Cell Biology

2023 Hettleman Prizes awarded to five exceptional early-career … – UNC Research

The annual Phillip and Ruth Hettleman Prizes for Artistic and Scholarly Achievement have been awarded to five promising faculty members who exemplify groundbreaking and innovative research along with future career promise.

The late Phillip Hettleman, a member of the Carolina class of 1921, and his wife Ruth established their prestigious named award in 1986 to recognize the achievements of outstanding junior faculty. The recipients of the $8,000 prize will be recognized at the November 3 Faculty Council Meeting. They will also deliver a presentation on their research during University Research Week on October 24 from 3 to 5 p.m. in the School of Social Works Tate-Turner-Kuralt Auditorium.

This years Hettleman Prize awardees are: Yaiza Canzani, associate professor in the Department of Mathematics within the College of Arts and Sciences; Brian Conlon, associate professor in the Department of Microbiology and Immunology within the School of Medicine; Angel Hsu, assistant professor in the Department of Public Policy within the College of Arts and Sciences; Pengda Liu, associate professor in the Department of Biochemistry and Biophysics within the School of Medicine; and Alex Worsnip, associate professor in the Department of Philosophy within the College of Arts and Sciences.

Yaiza Canzanis research focuses on understanding the behavior of Laplace eigenfunctions, which play a crucial role in explaining physical phenomena such as wave propagation, heat conduction, acoustics and quantum evolution.

Canzanis work bridges microlocal analysis, partial differential equations, probability, geometry, and dynamical systems. Her scholarship is internationally recognized she was awarded a Sloan Fellowship, the Sadosky Research Prize in Analysis, and a National Science Foundation CAREER grant.

In his nomination letter for Canzani, Bowman and Gordon Gray Distinguished Term Professor of Mathematics Jason Metcalfe says, Within an extremely active and competitive field of mathematics Canzani is developing transformative tools that will have an immense and long-lasting impact. She is obtaining historic results and is an elite scholar whose promise for discovery cannot be exceeded.

Over the past several years, Canzani developed a research program that aims to describe how Laplace eigenfunctions concentrate near a given point by understanding how they behave when localized to tubes centered along the geodesics that run through the point.

Canzani received her doctorate from McGill University. She was a Benjamin Peirce Fellow at Harvard University and a member of the Institute for Advanced Study.

Brian Conlon is a leader in the field of antibiotic resistance and focuses on alternative strategies to treating infections with existing antibiotics. He aims to make previously ineffective treatments work better by manipulating how the treatment is delivered on a microbial level and reversing resistance by tricking the bacteria into responding to medication.

Conlon also researches how diabetes impacts treatment for antimicrobial resistance, and how to make the battleground inside someones body more hospitable to treatment by pairing an antibiotic with another drug.

His finding that innate immune cells can inhibit antibiotic activity is a major discovery and paves the way for the future development of therapeutics to augment the immune response and make antibiotics work better in patients, says Craig Cameron, professor and chair of the Department of Microbiology and Immunology, in his nomination letter for Conlon.

As a postdoctoral researcher Conlon published nine papers and his work appeared in the journals Nature and Nature Microbiology. Since establishing his lab at Carolina in 2016, Conlon has published 17 papers in journals including PLoS Biology, Cell Chemical Biology, eLife, and Nature Microbiology. His work has also led to two patents that promise to form the basis of novel therapeutic developments.

Conlon earned a doctorate in microbiology from University College Dublin and completed postdoctoral training at the Antimicrobial Discovery Center at Northeastern University.

Angel Hsu applies data-driven approaches to evaluate climate and environmental policy, primarily at the state and local levels. She leads The Data-Driven EnviroLab, frequently calling upon others from different disciplines to collaborate on research.

Collectively, her work has been influential in shaping the research agenda among those studying global climate governance and developing the quantitative approaches used to assess the impact and performance of subnational and non-state actors.

In his nomination letter for Hsu, Daniel P. Gitterman, Duncan MacRae 09 and Rebecca Kyle MacRae Professor of Public Policy, says, Hsu has made important theoretical, substantive, and methodological contributions to climate policy. Her research is highly visible and influential, and her trajectory and future promise are highly positive. Her contributions to research, teaching and service at Carolina are exemplary.

Hsus work has been published in several leading journals, including Nature, Environmental Research Letters, and Climate Policy, contributing novel research in ways that are indicative of her status as a leading scholar in global environmental policy and her engagement in timely policy debates.

Hsu earned an MPhil in environmental policy from the University of Cambridge and a doctorate in environmental policy from the Yale School of Environment. Following her PhD, she served for two years as a postdoctoral associate with the Urbanization and Global Change Group at Yale University.

Pengda Liu studies cancer biology and the molecular mechanisms underlying aberrant cell signaling events in human cancer. He is using this knowledge to develop novel anti-cancer therapies.

He has established a highly productive lab at UNC-Chapel Hill as an independent and collaborative investigator. Both styles of research have led to ground-breaking discoveries and to highly cited articles. Liu has an innovative approach, melding bioengineering expertise with hi-tech biochemistry, cell biology, genetics, and applying this to drug development. His lab focuses on two key cellular signaling pathways that can lead to disease and cancer when mutated.

In her nomination letter for Liu, professor and chair of the Department of Biochemistry and Biophysics Jean Cook says, Liu has made seminal discoveries, and his research has great promise for future clinical advances. We believe that he represents the best in research, mentoring, teaching, and service that the School of Medicine has to offer.

His postdoctoral work was published in high-impact journals, including Nature, Cancer Discovery, Nature Cell Biology, and Molecular Cell. In his seven years at Carolina, Liu has published 24 original research articles, seven review articles and one book chapter.

Liu earned his doctoral degree from East Carolina University and completed postdoctoral studies at Harvard University.

Alex Worsnips research of epistemology the theory of knowledge has made groundbreaking advances in the understanding of the nature of rationality. He proposes that there are two fundamentally distinct kinds of rationality substantive and structural with neither being reducible to the other, which has fascinating motivations and profound payoffs.

