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Bruker Introduces Breakthrough MALDI-2 Source on timsTOF fleX, and Further Innovations in CCS-Enabled 4D Proteomics on timsTOF – Business Wire

BILLERICA, Mass.--(BUSINESS WIRE)--At the virtual ASMS 2020 Reboot conference, Bruker Corporation (Nasdaq: BRKR) today announces a major advance in matrix-assisted laser desorption ionization (MALDI) with the launch of the worlds first commercial MALDI-2 post-ionization (PI) source, which is now available as an option on the timsTOF fleX ESI/MALDI mass spectrometer. The novel MALDI-2 technology can offer one or two orders of magnitude higher sensitivity for many small molecules and lipids. MALDI-2 increases the applications range of MALDI mass spectrometry and imaging even further.

Moreover, Bruker launches additional unique TIMS/PASEF-enabled 4D proteomics methods that leverage the large-scale, real-time availability of accurate collision cross sections (CCS) for tens of thousands of measured peptides per 4D nanoLC-CCS-MS/MS run. These new methods and software include prm-PASEF, short-gradient dia-PASEF, MOMA, and Run and Done proteomics using a novel GPU-based real-time search engine. In addition to further enhanced peptide, protein and PTM identification, these CCS-enabled innovations allow for sustained, ultra-high sensitivity LFQ performance, and for truly high-throughput methods for 4D proteomics, 4D lipidomics and 4D metabolomics on the exceptionally robust timsTOF Pro platform.

A. SpatialOMx and Translational Mass Spectrometry Imaging on timsTOF fleX

The innovative MALDI-2 PI source increases both the sensitivity and range of applications of MALDI very significantly. MALDI-2 requires a second laser (266 nm) fired orthogonally into the expanding MALDI plume that is generated by Brukers proprietary primary SmartBeam 3D (355 nm) laser. An optimized flexMatrix formulation is recommended for MALDI-2. The new MALDI-2 source is now available as an option on the timsTOF flex ESI/MALDI instrument.

Professor Klaus Dreisewerd, Leader Section for Biomedical Mass Spectrometry at the University of Muenster in Germany, and the pioneer of MALDI-2, said: In the last 35 years, MALDI has become a unique and rapid analytical tool for a wide variety of applications. We developed MALDI-2 to significantly extend the technique by providing much higher sensitivity for small molecules, and the inclusion of chemical classes that did not ionize efficiently with MALDI. The MALDI-2 powered timsTOF fleX will take MALDI to new scientific and analytical frontiers.

Dr. Michael Easterling, Global MS Imaging Director at Bruker Daltonics, added: The growing value of MALDI Imaging and SpatialOMx for tissue-specific models in drug development drives demand for even higher sensitivity and versatility. With its dramatically increased sensitivity and accessible range of chemical classes, the novel MALDI-2 source option can now further enhance mass spectrometry-based, non-targeted tissue analysis.

Bruker now also offers a MALDI-2 compound reference library for its MetaboScape metabolomics software, which was created during various academic and pharma collaborations. MetaboScape provides automatic analyte annotation within the SCiLS Lab MALDI imaging software, including CCS-algorithms that improve the confidence of annotation for many metabolites, glycans and lipids directly in tissue images.

B. CCS-Enabled 4D Proteomics Innovations on timsTOF Platform

prm-PASEF for Translational Quantitative 4D Proteomics

Brukers revolutionary timsTOF Pro has been further enhanced by combining PASEF with parallel reaction monitoring (PRM) for label-free quantitative proteomics. This unique mode of prm-PASEF takes advantage of the 4th dimension of separation using TIMS to improve selectivity and sensitivity, combined with the speed of PASEF to increase the number of precursor targets. Working closely with the Skyline team to enable prm-PASEF methods, Skyline software can now analyze the prm-PASEF data and produce quantitative reports.

The group of Prof. Gunnar Dittmar from the Luxembourg Institute of Health and Prof. Antoin Lesur, who both worked on the prm-PASEF workflow development, commented: We have been extremely impressed by the early results from prm-PASEF on the timsTOF Pro in our lab. The sensitivity and speed of prm-PASEF already rivals that of PRM methods that have been developed over many years on other platforms.

Dr. Jarrod Marto, Associate Professor at the Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Womens Hospital added: We have made tremendous progress since initiating co-development of prm-PASEF with the Bruker Team. The unique combination of acquisition speed and integrated ion mobility on the timsTOF Pro enable us to robustly quantify potential biomarker candidates across clinical cohorts. Moreover, real-time adjustment of acquisition parameters with prm-PASEF LIVE will push usability and throughput even further.

Large-Scale, High-Precision Peptide CCS Measurements for Deep Learning

Peptide collisional cross sections (CCS) measured at large scale and with high precision by the unique TIMS technology deliver added dimensionality for increased confidence of identification in 4D proteomics. A new study by Florian Meier et. al., entitled Deep learning the collisional cross sections of the peptide universe from a million training samples, and submitted to bioRxiv, (2020.05.19.102285; doi: https://doi.org/10.1101/2020.05.19.102285), uses a deep learning training set of 570,000 CCS values measured in 360 LC/MS runs of fractionated digests of five organisms, run on a timsTOF Pro system.

Professor Matthias Mann, Director at the Max Planck Institute of Biochemistry, Germany, commented: The size and shape of peptide ions in the gas phase are an under-explored dimension for mass spectrometry-based proteomics. CCS values can now be predicted for any peptide and organism, forming a basis for advanced proteomics workflows that make full use of the additional information.

Short-gradient dia-PASEF and Mobility Offset Mass Aligned (MOMA) for 4D Proteomics

New short-gradient methods have been developed using the dia-PASEF workflow, which is finding increasing use in many timsTOF Pro labs. Dia-PASEF can provide a meaningful advance in data completeness, and the dia-PASEF workflow is now supported by Bioinformatics Solutions Inc. PEAKS and Biognosys Spectronaut software.

Dr. Lukas Reiter, Chief Technology Officer of Biognosys commented: With the Spectronaut 14 launch, we have complete support for the timsTOF Pro: Fast library generation from PASEF and ion mobility calibration for a more specific targeted extraction in Spectronaut. Furthermore, we have added directDIA support for the timsTOF Pro. We are also excited to have a timsTOF Pro in our lab to further speed up our software development for this new and exciting platform.

Dr. Gary Kruppa, Vice President for Proteomics at Bruker Daltonics, added: With the launch of prm-PASEF, the growing success of dia-PASEF, and the trend towards shorter gradients that take advantage of the robustness, sensitivity and unmatched duty-cycle of PASEF, the timsTOF Pro provides the capabilities to make 4D-proteomics translational reality. Furthermore, the unique MOMA feature of TIMS allows for targeting isobaric precursors at similar retention times for MS/MS acquisition. Having MOMA capability helps improve the depth of coverage using short gradients, and this is important to our translational research proteomics users who are running >50 samples per day per timsTOF Pro.

Run & Done Real-Time Search Developed by Yates Lab for High-Throughput 4D Proteomics

Bruker announces the availability of the proteomic pipeline (IP2) with a GPU-based search engine incorporating the ProLuCID database search tool from the laboratory of Professor John Yates at The Scripps Research Institute based in LaJolla, CA. This unique GPU-based IP2 software has been developed by Dr. Robin Park and allows timsTOF Pro 4D data to be searched in real-time during acquisition, with search results available at the end of the run.

Prof. John Yates III and Dr. Robin Park said: The co-evolution of computational advances with mass spectrometry sensitivity and scan speed have enabled more accurate, large-scale data analysis approaches that help answer many biological questions. GPU-based search engines designed to simultaneously execute many parallel instruction threads can reduce search times to the point where the search results can be converted into real-time input to drive tandem MS acquisition. This becomes an exciting part in our partnership with Bruker, as it will utilize the timsTOF Pro even more intelligently.

Dr. Rohan Thakur, Executive Vice President of Life Sciences Mass Spectrometry at Bruker Daltonics, added: The IP2/GPU solution provides a software infrastructure thats amenable to supporting plug-in applications from our third-party software partners that take advantage of high-performance cluster or cloud capabilities. We are committed to our strategy of open data file formats to facilitate community-driven software development, including our third-party partners through API access for the benefit of the timsTOF user community.

Featured speakers at our eXceed symposia and breakfast events. For more detailed information on our eXceed Symposia and Breakfast Workshops please visit http://www.bruker.com/events/2020/asms-2020-reboot.

Bruker will host a virtual scientific and trade press conference on Monday, June 1st, 2020, at 8:00 am CDT, including Bruker management and guest speaker Professor John Yates.

Customers are invited to visit Brukers ASMS 2020 Reboot virtual hospitality suite throughout the conference.

About Bruker Corporation (Nasdaq: BRKR)

Bruker is enabling scientists to make breakthrough discoveries and develop new applications that improve the quality of human life. Brukers high-performance scientific instruments and high-value analytical and diagnostic solutions enable scientists to explore life and materials at molecular, cellular and microscopic levels.

