tbuckley/cabot-search huggingface dataset:
Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model
Authors: Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A. LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A. DePinho
Journal: Cancer Discovery (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy (IO). In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. In this study, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust antitumor regression in iKPC mice bearing large autochthonous tumors. Whereas untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T-cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside IO as a potential PDAC treatment avenue, warranting clinical investigation. Significance: Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Authors: Chia-Lin Chen, Hidekazu Tsukamoto, Jian-Chang Liu, Claudine Kashiwabara, Douglas Feldman, Linda Sher, Steven Dooley, Samuel W. French, Lopa Mishra, Lydia Petrovic, Joseph H. Jeong, Keigo Machida
Journal: Journal of Clinical Investigation (2024)
IL-7–dependent and –independent lineages of IL-7R–dependent human T cells
Authors: Carlos A Arango-Franco, Masato Ogishi, Susanne Unger, Ottavia M Delmonte, Julio César Orrego, Ahmad Yatim, Margarita M Velasquez-Lopera, Andrés F Zea-Vera, Jonathan Bohlen, Marwa Chbihi, Antoine Fayand, Juan Pablo Sánchez, Julian Rojas, Yoann Seeleuthner, Tom Le Voyer, Quentin Philippot, Kathryn J Payne, Adrian Gervais, Lucia V Erazo-Borrás, Luis A Correa-Londoño, Axel Cederholm, Alejandro Gallón-Duque, Pedro Goncalves, Jean-Marc Doisne, Liran Horev, Bénédicte Charmeteau-de Muylder, Jesús Á Álvarez, Diana M Arboleda, Lizet Pérez-Zapata, Estefanía Vásquez-Echeverri, Marcela Moncada-Vélez, Juan A López, Yolanda Caicedo, Boaz Palterer, Pablo J Patiño, Carlos J Montoya, Matthieu Chaldebas, Peng Zhang, Tina Nguyen, Cindy S Ma, Mohamed Jeljeli, Juan F Alzate, Felipe Cabarcas, Taushif Khan, Darawan Rinchai, Jean-Luc Prétet, Bertrand Boisson, Nico Marr, Ruba Ibrahim, Vered Molho-Pessach, Stéphanie Boisson-Dupuis, Dimitra Kiritsi, João T Barata, Nils Landegren, Bénédicte Neven, Laurent Abel, Andrea Lisco, Vivien Béziat, Emmanuelle Jouanguy, Jacinta Bustamante, James P Di Santo, Stuart G Tangye, Luigi D Notarangelo, Rémi Cheynier, Ken Natsuga, Andrés A Arias, José Luis Franco, Klaus Warnatz, Jean-Laurent Casanova, Anne Puel
Journal: Journal of Clinical Investigation (2024)

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study
Authors: Idris Bahce, Chris Dickhoff, Famke L Schneiders, Joris Veltman, David J Heineman, Sayed M S Hashemi, Anne Vrijmoet, Ilias Houda, Ezgi B Ulas, Joyce Bakker, Peter van de Ven, Natalja Bouwhuis, Lilian J Meijboom, Daniela E Oprea-Lager, Febe van Maldegem, Marieke F Fransen, Tanja D de Gruijl, Teodora Radonic, Suresh Senan
Journal: Journal for ImmunoTherapy of Cancer (2024)

In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC.
Nuclear translocation of plasma membrane protein ADCY7 potentiates T cell-mediated antitumour immunity in HCC
Authors: Jianan Chen, Youhai Jiang, Minghui Hou, Chunliang Liu, Erdong Liu, Yali Zong, Xiang Wang, Zhengyuan Meng, Mingye Gu, Yu Su, Hongyang Wang, Jing Fu
Journal: Gut (2024)

