In the cover paper of this week's issue of Oncotarget (Volume 12, Issue 8), titled, "Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas," researchers examined five potential biomarkers across 18 different histologic subtypes of sarcoma in 163 tissue samples. Immunohistochemical staining, statistical analysis, and correlation-based network analysis revealed promising results.



Researchers from the University of Iowa, University of Alabama at Birmingham, and the Mayo Clinic, report the need for additional prognostic and therapeutic biomarkers to predict clinical behavior across different histological types of sarcoma. 



“Although the French (FNCLCC) and NCI grading schemes have been adopted for many sarcomas, there is a substantial subset of sarcomas for which the grading scheme does not adequately predict clinical behavior.”

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DOI: https://doi.org/10.18632/oncotarget.27928
Full text: https://www.oncotarget.com/article/27928/text/

Correspondence to: Munir R. Tanas - munir-tanas@uiowa.edu

About Oncotarget:

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls

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Oncotarget

Oncotarget: A New Potential Network of Biomarkers Useful Across Sarcomas

Pelotonia has changed Joe Apgar’s life. “I’ll never forget how I felt in the moment someone told me I had cancer,” the CEO of Pelotonia said in this episode. “You feel completely lost and by yourself and you don’t have answers to the questions running around through your head.” Apgar was diagnosed with testicular cancer while a student at Penn State. Pelotonia is the fundraising cycling event that has raised more than $285 million for cancer research at the James. Apgar first rode in 2011, soon after he moved to Columbus to work for Rockbridge Capital, a private equity firm that sponsors a Pelotonia team Apgar helped create. “I remember standing at my first opening ceremony [of Pelotonia] and how uplifted and excited and supported I felt … that’s when I could flip the switch on it and feel empowered by my own story and experience,” Apgar said of the start of his first ride and crossing the finish line. Apgar talked about his cancer journey, how he connected with a James physician for his follow-up cancer care, his Pelotonia experiences as a rider and leader, and the future of the event. Apgar also talked about the importance of the Pelotonia “community” and how it has helped connect members of the James team with riders, volunteers and donors. “I think [the Pelotonia founders] hoped that some of this sense of community would happen, but I don’t think anyone could have dreamed it would happen at the scale it has,” he said.

Episode 163: The Incredible Impact of Pelotonia, with CEO Joe Apgar

BUFFALO, NY- May 6, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 3, 2024, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.”

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. In this new study, researchers Shengliang Zhang and Wafik S. El-Deiry from Brown University and Lifespan Health System examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. 

“We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells.”

The researchers further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. 

Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. 

“A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.”

DOI - https://doi.org/10.18632/oncotarget.28582

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

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About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Transfected SARS-CoV-2 Spike DNA Suppresses Cancer Cell Response to Chemotherapy

In this episode, Dr. David Bishop, a Specialist Anesthesiologist and Head of the Clinical Unit of Anaesthesia at Edendale Hospital in Pietermaritzburg talks about a vital topic and his recent publication, Tranexamic acid at cesarean delivery: drug-error deaths.



Tranexamic acid at cesarean delivery: drug-error deaths

https://pubmed.ncbi.nlm.nih.gov/36300729/

Spinal tranexamic acid - a new killer in town

https://pubmed.ncbi.nlm.nih.gov/30985919/

 

YouTube publication (Tranexamic acid during CS: Drug error warning (https://www.youtube.com/watch?v=jeFtFWeMwkw&t=184s)



Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

https://pubmed.ncbi.nlm.nih.gov/28456509/

Tranexamic Acid: Drug error deaths

BUFFALO, NY- May 7, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 8, entitled, “Associations among NMR-measured inflammatory and metabolic biomarkers and accelerated aging in cardiac catheterization patients.”

Research into aging has grown substantially with the creation of molecular biomarkers of biological age that can be used to determine age acceleration. Concurrently, nuclear magnetic resonance (NMR) assessment of biomarkers of inflammation and metabolism provides researchers with new ways to examine intermediate risk factors for chronic disease.

In this new study, researchers Henry Raab, Elizabeth R. Hauser, Lydia Coulter Kwee, Svati H. Shah, William E. Kraus, and Cavin K. Ward-Caviness from the U.S. Environmental Protection Agency and Duke University used data from a cardiac catheterization cohort to examine associations between biomarkers of cardiometabolic health and accelerated aging assessed using both gene expression (Transcriptomic Age) and DNA methylation (Hannum Age, GrimAge, Horvath Age, and Phenotypic Age). 

