المؤلفون: Garcia, Christopher, Velez, Leandro M, Ujagar, Naveena, Del Mundo, Zena, Nguyen, Thu, Fox, Chelsea, Mark, Adam, Fisch, Kathleen M, Lawson, Mark A, Duleba, Antoni J, Seldin, Marcus M, Nicholas, Dequina A

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Infertility, Contraception/Reproduction, Women's Health, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Female, Animals, Mice, Lipopolysaccharides, Pituitary Gland, Gene Expression Profiling, Transcriptome, Gonadotropins, Pituitary, Pituitary Diseases, Inflammation, pituitary, FSH & LH, lipopolysaccharide, inflammation, estrous, secretion, Nutrition and Dietetics, Clinical sciences

الوصف: IntroductionFemale reproductive function depends on a choreographed sequence of hormonal secretion and action, where specific stresses such as inflammation exert profound disruptions. Specifically, acute LPS-induced inflammation inhibits gonadotropin production and secretion from the pituitary, thereby impacting the downstream production of sex hormones. These outcomes have only been observed in acute inflammatory stress and little is known about the mechanisms by which chronic inflammation affects reproduction. In this study we seek to understand the chronic effects of LPS on pituitary function and consequent luteinizing and follicle stimulating hormone secretion.MethodsA chronic inflammatory state was induced in female mice by twice weekly injections with LPS over 6 weeks. Serum gonadotropins were measured and bulk RNAseq was performed on the pituitaries from these mice, along with basic measurements of reproductive biology.ResultsSurprisingly, serum luteinizing and follicle stimulating hormone was not inhibited and instead we found it was increased with repeated LPS treatments.DiscussionAnalysis of bulk RNA-sequencing of murine pituitary revealed paracrine activation of TGFβ pathways as a potential mechanism regulating FSH secretion in response to chronic LPS. These results provide a framework with which to begin dissecting the impacts of chronic inflammation on reproductive physiology.

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الوصول الحر: https://escholarship.org/uc/item/4wk7193xTest
https://escholarship.org/content/qt4wk7193x/qt4wk7193x.pdfTest

المؤلفون: Cooke, Esther J, Joseph, Bilgimol C, Nasamran, Chanond A, Fisch, Kathleen M, von Drygalski, Annette

المصدر: Journal of Thrombosis and Haemostasis. 21(9)

مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Rare Diseases, Hematology, Aetiology, 2.1 Biological and endogenous factors, Mice, Humans, Animals, Factor VIII, Hemarthrosis, Hemophilia A, Lymphangiogenesis, Hemostatics, Disease Models, Animal, Iron, hemarthrosis, hemophilia, inflammation, iron, lymphangiogenesis, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences

الوصف: BackgroundMechanisms of iron clearance from hemophilic joints are unknown.ObjectivesTo better understand mechanisms of iron clearance following joint bleeding in a mouse model of hemophilia.MethodsHemarthrosis was induced by subpatellar puncture in factor VIII (FVIII)-deficient (FVII-/-) mice, +/- periprocedural recombinant human FVIII, and hypocoagulable (HypoBALB/c) mice. HypoBALB/c mice experienced transient FVIII deficiency (anti-FVIII antibody) at the time of injury combined with warfarin-induced hypocoagulability. Synovial tissue was harvested weekly up to 6 weeks after injury for histological analysis, ferric iron and macrophage accumulation (CD68), blood and lymphatic vessel remodeling (αSMA; LYVE1). Synovial RNA sequencing was performed for FVIII-/- mice at days 0, 3, and 14 after injury to quantify expression changes of iron regulators and lymphatic markers.ResultsBleed volumes were similar in FVIII-/- and HypoBALB/c mice. However, pronounced and prolonged synovial iron accumulation colocalizing with macrophages and impaired lymphangiogenesis were detected only in FVIII-/- mice and were prevented by periprocedural FVIII. Gene expression changes involved in iron handling (some genes with dual roles in inflammation) and lymphatic markers supported proinflammatory milieu with iron retention and disturbed lymphangiogenesis.ConclusionAccumulation and delayed clearance of iron-laden macrophages were associated with defective lymphangiogenesis after hemarthrosis in FVIII-/- mice. The absence of such findings in HypoBALB/c mice suggests that intact lymphatics are required for removal of iron-laden macrophages and that these processes depend on FVIII availability. Studies to elucidate the biological mechanisms of disturbed lymphangiogenesis in hemophilia appear critical to develop new therapeutic targets.