Background The potency of T cell-mediated responses is a determinant of immunotherapy effectiveness in treating malignancies; however, the clinical efficacy of T-cell therapies has been limited in hepatocellular carcinoma (HCC) owing to the extensive immunosuppressive microenvironment. Objective Here, we aimed to investigate the key genes contributing to immune escape in HCC and raise a new therapeutic strategy for remoulding the HCC microenvironment. Design The genome-wide in vivo clustered regularly interspaced short palindromic repeats (CRISPR) screen library was conducted to identify the key genes associated with immune tolerance. Single-cell RNA-seq (scRNA-seq), flow cytometry, HCC mouse models, chromatin immunoprecipitation and coimmunoprecipitation were used to explore the function and mechanism of adenylate cyclase 7 (ADCY7) in HCC immune surveillance. Results Here, a genome-wide in vivo CRISPR screen identified a novel immune modulator-ADCY7. The transmembrane protein ADCY7 undergoes subcellular translocation via caveolae-mediated endocytosis and then translocates to the nucleus with the help of leucine-rich repeat-containing protein 59 (LRRC59) and karyopherin subunit beta 1 (KPNB1). In the nucleus, it functions as a transcription cofactor of CCAAT/enhancer binding protein alpha (CEBPA) to induce CCL5 transcription, thereby increasing CD8 + T cell infiltration to restrain HCC progression. Furthermore, ADCY7 can be secreted as exosomes and enter neighbouring tumour cells to promote CCL5 induction. Exosomes with high ADCY7 levels promote intratumoural infiltration of CD8 + T cells and suppress HCC tumour growth. Conclusion We delineate the unconventional function and subcellular location of ADCY7, highlighting its pivotal role in T cell-mediated immunity in HCC and its potential as a promising treatment target.
Spatial single-cell profiling and neighbourhood analysis reveal the determinants of immune architecture connected to checkpoint inhibitor therapy outcome in hepatocellular carcinoma
Authors: Henrike Salié, Lara Wischer, Antonio D'Alessio, Ira Godbole, Yuan Suo, Patricia Otto-Mora, Juergen Beck, Olaf Neumann, Albrecht Stenzinger, Peter Schirmacher, Claudia A M Fulgenzi, Andreas Blaumeiser, Melanie Boerries, Natascha Roehlen, Michael Schultheiß, Maike Hofmann, Robert Thimme, David J Pinato, Thomas Longerich, Bertram Bengsch
Journal: Gut (2024)

Background The determinants of the response to checkpoint immunotherapy in hepatocellular carcinoma (HCC) remain poorly understood. The organisation of the immune response in the tumour microenvironment (TME) is expected to govern immunotherapy outcomes but spatial immunotypes remain poorly defined. Objective We hypothesised that the deconvolution of spatial immune network architectures could identify clinically relevant immunotypes in HCC. Design We conducted highly multiplexed imaging mass cytometry on HCC tissues from 101 patients. We performed in-depth spatial single-cell analysis in a discovery and validation cohort to deconvolute the determinants of the heterogeneity of HCC immune architecture and develop a spatial immune classification that was tested for the prediction of immune checkpoint inhibitor (ICI) therapy. Results Bioinformatic analysis identified 23 major immune, stroma, parenchymal and tumour cell types in the HCC TME. Unsupervised neighbourhood detection based on the spatial interaction of immune cells identified three immune architectures with differing involvement of immune cells and immune checkpoints dominated by either CD8 T-cells, myeloid immune cells or B- and CD4 T-cells. We used these to define three major spatial HCC immunotypes that reflect a higher level of intratumour immune cell organisation: depleted, compartmentalised and enriched. Progression-free survival under ICI therapy differed significantly between the spatial immune types with improved survival of enriched patients. In patients with intratumour heterogeneity, the presence of one enriched area governed long-term survival.
Associations between Changes in Exposure to Air Pollutants due to Relocation and the Incidence of 14 Major Disease Categories and All-Cause Mortality: A Natural Experiment Study
Authors: Ge Chen, Zhengmin (Min) Qian, Junguo Zhang, Xiaojie Wang, Zilong Zhang, Miao Cai, Lauren D. Arnold, Chad Abresch, Chuangshi Wang, Yiming Liu, Qi Fan, Hualiang Lin
Journal: Environmental Health Perspectives (2024)

Though observational studies have widely linked air pollution exposure to various chronic diseases, evidence comparing different exposures in the same people is limited. This study examined associations between changes in air pollution exposure due to relocation and the incidence and mortality of 14 major diseases.
Impact of margin thermal ablation after endoscopic mucosal resection of large (≥20 mm) non-pedunculated colonic polyps on long-term recurrence
Authors: Timothy O'Sullivan, Francesco Vito Mandarino, Julia L Gauci, Anthony M Whitfield, Clarence Kerrison, James Elhindi, Catarina Neto do Nascimento, Sunil Gupta, Oliver Cronin, Anthony Sakiris, Juan Francisco Prieto Aparicio, Sophie Arndtz, Gregor Brown, Spiro Raftopoulos, David Tate, Eric Y Lee, Stephen J Williams, Nicholas Burgess, Michael J Bourke
Journal: Gut (2024)

The efficacy of colorectal endoscopic mucosal resection (EMR) is limited by recurrence and the necessity for conservative surveillance. Margin thermal ablation (MTA) after EMR has reduced the incidence of recurrence at the first surveillance colonoscopy at 6 months (SC1). Whether this effect is durable to second surveillance colonoscopy (SC2) is unknown. We evaluated long-term surveillance outcomes in a cohort of LNPCPs that have undergone MTA.
Occurrence and predictors of laboratory abnormalities during outpatient parenteral antimicrobial therapy – a multicenter cohort study to inform laboratory test monitoring
Authors: Hester H Stoorvogel, Maartje van Egmond, Heiman F L Wertheim, Jeroen A Schouten, Marlies E J L Hulscher, Lars Peeters, Yvonne Kiers, Sofie Koenders, Tom Sprong, Suzan P van Mens, Mirjam Tromp, Olivier Richel, Reinier Akkermans, Jaap Ten Oever
Journal: Journal of Infection (2024)
Medicaid Accountable Care Organizations and Disparities in Pediatric Asthma Care
Authors: Kimberley H. Geissler, Meng-Shiou Shieh, Arlene S. Ash, Peter K. Lindenauer, Jerry A. Krishnan, Sarah L. Goff
Journal: JAMA Pediatrics (2024)