“This study utilizes the CATHGEN cohort from the Jiang et al. study to investigate associations between multiple epigenetic and transcriptomic aging biomarkers and a broad array of NMR-based measures of inflammation, lipid homeostasis, and diabetes risk.”

Linear regression models were used to associate accelerated aging with each outcome (cardiometabolic health biomarkers) while adjusting for chronological age, sex, race, and neighborhood socioeconomic status. Their study shows a robust association between GlycA and GrimAge (5.71, 95% CI = 4.36, 7.05, P = 7.94 × 10−16), Hannum Age (1.81, 95% CI = 0.65, 2.98, P = 2.30 × 10−3), and Phenotypic Age (2.88, 95% CI = 1.91, 3.87, P = 1.21 × 10−8). The researchers also saw inverse associations between apolipoprotein A-1 and aging biomarkers. 

“These associations provide insight into the relationship between aging and cardiometabolic health that may be informative for vulnerable populations.”

DOI - https://doi.org/10.18632/aging.205758

Corresponding authors - Cavin K. Ward-Caviness - ward-caviness.cavin@epa.gov

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Keywords - aging, biological aging, NMR, biomarkers, cardiac catheterization

About Aging-US

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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Aging (Aging-US)

Inflammatory and Metabolic Biomarkers and Accelerated Aging in Cardiac Catheterization Patients

Welcome to this week’s episode of YJBM Science News, where we discuss the recent news in healthcare and science across the Yale community. Today, our hosts Mara and Samantha will share some of the most intriguing topics of the past two weeks.

Links:
https://www.pnas.org/doi/10.1073/pnas.2319566121
https://www.aeaweb.org/articles?id=10.1257/aeri.20230340
https://www.pnas.org/doi/10.1073/pnas.2320713121
https://www.nber.org/papers/w32354

YJBM Science News Podcast: Episode 18

BUFFALO, NY- May 8, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 7, 2024, entitled, “Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.”

The sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. In this new study, researchers Kevin C. Ma, Esther Mena, Liza Lindenberg, Nathan S. Lay, Phillip Eclarinal, Deborah E. Citrin, Peter A. Pinto, Bradford J. Wood, William L. Dahut, James L. Gulley, Ravi A. Madan, Peter L. Choyke, Ismail Baris Turkbey, and Stephanie A. Harmon from the National Institutes of Health’s National Cancer Institute proposed an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans.

“AI-generated PET images has clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality in prostate cancer patients.”

Methods: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA (prostate-specific membrane antigen) PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling.

Results: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05).

“The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.”

DOI - https://doi.org/10.18632/oncotarget.28583

Correspondence to - Stephanie A. Harmon - stephanie.harmon@nih.gov

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About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Deep Learning-based Whole-body Prostate-specific Membrane Antigen PET/CT Attenuation Correction

BUFFALO, NY- May 8, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 8, entitled, “The association between neighborhood deprivation and DNA methylation in an autopsy cohort.”

Previous research has found that living in a disadvantaged neighborhood is associated with poor health outcomes. Living in disadvantaged neighborhoods may alter inflammation and immune response in the body, which could be reflected in epigenetic mechanisms such as DNA methylation (DNAm). In this new study, researchers Lindsay Pett, Zhenjiang Li, Sarina Abrishamcar, Kenyaita Hodge, Todd Everson, Grace Christensen, Marla Gearing, Michael S. Kobor, Chaini Konwar, Julia L. MacIsaac, Kristy Dever, Aliza P. Wingo, Allan Levey, James J. Lah, Thomas S. Wingo, and Anke Hüls from Emory University, University of British Columbia, BC Children’s Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, and Atlanta VA Medical Center used robust linear regression models to conduct an epigenome-wide association study examining the association between neighborhood deprivation (Area Deprivation Index; ADI), and DNAm in brain tissue from 159 donors enrolled in the Emory Goizueta Alzheimer’s Disease Research Center (Georgia, USA). 

“We found one CpG site (cg26514961, gene PLXNC1) significantly associated with ADI after controlling for covariates and multiple testing (p-value=5.0e-8).”

Effect modification by APOE ε4 was statistically significant for the top ten CpG sites from the EWAS of ADI, indicating that the observed associations between ADI and DNAm were mainly driven by donors who carried at least one APOE ε4 allele. Four of the top ten CpG sites showed a significant concordance between brain tissue and tissues that are easily accessible in living individuals (blood, buccal cells, saliva), including DNAm in cg26514961 (PLXNC1). This study identified one CpG site (cg26514961, PLXNC1 gene) that was significantly associated with neighborhood deprivation in brain tissue. PLXNC1 is related to immune response, which may be one biological pathway how neighborhood conditions affect health. 

