المؤلفون: Cossarini, Francesca, D’Souza, Darwin, Roudko, Vladimir, Aberg, Judith, Mehandru, Saurabh

المصدر: Journal of Clinical and Translational Science ; volume 8, issue s1, page 148-148 ; ISSN 2059-8661

الوصف: OBJECTIVES/GOALS: The major obstacle to an effective cure or remission for HIV infection is the integration of HIV into the genome of long-lived resting cells which constitute the so-called viral reservoir. With this study we want to elucidate the changes of the gut-associated HIV reservoir at different stages of viral suppression METHODS/STUDY POPULATION: Recent studies have shown that after long-term (>7 years) clinical suppression of peripheral HIV RNA, the circulating viral reservoir does not seem to decline further and, in fact may expand. The gastrointestinal associated lymphoid tissue (GALT) harbors by far the largest fraction of the latently infected cells, however not much is known about its changes over time.We thus quantified the HIV viral reservoir in the GALT by identifying HIV viral transcripts via 10X single-cell RNA sequencing at two GALT-sites in five PWH and compared the amount of HIV RNA found in the group of PWH with early (< 7years) vs late (> 7years) peripheral virological suppression (plasma HIV RNA <20copies/mL). RESULTS/ANTICIPATED RESULTS: Study participants had been diagnosed with HIV infection for a median (IQR) of 31 (32-34) years and had consistently undetectable peripheral blood HIV RNA for the previous 8 (4-15) years. In PWH with consistent viral suppression < 7yrs, 4 (2-6) HIV transcripts were identified in the ileum and 25 (13 – 38) in the colon. In PWH with consistent viral suppression > 7yrs, 0 (0-4) HIV transcripts were identified in the ileum and 7 (14-11) in the colon. Based on these preliminary results we plan to expand our cohort and confirm these results using Proviral DNA quantification. We anticipate that the viral decay in the GALT will follow a slower dynamic than what has been reported for the peripheral blood achieving a steady state after more than 7 years of peripheral viral suppression. DISCUSSION/SIGNIFICANCE: Despite the remarkable progress the survival and quality of life of PWH, after forty years from its first discovery, HIV infection ...

الإتاحة: https://doi.org/10.1017/cts.2024.424Test
https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S2059866124004242Test

المؤلفون: Janssen, Henrike, Kahles, Florian, Liu, Dan, Downey, Jeffrey, Koekkoek, Laura L., Roudko, Vladimir, D’Souza, Darwin, McAlpine, Cameron S., Halle, Lennard, Poller, Wolfram C., Chan, Christopher T., He, Shun, Mindur, John E., Kiss, Máté G., Singh, Sumnima, Anzai, Atsushi, Iwamoto, Yoshiko, Kohler, Rainer H., Chetal, Kashish, Sadreyev, Ruslan I., Weissleder, Ralph, Kim-Schulze, Seunghee, Merad, Miriam, Nahrendorf, Matthias, Swirski, Filip K.

المساهمون: Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, Deutsche Herzstiftung, National Institutes of Health, Cure Alzheimer's Fund, NHLBI

المصدر: Immunity ; volume 56, issue 4, page 783-796.e7 ; ISSN 1074-7613

الإتاحة: https://doi.org/10.1016/j.immuni.2023.01.024Test
https://api.elsevier.com/content/article/PII:S1074761323000365?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1074761323000365?httpAccept=text/plainTest

المؤلفون: Naidoo, Michael, Jones, Leanne, Conboy, Benjamin, Hamarneh, Wael, D'Souza, Darwin, Anthony, Karen, Machado, Lee

المصدر: Naidoo , M , Jones , L , Conboy , B , Hamarneh , W , D'Souza , D , Anthony , K & Machado , L 2022 , ' Duchenne muscular dystrophy gene expression is an independent prognostic marker for IDH mutant low-grade glioma ' , Cancer Research UK Brain Tumour Conference , London , 5/09/22 - 7/09/22 .

مصطلحات موضوعية: Duchenne muscular dystrophy, Dystrophin, Dp71, Glioma, low grade glioma, Brain tumour, Biomarker, Cancer, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being

الوصف: The Duchenne muscular dystrophy (DMD) gene is the largest known human gene spanning a genomic range over 2Mb. It encodes multiple protein products of varying size and function. Several studies have emerged showing that muscular dystrophy mouse models are prone to develop spontaneous soft tissue sarcomas (STS). High DMD expression has been linked to several cancers, including low-grade glioma (LGG), improving prognosis in some and worsening prognosis in others. Although literature has previously linked the DMD gene to numerous cancers, none have considered the many gene products produced by the DMD gene. Dp71 is a ubiquitous dystrophin protein and the predominant DMD product in the brain.

