tbuckley/cabot-search huggingface dataset:
Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids
Authors: Mattia Francesco Maria Gerli, Giuseppe Calà, Max Arran Beesley, Beatrice Sina, Lucinda Tullie, Kylin Yunyan Sun, Francesco Panariello, Federica Michielin, Joseph R. Davidson, Francesca Maria Russo, Brendan C. Jones, Dani Do Hyang Lee, Savvas Savvidis, Theodoros Xenakis, Ian C. Simcock, Anna A. Straatman-Iwanowska, Robert A. Hirst, Anna L. David, Christopher O’Callaghan, Alessandro Olivo, Simon Eaton, Stavros P. Loukogeorgakis, Davide Cacchiarelli, Jan Deprest, Vivian S. W. Li, Giovanni Giuseppe Giobbe, Paolo De Coppi
Journal: Nature Medicine (2024)

Abstract Isolation of tissue-specific fetal stem cells and derivation of primary organoids is limited to samples obtained from termination of pregnancies, hampering prenatal investigation of fetal development and congenital diseases. Therefore, new patient-specific in vitro models are needed. To this aim, isolation and expansion of fetal stem cells during pregnancy, without the need for tissue samples or reprogramming, would be advantageous. Amniotic fluid (AF) is a source of cells from multiple developing organs. Using single-cell analysis, we characterized the cellular identities present in human AF. We identified and isolated viable epithelial stem/progenitor cells of fetal gastrointestinal, renal and pulmonary origin. Upon culture, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule and lung identity. AF organoids exhibit transcriptomic, protein expression and functional features of their tissue of origin. With relevance for prenatal disease modeling, we derived lung organoids from AF and tracheal fluid cells of congenital diaphragmatic hernia fetuses, recapitulating some features of the disease. AF organoids are derived in a timeline compatible with prenatal intervention, potentially allowing investigation of therapeutic tools and regenerative medicine strategies personalized to the fetus at clinically relevant developmental stages.
Abstract IA021: Mutational processes as determinants of immune evasion in ovarian cancer
Authors: Sohrab P. Shah
Journal: Cancer Research (2024)

Abstract High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, tumor heterogeneity and intraperitoneal spread. Immunotherapies have had limited efficacy in HGSOC, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumor foci determine the immunological states of the tumor microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumors harbored inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumors exhibited elevated immunosuppressive TGFβ signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumors and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research. Citation Format: Sohrab P. Shah. Mutational processes as determinants of immune evasion in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA021.
Vascular Endothelial Growth Factor Inhibitors and the Risk of Aortic Aneurysm and Aortic Dissection
Authors: Chia-Wei Wu, Hsin-Yi Huang, Shin-Yi Lin, Chi-Chuan Wang, Chih-Fen Huang, I-Hui Wu
Journal: JAMA Network Open (2024)

Importance Vascular endothelial growth factor pathway inhibitors (VPIs) pose a concern for aortic aneurysm (AA) and aortic dissection (AD), signaling potential vascular disease development. Objective To investigate VPI-associated AA and AD. Design, Setting, and Participants This case-control study with a nested design used full population data from a national claims database in Taiwan between 2011 and 2019. Eligible participants were aged 20 years or older with kidney, hepatic, gastrointestinal, or pancreatic cancer diagnosed between January 1, 2012, and December 31, 2019. The first cancer diagnosis date was defined as the cohort entry date. Cases were patients who received a diagnosis of AA or AD in hospitalizations or emergency visits between the cohort entry date and December 31, 2019. Controls were matched by ratio (up to 1:5) based on age, sex, cancer type, cohort entry date, and the index date (ie, the first AA or AD event date). Data analysis was performed between January 2022 and December 2023. Exposures Use of the oral VPIs sorafenib, sunitinib, and pazopanib between cohort entry date and index date. Main Outcomes and Measures In the primary analysis, AA and AD were evaluated compositely, while in the secondary analyses, they were evaluated separately. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to assess the association with VPI use (sorafenib, sunitinib, and pazopanib) considering various VPI exposure windows and cumulative use. Results A total of 1461 cases were included (mean [SD] age, 73.0 [12.3] years; 1118 male patients [76.5%]), matched to 7198 controls. AA or AD risk increased with a VPI exposure of 100 days or less before the index date (aOR, 2.10; 95% CI, 1.40-3.15), mainly from VPI-associated AD (aOR, 3.09; 95% CI, 1.77-5.39). Longer VPI duration (68 days or more: aOR, 2.64; 95% CI, 1.66-4.19) and higher cumulative dose (61 or more defined daily doses: aOR, 2.65; 95% CI, 1.66-4.23) increased the risk. Conclusions and Relevance The use of the 3 study VPIs (sorafenib, sunitinib, and pazopanib) was associated with an increased risk of AA and AD in patients with cancer, essentially all of the risk from VPI-associated AD. Future studies are needed to determine the risk factors of VPI-associated AA and AD, as well as to establish a class effect.
Propensity Score-Weighted Analysis of Postoperative Infection in Patients With and Without Preoperative Urine Culture
Authors: William J. O’Brien, Marin L. Schweizer, Judith Strymish, Brice F. Beck, Vanessa Au, Jeffrey A. Chan, Madisen Brown, Kamal M. F. Itani, Kimberly C. Dukes, Julia Friberg Walhof, Kalpana Gupta
Journal: JAMA Network Open (2024)

