tbuckley/cabot-search huggingface dataset:
Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms
Authors: Juan Ibarra, Yassmin A. Elbanna, Katarzyna Kurylowicz, Michele Ciboddo, Harrison S. Greenbaum, Nicole S. Arellano, Deborah Rodriguez, Maria Evers, Althea Bock-Hughes, Chenyu Liu, Quinn Smith, Julian Lutze, Julian Baumeister, Milena Kalmer, Kathrin Olschok, Benjamin Nicholson, Diane Silva, Luke Maxwell, Jonathan Dowgielewicz, Elisa Rumi, Daniela Pietra, Ilaria Carola Casetti, Silvia Catricala, Steffen Koschmieder, Sandeep Gurbuxani, Rebekka K. Schneider, Scott A. Oakes, Shannon E. Elf
Journal: Blood Cancer Discovery (2022)

Abstract Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2+ binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo. Significance: Current targeted therapies for CALR-mutated MPNs are not curative and fail to differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type–specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs. This article is highlighted in the In This Issue feature, p. 265
Reduced risk of hospitalisation among reported COVID-19 cases infected with the SARS-CoV-2 Omicron BA.1 variant compared with the Delta variant, Norway, December 2021 to January 2022
Authors: Lamprini Veneti, Håkon Bøås, Anja Bråthen Kristoffersen, Jeanette Stålcrantz, Karoline Bragstad, Olav Hungnes, Margrethe Larsdatter Storm, Nina Aasand, Gunnar Rø, Jostein Starrfelt, Elina Seppälä, Reidar Kvåle, Line Vold, Karin Nygård, Eirik Alnes Buanes, Robert Whittaker
Journal: Eurosurveillance (2022)

We included 39,524 COVID-19 Omicron and 51,481 Delta cases reported in Norway from December 2021 to January 2022. We estimated a 73% reduced risk of hospitalisation (adjusted hazard ratio: 0.27; 95% confidence interval: 0.20-0.36) for Omicron compared with Delta. Compared with unvaccinated groups, Omicron cases who had completed primary two-dose vaccination 7-179 days before diagnosis had a lower reduced risk than Delta (66% vs 93%). People vaccinated with three doses had a similar risk reduction (86% vs 88%).
Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia
Authors: Meghali Goswami, Gege Gui, Laura W Dillon, Katherine E Lindblad, Julie Thompson, Janet Valdez, Dong-Yun Kim, Jack Y Ghannam, Karolyn A Oetjen, Christin B Destefano, Dana M Smith, Hanna Tekleab, Yeusheng Li, Pradeep Dagur, Thomas Hughes, Jennifer L Marté, Jaydira del Rivero, Joanna Klubo-Gwiezdzinksa, James L Gulley, Katherine R Calvo, Catherine Lai, Christopher S Hourigan
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The powerful ‘graft versus leukemia’ effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. Methods We report here the results of 17 H-0026 (PD-AML, NCT02996474 ), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). Results In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. Conclusion Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
Intravascular imaging assessment of pharmacotherapies targeting atherosclerosis: advantages and limitations in predicting their prognostic implications
Authors: Vincenzo Tufaro, Patrick Washington Serruys, Lorenz Räber, Martin Richard Bennett, Ryo Torii, Sophie Zhaotao Gu, Yoshinobu Onuma, Anthony Mathur, Andreas Baumbach, Christos Vasileios Bourantas
Journal: Cardiovascular Research (2022)

Abstract Intravascular imaging has been often used over the recent years to examine the efficacy of emerging therapies targeting plaque evolution. Serial intravascular ultrasound, optical coherence tomography, or near-infrared spectroscopy-intravascular ultrasound studies have allowed us to evaluate the effects of different therapies on plaque burden and morphology, providing unique mechanistic insights about the mode of action of these treatments. Plaque burden reduction, a decrease in necrotic core component or macrophage accumulation—which has been associated with inflammation—and an increase in fibrous cap thickness over fibroatheromas have been used as surrogate endpoints to assess the value of several drugs in inhibiting plaque evolution and improving clinical outcomes. However, some reports have demonstrated weak associations between the effects of novel treatments on coronary atheroma and composition and their prognostic implications. This review examines the value of invasive imaging in assessing pharmacotherapies targeting atherosclerosis. It summarizes the findings of serial intravascular imaging studies assessing the effects of different drugs on atheroma burden and morphology and compares them with the results of large-scale trials evaluating their impact on clinical outcome. Furthermore, it highlights the limited efficacy of established intravascular imaging surrogate endpoints in predicting the prognostic value of these pharmacotherapies and introduces alternative imaging endpoints based on multimodality/hybrid intravascular imaging that may enable more accurate assessment of the athero-protective and prognostic effects of emerging therapies.
Abstract 10914: Refining Genotype-Phenotype Correlations for Post-Mortem Genetic Testing of Sudden Cardiac Death: From the POST SCD Study
Authors: Christopher C Cheung, Julianne Wojciak, Meghan Tanel, Andrew Connolly, W. Patrick Devine, Ellen Moffatt, Zian H Tseng
Journal: Circulation (2021)

