Drug Discovery

Aging (Aging-US)

Aging-US published this research paper in Volume 14, Issue 17, entitled, "Fetal programming: in utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging" by researchers from the Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia, Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.

DOI - https://doi.org/10.18632/aging.204269

Corresponding authors - Abdel Halim Harrath - hharrath@ksu.edu.sa 

Abstract

In this study we investigated the effects of multigenerational exposures to acrylamide (ACR) on ovarian function. Fifty-day-old Wistar albino female rats were divided into the control and ACR-treated groups (2.5, 10, and 20 mg/kg/day) from day 6 of pregnancy until delivery. The obtained females of the first (AF1) and second generation (AF2) were euthanized at 4 weeks of age, and plasma and ovary samples were collected. We found that in utero multigenerational exposure to ACR reduced fertility and ovarian function in AF1 through inducing histopathological changes as evidenced by the appearance of cysts and degenerating follicles, oocyte vacuolization, and pyknosis in granulosa cells. TMR red positive cells confirmed by TUNEL assay were mostly detected in the stroma of the treated groups. Estradiol and IGF-1 concentrations significantly decreased as a result of decreased CYP19 gene and its protein expression. However, ACR exposure in AF2 led to early ovarian aging as evidenced by high estradiol and progesterone levels among all treated groups compared to control group, corresponding to the upregulation of the CYP19 gene and protein expression. The apoptotic cells of the stroma were greatly detected compared to that in the control group, whereas no significant difference was reported in ESR1 and ESR2 gene expression. This study confirms the developmental adverse effects of ACR on ovarian function and fertility in at least two consecutive generations. It emphasizes the need for more effective strategies during pregnancy, such as eating healthy foods and avoiding consumption of ACR-rich products, including fried foods and coffee.

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Keywords - aging, acrylamide, transgeneration, apoptosis, female fertility, ovary aging

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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Trending With Impact: Effects of Multigenerational Exposures to Acrylamide on Ovarian Function

Oncotarget

Oncotarget published this research paper on September 14, 2022 in Volume 13, entitled, "Site of analysis matters - Ongoing complete response to Nivolumab in a patient with HIV/HPV related metastatic anal cancer and MLH1 mutation" by researchers from Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Universitäres Centrum für Tumorerkrankungen (UCT), Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Klinik für Strahlentherapie und Onkologie, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Medizinische Klinik 1, Schwerpunkte Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Frankfurt 60590, Germany; Centrum für Hämatologie und Onkologie, Frankfurt 60389, Germany.

DOI - https://doi.org/10.18632/oncotarget.28274

Correspondence to - Oliver Waidmann - oliver.waidmann@kgu.de

Abstract

Anal cancer is a rare disease with increasing incidence. In patients with locally recurrent or metastatic disease which cannot be treated with chemoradiotherapy or salvage surgery systemic first-line chemotherapy with carboplatin and paclitaxel is standard of care. For patients who progress after first-line therapy and are still eligible for second-line therapy Programmed cell death protein 1 (PD-1) antibodies are potential therapeutic options. However, prediction of response to immunotherapy is still challenging including anal cancer. We report here to our knowledge the first anal cancer case with microsatellite instability (MSI) due to MLH1 mutation and a deep and ongoing response to Nivolumab treatment. Namely, thorough analysis of the primary tumor as well as metastatic sites by next generation sequencing (NGS) revealed that MSI was formally only found in the metastatic sites but not in the primary tumor. Concomitantly, tumor mutational burden (TMB) was higher in the metastatic site than in the primary tumor. Therefore, we conclude that all anal cancer patients should be tested for MSI and whenever possible molecular analysis should be performed rather from metastatic sites than from the primary tumor.

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Keywords - anal cancer, microsatellite instability, immunotherapy, high-throughput nucleotide sequencing, nivolumab

About Oncotarget

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.

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Trending With Impact: HIV/HPV-Related Metastatic Colorectal Cancer Response to Nivolumab

Oxford Nanopore Technologies

The genetics behind cancer are both diverse and complex, with many abnormalities causing, contributing, or indicating the disease. Using nanopore sequencing, scientists can resolve variants and epigenetic modifications across the entire genome, target large panels or single genes, and detect known and novel full-length transcripts – for the most comprehensive insight into cancer genomes.

In this short, impactful video, scientists share how nanopore sequencing has made their work possible, leading to greater understanding of cancer, and how some of their own life experiences prompted them to pursue a career in this area.

[url][link]https://nanoporetech.com/accelerating-cancer-research-through-comprehensive-genomic-analysis?utm_campaign=Cancer%202022&utm_source=tech_networks&utm_medium=video[/link][name]Download this white paper to learn more about nanopore sequencing in cancer research[/name][/url]

[url][link]https://nanoporetech.com/resource-centre/rapid-low-cost-detection-genomic-aberrations-flongle?utm_campaign=Cancer%202022&utm_source=tech_networks&utm_medium=video[/link][name]Read this case study on rapid, low-cost detection of genomic aberrations[/name][/url]

Nanopore Sequencing: The Most Comprehensive Insight Into Cancer

Creative Proteomics videos

Equipped with advanced tandem mass spectrometry for determination of lipid composition, powerful bioinformatic analytic systems, and a panel of experienced scientists and technicians, Creative Proteomics provide customer-tailored service with rapid analysis procedures and easy to read report, to speed up your scientific research.
https://www.creative-proteomics.com/services/targeted-lipidomics.htm

Mass Spectrometry Based Lipidomics

Oncotarget published this research paper on September 14, 2022 in Volume 13, entitled, "Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy" by researchers from the Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, Department of Urology, West China Hospital/School of Medicine, Chengdu City, Sichuan Province, PR China, Karmanos Cancer Institute, Wayne State University, Detroit, MI, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, Department of Human Genetics, University of California, Los Angeles, CA.