In close cooperation with our customers, Bruker is enabling innovation, improved productivity and customer success in life science molecular research, in applied and pharma applications, in microscopy and nanoanalysis, and in industrial applications, as well as in cell biology, preclinical imaging, clinical phenomics and proteomics research and clinical microbiology. For more information, please visit: http://www.bruker.com.

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Bruker Introduces Breakthrough MALDI-2 Source on timsTOF fleX, and Further Innovations in CCS-Enabled 4D Proteomics on timsTOF - Business Wire

Some autoimmune diseases are work of overzealous T cells, researchers say – The Times of Israel

Israeli researchers say they have found that autoimmune diseases, such as diabetes or thyroid dysfunctions, are generated by immune cells that become overzealous in their protective mission and end up causing harm and they created a mathematical model that demonstrates this.

In a study published in Immunity, scientists at Rehovots Weizmann Institute of Science, decided to find out why some organs are susceptible to autoimmune diseases while others are not. For example, the thyroid gland is often attacked by the autoimmune disease thyroiditis an inflammation of the thyroid gland that can cause fatigue, weight gain, confusion and depression while other organs, like the parathyroid gland, in charge of regulating the amount of calcium in the blood and bones, are almost never hit by autoimmune diseases.

Our model suggests that immune cells play an important role in healthy people, because they clear away mutant cells that secrete too many hormones, said Yael Korem Kohanim, a research student who led the study. It is when this process goes wrong that people develop an autoimmune disease.

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Korem Kohanim works in the lab of Prof. Uri Alon in the Institutes Molecular Cell Biology Department.

Illustrative image of a woman checking blood sugar levels; type-1 diabetes is an autoimmune disease that affects one organ (Ta Nu; iStock by Getty Images)

Autoimmune diseases can be divided into two types: systemic ones like lupus that attack many organs in the body, and the ones like type-1 diabetes that affect just one organ. One of the biggest questions about this second, organ-specific type of autoimmune disease is why some organs get the diseases while others do not.

These organ-specific autoimmune diseases tend to follow a similar pattern: They are found in children or young adults and they involve the destruction of cells that secrete hormones that are essential to good health. In people with autoimmune disease, immune cells called T cells somehow identify these essential hormone cells as dangerous and eradicate them on contact.

In their study, Korem Kohanim, Alon and other researchers decided to find out why this is and if T cells, in charge of protecting us from diseases by regulating our immune response, are tasked naturally to kill these cells.

Yael Korem Kohanim, research student at the Weizmann Institute (Courtesy)

They hypothesized that T cells may act as an extra layer of protection to make sure that the amounts of essential hormones secreted by the cells stay within narrow limits: both too little and too much of these hormones, such as insulin, thyroid hormones, and cortisol, can be damaging.

When demand for the hormone rises for example, a demand for insulin when glucose is sensed in the blood cells not only increase production of the hormone, they ramp up cell division to help meet that demand.

But cell division carries risks, as a certain percentage of the new cells is likely to carry mutations. Most such mutations are harmless, but if somehow a cell misreads the demand for insulin as high instead of low, the result can be deadly: the cell will continue not only to pump out extra hormones, it will divide again and again to produce new cells with the same mutation, which will then divide again and produce even more of the hormone.

The role of T cells thus could also be to curb the over-secreting cells in healthy organs, by removing cells that threaten to secrete too much hormone. The scientists thus hypothesized that in the case of autoimmune diseases, the T cells might be primed to accomplish the task of curbing the hormones but get overzealous and kill off non-mutant cells as well.

To determine if their hypothesis was reasonable, the researchers created a mathematical model for the functioning of healthy organs in which T cells help to keep hormone levels where they should be.

The model backs up the hypothesis, and shows that the organs stay fit and productive as long as the T cells continue to be highly selective and most of their targets are mutated cells. When they are too active, the organs are stricken by an autoimmune disease, the model shows.

Illustrative image of a weighing scale, balance (artisteer; iStock by Getty Images)

Thus, the researchers say, autoimmune diseases could be the result of a trade-off: on one hand T cells are meant to prevent the overproduction of hormones, but on the other hand they could cause a reduced production in some people, if they become too active.

We think that autoimmune diseases do not come out of nowhere, said Korem Kohanim. They are a malfunction, but one of a physiological system that is already in place.

Some people are more prone to this T cell over-activity, she said, due to a variety of risk factors like viral inflammations or genetics.

The scientists also looked at whether organs that do not develop autoimmune diseases do not have T cell protection. And indeed they dont. That is why these organs dont get autoimmune diseases, but they do suffer from illnesses due to the hyper-secretion of hormones.

The parathyroid gland, for example, explained Korem Kohanim, doesnt get autoimmune diseases but does get a disease called primary hyperparathyroidism in which a benign tumor of parathyroid cells secretes too much of the hyperparathyroid hormone.

Now the scientists want to see via experiments if their claims can be proven.

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Some autoimmune diseases are work of overzealous T cells, researchers say - The Times of Israel

Boundless Bio Presents Data Assessing the Relationship Between Extrachromosomal DNA and Biomarker Signatures Associated with Response to Checkpoint…

SAN DIEGO--(BUSINESS WIRE)--Boundless Bio, a company interrogating and targeting extrachromosomal DNA (ecDNA) in aggressive cancers, today will present data at the 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting that highlight ecDNAs relationship with biomarkers associated with response to immunotherapy in gastric cancer and therefore the importance of identifying ecDNA patient populations.

The poster, Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to checkpoint inhibitor treatment in gastric cancer patients, will be presented on Friday, May 29, in ASCOs Developmental Therapeutics Immunotherapy session. The presentation can be accessed starting at 8:00 a.m. EDT (Abstract 3123, Presentation 187) as part of ASCOs on-demand content; ASCO is being held virtually this year due to COVID-19.

ecDNA are identified with high frequency across many solid tumor types and thought to be one of the key drivers of the most aggressive cancers specifically, those cancers characterized by high copy number amplifications of oncogenes. Tumors enabled by ecDNA have a distinct fitness advantage of producing multiple oncogene copies, which drives tumor aggressiveness, rapid progression, and resistance to standard treatment options.

The analysis being presented today demonstrates that the presence of ecDNA in gastric cancer is negatively associated with biomarkers typically associated with response to checkpoint inhibitor therapies. The implication is that the presence of ecDNA in solid tumors potentially renders these cancers unresponsive to immunotherapy and highlights the importance of creating therapies that directly address cancer cells ability to employ ecDNA to grow and resist standard of care treatments, said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. Boundless Bio is committed to continuing to elucidate the role of ecDNA in cancer biology, oncogene amplification, and tumor adaptability and to bringing the first medicines leveraging these insights to patients with intractable cancers.

Study Details

The analysis examined whether patients with gastric tumors that possess ecDNA represent a subset of patients that lack biomarkers associated with clinical response to anti-PD-1 checkpoint inhibitor therapy. Boundless Bio researchers employed computational analysis to determine the ecDNA status of a cohort of gastric cancer patients (N = 108) whose whole genome sequencing data were publicly available in The Cancer Genome Atlas (TCGA). The cohort was grouped into five molecular subtypes:

Additionally, the relationships among the molecular subtypes above and common biomarker signatures associated with response to checkpoint inhibitors were assessed:

The analysis found that 32% of gastric cancer patients in the cohort were positive for ecDNA signatures, and those ecDNA+ patients were mutually exclusive from the 23% of patients who showed MSI high (MSI-H), which is associated with response to checkpoint inhibitors, such as pembrolizumab, in gastric cancer. Further, it found that the ecDNA-positive subtype had statistically significantly lower TIS than all of the other molecular subtypes (p-value < 0.05), except for the tumors marked by the CIN subtype (p-value = 0.09). The ecDNA-positive subtype also had lower PD-L1 expression than all the other molecular subtypes but the GS and CIN subtypes.

Overall, the analysis demonstrated that patients whose tumors are ecDNA positive are a unique population that displays a signature that lacks the hallmark biomarkers that predict response to checkpoint inhibitor therapy, implying that ecDNA+ patients may not respond to standard of care immunotherapies. Boundless Bio is developing novel therapeutic strategies directed to mechanisms critical for ecDNA function in cancer.

About ecDNA

Extrachromosomal DNA, or ecDNA, are large circles of DNA containing genes that are outside the cells chromosomes and can make many copies of themselves. ecDNA can be rapidly replicated within the cell, causing high numbers of oncogene copies, a trait that can be passed to daughter cells in asymmetric ways during cell division. Cells have the ability to upregulate or downregulate ecDNA and resulting oncogenes to ensure survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells primary mechanisms of recurrence and treatment evasion. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

About Boundless Bio

Boundless Bio is a biotechnology company focused on interrogating a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies to patients with previously intractable cancers. For more information, visit http://www.boundlessbio.com. Follow us on LinkedIn and Twitter.

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Boundless Bio Presents Data Assessing the Relationship Between Extrachromosomal DNA and Biomarker Signatures Associated with Response to Checkpoint...

