Med (New York, N.y.)最新文献

{"title":"Invariant Natural Killer T cells coordinate removal of senescent cells.","authors":"Shivani Arora,&nbsp;Peter J Thompson,&nbsp;Yao Wang,&nbsp;Aritra Bhattacharyya,&nbsp;Hara Apostolopoulou,&nbsp;Rachel Hatano,&nbsp;Ram P Naikawadi,&nbsp;Ajit Shah,&nbsp;Paul J Wolters,&nbsp;Suneil Koliwad,&nbsp;Mallar Bhattacharya,&nbsp;Anil Bhushan","doi":"10.1016/j.medj.2021.04.014","DOIUrl":"https://doi.org/10.1016/j.medj.2021.04.014","url":null,"abstract":"<p><strong>Background: </strong>The failure of immune surveillance to remove senescent cells drive age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.</p><p><strong>Methods: </strong>We identify a class of lipid-activated T cells, invariant natural killer T cells (iNKTs) are involved in the removal of pathologic senescent cells. We use two disease models in which senescent cells accumulate to test whether activation of iNKT cells was sufficient to eliminate senescent cells in vivo.</p><p><strong>Findings: </strong>Senescent preadipocytes accumulate in white adipose tissue of chronic high-fat diet (HFD) fed mice, and activation of iNKT cells with the prototypical glycolipid antigen alpha-galactosylceramide (αGalCer) led to a reduction of these cells with improved glucose control. Similarly, senescent cells accumulate within the lungs of mice injured by inhalational bleomycin, and αGalCer-induced activation of iNKT cells greatly limited this accumulation, decreased the lung fibrosis and improved survival. Furthermore, co-culture experiments showed that the preferential cytotoxic activity of iNKT cells to senescent cells is conserved in human cells.</p><p><strong>Conclusions: </strong>These results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for anti-senescence therapies that target these cells and their mechanism of activation.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"938-950"},"PeriodicalIF":17.0,"publicationDate":"2021-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.04.014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39492445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why is COVID-19 associated with mental illness?","authors":"Maxime Taquet,&nbsp;Paul J Harrison","doi":"10.1016/j.medj.2021.06.009","DOIUrl":"https://doi.org/10.1016/j.medj.2021.06.009","url":null,"abstract":"<p><p>The COVID-19 pandemic has taken a toll on people's mental health. Besides the indirect impact of the pandemic, a diagnosis of COVID-19 is itself associated with a greater risk of subsequent mental illness. Conversely, people with an existing psychiatric diagnosis are at an increased risk of getting COVID-19. Here, we discuss why this is the case.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"899-902"},"PeriodicalIF":17.0,"publicationDate":"2021-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.06.009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39221857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations in T and B cell function persist in convalescent COVID-19 patients.","authors":"Halima A Shuwa, Tovah N Shaw, Sean B Knight, Kelly Wemyss, Flora A McClure, Laurence Pearmain, Ian Prise, Christopher Jagger, David J Morgan, Saba Khan, Oliver Brand, Elizabeth R Mann, Andrew Ustianowski, Nawar Diar Bakerly, Paul Dark, Christopher E Brightling, Seema Brij, Timothy Felton, Angela Simpson, John R Grainger, Tracy Hussell, Joanne E Konkel, Madhvi Menon","doi":"10.1016/j.medj.2021.03.013","DOIUrl":"10.1016/j.medj.2021.03.013","url":null,"abstract":"<p><strong>Background: </strong>Emerging studies indicate that some coronavirus disease 2019 (COVID-19) patients suffer from persistent symptoms, including breathlessness and chronic fatigue; however, the long-term immune response in these patients presently remains ill-defined.</p><p><strong>Methods: </strong>Here, we describe the phenotypic and functional characteristics of B and T cells in hospitalized COVID-19 patients during acute disease and at 3-6 months of convalescence.</p><p><strong>Findings: </strong>We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8⁺ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6⁺ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10⁺ B cells was associated with the resolution of lung pathology.</p><p><strong>Conclusions: </strong>Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with 1 subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalization with COVID-19 could affect longer-term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients.</p><p><strong>Funding: </strong>Provided by UKRI, Lister Institute of Preventative Medicine, the Wellcome Trust, The Kennedy Trust for Rheumatology Research, and 3M Global Giving.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"720-735.e4"},"PeriodicalIF":0.0,"publicationDate":"2021-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25562660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Turning enemies into allies-reprogramming tumor-associated macrophages for cancer therapy.","authors":"Martina Molgora,&nbsp;Marco Colonna","doi":"10.1016/j.medj.2021.05.001","DOIUrl":"https://doi.org/10.1016/j.medj.2021.05.001","url":null,"abstract":"<p><p>Checkpoint blockade therapies that target inhibitory receptors on T cells have revolutionized clinical oncology. Antibodies targeting CTLA-4 or the PD-1/PD-L1 axis are now successfully used alone or in combination with chemotherapy for numerous tumor types. Despite the clinical success of checkpoint blockade therapies, tumors exploit multiple mechanisms to escape or subvert the anti-tumor T cell response. Within the tumor microenvironment, tumor-associated macrophages (TAM) can suppress T cell responses and facilitate tumor growth in various ways, ultimately debilitating clinical responses to T cell checkpoint inhibitors. There is therefore significant interest in identifying biologicals and drugs that target immunosuppressive TAM within the tumor microenvironment and can be combined with immune checkpoint inhibitors. Here we review approaches that are currently being evaluated to convert immunosuppressive TAM into immunostimulatory macrophages that promote T cell responses and tumor elimination. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment that impact anti-tumor immune responses and susceptibility to checkpoint blockade. TAMs are very heterogeneous and can be either immunosuppressive or immunostimulatory. Here, Molgora and Colonna review current strategies that aim to reprogram TAMs to enhance rather than inhibit immune responses.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"666-681"},"PeriodicalIF":17.0,"publicationDate":"2021-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.05.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39122837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system.","authors":"Sonam Verma,&nbsp;Chetanchandra S Joshi,&nbsp;Rachel B Silverstein,&nbsp;Mai He,&nbsp;Ebony B Carter,&nbsp;Indira U Mysorekar","doi":"10.1016/j.medj.2021.04.009","DOIUrl":"https://doi.org/10.1016/j.medj.2021.04.009","url":null,"abstract":"<p><strong>Background: </strong>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear.</p><p><strong>Methods: </strong>We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA <i>in situ</i> hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S).</p><p><strong>Findings: </strong>Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT₁R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT₂R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia.</p><p><strong>Conclusions: </strong>SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women.</p><p><strong>Funding: </strong>NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"575-590.e5"},"PeriodicalIF":17.0,"publicationDate":"2021-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.04.009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38886615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A public health antibody screening indicates a marked increase of SARS-CoV-2 exposure rate in children during the second wave.","authors":"Markus Hippich,&nbsp;Philipp Sifft,&nbsp;Jose Zapardiel-Gonzalo,&nbsp;Merle M Böhmer,&nbsp;Vito Lampasona,&nbsp;Ezio Bonifacio,&nbsp;Anette-Gabriele Ziegler","doi":"10.1016/j.medj.2021.03.019","DOIUrl":"https://doi.org/10.1016/j.medj.2021.03.019","url":null,"abstract":"","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"571-572"},"PeriodicalIF":17.0,"publicationDate":"2021-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.03.019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25580376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19: The therapeutic landscape.","authors":"Catharine I Paules,&nbsp;Anthony S Fauci","doi":"10.1016/j.medj.2021.04.015","DOIUrl":"https://doi.org/10.1016/j.medj.2021.04.015","url":null,"abstract":"<p><p>Therapeutics for hospitalized COVID-19 patients were identified through a robust research response with several lessons learned: clinical trial data should guide therapeutic use, results should not be extrapolated between disease stages, and robust studies should be designed to give clinically relevant data. These lessons should be applied to the outpatient research response.