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الوصول الحر: https://escholarship.org/uc/item/3h52s30dTest

المؤلفون: Morey, Robert, Bui, Tony, Fisch, Kathleen M, Horii, Mariko

مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Pediatric, Regenerative Medicine, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Embryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Nonembryonic - Human, Contraception/Reproduction, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Animals, Mice, Humans, Pregnancy, Female, Placentation, Placenta, Trophoblasts, Pluripotent Stem Cells, Cell Differentiation, Disease modeling, Human pluripotent stem cells, Trophoblast organoid, Trophoblast stem cells, Biochemistry and Cell Biology, Clinical Sciences, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine, Biochemistry and cell biology, Reproductive medicine, Midwifery

الوصف: Our current knowledge of the cellular and molecular mechanisms of placental epithelial cells, trophoblast, primarily came from the use of mouse trophoblast stem cells and tumor-derived or immortalized human trophoblast cell lines. This was mainly due to the difficulties in maintaining primary trophoblast in culture and establishing human trophoblast stem cell (hTSC) lines. However, in-depth characterization of these cellular models and in vivo human trophoblast have revealed significant discrepancies. For the past two decades, multiple groups have shown that human pluripotent stem cells (hPSCs) can be differentiated into trophoblast, and thus could be used as a model for normal and disease trophoblast differentiation. During this time, trophoblast differentiation protocols have evolved, enabling researchers to study cellular characteristics at trophectoderm (TE), trophoblast stem cells (TSC), syncytiotrophoblast (STB), and extravillous trophoblast (EVT) stages. Recently, several groups reported methods to derive hTSC from pre-implantation blastocyst or early gestation placenta, and trophoblast organoids from early gestation placenta, drastically changing the landscape of trophoblast research. These culture conditions have been rapidly applied to generate hPSC-derived TSC and trophoblast organoids. As a result of these technological advancements, the field's capacity to better understand trophoblast differentiation and their involvement in pregnancy related disease has greatly expanded. Here, we present in vitro models of human trophoblast differentiation, describing both primary and hPSC-derived TSC, maintained as monolayers and 3-dimensional trophoblast organoids, as a tool to study early placental development and disease in multiple settings.

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الوصول الحر: https://escholarship.org/uc/item/7137n709Test

المؤلفون: Knorr, Jana, Kaufmann, Benedikt, Inzaugarat, Maria Eugenia, Holtmann, Theresa Maria, Geisler, Lukas, Hundertmark, Jana, Kohlhepp, Marlene Sophia, Boosheri, Laela M, Chilin‐Fuentes, Daisy R, Birmingham, Amanda, Fisch, Kathleen M, Schilling, Joel D, Loosen, Sven H, Trautwein, Christian, Roderburg, Christoph, Demir, Münevver, Tacke, Frank, Hoffman, Hal M, Feldstein, Ariel E, Wree, Alexander

المصدر: Hepatology. 77(6)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Liver Disease, Digestive Diseases, Nutrition, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Oral and gastrointestinal, Mice, Animals, Inflammasomes, Hepatic Stellate Cells, Interleukin-18, NLR Family, Pyrin Domain-Containing 3 Protein, Liver Cirrhosis, Fibrosis, Carrier Proteins, Liver, Medical Biochemistry and Metabolomics, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background and aimsNucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.Approach and resultsWe observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . Treatment of cultured primary murine HSC with recombinant mouse IL-18 accelerated their transdifferentiation into myofibroblasts. In vivo , IL-18 receptor-deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC-specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH-induced fibrosis by feeding a choline-deficient, L-amino acid-defined, high fat diet showed that genes related to IL-18 and its downstream signaling were significantly upregulated, and Il18-/- mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin-positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL-18 signaling was blocked by its naturally occurring antagonist IL-18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell-specific NLRP3 gain-of-function was rescued by IL-18BP.ConclusionsOur study highlights the role of IL-18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL-18 as a target to treat liver fibrosis.

