tbuckley/cabot-search huggingface dataset:
Management of Crohn Disease
Authors: Kelly Cushing, Peter D. R. Higgins
Journal: JAMA (2021)

<h3>Importance</h3> Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance. <h3>Observations</h3> The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti–tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy. <h3>Conclusions and Relevance</h3> The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.
CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer
Authors: Moran Yang, Jiaqi Lu, Guodong Zhang, Yiying Wang, Mengdi He, Qing Xu, Congjian Xu, Haiou Liu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Most patients with high-grade serous ovarian cancer (HGSC) lack an effective response to immune checkpoint blockade, highlighting the need for more knowledge about what is required for successful treatment. As follicular cytotoxic CXCR5 + CD8 + T cells are maintained by reinvigoration by immune checkpoint blockade in tumors, we attempted to reveal the relationship between CXCR5 + CD8 + T cells and the tumor microenvironment to predict immunotherapy responses in HGSC. Methods 264 patients with HGSC from two cohorts and 340 HGSC cases from The Cancer Genome Atlas cohort were enrolled. Ex vivo and in vivo studies were conducted with human HGSC tumors and murine tumor models. The spatial correlation between CXC-chemokine ligand 13 (CXCL13), CXCR5, CD8, and CD20 was evaluated by immunohistochemistry and immunofluorescence. Survival was compared between different subsets of patients using Kaplan-Meier analysis. The therapeutic effect of CXCL13 and programmed cell death-1 (PD-1) blockade was validated using human HGSC tumors and murine models. Results High CXCL13 expression was associated with prolonged survival. Tumors with high CXCL13 expression exhibited increased infiltration of activated and CXCR5-expressing CD8 + T cells. Incubation with CXCL13 facilitated expansion and activation of CXCR5 + CD8 + T cells ex vivo. CXCR5 + CD8 + T cells appeared in closer proximity to CXCL13 in tumors and chemotaxis towards CXCL13 in vitro. The combination of CXCL13, CXCR5, and CD8 + T cells was an independent predictor for survival. In addition, CXCL13 was associated with clusters of CD20 + B cells. CD20 + B cells predicted better patient survival in the presence of CXCL13. Histological evaluation highlighted colocalization of CXCL13 with tertiary lymphoid structures (TLSs). TLSs carried prognostic benefit only in the presence of CXCL13. CXCL13 in combination with anti-PD-1 therapy retarded tumor growth in a CD8 + T-cell-dependent manner, resulting in increased infiltration of cytotoxic CD8 + T cells and CXCR5 + CD8 + T cells. Conclusions These data define a critical role of CXCL13 in shaping antitumor microenvironment by facilitating the maintenance of CXCR5 + CD8 + T cells in TLSs and support a clinical investigation for a combination of CXCL13 and PD-1 blockade therapy in HGSC.
More on STAT1 Gain of Function, Type 1 Diabetes, and JAK Inhibition
Authors: Mark S Anderson, Natalia S Chaimowitz, Lisa R Forbes
Journal: New England Journal of Medicine (2021)

To the Editor: Chaimowitz et al. (Oct.8 issue) 1 report diabetes remission following ruxolitinib treatment in a patient with a signal transducer and activator of transcription 1 (STAT1) gain-offunction mutation. 1This work is exciting and important, but we believe the authors were incorrect in referring to the diabetes in this monogenic autoimmune syndrome as type 1 diabetes.Although both type 1 diabetes and diabetes in monogenic autoimmune syndromes are autoimmune diseases, with the associated islet autoantibodies, there is a crucial difference in their genetic susceptibility and hence their cause.Type 1 diabetes is a polygenic autoimmune disease with well-described associations with common variants in the HLA locus. 2 In contrast, the diabetes described by Chaimowitz et al. is caused by a highly penetrant variant in a single gene in a monogenic autoimmune form of diabetes and is not associated with HLA. 3,4Specific immunomodulatory therapy can be chosen on the basis of the specific gene or pathway involved in monogenic autoimmunity, as shown by the authors, but the difference in causation means it is unlikely that the same therapy will prevent the development of the far more common type 1 diabetes. 5We believe that diabetes in any monogenic autoimmune condition should be referred to as monogenic autoimmune diabetes and should include its gene name -in this case, STAT1-monogenic autoimmune diabetes -rather than being referred to by the term "type 1 diabetes."
Homology-mediated inter-chromosomal interactions in hexaploid wheat lead to specific subgenome territories following polyploidization and introgression
Authors: Jizeng Jia, Yilin Xie, Jingfei Cheng, Chuizheng Kong, Meiyue Wang, Lifeng Gao, Fei Zhao, Jingyu Guo, Kai Wang, Guangwei Li, Dangqun Cui, Tiezhu Hu, Guangyao Zhao, Daowen Wang, Zhengang Ru, Yijing Zhang
Journal: Genome biology (2021)