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"493-497"},"PeriodicalIF":17.0,"publicationDate":"2021-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.04.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38908514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isotope tracing reveals glycolysis and oxidative metabolism in childhood tumors of multiple histologies.","authors":"Kendra Johnston,&nbsp;Panayotis Pachnis,&nbsp;Alpaslan Tasdogan,&nbsp;Brandon Faubert,&nbsp;Lauren G Zacharias,&nbsp;Hieu Sy Vu,&nbsp;Laurie Rodgers-Augustyniak,&nbsp;Allison Johnson,&nbsp;Fang Huang,&nbsp;Sean Ricciardo,&nbsp;Zhiyu Zhao,&nbsp;Thomas P Mathews,&nbsp;Tanya Watt,&nbsp;Patrick Leavey,&nbsp;Ralph J DeBerardinis","doi":"10.1016/j.medj.2021.01.002","DOIUrl":"https://doi.org/10.1016/j.medj.2021.01.002","url":null,"abstract":"<p><strong>Background: </strong>Survival among children with high-risk solid tumors remains poor. Reprogrammed metabolism promotes tumor growth and may contain therapeutic liabilities. Tumor metabolism has been assessed in adults using intra-operative ¹³C-glucose infusions. Pediatric tumors differ from adult cancers in their low mutational burden and derivation from embryonic tissues. Here we used ¹³C infusions to examine tumor metabolism in children, comparing phenotypes among tumor types and between childhood and adult cancers.</p><p><strong>Methods: </strong>Patients recruited to study NCT03686566 received an intra-operative infusion of [U-¹³C]glucose during tumor resection to evaluate central carbon pathways in the tumor, with concurrent metabolomics to provide a broad overview of metabolism. Differential characteristics were determined using multiple comparison tests and mixed effect analyses.</p><p><strong>Findings: </strong>We studied 23 tumors from 22 patients. All tumors analyzed by [U-¹³C]glucose contained labeling in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Labeling in the TCA cycle indicated activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), with PDH predominating. Neuroblastomas had high lactate labeling relative to other childhood cancers and lung cancer, and were distinguished by abundant tyrosine catabolites consistent with catecholamine synthesis.</p><p><strong>Conclusions: </strong>Intra-operative [U¹³C]glucose infusions are safe and informative in pediatric cancer. Tumors of various histologies use glycolysis and oxidative metabolism, with subtype-selective differences evident from this small cohort. Expanding this cohort may uncover predictive biomarkers and therapeutic targets from tumor metabolism.</p><p><strong>Funding: </strong>N.C.I grants to P.L. (R21CA220090-01A1) and R.J.D. (R35CA22044901); H.H.M.I. funding to R.J.D.; Children's Clinical Research Advisory Committee funding to K.J.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"395-410"},"PeriodicalIF":17.0,"publicationDate":"2021-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.01.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38812014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Planetary health is human health","authors":"Salvatore Fabbiano, Elena Bellafante, S. Ramu, Nikla R. Emambokus","doi":"10.1016/J.MEDJ.2021.03.008","DOIUrl":"https://doi.org/10.1016/J.MEDJ.2021.03.008","url":null,"abstract":"","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116996354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can COVID-19 innovations and systems help low- and middle-income countries to re-imagine healthcare delivery?","authors":"Senjuti Saha,&nbsp;Madhukar Pai","doi":"10.1016/j.medj.2021.02.008","DOIUrl":"https://doi.org/10.1016/j.medj.2021.02.008","url":null,"abstract":"<p><p>Several low- and middle-income countries (LMICs) have responded to COVID-19 much better than expected-despite little help from high-income nations. LMICs can learn from the COVID-19 experience and re-imagine healthcare delivery. Using Bangladesh and India as examples, we explain how COVID-19 investments and systems can be leveraged to fight endemic infectious diseases.</p>","PeriodicalId":272244,"journal":{"name":"Med (New York, N.y.)","volume":" ","pages":"369-373"},"PeriodicalIF":17.0,"publicationDate":"2021-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.medj.2021.02.008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25449989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}