Worsnip made these advances in his field through a series of widely acclaimed articles published in top philosophy journals including the Journal of Philosophy, Mind, and Ethics. His work on rationality culminated in a book, Fitting Things Together: Coherence and the Demands of Structural Rationality, which was published by Oxford University Press in 2021. He also won the prestigious Young Epistemologist Prize from Rutgers University in 2019.

Worsnips work has received a great deal of attention from other philosophers, including significant and widespread attention in articles appearing even before Worsnips own paper had appeared in print, says Theda Perdue Distinguished Professor of Philosophy Marc Lange in his nomination letter for Worsnip.

Worsnips most recent and current research concerns the application of epistemology to social and political issues, with particular attention to the epistemic responsibilities of ordinary citizens in a democracy. For example, he has argued that being an epistemically responsible participant in democratic deliberation requires consuming news from sources of different politically partisan affiliations. Since 2022, he has been director of the Applied Epistemology Project at UNC.

Worsnip earned a BPhil in philosophy from the University of Oxford and his doctorate from Yale University. He completed postdoctoral training at New York University.

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2023 Hettleman Prizes awarded to five exceptional early-career ... - UNC Research

Cell Biology

Faeth Therapeutics Announces National Academy of Medicine … – BioSpace

AUSTIN, Texas--(BUSINESS WIRE)-- Faeth Therapeutics, a leader in metabolic oncology research and treatment innovation, proudly announces the induction of its co-founder, Dr. Siddhartha Mukherjee, Assistant Professor at Columbia, Pulitzer Prize Winner, and one of Time 100's Most Influential People, into the esteemed National Academy of Medicine (NAM).

Dr. Mukherjee was honored for contributing important research in the immunotherapy of myeloid malignancies, such as Acute Myeloid Leukemia, for establishing international centers for immunotherapy for childhood cancers, and for the discovery of tissue-resident stem cells. His book, The Emperor of All Maladies, won the Pulitzer Prize and was nominated by Time as among the centurys 100 most influential books, introducing millions to modern cancer research. This recognition accentuates the collective dedication and caliber of Faeth's team and the company's commitment to advancing the realm of cancer care.

With Dr. Mukherjee's recent induction into the National Academy of Medicine, he joins fellow Faeth co-founders who have previously received this honor from the National Academy of Science: Karen Vousden, PhD, Chief Scientist of CRUK, Group Leader at the Crick Institute, and Director at Bristol Myers Squibb; Lew Cantley, PhD, Professor of Cell Biology at the Dana Farber Cancer Institute at Harvard University; Greg Hannon, PhD, Director of CRUK Cambridge Institute; and Scott Lowe, PhD, Chair of Cancer Biology & Genetics at Memorial Sloan Kettering, underlining the depth of Faeth Therapeutics' commitment to scientific excellence and innovation.

"Dr. Mukherjee's induction into the National Academy of Medicine reaffirms Faeth Therapeutics' dedication to unparalleled scientific rigor and innovation. We are immensely proud to have such an impressive team of co-founders driving our mission to redefine and elevate standards in oncology care," said Anand Parikh, J.D., Chief Executive Officer of Faeth Therapeutics.

Mukherjee is one of 100 new members announced by the academy. In the National Academy of Medicine, members are elected by their colleagues as a testament to their exceptional accomplishments. Being inducted into the academy represents one of the most prestigious accolades within the realm of medicine.

About Faeth Therapeutics

Faeth Therapeutics is a clinical-stage biotechnology company focused on bringing breakthrough research in metabolic oncology into the clinic. The company leverages its machine-learning platform to identify therapeutic programs that combine traditional therapeutics and a dietary metabolic regimen to enhance outcomes, with the goal of transforming the treatment landscape. Lead asset, FTH-001, combines serabelisib and an insulin-suppressing regimen to slow tumor growth via PI3K pathway inhibition. Faeths scientific founders include industry leaders Drs. Lew Cantley, Sid Mukherjee, Karen Vousden. For additional information, visit http://www.faeththerapeutics.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20231013531071/en/

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Faeth Therapeutics Announces National Academy of Medicine ... - BioSpace

Cell Biology

Finding the golden ticket? Cyclin T1 is required for HIV-1 latency … – Fred Hutch News Service

More than 20 years after the discovery of combination antiretroviral therapy (ART), complete eradication of HIV infection has not yet been achieved. While ART controls viral replication, it is not a cure. This is due to HIV latency, in which the virus is hidden in an inactive state in the genomes of long-living host cells (such as memory CD4 T cells). This allows the virus to evade immune surveillance. As ART acts on the viral replication machinery, latent HIV that is not actively replicating can escape ART. Thus, a cure for HIV requires the ability to either eliminate the latent reservoir or to permanently silence the provirus in the reservoir (or a combination of both).

To improve our understanding of what host genes are require forHIV to emerge from latency, ina newstudy published inViruses, researchers from the Emerman lab in the Human Biology and Basic Sciences Divisions reported that the host factor Cyclin T1 is required for promoting HIV reactivation under a large variety of conditions that would otherwise activate it.

Terry Hafer, the lead author of the study and a graduate student in the Emerman lab, performed a latency HIV-CRISPR screen to identify host factors required for HIV to come out of latency in the presence of small molecule latency reactivation agents (LRAs). Cyclin T1 (CCNT1) was the top hit on the screen.It has been shown previously that Cyclin T1 and Cyclin-dependent kinase 9 (CDK9) form a complex with the positive transcription elongation factor b (P-TEFb) to promote HIV transcription elongation. Cyclin T1 and its role in viral transcription elongation is not novel, said Hafer.But what was striking for us was that Cyclin T1 has always been implicated as an essential gene for its role in transcription elongation as part of the P-TEFb complex, he added. Knockouts of Cyclin T1 showed that cyclin T1 loss impacted HIV gene transcription far more than any other host gene, however, Cyclin T1 knockout did not have noticeable effects on host cell function, Hafer explained.

