Cancer Research

Aging

Aging-US published this trending research paper on September 9, 2021, entitled, “Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients” by researchers from the School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel-Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel; Sagol Center for Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Be’er Ya’akov, Israel.

Abstract
Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer’s disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.

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DOI - https://doi.org/10.18632/aging.203485

Full text - https://www.aging-us.com/article/203485/text

Correspondence to: Uri Ashery email: uria@tauex.tau.ac.il

Keywords: Alzheimer's disease, hyperbaric oxygen therapy, vascular dysfunction, cerebral blood flow, amyloid burden, 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.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

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Trending with Impact: Hyperbaric Oxygen Therapy Alleviates Vascular Dysfunction and Amyloid Burden

Oncotarget

Oncotarget published this trending review on August 17, 2021, entitled, "Role of microRNAs in glioblastoma" by researchers from the Precision Health Program, Michigan State University, East Lansing, MI; Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.

Abstract:
Glioblastoma is the most common and aggressive primary human brain cancer. MicroRNAs (miRNAs) are a set of small endogenous non-coding RNA molecules which play critical roles in different biological processes including cancer. The realization of miRNA regulatory functions in GBM has demonstrated that these molecules play a critical role in its initiation, progression and response to therapy. In this review we discuss the studies related to miRNA discovery and function in glioblastoma. We first summarize the typical miRNAs and their roles in GBM. Then we debate the potential for miRNA-based therapy for glioblastoma, including various delivery strategies. We surmise that future directions identified by these studies will point towards the necessity for therapeutic development and optimization to improve the outcomes for patients with glioblastoma.

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DOI - https://doi.org/10.18632/oncotarget.28039

Full text - https://www.oncotarget.com/article/28039/text/

Correspondence to - Anna Moore - moorea57@msu.edu

Keywords - glioblastoma, microRNA, miRNA-based therapies, miRNA delivery

About Oncotarget

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

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Trending with Impact: The Role of MicroRNAs in Glioblastoma

Sekisui XenoTech

Presenter: Pallavi Limaye, Ph.D., DABT, SEKISUI XenoTech Director of Scientific Consulting

Abstract:
Aldehyde oxidase (AO) enzyme has gained increasing attention in drug development as one of the alternative approaches to reduce P450-mediated drug metabolism liability. However, clinical failure due to poor prediction of AO-mediated clearance is a major hurdle in development of drugs that are AO substrates. In vitro to in vivo extrapolation underpredicts AO-mediated drug clearance owing to several factors including lack of reliable representative animal models, marked species differences, significant inter-individual variability, substrate-specific activity, and discrepancy between absolute concentration and activity. To tackle these issues related to underprediction of AO-mediated drug clearance, in vitro tools to extrapolate in vivo clearance involving a yardstick approach are proposed. AO-metabolism is an attractive strategy to reduce P450-mediated drug metabolism liability but careful consideration of the unique challenges is essential.

Key concepts discussed in this webinar will include:
 - Wide range of AO substrates – Functional groups
 - AO substrate drugs that faced clinical failure unanticipated drug clearance
 - Underprediction and Factors affecting AO expression
   - Age, Disease state, Alcohol consumption, Pharmacogenomics
   - Species differences
   - Inter-individual variability
   - Sample handling, Freeze-thaw cycles, Fresh vs. Frozen tissue
 - In vitro AO inhibition and fm AO determination
 - In vitro yardstick approach

Request a copy of the slides: https://www.xenotech.com/about/events/webinar-underprediction-of-drug-clearance-by-aldehyde-oxidase-ao-mediated-drug-metabolism-important-considerations-for-in-vitro-assessment/
Questions, comments and requests: https://www.xenotech.com/contact/
More information on our research services and test systems: https://www.xenotech.com
Other previously aired webinars: https://www.xenotech.com/access-adme-research-resources/resource-type/webinar/
Upcoming webinar notifications: https://www.xenotech.com/contact/newsletter-sign-up/
Request a webinar topic: https://www.xenotech.com/contact/webinar-seminar-request/