Board elects two members, honors three life trustees – University of Rochester

May 26, 2020

At a virtual May meeting, the University of Rochester Board of Trustees elected two new board members and recognized three individuals who become life trustees.

I am thrilled to welcome Betsy Ward and Martin Sanders to the board, said Board Chair Rich Handler 83. Its during an unprecedented time in the Universitys history that they are joining us, and their expertise and commitment to the University are needed now more than ever. I also want to express my gratitude to our new life trustees for their distinguished service over many years. We look forward to their continued engagement with the University.

University President Sarah Mangelsdorf said, I wish to welcome our newly elected members to the board and thank them in advance for their commitment. Im also very grateful to our newest life trustees, all of whom have made invaluable contributions to the University and provided wise counsel and support to me in my first year as president.

With current circumstances resulting from the COVID-19 pandemic, both new and life trustees will be recognized in person at a later date.

Martin Sanders is cofounder and CEO of Io Therapeutics, Inc., a privately held company based in Santa Ana, California, that develops treatments for Parkinsons disease, Alzheimers disease, multiple sclerosis, and various cancers. He is also the executive chairman of the companys board of directors.

Sanders, a medical doctor, has had a long career in clinical medicine, basic laboratory research in immunology, drug discovery research, pharmaceutical product development, patient care, venture capital investment, and serial company formation in the life sciences. He holds many patents, including one that was granted in March 2020 for treating nervous system disorders. Dedicated to bringing new treatments to people suffering from Parkinsons disease, cancer, migraines, and blindness, he has served as an advisor to more than 50 biopharmaceutical companies in the areas of preclinical and clinical product development since 1992.

Sanders is a passionate supporter of the arts and believes that art and music play a role in good health. In 2018, he and his wife, Corazon, established the Martin E. and Corazon D. Sanders Professorship in Voice at the Eastman School of Music in appreciation of their daughter, Lauras, voice teacher. Laura earned her bachelors degree in 2016 and a masters degree in 2018 in voice and opera from Eastman. Through the Sanderss generosity, Eastman celebrated the first installation of a performance faculty member into an endowed position. In addition, Martin Sanders is a member of the Eastman School of Music National Council and the University of Rochester Volunteer Task Force.

He received his medical degree from the University of Chicago; served as an intern and resident in internal medicine at Washington University Medical Center in St. Louis; and completed three postdoctoral fellowships in allergy/clinical immunology at the National Institute of Allergy and Infectious Diseases, in rheumatology at Johns Hopkins Medical School, and in cancer immunology at the immunology branch of the National Cancer Institute. He is board certified in internal medicine and in subspecialties allergy/clinical immunology and rheumatology.

Elizabeth (Betsy) Ward 86 is the chief financial officer at MassMutual, leading the finance department at the nearly 170-year-old life insurance company into a new era, with a focus on connecting finance to broader strategic planning. Before becoming CFO in 2016, she held several prominent positions at the Springfield, Massachusettsbased company, including chief enterprise risk officer and managing director at a couple of their subsidiary asset management firms.

Ward serves on the US Department of the Treasurys Federal Advisory Committee on Insurance and has been a member of the American Academy of Actuaries and the Fellow Society of Actuaries since the early 1990s. She has been a key contributor to global risk management through her work leading various industry groups. She has also served on federal committees on supervisory requirements and research, focusing on the effective groupwide supervision of insurance groups and seeking to narrow the gaps among global regulatory regimes.

Ward earned a bachelors degree in economics and Spanish from the University, while also studying flute through lessons at the Eastman School of Music. Music continues to play an important role in her life. She serves on the board of directors of the Community Music School of Springfield and continues to perform on flute in local classical ensembles, and as an alto singer with chamber choirs and chorales in Connecticut and Massachusetts.

In November 2019, Ward was the keynote speaker at the Universitys Simon Womens Conference. In 2012, she was named by Diversity Journal as a Woman Worth Watching in Financial Services, and in 2014, she was cited by Insurance Risk magazine as CRO of the Year.

At the May meeting, the board approved the transition of three individuals to life trustee status. Together the individuals have provided years of distinguished service to the board and their philanthropy has supported the creation of new facilities, scholarships, professorships, and other initiatives throughout the University.

Kathleen Murray 77 has been a board member since 2010, serving at different times on the Academic Affairs, Audit and Risk Assessment, Executive, Facilities, Human Resources, and Nominations and Board Practices committees. In her role as trustee, she has lent her business expertise to assist leadership in complex strategic, financial, and managerial issues, as well as supported key University goals through service on the Diversity Advisory Council, the NY Metro Women Steering Committee (for which she is chair emeritus), River Campus Libraries National Council, and Meliora Campaign Cabinet Chair.

In Arts, Sciences & Engineering, she established the Kathleen McMorran Murray 74 Endowed Scholarship Fund and Rochester Annual Fund. She has also exemplified generosity to other units of the University, particularly to the College Annual Fund, Diversity Program Fund, and the River Campus Libraries Annual Fund.

Francis Price 74, 75S (MBA) has provided business, financial and strategic advice to the University since he joined the Board in 1995. He has served on the Academic Affairs, Executive, Executive Alternate, Financial Planning (now Strategic and Financial Planning), Health Affairs, Nominations and Board Practices, and Student Affairs (now Student Life) committees during his tenure.

Price has additionally served on the Memorial Art Gallery Board of Managers, Diversity Initiative Campaign Committee; Hajim School of Engineering Visiting Committee; Los Angeles Regional Cabinet; and the Multicultural Alumni Advisory Council Executive Committee. In 2016, he volunteered his time to serve as the inaugural chair of the Public Safety Review Board.

He has generously supported the David T. Kearns Center, African-American Institute Gift Account, and the College Annual Fund.

E. Philip Saunders has provided distinguished service to the University as a member of the Board of Trustees since 2015. He has encouraged valuable discussions and principled engagement in a wide range of issues affecting the University. He has served with distinction on the Health Boards Affairs Committee, and served as Rochester Philanthropy Council chair; Medical Center Campaign Cabinet cochair; Medical Center Meliora Campaign vice-chair; and George Eastman Circle Rochester Leadership Council chair.

Saunders has provided extraordinary philanthropic support to the University. In 2011, he contributed $10 million to the University of Rochester Medical Center to support neuromuscular disease and translational research. The Saunders Research Building, home to the Clinical and Translational Science Institute, clinical research programs, and academic departments, was named in his honor. His gift also supports the Saunders Family Distinguished Professorship in Neuromuscular Research and the E. Philip and Carole Saunders Professorship in Neuromuscular Research. He served as a cochair of the Medical Centers campaign in support of The Meliora Challenge and honorary chair of the George Eastman Circle Rochester Leadership Council. He greatly influenced and encouraged philanthropy with the creation of the highly successful George Eastman Circle Plus One outreach concept, inspiring other units of the University to adopt the concept to increase engagement.

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Board elects two members, honors three life trustees - University of Rochester

Study reveals factors influencing outcomes in kidney cancer treated with immunotherapy – Science Codex

BOSTON - By analyzing tumors from patients treated with immunotherapy for advanced kidney cancer in three clinical trials, Dana-Farber Cancer Institute scientists have identified several features of the tumors that influence their response to immune checkpoint inhibitor drugs.

The research was presented during the Clinical Science Symposium at the American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in Nature Medicine. The researchers say the study provides important clues about kidney cancer genetics and its interaction with the immune system that may prove to be vital in our ability to predict which patients are likely to benefit from immunotherapy drugs, which have been approved for first- and second-line treatment in the disease, but which don't work in all patients. The study showed that features that are typically linked to immunotherapy response or resistance in other types of cancer don't work the same way in advanced clear cell renal cell cancer (ccRCC).

"Kidney cancer breaks all those rules," said David Braun, MD, PhD, a Dana-Farber kidney cancer specialist and first author of the report. Co-senior authors are Toni Choueiri, MD, Catherine J. Wu, MD, Sachet A. Shukla, PhD, and Sabina Signoretti, MD all of Dana-Farber. Other authors are from the Broad Institute of MIT and Harvard, Bristol Myers Squibb, and Brigham and Women's Hospital.

Clear cell renal cell cancer is the most common form of kidney cancer. There are about 74,000 new cases of kidney cancer in the United States each year, and about 15,000 deaths. Checkpoint inhibitor immunotherapy drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo) used in advanced kidney cancer work by blocking PD-1, a protein on immune T cells that normally keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against kidney cancer cells.

PD-1 checkpoint inhibitors have brought a powerful new weapon to bear on advanced kidney cancer, which generally doesn't respond to standard chemotherapy. In cancers such as melanoma and lung cancer, checkpoint inhibitors - drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) - tend to be more effective against tumors with a "high mutational burden," that is, their DNA is riddled with many mutations. Advanced clear cell renal cell cancer, by contrast, has a moderate number of mutations yet is relatively responsive to checkpoint inhibitors - and scientists don't know why that is. Another puzzling difference is that in melanoma and some other cancers, tumors that are infiltrated with large numbers of immune CD8 T cells, creating what's termed an inflamed or "hot" environment within the tumor, respond better to PD-1 blockade. But the reverse is true in advanced kidney cancer - high infiltration by CD8 T cells is associated with a worse outcome.

