tbuckley/cabot-search huggingface dataset:
Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma
Authors: Chi Leung Chiang, Kenneth Sik Kwan Chan, Keith Wan Hang Chiu, Francis Ann Shing Lee, Wenqi Chen, Natalie Sean Man Wong, Ryan Lok Man Ho, Venus Wan Yan Lee, Kwan Man, Feng Ming (Spring) Kong, Albert Chi Yan Chan
Journal: JAMA Oncology (2024)

Importance Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking. Objective To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol. Design, Setting, and Participants This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued. Exposure All patients had received stereotactic body radiotherapy followed by anti–programmed cell death protein 1 or anti–programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy. Main Outcomes and Measures The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses. Results A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P &amp;amp;lt; .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR. Conclusions and Relevance This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.
Oral Microbiome and Subsequent Risk of Head and Neck Squamous Cell Cancer
Authors: Soyoung Kwak, Chan Wang, Mykhaylo Usyk, Feng Wu, Neal D. Freedman, Wen-Yi Huang, Marjorie L. McCullough, Caroline Y. Um, Martha J. Shrubsole, Qiuyin Cai, Huilin Li, Jiyoung Ahn, Richard B. Hayes
Journal: JAMA Oncology (2024)

Importance The oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies. Objective To test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development. Design, Setting, and Participants Prospective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023. Exposures Characterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota. Main Outcomes and Measures The primary outcome was HNSCC incidence. Results The study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae , Streptococcus sanguinis , and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified. Conclusions and Relevance This case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.
TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M
Authors: Yi Zhou, Shu Zhang, Guoteng Qiu, Xue Wang, Andrew Yonemura, Hongwei Xu, Guofei Cui, Shanshan Deng, Joanne Chun, Nianyong Chen, Meng Xu, Xinhua Song, Jingwen Wang, Zijing Xu, Youping Deng, Matthias Evert, Diego F Calvisi, Shumei Lin, Haichuan Wang, Xin Chen
Journal: Journal of Clinical Investigation (2024)

Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC are key molecular events in HCC. In this study, we explored the roles of tuberous sclerosis complex/mTORC1 (TSC/mTORC1) and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had a minimal effect on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablation of TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E acted downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production
Authors: Chuangyu Wen, Liangliang Wang, András Piffkó, Dapeng Chen, Xianbin Yu, Katarzyna Zawieracz, Jason Bugno, Kaiting Yang, Emile Z Naccasha, Fei Ji, Jiaai Wang, Xiaona Huang, Stephen Y Luo, Lei Tan, Bin Shen, Cheng Luo, Megan E McNerney, Steven J Chmura, Ainhoa Arina, Sean P Pitroda, Chuan He, Hua Liang, Ralph R Weichselbaum
Journal: Journal of Clinical Investigation (2024)

RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from cancer patients, but not in other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
Characterization of Fibroblast Growth Factor Receptor Alterations and Activation in Patients with High-Risk Non-Muscle Invasive Bladder Cancer
Authors: Joel R. Eisner, Florus C. de Jong, Yoichiro Shibata, Gregory M. Mayhew, James M. Davison, Jenna Carcione, Kirk L. Pappan, Shibu Thomas, Spyros Triantos, Ademi Santiago-Walker, Mahadi Baig, Michael V. Milburn, Kirk D. Beebe, Tahlita C.M. Zuiverloon
Journal: Clinical Cancer Research (2024)

The GARNER study investigated fibroblast growth factor receptor (FGFR) alteration (ALT) frequency and the clinical outcome relationship with Bacillus Calmette-Guérin (BCG) treatment in high-risk non-muscle invasive bladder cancer (HR-NMIBC). An FGFR predictive response signature (FGFR-PRS) was discovered that identifies patients with an activated FGFR pathway who could potentially benefit from FGFR-targeted therapy beyond those who are FGFR ALT (+).
The Tumour Immune Microenvironment Drives Survival Outcomes and Therapeutic Response in an Integrated Molecular Analysis of Gastric Adenocarcinoma
Authors: Daniel Skubleny, Kieran Purich, David R. McLean, Sebastiao N. Martins-Filho, Klaus Buttenschoen, Erika Haase, Michael McCall, Sunita Ghosh, Jennifer L. Spratlin, Daniel E. Schiller, Gina R. Rayat
Journal: Clinical Cancer Research (2024)

