المؤلفون: Dmitrii Pavlov, Anna Gorlova, Abrar Haque, Carlos Cavalcante, Evgeniy Svirin, Alisa Burova, Elizaveta Grigorieva, Elizaveta Sheveleva, Dmitry Malin, Sofia Efimochkina, Andrey Proshin, Aleksei Umriukhin, Sergey Morozov, Tatyana Strekalova

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 14, p 11712 (2023)

مصطلحات موضوعية: ultrasound radiation, systemic inflammation, pro-inflammatory cytokines, depression, memory, offspring, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Neurodevelopmental disorders stemming from maternal immune activation can significantly affect a child’s life. A major limitation in pre-clinical studies is the scarcity of valid animal models that accurately mimic these challenges. Among the available models, administration of lipopolysaccharide (LPS) to pregnant females is a widely used paradigm. Previous studies have reported that a model of ‘emotional stress’, involving chronic exposure of rodents to ultrasonic frequencies, induces neuroinflammation, aberrant neuroplasticity, and behavioral deficits. In this study, we explored whether this model is a suitable paradigm for maternal stress and promotes neurodevelopmental abnormalities in the offspring of stressed females. Pregnant dams were exposed to ultrasound stress for 21 days. A separate group was injected with LPS on embryonic days E11.5 and E12.5 to mimic prenatal infection. The behavior of the dams and their female offspring was assessed using the sucrose test, open field test, and elevated plus maze. Additionally, the three-chamber sociability test and Barnes maze were used in the offspring groups. ELISA and qPCR were used to examine pro-inflammatory changes in the blood and hippocampus of adult females. Ultrasound-exposed adult females developed a depressive-like syndrome, hippocampal overexpression of GSK-3β, IL-1β, and IL-6 and increased serum concentrations of IL-1β, IL-6, IL-17, RANTES, and TNFα. The female offspring also displayed depressive-like behavior, as well as cognitive deficits. These abnormalities were comparable to the behavioral changes induced by LPS. The ultrasound stress model can be a promising animal paradigm of neurodevelopmental pathology associated with prenatal ‘emotional stress’.

وصف الملف: electronic resource

Relation: https://www.mdpi.com/1422-0067/24/14/11712; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067

URL الوصول: https://doaj.org/article/eea3eb9e51544f49b4cdde8584ca9d67

المؤلفون: David F. Jarrard, Vincent L. Cryns, Kyle A. Richards, Dmitry Malin, Tyler Etheridge, Joseph Gawdzik, Adam Schultz, Mikolaj J. Filon, Tariq A. Khemees, Shivashankar Damodaran, Bing Yang

الوصف: The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo. Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02a68edb553efee842491ff4568a7673
https://doi.org/10.1158/1535-7163.c.6542298

المؤلفون: David F. Jarrard, Vincent L. Cryns, Kyle A. Richards, Dmitry Malin, Tyler Etheridge, Joseph Gawdzik, Adam Schultz, Mikolaj J. Filon, Tariq A. Khemees, Shivashankar Damodaran, Bing Yang

الوصف: All supplementary table

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::273a894f38ad61b04579a09f61ce5d28
https://doi.org/10.1158/1535-7163.22519107

المؤلفون: Vincent L. Cryns, David M. Good, Dmitry Malin, Elena Strekalova

الوصف: Supplementary Figure S2. Methioninase sensitizes TNBC cells to lexatumumab.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14cd40234d4282c294a95e66a2ad356a
https://doi.org/10.1158/1078-0432.22461236

المؤلفون: Vincent L. Cryns, Carey K. Anders, Eric V. Shusta, Lisa Carey, Matt Ewend, Joseph Geradts, Kimberly Blackwell, Erika Hamilton, Karen Fritchie, Chad Livasy, Andrey Ugolkov, C. Ryan Miller, Barbara Adamo, Abraham Al Ahmad, Allison M. Deal, Vladimir Petrovic, Elena Strekalova, Dmitry Malin

الوصف: PDF file - 797K, Figure S1. Barrier phenotype of human brain microvascular endothelial cells and astrocytes in monocultures and co-cultures. Figure S2. alpha/beta-crystallin does not affect cell viability of TNBC cells in standard monolayer culture. Figure S3. alpha/beta-crystallin overexpression increases liver metastases in an orthotopic model of TNBC. Figure S4. Silencing alpha/beta-crystallin inhibits liver metastases in an orthotopic model of TNBC. Figure S5. alpha/beta-crystallin does not affect proliferation or apoptosis in primary mammary tumors and brain metastatic lesions determined at autopsy. Table S1. Patient characteristics Table S2. alpha/beta-crystallin expression in paired tumors. Table S3. Association of alpha/beta-crystallin expression with breast cancer subtype. Table S4. Incidence of metastases in mice in orthotopic models of TNBC .

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::037114286fb81617e95760c4df77ea6b
https://doi.org/10.1158/1078-0432.22450124

المؤلفون: Vincent L. Cryns, David M. Good, Dmitry Malin, Elena Strekalova

الوصف: Supplementary methods and legends

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d57da44916b542acfc79868fbc9e940
https://doi.org/10.1158/1078-0432.22461227

المؤلفون: Vincent L. Cryns, Carey K. Anders, Eric V. Shusta, Lisa Carey, Matt Ewend, Joseph Geradts, Kimberly Blackwell, Erika Hamilton, Karen Fritchie, Chad Livasy, Andrey Ugolkov, C. Ryan Miller, Barbara Adamo, Abraham Al Ahmad, Allison M. Deal, Vladimir Petrovic, Elena Strekalova, Dmitry Malin

الوصف: Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::266e61780d81213be1d293febd4331de
https://doi.org/10.1158/1078-0432.c.6521858

المؤلفون: Vincent L. Cryns, David M. Good, Dmitry Malin, Elena Strekalova

الوصف: Supplementary Table S1. Composition of diets.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b4d85ad4520f3eebf345864b8df6cf6
https://doi.org/10.1158/1078-0432.22461233

المؤلفون: Vincent L. Cryns, David M. Good, Dmitry Malin, Elena Strekalova

الوصف: Purpose: Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.Experimental Design: Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination.Results: Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model.Conclusions: Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780–91. ©2015 AACR.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1da6fbf6770f844930d9cac546b7ee7
https://doi.org/10.1158/1078-0432.c.6524726

المؤلفون: David F. Jarrard, Tariq A. Khemees, Shivashankar Damodaran, Bing Yang, Mikolaj Filon, Dmitry Malin, Tyler Etheridge, Kyle A. Richards, Adam Schultz, Vincent L. Cryns, Joseph Gawdzik

المصدر: Molecular Cancer Therapeutics. 19:2278-2287

مصطلحات موضوعية: Male, 0301 basic medicine, Senescence, Cancer Research, mTORC1, AMP-Activated Protein Kinases, Models, Biological, Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Cell Line, Tumor, Animals, Humans, Medicine, Protein kinase B, Cellular Senescence, PI3K/AKT/mTOR pathway, business.industry, Prostatic Neoplasms, medicine.disease, Xenograft Model Antitumor Assays, Metformin, XIAP, Disease Models, Animal, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, Androgens, Cancer research, Energy Metabolism, Synthetic Lethal Mutations, business, Proto-Oncogene Proteins c-akt, Signal Transduction, medicine.drug

الوصف: The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo. Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8732df1c9ca5d6f91fa3bc3fe362a9b5
https://doi.org/10.1158/1535-7163.mct-19-1141