In this study, the scientists analyzed 592 tumors collected from patients with advanced kidney cancer who were enrolled in clinical trials of PD-1 blocking drugs. They used whole-exome and RNA sequencing and other methods to uncover the genomic changes and other factors that were associated with how the patients' tumors responded to the drugs - specifically, the patients' progression-free survival and overall survival.

The study was aimed at determining what features of advanced kidney cancer cells were associated with their response or resistance to PD-1 inhibitors. In analyzing the tumors from advanced ccRCC patients treated with PD-1 inhibitors, the investigators looked for biomarkers - genetic changes, mutations, copy number alterations, and so forth - in the genomes of the kidney cancer cells that might be correlated with patient outcomes - such as progression-free survival and overall survival.

Braun said that some of the most interesting findings were characteristics of the kidney tumors that - unlike with other types of cancer - did not influence responsiveness to PD-1 inhibitor drugs. For example, tumors containing a large number of neoantigens - proteins made by cancer-related DNA mutations that may make the tumors more responsive to immunotherapy, but this proved not to be true of the kidney tumors. Also, even though the kidney tumors were heavily infiltrated by CD8 immune T cells - which causes other kinds of cancer to provoke a strong immune attack against the tumors - this actually led to no difference in outcome for these kidney cancer patients. "To our surprise, the immunologically 'hot' tumors did not respond any better than the 'cold' tumors," said Braun.

Another factor that affects responsiveness in some types of cancer - the specific HLA molecules inherited by individuals that present antigens to the immune system - didn't affect the immune response to advanced kidney tumors. "That surprised us," said Dr. Wu, chief of Division of Stem Cell Transplantation and Cellular Therapies. "We reasonably hypothesized that the potential of the patient's immune system to present and react to a greater diversity of antigens may be associated with better outcomes, but clearly kidney cancer does not fit the standard mold," noted Wu.

"However, we did uncover some factors that may explain the unexpected observations," said Dr. Shukla who leads the computational group at the Dana-Farber Translational Immunogenomics Laboratory. The study uncovered that advanced kidney tumors heavily infiltrated with CD8 T cells did not respond well to immune checkpoint blockers even though they were immunologically "hot" tumors. The scientists, with their comprehensive analysis of changes in the kidney tumors' genomes, found that the tumors were depleted of mutated PBRM1 genes - which are correlated with improved survival with PD-1 blockade therapy - and also had an abundance of deletions of a chromosomal segment known as 9p21.3, which is associated with worse outcomes with PD-1 blockade. "We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy," explained Shukla, "while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond."

"Our work highlights the importance of integrating genomic data with immunopathologic data generated through painstaking review by expert pathologists," said Dr. Signoretti, professor of pathology at Harvard Medical School. "Our findings reveal that interactions between immune T cell infiltration and alterations in the tumor DNA (such as inactivation of the PBRM1 gene and the abundance of 9p21.3 deletions) can be important influences on tumors' response to PD-1 blockade - perhaps not only in kidney cancer but in other types of tumors as well."

"The current study provides critical insights into immunogenomic mechanisms contributing to response and resistance to immunotherapy in clear cell renal cell cancer," said Dr. Choueiri, director of the Lank Center for Genitourinary Oncology and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "The detailed clinical, genomic, transcriptomic, and immunopathology data produced by this study will serve as a valuable resource for the cancer immunology community. This work, therefore, will be important for ongoing research in precision medicine and immuno-oncology, helping to identify which patients are likely to respond to current therapies, and providing fundamental information to aid in development of rational combination therapies to overcome resistance in the future."

"One notable thing," said Choueiri, "is the collaboration between multiple disciplines and stakeholders: Immunology, pathology, genetics, computational and clinical expertise all converged on one tumor, while involving academic and industry stakeholders."

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Study reveals factors influencing outcomes in kidney cancer treated with immunotherapy - Science Codex

Learning how the coronavirus affects the body offers clues to fight COVID-19 – CBC.ca

This is an excerpt fromSecond Opinion, aweeklyroundup of eclectic and under-the-radar health and medical science news emailed to subscribers every Saturday morning.If you haven't subscribed yet, you can do that byclicking here.

The devastating damage that the novel coronavirus inflicts on the human body can set off inflammatory havoc. As we learn more, doctors are gaining clues to hopefully prevent deaths and improve treatment.

Last December, COVID-19 entered the world stage as a flu-like illness causing fever, dry cough and a sore throat.

Since then, the list of how the illness can present has expanded, and expanded again, to include gastrointestinal symptoms like diarrhea, general aches, loss of taste and smell and serious blood-clotting problems, among others.

Of the more than five million infections globally so far, 2.4 million have recovered.

Most infected people have so few symptoms they are better off at home. The minority of serious infections in patients mainly those over 65, though no age group is left unscathed can confound health professionals caring for them.

The illness can worsen to a severe stage called Acute Respiratory Distress Syndrome, which includes severe lung inflammation and damage. These are often the patients who are admitted to intensive care units and need life support such as ventilation.

Dr. Lynora Saxinger, an infectious disease physician at the University of Alberta, co-chairs a provincial scientific advisory board reviewing how COVID-19 manifests and what it means for reducing transmission and extending treatment beyond current care measures.

"The landscape shifts really quickly," Saxinger said. "We just want to make sure that we're not missing [what] could be spreading, because that's where we're going to run into trouble."

As initial anecdotes about inflammatory-like effects such as blood-clotting complications mounted into a clearer signal for caution, clinicians adapted their care while scientists worked to understand why it happens.

Now, Saxinger said there's more evidence of clotting damage in both large and small blood vessels."This virus is doing different things in the body."

Experts say some of these inflammatory effects look to be unique to this particular coronavirus, which is known asSARS CoV-2.

Dr. Zain Chagla, an associate professor of infectious disease at McMaster University in Hamilton, Ont., said the wide extent of clotting with this virusdiffers from other infections, including from the deadly SARS and MERS coronaviruses.WithCOVID-19, the clots occur in veins in the legs and lungs, as well as in arterial ones that cause strokes and can lead surgeons to resort to amputating a patient's limbs.

Medical researchers have also found tiny clots that damaged tissue throughout the body in hospitalized patients and in autopsies.

Chagla said this means that "from a therapeutic standpoint," it might be better to give patients a low dose of heparin,an anticoagulant or blood thinner. It's often used before surgery and in a variety of medical conditions to prevent and treat clots.

Clinical trial researchers are also exploring the use of high-dose anti-coagulants in carefully selected patients, Chagla said.

This week, Health Minister Patty Hajdu announced an accelerated path for clinical trials to help find answers to urgent COVID-19 diagnosis, treatment, mitigation or prevention questions while keeping patients safe.

On Friday, Montserrat Puig of the U.S. Food and Drug Administration and her team published what they called a road map for effective treatment of COVID-19, based on both repurposing existing approved drugs as well as those still under development.

The review, published in Frontiers in Immunology, unravels factors leading to the "cytokine storm" that can rampage in people with severe COVID-19. Cytokines are small molecules released by the body's immune system to co-ordinate response against an infection or injury, ranging from a mild fever to suspected deaths in the 1918 flu pandemic.

Scientists are still working to understand the key events in cells, tissues and the body's immune system that tips the balance from a normal, protective, "hey, come help" call for reinforcements to an unnecessary, four-alarmcall that leads to a life-threatening overreaction.

Puig wrote that potential drugs include those that could block the virus from entering our cells in the first place, antivirals to stop the virus from making copies of itselfand therapies called monoclonal antibodies that dampen the haywire response from cytokines.

People who develop symptoms of COVID-19 do so within 14 days, and it mostly occurs about five days after exposure.

Saxinger said when patients struggle with congested lungs and poor blood pressure control, it's often a manifestation of lung inflammation in response to the infection.

She said there's also an arc to the story of how the disease marches through the body from initial infection to damage to recovery or death.

"The initial infection triggersthis body-wide response that is devastating," Saxinger said. "Then, when the infection itself might be coming under control, it's almost like you unleash this storm of immune reactivity and inflammation."

Once the storm is set off, doctors say treating the infection itself is unlikely to help much.

So, what could help? As physicians report more symptoms, scientists working in parallel are exploring why and how the virus replicates in some tissues and organs so well.

Matthew Miller, an associate professor of infectious disease and immunology at McMaster, is following the scientific advances.

The virus seems to use a receptor called ACE2 to enter human cells. Miller said many groups of researchers are working to understand what cells in our body have active proteins where the virus might be able to replicate and cause disease.

"Knowing what cells a virus is capable of infecting is really important, because it can help us anticipate what types of diseases or what types of symptoms it might cause," Miller said.

It's thought that the infectious dose a person is exposed to,as well as minute, genetic differences in the individual and whether theyhave underlying health conditions (like heart disease or diabetes)all play a role in how COVID-19 manifests.