Polyploidization and introgression are major events driving plant genome evolution and influencing crop breeding. However, the mechanisms underlying the higher-order chromatin organization of subgenomes and alien chromosomes are largely unknown.
Control of a COVID-19 outbreak in a nursing home by general screening and cohort isolation in Germany, March to May 2020
Authors: Manuel Krone, Annette Noffz, Elisabeth Richter, Ulrich Vogel, Michael Schwab
Journal: Eurosurveillance (2021)

Elderly care facilities have become a major focus of coronavirus disease (COVID-19) control. Here, we describe an outbreak of COVID-19 in a nursing home in Germany from 8 March to 4 May 2020 (58 days), and the effect of an intervention of general screening and cohort isolation. COVID-19 cases among residents and staff were recorded on a daily basis from the first positive SARS-CoV-2 test from a resident on 8 March 2020, until 4 May 2020 when the last staff member was classified COVID-19 negative. Eighty of 160 residents (50%) and 37 of 135 staff members (27%) tested positive for SARS-CoV-2. Twenty-seven of the 80 residents were asymptomatic but tested positive during the first general screening. Cohort isolation of SARS-CoV-2 positive residents by reorganising the facility proved to be a major effort. After the intervention, four further asymptomatic residents tested positive in follow-up screenings within a period of 6 days, and were possibly infected prior to the intervention. Thereafter, no further infections were recorded among residents. The described outbreak was controlled by implementing general screening and rigorous cohort isolation, providing a blueprint for similar facilities.
3D scaffold-free microlivers with drug metabolic function generated by lineage-reprogrammed hepatocytes from human fibroblasts
Authors: Zuyan Lu, Shiny Amala Priya Rajan, Qianqian Song, Yu Zhao, Meimei Wan, Julio Aleman, Aleksander Skardal, Colin Bishop, Anthony Atala, Baisong Lu
Journal: Biomaterials (2021)
Bisphosphonates inhibit osteopontin induced prostate cancer cell motility by attenuating MMP-9 activity
Authors: Bhavik S. Desai, Meenakshi Chellaiah
Journal: Cancer Research (2006)

3290  Osteopontin (OPN) has been identified to have a role in the determination of osteotropism and growth of prostate cancer cells. In osteoclasts, we have demonstrated that binding of OPN to αvβ3 initiates intracellular signals required for the surface expression of the receptor CD44. In order to study the regulatory role of OPN/αvβ3 signaling in prostate cancer, we have generated prostate cancer (PC3) cell lines genetically engineered for OPN expression. Stable PC3 cell lines over expressing OPN, mutant OPN (RGD→RGA) as well as OPN null PC3 cells using siRNA constructs to OPN were generated. Surface expression of CD44 by biotinylation and MMP-9 activity in the conditioned media was determined by zymogram analyses. An increase in CD44 surface expression as well as MMP 9 activity in the conditioned medium was observed in PC3/OPN cells as compared with PC3 cells. A decrease in MMP-9 activity as well as CD44 surface expression below the control level (PC3) was observed in PC3/OPN (RGD→RGA) or OPN-SiRNA transfected PC3 cells. OPN overexpression also seems to cause cytoskeletal changes by increasing co-localization of MMP-9 with actin. .OPN over expression significantly increases cell migration. In PC3/OPN (RGD→RGA) cells, the migration was found to be comparable to PC3 cells. Bisphosphonates have already been shown to be an effective inhibitor of osteoclast activation and function. Addition of alendronate or pamindronate to PC3 cells reduced the surface expression of CD44 as well as MMP-9 activity in the conditioned medium of PC3 cell lines in a time and dose-dependent manner. Immunostaining analysis with antibodies to MMP-9 and CD44 in non-permeablized PC3 cell lines or osteoclasts demonstrated a significant inhibition of surface colocalization of MMP-9 and CD44 by bisphosphonates treatment. Bisphosphonates also reduced the migration of PC3 cells in the wound closure assay. Our findings suggest that bisphosphonates down regulates MMP- 9 secretion and CD44 surface expression in both osteoclasts and prostate cancer cells contributing to possible reduction in invasive nature of prostate cancer cells and decreased bone resorption potential of osteoclasts. (Supported by NIH-NIAMS; AR46292 to MAC)
HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor
Authors: Matthew L. Hemming, Shannon Coy, Jia-Ren Lin, Jessica L. Andersen, Joanna Przybyl, Emanuele Mazzola, Amr H. Abdelhamid Ahmed, Matt van de Rijn, Peter K. Sorger, Scott A. Armstrong, George D. Demetri, Sandro Santagata
Journal: Clinical Cancer Research (2021)

Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern. Here, we characterize two divergent transcriptional programs maintained by HAND1 and BARX1, and evaluate their association with clinical outcomes.We evaluated RNA sequencing and TF chromatin immunoprecipitation with sequencing in GIST samples and cultured cells for transcriptional programs associated with HAND1 and BARX1. Multiplexed tissue-based cyclic immunofluorescence and IHC evaluated tissue- and cell-level expression of TFs and their association with clinical factors.We show that HAND1 is expressed in aggressive GIST, modulating KIT and core TF expression and supporting proliferative cellular programs. In contrast, BARX1 is expressed in indolent and micro-GISTs. HAND1 and BARX1 expression were superior predictors of relapse-free survival, as compared with standard risk stratification, and they predict progression-free survival on imatinib. Reflecting the developmental origins of accessory TF programs, HAND1 was expressed solely in small intestine ICCs, whereas BARX1 expression was restricted to gastric ICCs.Our results define anatomic and transcriptional determinants of GIST and molecular origins of clinical phenotypes. Assessment of HAND1 and BARX1 expression in GIST may provide prognostic information and improve clinical decisions on the administration of adjuvant therapy.
Maternal Elimination Diet and Symptoms of Cow’s Milk Allergy in Breastfed Infants—Reply
Authors: Daniel Munblit, Debra J. Palmer, Robert J. Boyle
Journal: JAMA Pediatrics (2021)

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Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren’s syndrome by modulating the function of myeloid-derived suppressor cells
Authors: Ke Rui, Yue Hong, Qiugang Zhu, Xiaofei Shi, Fan Xiao, Hailong Fu, Qing Yin, Yida Xing, Xinfeng Wu, Xiaodan Kong, Huaxi Xu, Jie Tian, Shengjun Wang, Liwei Lu
Journal: Cellular and Molecular Immunology (2021)

Abstract Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands. Our previous studies showed that myeloid-derived suppressor cells (MDSCs) exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren’s syndrome (ESS), but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS. In this study, we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels. Moreover, treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice. Mechanistically, OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs. In addition, the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling, indicating an autocrine pathway of MDSC functional modulation by IL-6. Taken together, our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs, possibly constituting a new strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.
Cardiovascular Complications of Opioid Use
Authors: Mori J. Krantz, Robert B. Palmer, Mark C.P. Haigney
Journal: Journal of the American College of Cardiology (2021)

Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent μ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.
Differential Documentation of Race in the First Line of the History of Present Illness
Authors: Jessica R. Balderston, Zachary M. Gertz, Raees Seedat, Jackson L. Rankin, Amanda W. Hayes, Viviana A. Rodriguez, Gregory J. Golladay
Journal: JAMA Internal Medicine (2021)

This cross-sectional study assesses medical records for evidence of racial bias in clinician documentation among patients admitted for breast cancer, sickle cell disease with crisis, status epilepticus, hypertensive emergency, pneumonia, or motor vehicle collision.
The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults
Authors: Yael Renert-Yuval, Ester Del Duca, Ana B. Pavel, Milie Fang, Rachel Lefferdink, Jianni Wu, Aisleen Diaz, Yeriel D. Estrada, Talia Canter, Ning Zhang, Annette Wagner, Sarah Chamlin, James G. Krueger, Emma Guttman-Yassky, Amy S. Paller
Journal: Journal of Allergy and Clinical Immunology (2021)
Changes in Cardiovascular Biomarkers Associated With the Sodium–Glucose Cotransporter 2 (SGLT2) Inhibitor Ertugliflozin in Patients With Chronic Kidney Disease and Type 2 Diabetes
Authors: Patrick R. Lawler, Hongyan Liu, Claudia Frankfurter, Leif Erik Lovblom, Yuliya Lytvyn, Dylan Burger, Kevin D. Burns, Davor Brinc, David Z.I. Cherney
Journal: Diabetes Care (2021)

