tbuckley/cabot-search huggingface dataset:
An ILC2-chitinase circuit restores lung homeostasis after epithelial injury
Authors: Haerin Jung, Do-Hyun Kim, Roberto Efraín Díaz, J. Michael White, Summer Rucknagel, Lauryn Mosby, Yilin Wang, Sanjana Reddy, Emma S. Winkler, Ahmed O. Hassan, Baoling Ying, Michael S. Diamond, Richard M. Locksley, James S. Fraser, Steven J. Van Dyken
Journal: Science Immunology (2024)

Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.
Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation
Authors: Yuta Kobayashi, Matias A Bustos, Yoshinori Hayashi, Qiang Yu, Dave Hoon
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Immune checkpoint inhibitor (ICIs)-based therapies are the standard of care treatment for patients with metastatic melanoma (MM). The stimulator of interferon genes (STING) signaling pathway is critical in controlling immune responses to ICIs. Interferon (IFN)-γ-inducible protein 16 (IFI16) is a cytosolic DNA sensor that activates the STING signaling pathway. The link between IFI16 and STING signaling pathway on IFN-γ stimulation and the connection to ICIs response remains not completely understood. Methods Deconvolution analyses were performed using the TCGA-SKCM, GSE91061, and PRJEB23709 public RNA sequencing (RNA-seq) data sets that contained RNA-seq for patients with MM. Functional assays combined with cytokine arrays were performed using MM cell lines to validate in silico data. Multiplex immunofluorescence was performed on untreated or pretreatment tumor samples from patients with MM. Results Deconvolution analysis showed that high- IFI16 levels in melanoma cells were associated with a good prognosis in patients with MM and positively correlated with M1-macrophage infiltration. Functional assays using MM cell lines demonstrated that IFI16 is a key molecule to sense cytosolic DNA and activate STING and nuclear factor kappa B (NF-κB) signaling pathways, independent of cyclic GMP-AMP synthase or absent in melanoma 2, on IFN-γ stimulation. IFI16 knockdown significantly decreased CXCL10 and ICAM1 secretion. EZH2 inhibitor reversed the repressive epigenetic control on IFI16 to promote STING and NF-κB signaling pathways on IFN-γ stimulation. Increased IFI16, ICAM1, and CXCL10 levels in tumor samples from patients with MM were positively correlated with M1-macrophage infiltration and a significantly better response to ICIs. Conclusions This study identifies IFI16 as a key sensor during IFN-γ stimulation associated with ICI response, and it proposes the epigenetic EZH2 inhibitor as an alternative treatment strategy to overcome ICI resistance in patients with MM.
Programmable bacteria synergize with PD-1 blockade to overcome cancer cell–intrinsic immune resistance mechanisms
Authors: Fangda Li, Zaofeng Yang, Thomas M. Savage, Rosa L. Vincent, Kenia de los Santos-Alexis, Alexander Ahn, Mathieu Rouanne, Dylan L. Mariuzza, Tal Danino, Nicholas Arpaia
Journal: Science Immunology (2024)

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3 − CD4 + and CD8 + T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.
A non-randomized pragmatic historically controlled trial evaluating the effectiveness and safety of a bedaquiline or a linezolid-based short regimen for rifampicin-resistant tuberculosis
Authors: Joan Martínez-Campreciós, Maria Luisa Aznar, Adriano Zacarias, Rafael Terán, Arlete Nindia, Juan Espinosa-Pereiro, Sandra Aixut, Maria Eugenia Ramos, Marcos José Nicolau, Elena Sulleiro, Maria Teresa Tórtola, Adrián Sánchez-Montalvá, Israel Molina
Journal: Journal of Infection (2024)
Classifying interstitial lung diseases in a fractal lung: a morphologist's view “<i>anno Domini</i>2000”
Authors: E.K. Verbeken
Journal: European Respiratory Journal (2001)

