Cell Science

Oncotarget

Intraventricular Immunovirotherapy; A Translational Step Forward | Oncotarget
Copy: Oncotarget published this trending research perspective in Volume 14, entitled, “Intraventricular immunovirotherapy; a translational step forward" by the researchers from the Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA; Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.

DOI - https://doi.org/10.18632/oncotarget.28343

Correspondence to - Joshua D. Bernstock - jbernstock@bwh.harvard.edu, Gregory K. Friedman - gfriedman@uabmc.edu

Abstract

Oncolytic virotherapy with intratumoral engineered type-1 herpes simplex virus (HSV) has been proven safe with promising efficacy in recent clinical trials for treatment of both pediatric and adult high-grade glioma. However, this approach excludes patients with tumors in surgically inaccessible and/or eloquent brain regions. Current delivery methods are also unable to access/treat those patients with metastatic disease in the spinal cord and/or leptomeningeal disease. A recent preclinical study has paved the way for clinical translation of intraventricular administration of oHSV by identifying and mitigating the toxicity associated with this route for therapeutic benefit in murine models of disseminated medulloblastoma. This work may ultimately allow for targeting of intractable disease and provides a feasible option for the repetitive dosing of clinically relevant immunovirotherapy, G207.

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Keywords - oncolytic virotherapy, herpes simplex virus (HSV), G207, intraventricular therapy, leptomeningeal disease

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. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Intraventricular Immunovirotherapy; A Translational Step Forward

Aging (Aging-US)

Aging-US published this trending research paper in Volume 15, Issue 1, entitled, "The innate immune signaling component FBXC-58 mediates dietary restriction effects on healthy aging in Caenorhabditis elegans" by researchers from the Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun 55365, South Korea; Department of Food Biotechnology, University of Science and Technology, Daejeon-si 34113, South Korea. 

DOI - https://doi.org/10.18632/aging.204477

Corresponding author - Jeong-Hoon Hahm - hahmjh@kfri.re.kr , Jiyun Ahn - jyan@kfri.re.kr 

Abstract

Dietary restriction (DR) is a highly effective and reproducible intervention that prolongs longevity in many organisms. The molecular mechanism of action of DR is tightly connected with the immune system; however, the detailed mechanisms and effective downstream factors of immunity that mediate the beneficial effects of DR on aging remain unknown. Here, to investigate the immune signaling that mediates DR effects, we used Caenorhabditis elegans, which has been widely used in research, to understand the underlying molecular mechanisms of aging and immunity. We found that the F-box gene, fbxc-58, a regulator of the innate immune response, is a novel mediator of DR effects on extending the health span of C. elegans. fbxc-58 is upregulated by DR and is necessary for DR-induced lifespan extension and physical health improvement in C. elegans. Furthermore, through DR, fbxc-58 prevents disintegration of the mitochondrial network in body wall muscle during aging. We found that fbxc-58 is a downstream target of the ZIP-2 and PHA-4 transcription factors, the well-known DR mediator, and fbxc-58 extends longevity in DR through an S6 kinase-dependent pathway. We propose that the novel DR effector, fbxc-58, could provide a new mechanistic understanding of the effects of DR on healthy aging and elucidate the signaling mechanisms that link immunity and DR effects with aging.

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Keywords - dietary restriction, aging, innate immunity, F-box protein, Caenorhabditis elegans

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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FBXC-58 Mediates Dietary Restriction Effects in Healthy Aging C. Elegans

XenoTech

Presenter:  Chris Bohl, Ph.D., Global Technical Support Manager

This ADME 101 video provides an overview of different types of subcellular fractions, such as microsomes, S9, cytosol, lysosomes and homogenate, and their unique benefits for use in various types of in vitro ADMET/DMPK & Drug-Drug Interaction studies. This short, information-packed webinar features:

The different types of subcellular fractions
How they are made
Who uses them, for which studies, and why
Advantages of the test systems
Different preparation options
Whether to use a NADPH regenerating system or 1mM NADPH
How tissue is procured and more...

Download slides: https://www.xenotech.com/webinar-slides/sekisui-xenotech-guide-to-subcellular-fractions.pdf
Questions, comments and requests: https://www.xenotech.com/contact-us 
More information on our research services and test systems: https://www.xenotech.com
Other previously aired webinars: https://www.xenotech.com/scientific-resources/webinar-series
Upcoming webinar notifications: https://www.xenotech.com/newsletter-signup
Request a webinar topic: https://www.xenotech.com/scientific-resources/upcoming-webinars

About the presenter: Dr. Chris Bohl received his PhD from the School of Biological Sciences from the University of Nebraska – Lincoln and has been with XenoTech since 2014, first operating as a research scientist before becoming the Senior Manager of Technical Support for Products.

ADME 101 Guide to Subcellular Fractions and When to Use Which Test System

Hamilton Company (Robotics)

In this video, Oxford Biomedica, an innovative global gene and cell therapy company with operations in the UK and US, describes the automation of an assay requiring a 10-day cell-based workflow, using an integrated Hamilton Microlab STAR liquid handler and CECULA's Graphical User Interface (GUI).

