tbuckley/cabot-search huggingface dataset:
Guns, Depression, and Suicide Prevention: Is It Time for Universal Home Safety Screening?
Authors: Eric D. Caine
Journal: JAMA Network Open (2022)

Roy H. Perlis, MD, MSc; Matthew D. Simonson, PhD; Jon Green, PhD; Jennifer Lin, BA; Alauna Safarpour, PhD; Kristin Lunz Trujillo, PhD; Alexi Quintana, BA; Hanyu Chwe, BA; John Della Volpe, BA; Katherine Ognyanova, PhD; Mauricio Santillana, PhD; James Druckman, PhD; David Lazer, PhD; Matthew A. Baum, PhD
Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria
Authors: Haoran An, Chenyun Qian, Yijia Huang, Jing Li, Xianbin Tian, Jiaying Feng, Jiao Hu, Yujie Fang, Fangfang Jiao, Yuna Zeng, Xueting Huang, Xianbin Meng, Xue Liu, Xin Lin, Zhutian Zeng, Martin Guilliams, Alain Beschin, Yongwen Chen, Yuzhang Wu, Jing Wang, Marco Rinaldo Oggioni, John Leong, Jan-Willem Veening, Haiteng Deng, Rong Zhang, Hui Wang, Jiang Wu, Yan Cui, Jing-Ren Zhang
Journal: The Journal of Experimental Medicine (2022)

Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) “untouchable” for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.
Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms
Authors: Guido Rindi, Ozgur Mete, Silvia Uccella, Olca Basturk, Stefano La Rosa, Lodewijk A. A. Brosens, Shereen Ezzat, Wouter W. de Herder, David S. Klimstra, Mauro Papotti, Sylvia L. Asa
Journal: Endocrine Pathology (2022)
Biased Evaluation in Cancer Drug Trials—How Use of Progression-Free Survival as the Primary End Point Can Mislead
Authors: Ian F. Tannock, Gregory R. Pond, Christopher M. Booth
Journal: JAMA Oncology (2022)

This Viewpoint discusses whether the use of progression-free survival as the primary end point in cancer drug trials can result in misleading interpretations of improved overall survival and quality of life.
Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway
Authors: Ye Shen, Jason S Eng, Flordeliza Fajardo, Lingming Liang, Cong Li, Patrick Collins, Donato Tedesco, Olivier Nolan-Stevaux
Journal: Journal for ImmunoTherapy of Cancer (2022)

Bispecific T-cell engager (BiTE) molecules induce redirected lysis of cancer cells by T cells and are an emerging modality for solid tumor immunotherapy. While signs of clinical activity have been demonstrated, efficacy of T-cell engagers (TCEs) in solid tumors settings, molecular determinants of response, and underlying mechanisms of resistance to BiTE therapy require more investigation.To uncover cancer cell-intrinsic genetic modifiers of TCE-mediated cytotoxicity, we performed genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loss-of-function and CRISPRa (CRISPR activation) gain-of-function screens using TCEs against two distinct tumor-associated antigens (TAAs). By using in vitro T-cell cytotoxicity assays and in vivo efficacy studies, we validated the roles of two common pathways identified in our screen, T-cell costimulation pathway and apoptosis pathway, as key modifiers of BiTE activity.Our genetic screens uncovered TAAs-independent cancer cell-intrinsic genes with functions in autophagy, T-cell costimulation, the apoptosis pathway, chromatin remodeling, and cytokine signaling that altered responsiveness to BiTE-mediated killing. Notably, loss of CD58 (the ligand of the CD2 T-cell costimulatory receptor), a gene frequently altered in cancer, led to decreased TCE-mediated cytotoxicity, T-cell activation and antitumor efficacy in vitro and in vivo. Moreover, the effects of CD58 loss were synergistically compounded by concurrent loss of CD80/CD86 (ligands for the CD28 T-cell costimulatory receptor), whereas joint CD2 and CD28 costimulation additively enhanced TCE-mediated killing, indicating non-redundant costimulatory mechanisms between the two pathways. Additionally, loss of CFLAR (Caspase-8 and FADD Like Apoptosis Regulator), BCL2L1, and BID (BH3 Interacting Domain Death Agonist) induced profound changes in sensitivity to TCEs, indicating that key regulators of apoptosis, which are frequently altered in cancer, impact tumor responsiveness to BiTE therapy.This study demonstrates that genetic alterations central to carcinogenesis and commonly detected in cancer samples lead to significant modulation of BiTE antitumor activity in vitro and in vivo, findings with relevance for a better understanding of patient responses to BiTE therapy and novel combinations that enhance TCE efficacy.
Reported Cases of End-Stage Kidney Disease — United States, 2000–2019
Authors: Nilka Ríos Burrows, Alain Koyama, Meda E. Pavkov
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