Interstitial lung diseases (ILDs) remain a challenging problem for the pathologist. New insights in aetiology and pathogenesis, new diagnostic tools and successful research have led to a renewed interest in ILDs during the last few years, and highlighted the need for a novel classification, particularly of the chronic and/or idiopathic categories of interstitial pneumonias. The present paper compares the terminology of the latter categories in current and previous classifications and briefly discusses the pathological basis for the classifications of ILDs in general, and for the idiopathic interstitial pneumonias (IIPs) in particular. The difference between high versus low morphological specificity determines the pathological classifications. The classification of IIPs relies upon a pattern recognition taking temporal and spatial distribution into consideration. The last section of this paper discusses recent research opposing the conventional pathological approach, analogous to the mechanical two-compartment model of the lung, in which a discontinuity is considered between these two compartments, and thus, a distinction is made between interstitial lung diseases with and without bronchiolitis. In the recent “fractal” concept, the continuity of the lung architecture is emphasized: the lung is a so-called fractal tree with noninteger dimensions. In this fractal model, an interstitial lung disease effects a peripheral part of the pulmonary fractal tree and this may or may not include bronchioles.
Centromere Landscapes Resolved from Hundreds of Human Genomes
Authors: Shenghan Gao, Yimeng Zhang, Stephen J Bush, Bo Wang, Xiaofei Yang, Kai Ye
Journal: Genomics Proteomics & Bioinformatics (2024)

Abstract High-fidelity (HiFi) sequencing has facilitated the assembly and analysis of the most repetitive region of the genome, the centromere. Nevertheless, our current understanding of human centromeres is based on a relatively small number of telomere-to-telomere assemblies, which has not yet captured its full diversity. In this study, we investigated the genomic diversity of human centromere higher order repeats (HORs) via both HiFi reads and haplotype-resolved assemblies from hundreds of samples drawn from ongoing pangenome-sequencing projects and reprocessed them via a novel HOR annotation pipeline, HiCAT-human. We used this wealth of data to provide a global survey of the centromeric HOR landscape; in particular, we found that 23 HORs presented significant copy number variability between populations. We detected three centromere genotypes with unbalanced population frequencies on chromosomes 5, 8, and 17. An inter-assembly comparison of HOR loci further revealed that while HOR array structures are diverse, they nevertheless tend to form a number of specific landscapes, each exhibiting different levels of HOR subunit expansion and possibly reflecting a cyclical evolutionary transition from homogeneous to nested structures and back.
Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis
Authors: Per Karlsson, Anthony Fyles, S Laura Chang, Bradley Arrick, Frederick L Baehner, Per Malmström, Mårtin Fernö, Erik Holmberg, Martin Sjöström, Fei-Fei Liu, David A Cameron, Linda J Williams, John M S Bartlett, Joanna Dunlop, Jacqueline Caldwell, Joseph F Loane, Elizabeth Mallon, Tammy Piper, Ian Kunkler, Felix Y Feng, Corey W Speers, Lori J Pierce, John P Bennett, Karen J Taylor
Journal: JNCI Journal of the National Cancer Institute (2024)

There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates.
Racial disparities in prostate cancer in the UK and the USA: similarities, differences and steps forwards
Authors: Edward Christopher Dee, Rebecca Todd, Kenrick Ng, Gloryanne Aidoo-Micah, Troy B. Amen, Zoe Moon, Randy Vince, Vinayak Muralidhar, Katherine Mutsvangwa, Garth Funston, Luke T. A. Mounce, Elias Pintus, Kosj Yamoah, Daniel E. Spratt, Brandon A. Mahal, Jonathan Shamash, Robert Horne, Paul L. Nguyen
Journal: Nature Reviews Urology (2024)
Single-cell transcriptomics of pediatric Burkitt lymphoma reveals intra-tumor heterogeneity and markers of therapy resistance
Authors: Clarissa Corinaldesi, Antony B. Holmes, Gaia Martire, Anna Tosato, Domenico Rizzato, Federica Lovisa, Ilaria Gallingani, Qiong Shen, Lavinia Ferrone, Marian Harris, Kimberly Davies, Luca Molinaro, Umberto Mortara, Angelo Paolo Dei Tos, Kenneth Ofori, Emanuele S. G. D’Amore, Roberto Chiarle, Bo Ngan, Elisa Carraro, Marta Pillon, Shafinaz Hussein, Govind Bhagat, Marco Pizzi, Lara Mussolin, Katia Basso
Journal: Leukemia (2024)