The latency HIV-CRISPR screen was performed on infected Jurkat T cells (J-Lats 10.6 and 5A8) using a HIV dependency factor gene library (HIV-Dep). Here is the catch, the guide RNAs have been modified to be incorporated into the newly produced virions of the infected cells after LRA treatment. The idea behind this was that if a cell lacks a gene that is essential for latency, HIV will not reactivate. Consequently, the specific guide RNA (targetinga gene essential for reactivation) will not be packaged into newly formed virions.By performing deep sequencing, the team was able to identify guide RNA sequences that are underrepresented in the pool of released viruses. One of the top hits on the screen was Cyclin T1 (CCNT1). To validate the screen, the team knocked out CCNT1 in J-Lats cells, followed by treatment with several LRAs. In all treatments, wild-type (WT) CCNT1 cells were able to reactivate HIV, but KO CCNT1 cells failed to reactivate HIV in the presence of LRAs, indicating that Cyclin T1 is essential for HIV reactivation from latency. Moreover, loss of CCNT1 did not affect the expression of CCNT2, a paralog of CCNT1 that also binds to CDK9 as part of complex p-TEFb, suggesting that CCNT1 plays a unique role. Furthermore, CCNT1 KO did not affect cell proliferation in the J-Lat model. The findings were validated in primary CD4 T cells (the primary target of HIV in infected individuals) as well as the loss of CCTN1 did not affect the activation of primary CD4 T cells.

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Finding the golden ticket? Cyclin T1 is required for HIV-1 latency ... - Fred Hutch News Service

Cell Biology

From Migrant Farm Worker to Duke Scientist, Everardo Macias … – Duke University School of Medicine

Everardo Macias, PhD, assistant professor of pathology at Duke University School of Medicine, explores the complexities of prostate cancer, the second leading cause of cancer death in men.

His quest to find innovative cancer treatments mirrors his own incredible journey from a migrant farm worker to a groundbreaking scientist.

Years ago, the future he envisioned for himself was entirely different. A first-generation high school graduate working in the fields of Minnesota as a migrant farm worker, he never even planned to go to college.

Today, with human cancer genetics and advanced gene testing, hes tackling one of prostate cancers trickiest players: cancer cells that dodge usual treatments. In lab studies, his method of targeting a protein called NUAK2 successfully slowed down the lethal spread of these cells.

Although still in its preliminary stages, with one in eight men facing prostate cancer in their lifetime, every breakthrough counts.

It still baffles me how traveling in the back of a pickup truck one summer in high school got me all the way to Duke, said Macias, a member of the Duke Cancer Institute and an assistant research professor in the Department of Cell Biology.

A harrowing ride across the country, inadvertently set him on a course for higher education and a career in science.

Beyond academia, he celebrates his roots with a renowned food truck, Evelyn's Tex Mex BBQ, named after his daughter and operated with wife Lucia Collado and stepson Frank. ("Smoking good food with a little bit Tex, y un poco de Mex.")

As a Hispanic of Mexican American descent with roots in a small Texas town, my journey to becoming an independent investigator has been enriched tremendously by great mentorship and programs geared toward increasing diversity in biomedical research.

His career researching druggable targets for prostate cancer illustrates the power education and mentorship.

As a child, Macias moved back and forth between the United States and Aguascalientes, Mexico. After his parents separated, he and his four siblings settled with their mother in Sabinal, a small town in Southwest Texas.

In the summer prior to his senior year in high school, Macias traveled to northern Minnesota in the back of a pickup truck for three days with another family to work as a migrant farm worker on sugar beet farms.

Although it was far from home and the work was back-breaking, the pay was better than working on local farms in Texas. For decades, a predominantly Mexican workforce has migrated around the United States, harvesting the countrys food.

The jobs can offer government-backed benefits to address job training and seasonal unemployment, but its a way of life thats rife with labor rights violations, poor housing, and financial instability.

When he returned for senior year, his guidance counselor mentioned an opportunity in Austin, Texas, at St. Edwards University: a College Assistance Migrant Program (CAMP) Scholarship that would pay for the first year of college.

At the time, he wanted to be an accountant, but when he started taking general chemistry and science classes, his professors said he had a knack for it.

Although I worked on farms in Mexico and Texas, I only worked one summer as a true migrant farm worker. When I met other students in the CAMP program who were bona-fide migrant farm workers for as long as they could remember, they told stories of what they went through and how much work and suffering it took. I knew I couldnt squander the opportunity, Macias said.

As an undergraduate at St. Edwards, he held summer internships at Monsanto, the St. Louis-based manufacturer of agricultural and biochemical products.

I realized that my life had taken a 180-degree turn, that I was now conducting research on transgenic seed varieties for a company whose products I was working with in fields just three years before, he said. It hit me how powerful higher education is. It was an ah-ha moment for me.

He earned a Bachelor of Science degree in chemistry from St. Edwards, but graduate school wasnt on the radar for Macias until his advisors recommended it.He would eventually earn a PhD in comparative biomedical sciences from North Carolina State University.

After refining his expertise during postdoctoral fellowships at the University of North Carolina at Chapel Hill and the University of Texas-Austin, he made a significant transition, trading his Tar Heel blue for the Blue Devil spirit.

From 2013-2015, he served as a project scientist in the Department of Surgery at Duke. After a stint as an assistant professor at Cedars-Sinai in Los Angeles in 2015, he rejoined Duke in 2018 as a cancer researcher.

Everardo is working at the cutting edge of prostate cancer research, said Jiaoti Huang, MD, PhD, professor and chair of the Duke Department of Pathology and member of the Duke Cancer Institute who collaborates with Macias.

His trajectory demonstrates his personal quality, perseverance, determination, and the opportunities this great country affords people of different backgrounds. His story is an inspiration to us all.

From diagnosis to treatment, the prostate cancer journey is fraught with challenges, chief among them is the task of distinguishing between deadly and less severe cases.