وصف الملف: application/pdf

العلاقة: https://pure.northampton.ac.uk/en/publications/c5916de0-94fc-42e0-b16e-b300e80cd7f4Test

الإتاحة: https://pure.northampton.ac.uk/en/publications/c5916de0-94fc-42e0-b16e-b300e80cd7f4Test
http://nectar.northampton.ac.uk/id/document/37352Test

المؤلفون: van der Heide, Verena, Jangra, Sonia, Cohen, Phillip, Rathnasinghe, Raveen, Aslam, Sadaf, Aydillo, Teresa, Geanon, Daniel, Handler, Diana, Kelley, Geoffrey, Lee, Brian, Rahman, Adeeb, Dawson, Travis, Qi, Jingjing, D'Souza, Darwin, Kim-Schulze, Seunghee, Panzer, Julia K., Caicedo, Alejandro, Kusmartseva, Irina, Posgai, Amanda L., Atkinson, Mark A., Albrecht, Randy A., García-Sastre, Adolfo, Rosenberg, Brad R., Schotsaert, Michael, Homann, Dirk

المساهمون: JPB Foundation, Juvenile Diabetes Research Foundation United States of America, National Institutes of Health, Open Philanthropy Project, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Defense Advanced Research Projects Agency

المصدر: Cell Reports ; volume 38, issue 11, page 110508 ; ISSN 2211-1247

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الإتاحة: https://doi.org/10.1016/j.celrep.2022.110508Test
https://api.elsevier.com/content/article/PII:S2211124722002443?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2211124722002443?httpAccept=text/plainTest

المؤلفون: Bullerwell, Charles E., Robichaud, Philippe Pierre, Deprez, Pierre M. L., Joy, Andrew P., Wajnberg, Gabriel, D’Souza, Darwin, Chacko, Simi, Fournier, Sébastien, Crapoulet, Nicolas, Barnett, David A., Lewis, Stephen M., Ouellette, Rodney J.

المصدر: Scientific Reports ; volume 11, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: PAX5 and EBF1 work synergistically to regulate genes that are involved in B lymphocyte differentiation. We used the KIS-1 diffuse large B cell lymphoma cell line, which is reported to have elevated levels of PAX5 expression, to investigate the mechanism of EBF1- and PAX5-regulated gene expression. We demonstrate the lack of expression of hallmark B cell genes, including CD19 , CD79b , and EBF1 , in the KIS-1 cell line. Upon restoration of EBF1 expression we observed activation of CD19 , CD79b and other genes with critical roles in B cell differentiation. Mass spectrometry analyses of proteins co-immunoprecipitated with PAX5 in KIS-1 identified components of the MLL H3K4 methylation complex, which drives histone modifications associated with transcription activation. Immunoblotting showed a stronger association of this complex with PAX5 in the presence of EBF1. Silencing of KMT2A, the catalytic component of MLL, repressed the ability of exogenous EBF1 to activate transcription of both CD19 and CD79b in KIS-1 cells. We also find association of PAX5 with the MLL complex and decreased CD19 expression following silencing of KMT2A in other human B cell lines. These data support an important role for the MLL complex in PAX5-mediated transcription regulation.

الإتاحة: https://doi.org/10.1038/s41598-021-81000-5Test
https://www.nature.com/articles/s41598-021-81000-5.pdfTest
https://www.nature.com/articles/s41598-021-81000-5Test

المؤلفون: Magen, Assaf, Hamon, Pauline, Fiaschi, Nathalie, Soong, Brian Y, Park, Matthew D, Mattiuz, Raphaël, Humblin, Etienne, Troncoso, Leanna, D'souza, Darwin, Dawson, Travis, Kim, Joel, Hamel, Steven, Buckup, Mark, Chang, Christie, Tabachnikova, Alexandra, Schwartz, Hara, Malissen, Nausicaa, Lavin, Yonit, Soares-Schanoski, Alessandra, Giotti, Bruno, Hegde, Samarth, Ioannou, Giorgio, Gonzalez-Kozlova, Edgar, Hennequin, Clotilde, Le Berichel, Jessica, Zhao, Zhen, Ward, Stephen C, Fiel, Isabel, Kou, Baijun, Dobosz, Michael, Li, Lianjie, Adler, Christina, Ni, Min, Wei, Yi, Wang, Wei, Atwal, Gurinder S, Kundu, Kunal, Cygan, Kamil J, Tsankov, Alexander M, Rahman, Adeeb, Price, Colles, Fernandez, Nicolas, He, Jiang, Gupta, Namita T, Kim-Schulze, Seunghee, Gnjatic, Sacha, Kenigsberg, Ephraim, Deering, Raquel P, Schwartz, Myron, Marron, Thomas U, Thurston, Gavin, Kamphorst, Alice O, Merad, Miriam

المصدر: Nat Med ; ISSN:1546-170X ; Volume:29 ; Issue:6

الوصف: Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+ T helper cells ("CXCL13+ TH") and Granzyme K+ PD-1+ effector-like CD8+ T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+ T cells dominated in nonresponders. CD4+ and CD8+ T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+ (Progenitor-exhausted) CD8+ T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+ T cell differentiation occurs upon ICB. We found that these Progenitor CD8+ T cells interact with CXCL13+ TH within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ TH control the differentiation of tumor-specific Progenitor exhasuted CD8+ T cells following ICB.