For now, medical researchers are exploring how ramping up a beneficial aspect of the immune response that cells normally use to kill off a virus could be complemented with "immune modulators" to tamp down overreactions. It's a delicate balance and timing is key.

Miller said as we learn more about the unique features of SARS-CoV-2, governments and public health officials have been forced to "learn on the fly" and adapt pandemic plans built for a different respiratory infection:influenza, commonly called flu.

"One of the areas that this pandemic has really brought to light is that there's not enough focus on prevention control measures," he said.

Countries imposed and eased lockdowns without a firm grasp on what measures work best for this particular virus, leading to differences across the globe and shifting recommendations on wearing masks or physical distancing.

"I think we're all learning that we don't understand nearly as well as we should," Miller said.

WATCH | Why we should expect waves of COVID-19:

Public health basics like staying home when sick, handwashing and cough etiquette apply to all respiratory pathogens. It's the specifics that are still a work in progress.

For Saxinger, these knowledge gaps mean that understanding COVID-19 will be a long-term effort.

"It's not just going to be a one, we're done," Saxinger said. "We are all going to have to figure out the best way to manage people and try to give them the best outcomes possible."

To read the entireSecond Opinionnewsletter every Saturday morning, subscribe byclicking here.

Link:
Learning how the coronavirus affects the body offers clues to fight COVID-19 - CBC.ca

Indira IVF to resume in-vitro fertilisation services – Express Healthcare

All safety protocols directed by authorities will be followed to ensure safety of patients, doctors, working staff

In March, the Human Fertilisation and Embryology Authority (HFEA) ordered to pause the IVF treatment procedures in the UK. After the massive Coronavirus hit,IVFclinics were asked to postpone its services amidst the lockdown. There has been too much fear about the patients contracting the virus and they are taking all the measures to curb it. Recently, European Society of Human Reproduction and Embryology, The American Society for Reproductive Medicine and Indian health department have asked clinics to start essential services in a phased manner with all necessary safety measures.

Working as per the guidelines provided by the authorities, Indira IVF has taken a decision to restart its in-vitro fertilisation (IVF) services. All 89 clinics are open for patients who are seeking treatment with all the precautionary measures as per the guidelines provided by the Government of India.

With the current number of cases increasing aggressively, hospitals and clinics are advised to remain vigilant in the safety protocols and take all the required safety measures. Relentless adherence to safety protocols is a must.

Keeping into consideration the current COVID-19 condition, Indira IVF is following all safety protocols directed by the authorities to ensure the safety of patients, doctors and the working staff.

To ensure a safe and clean environment, the company has come up with precautions including:

Mandatory checking of temperature for all who enter the premises

Self-declaration form by the patients to identify the high-risk patients

Proper precautionary measure should be taken by the patients, doctors, and staff like gloves, masks, and others

Regular disinfection of the hospital facility

Strict sanitisation protocols

Social distancing and entry only by prior appointment

Speaking about the same, Nitiz Murdia, Marketing Director, Indira IVFsaid In this difficult time, we are keeping our focus to minimise visits a patient makes to the clinic for IVF treatment by offering tele-consultation with the treating fertility specialist. We are also taking special precaution at all our 88 clinics across pan India to strictly follow health and hygiene guidelines issued by the government for the safety of our staff and our patients. To live with COVID-19 virus is now the new way to live life hence its our collective responsibility to take all the necessary precautions to safeguard our-self as well as our family members from this virus.

Fertility clinics have shut down its services since March after the lockdown was announced. But today, fertility hospitals are trying to resume their operations.The reopening is happening in phases with new safety measures being put in place.

Speaking about the present scenario,Dr Kshitiz Murdia, Chief Operating Officer, Indira IVFsaid The impact of Coronavirus has greatly affected infertile couples who have planned to undergo treatment in summers; due to lockdown conditions in the city, couples had to postpone their treatment. The good news is that now they will be able to re-start their treatment at Indira IVF clinics. To tackle the previous load of the IVF patients, we are giving priority to patients whose embryos were frozen with us but due to lockdown they couldnt undergo embryo transfer procedure followed by other patients.

Read more:
Indira IVF to resume in-vitro fertilisation services - Express Healthcare

Reconstructing the time since death using noninvasive thermometry and numerical analysis – Science Advances

Abstract

The early postmortem interval (PMI), i.e., the time shortly after death, can aid in the temporal reconstruction of a suspected crime and therefore provides crucial information in forensic investigations. Currently, this information is often derived from an empirical model (Henssges nomogram) describing posthumous body cooling under standard conditions. However, nonstandard conditions necessitate the use of subjective correction factors or preclude the use of Henssges nomogram altogether. To address this, we developed a powerful method for early PMI reconstruction using skin thermometry in conjunction with a comprehensive thermodynamic finite-difference model, which we validated using deceased human bodies. PMIs reconstructed using this approach, on average, deviated no more than 38 minutes from their corresponding true PMIs (which ranged from 5 to 50 hours), significantly improving on the 3 to 7 hours uncertainty of the gold standard. Together, these aspects render this approach a widely applicable, i.e., forensically relevant, method for thermometric early PMI reconstruction.

The early postmortem interval (PMI), i.e., the time shortly after death, plays a key role in forensic investigations, as it aids in the temporal reconstruction of events. Consequently, the development of a method to determine the PMI remains one of the most important challenges in forensic medicine to date (1). In its pursuit, many pathophysiological changes have been investigated as potential measures of the PMI. These measures can be divided into two groups. The first relies on sampling of tissue or bodily fluids (2), followed by laboratory examinations to quantify, e.g., nucleic acid degradation (3), changes in the ocular potassium concentration (4, 5), and microbial (6) and metabolomic (7) changes. In contrast, the second group involves probing optical, mechanical, or thermal changes in human tissue (812). This latter group does not require any sample extraction or laboratory examinations; these pathophysiological changes can therefore be quantified directly at the crime scene.

Of these measures, the change in body temperature is most frequently probed to determine the PMI in the early postmortem period. Thermometric PMI determination was first introduced in the 19th century (13), and since then, many models have been developed aiming to map postmortem body temperature to time since death (1316). The current gold standard in forensic practice is a model by Henssge (1719), relating rectal (core) temperature to PMI. Usually presented in the form of a nomogram, this model is based on a limited set of measurements and the underlying assumption that the postmortem rectal temperature of any given human body follows a typical cooling curve. In Henssges model, this typical cooling curve is described by a double exponential decay, the exponents of which are derived empirically and related to the victims body weight, its coverage, and surface contact. While this approach is widely used, it is subject to substantial limitations. First, the underlying dataset was acquired under standardized conditions; deviations from these standard conditions necessitate the use of subjective correction factors or preclude the use of Henssges nomogram altogether. Moreover, use of this model requires an invasive measurement of the victims rectal temperature, risking contamination, and destruction of other traces. Last, the model classifies human bodies only by weight, thereby introducing a consequential thermodynamic degree of freedom: under identical circumstances, two bodies of equal weight but different stature or body composition (body fat percentage) will cool at different rates. As a result, the uncertainties of PMIs determined using Henssges nomogram vary broadly from 3 to 7 hours on a 20-hour time scale.

More rigorous, i.e., nonsubjective, approaches to thermometric early PMI determination have been developed (2024). In these approaches, the thermodynamic processes governing body cooling are modeled using numerical methods, e.g., finite elements. While these efforts expand the applicability of thermometric PMI determination in theory, in practice, they are subject to considerable limitations. First, some require computed tomography (CT) data, which are not commonly available in forensic case work. Second, their computational implementation necessitates highly specialized technical expertise. Last, and perhaps most importantly, none of these approaches have been validated using human bodies. Consequently, there is a clear need to develop and validate a numerical approach to early PMI reconstruction straddling the divide between model complexity and usability in forensic practice.

To address this, we developed an approach that overcomes the above limitations by using a simplified but versatile numerical (finite difference) model. Body posture, stature, and composition as well as (time-dependent) environmental variables such as contact surface, (partial) submersion in water, and (partial) coverage by clothes are all readily integrated in our model (including environmental changes before and after discovery of the body), rendering it applicable in a wide variety of forensic cases. Furthermore, it allows computation of the body temperature at external body locations, in turn, enabling a noninvasive experimental protocol. We validated and benchmarked our approach using deceased human bodies. To this end, we recorded time-resolved skin temperature curves, at several body locations, on deceased human subjects and then evaluated the performance (accuracy and precision) of PMI reconstruction using our model. To determine the accuracy, we compared measured abdominal skin temperatures of four deceased subjects to their corresponding numerical predictions to reconstruct a wide range of PMIs, ranging from 5 to 50 hours since death. Next, we determined the variability in these PMI reconstructions resulting from uncertainty in the model input parameters. The outcome of this evaluation has important practical implications, as in forensic practice, some of these parameters will only be known within parameter-specific margins of error.