About the Presenter:
Pallavi Limaye is a Director in the Scientific Consulting department. Pallavi received her Ph.D. in Toxicology from The University of Louisiana. Dr. Limaye originally joined SEKISUI XenoTech in 2011 as a Research Scientist and served as a study director for in vitro drug metabolism studies. In 2020, she joined SEKISUI XenoTech’s consulting team and provides input on drug-drug interaction study needs for sponsors. Dr. Limaye has published several original research articles in various journals and has also contributed many book chapters in the field of toxicology and liver pathobiology. She is also actively involved in scientific societies and currently serves on the E-Learning Subcommittee of The American College of Toxicology and is the current President of the Central States regional chapter of The Society of Toxicology.

Underprediction of Drug Clearance by Aldehyde Oxidase (AO)–Mediated Drug Metabolism (Webinar)

Aging-US published this high-scoring research paper on August 15, 2019, entitled, “Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age,” by researchers from the Department of Bioengineering and QB3 Institute, University of California, Berkeley, Berkeley, CA; Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA.

Abstract:
We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. The dose of Alk5 inhibitor (Alk5i) was reduced by 10-fold and the duration of treatment was shortened (to minimize overt skewing of cell-signaling pathways), yet the positive outcomes were broadened, as compared with our previous studies. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging.

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DOI - https://doi.org/10.18632/aging.102148

Full text - https://www.aging-us.com/article/102148/text

Correspondence to: Irina M. Conboy email: iconboy@berkeley.edu

Keywords: muscle repair, TGF-beta, oxytocin, neurogenesis, neuro-inflammation, cognition, liver health

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.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

Twitter - https://twitter.com/AgingJrnl​
Facebook - https://www.facebook.com/AgingUS/​
SoundCloud - https://soundcloud.com/aging-us​
YouTube - https://www.youtube.com/agingus​
LinkedIn -  https://www.linkedin.com/company/aging​

Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com​​ or connect with @ImpactJrnls

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Top-Performer: TGF-beta and Oxytocin Reversed to Reverse Aging

Oncotarget published this trending research paper on July 20, 2021, entitled, “Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis” by researchers from Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts, Lowell, MA; Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada; Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, Ontario, Canada; Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo FG, Italy; Department of Internal Medicine, University of Chicago, Chicago, IL; Q.P.S. Holdings LLC, Pencader Corporate Center, Newark, DE; Institute of Biomedical Engineering, The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, Canada; Department of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, Assam, India; Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA.

Abstract:
Objective: Aberrations in the PI3K/AKT/mTOR survival pathway in many cancers are the most common genomic abnormalities. The phytochemical and bioactive agent sulforaphane (SFN) has nutrigenomic potential in activating the expression of several cellular protective genes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is primarily related to mechanisms of endogenous cellular defense and survival. The efficacy of SFN in combination with acetazolamide (AZ) was investigated in reducing typical H727 and atypical H720 BC survival, migration potential, and apoptosis in vitro and in vivo preclinical xenograft tissues.

Materials and Methods: Microscopic imaging, immunocytochemistry, wound healing assay, caspase-cleaved cytokeratin 18 (M30, CCK18) CytoDeath ELISA assay, immunofluorescence labeling assays for apoptosis, hypoxia, Western Blotting, Tunnel assay, measurement of 5-HT secretion by carbon fiber amperometry assay, quantitative methylation-specific PCR (qMSP), morphologic changes, cell viability, apoptosis activity and the expression levels of phospho-Akt1, Akt1, HIF-1α, PI3K, p21, CAIX, 5-HT, phospho-mTOR, and mTOR in xenografts derived from typical H727 and atypical H720 BC cell lines.