Patients with type 2 diabetes are at high risk of developing renal and cardiovascular complications. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have garnered interest due to their glucose-independent cardiorenal protective effects, as reported in trials including participants with and without diabetes, such as Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) (1,2). These trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease (CVD) risk, especially hospitalization for heart failure (1,2). Despite these clinical benefits, the underlying physiological mechanisms of SGLT2 inhibitors are incompletely understood, particularly in patients with chronic kidney disease (CKD). Accordingly, this analysis examined the impact of treatment with an SGLT2 inhibitor, ertugliflozin, on markers of plasma volume contraction and myocardial strain in participants with type 2 diabetes and moderate CKD.

We performed a post hoc exploratory analysis in a subset of 231 participants from the eValuation of ERTugliflozin efficacy and Safety (VERTIS) RENAL trial (clinical trial reg. no. NCT01986855, ClinicalTrials.gov) with type 2 diabetes and stage 3 CKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) who were randomized to SGLT2 inhibitor therapy with ertugliflozin (5 mg or 15 mg daily; pooled herein) or placebo (3). Clinical and biomarker measurements were obtained at baseline and 26 weeks and 52 weeks postrandomization. Biomarkers were quantified with Luminex xMAP (cardiac troponin, renin, and N-terminal pro B-type natriuretic peptide [NT-proBNP]) or ELISA (atrial natriuretic peptide [ANP], human erythropoietin [EPO], ACE, and ACE2). Aldosterone was quantified by DiaSorin LIAISON XL Analyzer based on competitive chemiluminescent immunoassay. Differences in longitudinal changes in biomarkers among participants receiving either …
Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation
Authors: Chunqi Liu, Liang Wang, Xiaocong Liu, Yuping Tan, Lei Tao, Yuzhou Xiao, Pengchi Deng, Huijuan Wang, Qianyi Deng, Yiyun Lin, Hui Jie, Huaqin Zhang, Jing Zhang, Yong Peng, Hu Zhang, Zongguang Zhou, Qingxiang Sun, Xiaobo Cen, Yinglan Zhao
Journal: Theranostics (2021)

Introduction: Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in serine-glycine metabolism to drive cancer cell proliferation. However, the nonmetabolic function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Methods: SHMT2 expression in human CRC cells was identified by western blot and immunofluorescence assay. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown or overexpression were explored through in vitro and in vivo assays. Immunofluorescence, mRNA-seq, co-immunoprecipitation, chromatin immunoprecipitation-qPCR and immunohistochemistry assays were used to investigate the underlying mechanisms behind the SHMT2 nonmetabolic function. Results: We demonstrated that SHMT2 was distributed in the cytoplasm and nucleus of human CRC cells. SHMT2 knockdown resulted in the significant inhibition of CRC cell proliferation, which was not restored by serine, glycine, or formate supplementation. The invasion and migration of CRC cells were suppressed after SHMT2 knockdown. Mechanistically, SHMT2 interacted with β-catenin in the cytoplasm. This interaction inhibited the ubiquitylation-mediated degradation of β-catenin and subsequently modulated the expression of its target genes, leading to the promotion of CRC cell proliferation and metastasis. Notably, the lysine 64 residue on SHMT2 (SHMT2K64) mediated its interaction with β-catenin. Moreover, transcription factor TCF4 interacted with β-catenin, which in turn increased SHMT2 expression, forming an SHMT2/β-catenin positive feedback loop. In vivo xenograft experiments confirmed that SHMT2 promoted the growth and metastasis of CRC cells. Finally, the level of SHMT2 was found to be significantly increased in human CRC tissues. The SHMT2 level was correlated with an increased level of β-catenin, associated with CRC progression and predicted poor patient survival. Conclusion: Taken together, our findings reveal a novel nonmetabolic function of SHMT2 in which it stabilizes β-catenin to prevent its ubiquitylation-mediated degradation and provide a potential therapeutic strategy for CRC therapy.