Introduction: The POST SCD (POstmortem Systematic InvesTigation of Sudden Cardiac Death) Study is the only prospective unbiased sudden cardiac death (SCD) cohort to use comprehensive postmortem investigation to refine the SCD phenotype to true cardiac and arrhythmic causes. Most postmortem genetic testing focuses on genotypes while tolerating a SCD phenotype that is presumed cardiac. Hypothesis: We hypothesize that a comprehensive postmortem evaluation following presumed SCD will refine genotype-phenotype associations and interpretation of postmortem genetic testing. Methods: The POST SCD study prospectively identified all deaths attributed to out-of-hospital cardiac arrest between 18-90 years of age in San Francisco County between February 2011-March 2014 (20,440 deaths reviewed). Medical record review identified 525 presumed SCDs that met World Health Organization criteria. Comprehensive autopsy, toxicology, and histology ruled out non-arrhythmic causes (overdose, hemorrhage, PE) to arrive at 293 sudden arrhythmic deaths (SADs). In the first 30 SADs with high suspicion for heritable cause, a comprehensive 300-gene cardiac/arrhythmia panel was performed, then whole exome testing in cases with negative or non-contributory panel. Results: By pathologic criteria, the 30 autopsy-defined SADs (21 males [70%], median age 53 years) for genetic testing included dilated cardiomyopathy (37%), hypertrophic cardiomyopathy (HCM; 10%), hypertrophy without pathologic features of HCM (33%), primary electrical disease (10%), arrhythmogenic cardiomyopathy (3%), mitral valve prolapse (3%), or non-compaction (3%). In 3 SADs, we identified 4 pathogenic/likely pathogenic (P/LP) variants in APOB , MYBPC3 , GAA , and TTN , but 3 of 4 ( APOB, GAA , TTN ) were non-contributory to SCD. There were 61 variants of uncertain significance in 24 patients (80%). Further exome testing in 7 SADs identified no compelling variants. Conclusions: Postmortem genetic testing identified P/LP variants in 10% of autopsy-proven SADs with high suspicion for heritable cause, but detailed postmortem phenotyping excluded 75% as non-contributory to SCD. These results highlight the importance of comprehensive autopsy evaluation to refine genotype-phenotype correlations.
Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials
Authors: Gina L Mazza, Carolyn Mead-Harvey, John Mascarenhas, Abdulraheem Yacoub, Heidi E Kosiorek, Ronald Hoffman, Amylou C Dueck, Ruben A Mesa
Journal: The Lancet Haematology (2021)
Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas
Authors: Szu-Chun Yang, Yi-Chen Yeh, Yi-Lin Chen, Chao-Hua Chiu
Journal: Journal of the National Comprehensive Cancer Network (2022)

This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation.We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed.Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US $1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US $568 in Taiwan.In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.
Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial
Authors: Ioannis Psallidas, Maged Hassan, Ahmed Yousuf, Tracy Duncan, Shahul Leyakathali Khan, Kevin G Blyth, Matthew Evison, John P Corcoran, Simon Barnes, Raja Reddy, Peter I Bonta, Rahul Bhatnagar, Gayathri Kagithala, Melissa Dobson, Ruth Knight, Susan J Dutton, Ramon Luengo-Fernandez, Emma Hedley, Hania Piotrowska, Louise Brown, Kamal Abi Musa Asa'ari, Rachel M Mercer, Rachelle Asciak, Eihab O Bedawi, Rob J Hallifax, Mark Slade, Rachel Benamore, Anthony Edey, Robert F Miller, Nick A Maskell, Najib M Rahman
Journal: The Lancet Respiratory Medicine (2021)
Abstract P176: Reliability Of The Electronic Health Record’s Problem List In Describing Multimorbidity In Patients With Heart Failure In The Emergency Department
Authors: Brandon King, Michelle Meyer, Patricia Chang, Jo E Rodgers, Srihari V Chari, Karen Richardson, Tommy Bohrmann, Martin Casey
Journal: Circulation (2022)