Results: Combining AZ+SFN reduced tumor cell survival compared to each agent alone, both in vitro and in vivo xenograft tissues. AZ+SFN targeted multiple pathways involved in cell cycle, serotonin secretion, survival, and growth pathways, highlighting its therapeutic approach. Both H727 and H720 cells were associated with induction of apoptosis, upregulation of the p21 cell cycle inhibitor, and downregulation of the PI3K/Akt/mTOR pathway, suggesting that the PI3K/Akt/mTOR pathway is a primary target of the AZ+SFN combination therapy.

Conclusions: Combining SFN+AZ significantly inhibits the PI3K/Akt/mTOR pathway and significantly reducing 5-HT secretion in carcinoid syndrome.

Press release -  https://www.oncotarget.com/news/pr/disabling-the-pi3k-akt-mtor-survival-pathway-and-inducing-apoptosis/

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DOI - https://doi.org/10.18632/oncotarget.28011

Full text - https://www.oncotarget.com/article/28011/text/

Correspondence to - Herman Yeger - hermie@sickkids.ca, Reza Bayat Mokhtari - rbm7@queensu.ca, and Myron R. Szewczuk - szewczuk@queensu.ca

Keywords - sulforaphane, acetazolamide, bronchial carcinoid tumors, serotonin, carbonic anhydrase

About Oncotarget

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

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Top-Performer: Sulforaphane in Nutrigenomic Cancer Therapy

Aging-US published this trending research paper - selected as the cover for Volume 13, Issue 17 - on September 7, 2021, entitled, “Reduced uremic metabolites are prominent feature of sarcopenia, distinct from antioxidative markers for frailty” by researchers from the Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan; G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Okinawa, Japan.

Abstract
Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility, and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collected from 19 elderly participants in our frailty study. Among 131 metabolites, we identified 22 sarcopenia markers, distinct from 15 frailty markers, mainly including antioxidants, although sarcopenia overlaps clinically with physical frailty. Notably, 21 metabolites that decline in sarcopenia or low SMI are uremic compounds that increase in kidney dysfunction. These comprise TCA cycle, urea cycle, nitrogen, and methylated metabolites. Sarcopenia markers imply a close link between muscle and kidney function, while frailty markers define a state vulnerable to oxidative stress.

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DOI - https://doi.org/10.18632/aging.203498

Full text - https://www.aging-us.com/article/203498/text

Correspondence to: Mitsuhiro Yanagida email: myanagid@gmail.com

Keywords: sarcopenia, muscle mass, metabolomics, frailty, uremic metabolites, 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.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

Twitter - https://twitter.com/AgingJrnl
Facebook - https://www.facebook.com/AgingUS/
SoundCloud - https://soundcloud.com/aging-us​
YouTube - https://www.youtube.com/agingus​
LinkedIn -  https://www.linkedin.com/company/aging​

Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com​​ or connect with @ImpactJrnls

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Trending with Impact: DNA Markers Distinguish Sarcopenia from Frailty

Oncotarget published this trending research perspective on March 16, 2021, entitled, "Pancreatic cancer driver mutations are targetable through distant alternative RNA splicing dependencies" by researchers from the Medical Scientist Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD; Departments of Molecular and Systems Biology, Surgery, and Medicine, Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Lebanon, NH; Department of Therapeutic Radiology, Yale University, New Haven, CT; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT; Department of Pathology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY.

Abstract:
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, has one of the highest case fatality rates of all known solid malignancies. Over the past decade, several landmark studies have established mutations in KRAS and TP53 as the predominant drivers of PDAC pathogenesis and therapeutic resistance, though treatment options for PDACs and other tumors with these mutations remain extremely limited. Hampered by late tumor discovery and diagnosis, clinicians are often faced with using aggressive and non-specific chemotherapies to treat advanced disease. Clinically meaningful responses to targeted therapy are often limited to the minority of patients with susceptible PDACs, and immunotherapies have routinely encountered roadblocks in effective activation of tumor-infiltrating immune cells. Alternative RNA splicing (ARS) has recently gained traction in the PDAC literature as a field from which we may better understand and treat complex mechanisms of PDAC initiation, progression, and therapeutic resistance. Here, we review PDAC pathogenesis as it relates to fundamental ARS biology, with an extension to implications for PDAC patient clinical management.

