservation.

The extent to which conserved symbiosis genes also fulfill often opposing roles during pathogen-plant interactions is being explored through studies of pathogen infections in plants capable of supporting symbiotic relationships. The development of plant-microbe systems in genetically tractable species covering the diversity of land plant lineagesincluding angiosperms and bryophytes, such as the liverwort Marchantia polymorphamakes it possible to test hypotheses that emerge from phylogenetic analyses, linking genetic and functional conservation across land plants. Studies in bryophytes illustrate the range of possibilities for pathogen management: ancient genes, such as membrane receptors that perceive fungus-derived chitin; pathways with bryophyte cladespecific components, such as phenylpropanoid-derived auronidin stress metabolites; and jasmonate-like hormonal signaling for immunity.

Only a few plant-microbe interactions have been studied in depth, and those in only a few land plant lineages. Future investigations of interactions occurring across the diversity of plants may unravel new types of symbiotic or pathogenic interactions. The occurrence of microbe-sensing genes in streptophyte algae, harboring the closest algal relative to land plants, suggest the existence of overlooked and potentially ancient symbiotic associations. Genetically tractable plant-microbe model systems in diverse streptophyte algae, hornworts, liverworts, ferns, and the so far unsampled diversity of seed plants will enable dissection of the spectrum of molecular mechanisms that regulate the breadth of interactions occurring in plants. The actual function of the symbiotic genes present in bryophyte genomes also remains to be determined. Furthermore, our understanding of plant-microbe interactions will be enriched by more often combining evolutionary concepts with mechanistic studies. More efforts are needed to decipher the molecular changes that have enabled the emergence of new interactions, signaling pathways, and enzymatic specificities to support symbiosis and to protect against pathogens. Microbes manipulate plant processes, and complementary microbial studies are key to gaining a complete picture of plant-microbe evolution. Knowing the rules of engagement between distantly related plants and their microbes then helps genetic transplantation approaches into crops and the orthogonal engineering of bioprocesses aimed at achieving quantitative resistance against pathogens, improving phosphate uptake, or establishing nitrogen-fixing associations for efficient use in sustainable agriculture.

Some pathogens such as oomycetes are able to infect a wide range of extant plant lineages, including bryophytes (left), and plant pathogen interactions often evolve at a fast pace. By contrast, some symbiotic interactions that look exactly as they do today can be found in the most ancient land plant fossils, here depicted as an illustration of the Rhynie chert fossil plant Aglaophyton major (right). Still, both types of plant-microbe interactions feature evolutionarily ancient as well as rapidly evolving aspects. Extending plant-microbe studies across diverse groups of plant lineages has enriched our understanding of these processes and their evolution.

During 450 million years of diversification on land, plants and microbes have evolved together. This is reflected in todays continuum of associations, ranging from parasitism to mutualism. Through phylogenetics, cell biology, and reverse genetics extending beyond flowering plants into bryophytes, scientists have started to unravel the genetic basis and evolutionary trajectories of plant-microbe associations. Protection against pathogens and support of beneficial, symbiotic, microorganisms are sustained by a blend of conserved and clade-specific plant mechanisms evolving at different speeds. We propose that symbiosis consistently emerges from the co-option of protection mechanisms and general cell biology principles. Exploring and harnessing the diversity of molecular mechanisms used in nonflowering plant-microbe interactions may extend the possibilities for engineering symbiosis-competent and pathogen-resilient crops.

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Plant evolution driven by interactions with symbiotic and pathogenic microbes - Science Magazine