Introduction: Patients with heart failure (HF) often suffer from multimorbidity, the co-occurrence of two or more chronic conditions. Electronic health records (EHRs) store data on chronic conditions within the problem list, which can be readily extracted for research purposes. Objective: To assess the reliability in using the EHR-based problem list to identify comorbid conditions among patients with HF in the emergency department. Methods: A retrospective chart review study was performed on a random sample of 200 patients age &gt;65 years with a diagnosis of HF who presented to an academic emergency department (ED) in 2019 (mean age 78.3 years old, 52.5% women). Manual chart review was performed by a trained medical student (BK) as the gold standard in identifying additional chronic conditions in patients with HF. All diagnoses were mapped to International Classification of Diseases, Tenth Revision, Clinical Modification diagnostic codes and classified into 38 domains using the Agency for Healthcare Research Quality’s Elixhauser Comorbidity Software. We computed sensitivity, specificity, positive predictive value, and negative predictive value of using the EHR’s problem list to capture each domain. We calculated the intra-class correlation coefficient (ICC) to estimate reliability in the total number of domains captured by each method. Results: Our chart review found that patients with HF had a mean of 5.4 chronic conditions (SD 2.1). In comparison, the EHR's problem list identified a mean of 4.0 chronic conditions (SD 2.0). The five most prevalent domains were hypertension, diabetes, obesity, chronic pulmonary disease, and renal failure. Specificities for the five most prevalent domains were at least 97% whereas sensitivities were considerably lower and varied widely (28.6%-80.7%; Table 1). The ICC comparing chart review to the problem list was 0.77 (95% CI: 0.68-0.80). Conclusion: Multimorbidity in patients with HF in the ED was captured with good reliability using the EHR problem list.
Antibacterial PDT nanoplatform capable of releasing therapeutic gas for synergistic and enhanced treatment against deep infections
Authors: Bingshuai Zhou, Xiaolin Sun, Biao Dong, Siyao Yu, Liang Cheng, Songtao Hu, Wei Liu, Lin Xu, Xue Bai, Lin Wang, Hongwei Song
Journal: Theranostics (2022)

Antibacterial photodynamic therapy (aPDT) has emerged as an attractive treatment option for efficient removal of pathogenic bacteria. However, aPDT in deep tissue will encounter difficulties such as limited light penetration depth, insufficient oxygen (O2) supply and inability to eliminate inflammation introduced by bacteria, which hinders its clinical application. Herein, the near infrared (NIR) strategy of simultaneously generating O2 and CO was developed for aPDT based antibacterial therapy and mitigation of deep infection inflammation. Methods: We prepared NIR-mediated multifunctional aPDT nanoplatform (POS-UCNPs/ICG) producing therapeutic gas of O2 and CO. The CO, O2 and ROS generation of the nanoplatform were characterized by dye probes, respectively. The antibacterial activity and anti-inflammation of POS-UCNPs/ICG were demonstrated in vitro and in vivo. In addition, the therapeutic effects in vivo were serially analyzed by immunofluorescence staining, Masson's staining, hematoxylin and eosin staining, colony formation units (CFU) and so on. Results: NIR-mediated multifunctional aPDT nanoplatform was realized by combining the up-conversion nanoparticles (UCNPs) and partially oxidized SnS2 (POS) nanosheets (NSs) as well as indocyanine green (ICG). Using a single 808 nm light, aPDT can be achieved via ICG molecules, meanwhile, O2/CO can be generated by POS NSs through upconversion light excitation. During the aPDT process, O2 can enhance aPDT, while CO can regulate inflammation through the PI3K/NF-κB pathway. Therefore, POS-UCNPs/ICG groups had a highest percentage of healing area up to 91.55±1.26% in mouse abscess model. Conclusion: Due to enhanced aPDT and anti-inflammatory collaborative therapy, the POS-UCNPs/ICG composites showed remarkably accelerated recovery in animal abscess models. Such NIR light responsive nanoplatform with optimized antibacterial capacity and immunomodulatory functions is promising for clinical therapeutics of bacteria-induced infections.
P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance
Authors: Yuke He, Antonia E. Gallman, Chengmei Xie, Qian Shen, Jianyang Ma, Finn D. Wolfreys, Moriah Sandy, Todor Arsov, Xiaoqian Wu, Yuting Qin, Pingjing Zhang, Simon Jiang, Maurice Stanley, Philip Wu, Jingjing Tan, Huihua Ding, Haiyan Xue, Wei Chen, Jinping Xu, Lindsey A. Criswell, Joanne Nititham, Marcin Adamski, A. Richard Kitching, Matthew C. Cook, Lanfang Cao, Nan Shen, Jason G. Cyster, Carola G. Vinuesa
Journal: The Journal of Experimental Medicine (2021)