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DOI - https://doi.org/10.18632/oncotarget.27901

Full text - https://www.oncotarget.com/article/27901/text/

Correspondence to - Luisa F. Escobar-Hoyos - luisa.escobar-hoyos@yale.edu

Keywords - pancreatic cancer, RNA splicing, targeted therapy, KRAS, TP53

About Oncotarget

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

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Trending with Impact: Alternative RNA Splicing in Pancreatic Cancer

Oncotarget’s cover paper this week (Volume 12, Issue 19) is entitled, "Nanoparticle T cell engagers for the treatment of acute myeloid leukemia," by researchers from the Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University McKelvey School of Engineering, St. Louis, MO;  Department of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Abstract:
Acute myeloid leukemia (AML) is the most common type of leukemia and has a 5-year survival rate of 25%. The standard-of-care for AML has not changed in the past few decades. Promising immunotherapy options are being developed for the treatment of AML; yet, these regimens require highly laborious and sophisticated techniques. We create nanoTCEs using liposomes conjugated to monoclonal antibodies to enable specific binding. We also recreate the bone marrow niche using our 3D culture system and use immunocompromised mice to enable use of human AML and T cells with nanoTCEs. We show that CD33 is ubiquitously present on AML cells. The CD33 nanoTCEs bind preferentially to AML cells compared to Isotype. We show that nanoTCEs effectively activate T cells and induce AML killing in vitro and in vivo. Our findings suggest that our nanoTCE technology is a novel and promising immuno-therapy for the treatment of AML and provides a basis for supplemental investigations for the validation of using nanoTCEs in larger animals and patients.

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DOI - https://doi.org/10.18632/oncotarget.28054

Full text - https://www.oncotarget.com/article/28054/text/

Correspondence to - Abdel Kareem Azab - kareem.azab@wustl.edu

Keywords - acute myeloid leukemia, T cell engagers, nanoparticles, 3D tissue culture model

About Oncotarget

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

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Nanoparticles Target Acute Myeloid Leukemia

View the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 19.
https://www.oncotarget.com/archive/v12/i19/

Cover Paper - “Nanoparticle T cell engagers for the treatment of acute myeloid leukemia” 
https://doi.org/10.18632/oncotarget.28054


News - “Old drug, new trick: proton pump inhibitors find new purpose in cancer care” 
https://doi.org/10.18632/oncotarget.28053 (PDF Download)

Research Paper - “Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids” 
https://doi.org/10.18632/oncotarget.28058

Research Paper - “Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer” https://doi.org/10.18632/oncotarget.28059

Research Paper - “The antitumoral effects of chemerin are independent from leukocyte recruitment and mediated by inhibition of neoangiogenesis” https://doi.org/10.18632/oncotarget.28056

Research Paper - “Exploratory comparisons between different anti-mitotics in clinically-used drug combination in triple negative breast cancer” 
https://doi.org/10.18632/oncotarget.28068


Research Paper - “High expression of Myosin 1g in pediatric acute lymphoblastic leukemia” https://doi.org/10.18632/oncotarget.28055

Case Report - “Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition” https://doi.org/10.18632/oncotarget.28062

Research Perspective - “Towards precision oncology in angiosarcomas using next generation “omic” technologies” https://doi.org/10.18632/oncotarget.27996

Research Perspective - “Targeting AP-1 transcription factors by CRISPR in the prostate” https://doi.org/10.18632/oncotarget.27997

Research Perspective - “The role of dynamic phenotypes in cancer”
https://doi.org/10.18632/oncotarget.28006

Keywords - colon organoids, acute myeloid leukemia, prostate cancer, chemerin, KIF11 inhibition, breast cancer, acute lymphoblastic leukemia, ALK inhibitors, rare cancer, dynamic phenotype, Lung cancer, cancer, science, research, oncology


About Oncotarget

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

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

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