Very rarely, prostate cancer starts in neuroendocrine cells. Some prostate cancers become resistant to treatment and turn into neuroendocrine tumors, which are more aggressive and have a poorer outlook.

In 2022, Macias earned a Department of Defense Prostate Cancer Research Program (PCRP) Idea Development Award to pursue new treatments for neuroendocrine tumors. The DOD recently committed to funding Macias research for three more years.

Hes principal investigator of the DOD grant that includes Huang and co-investigators, Ming Chen, PhD, associate professor in pathology; and Jung Wook Park, PhD, assistant professor of pathology.

Macias lab delves into the genetics behind tumor growth, focusing on targets with tangible clinical implications. Through functional genomic screens, he has identified lesser-known protein kinases that are critical to prostate cancer tumor growth.Kinases are high-value targets because they are potentially susceptible to drug treatments.

In lab experiments, Macias and colleagues discovered that blocking NUAK2, a protein kinase prevalent in prostate cancer cells, curtailed neuroendocrine tumor cell growth.

In human cancer samples, NUAK2 gene levels were found to be highest in the lethal neuroendocrine prostate cancer subtype, Macias said. NUAK2 may be a key factor in taking on these tough tumors.

Using his research as a starting point, he collaborates with medicinal chemists and structural biologists to pinpoint pharmacological molecules in cancer cells to target with medicines, aiming for an approach that could save lives from prostate cancer.

In a career backed by major grants and teamwork with top-notch scientists, he ranks mentoring his first graduate student, Amelia Schirmer, PhD, a skilled cancer researcher, as one of his proudest achievements.

"He took a chance on me as his first student, said Schirmer who credits Macias for a productive graduate experience at Duke. I learned a lot and I will always be grateful for Dr. Macias and his mentorship.

Macias is one of nearly 40 Duke faculty mentors in the Duke Preparing Research Scholars in Biomedical Sciences Post-Baccalaureate Research Education Program (PRIME-PREP).

READ MORE: Duke University PRIME-PREP

Additionally, Macias has mentored two undergraduate Duke University students who graduated with first-author publications. The students, Peter Nam and Megan Zhao, are now applying to medical school.

When I joined the Macias lab, I had little idea of what research entailed, (but) Dr. Macias took me under his wing and showed me all that it could be, Zhao said.

He readily spent hours each week sitting with me, drawing diagrams and explaining figures, she said. Not only did he take the time to explain the purpose of each experiment we were doing, but he also trusted me to explore on my own, whether through designing next steps or troubleshooting new lab protocols.

Under his direction, Zhao went from washing glassware and taking inventory to conducting mouse studies and presenting at conferences.

Beyond the tangibles of posters and papers, Dr. Macias taught me that research comes to life in the form of a compelling story, she said. Along the way, he gave me the courage to tell my story as I work towards my dream of becoming a clinician.

The experience of working in the Macias lab for three years was just as enriching for Nam, who said Dr. Macias went out of his way to make me feel like a valued part of the research group. He ensured that I had meaningful experiences that supported my career path, from experiment design to manuscript preparation.

Macias said he has a deep commitment to mentoring aspiring researchers, especially from rural and underrepresented backgrounds, and hes actively involved in graduate admissions, summer research programs, and lab mentoring.

I believe its as simple as having a mentor of similar heritage, or who may have had a comparable upbringing as you, to make seeking guidance in academia much more approachable, he said.

Jamie Botta is a communications strategist for the Department of Pathology at the Duke University School of Medicine.

Photos by Jim Rogalski and Steve Conlon.

Main Photo: Everardo Machias, PhD, assistant professor in the Department of Pathology, assistant research professor in the Department of Cell Biology, and a member of the Duke Cancer Institute.

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From Migrant Farm Worker to Duke Scientist, Everardo Macias ... - Duke University School of Medicine

Cell Biology

Molecule discovered that grows bigger and stronger muscles – Earth.com

Over the years, scientists have embarked on anti-aging research to provide drugs and treatments that can slow or reverse aging and treat age-related diseases.Now, scientists at Stanford University have discovered an aging-related protein that can stimulate growth of stronger and larger muscles.

The 15-PGDH protein is the latest discovery by the Stanford scientists, who are working on possible treatments for diminished strength and paralysis due to trauma, heritable neuromuscular diseases, or aging.

Using a mouse model, the researchers injected a 15-PGDH-blocking molecule in older mice. They followed the simulated injuries to the sciatic nerves of the injected mice with treatments.

This led to more prostaglandin E2 (PGE2) production, followed by the growth of stronger and larger muscle fibers in the mice.

By inhibiting the 15-PGDH, also known as gerozyme, the researchers significantly improved the endurance and strength of the muscles grown in the lab.

The researchers found that 15-prostaglandin dehydrogenase (15-PGDH), which accumulates with age and promotes muscle atrophy, markedly increased in denervated mouse myofibers and aggregated in target fibers, hallmarks of chronic nerve damage in human myogenic neuropathies, noted Melissa L. Norton, the editor of the published study.

Treating older mice with chronic muscle denervation with the 15-PGDH inhibitor enhanced the motor neurons and rejuvenated the neuromuscular junctions and function.

This could potentially help older adults who experience increasingly weaker muscles with age and people dealing with muscle-wasting diseases like amyotrophic lateral sclerosis (ALS).

Our data suggests that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease or aging, the researchers noted in their report.

Although this latest study expands on existing evidence of protein regulating muscle function during aging in mice, the researchers have described it as unique.

Study co-author Dr. Helen Blau is the director of the Baxter Laboratory for Stem Cell Biology at Stanford.

This is the first time a drug treatment has been shown to affect both muscle fibers and the motor neurons that stimulate them to contract, speeding up healing and restoring strength and muscle mass, said Dr. Blau.

The Stanford scientists want to build on their findings to see if this mechanism can be transitioned into real-life treatments and therapy.

Our next steps will be to examine whether blocking 15-PGDH function in people with conditions like spinal muscular atrophy, in combination with gene therapy or other treatments, can increase lost muscle strength, said Dr. Blau.