We performed an integrated analysis of molecular classification systems proposed by The Cancer Genome Atlas (TCGA), the Asian Cancer Research Group (ACRG) and the Tumour Microenvironment Score (TME) to identify which classification scheme(s) are most promising to pursue in subsequent translational investigations.
A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism
Authors: Marianna Decet, Patrick Scott, Sabine Kuenen, Douja Meftah, Jef Swerts, Carles Calatayud, Sandra F Gallego, Natalie Kaempf, Eliana Nachman, Roman Praschberger, Nils Schoovaerts, Chris C Tang, David Eidelberg, Samir Al Adawi, Abdullah Al Asmi, Ramachandiran Nandhagopal, Patrik Verstreken
Journal: Cell Reports Medicine (2024)
A living organoid biobank of patients with Crohn’s disease reveals molecular subtypes for personalized therapeutics
Authors: Courtney Tindle, Ayden G Fonseca, Sahar Taheri, Gajanan D Katkar, Jasper Lee, Priti Maity, Ibrahim M Sayed, Stella-Rita Ibeawuchi, Eleadah Vidales, Rama F Pranadinata, Mackenzie Fuller, Dominik L Stec, Mahitha Shree Anandachar, Kevin Perry, Helen N Le, Jason Ear, Brigid S Boland, William J Sandborn, Debashis Sahoo, Soumita Das, Pradipta Ghosh
Journal: Cell Reports Medicine (2024)
ERS technical standard: Global Lung Function Initiative reference values for multiple breath washout indices
Authors: Kathryn A Ramsey, Sanja Stanojevic, Luis Chavez, Noah Johnson, Cole Bowerman, Graham L Hall, Philipp Latzin, Katherine O'Neill, Paul D Robinson, Mirjam Stahl, Daniel J Weiner, Annelies M Zwitserloot, Alex Horsley
Journal: European Respiratory Journal (2024)

Background Multiple breath washout is a lung function test based on tidal breathing that assesses lung volume and ventilation distribution. The aim of this analysis was to use the Global Lung Function Initiative methodology to develop all-age reference equations for the multiple breath washout indices lung clearance index (LCI) and functional residual capacity (FRC). Methods Multiple breath washout data from healthy individuals were collated from sites. Data were re-analysed using the latest software versions. Reference equations were derived using the lambda-mu-sigma (LMS) method using the generalised additive models of location shape and scale programme in R. The impact of equipment type, inert tracer gas, and equipment dead space volume on the derived reference ranges were investigated. Results Data from 23 sites (n=3647 test occasions) were submitted. Reference equations were derived from 1581 unique observations from participants between the ages of 2 and 81 years. Equipment type, inert tracer gas, and equipment dead space volume did not significantly affect the prediction equations for either LCI or FRC. Reference equations for LCI include age as the only predictor, whereas sex-specific reference equations for FRC included height and age. Conclusions Global Lung Function Initiative reference equations for multiple breath washout variables provide a standard for reporting and interpretation of LCI and FRC.
Airway Tapering in Chronic Obstructive Pulmonary Disease
Authors: Sandeep Bodduluri, Arie Nakhmani, Abhilash S Kizhakke Puliyakote, Joseph M Reinhardt, Mark T Dransfield, Surya P Bhatt
Journal: European Respiratory Journal (2024)