To reconstruct the PMI from a measured body temperature, we developed a finite difference model (see Materials and Methods and section S1) allowing time- and spatially resolved simulation of the body temperature following death. To this end, the model uses a discretized three-dimensional representation of the body and its surroundings to calculate the heat exchange between the involved materials. By repeating this calculation for consecutive time intervals, the change in body temperature can be simulated. The sum of the necessary computational repetitions required to reach a location-specific measured reference temperature then corresponds to the numerically reconstructed PMI.

To determine the model accuracy, we first tested our finite difference model on a simple system for which an analytical solution exists. To this end, we solved the problem of a solid sphere cooling in air using our finite difference algorithm. The resulting numerical solution was then compared to the analytical solution (25) at different spatial positions on the sphere as well as different points in time (Fig. 1). The numerical simulations are in close agreement with the analytical solution demonstrating the accuracy of the computational implementation.

Evolution of the temperature distribution of a solid sphere (radius = 30 cm) with a thermal conductivity of 0.55 Wm1 K1 cooling in air (20C). The blue lines correspond to the analytical solutions, while the red lines represent the numerical solutions yielded by our model. (A) Sphere temperature as a function of time at two locations: in the center and on the surface. (B) The sphere temperature as a function of radial distance at five distinct time points.

Next, we evaluated the capacity of our model to describe the change in skin temperature for recently deceased human subjects. To this end, we recorded skin cooling curves for four deceased subjects lying on a medical dissection table and stored at 2 to 4C. These measurements were performed at specific body locations (abdomen, chest, forehead, and thigh) and compared with the corresponding model predictions. These results are presented as a function of PMI in Fig. 2. The change in environmental temperature following storage in the mortuary refrigeration unit is included in the computation and manifests as a change in cooling rate, i.e., as an inflection point, in all simulated temperature curves.

Measured and simulated skin temperature as a function of PMI of different locations of a deceased (A) 79-year-old male, (B) 60-year-old male, (C) 94-year-old female, and a (D) 61-year-old female body in the AMC morgue. The blue solid lines correspond to the measured data, while the red dashed lines denote the simulated data. The inflection point in the simulated curves corresponds to the change in environmental temperature upon storage of the body in the mortuary refrigeration unit.

Figure 2A shows numerical and experimental data of a 79-year-old male weighing 64.5 kg, with a body length of 169 cm and with a calculated fat percentage of 29% wearing a shirt and a diaper. The body was additionally covered with a sheet, and the subjects head was resting on a pillow. This case-specific coverage and surface contact were included in the simulations by assigning the thermal conductivities of the clothes and the pillow to the appropriate locations in the grid. Skin temperatures were recorded between 6 and 30 hours postmortem. All numerically derived temperature curves are in excellent agreement with the measured cooling curves. Figure 2B depicts simulated and measured data of a 60-year-old male with a body weight of 99 kg, a body length of 181 cm, and a calculated body fat percentage of 29%. Besides a long-sleeved shirt and a diaper, the subject also had long and facial hair; all coverage was included in the simulations by adjusting the thermal properties of the corresponding grid elements accordingly. Skin temperatures were measured between 21 and 43 hours after death. While simulation and experiment are in close agreement for the abdomen and the forehead, the measured temperatures of the chest and the thigh exceed the simulated ones at these locations. The subject of the experiment summarized in Fig. 2C was a 94-year-old female and weighed 39 kg with a body length of 159 cm and a computed fat percentage of 21%. Skin temperatures were measured between 24 and 45 hours postmortem during which the subject was naked. Despite the progressed cooling state upon arrival, the simulated temperatures are still in close agreement with the measured temperatures. Only the simulated temperatures of the chest and the thigh exhibit moderate deviations from the measured data. Last, Fig. 2D depicts the measured and simulated location-specific skin cooling curves of a 61-year-old female with a body weight of 87 kg, a body length of 157 cm, and an estimated fat percentage of 34%. This subject also wore a shirt and a diaper; however, no sheet or a pillow was present. Again, the clothes were incorporated by assigning the respective thermal conductivities to the appropriate locations within the grid. Thermal measurements took place at PMIs ranging from 26 to 50 hours. The simulated cooling curves are generally in good agreement with the measured curves. For three of the four measurement locations, however, small deviations are visible: While the time-dependent temperatures are underestimated for the forehead, they are overestimated for the thigh and the chest. Notwithstanding, all simulated decay rates accurately model those of the measured temperatures.

Using both the measured and simulated abdominal data shown in Fig. 2, we reconstructed PMIs for each measurement time point of all subjects. By comparing these reconstructed PMIs to their corresponding true values (which ranged from 5 to 50 hours), we determined the accuracy of our method for PMI reconstruction. Figure 3A shows the numerically reconstructed PMIs as a function of the true PMI. The absolute errors of the PMI reconstructions (PMI) are shown in Fig. 3B. All reconstructed PMIs lie within at least 3.2 hours of the true PMI, while the average PMI is 38 min. Moreover, 83.3% of the reconstructed PMIs deviate no more than 1 hour from their corresponding true PMI. Next, we investigated the extent to which this error depends on the uncertainty in the model input parameters. To this end, we chose a specific set of input parameters as a starting point, yielding a reference PMI. We then systematically and sequentially varied these input parameters and compared the resulting reconstructed PMIs to this reference PMI. The results of this parameter sensitivity analysis are summarized in Fig. 4 and fig. S2. Both figures show the maximum error of the reconstructed PMI as a function of the variation in five model input parameters: initial body temperature (Fig. 4A), body fat percentage (Fig. 4B), thermal conductivity of the clothes (Fig. 4C), thermal conductivity of adipose tissue (fig. S2A), and thermal conductivity of nonadipose tissue (fig. S2B). The black stars denote the values for the reference dataset. Of these parameters, variation in the thermal conductivity of the clothes induces the largest variation in reconstructed PMI. On average, the reconstructed PMIs deviate no more than 2 hours from the reference PMI. Moreover, the deviation in reconstructed PMI induced by uncertainty in the thermal conductivity of the clothes, adipose tissue, and nonadipose tissue or the body fat percentage is independent of the environmental temperature. In contrast, the extent to which uncertainty in the initial body temperature induces deviation in the reconstructed PMI depends on the environmental temperature. Together, these results demonstrate that the accuracy of our method surpasses that of the gold standard even in cases where input parameters are known only within a margin of uncertainty.

(A) Comparison of true versus reconstructed PMIs using the abdominal reference measurements of four different bodies (each indicated by a different marker color). (B) Absolute error, i.e., difference, between the reconstructed and correspdoning true PMIs shown in (A).

Effect of uncertainty in the model input parameters (A) initial body temperature, (B) body fat percentage, and (C) thermal conductivity of the clothes on the estimated PMIs. Circles and upward pointing triangles denote results for the parameter variations at environmental temperature (ET) values of 10 and 20C, respectively. Negative values of the PMI deviation correspond to an underestimation of the true PMI, while positive values indicate overestimation.

In this study, we developed and validated an advanced approach to describe postmortem body cooling. Computational robustness and numerical accuracy of this approach were established by solving the heat exchange problem for a simple geometry both analytically and numerically and demonstrating close agreement of these solutions. Overall, we found the predicted cooling curves of (partially) clothed human bodies to be in close agreement with the measured temperatures (mean deviation of 1C) of subjects spanning large ranges in age (60 to 94 years), weight (39 to 99 kg), body length (157 to 181 cm), and fat percentage (21 to 34%) showcasing the broad applicability of the model. To demonstrate the feasibility of PMI reconstruction, we used our model in conjunction with measured abdominal temperature curves of four subjects to reconstruct PMIs ranging from 5 to 50 hours. We found the maximum and average error of these reconstructed PMIs to be as low as 3.2 hours and 38 min, respectively. Moreover, 83.3% of the reconstructed PMIs deviate no more than 1 hour from their corresponding true PMIs. Parameter sensitivity analysis revealed the extent to which these errors depend on uncertainties in the studied model input parameters. Errors of the reconstructed PMIs induced by parameter-specific uncertainties remain within 2.5 hours for true PMIs ranging from 6 to 40 hours. While the errors induced by uncertainty in the thermal conductivity of the clothes and the body fat percentage are independent of the environmental temperature, the effect of uncertainty in the initial body temperature clearly is not. This latter finding is in agreement with the results of a similar study (26). The initial body temperature determines the temperature gradient between the body and its surroundings; this gradient, in turn, is the fundamental property underlying and driving the heat exchange process. Therefore, uncertainty in the initial body temperature plays a bigger role at higher environmental temperatures. Notwithstanding, these results represent a notable improvement over the current gold standard (Henssges nomogram) where uncertainties range from 3 to 7 hours.