Download the Case Study here: https://hubs.li/Q01xk4kF0

Automating Cell-Based Assays to Determine Viral Vector Titer – Oxford Biomedica & Hamilton Robotics

Oncotarget published this trending research paper in Volume 14, entitled, “Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels" by the researchers from Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig 04103, Germany; Institute of Pathology, Medical Faculty, University of Leipzig, Leipzig 04103, Germany; Department of Dermatology, University Hospital Essen, University Duisburg-Essen, and German Cancer Consortium (DKTK) partner site Essen/Düsseldorf, Essen 45122, Germany.

DOI - https://doi.org/10.18632/oncotarget.28342

Correspondence to - Christina Kuhn - Christina.Kuhn@medizin.uni-leipzig.de 

Abstract

Overexpression of the dihydrolipoamide S-succinyltransferase (DLST) is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with DLST amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with DLST amplifications or high mRNA levels, suggesting a vulnerability of DLST-altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased DLST expression in cell lines with driver mutations in KRAS supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and DLST-activated tumors.

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Keywords - neuroblastoma, drug sensitivity, drug resistance, drug repurposing, DLST

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. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Drugs Associated With Sensitivity of Cancer Cell Lines With DLST or High mRNA Levels

Aging-US published this research paper in Volume 15, Issue 1, entitled, "Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization" by researchers from the Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL; BIO5 Institute and Department of Nutritional Sciences, University of Arizona, Tucson, AZ; Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL.

DOI - https://doi.org/10.18632/aging.204480

Corresponding author - Jing Chen - jing.chen@childrens.harvard.edu 

Abstract

Choroidal neovascularization (CNV) causes acute vision loss in neovascular age-related macular degeneration (AMD). Genetic variations of the nuclear receptor RAR-related orphan receptor alpha (RORα) have been linked with neovascular AMD, yet its specific role in pathological CNV development is not entirely clear. In this study, we showed that Rora was highly expressed in the mouse choroid compared with the retina, and genetic loss of RORα in Staggerer mice (Rorasg/sg) led to increased expression levels of Vegfr2 and Tnfa in the choroid and retinal pigment epithelium (RPE) complex. In a mouse model of laser-induced CNV, RORα expression was highly increased in the choroidal/RPE complex post-laser, and loss of RORα in Rorasg/sg eyes significantly worsened CNV with increased lesion size and vascular leakage, associated with increased levels of VEGFR2 and TNFα proteins. Pharmacological inhibition of RORα also worsened CNV. In addition, both genetic deficiency and inhibition of RORα substantially increased vascular growth in isolated mouse choroidal explants ex vivo. RORα inhibition also promoted angiogenic function of human choroidal endothelial cell culture. Together, our results suggest that RORα negatively regulates pathological CNV development in part by modulating angiogenic response of the choroidal endothelium and inflammatory environment in the choroid/RPE complex.
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Keywords - age-related macular degeneration, angiogenesis, choroidal neovascularization, inflammation, nuclear receptors, RORα, VEGFR2, TNFα

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 https://www.Aging-US.com​​ and connect with us:

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Genetic Deficiency and Pharmacological Modulation of RORα Regulate Laser-Induced CNV 

Oncotarget published this research paper in Volume 14, entitled, “Targeting CD74 in B-cell non-Hodgkin lymphoma with the antibody-drug conjugate STRO-001" by the researchers from the Research Development, Sutro Biopharma, South San Francisco, CA; Clinical Development, Sutro Biopharma, South San Francisco, CA.

DOI - https://doi.org/10.18632/oncotarget.28341

Correspondence to - Xiaofan Li - xli@sutrobio.com, and Arturo Molina - amolina@sutrobio.com

Abstract

Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated in vivo for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.
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Keywords - CD74, antibody-drug conjugate, non-Hodgkin lymphoma, xenograft models, STRO-001

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. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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

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Targeting CD74 in B-cell Non-Hodgkin Lymphoma With Antibody-Drug Conjugate STRO-001

Aging-US published this research paper as the cover for Volume 15, Issue 1, entitled, "Single-cell transcriptomics of peripheral blood in the aging mouse" by researchers from the Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI; Center for Computational Molecular Biology, Brown University, Providence, RI; Center on the Biology of Aging, Brown University, Providence, RI.

DOI - https://doi.org/10.18632/aging.204471

Corresponding author - Nicola Neretti - nicola_neretti@brown.edu

Abstract

Compositional and transcriptional changes in the hematopoietic system have been used as biomarkers of immunosenescence and aging. Here, we use single-cell RNA-sequencing to study the aging peripheral blood in mice and characterize the changes in cell-type composition and transcriptional profiles associated with age. We identified 17 clusters from a total of 14,588 single cells. We detected a general upregulation of antigen processing and presentation and chemokine signaling pathways and a downregulation of genes involved in ribosome pathways with age. In old peripheral blood, we also observed an increased percentage of cells expressing senescence markers (Cdkn1a, and Cdkn2a). In addition, we detected a cluster of activated T cells exclusively found in old blood, with lower expression of Cd28 and higher expression of Bcl2 and Cdkn2a, suggesting that the cells are senescent and resistant to apoptosis.

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Keywords - aging, single-cell transcriptomics, senescence, peripheral blood

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 https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
Pinterest - https://www.pinterest.com/AgingUS/

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Single-cell Transcriptomics of Peripheral Blood in the Aging Mouse

Technology Networks

Speaking at ‘Advances in proteomics & Metabolomics’ 2022, Charlotte Stadler from SciLifeLab presented her talk on the generation of highly multiplexed immunofluorescence data and bridging the gap between research and conventional clinical pathology.

Cell Science

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