We are also looking at ALS to see if something like this might help these patients. Its really exciting that we are able to affect both muscle function and motor neuron growth.

Weak muscle strength is a huge problem among elders. According to a study by the Centers for Disease Control and Prevention (CDC), five percent of adults aged 60 and over have weak muscle strength, while 13 percent have intermediate muscle strength.

But muscle weakness isnt just a concern for older people. It starts creeping in as early as your 50s and comes with a great economic cost. Weaker muscles reduce the ability to move around, work, and care for oneself. This condition also increases the risk of injuries.

The good news is that science is making promising strides toward addressing this widespread problem. With continued research and advancement, a lasting solution for muscle weakness may be on the horizon.

The study can be found in the journal Science Translational Medicine.

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Molecule discovered that grows bigger and stronger muscles - Earth.com

Cell Biology

Spermidine May Improve Egg Health and Fertility – Lifespan.io News

Reporters publishing in Nature Aging have identified a metabolite that appears to restore the age-related loss of quality of egg cells (oocytes) in mice.

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While it was originally found in semen, the metabolite spermidine has been found in many different tissues, including ovaries [1]. This molecule has been found to be involved in the regulation of multiple fundamental aspects of metabolism and aging, reducing inflammation and influencing oxidative stress, genomic stability, mitochondrial maintenance, and proteostasis [2].

Previous work has found that spermidine administration lengthens the lifespan of model organisms and human cells by inducing autophagy [3]. Other work has found that it improves memory [4] and heart function [5] in mice.

As researchers have previously found that other metabolic molecules, such as NMN, have positive effects on ovarian aging [6], this work sets out to discover whether spermidine may also have an impact.

The experimentation began with a comparison of the metabolome, the collection of metabolic biochemicals, in the the ovaries of younger and older mice. The differences were clear and substantial. Pathways related to steroid hormones were substantially upregulated in older animals, while pyrimidines and purines were downregulated, as was amino acid synthesis. Spermidine was also substantially downregulated.

The researchers then tested the effects of spermidine supplementation and found positive results. As expected, the supplement injection increased spermidine levels in ovaries. In older mice, the ovarian follicles are degenerated, but this appeared to have been partially restored through spermidine injection. The oocytes matured more quickly, and they became more receptive to sperm and more likely to be successfully fertilized.

Autophagy, as expected, was positively affected. In particular, mitophagy, the clearing-out of damaged mitochondria, was critical in the positive effects, which included a decrease in reactive oxygen species. Spermidine also had positive effects on other aspects of the metabolome. While spermidine did not restore the various pathways to the levels seen in young mice, it had substantial metabolic effects, including on the Wnt signaling pathway and the circadian rhythm.

The fertility of the mice was directly tested. Mice give birth to litters, and their litter size is affected by aging. Young mice often give birth to fourteen pups at a time, while older mice normally give birth to only three. However, older mice given spermidine gave birth to an average of six.

Chromosomes were also positively affected. The number of chromosomal aberrations and misalignments were significantly decreased by spermidine. This had downstream consequences: in addition to the increased fertilization rate, embryos from mice given spermidine were more likely to successfully divide and grow into pups.

The effects of spermidine are not unique to mice. Oocytes were taken from pigs and exposed to hydrogen peroxide, which led to an increase in reactive oxygen species. Spermidine was found to alleviate this increase, suggesting a potential improvement in fertility.

However, this does not prove that it increases fertility in pigs or humans. Only clinical trials can prove that, and given the long gestation time of people and the need for a sufficiently large trial, it may be some time before this or another supplement can be said to be clinically proven to improve fertility. However, if it does, it may give hope to aging women who want to birth more children.

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[1] Lefvre, P. L., Palin, M. F., & Murphy, B. D. (2011). Polyamines on the reproductive landscape. Endocrine reviews, 32(5), 694-712.

[2] Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.

[3] Eisenberg, T., Knauer, H., Schauer, A., Bttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., & Madeo, F. (2009). Induction of autophagy by spermidine promotes longevity. Nature cell biology, 11(11), 1305-1314.

[4] Wang, I. F., Guo, B. S., Liu, Y. C., Wu, C. C., Yang, C. H., Tsai, K. J., & Shen, C. K. J. (2012). Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proceedings of the National Academy of Sciences, 109(37), 15024-15029.

[5] Eisenberg, T., Abdellatif, M., Schroeder, S., Primessnig, U., Stekovic, S., Pendl, T., & Madeo, F. (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nature medicine, 22(12), 1428-1438.

[6] Miao, Y., Chen, J., Gao, Q., & Xiong, B. (2021). Generation and assessment of high-quality mouse oocytes and embryos following nicotinamide mononucleotide administration. STAR protocols, 2(1), 100298.

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Spermidine May Improve Egg Health and Fertility - Lifespan.io News

Cell Biology

Association for Molecular Pathology Publishes Best Practice … – Technology Networks

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The Association for Molecular Pathology (AMP), the premier global molecular diagnostic professional society, has published a set of 13 best practice recommendations for validating and reporting clinical circulating tumor DNA (ctDNA) or liquid biopsy assays and their related scientific publications. The manuscript, Recommendations for Cell-free DNA Assay Validations: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists (CAP), was released online ahead of publication in The Journal of Molecular Diagnostics.

One of the most important technological advances in molecular diagnostics over the past decade has been the ability to accurately detect and measure low abundance ctDNA in blood and body fluids, said Christina Lockwood, PhD, Chair of the AMP Liquid Biopsy Working Group and Professor and Division Head of Laboratory Genetics at the University of Washington School of Medicine. As with any emerging technology or methodology, the way these liquid biopsy assays are developed, validated, and reported can vary. This new report provides a set of evidence-based recommendations that can help promote standardization, transparency, and quality improvement among laboratories.