Importance Although recent guidelines recommend against performance of preoperative urine culture before nongenitourinary surgery, many clinicians still order preoperative urine cultures and prescribe antibiotics for treatment of asymptomatic bacteriuria in an effort to reduce infection risk. Objective To assess the association between preoperative urine culture testing and postoperative urinary tract infection (UTI) or surgical site infection (SSI), independent of baseline patient characteristics or type of surgery. Design, Setting, and Participants This cohort study analyzed surgical procedures performed from January 1, 2017, to December 31, 2019, at any of 112 US Department of Veterans Affairs (VA) medical centers. The cohort comprised VA enrollees who underwent major elective noncardiac, nonurological operations. Machine learning and inverse probability of treatment weighting (IPTW) were used to balance the characteristics between those who did and did not undergo a urine culture. Data analyses were performed between January 2023 and January 2024. Exposures Performance of urine culture within 30 days prior to surgery. Main Outcomes and Measures The 2 main outcomes were UTI and SSI occurring within 30 days after surgery. Weighted logistic regression was used to estimate odds ratios (ORs) for postoperative infection based on treatment status. Results A total of 250 389 VA enrollees who underwent 288 858 surgical procedures were included, with 88.9% (256 753) of surgical procedures received by males and 48.9% (141 340) received by patients 65 years or older. Baseline characteristics were well balanced among treatment groups after applying IPTW weights. Preoperative urine culture was performed for 10.5% of surgical procedures (30 384 of 288 858). The IPTW analysis found that preoperative urine culture was not associated with SSI (adjusted OR [AOR], 0.99; 95% CI, 0.90-1.10) or postoperative UTI (AOR, 1.18; 95% CI, 0.98-1.40). In analyses limited to orthopedic surgery and neurosurgery as a proxy for prosthetic implants, the adjusted risks for UTI and SSI were also not associated with preoperative urine culture performance. Conclusions and Relevance This cohort study found no association between performance of a preoperative urine culture and lower risk of postoperative UTI or SSI. The results support the deimplementation of urine cultures and associated antibiotic treatment prior to surgery, even when using prosthetic implants.
Abstract IA018: Epigenome targeting in ovarian cancer: preclinical models to clinic
Authors: Daniela Matei
Journal: Cancer Research (2024)

Abstract DNA methylation causes silencing of tumor suppressor (TSGs) and differentiation-associated genes, being linked to chemoresistance. Ovarian cancer (OC) is uniquely suited for epigenome targeting as a disease driven by loss of TSGs, rather than oncogenes. Hypomethylating agents (HMA) have been shown to re-sensitize OC to chemotherapy and immunotherapy. A novel HMA (4-thio-decitabine) effectively depleted DNMTs, induced global hypomethylation and transcriptional reprogramming leading to inhibition of OC cell proliferation and tumor growth. Mechanistically, among other gene sets, NTX-301 significantly altered the fatty acid metabolism pathway. A key enzyme in this pathway, the stearoyl co-A desaturase which regulates the last step in lipogenesis, converting saturated fatty acids into unsaturated fatty acids (UFAs) was potently inhibited by NTX-301. This led to depletion of UFAs in cells and tumors treated with the HMA and cell death through ferroptosis. In a clinical trial for women with recurrent, platinum resistant OC, epigenetic priming was used to enhance response to immune checkpoint inhibitors. Among 35 evaluable patients, the clinical benefit rate was 31.4% (95% CI: 16.9 – 49.3%). Methylomic and transcriptomic analyses revealed activation of pathways related to anti-tumor immunity in post-treatment biopsies. High dimensional immune profiling of PBMCs showed higher frequency of peripheral naive and/or central memory CD4+ T cells subsets and of classical monocytes in patients deriving clinical benefit. Multiplex immunohistochemistry indicated that baseline higher density of CD8+ T cells and CD20+ B cells in tumor tissue and presence of putative tertiary lymphoid structures were associated with clinical benefit. These results propose novel mechanisms by which HMAs exert anti-tumor activity in preclinical and clinical models. Citation Format: Daniela Matei. Epigenome targeting in ovarian cancer: preclinical models to clinic [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA018.
Noninferiority of Silver Diamine Fluoride vs Sealants for Reducing Dental Caries Prevalence and Incidence
Authors: Ryan Richard Ruff, Tamarinda J. Barry Godín, Richard Niederman
Journal: JAMA Pediatrics (2024)

Dental caries is the world's most prevalent noncommunicable disease and a source of health inequity; school dental sealant programs are a common preventive measure. Silver diamine fluoride (SDF) may provide an alternative therapy to prevent and control caries if shown to be noninferior to sealant treatment.
Abstract B055: Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer
Authors: Brendan Shay, Abram Handly-Santana, Xingping Qin, Jonathan Choniere, Kristopher Sarosiek, Joan S. Brugge, Elizabeth H. Stover
Journal: Cancer Research (2024)