DOI - https://doi.org/10.18632/oncotarget.28273

Correspondence to - Ranjit S. Bindra - Ranjit.Bindra@yale.edu, Brian Shuch - bshuch@mednet.ucla.edu

Abstract

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.

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Press release - https://www.oncotarget.com/index.php?journal=oncotarget&page=news&op=press&item=oncotarget-targeting-krebs-cycle-deficient-renal-cell-carcinoma-with-poly-adp-ribose-polymerase-inhibitors-and-low-dose-alkylating-chemotherapy

Keywords - cancer, FH, SDHB, renal cell carcinoma, PARP inhibitor, temozolomide

About Oncotarget

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.

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PARP Inhibitors and Low-Dose Chemo Targets Krebs-Cycle-Deficient Renal Cell Carcinoma

BÜCHI Labortechnik AG

Drying temperature-sensitive biotherapeutics saves costs, improves storage, stability and transportation possibilities. In this 5-minute lecture, gain expert advice on how to use spray drying and freeze drying to formulate biotherapeutic compounds:
-	Proteins
-	Enzymes
-	Biologics
-	Amino acids

💡 For additional information: https://bit.ly/3UnVvje


How To Dry Biotherapeutics

Dr. Balraj Singh from the Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, describes a recent research paper he co-authored that was published by Oncotarget, entitled, “Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine.”

DOI - https://doi.org/10.18632/oncotarget.27922

Correspondence to - Anthony Lucci - alucci@mdanderson.org, and Balraj Singh - bsingh@mdanderson.org

Abstract

Highly adaptable breast cancer cells that can opportunistically switch between proliferation and quiescence are often responsible for disease relapse. We have developed a function-based selection strategy for such resistant cells, exemplified by SUM149-MA and FC-IBC02-MA triple-negative breast cancer cells. We have also reported that a lengthy treatment with low-dose 6-mercaptopurine, a clinically useful anti-inflammatory drug, inhibits such resistant cells. To more rigorously test the clinical suitability of 6-mercaptopurine, here we investigated effects of further lowering its dose and the possibility of overcoming resistance to single-drug treatment by combining the drug with another ribonucleoside analog 5-azacitidine. We found that that a lengthy treatment with 1 μM 5-azacitidine, without a significant effect on cell proliferation, sensitized cancer cells to the inhibitory effects of low-dose 6-mercaptopurine. Importantly, treatment for several weeks with low doses of 6-mercaptopurine and/or 5-azacitidine did not render cancer cells resistant to chemotherapeutic drugs doxorubicin or paclitaxel. In fact, the cells became more sensitive to chemotherapeutic drugs upon treatment with 6-mercaptopurine and/or 5-azacitidine. Our analyses of protein markers of epithelial-to-mesenchymal transition indicated that treatments with 6-mercaptopurine and/or 5-azacitidine do not significantly reverse this process in our model. Our results showed that safe drugs such as low-dose 6-mercaptopurine singly or combined with 5-azacitidine, which are suitable for use prior to disease relapse, have a potential of inhibiting highly resistant triple-negative breast cancer cells.

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Press release - https://www.oncotarget.com/news/pr/inhibition-of-resistant-triple-negative-breast-cancer-cells/

Keywords - resistant TNBC, minimal residual disease, intratumor heterogeneity, breast cancer relapse, metastasis prevention

About Oncotarget

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.

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Behind the Study: Inhibition of Resistant Triple-negative Breast Cancer Cells

Oncotarget published this editorial on September 8, 2022 in Volume 13, entitled, "An ABC transporter as a potential target against SHH-Medulloblastoma: From Benchtop to Bedside" by researchers from the Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN.

DOI - https://doi.org/10.18632/oncotarget.28272

Correspondence to - John D. Schuetz - john.schuetz@stjude.org

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Press release - https://www.oncotarget.com/news/pr/oncotarget-an-abc-transporter-as-a-potential-target-against-shh-medulloblastoma-from-benchtop-to-bedside/

Keywords - cancer, editorial, transporter; chemotherapeutics

About Oncotarget

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.

To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us:

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Trending With Impact: An ABC Transporter as Potential Target Against SHH-Medulloblastoma

Sartorius - Infectious Disease

Since the onset of the pandemic, massive global demand for laboratory consumables has grown, and the need for pipette tips has more than tripled as a result. By prioritizing the manufacture of filter tips, converting existing production lines and running production 24/7, Sartorius could significantly increase output within a short period of time. Our ability to serve customers will be further improved as our second expansion nears completion in Kajaani, Finland.  

In this video, Matti Pilviö, Head of Operations, and Niklas Forsman, Regional Business Manager, provide insights into the measures that have - and will - be taken to help laboratories worldwide maintain operations.

Discover how Sartorius has significantly increased manufacturing output of filter tips in the following ways:
 

Prioritizing filter tip manufacturing
Introduction of new production lines
Running production 24/7

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