tbuckley/cabot-search huggingface dataset:
High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis
Authors: Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J. Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A. Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo, Sanjay K. Jain
Journal: Journal of Clinical Investigation (2022)

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.
Abstract MP25: Physical Activity And The Progression Of Coronary Artery Calcification
Authors: Laura F DeFina, Nina Radford, David Leonard, Stephen Farrell, Andjelka Pavlovic, Kerem Shuval, Beth B Wright, Benjamin D Levine
Journal: Circulation (2022)

Introduction: High volume endurance physical activity (PA) has been shown to associate with increased clinically relevant coronary artery calcification (CAC) but not mortality. A key issue is whether active individuals with CAC have progression of atherosclerosis in the setting of sustained high levels of PA. Hypothesis: We hypothesized that changes in CAC are not related to corresponding changes in PA volume. Further, we hypothesized the rate of CAC progression to ≥100 Agatston units (AU) does not depend on baseline PA level. Methods: The study included 6,525 men and 2,056 women with ≥2 assessments of PA and CAC (EBT scans (1997-2007) or MDCT scans (2007-2019)). All individuals had at least one follow-up visit (mean=1.8). We used mixed linear regression to relate within-person changes in square-root CAC to changes in PA volume, controlling for between-person effects. We used interval-censored proportional hazards regression to test if progression to CAC≥100 AU was related to baseline PA level: ≥3000, 1500-2999, and &lt;1500 MET·minutes/week (MET·min/wk). Covariates included age, smoking, BMI, glucose, cholesterol, systolic blood pressure, and statin use. In addition, the longitudinal analysis was adjusted for time since baseline, while the time-to-CAC-threshold analysis was adjusted for baseline CAC. Results: Mean baseline age was 50 years in men/51 years in women. Mean time to first follow-up was 4.5 years in men/5.1 years in women. PA levels increased by 100 MET·min/wk in men but were stable in women. Cardiorespiratory fitness was stable between visits. Within person changes in CAC were not associated with changes in PA volume (Table). At baseline, 5285 men and 1948 women had CAC&lt;100 AU; at follow-up, 1127 men and 136 women progressed to CAC≥100 AU. Neither PA ≥3000 nor 1500-2999 MET·min/wk exhibited significant risk of CAC progression versus &lt;1500 MET·min/wk. Estimated hazard ratios were ≤1 for both men and women. Conclusions: These results show no apparent risk of increasing CAC with sustained PA in active individuals.
Diffuse Tracheobronchial Tuberculosis With Left Pulmonary Tuberculosis Displayed on 18F-FDG PET/CT
Authors: Qiang Li, Lei Jiang
Journal: Clinical Nuclear Medicine (2022)

Abstract A 57-year-old woman was admitted to the hospital with persisting cough and sputum for 2 months. Chest CT revealed multiple nodules in the left lung. 18 F-FDG PET/CT scan was carried out to further evaluate these pulmonary lesions. In addition to multiple hypermetabolic nodules in the upper lobe of left lung, diffuse thickening of the trachea and left bronchial wall with increased FDG uptake was also found. Inflammatory granulation tissue with Mycobacterium tuberculosis was confirmed through the pathological examination of bronchoscopy.
Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity
Authors: Kezhong Chen, Jing Bai, Alexandre Reuben, Heng Zhao, Guannan Kang, Chunliu Zhang, Qingyi Qi, Yaping Xu, Shawna Hubert, Lianpeng Chang, Yanfang Guan, Lin Feng, Kai Zhang, Kaitai Zhang, Xin Yi, Xuefeng Xia, Shujun Cheng, Fan Yang, Jianjun Zhang, Jun Wang
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).
Venetoclax in Previously Treated Waldenström Macroglobulinemia
Authors: Jorge J. Castillo, John N. Allan, Tanya Siddiqi, Ranjana H. Advani, Kirsten Meid, Carly Leventoff, Timothy P. White, Catherine A. Flynn, Shayna Sarosiek, Andrew R. Branagan, Maria G. Demos, Maria L. Guerrera, Amanda Kofides, Xia Liu, Manit Munshi, Nicholas Tsakmaklis, Lian Xu, Guang Yang, Christopher J. Patterson, Zachary R. Hunter, Matthew S. Davids, Richard R. Furman, Steven P. Treon
Journal: Journal of Clinical Oncology (2021)

BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.
Reconstructing Complex Cancer Evolutionary Histories from Multiple Bulk DNA Samples Using Pairtree
Authors: Jeff A. Wintersinger, Stephanie M. Dobson, Ethan Kulman, Lincoln D. Stein, John E. Dick, Quaid Morris
Journal: Blood Cancer Discovery (2022)