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الوصول الحر: https://escholarship.org/uc/item/8zp1p43zTest

المؤلفون: Rios-Covian, David, Butcher, Lindsay D, Ablack, Amber L, Hartog, Gerco den, Matsubara, Mason T, Ly, Hong, Oates, Andrew W, Xu, Guorong, Fisch, Kathleen M, Ahrens, Eric T, Toden, Shusuke, Brown, Corrie C, Kim, Kenneth, Le, Dzung, Eckmann, Lars, Dhar, Bithika, Izumi, Tadahide, Ernst, Peter B, Crowe, Sheila E

المصدر: Antioxidants & Redox Signaling. 38(1-3)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Genetics, Digestive Diseases, 1.1 Normal biological development and functioning, Underpinning research, Mice, Animals, DNA Repair, Oxidative Stress, DNA Damage, Oxidation-Reduction, Disease Models, Animal, DNA-(Apurinic or Apyrimidinic Site) Lyase, Stomach, Endonucleases, Apex1, APE1, oxidative stress, DNA damage, cell differentiation, embryonic development, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics

الوصف: Aims: Though best known for its role in oxidative DNA damage repair, apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that regulates multiple host responses during oxidative stress, including the reductive activation of transcription factors. As knockout of the APE1-encoding gene, Apex1, is embryonically lethal, we sought to create a viable model with generalized inhibition of APE1 expression. Results: A hypomorphic (HM) mouse with decreased APE1 expression throughout the body was generated using a construct containing a neomycin resistance (NeoR) cassette knocked into the Apex1 site. Offspring were assessed for APE1 expression, breeding efficiency, and morphology with a focused examination of DNA damage in the stomach. Heterozygotic breeding pairs yielded 50% fewer HM mice than predicted by Mendelian genetics. APE1 expression was reduced up to 90% in the lungs, heart, stomach, and spleen. The HM offspring were typically smaller, and most had a malformed tail. Oxidative DNA damage was increased spontaneously in the stomachs of HM mice. Further, all changes were reversed when the NeoR cassette was removed. Primary gastric epithelial cells from HM mice differentiated more quickly and had more evidence of oxidative DNA damage after stimulation with Helicobacter pylori or a chemical carcinogen than control lines from wildtype mice. Innovation: A HM mouse with decreased APE1 expression throughout the body was generated and extensively characterized. Conclusion: The results suggest that HM mice enable studies of APE1's multiple functions throughout the body. The detailed characterization of the stomach showed that gastric epithelial cells from HM were more susceptible to DNA damage. Antioxid. Redox Signal. 38, 183-197.

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الوصول الحر: https://escholarship.org/uc/item/8cx3g5f4Test

المؤلفون: Honda, Asami, Hoeksema, Marten A, Sakai, Mashito, Lund, Sean J, Lakhdari, Omar, Butcher, Lindsay D, Rambaldo, Tara C, Sekiya, Neal M, Nasamran, Chanond A, Fisch, Kathleen M, Sajti, Eniko, Glass, Christopher K, Prince, Lawrence S

المصدر: The Journal of Immunology. 208(8)

مصطلحات موضوعية: Paediatrics, Biomedical and Clinical Sciences, Human Genome, Clinical Research, Pediatric, Vaccine Related, Genetics, Lung, Pediatric Research Initiative, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Good Health and Well Being, Animals, Chromatin, Macrophages, Alveolar, Mice, NF-kappa B, Transcription, Genetic, Immunology, Biochemistry and cell biology

الوصف: Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. In this study, we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs in mice. Although the core AM signature was similar, murine adult AMs expressed higher levels of genes involved in lipid metabolism, whereas neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by an assay for transposase-accessible chromatin followed by high-throughput sequencing (ATAC-seq) contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-κB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonatal and adult mice, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal mouse AMs retained high expression of some proinflammatory genes, suggesting that the differences in neonatal AMs result from both inherent cell properties and environmental influences.

