BUFFALO, NY- January 10, 2024 – A new #editorial paper was #published in Oncotarget's Volume 14 on December 22, 2023, entitled, “One more step toward treatment of PARP inhibitor-resistant ovarian cancers.”

Over 80% of ovarian cancer cases experience recurrence, resulting in roughly 12,000 annual deaths in the United States. While targeted therapies like poly (ADPribose) polymerase inhibitors (PARPis) have received FDA approval for both initial and recurrent treatments, extending median progression-free survival for individuals with homologous recombination repair (HRR) deficiency, the emergence of PARPi resistance remains a common challenge among patients. Consequently, addressing resistance to PARPi treatment in ovarian cancer has become a pressing therapeutic dilemma, necessitating innovative strategies. 

In this editorial, researchers Upasana Ray, Prabhu Thirusangu and Viji Shridhar from Mayo Clinic School of Medicine and Science responded to this unmet need with their current study, which unveiled promising findings related to the Pixatimod (PG545) drug, a sulfated small molecule compound. Engineered with a core structure mimicking heparan sulfate, this compound targets heparanase and heparin binding growth factor (HB-GF) signaling. 

“Our present study has revealed a previously unknown effect of PG545 in ovarian cancer cells, inducing DNA damage. The investigation unveiled that PG545 induces both single- and double-strand breaks in DNA while also promoting the autophagic degradation of RAD51, a critical DNA repair protein, thereby impeding the homologous recombination repair (HRR) pathway in cancer cells.”

DOI - https://doi.org/10.18632/oncotarget.28545

Correspondence to - Viji Shridhar - Shridhar.Vijayalakshmi@mayo.edu

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Keywords - cancer, ovarian cancer, PARP inhibitors, PG545, DNA damage, cell death

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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One More Step Toward Treatment of PARP Inhibitor-resistant Ovarian Cancers

The James Cancer and Aging Resiliency (CARE) clinic is a leader in treating older cancer patients. Patients have been treated with blood and bone marrow transplants (BMTs) for more than 40 years, but, initially, only younger patients were eligible. “There was a bar set as low as 40-years-old when this was a brand-new technology,” said Sarah Wall, MD, MPH, a James hematologist who specializes in treating patients with blood cancers. “Then it was 55 and 60 and 65 and now there is no official upper-age cutoff … it comes down to the individual patient.” In this episode, Wall explains the basics of BMTs. “There are two types, autologous, where a patient gets their own stem cells back, and allogeneic, in which we use donor cells,” she said. Improvements in the drugs used to treat graft-versus-host-disease (GVHD), which can occur in allogenic BMTs, have “really expanded the pool of donors for older adults who may only have siblings who are deceased or have had cancer themselves previously or some other disease that would make them ineligible,” Wall explained. “We have better drugs to prevent graft-versus-host-disease and to treat it when it does happen.” Several patients 70 and older have been treated with BMTs at the James. Wall said her oldest BMT patient is 80. “I have a [group] of the first three gentlemen 70 and older who I treated with a transplant all coming up to their five-year anniversary,” Wall said. “It’s a testament to them and to their families and caregiver support that they got through this. We’re the scaffolding they build this support on … and it’s very rewarding to be part of this and especially to open doors for people who thought they were closed.”

Episode 164:  - Treating Older Patients With Bone Marrow Transplants, with Dr. Sarah Wall

BUFFALO, NY- May 21, 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 9, entitled, “Germicidal lamps using UV-C radiation may pose health safety issues: a biomolecular analysis of their effects on apoptosis and senescence.”

The battle against the COVID-19 pandemic has spurred a heightened state of vigilance in global healthcare, leading to the proliferation of diverse sanitization methods. Among these approaches, germicidal lamps utilizing ultraviolet (UV) rays, particularly UV-C (wavelength ranging from 280 to 100 nm), have gained prominence for domestic use. 

These light-emitting diode (LED) lamps are designed to sanitize the air, objects, and surfaces. However, the prevailing concern is that these UV lamps are often introduced into the market without adequate accompanying information to ensure their safe utilization. Importantly, exposure to absorbed UV light can potentially trigger adverse biological responses, encompassing cell death and senescence.

In this new study, researchers Nicola Alessio, Alessia Ambrosino, Andrea Boggi, Domenico Aprile, Iole Pinto, Giovanni Galano, Umberto Galderisi, and Giovanni Di Bernardo from the University of Campania Luigi Vanvitelli, Regional Public Health Laboratory in Siena, Italy, ASL Napoli 1 Centro P.S.I. Napoli Est-Barra, and Temple University performed a series of investigations aimed at comprehending the biological repercussions of UV-C radiation exposure from readily available domestic lamps. 