In some of the subjects, there is an observable discrepancy between the simulated and measured temperatures of the chest. The deviation of the temperature of the chest may be a result of placing the temperature sensor on the sternum. Our model does not include the location of bones within the body. This, in turn, may lead to measured temperatures exceeding simulated ones: The higher thermal conductivity of bone will transport core body heat to the skin more efficiently than accounted for in the model (see fig. S1). This deviation can therefore easily be avoided in the future by placing the sensor next to the sternum. While we successfully validated our approach on cooling human bodies, all experimental work was conducted in a standardized environment (hospital morgue), significantly reducing the variability of many environmental parameters. Consequently, performance evaluation of the approach in forensic fieldwork is paramount in determining its added value to forensic practice. The parameter most likely to vary considerably in most cases will be the posture of the victim. Currently, our approach implements the body in a straight configuration (see Fig. 5). The required individualization of the virtual body posture could be addressed using photogrammetric image processing techniques, e.g., Structure from Motion (SfM). SfM allows noncontact measurement of the three-dimensional shapes of objects from two-dimensional images (27); this information (the dimensions and the posture of the body) could then serve to render the virtual body in a straightforward way. Furthermore, spatial coregistration of measured and simulated skin temperatures can be achieved through the addition of coded imaging targets, increasing modeling accuracy and potentially allowing the integration of thermal imaging. Similarly useful to the individualization of the virtual body could be the inclusion of postmortem CT scans (22): Besides improving the assignment of the different tissue types (28), this tomographic information would also allow both the inclusion of cavities filled with air (or other materials) and the locations of bones in the model, the latter addressing issues such as that of the sternum mentioned earlier. While integration of these data could potentially increase model accuracy, it may hamper practical applicability of the approach by the same token: The increased model complexity would manifest as a higher computational workload, larger datasets, and decreased ease of use. However, postmortem CT scans are increasingly performed in forensic practice, rendering the required information available for a larger number of cases.

(A) Material assignment of adipose tissue and nonadipose tissue as well as virtual probe locations (for the forehead, chest, abdomen, and thigh) within the model. The numbered red bars within the frontal cross sections indicate the location of the corresponding horizontal cross sections (above). (B) Simulated spatial temperature distributions (in C) of the body shown in (A) cooling in air: frontal cross sections of the computed temperature distributions at distinct time points (0, 5, 10, and 25 hours postmortem).

Improving the error margin in our PMI estimates necessitates the reduction of the uncertainty in the model input parameters. It would therefore also be desirable to measure the thermal properties, e.g., thermal conductivity, of the materials, which are in contact with the body, and hence relevant to the heat exchange problem, directly at the crime scene.

Last, another varying environmental parameter is the ambient temperature. An unknown ambient temperature significantly increases the uncertainty in the time of death estimate (23). However, in many situations, this information may be available as thermostat or meteorological data, in which case they could be easily included in the thermodynamic computations. Moreover, a general strength of our model is that multiple scenarios can be simulated to reconstruct a range of possible PMIs, the maximum and minimum of which can be reported as the most likely time frame for the PMI. While other numerical descriptions of the postmortem body cooling process exist, they lack either geometric accuracy (20) or experimental validation using deceased human bodies (20, 24). Moreover, currently, none of these approaches include modeling of (partial) clothing, (partial) contact with surfaces, or submersion in water. To our knowledge, we are the first to validate a numerical description of postmortem skin cooling with realistic and noninvasive measurements on deceased human bodies. Last, multiple (simultaneous) skin temperature measurements may reduce uncertainty in the PMI calculation by increasing the number of independent measurements. Together, these aspects render this study a considerable advance in the pursuit of a widely applicable, and hence forensically relevant, method for temperature-based PMI estimation.

Thermometric PMI reconstruction using the numerical approach outlined in the theory section (see section S1) requires modeling (discretization) of the body and its environment. Here, a discretized three-dimensional representation of the body and its surroundings is obtained as follows. First, the individual body parts are approximated as cones (e.g., arms and legs), ellipsoids (e.g., head), and cylinders (e.g., neck and torso), the proportions of which are dictated by standardized anatomical measurements (e.g., length of the arms and legs and the circumference of the head, torso, upper arms, and wrists). Second, these individual body parts are then assembled to form the entire body. Third, this simplified model of the body is placed within an isotropic cubic mesh (which is generated automatically based on the body dimensions) of desired cube size (in this study, 1 cm3) where it then serves to determine material (i.e., thermal properties) assignments on a cube-by-cube basis (see Fig. 5A). Similarly, to obtain spatially resolved temperature data for different time points, it is necessary to discretize the time before equilibrium into finite time intervals t, in our case 60 s (matching the sampling period of our temperature measurements). This, in turn, determines the number of computational iterations needed to simulate the heat exchange process: e.g., for a period of 24 hours, a t of 60 s corresponds to 1440 iterations.

Besides modeling the geometry of the body and its surroundings, it is crucial that the material composition of the computational representation (i.e., the cube-wise assignment of the thermal properties) closely resembles reality to ensure accurate simulation of the body temperature change. Important factors therefore include body fat percentage, coverage by clothes, and contact area with other surfaces, such as the floor or water. The bodys adipose tissue is modeled as an outer layer surrounding the individual body parts. To accurately model the layer thickness, we estimate the fat percentage using the U.S. Navy circumference method (see Fig. 5A) (29).

The thermal conductivities of the nonadipose tissue, adipose tissue, and the clothes (in our case cotton) were set to 0.55, 0.2, and 0.03 Wm1 K1, respectively (30, 31). For the emissivity , we used the emissivity of human skin, namely, 0.96 (32), while for the characteristic length of the convective heat transfer, we chose the characteristic length of a cylinder approximated by the width and depth of the torso of the virtual body (33). Last, the specific heat capacities of nonadipose tissue, adipose tissue, skin, and clothing were chosen as 4.5, 1.96, 3.77, and 4 JK1 cm3, respectively (30, 3436). All simulations and data analyses were carried out using custom-made scripts written in MATLAB (The MathWorks Inc., Natick, Massachusetts, USA) and executed on a laptop with 8 GB RAM and an Intel Core i5-8250U CPU operating at 1.6 GHz. Typically encountered runtimes of our simulations are on the order of 10 s to 20 s.

The accuracy of the finite difference model was validated by numerically solving the problem of a solid sphere (radius = 30 cm) of nonadipose tissue (thermal conductivity = 0.55 Wm1 K1) in air over a period of 50 hours. The spatial and temporal changes of the temperature distribution of the sphere were then compared to the corresponding analytical solutions (25).

Our finite difference approach yields spatially and temporally resolved computations of the postmortem body temperature (see Fig. 5B). This, in turn, allows for the temperature measurements to be performed on the surface (i.e., the skin) of the body rather than rectally as required for the use of Henssges nomogram. To validate this approach, we conducted postmortem skin temperature measurements on deceased subjects available through the body donation program of the Department of Medical Biology, Section Clinical Anatomy and Embryology, of the Amsterdam University Medical Centers [location Academic Medical Center (AMC)] in The Netherlands. The donation of these bodies to science occurred in accordance with Dutch legislation and the regulations of the medical ethical committee of the Amsterdam UMC, location AMC. Bodies were included if they were suitably warm to ensure a measurable change in skin temperature. All measurements were performed in the AMC morgue using small ( = 16 mm) contact temperature sensors (DS1922L iButtons, Thermochron, USA) attached to the bodies using adhesive tape. Using this approach, skin cooling datasets were gathered from four deceased subjects, two males and two females, aged between 60 and 94 years. The body weights, body lengths, and calculated fat percentages of the subjects ranged from 39 to 99 kg, 157 and 181 cm, and from 21 to 34%, respectively. The amount of clothing and surface contact with insulating materials as well as the PMI at the beginning of the measurements varied between experiments. As all of these are input parameters in our model, their variation between experiments was accounted for by adjusting them accordingly in the respective calculations.

Reconstruction of the time since death, using our model, comprises computation of the heat exchange until a measured location-specific reference temperature is reached. The sum of the necessary computational time steps, i.e., n*t, required to reach the measured temperature then corresponds to the numerically reconstructed PMI (see section S1). The accuracy of this numerical PMI reconstruction was evaluated using abdominal skin temperatures of four deceased subjects comprising 96 measurement time points, i.e., true PMIs, between 5 and 50 hours with the corresponding measured abdominal reference temperatures ranging from 28 to 5C.

Our computational approach requires the values of several physical quantities (model parameters): the initial body temperature, the environmental temperature, the body fat percentage, and, if applicable, the thermal conductivity of the clothes and the floor, the floor temperature, as well as the flow speed of the surrounding medium (e.g., air). The extent to which uncertainty in these input parameters generates variation in our PMI predictions was evaluated by simulating the cooling of a body for 13 different sets of model input parameters at two different environmental temperatures (10 and 20C) yielding a total of 26 set-specific simulations. These 26 parameter sets were generated as follows: For both environmental temperatures, an original set of input parameters was chosen (see Table 1). Subsequently, we assigned physiologically and physically reasonable parameter ranges for three of the seven parameters, namely, initial body temperature, thermal conductivity of the clothes, and fat percentage of the body (see Table 1). This particular choice of parameters to investigate was motivated by their likelihood of being unknown and/or exhibit most variation in forensic casework. Next, for each of these three parameters, four (equidistant) values were chosen within their respective parameter ranges. Together with the original set of input parameters, this yields 13 separate sets of model parameters (see table S1) for each environmental temperature, i.e., 26 separate cooling simulations in total. For each of the two environmental temperatures, skin temperatures (of the abdomen, chest, upper arm, and thigh) simulated using the original parameter set served as a reference in the calculation of the deviation in predicted PMIs. The reference temperature ranged from 34.7 to 10.6C (environmental temperature = 10C) and 35.6 to 20.4C (environmental temperature = 20C) corresponding to true PMIs between 6 and 40 hours. Deviations from these true PMIs were then calculated for each of the four body locations for all 12 parameter sets for both environmental temperatures. Last, we determined the maximum deviation in reconstructed PMI (over all reference temperatures, i.e., reference PMIs, and body locations) for every parameter set for both environmental temperatures yielding a total of 24 data points. In addition, we investigated the parameter sensitivity of our model with respect to two more model parameters: the thermal conductivities of adipose and nonadipose tissue. Here, we chose two equidistant values on either side of the original parameter value within their respective parameter ranges (see Table 1) and calculated the maximum deviation in PMI at two environmental temperatures (10 and 20C). The results are summarized in fig. S2.