Background Luminal narrowing is a hallmark feature of airway remodeling in COPD, but current measures focus on airway wall remodeling. Quantification of the natural increase in cumulative cross-sectional area along the length of the human airway tree can facilitate assessment of airway narrowing. Methods We analysed the airway trees of 7641 subjects enrolled in the multicenter COPDGene cohort. Airway luminal tapering was assessed by estimating the slope of the change in cumulative cross-sectional area along the length of the airway tree over successive generations (T-Slope). We performed multivariable regression analyses to test the associations between T-Slope and lung function, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea score, 6-minute walk distance (6 MWD), FEV 1 change, exacerbations, and all-cause mortality after adjusting for demographics, %CT emphysema, and total airway count. Results The T-Slope decreased with increasing COPD severity: 2.69 (0.70) in nonsmokers and 2.33 (0.70), 2.11 (0.65), 1.78 (0.58), 1.60 (0.53), and 1.57 (0.52) in GOLD stages 0 through 4 respectively (Jonckheere-Terpstra p=0.04). On multivariable analyses, the T-Slope was independently associated with FEV 1 (β=0.13 L, 95% CI 0.10 to 0.15, p&lt;0.001), 6MWD (β=15.0 m, 95%CI 10.8 to 19.2, p&lt;0.001), change in FEV 1 (β=−4.50 ml·year −1 , 95% CI −7.32 to −1.67; p=0.001), exacerbations (IRR=0.78, 95% CI 0.73 to 0.83, p&lt;0.001), and mortality (HR=0.79, 95% CI 0.72 to 0.86, p&lt;0.001). Conclusion T-Slope is a measure of airway luminal remodeling and is associated with respiratory morbidity and mortality.
Multidisciplinary Management of Adult Patients with Chylothorax: A Consensus Statement
Authors: Abhinav Agrawal, Udit Chaddha, Samira Shojaee, Gregory Nadolski, Moishe Liberman, Y C Gary Lee, Najib Rahman, Janani S Reisenauer, Mark K Ferguson, Malcolm M DeCamp, Erin A Gillaspie, Eihab O Bedawi, Brian Currie, David J Feller-Kopman, Ajinkya Desai, Kazuhiro Yasufuku, Vivian Bishay, Yaron Gesthalter, Horiana Grosu, Jeffrey Forris Beecham Chick, Robert Lentz, K Pallav Kolli, Andrew Kaufman, Ravindra M Mehta, Kush Desai, Heather Davis, Uzair K Ghori, Fabien Maldonado
Journal: European Respiratory Journal (2024)

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and four specialties (pulmonary, interventional radiology, thoracic surgery and nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing seven clinically relevant PICO (Patient, Intervention, Comparison and Outcome) questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these seven PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and informing future research.
Single cell sequencing reveals cellular landscape alterations in the airway mucosa of patients with pulmonary long COVID
Authors: Firoozeh V Gerayeli, Hye Yun Park, Stephen Milne, Xuan Li, Chen Xi Yang, Josie Tuong, Rachel L Eddy, Seyed Milad Vahedi, Elizabeth Guinto, Chung Y Cheung, Julia Sw Yang, Cassie Gilchrist, Dina Yehia, Tara Stach, Hong Dang, Clarus Leung, Tawimas Shaipanich, Jonathon Leipsic, Graeme J Koelwyn, Janice M Leung, Don D Sin
Journal: European Respiratory Journal (2024)

To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms. Adults with and without long COVID were recruited from the general community in Greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had no history of acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced. A total of 56 906 cells were recovered for the downstream analysis, with 34 840 cells belonging to the PLC group, which strikingly showed a unique cluster of neutrophils in the PLC group (p&lt;0.05). Ingenuity Pathway Analysis revealed that the neutrophil degranulation pathway was enriched across epithelial cell clusters. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of inflammatory chemokines and epithelial barrier dysfunction across epithelial cell clusters, as well as over-expression of mucin genes across secretory cell clusters. In conclusion, a single-cell transcriptomic landscape of the small airways suggest that neutrophils may play a significant role in mediating the chronic small airway inflammation driving pulmonary symptoms of long COVID.
Facts and hopes for PET imaging-derived immunotherapy biomarkers
Authors: Derk Jan A. de Groot, Marjolijn N. Lub-de Hooge, Tom van Meerten, Adrienne H. Brouwers, Elisabeth G.E. de Vries
Journal: Clinical Cancer Research (2024)