“Our focus centered on epithelial retinal cells, keratinocytes, and fibroblasts, components of the skin and ocular targets frequently exposed to UV irradiation.”

Their findings underscore the potential harm associated with even brief exposure to UV, leading to irreversible and detrimental alterations in both skin cells and retinal cells of the eye. Notably, epithelial retinal cells exhibited heightened sensitivity, marked by substantial apoptosis. In contrast, keratinocytes demonstrated resilience to apoptosis even at elevated UV doses, though they were prone to senescence. Meanwhile, fibroblasts displayed a gradual amplification of both senescence and apoptosis as radiation doses escalated.

“In summary, despite the potential benefits offered by UV-C in deactivating pathogens like SARS-CoV-2, it remains evident that the concurrent risks posed by UV-C to human health cannot be ignored.”

DOI - https://doi.org/10.18632/aging.205787

Corresponding authors - Umberto Galderisi - umberto.galderisi@unicampania.it, and Giovanni Di Bernardo - gianni.dibernardo@unicampania.it

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Keywords - aging, senescence, apoptosis, UV light, public health

About Aging-US

Aging publishes research papers in all fields of aging research, including but not limited to aging processes (from yeast to mammals), cellular senescence, age-related diseases (such as cancer and Alzheimer’s disease) and their prevention and treatment, anti-aging strategies and drug development, and, importantly, the role of signal transduction pathways in aging (such as mTOR) and potential approaches to modulate these signaling pathways to extend lifespan.

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Aging (Aging-US)

Germicidal Lamps Using UV-C Radiation May Pose Health Safety Issues

Dr. Leonid Peshkin from the Department of Systems Biology at Harvard Medical School details a research perspective he co-authored that was published by Aging (Aging-US) in Volume 16, Issue 4, entitled, “On standardization of controls in lifespan studies.”
#aging #author #interview #researcher#data #standardization #lifespan #longevity #study #perspective #openaccess #openscience #peerreview #journal #publication #publishing #meded #spotlight #agingshort #video

DOI - https://doi.org/10.18632/aging.205604

Corresponding author - Leonid Peshkin - pesha@hms.harvard.edu

Video interview - https://www.youtube.com/watch?v=N_tL2aTN2Jw

Interview transcript - https://aging-us.net/2024/05/22/behind-the-study-on-standardization-of-controls-in-lifespan-studies/

Abstract

The search for interventions to slow down and even reverse aging is a burgeoning field. The literature cites hundreds of supposedly beneficial pharmacological and genetic interventions in model organisms: mice, rats, flies and worms, where research into physiology is routinely accompanied by lifespan data. However, when experimental animals from one article live as long as controls from another article, comparing the results of interventions across studies can yield misleading outcomes. Theoretically, all lifespan data are ripe for re-analysis: we could contrast the molecular targets and pathways across studies and help focus the further search for interventions. Alas, the results of most longevity studies are difficult to compare. This is in part because there are no clear, universally accepted standards for conducting such experiments or even for reporting such data. The situation is worsened by the fact that the authors often do not describe experimental conditions completely. As a result, works on longevity make up a set of precedents, each of which might be interesting in its own right, yet incoherent and incomparable at least for the reason that in a general context, it may indicate, for example, not prolonging the life of an average organism, but compensating for any genetic abnormalities of a particular sample or inappropriate living conditions. Here we point out specific issues and propose solutions for quality control by checking both inter- and intra-study consistency of lifespan data.

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Keywords - aging, animal disease models, survival modeling, data standardization

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Behind the Study: Standardization of Controls in Lifespan Studies

Behind the Study: On Standardization of Controls in Lifespan Studies

BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.”

In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. 

“GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).”

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. 

GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. 

Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. 

“Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.”

DOI - https://doi.org/10.18632/oncotarget.28586

Correspondence to - Paul Dent - paul.dent@vcuhealth.org

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib

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.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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GZ17-6.02 Kills Uveal Melanoma Cells

BUFFALO, NY- May 22, 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 9, entitled, “Cell type-dependent modulation of senescence features using Weo electrolyzed water.”

Electrolyzed-reduced water has powerful antioxidant properties with constituents that scavenge reactive oxygen species (ROS), which are known to be produced by several intrinsic and extrinsic processes. When there is an imbalance between ROS production and antioxidant defenses, oxidative stress occurs. Persistent oxidative stress leads to cellular senescence, an important hallmark of aging, and is involved in several age-related conditions and illnesses. 