Abstract Clear cell ovarian cancer is a rare subtype of ovarian cancer with a poor prognosis in advanced-stage disease and increased resistance to standard-of-care treatments including platinum chemotherapy. Previously, we found that multiple clear cell ovarian cancer cell lines are sensitive to inhibition of BCL-XL, a pro-survival member of the BCL-2 family of proteins that control mitochondrial apoptosis. Adding a BCL-XL inhibitor also enhances cell death in clear cell ovarian cancer cell lines treated with standard-of-care drugs including cisplatin, paclitaxel, and poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. To more broadly identify compounds that affect the viability of clear cell ovarian cancer cell lines, either alone or in combination with BCL-XL inhibition, we applied a chemical screening approach. We designed an anchor screen strategy in which a chemical library of clinically relevant compounds (Selleck bioactive compound library; 1,902 compounds) was screened against clear cell ovarian cancer cell lines in two sets: library compounds only, or library compounds combined with BCL-XL inhibitor A1331852 at a fixed concentration (IC25 for each cell line). Fold-change in cell number compared to controls and Z-scores were calculated to identify compounds with single-agent activity in clear cell ovarian cancer and/or with enhanced activity in the presence of A1331852. Initial screening data from JHOC5 and OVISE cell lines identified compounds with targets such as SYK and other tyrosine kinases, PI3K/AKT, and BCL2, as well as chemotherapies, which demonstrated increased activity in the presence of BCL-XL inhibition. Screening of additional cell lines and validation of candidate hits is ongoing to identify agents that are active alone or in combination with BCL-XL inhibition against clear cell ovarian cancer. Citation Format: Brendan Shay, Abram Handly-Santana, Xingping Qin, Jonathan Choniere, Kristopher Sarosiek, Joan S. Brugge, Elizabeth H. Stover. Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B055.
The 14th International Podocyte Conference 2023: from podocyte biology to glomerular medicine
Authors: Sybille Koehler, Felicitas E. Hengel, Bernhard Dumoulin, Laurel Damashek, Lawrence B. Holzman, Katalin Susztak, Tobias B. Huber
Journal: Kidney International (2024)

The 14th International Podocyte Conference took place in Philadelphia, Pennsylvania, USA from May 23 to 26, 2023. It commenced with an early-career researchers' meeting on May 23, providing young scientists with a platform to present and discuss their research findings. Throughout the main conference, 29 speakers across 9 sessions shared their insights on podocyte biology, glomerular medicine, novel technologic advancements, and translational approaches. Additionally, the event featured 3 keynote lectures addressing engineered chimeric antigen receptor T cell- and mRNA-based therapies and the use of biobanks for enhanced disease comprehension. Furthermore, 4 brief oral abstract sessions allowed scientists to present their findings to a broad audience. The program also included a panel discussion addressing the challenges of conducting human research within the American Black community. Remarkably, after a 5-year hiatus from in-person conferences, the 14th International Podocyte Conference successfully convened scientists from around the globe, fostering the presentation and discussion of crucial research findings, as summarized in this review. Furthermore, to ensure continuous and sustainable education, research, translation, and trial medicine related to podocyte and glomerular diseases for the benefit of patients, the International Society of Glomerular Disease was officially launched during the conference.
Screen Time and Parent-Child Talk When Children Are Aged 12 to 36 Months
Authors: Mary E. Brushe, Dandara G. Haag, Edward C. Melhuish, Sheena Reilly, Tess Gregory
Journal: JAMA Pediatrics (2024)

Growing up in a language-rich home environment is important for children's language development in the early years. The concept of "technoference" (technology-based interference) suggests that screen time may be interfering with opportunities for talk and interactions between parent and child; however, limited longitudinal evidence exists exploring this association.
Transforming Otoscopy Using Artificial Intelligence
Authors: Hojjat Salmasian, Lisa Biggs
Journal: JAMA Pediatrics (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Listening Deeply
Authors: Kenneth E. Covinsky
Journal: JAMA Internal Medicine (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy
Authors: Benjamin Madden, Raman Deep Singh, Mark Haas, Lilian M.P. Palma, Alok Sharma, Maria J. Vargas, LouAnn Gross, Vivian Negron, Torell Nate, M. Cristine Charlesworth, Jason D. Theis, Samih H. Nasr, Karl A. Nath, Fernando C. Fervenza, Sanjeev Sethi
Journal: Kidney International (2024)

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.
No Science Supports the Diagnostic Methods for Abusive Head Trauma
Authors: Chris Brook, Cyrille Rossant, Keith A. Findley
Journal: JAMA Pediatrics (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
The Fats and the Furious: Unraveling the Role of Macrophage Lipid Metabolism in Sarcoidosis
Authors: Anneka Hutton, Jessy S. Deshane
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

" The Fats and the Furious: Unraveling the Role of Macrophage Lipid Metabolism in Sarcoidosis ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.