العلاقة: https://doi.org/10.1038/s41591-023-02345-0Test; https://pubmed.ncbi.nlm.nih.gov/37322116Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11027932Test/

الإتاحة: https://doi.org/10.1038/s41591-023-02345-0Test
https://pubmed.ncbi.nlm.nih.gov/37322116Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11027932Test/

المؤلفون: Park, Matthew D., Reyes-Torres, Ivan, LeBerichel, Jessica, Hamon, Pauline, LaMarche, Nelson M., Hegde, Samarth, Belabed, Meriem, Troncoso, Leanna, Grout, John A., Magen, Assaf, Humblin, Etienne, Nair, Achuth, Molgora, Martina, Hou, Jinchao, Newman, Jenna H., Farkas, Adam M., Leader, Andrew M., Dawson, Travis, D’Souza, Darwin, Hamel, Steven, Sanchez-Paulete, Alfonso Rodriguez, Maier, Barbara, Bhardwaj, Nina, Martin, Jerome C., Kamphorst, Alice O., Kenigsberg, Ephraim, Casanova-Acebes, Maria, Horowitz, Amir, Brown, Brian D., De Andrade, Lucas Ferrari, Colonna, Marco, Marron, Thomas U., Merad, Miriam

المصدر: Nature Immunology ; volume 24, issue 5, page 792-801 ; ISSN 1529-2908 1529-2916

مصطلحات موضوعية: Immunology, Immunology and Allergy

الإتاحة: https://doi.org/10.1038/s41590-023-01475-4Test
https://www.nature.com/articles/s41590-023-01475-4.pdfTest
https://www.nature.com/articles/s41590-023-01475-4Test

المؤلفون: Pilcher, William, Yao, Lijun, Kozlova, Edgar Gonzalez, Pita-Juarez, Yered, Karagkouni, Dimitra, Ma, Yuling, Thomas, Beena, Satpathy, Sarthak, Bhasin, Swati, Song, Yizhe, Wang, Julia, Dawson, Travis, D'souza, Darwin, Network, Immune, Schulman, Jessica, Pabustan, Nick, Cook, April, Cho, Hearn Jay, Mulligan, George, Hamilton, Mark, Kourelis, Taxiarchis, Vlachos, Ioannis, Gnjatic, Sacha, Ding, Li, Bhasin, Manoj

المصدر: Clinical Lymphoma Myeloma and Leukemia ; volume 23, page S263-S264 ; ISSN 2152-2650

مصطلحات موضوعية: Cancer Research, Oncology, Hematology

الإتاحة: https://doi.org/10.1016/s2152-2650Test(23)02022-0
https://api.elsevier.com/content/article/PII:S2152265023020220?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2152265023020220?httpAccept=text/plainTest

المؤلفون: Chen, Steven T., Park, Matthew D., Del Valle, Diane Marie, Buckup, Mark, Tabachnikova, Alexandra, Thompson, Ryan C., Simons, Nicole W., Mouskas, Konstantinos, Lee, Brian, Geanon, Daniel, D’Souza, Darwin, Dawson, Travis, Marvin, Robert, Nie, Kai, Zhao, Zhen, LeBerichel, Jessica, Chang, Christie, Jamal, Hajra, Akturk, Guray, Chaddha, Udit, Mathews, Kusum, Acquah, Samuel, Brown, Stacey-Ann, Reiss, Michelle, Harkin, Timothy, Feldmann, Marc, Powell, Charles A., Hook, Jaime L., Kim-Schulze, Seunghee, Rahman, Adeeb H., Brown, Brian D., Beckmann, Noam D., Gnjatic, Sacha, Kenigsberg, Ephraim, Charney, Alexander W., Merad, Miriam

المصدر: Science Translational Medicine ; volume 14, issue 662 ; ISSN 1946-6234 1946-6242

الوصف: Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue–resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

الإتاحة: https://doi.org/10.1126/scitranslmed.abn5168Test

المؤلفون: Chen, Steven T., Park, Matthew D., Del Valle, Diane Marie, Buckup, Mark, Tabachnikova, Alexandra, Simons, Nicole W., Mouskas, Konstantinos, Lee, Brian, Geanon, Daniel, D’Souza, Darwin, Dawson, Travis, Marvin, Robert, Nie, Kai, Thompson, Ryan C., Zhao, Zhen, LeBerichel, Jessica, Chang, Christie, Jamal, Hajra, Chaddha, Udit, Mathews, Kusum, Acquah, Samuel, Brown, Stacey-Ann, Reiss, Michelle, Harkin, Timothy, Feldmann, Marc, Powell, Charles A., Hook, Jaime L., Kim-Schulze, Seunghee, Rahman, Adeeb H., Brown, Brian D., Beckmann, Noam D., Gnjatic, Sacha, Kenigsberg, Ephraim, Charney, Alexander W., Merad, Miriam

المصدر: bioRxiv
article-version (status) pre
article-version (number) 1

مصطلحات موضوعية: Macrophages, Macrophages, Alveolar, COVID-19, Humans, Lung, Article, Monocytes

الوصف: Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::41813ab3db030cfdc7725825852d0bc8Test
http://europepmc.org/articles/PMC8764718Test