Abstract Cancers are composed of genetically distinct subpopulations of malignant cells. DNA-sequencing data can be used to determine the somatic point mutations specific to each population and build clone trees describing the evolutionary relationships between them. These clone trees can reveal critical points in disease development and inform treatment. Pairtree is a new method that constructs more accurate and detailed clone trees than previously possible using variant allele frequency data from one or more bulk cancer samples. It does so by first building a Pairs Tensor that captures the evolutionary relationships between pairs of subpopulations, and then it uses these relations to constrain clone trees and infer violations of the infinite sites assumption. Pairtree can accurately build clone trees using up to 100 samples per cancer that contain 30 or more subclonal populations. On 14 B-progenitor acute lymphoblastic leukemias, Pairtree replicates or improves upon expert-derived clone tree reconstructions. Significance: Clone trees illustrate the evolutionary history of a cancer and can provide insights into how the disease changed through time (e.g., between diagnosis and relapse). Pairtree uses DNA-sequencing data from many samples of the same cancer to build more detailed and accurate clone trees than previously possible. See related commentary by Miller, p. 176. This article is highlighted in the In This Issue feature, p. 171.
TRENDS IN BLEEDING EVENTS AMONG PATIENTS WITH ACUTE CORONARY SYNDROME IN CHINA, 2015 TO 2019: INSIGHTS FROM THE CCC-ACS PROJECT
Authors: Xiao Wang, Guanqi Zhao, Mengge Zhou, Changsheng Ma, Junbo Ge, Yong Huo, Sidney C Smith, Gregg C Fonarow, Yongchen Hao, Jun Liu, Louise Morgan, Wei Gong, Yan Yan, Jing Liu, Dong Zhao, Yaling Han, Shaoping Nie
Journal: Journal of the American College of Cardiology (2022)
CD4<sup>+</sup>T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1–Dependent
Authors: Iulia Popescu, Mark E. Snyder, Carlo J. Iasella, Stefanie J. Hannan, Ritchie Koshy, Robin Burke, Antu Das, Mark J. Brown, Emily J. Lyons, Sophia C. Lieber, Xiaoping Chen, John C. Sembrat, Payal Bhatt, Evan Deng, Xiaojing An, Kelsey Linstrum, Georgios Kitsios, Ioannis Konstantinidis, Melissa Saul, Daniel J. Kass, Jonathan K. Alder, Bill B. Chen, Elizabeth A. Lendermon, Silpa Kilaru, Bruce Johnson, Joseph M. Pilewski, Joseph E. Kiss, Alan H. Wells, Alison Morris, Bryan J. McVerry, Deborah K. McMahon, Darrell J. Triulzi, Kong Chen, Pablo G. Sanchez, John F. McDyer
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = −0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1–dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.
BAFF Attenuates Immunosuppressive Monocytes in the Melanoma Tumor Microenvironment
Authors: Wei Liu, Paweł Stachura, Haifeng C. Xu, Renáta Váraljai, Prashant Shinde, Nikkitha Umesh Ganesh, Matthias Mack, Anke Van Lierop, Anfei Huang, Balamurugan Sundaram, Karl S. Lang, Daniel Picard, Ute Fischer, Marc Remke, Bernhard Homey, Alexander Roesch, Dieter Häussinger, Philipp A. Lang, Arndt Borkhardt, Aleksandra A. Pandyra
Journal: Cancer Research (2021)

Abstract Emerging evidence indicates B-cell activating factor (BAFF, Tnfsf13b) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly in vivo than control tumors. The tumor microenvironment (TME) of BAFF-overexpressing tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functional importance of monocytes for the phenotype of BAFF-mediated tumor growth delay. RNA sequencing analysis confirmed that monocytes isolated from BAFF-overexpressing tumors were characterized by a less exhaustive phenotype and were enriched for in genes involved in activating adaptive immune responses and NF-κB signaling. Evaluation of patients with late-stage metastatic melanoma treated with inhibitors of the PD-1/PD-L1 axis demonstrated a stratification of patients with high and low BAFF plasma levels. Patients with high BAFF levels experienced lower responses to anti-PD-1 immunotherapies. In summary, these results show that BAFF, through its effect on tumor-infiltrating monocytes, not only impacts primary tumor growth but can serve as a biomarker to predict response to anti-PD-1 immunotherapy in advanced disease. Significance: The BAFF cytokine regulates monocytes in the melanoma microenvironment to suppress tumor growth, highlighting the importance of BAFF in antitumor immunity.
Reply to C. Pöttgen et al and Y.-H. Lin et al
Authors: Maarten C. C. M. Hulshof, Hanneke W. M. van Laarhoven
Journal: Journal of Clinical Oncology (2021)