Importance Nearly 6 million children in the US have asthma, and over one-third of US children are insured by Medicaid. Although 23 state Medicaid programs have experimented with accountable care organizations (ACOs), little is known about ACOs’ effects on longstanding insurance-based disparities in pediatric asthma care and outcomes. Objective To determine associations between Massachusetts Medicaid ACO implementation in March 2018 and changes in care quality and use for children with asthma. Design, Setting, and Participants Using data from the Massachusetts All Payer Claims Database from January 1, 2014, to December 31, 2020, we determined child-years with asthma and used difference-in-differences (DiD) estimates to compare asthma quality of care and emergency department (ED) or hospital use for child-years with Medicaid vs private insurance for 3 year periods before and after ACO implementation for children aged 2 to 17 years. Regression models accounted for demographic and community characteristics and health status. Data analysis was conducted between January 2022 and June 2024. Exposure Massachusetts Medicaid ACO implementation. Main Outcomes and Measures Primary outcomes were binary measures in a calendar year of (1) any routine outpatient asthma visit, (2) asthma medication ratio (AMR) greater than 0.5, and (3) any ED or hospital use with asthma. To determine the statistical significance of differences in descriptive statistics between groups, χ 2 and t tests were used. Results Among 376 509 child-year observations, 268 338 (71.27%) were insured by Medicaid and 73 633 (19.56%) had persistent asthma. There was no significant change in rates of routine asthma visits for Medicaid-insured child-years vs privately insured child-years post-ACO implementation (DiD, −0.4 percentage points [pp]; 95% CI, −1.4 to 0.6 pp). There was an increase in the proportion with AMR greater than 0.5 for Medicaid-insured child-years vs privately insured in the postimplementation period (DiD, 3.7 pp; 95% CI, 2.0-5.4 pp), with absolute declines in both groups postimplementation. There was an increase in any ED or hospital use for Medicaid-insured child-years vs privately insured postimplementation (DiD, 2.1 pp; 95% CI, 1.2-3.0 pp), an 8% increase from the preperiod Medicaid use rate. Conclusions and Relevance Introduction of Massachusetts Medicaid ACOs was associated with persistent insurance-based disparities in routine asthma visit rates; a narrowing in disparities in appropriate AMR rates due to reductions in appropriate rates among those with private insurance; and worsening disparities in any ED or hospital use for Medicaid-insured children with asthma compared to children with private insurance. Continued study of changes in pediatric asthma care delivery is warranted in relation to major Medicaid financing and delivery system reforms.
Risk of Dementia Diagnosis After Injurious Falls in Older Adults
Authors: Alexander J. Ordoobadi, Hiba Dhanani, Samir R. Tulebaev, Ali Salim, Zara Cooper, Molly P. Jarman
Journal: JAMA Network Open (2024)