Current immunotherapies have brought major progress in cancer treatments, but not all patients benefit. Therefore, insight into reasons for treatment failure and optimal biomarkers for patient selection are warranted. Current approved biomarkers for cancer immunotherapy do not provide insight into characteristics across tumor lesions in a patient or their heterogeneity. Here, whole-body positron emission tomography (PET) imaging with specific tracers may provide support. Moreover, the biodistribution of cell therapies and complex molecules, such as bispecific antibodies, can be visualized by PET imaging, and repeat PET imaging allows to study the whole-body kinetics of the immune response. In this review, we present the status of using PET imaging-derived biomarkers for patients with cancer receiving immunotherapy. Next, the hopes and scientific challenges ahead to optimize current PET imaging biomarker development and to discover novel PET-derived baseline and dynamic biomarkers to potentially guide us in drug development and more precise patient and therapy selection will be discussed.
Inflammatory plasma protein levels are elevated years before sarcoidosis diagnosis: a nested case-control study in Sweden
Authors: Elizabeth V Arkema, Michael C Sachs, Annica Dominicus, Anders Eklund, Anna Smed-Sörensen, Johan Grunewald, Anders Blomberg
Journal: European Respiratory Journal (2024)

Sarcoidosis is an immune-mediated inflammatory disease whose natural development is not well understood. We aimed to determine if inflammatory plasma protein levels are elevated before sarcoidosis diagnosis compared to controls. Furthermore, we investigated which proteins are increased and how long before diagnosis they are increased. Cases with sarcoidosis and controls matched 2:1 on sex, birthdate, subcohort and sample date were identified in the Northern Sweden Health and Disease Study to perform a nested case-control study. Cases were validated and included if they provided ≥1 plasma sample ≥2 years before sarcoidosis diagnosis. Plasma protein levels were measured using the Olink Inflammation panel and expressed in Normalized Protein eXpression values. Unconditional logistic regression models adjusted for age, sex, subcohort and time since sampling were used to estimate log odds ratios with 95% confidence intervals for each protein overall and by time to diagnosis. p-values were adjusted for multiple comparisons using the Benjamini-Hochberg method. We included 152 cases and 341 controls. Mean time between sample and sarcoidosis diagnosis was 13.4 years. Forty-four proteins were significantly elevated prior to sarcoidosis compared to controls in multivariable-adjusted analyses. The ten proteins with the lowest p-values were CCL3, CCL19, CDCP1, CXCL9, CXCL10, IFNγ, IL-12B, MCP-3, TNF, and TNFRSF9. Fewer proteins were associated with sarcoidosis in samples taken longer before diagnosis. Restricting to samples taken ≥10 years prior to sarcoidosis diagnosis, 27 proteins remained statistically significant. Several inflammatory proteins were elevated in plasma many years before sarcoidosis onset compared to controls, revealing a preclinical phase characterised by inflammation.
Fractional Doses of Pneumococcal Conjugate Vaccine — A Noninferiority Trial
Authors: Katherine E. Gallagher, Ruth Lucinde, Christian Bottomley, Mary Kaniu, Badaud Suaad, Mary Mutahi, Laura Mwalekwa, Sarah Ragab, Louise Twi-Yeboah, James A. Berkley, Mainga Hamaluba, Angela Karani, Jimmy Shangala, Mark Otiende, Elizabeth Gardiner, Daisy Mugo, Peter G. Smith, Collins Tabu, Fred Were, David Goldblatt, J. Anthony G. Scott
Journal: New England Journal of Medicine (2024)

Pneumococcal conjugate vaccines are an expensive component of the routine immunization schedule. Fractional-dose regimens may be one option to increase the sustainability of the vaccine program.