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The AMP Clinical Practice Committees Liquid Biopsy Working Group, including organizational representation from the American Society of Clinical Oncology (ASCO) and CAP, developed a set of recommendations for validating, reporting, and publishing clinical ctDNA assays. The recommendations are based on a review of more than 1,200 publications that describe ctDNA assay performance in patients with lymphoma and solid tumor malignancies and subject matter expert professional experience. The recommendations include reporting key pre-analytical considerations and assay performance metrics.

This new report was meant to summarize the current collective state of knowledge and assist clinical laboratory professionals with liquid biopsy assay validation, said Susan Hsiao, MD, PhD, 2023 AMP Clinical Practice Committee Chair and Associate Professor of Pathology and Cell Biology at Columbia University Irving Medical Center. As part of our ongoing commitment to improving clinical practice and patient care, AMP will continue to reassess and modify our recommendations as these technologies become more sensitive and additional trials are available to evaluate assay performance and clinical utility.

Reference: Lockwood CM, Borsu L, Cankovic M, et al. Recommendations for cell-free DNA assay validations. J Mol Diag. Published online October 2023:S1525157823002192. doi: 10.1016/j.jmoldx.2023.09.004

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Association for Molecular Pathology Publishes Best Practice ... - Technology Networks

Cell Biology

SGIOY: 3 Biotech Stocks With Potential Future Gains – StockNews.com

The pharmaceutical industry has grown substantially in recent years, and the rising demand and tech integration make its outlook promising. Moreover, the industrys ability to maintain stability despite economic uncertainties makes it an attractive investment destination.

Given the favorable industry backdrop, investors could consider buying quality pharma stocks Shionogi & Co., Ltd. (SGIOY), Exelixis, Inc. (EXEL), and Jazz Pharmaceuticals plc (JAZZ) to beat the market.

The pharmaceutical market is experiencing robust growth driven by innovative drugs and increased healthcare demand, especially in emerging markets. Original prescription drugs dominate the market, with a few blockbuster drugs generating over $1 billion in revenue annually.

The industrys growth is also propelled by innovations like cell and gene therapy, mRNA vaccine technology, improving supply chains, and evolving product offerings. As per Statista, the global pharmaceutical market revenue is projected to reach $1.16 trillion this year.

Additionally, progress in the field of cancer biology and the increasing prevalence of severe diseases make precision medicine indispensable. Moreover, ongoing technological advancements and breakthroughs in cell biology continue to drive the market forward.

The Precision Medicine market is expected to grow from $77.02 billion this year to $99.24 billion by 2028, registering a CAGR of 5.2%.

Furthermore, the pharmaceutical industry increasingly embraces artificial intelligence (AI). Strategic investments in AI partnerships are growing, underlining the importance of AI in pharmaceutical advancements. The pharmaceutical industry is also experiencing growth in generative AI for drug discovery, driven by the availability of extensive datasets and collaborative efforts.

The global generative AI in drug discovery market size is projected to surpass around $1.13 billion by 2032, expanding at a CAGR of 27.1%.

Considering these conducive trends, lets analyze the fundamentals of three Biotech picks, beginning with the third choice.

Stock #3: Shionogi & Co., Ltd. (SGIOY)

Headquartered in Osaka, Japan, SGIOY engages in the research, development, manufacture, and distribution of pharmaceuticals, diagnostic reagents, and medical devices. The companys offerings include Fetroja, a multidrug-resistant bacterial infection treatment; Xofluza, an influenza virus drug; and Tivicay, an anti-HIV drug.

On October 12, 2023, SGIOY presented real-world evidence (RWE) at IDWeek2023, suggesting that the use of Fetroja (cefiderocol) effectively treats Gram-negative infections, particularly in patients who received it earlier (within 6-20 days of diagnosis), resulting in lower in-hospital all-cause mortality (IHACM).

The study highlights the clinical utility of Fetroja in the treatment of challenging Gram-negative infections, addressing a significant health concern related to antimicrobial resistance.

On October 6, SGIOY acquired 1,129,800 shares of its common stock, valued at 7.42 billion ($49.56 million) between September 1, 2023, and September 30, 2023. This acquisition aligns with the boards resolution on July 31, 2023, to acquire up to 12,500,000 shares with a maximum cost of 75 billion ($501.29 million) from August 1, 2023, to March 31, 2024. As of September 30, 2023, SGIOY had acquired 3,052,200 shares valued at 19.43 billion ($129.88 million).

SGIOYs revenue grew 52.2% year-over-year to 109.31 billion ($730.62 million) in the fiscal first quarter that ended June 30, 2023. The companys operating profit rose 274.9% year-over-year to 46.59 billion ($311.40 million).

In addition, profit attributable to owners of the parent rose 22.6% from the prior years quarter to 42.56 billion ($286.61 million), and EPS amounted to 144.57 billion, up 25.6% year-over-year.

SGIOYs revenue for the current fiscal year ending March 2024 is likely to rise 5.3% year-over-year to $2.90 billion. Its EPS is expected to be $0.94 in the same year. Also, it has surpassed the consensus revenue estimates in each of the trailing four quarters, which is remarkable.

The stock has gained 7% over the past three months to close the last trading session at $11.23.

SGIOYs POWR Ratings reflect this promising outlook. The stock has an overall rating of B, equating to a Buy in our proprietary rating system. The POWR Ratings are calculated by considering 118 different factors, with each factor weighted to an optimal degree.

SGIOY has a B for Growth, Value, and Quality. It is ranked #15 in the 359-stock Biotech industry.

In addition to the highlighted POWR Ratings, one can see SGIOYs ratings for Stability, Momentum, and Sentiment here.

Stock #2: Exelixis, Inc. (EXEL)

EXEL explores, develops, and markets novel cancer treatments. The company provides CABOMETYX tablets for advanced renal cell carcinoma patients with previous anti-angiogenic therapy and COMETRIQ capsules for progressive and metastatic medullary thyroid cancer treatment.

On September 12, EXEL and Insilico Medicine, a global clinical-stage biotechnology company powered by generative AI, unveiled an exclusive license agreement, granting EXEL global rights to develop and commercialize ISM3091, a potentially best-in-class small molecule inhibitor of USP1, which has emerged as a synthetic lethal target in the context of BRCA-mutated tumors.