Importance Emerging evidence suggests that mild cognitive impairment, which is a precursor to Alzheimer disease and related dementias (ADRD), places older adults at increased risk for falls. However, the risk that an older adult develops dementia after experiencing a fall is unknown. Objective To determine the risk of new ADRD diagnosis after a fall in older adults. Design, Setting, and Participants This retrospective cohort study examined Medicare Fee-for-Service data from 2014 to 2015, with follow-up data available for at least 1 year after the index encounter. Participants included adults aged 66 years and older who experienced a traumatic injury that resulted in an emergency department (ED) or inpatient encounter and did not have a preexisting diagnosis of dementia. Data analysis was performed from August 2023 to July 2024. Exposures Experiencing a fall compared with other mechanisms of injury, defined by International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 external cause of injury codes. Main Outcomes and Measures The hazard of new ADRD diagnosis within 1 year of a fall, assessed by performing a Cox multivariable competing risk model that controlled for potential confounders while accounting for the competing risk of death. Results The study included 2 453 655 older adult patients who experienced a traumatic injury; 1 522 656 (62.1%) were female; 124 396 (5.1%) were Black and 2 232 102 (91.0%) were White; and the mean (SD) age was 78.1 (8.1) years. The mechanism of injury was a fall in 1 228 847 incidents (50.1%). ADRD was more frequently diagnosed within 1 year of a fall compared with other injury mechanisms (10.6% [129 910 of 1 228 847] vs 6.1% [74 799 of 1 224 808]; P &amp;amp;lt; .001). The unadjusted hazard ratio (HR) of incident dementia diagnosis after a fall was 1.63 (95% CI, 1.61-1.64; P &amp;amp;lt; .001). On multivariable Cox competing risk analysis, falling was independently associated with an increased risk of dementia diagnosis among older adults (HR, 1.21 [95% CI, 1.20-1.21]; P &amp;amp;lt; .001) after controlling for patient demographics, medical comorbidities, and injury characteristics, while accounting for the competing risk of death. Among the subset of older adults without a recent skilled nursing facility admission, the HR was 1.27 (95% CI, 1.26-1.28; P &amp;amp;lt; .001). Conclusions and Relevance In this cohort study, new ADRD diagnoses were more common after falls compared with other mechanisms of injury, with 10.6% of older adults being diagnosed with ADRD in the first year after a fall. To improve the early identification of ADRD, this study’s findings suggest support for the implementation of cognitive screening in older adults who experience an injurious fall that results in an ED visit or hospital admission.
Cause-Specific Mortality Rates Among the US Black Population
Authors: Adith S. Arun, César Caraballo, Mitsuaki Sawano, Yuan Lu, Rohan Khera, Clyde W. Yancy, Harlan M. Krumholz
Journal: JAMA Network Open (2024)

This cross-sectional study examines the specific causes of death associated with the disparities in all-cause mortality between non-Hispanic Black and non-Hispanic White populations, as well as their changes over time.
Tumor Hypoxia on <sup>18</sup>F-fluoromisonidazole Positron Emission Tomography and Distant Metastasis From Head and Neck Squamous Cell Carcinoma
Authors: Chengcheng Gui, Rick Wray, Heiko Schöder, Joseph O. Deasy, Milan Grkovski, John L. Humm, Richard J. Wong, Eric J. Sherman, Nadeem Riaz, Nancy Y. Lee
Journal: JAMA Network Open (2024)

Importance Given high rates of locoregional control after definitive management of head and neck squamous cell carcinoma (HNSCC), better methods are needed to project distant metastasis (DM) risk. Tumor hypoxia on 18 F-fluoromisonidazole (FMISO) positron emission tomography (PET) is associated with locoregional failure, but data demonstrating an association with DM are limited. Objective To determine whether tumor hypoxia on FMISO PET is associated with DM risk after chemoradiotherapy (CRT) for HNSCC. Design, Setting, and Participants This cohort study assessed patients with HNSCC enrolled in 2 prospective clinical trials at a single academic referral center from 2004 to 2021 in which participants received FMISO PET before and during CRT. Data analysis occurred from May 2023 to May 2024. Exposures FMISO PET scans before and 1 to 2 weeks after starting CRT were evaluated for tumor hypoxia by nuclear medicine physicians. Main Outcomes and Measures The primary outcome was DM, defined as biopsy-proven HNSCC outside the primary site and regional lymph nodes. Time to DM was modeled with competing risk regression, with death as a competing risk. Overall survival (OS) was assessed secondarily and modeled with Cox regression. Results Among 281 patients (median [range] age at CRT, 58.7 [25.5-85.6] years; 251 male [89.3%]) included in this study, 242 (86.1%) had oropharyngeal primary cancer, and 266 (94.7%) had human papillomavirus–positive disease. Of all patients, 217 (77.2%) had T stage 1 or 2, and 231 patients (82.2%) had N stage 2b or less. De-escalated 30 Gy CRT was delivered to 144 patients (51.2%), and the remainder received standard 70 Gy CRT. On FMISO PET examination, 73 patients (26.0%) had hypoxia-negative disease before CRT, 138 patients (49.1%) had hypoxia-positive disease before CRT and then hypoxia-negative disease during CRT, and 70 patients (24.9%) persistently had hypoxia-positive disease before and during CRT. At a median (IQR) 58 (46-91) months of follow-up, 12 DM events and 22 deaths were observed. Persistent intratreatment hypoxia was associated with increased DM risk (hazard ratio, 3.51; 95% CI, 1.05-11.79; P = .04) and worse OS (hazard ratio, 2.66; 95% CI, 1.14-6.19; P = .02). No patients with hypoxia-negative disease before CRT experienced DM. Conclusions and Relevance In this cohort study using pooled analysis of prospective nonrandomized clinical trials incorporating FMISO PET in the definitive management of HNSCC, persistent intratreatment hypoxia was associated with increased risk of DM and worse OS. Conversely, all patients with hypoxia-negative disease before treatment remained free of DM. These findings suggest that pretreatment and intratreatment FMISO PET results may serve as biomarkers for DM risk and aid in identifying candidates for escalated therapeutic strategies.