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a “de novo” variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.
Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621
Authors: Maureen M. O'Brien, Lingyun Ji, Nirali N. Shah, Susan R. Rheingold, Deepa Bhojwani, Constance M. Yuan, Xinxin Xu, Joanna S. Yi, Andrew C. Harris, Patrick A. Brown, Michael J. Borowitz, Olga Militano, John Kairalla, Meenakshi Devidas, Elizabeth A. Raetz, Lia Gore, Mignon L. Loh
Journal: Journal of Clinical Oncology (2022)

Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
Author correction to ‘Ruscogenin alleviates LPS-triggered pulmonary endothelial barrier dysfunction through targeting NMMHC IIA to modulate TLR4 signaling’ [Acta Pharmaceutica Sinica B 12 (2022) 1198–1212]
Authors: Yunhao Wu, Xiu Yu, Yuwei Wang, Yalin Huang, Jiahui Tang, Shuaishuai Gong, Siyu Jiang, Yuanli Xia, Fang Li, Boyang Yu, Yuanyuan Zhang, Junping Kou
Journal: Acta Pharmaceutica Sinica B (2022)

[This corrects the article DOI: 10.1016/j.apsb.2021.09.017.].
Abstract 027: Cumulative Consumption Of Sulfur Amino Acids And Risks Of Cardiovascular Disease And Mortality; Analysis Of Two Prospective Cohort Studies
Authors: Laila Al-Shaar, Xinyuan Zhang, Xiang Gao, Penny M Kris-etherton, Qi Sun, Eric B Rimm, Walter Willett, Richie John
Journal: Circulation (2022)

Background: Preclinical studies suggested that high intakes of sulfur amino acids (SAA), including methionine and cysteine, may increase risk of age-related chronic diseases. Until now, no epidemiologic studies have investigated habitual dietary intake of SAA in relation to risk of cardiovascular disease (CVD) and mortality. Methods: We prospectively followed 120,699 participants in the Nurses’ Health Study (1984-2016) and Health Professionals Follow-up Study (1986-2016) cohorts who had no known history of cancer, CVD, or diabetes at baseline. Diet was assessed using a validated food frequency questionnaire that was updated every 2-4 years. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD and all-cause and CVD mortality across quintiles of energy adjusted SAA intake. Results: During up to 32 years of follow up, we documented 13,547 incident CVD events and 33,958 deaths, of which 7637 were due to CVD. Participants on average consumed more than 2-fold the recommended daily allowance of SAA (19 mg/kg/day), and the main food sources included beef, chicken, and milk. After adjustment for non-dietary and dietary risk factors including total energy intake, higher SAA intake was significantly associated with higher risks of CVD, CVD mortality, and all-cause mortality in men and women. In the meta-analysis combining both cohorts, comparing participants in the highest quintile with those in the lowest quintile of SAA intake, HRs (95% CI) were 1.12 (1.05, 1.20) for CVD, 1.28 (1.11, 1.47) for CVD mortality, and 1.15 (1.11, 1.19) for all-cause mortality. These associations were similar across strata of age, body mass index, physical activity, ratio of animal to plant protein, smoking, and alcohol consumption (p interaction &gt; 0.05 for all), and they remained significant after further adjustment for total protein intake. Conclusions: Our data suggest that high SAA intake is associated with greater risks of CVD and mortality in men and women.