“The concordance between brain and other tissues for our top CpG sites could make them potential candidates for biomarkers in living individuals.”

DOI - https://doi.org/10.18632/aging.205764

Corresponding author - Anke Hüls - anke.huels@emory.edu

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About Aging-US

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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Association Between Neighborhood Deprivation and DNA Methylation in an Autopsy Cohort

BUFFALO, NY- May 9, 2024 – A new review #paper was #published in advance by Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), entitled, “The beginning of becoming a human.”

According to birth certificates, the life of a child begins once their body comes out of the mother’s womb. In this new review, researchers Polina A. Loseva and Vadim N. Gladyshev from Harvard Medical School pose the controversial question: when does their organismal life begin? Science holds a palette of answers—depending on how one defines a human life.

In 1984, a commission on the regulatory framework for human embryo experimentation opted not to answer this question, instead setting a boundary, 14 days post-fertilization, beyond which any experiments were forbidden. Recently, as the reproductive technologies developed and the demand for experimentation grew stronger, this boundary may be set aside leaving the ultimate decision to local oversight committees. 

While science has not come closer to setting a zero point for human life, there has been significant progress in our understanding of early mammalian embryogenesis. It has become clear that the 14-day stage does in fact possess features, which make it a foundational time point for a developing human. Importantly, this stage defines the separation of soma from the germline and marks the boundary between rejuvenation and aging. 

“We explore how different levels of life organization emerge during human development and suggest a new meaning for the 14-day stage in organismal life that is grounded in recent mechanistic advances and insights from aging studies.”

DOI - https://doi.org/10.18632/aging.205824

Corresponding authors - Polina A. Loseva - polina.loseva89@gmail.com, and Vadim N. Gladyshev - vgladyshev@rics.bwh.harvard.edu

Video short - https://www.youtube.com/watch?v=8LYjXYaePaM

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Keywords - aging, human, life, 14-day rule

About Aging-US

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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The Beginning of Becoming a Human: A Review

The profound impact of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been felt across various domains, including the realm of cancer research and treatment. As scientists delve deeper into the intricate mechanisms of this viral pathogen, intriguing revelations have emerged regarding its potential influence on cellular processes pivotal to cancer development and progression. 

In a new study, researchers Wafik S. El-Deiry and Shengliang Zhang from Brown University and Lifespan Health System shed light on the intricate interplay between the SARS-CoV-2 spike protein and the tumor suppressor p53, a key guardian of genomic integrity. On May 3, 2024, they published their new research paper in Oncotarget’s Volume 15, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.”

In this study, researchers El-Deiry and Zhang uncovered a hitherto unknown facet of the SARS-CoV-2 spike protein’s impact on cancer cells. Their findings, meticulously detailed in their research paper, have ignited a newfound curiosity within the scientific community.

Full blog - https://www.oncotarget.org/2024/05/09/sars-cov-2-spike-protein-disrupts-p53-tumor-suppressor-pathway/

Paper DOI - https://doi.org/10.18632/oncotarget.28582

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

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Keywords - cancer, SARS-COV2 spike, p53, MDM2, chemotherapy

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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SARS-CoV-2 Spike Protein Disrupts p53 Tumor Suppressor Pathway

Dr. Chang-Yi Cui and Alexandra G. Zonnefeld from the Laboratory of Genetics and Genomics, National Institute on Aging in Baltimore, MD, discuss a research paper they co-authored that was published by Aging (Aging-US) in Volume 16, Issue 8, entitled, “Characterization of age-associated gene expression changes in mouse sweat glands.”

DOI - https://doi.org/10.18632/aging.205776

Corresponding authors - Chang-Yi Cui - cuic@mail.nih.gov, and Myriam Gorospe - gorospem@grc.nia.nih.gov

Video interview - https://www.youtube.com/watch?v=7A_TREuSv54

Abstract

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding ‘core secretory’ proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the ‘core secretory’ category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.

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Keywords - aging, FOXA1, BEST2, FOXC1, ectodysplasin/Eda, Tabby

About Aging-US

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Behind the Study: Characterization of Age-associated Gene Expression Changes in Mouse Sweat Glands

Behind the Study: Age-associated Gene Expression Changes in Mouse Sweat Glands

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form and then quickly released to Pubmed.

Oncotarget is now indexed by MEDLINE, PubMed and PMC/PubMed.

Read about the Oncotarget Scientific Integrity Process: https://www.oncotarget.com/scientific_integrity/

Oncotarget: A New Potential Network of Biomarkers Useful Across Sarcomas

Oncotarget Podcast

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