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الوصول الحر: https://escholarship.org/uc/item/5wk3z485Test

المؤلفون: Podvin, Sonia, Rosenthal, Sara Brin, Poon, William, Wei, Enlin, Fisch, Kathleen M, Hook, Vivian

المصدر: Journal of Huntington's Disease. 11(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Genetics, Rare Diseases, Neurodegenerative, Huntington's Disease, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Humans, Huntingtin Protein, Huntington Disease, Mice, Mice, Transgenic, Nerve Tissue Proteins, Neurodegenerative Diseases, Nuclear Proteins, Protein Interaction Maps, Huntingtin, mutant, wild-type, protein interactors, networks, translation, signaling, mitochondria, chromatin, trafficking

الوصف: BackgroundHuntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat (CAG) expansions in the human HTT gene encoding the huntingtin protein (Htt) with an expanded polyglutamine tract.ObjectiveHD models from yeast to transgenic mice have investigated proteins interacting with mutant Htt that may initiate molecular pathways of cell death. There is a paucity of datasets of published Htt protein interactions that include the criteria of 1) defining fragments or full-length Htt forms, 2) indicating the number of poly-glutamines of the mutant and wild-type Htt forms, and 3) evaluating native Htt interaction complexes. This research evaluated such interactor data to gain understanding of Htt dysregulation of cellular pathways.MethodsHtt interacting proteins were compiled from the literature that meet our criteria and were subjected to network analysis via clustering, gene ontology, and KEGG pathways using rigorous statistical methods.ResultsThe compiled data of Htt interactors found that both mutant and wild-type Htt interact with more than 2,971 proteins. Application of a community detection algorithm to all known Htt interactors identified significant signal transduction, membrane trafficking, chromatin, and mitochondrial clusters, among others. Binomial analyses of a subset of reported protein interactor information determined that chromatin organization, signal transduction and endocytosis were diminished, while mitochondria, translation and membrane trafficking had enriched overall edge effects.ConclusionThe data support the hypothesis that mutant Htt disrupts multiple cellular processes causing toxicity. This dataset is an open resource to aid researchers in formulating hypotheses of HD mechanisms of pathogenesis.

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الوصول الحر: https://escholarship.org/uc/item/5hj2d8prTest

المؤلفون: Gonzalez, Carlos G, Mills, Robert H, Kordahi, Melissa C, Carrillo-Terrazas, Marvic, Secaira-Morocho, Henry, Widjaja, Christella E, Tsai, Matthew S, Mittal, Yash, Yee, Brian A, Vargas, Fernando, Weldon, Kelly, Gauglitz, Julia M, Delaroque, Clara, Sauceda, Consuelo, Rossitto, Leigh-Ana, Ackermann, Gail, Humphrey, Gregory, Swafford, Austin D, Siegel, Corey A, Buckey, Jay C, Raffals, Laura E, Sadler, Charlotte, Lindholm, Peter, Fisch, Kathleen M, Valaseck, Mark, Suriawinata, Arief, Yeo, Gene W, Ghosh, Pradipta, Chang, John T, Chu, Hiutung, Dorrestein, Pieter, Zhu, Qiyun, Chassaing, Benoit, Knight, Rob, Gonzalez, David J, Dulai, Parambir S

المصدر: Cellular and Molecular Gastroenterology and Hepatology. 14(1)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Biochemistry and Metabolomics, Inflammatory Bowel Disease, Nutrition, Clinical Research, Biotechnology, Genetics, Autoimmune Disease, Digestive Diseases, Animals, Colitis, Ulcerative, Humans, Hyperbaric Oxygenation, Interleukin-10, Mice, Microbiota, RNA, Ribosomal, 16S, Biochemistry and cell biology, Clinical sciences