The partnership leverages EXELs clinical development expertise and highlights ISM3091s potential in addressing various BRCA-mutant tumors, including those found in ovarian, prostate, and breast cancer.

On August 24, the Alliance for Clinical Trials in Oncologys independent Data and Safety Monitoring Board (DSMB) unanimously recommended prematurely concluding the phase 3 CABINET pivotal trial due to an exceptional surge in efficacy observed at an interim analysis.

This outcome positions EXEL as an oncology innovator, particularly in addressing advanced pancreatic or extra-pancreatic neuroendocrine tumors where no established standard of care exists post-therapy.

In the second quarter that ended June 30, 2023, EXELs total revenues increased 12% year-over-year to $469.85 million. Its income before income taxes rose 13.4% from the year-ago quarter to $100.39 million. The companys non-GAAP net income and non-GAAP net income per share stood at $100.30 million and $0.31, up 11.8% and 10.7% year-over-year, respectively.

EXEL reaffirms its fiscal year 2023 financial guidance, with expectations of total revenues between $1.78 billion and $1.88 billion. Net product revenues are estimated to fall within the range of $1.58 billion to $1.68 billion, while the cost of goods sold is projected to be 4.0% to 5.0% of net product revenues.

Analysts expect EXELs revenue to increase 14.7% year-over-year to $472.33 million in the fiscal third quarter that ended September 2023. The companys EPS for the to-be-announced quarter is expected to be $0.18. Moreover, EXEL exceeded the consensus revenue and EPS estimates in three of the four trailing quarters.

The stock has gained 36.4% over the past year and 10.4% over the past three months, closing the last trading session at $21.36.

EXELs robust prospects are reflected in its POWR Ratings. The stock has an overall rating of B, which translates to a Buy in our proprietary rating system.

EXEL has an A grade for Value and Quality and a B for Sentiment. It is ranked #11 in the same industry. Click here to access EXELs additional ratings for Growth, Momentum, and Stability.

Stock #1: Jazz Pharmaceuticals plc (JAZZ)

JAZZ identifies, develops, and commercializes pharmaceutical products for unmet medical needs in the United States, Europe, and internationally. The company has a portfolio of products and product candidates focusing on neuroscience, including sleep medicine and movement disorders, and oncology, such as hematologic and solid tumors.

On September 21, JAZZ announced that the European Commission had granted marketing authorization for Enrylaze (JZP458), a recombinant Erwinia asparaginase, for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in patients who are hypersensitive or have silent inactivation to E. coli-derived asparaginase.

Enrylaze, known as Rylaze in the United States and Canada, is a new Erwinia-derived asparaginase with a safe profile. This approval is significant in ensuring patients can complete their asparaginase treatment regimen for improved outcomes in ALL and LBL.

On August 2, JAZZ announced that it had entered into a Letter of Intent (LOI) with the Pan-Canadian Pharmaceutical Alliance (pCPA) for Rylaze in Canada.

During the fiscal second quarter that ended June 30, 2023, JAZZs total revenues increased 2.6% year-over-year to $957.32 million. Its income from operations rose 84.3% year-over-year to $157.64 million, and non-GAAP net income rose 6.4% year-over-year to $325.13 million.

Moreover, its adjusted earnings per share increased 4.9% from the year-ago quarter to $4.51.

JAZZ anticipates strong performance across key metrics in its non-GAAP financial guidance for 2023. The company expects a gross margin of 93% and SG&A expenses in the range of $1.05 billion to $1.11 billion, representing 27% to 30% of total revenues. Research and development (R&D) expenses are projected to be between $675 million and $725 million, comprising 17% to 19% of total revenues.

Additionally, the company had projected a net income of $1.29 billion to $1.34 billion, resulting in a net income per diluted share between $18.15 and $19.00.

Street expects JAZZs revenue for the quarter that ended September 2023 to increase 3.1% year-over-year to $970.04 million. Its EPS for the same quarter is likely to amount to $4.90.

Shares of JAZZ rose marginally intraday to close the last trading session at $129.12.

Unsurprisingly, JAZZ has an overall rating of A, which translates to a Strong Buy in our proprietary rating system.

It has an A grade for Value and a B for Growth and Quality. It is ranked #3 in the same industry. Click here to access JAZZs Momentum, Stability, and Sentiment ratings.

What To Do Next?

Get your hands on this special report with 3 low priced companies with tremendous upside potential even in todays volatile markets:

3 Stocks to DOUBLE This Year >

SGIOY shares were trading at $11.40 per share on Monday morning, up $0.17 (+1.51%). Year-to-date, SGIOY has declined -7.92%, versus a 14.99% rise in the benchmark S&P 500 index during the same period.

Her interest in risky instruments and passion for writing made Kritika an analyst and financial journalist. She earned her bachelor's degree in commerce and is currently pursuing the CFA program. With her fundamental approach, she aims to help investors identify untapped investment opportunities. More...

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SGIOY: 3 Biotech Stocks With Potential Future Gains - StockNews.com

Cell Biology

A new cell type with links to gastric cancer steps up for its mugshot – Fred Hutch News Service

Deep inside the stomachs of an estimated half of the worlds population lurks a bacterium known as Helicobacter pylori, a bug that means business. While many people are infected and never even know, in some cases chronic H. pylori infections predispose individuals to develop gastric (stomach) cancer, the fifth most common cancer type worldwide. The Salama Lab in the Human Biology Division at Fred Hutchinson Cancer Center has built its reputation studying this enigmatic bug, focusing on the bacterium, the host, and everything in between. A recent study from the labpublished in Cancer Research Communications and helmed by former postdoc Dr. Valerie OBrientakes the team into uncharted territory and promises a greater understanding of how H. pylori promotes gastric disease.