End-stage kidney disease (ESKD) (kidney failure requiring dialysis or transplantation) is a costly and disabling condition that often results in premature death (1). During 2019, Medicare fee-for-service expenditures for ESKD were $37.3 billion, accounting for approximately 7% of Medicare paid claims costs (1). Diabetes and hypertension remain the leading causes of ESKD, accounting for 47% and 29%, respectively, of patients who began ESKD treatment in 2019 (1). Compared with White persons, Black, Hispanic, and American Indian or Alaska Native persons are more likely to develop ESKD (1,2) and to have diagnosed diabetes (3). After declining for more than a decade, the incidence rate of ESKD with diabetes reported as the primary cause (ESKD from diabetes) has leveled off since 2010 (1,4). Further, after increasing for many years, the prevalence of diagnosed diabetes has also leveled off (4). Although these flattening trends in rates are important from a population perspective, the trend in the number of ESKD cases is important from a health systems resources perspective. Using United States Renal Data System (USRDS) 2000-2019 data, CDC examined trends in the number of incident and prevalent ESKD cases by demographic characteristics and by primary cause of ESKD. During 2000-2019, the number of incident ESKD cases increased by 41.8%, and the number of prevalent ESKD cases increased by 118.7%. Higher percentage changes in both incident and prevalent ESKD cases were among Asian, Hispanic, and Native Hawaiian or other Pacific Islander persons and among cases with hypertension or diabetes as the primary cause. Interventions to improve care and better manage ESKD risk factors among persons with diabetes and hypertension, along with increased use of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB), and sodium-glucose cotransporter 2 (SGLT2) inhibitors shown to have kidney-protective benefits (5,6) might slow the increase and eventually reverse the trend in incident ESKD cases.
DNA demethylation affects imprinted gene expression in maize endosperm
Authors: Qiang Xu, Leiming Wu, Zhixiang Luo, Mei Zhang, Jinsheng Lai, Lin Li, Nathan M. Springer, Qing Li
Journal: Genome biology (2022)

Abstract Background DNA demethylation occurs in many species and is involved in diverse biological processes. However, the occurrence and role of DNA demethylation in maize remain unknown. Results We analyze loss-of-function mutants of two major genes encoding DNA demethylases. No significant change in DNA methylation has been detected in these mutants. However, we detect increased DNA methylation levels in the mutants around genes and some transposons. The increase in DNA methylation is accompanied by alteration in gene expression, with a tendency to show downregulation, especially for the genes that are preferentially expressed in endosperm. Imprinted expression of both maternally and paternally expressed genes changes in F 1 hybrid with the mutant as female and the wild-type as male parental line, but not in the reciprocal hybrid. This alteration in gene expression is accompanied by allele-specific DNA methylation differences, suggesting that removal of DNA methylation of the maternal allele is required for the proper expression of these imprinted genes. Finally, we demonstrate that hypermethylation in the double mutant is associated with reduced binding of transcription factor to its target, and altered gene expression. Conclusions Our results suggest that active removal of DNA methylation is important for transcription factor binding and proper gene expression in maize endosperm.
Re: Sarah P. Psutka, Roman Gulati, Michael A.S. Jewett, et al. A Clinical Decision Aid to Support Personalized Treatment Selection for Patients with Clinical T1 Renal Masses: Results from a Multi-institutional Competing-risks Analysis. Eur Urol. 2022;81:576–85.
Authors: Francesco Montorsi, Umberto Capitanio, Giuseppe Rosiello, Alessandro Larcher
Journal: European Urology (2022)
Estimated Life-Years Gained Free of New or Recurrent Major Cardiovascular Events With the Addition of Semaglutide to Standard of Care in People With Type 2 Diabetes and High Cardiovascular Risk
Authors: Jan Westerink, Kasper Sommer Matthiessen, Solomon Nuhoho, Udi Fainberg, Michael Lyng Wolden, Helena Bleken Østergaard, Frank Visseren, Naveed Sattar
Journal: Diabetes Care (2022)