الوصف: Background & aimsHyperbaric oxygen therapy (HBOT) is a promising treatment for moderate-to-severe ulcerative colitis. However, our current understanding of the host and microbial response to HBOT remains unclear. This study examined the molecular mechanisms underpinning HBOT using a multi-omic strategy.MethodsPre- and post-intervention mucosal biopsies, tissue, and fecal samples were collected from HBOT phase 2 clinical trials. Biopsies and fecal samples were subjected to shotgun metaproteomics, metabolomics, 16s rRNA sequencing, and metagenomics. Tissue was subjected to bulk RNA sequencing and digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed. Fecal samples were also used for colonization experiments in IL10-/- germ-free UC mouse models.ResultsProteomics identified negative associations between HBOT response and neutrophil azurophilic granule abundance. DSP identified an HBOT-specific reduction of neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with a proportional increase in Firmicutes and a secondary bile acid lithocholic acid. A major source of the reduction in diversity was the loss of mucus-adherent taxa, resulting in increased MUC2 levels post-HBOT. Targeted database searching revealed strain-level associations between Akkermansia muciniphila and HBOT response status. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared with non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses.ConclusionsHBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A muciniphila, may contribute to HBOT non-response.

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الوصول الحر: https://escholarship.org/uc/item/4cf9h3d3Test

المؤلفون: Zhou, Yixuan, Bastian, Ingmar Niels, Long, Mark D, Dow, Michelle, Li, Weihua, Liu, Tao, Ngu, Rachael Katie, Antonucci, Laura, Huang, Jian Yu, Phung, Qui T, Zhao, Xi-He, Banerjee, Sourav, Lin, Xue-Jia, Wang, Hongxia, Dang, Brian, Choi, Sylvia, Karin, Daniel, Su, Hua, Ellisman, Mark H, Jamieson, Christina, Bosenberg, Marcus, Cheng, Zhang, Haybaeck, Johannes, Kenner, Lukas, Fisch, Kathleen M, Bourgon, Richard, Hernandez, Genevive, Lill, Jennie R, Liu, Song, Carter, Hannah, Mellman, Ira, Karin, Michael, Shalapour, Shabnam

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 118(8)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Animals, Antigen Presentation, Antineoplastic Agents, Apoptosis, B7-H1 Antigen, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Cell Proliferation, Drug Therapy, Combination, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class I, Humans, Immune Checkpoint Inhibitors, Immunotherapy, Mice, NF-kappa B, Neoplasms, Oxaliplatin, Prognosis, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, p300-CBP Transcription Factors, histone acetylation, MHC-I, antigen presentation, immune checkpoint inhibitors, NF-κB

الوصف: Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

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الوصول الحر: https://escholarship.org/uc/item/6c06q71dTest

المؤلفون: Ren, Shuling, Gaykalova, Daria A, Guo, Theresa, Favorov, Alexander V, Fertig, Elana J, Tamayo, Pablo, Callejas-Valera, Juan Luis, Allevato, Mike, Gilardi, Mara, Santos, Jessica, Fukusumi, Takahito, Sakai, Akihiro, Ando, Mizuo, Sadat, Sayed, Liu, Chao, Xu, Guorong, Fisch, Kathleen M, Wang, Zhiyong, Molinolo, Alfredo A, Gutkind, J Silvio, Ideker, Trey, Koch, Wayne M, Califano, Joseph A

المصدر: Oncogene. 39(40)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Cervical Cancer, Infectious Diseases, Genetics, Human Genome, Sexually Transmitted Infections, Aetiology, 2.1 Biological and endogenous factors, Animals, Antineoplastic Combined Chemotherapy Protocols, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Datasets as Topic, Disease Models, Animal, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Viral, Host-Pathogen Interactions, Human papillomavirus 16, Humans, Mice, Mice, Transgenic, Oncogene Proteins, Viral, Papillomavirus Infections, Pharyngeal Neoplasms, Primary Cell Culture, Receptors, Fibroblast Growth Factor, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, TOR Serine-Threonine Kinases, Tumor Suppressor Protein p53, Uterine Cervical Neoplasms, Clinical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/965152qsTest