We thank our colleagues P öttgen et al 1 for their interest in and comments on our article. 2We agree with them that for several tumor types and anatomic locations, it has been demonstrated that radiation dose intensification leads to improved local tumor control.In fact, this was the rationale for the ARTDECO study in esophageal cancer.However, unexpectedly, and disappointingly, we could not demonstrate a dose-effect relationship when escalating the dose in the primary tumor from 50.4 to 61.6 Gy in 28 fractions, with concurrent chemotherapy.Importantly, this does not exclude a dose-effect relationship above 61.6Gy; indeed, we now believe that doses higher than 61.6 Gy (for example, in the region of 70 Gy) are probably needed to significantly improve local tumor control. 2 At the most extreme end of the spectrum, very high doses such as those used in stereotactic ablative radiotherapy may substantially enhance tumor elimination, but it is unlikely that even small volumes of tumorinfiltrated esophagus can tolerate such doses, leading to a risk of severe and fatal toxicity such as esophageal perforation and bleeding.
Abstract P108: Natural Language Processing Extracted Social And Behavioral Determinants Of Health And Newer Glucose-lowering Drug Initiation Among Real-world Patients With Type 2 Diabetes
Authors: Jingchuan Guo, Yonghui Wu, Yi Guo, Aokun Chen, Zehao Yu, Xi Yang, Jared W Magnani, Inmaculada Hernandez, LaToya O'Neal, Elizabeth Shenkman, Jiang Bian
Journal: Circulation (2022)

Background: Sodium-glucose cotransporter-2 inhibitors ( SGLT2i ) and glucagon-like peptide-1 receptor agonists ( GLP1a ) are two newer glucose-lowering drugs ( GLD ) that can reduce cardiovascular disease ( CVD ) risk in patients with type 2 diabetes ( T2D ). Yet, uptake of these newer drugs remains low, especially among racial minority groups. Prior studies evaluating factors associated with underuse of SGLT2i/GLP1a primarily relied on claims or structured electronic health records ( EHR ) data, which contain little information on patients' social and behavioral determinants of health ( SBDoH ). We hypothesized that SBDoH would affect the use of these cardioprotective drugs among real world patients with T2D. Methods: EHR from University of Florida Health system were used to identify T2D patients who initiated a second line GLD in 2015-2020. We used a deep learning based natural language processing (NLP) pipeline to extract SBDoH from clinical notes: employment, housing, marital status, smoking, alcohol use and drug use. We constructed a multilevel logistic regression to determine the association of race/ethnicity and SBDoH with initiation of SGLT2i/GLP1a versus other second line GLDs, including zip codes as random effect and adjusting for clinical factors. Results: Of 2,964 patients in the cohort, mean age was 59 (14) years and 56% were females. In the adjusted model ( Table ), Black race, male sex, unemployment, housing insecurity, being unmarried, smoking, and drug use were associated with lower likelihood of initiating SGLT2i/GLP1a. In subgroup analyses by race, housing insecurity was only a risk factor for non-initiation of SGLT2i/GLP1a among Black patients, and smoking and drug use were only risk factors for White patients. Conclusion: Social and behavioral risk factors contribute to racial disparities in access to novel GLDs. Advanced NLP methods and EHR data enabled us to investigate the social risk associated with real-world treatment access.
A Dual PI3K/HDAC Inhibitor Induces Immunogenic Ferroptosis to Potentiate Cancer Immune Checkpoint Therapy
Authors: Fushun Fan, Pei Liu, Rudi Bao, Jian Chen, Minhua Zhou, Zhenxian Mo, Yaru Ma, Haiqi Liu, Yiping Zhou, Xiong Cai, Changgeng Qian, Xinjian Liu
Journal: Cancer Research (2021)

The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale to develop novel agents suitable for combinatorial regimens with immunotherapy to improve clinical outcomes. In this study, we developed a dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth and potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis in cancer cells. Treatment with BEBT-908 promoted ferroptotic cell death of cancer cells by hyperacetylating p53 and facilitating the expression of ferroptotic signaling. Furthermore, BEBT-908 promoted a proinflammatory tumor microenvironment that activated host antitumor immune responses and potentiated immune checkpoint blockade therapy. Mechanistically, BEBT-908-induced ferroptosis led to upregulation of MHC class I and activation of endogenous IFNγ signaling in cancer cells via the STAT1 signaling pathway. The dual PI3K/HDAC inhibitor BEBT-908 is a promising targeted therapeutic agent against multiple cancer types that promotes immunogenic ferroptosis and enhances the efficacy of immunotherapy. SIGNIFICANCE: The dual PI3K/HDAC inhibitor BEBT-908 elicits potent antitumor responses, effectively inducing immunogenic ferroptosis of tumor cells and potentiating cancer immunotherapy.
Sensing of RNA stress by mTORC1 drives autoinflammation
Authors: Min Ae Lee-Kirsch
Journal: Journal of Clinical Investigation (2022)

Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.