In this new study, researchers Brenda L. Court-Vazquez, Shirley A. Arroyo-Vizcarrondo, Jonathan A. Poli, Lara Nyman, Kelly Halderman, Anthony Ginter, and Pierre-Yves Desprez from Weo LLC and California Pacific Medical Center investigated whether Weo electrolyzed water (WEW) could modulate the phenotype of senescent cells. 

“The focus of this study was to utilize two different cell types, human normal fibroblasts and human breast cancer cells, to investigate the impact of Weo electrolyzed water (WEW) on markers of cellular senescence, inflammation, and stress response genes.”

The researchers compared normal human lung fibroblasts (BJ) and breast cancer cells (T47D) treated with hydrogen peroxide (H2O2) to induce senescence. They assessed the molecular impact of WEW on markers of cellular senescence, senescence-associated secretory phenotype (SASP) factors, and stress response genes. Treatment with WEW modulated markers of cellular senescence, such as the senescence-associated β-galactosidase (SA-β-gal) activity, EdU incorporation and p21 expression, similarly in both cell types. 

However, WEW modulated the expression of SASP factors and stress response genes in a cell type-dependent and opposite fashion, significantly decreasing them in BJ cells, while stimulating their expression in T47D cells. Reduction in the expression of SASP factors and stress-related genes in BJ cells suggests that WEW acts as a protective factor, thereby reducing oxidative stress in normal cells, while making cancer cells more sensitive to the effects of cellular stress, thus increasing their elimination and consequently reducing their deleterious effects. 

“In conclusion, we have shown here that the new technology developed by Weo, WEW, could attenuate the overall process of cellular senescence in both normal BJ fibroblasts and cancer T47D cells.”

DOI - https://doi.org/10.18632/aging.205789

Corresponding authors - Brenda L. Court-Vazquez - bco@we-o.com, and Pierre-Yves Desprez - pydesprez@cpmcri.org

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Keywords - aging, cellular senescence, senescence-associated secretory phenotype, oxidative stress, lung fibroblasts, breast cancer cells, senomorphic

About Aging-US

Aging publishes research papers in all fields of aging research, including but not limited to aging processes (from yeast to mammals), cellular senescence, age-related diseases (such as cancer and Alzheimer’s disease) and their prevention and treatment, anti-aging strategies and drug development, and, importantly, the role of signal transduction pathways in aging (such as mTOR) and potential approaches to modulate these signaling pathways to extend lifespan.

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Modulation of Senescence Features Using Weo Electrolyzed Water

In this episode, Dr. Ron George provides a tour de force of our past and present labor analgesia management. We discuss his recent publication, Modern Labor Epidural Analgesia: Implications for Labor Outcomes and Maternal-Fetal Health.
https://pubmed.ncbi.nlm.nih.gov/37164496/
The Most Influential Publications in Obstetric Anesthesiology, 1998–2017: Utilizing the Delphi Method for Expert Consensus
https://pubmed.ncbi.nlm.nih.gov/32282388/
Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial
https://pubmed.ncbi.nlm.nih.gov/11454372/
A comparison of a basal infusion with automated mandatory boluses in parturient-controlled epidural analgesia during labor
https://pubmed.ncbi.nlm.nih.gov/17312228/
The risk of cesarean delivery with neuraxial analgesia given early versus late in labor
https://pubmed.ncbi.nlm.nih.gov/15716559/

Modern Labor Epidural Analgesia

Executive Director of El Hogar Denise Vargas joins us to talk about entrepreneurship. She helps us think in an entrepreneurial way about ministry and grounds innovation in community. We also take a while to chat about Vargas’s life as a poet, to hear some of her poetry, and to talk about how poetry intersects with the work she does at El Hogar.

22: Entrepreneurship with Denise Vargas

Professors Amy Carr and Christine Helmer join Hannah to talk about their new, timely book, Ordinary Faith in Polarized Times: Justification and the Pursuit of Justice. We take a moment in this season leading up to the presidential election to discuss high-conflict times and how we can move toward good conflict. We talk about how Christians can create space for conversation because of their status of belonging due to justification. We discuss how Christians can listen to each other, discuss hot-button issues, and navigate difference.

23: Ordinary Faith in Polarized Times with Amy Carr and Christine Helmer

Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient’s eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger.

While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success.

In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Full blog - https://www.oncotarget.org/2024/05/23/combating-doxorubicin-resistant-acute-myeloid-leukemia/

Paper DOI - https://doi.org/10.18632/oncotarget.28579

Correspondence to - Simonetta I. Gaumond - sxg1204@miami.edu

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Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602

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.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Combating Doxorubicin-Resistant Acute Myeloid Leukemia

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/

One More Step Toward Treatment of PARP Inhibitor-resistant Ovarian Cancers

Oncotarget Podcast

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