Parameters used in the parameter sensitivity study. Model input parameters and, where applicable, chosen parameter ranges. N.A., not applicable.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

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Acknowledgments: We thank M. Clerkx, R.-J. Oostra, H. Boesveld, J. Woertman, M. van den Born, and B. F. L. Oude Grotebevelsburg for help in carrying out measurements and improving the algorithm. Funding: Ministerie van Veiligheid en Justitie, Innovatieproject ronde 2019 Therminus. Author contributions: L.S.W. developed software, performed measurements, and analyzed data. R.J.M.H., G.J.E., and H.V. performed measurements. H.J.J.H. partly developed the theoretical framework. S.S. developed software. M.C.G.A. performed measurements, partly developed the theoretical framework, and conceived and supervised the project. All authors contributed to planning, design of experiments, discussion of results, and writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Reconstructing the time since death using noninvasive thermometry and numerical analysis - Science Advances

Genetic genealogy companies Ancestry, 23andMe begin COVID-19 research – Detroit Free Press

Ancestry and 23andMe offer direct-to-consumer DNA tests.(Photo: Reviewed.com/Jackson Ruckar)

It's a question that has vexed researchers from the beginning of the coronavirus outbreak: Why do some people get severely ill and die from COVID-19, while others have mild symptoms or none at all?

Now, scientists at two direct-to-consumer genealogy DNA companies hope to use the genomesthey've collected from millions of people over the years to see if they can find a genetic explanation toanswer that question.

Both 23andMe and Ancestry have launched COVID-19 studies, asking U.S. adult customers who've already submitted DNA samples to answer online questions about how the virus affected or didn't affect them.

"From the early days ... I think it was clear to all of us that some people were getting very, very sick when they were affected with coronavirus, and some people had hardly any symptoms at all," said Dr. Catherine Ball,chief scientific officer at Utah-based Ancestry."It turns out that there are plenty of people who have no symptoms. The spectrum of human response to the same pathogen is unusual.

"And even with a bunch of comorbidities and other problems, it's still remarkably divergent in different people, even if they have the same age and have the same overall health. And soto geneticists, that looks like there's a genetic factor in whether people become infected in the first placeor have serious or mild symptoms."

With 16 million people who've already spit in vials and sent them to Ancestryfor genetic testing to find blood relatives who might be closely or distantly related or learn how much of their DNA suggests their relatives came from Africa or Asia or were Native American or European, Ball said the companyknew it had a potentially useful data pool to tap for COVID-19 research.

"We clearly want to take the opportunity to unleash that power to be able to see if there are genetic signals, and be able to help researchers and people making drugs and therapeutics and vaccines dosmarter work faster," she said.

Dr. Catherine Ball, chief scientific officer for Utah-based Ancestry.(Photo: Ancestry)

Of those 16 million DNA customers through Ancestry, so far about 500,000people have already taken an online survey to participate in the company'scoronavirus research.

At 23andMe, principal scientist Adam Auton said the California-based company's COVID-19 genome-wide association study launched in April.

About 10 million of itsgenotype customers are eligible for the study, he said.Of them, about 80%have consented to participate in research, and600,000 customers have opted into the COVID-19 study.

"It is a really quite tremendous response to the study and I think shows that people really do want to try and contribute to help understand and fight this disease," said Auton.

Both Ancestry and 23andMeacknowledge that the bigger the sample size, the better their research will be.

"Never ask a scientisthow much data she needsbecause she always needs more," Ball said. "We're really hoping to get a minimum of a million respondentsbecause we need to have a decent number of people who have tested positive to give us a statistical signal."

So far, about9,000 people in 23andMe'sCOVID-19 study reported that theytested positive for coronavirus.

"That's a pretty substantial number," Auton said. "However, it's the nature of genetic studies that we really need very large numbers of people to be able to draw connections between the genetic information and people's health information."

A worker at 23andMe performs DNA testing on samples provided by customers.(Photo: 23andMe)

Since the pandemic began,about 1.6million people in the United States, a country of 330 million, have tested positive for COVID-19. As the virus continues to spread,and more people get coronavirus diagnoses, the companies suspect that the number of people who will go on to enroll in their studies also is likely to rise.

"We understand this is an evolving situation," Ball said. "And while we can't shelter in place forever, at some point, as we're opening up our cities and states, more people will start contracting the virus."

Anyone who may have already filled out anonline COVID-19 survey on Ancestry.com or 23andMe.com, saying they had not yet had the virus, can go back and revise their answers later to reflect that they've contracted it.

To expand its research of people who've had COVID-19 even more, Auton said 23andMeis now offering tomail a free DNA test kit to any U.S adult who was hospitalized with COVID-19, but has not yet submitted a DNA sample to the company.

"We are essentially asking if people have been hospitalized with COVID-19, and they have recovered, if they would like to participate inour research. They can come to our website and we'll offer them a free kit,"Auton said.

The contents of a 23andMe kit.(Photo: 23andMe)

"We're very much interested in trying to get the word out so that people to hear about this because really every data point is going to be pretty valuable."

23andMe has emailed customers in areas hardest hit so far in the pandemic including those in Michiganto let them know about its study, Auton said.

"The best thing that we can do to make a difference for COVID is to really publish the results that we find and make them available to the research and scientific communities," he said.

23andMe haspublishedmore than 150 studies in peer-reviewed scientific journals, "the majority of which come from collaboration with the broader academic and the scientific community," Auton said,since it launched in 2006with its direct-to-consumer DNA kit.

But the company ran afoul of the U.S. Food and Drug Administration in 2013, when the agency ordered 23andMeto halt the release of genetic health information to customers, saying the company had yet to prove its tests were"analytically or clinically validated."

After revamping, the company passed FDA muster in 2017, and got authorization tooffergenetic healthreports that outlinedrisk for 10conditions, including late-onset Alzheimers disease andParkinsons disease.

Ancestry is new to the health genetics business. It launched AncestryHealth in 2019, with the disclaimer that its tests are physician-ordered and not diagnostic, but offer "health insights" into whether a person might be a carrier for cystic fibrosis or sickle cell anemia or whether there's a genetic variant associated with a higher risk for breast cancer or colon cancer.

Ball said Ancestry also will seek to publish its COVID-19 research findings, too.

"We will be doing our very best to publish our findings as quickly as possible, and making them as useful to clinicians and other researchers as quickly as possible," she said.

Ancestry DNA(Photo: Melissa Rorech)

Both companies are looking for research partners for the coronavirus studies. Ancestry has had nibbles from universities, biotech and pharmaceutical companies, but Ball said, right now, the focus is on safeguarding the privacy of its customers.

"We typically do not share data out with third parties," Ball said. "That's an unusual activity for us.

"We will not be sharingpersonal data. Everything will be de-identified. So names, email addresses, your address, your ZIP code, your phone number, all that stuff will be stripped and will not be shared. We do want to still be very conservative because it is people's genetic data."

At 23andMe, individual-level data is never shared with a third party "without explicit additional consent from participants," Auton said.

"The information that we're talking about here, where we would be working with the academic community, is all aggregated at a very high level. So it's really just information about whether a specific genetic variant is associated with the disease. It doesn't contain any information about the individuals in the study."

Ball urged people to consider participating in this research for the common good.

"The people who came to AncestryDNA were interested in finding out about their ancestors, their past and their history," she said."This is our chancein this moment of history ... to take 5-10 minutes ... and do our best to help our community of friends or familyand the people who we don't even know who will be coming along later.

"It's our chance to contribute to the benefit of everybody. And I think right now, it'san opportunity that resonates with a lot of people."

Auton said the research could lead to therapies or treatments for people sickened by COVID-19.

"Hopefully, that can make a difference," he said.

Contact Kristen Jordan Shamus: 313-222-5997 or kshamus@freepress.com. Follow her on Twitter @kristenshamus.

Read or Share this story: https://www.freep.com/story/news/health/2020/05/26/genes-dna-ancestry-23-andme-coronavirus-covid-19/5223568002/

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Genetic genealogy companies Ancestry, 23andMe begin COVID-19 research - Detroit Free Press