OBJECTIVE Semaglutide, a glucagon-like peptide 1 receptor agonist, reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D) at high risk of cardiovascular disease (CVD) in a post hoc analysis of pooled data from Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN) 6 and Peptide Innovation for Early Diabetes Treatment (PIONEER) 6. We estimated the benefit of adding semaglutide to standard of care (SoC) on life-years free of new/recurrent CVD events in people with T2D at high risk of CVD. RESEARCH DESIGN AND METHODS The Diabetes Lifetime-perspective prediction (DIAL) competing risk–adjusted lifetime CVD risk model for people with T2D was developed previously. Baseline characteristics of the pooled cohort from SUSTAIN 6 and PIONEER 6 (POOLED cohort) (N = 6,480) were used to estimate individual life expectancy free of CVD for patients in the POOLED cohort. The hazard ratio of MACE from adding semaglutide to SoC was derived from the POOLED cohort (hazard ratio [HR] 0.76 [95% CI 0.62–0.92]) and combined with an individual’s risk to estimate their CVD benefit. RESULTS Adding semaglutide to SoC was associated with a wide distribution in life-years free of CVD gained, with a mean increase of 1.7 (95% CI 0.5–2.9) life-years. Estimated life-years free of CVD gained with semaglutide was dependent on baseline risk (life-years free of CVD gained in individuals with established CVD vs. those with cardiovascular risk factors only: 2.0 vs. 0.2) and age at treatment initiation. CONCLUSIONS Adding semaglutide to SoC was associated with a gain in life-years free of CVD events that was dependent on baseline CVD risk and age at treatment initiation. This study helps contextualize the results of semaglutide clinical trials.
A four-stage model for murine natural killer cell development in vivo
Authors: Shoubao Ma, Michael A. Caligiuri, Jianhua Yu
Journal: Journal of Hematology & Oncology (2022)

Abstract Natural killer (NK) cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. NK cells arise from hematopoietic stem cells in the bone marrow (BM) and undergo lineage specification and maturation. Despite the importance of NK cells for innate immunity and the development of innovative cancer therapy, the detailed steps linking NK progenitor (NKP) cell development through immature NK (iNK) cells to mature NK (mNK) cells are poorly defined. In this study, we found that CD49b, NK1.1, and NKp46 are sequentially acquired during the development of murine Lin − CD122 + NKP cells. Introducing NKp46 allows us to propose a four-stage developmental model, wherein CD122 + NK1.1 − CD49b − NKp46 − defines an NKP population, CD122 + NK1.1 − CD49b + NKp46 − and CD122 + NK1.1 + CD49b −/+ NKp46 − define iNK-a and iNK-b populations, respectively, and CD122 + NK1.1 + CD49b + NKp46 + defines an mNK population. These four NK cell populations are phenotypically distinct based on their expression of cell surface markers, transcription factors, and effector molecules. Using a differentiation assay ex vivo and adoptive transfer model in vivo, we confirmed that NK cell development follows our predicted four-stage model. Taken together, our findings establish two distinct populations of immature NK cells and define a model for mouse NK cell development.
PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
Authors: Natalie B Collins, Rose Al Abosy, Brian C Miller, Kevin Bi, Qihong Zhao, Michael Quigley, Jeffrey J Ishizuka, Kathleen B Yates, Hans W Pope, Robert T Manguso, Yashaswi Shrestha, Marc Wadsworth, Travis Hughes, Alex K Shalek, Jesse S Boehm, William C Hahn, John G Doench, W Nicholas Haining
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. Methods We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion. Results We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A&gt;G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8 + T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade. Conclusions PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.
Long-term results after resection of primary duodenal adenocarcinoma: A retrospective cohort study
Authors: Kristian K. Jensen, Jan H. Storkholm, Inna Chen, Stefan K. Burgdorf, Carsten P. Hansen
Journal: International Journal of Surgery (2022)