In order to understand the relationship between H. pylori and gastric cancer, explains Dr. Salama, its important to distinguish between the tissue inflammation that H. pylori causes and the development of gastric cancer. Indeed, the link between inflammation and carcinogenesis in the stomach is complicatedinflammation isnt strictly required for gastric cancer to develop, and many patients with stomach inflammation wont develop gastric cancer. To better clarify this relationship, Drs. OBrien and Salama turned to an innovative transgenic mouse model in which an oncogenic KRAS protein is artificially expressed the stomachs chief cells (the cells which produce and secrete digestive enzymes), which causes gastric dysplasia similar to what is seen in human patients prior to the development of gastric cancer. In what was a surprising finding, the team discovered that H. pylori-driven inflammation synergizes with oncogenic KRAS to worsen gastric dysplasia in these mice. This suggested that H. pylori may not merely plant the seeds of gastric cancer, but may also provide fertile ground for those seeds to grow. However, one big question remained: was H. pylori simply accelerating disease progression in these mice, or was it causing a different disease trajectory altogether?

In their most recent publication, Dr. OBrien and colleagues address this question by leveraging state-of-the-art single cell RNA sequencing (scRNA-seq) of stomach tissue from KRAS-expressing mice with or without concurrent H. pylori infection. By clustering cell types based on the expression of different marker genes and comparing these cell types between conditions, the team found that the combination of oncogenic KRAS expression and H. pylori infection resulted in the expansion of a specific type of pit cell (a different cell type found in the stomach lining) expressing a gene called Muc4. Importantly, they found very few Muc4-expressing pit cells in mice with oncogenic KRAS expression or H. pylori infection alone. Whats more, they found that expansion of these Muc4-expressing pit cells requires H. pylori-driven gastric inflammation and that these cells also express amphiregulin, an epithelial cell protein involved in cell growth and wound healing. But is any of this relevant to gastric cancers in patients? Strikingly, it appears soOBrien and colleagues found MUC4-expressing pit cells in human gastric cancer tissue samples, where they appear to increase in number over the course of disease progression and co-express markers of high cell proliferation. Future work will test whether this cell type helps drive active disease.

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A new cell type with links to gastric cancer steps up for its mugshot - Fred Hutch News Service

Cell Biology

Programmed cell death may be 1.8 billion year – EurekAlert

Apoptosis, often referred to as programmed cell death, is a fundamental process crucial to the growth and development of multicellular organisms. This process, or a primordial form of it, is also observed in single-celled eukaryotes like yeast and other microeukaryotes (aka protists). The origin of eukaryotic apoptosis remains an open question in biology. However, studies have noted that many apoptosis-initiating factors have a bacterial or mitochondrial origin, providing a clue into the evolutionary history of this widespread phenomenon. In a new study published in Genome Biology and Evolution, scientists from the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences reveal that many apoptotic factors may trace their origins to the time of mitochondrial domestication, suggesting remarkable conservation over the span of 1.8 billion years.

The processes triggering apoptosis exhibit striking similarities among various diverse eukaryotes: an increase in mitochondrial membrane permeability sets in motion a cascade of events involving proteins called apoptosis-inducing factors (AIFs), kickstarting the pathway that culminates in cell death. According to phylogenetic analyses, these AIFs usually have a bacterial/mitochondrial origin. To shed further light on the evolution of apoptosis across eukaryotes, a team led by Szymon Kaczanowski and Urszula Zielenkiewicz investigated the functional conservation of apoptotic factors through a yeast complementation test. The researchers replaced each of four apoptotic genes in yeast with related proteins from diverse eukaryotes and prokaryotes. They then treated the new yeast strains with apoptosis-inducing agents to evaluate whether the introduced genes maintained the ability to induce apoptosis in yeast.

Remarkably, the study found that distantly related proteins from plants, animals, slime molds, and bacteria were largely able to functionally substitute for the original yeast proteins. This surprising finding suggests that ancient mechanisms of cell death have been evolutionarily conserved since the domestication of mitochondria, says Kaczanowski and Zielenkiewicz, an event that occurred approximately 1.8 billion years ago.

The studys findings further support an endosymbiotic origin of apoptosis, a hypothesis that was first proposed by Guido Kroemer in 1997. Kroemer suggested that the bacterial precursors of mitochondria produced both toxins (apoptotic factors) and antitoxins (anti-apoptotic factors). In this scenario, the antitoxins acted as addiction molecules, ensuring the persistence of the symbiont. Driven by this evolutionary conflict between bacterial endosymbionts and hosts, the toxins eventually evolved into the apoptotic factors we recognize today.

Kaczanowski and Zielenkiewicz present an alternative scenario for the evolution of apoptosis. They propose that early protoeukaryotes were predators, relying on bacterial prey. These bacteria, in response to predation, produced toxins as a defense mechanism. Over time, these bacteria were domesticated to serve as mitochondria within eukaryotic cells, and their toxins evolved into apoptotic factors. The different families of AIFs present today and their sporadic distribution across distantly related eukaryotes suggest the existence of multiple redundant toxins in the protomitochondria and hint at a coevolutionary arms race between protomitochondria and their protoeukaryotic hosts.

Regardless of whether apoptosis originates from an endosymbiotic toxin/antitoxin system or from a predator/prey dynamic, the studys findings suggest that the intricate balance between life and death within eukaryotic cells is deeply rooted in the origin of mitochondria, opening up new avenues for research into the coevolution of mitochondria and eukaryotes, as well as the ancient origins of cell death mechanisms. Furthermore, a similar approach could be used to look at other ancient cellular mechanisms beyond programmed cell death and to ask to what extent conflicts among partners/participants have driven the evolution of genome features. Future studies may reveal the evolutionary history of other aging mechanisms and could make a significant contribution to aging studies, note Kaczanowski and Zielenkiewicz, emphasizing the broader implications of their research.

Genome Biology and Evolution

Observational study

Cells

Apoptotic Factors Are Evolutionarily Conserved Since Mitochondrial Domestication

11-Oct-2023

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Programmed cell death may be 1.8 billion year - EurekAlert