Radical resection of duodenal adenocarcinoma (DA) offers the possibility of cure. The outcome after operation and adjuvant therapy is mainly based on small numbers due to the low incidence of the disease. We examined the long-term outcome after surgical treatment of DA.This was a retrospective cohort study including all patients undergoing curatively intended resection for histologically confirmed DA at a single University hospital. Long-term survival was examined by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding.A total of 96 patients were included. The median follow-up was 3.7 years (IQR 2.9-4.3), during which 18 patients (18.5%) had recurrence and 35 (36.5%) patients had died. The 3- and 5-year overall survival was 66.3% (55.6-76.9%) and 58.2% (46.2-70.2%), respectively. In the multivariable analysis, adjuvant therapy was associated with decreased mortality (HR 0.29, CI 0.11-0.76, P = 0.011) whereas positive lymph node ratio >0.20 was associated with increased mortality.Radical operation for DA has a median overall 5-year-survival of more than 50%. The indication for adjuvant chemotherapy remains to be addressed.
Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis
Authors: Qi Wang, Haoming Zhou, Qingfa Bu, Song Wei, Lei Li, Jinren Zhou, Shun Zhou, Wantong Su, Mu Liu, Zheng Liu, Mingming Wang, Ling Lu
Journal: Journal of Hepatology (2022)

Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation, though the underlying mechanisms remain unclear. We aimed to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH.
Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors
Authors: Clare Vesely, Yien Ning Sophia Wong, Alexa Childs, Ayse U. Akarca, Pawan Dhami, Heli Vaikkinen, Lucia Conde, Javier Herrero, Olagunju Ogunbiyi, Amir Gander, Tu Vinh Luong, Chrissie Thirlwell, Martyn Caplin, Christos Toumpanakis, Karl Peggs, Sergio A. Quezada, Teresa Marafioti, Tim Meyer
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined. Experimental Design: Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration. Results: Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an “exclusion” phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio. Conclusions: Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit “excluded” T cells into the tumor microenvironment to treat patients with siNETs.
Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain
Authors: Samuel E. Marsh, Alec J. Walker, Tushar Kamath, Lasse Dissing-Olesen, Timothy R. Hammond, T. Yvanka de Soysa, Adam M. H. Young, Sarah Murphy, Abdulraouf Abdulraouf, Naeem Nadaf, Connor Dufort, Alicia C. Walker, Liliana E. Lucca, Velina Kozareva, Charles Vanderburg, Soyon Hong, Harry Bulstrode, Peter J. Hutchinson, Daniel J. Gaffney, David A. Hafler, Robin J. M. Franklin, Evan Z. Macosko, Beth Stevens
Journal: Nature Neuroscience (2022)
LATE STEROID WEANING AFTER HEART TRANSPLANT: IS IT SAFE?
Authors: James Deen, Jignesh K. Patel, Michelle Maya Kittleson, Tahli Singer-Englar, Nikhil Patel, Seong Kim, Lawrence S.C. Czer, Fardad Esmailian, Jon A. Kobashigawa
Journal: Journal of the American College of Cardiology (2022)
Elevated neutralization of Omicron with sera of COVID-19 recovered and breakthrough cases vaccinated with Covaxin than two dose naïve vaccinees
Authors: Pragya D. Yadav, Gajanan N. Sapkal, Rima R. Sahay, Deepak Y. Patil, Gururaj R. Deshpande, Rajlaxmi Jain, Dimpal A. Nyayanit, Anita M. Shete, Annasaheb Suryawanshi, Ashok Nandapurkar, Yogesh K. Gurav, Priya Abraham
Journal: Journal of Infection (2022)
Operative Autonomy of Surgical Residents and Patient Outcomes
Authors: Hemant Sharma, Bhavesh Devkaran, Abhishek Sharma
Journal: JAMA Surgery (2022)

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