Abstract Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in pediatric patients. While most patients are cured, a fraction of them are resistant to therapy. To investigate BL heterogeneity and the features distinguishing therapy responders (R) from non-responders (NR), we analyzed by single-cell (sc)-transcriptomics diagnostic EBV-negative BL specimens. Analysis of the non-tumor component revealed a predominance of immune cells and a small representation of fibroblasts, enriched in NR. Tumors displayed patient-specific features, as well as shared subpopulations that expressed transcripts related to cell cycle, signaling pathways and cell-of-origin signatures. Several transcripts were differentially expressed in R versus NR. The top candidate, Tropomyosin 2 (TPM2), a member of the tropomyosin actin filament binding protein family, was confirmed to be significantly higher in NR both at the transcript and protein level. Stratification of patients based on TPM2 expression at diagnosis significantly correlated with prognosis, independently of TP53 mutations. These results indicate that BL displays transcriptional heterogeneity and identify candidate biomarkers of therapy resistance.
Schwann cell-secreted frizzled-related protein 1 dictates neuroinflammation and peripheral nerve degeneration after neurotrauma
Authors: Xiangyun Yao, Lingchi Kong, Yi Qiao, David Brand, Juehong Li, Zhiwen Yan, Song Guo Zheng, Yun Qian, Cunyi Fan
Journal: Cell Reports Medicine (2024)
Single-cell profiling reveals a conserved role for hypoxia-inducible factor signaling during human craniotomy infection
Authors: Zachary Van Roy, Gunjan Kak, Lee E Korshoj, Joseph P Menousek, Cortney E Heim, Rachel W Fallet, James R Campbell, Carol R Geary, Bo Liu, Santhi Gorantla, Larisa Y Poluektova, Bin Duan, W Scott Campbell, William E Thorell, Tammy Kielian
Journal: Cell Reports Medicine (2024)
Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Scottish Cystic Fibrosis Group
Authors: FG Bollert, JY Paton, TG Marshall, J Calvert, AP Greening, JA Innes
Journal: European Respiratory Journal (1999)

Nebulized recombinant human deoxyribonuclease (DNase) reduces sputum viscosity and improves lung function in some cystic fibrosis patients, but individual responses are unpredictable. The aim of this study was to investigate how DNase can be targeted to those cystic fibrosis patients who would benefit most. The Scottish Cystic Fibrosis Group agreed on a randomized, double-blind, placebo-controlled n-of-1 assessment protocol. Patients underwent a maximum of three 4-week assessment periods (2 weeks saline, 2 weeks DNase each). Measurements performed at hospital (exercise, oximetry and spirometry) and home (symptom scores) were used to derive a scoring system to discriminate maximally between DNase and placebo effects. The data on 89 4-week assessments in 52 patients were reported. Twenty-four patients have completed the assessment process (12 responders and 12 nonresponders) to date. Forced expiratory volume in one second (FEVI) was the best discriminator of response, rising by &gt;200 mL after DNase in 33 of 89 (37%) assessments compared with 3 of 89 (3%) after saline. N-of-1 trials, while laborious, permitted genuine treatment effects to be quantified within individuals with confidence, permitting appropriate treatment targeting. This provides a model of how other new expensive therapies may be introduced to maximize patient benefit.
Information provision and financial incentives in Catalonia's public primary care (2010–2019): an interrupted time series analysis
Authors: Roger Esteban-Fabró, Ermengol Coma, Eduardo Hermosilla, Leonardo Méndez-Boo, Carolina Guiriguet, Gabriel Facchini, Catia Nicodemo, Josep Vidal-Alaball
Journal: The Lancet Regional Health - Europe (2024)
Bridging the digital divide to promote prevention and control of non-communicable diseases for all in China and beyond
Authors: Enying Gong, Hui Wang, Weiguo Zhu, Gauden Galea, Jian Xu, Lijing L Yan, Ruitai Shao
Journal: BMJ (2024)

<b>Ruitai Shao</b> and colleagues argue that the digital divide may exacerbate global disparities in prevention and control of non-communicable diseases and enlarge health inequity when effective digital health solutions are unevenly distributed
Burden of non-communicable diseases due to population ageing in China: challenges to healthcare delivery and long term care services
Authors: Yuebin Lv, Lin Fan, Jinhui Zhou, Enmin Ding, Ji Shen, Song Tang, Yao He, Xiaoming Shi
Journal: BMJ (2024)

China has made substantial progress in healthcare delivery to reduce the burden of non-communicable diseases due to population ageing, although challenges and opportunities in long term care services have been under-recognised, argue <b>Xiaoming Shi and colleagues</b>
Non-pharmacological interventions for prevention and treatment of non-communicable diseases with experiences from China
Authors: Jing Wu, Xiang Gao, Zuyao Yang, Yibing Yang, Gauden Galea, Longde Wang, Hongbing Shen
Journal: BMJ (2024)

<i>Non-pharmacological interventions for prevention of non-communicable diseases are undervalued, and clinicians and policy makers need to be more active in implementing them, say</i><b>Hongbing Shen and colleagues</b>
Frailty as a breakthrough point for multimorbidity management among older adults: challenges and opportunities in China
Authors: Xunliang Tong, Jian Xu, Enying Gong, Xinyue Zhang, Yanming Li, Ruitai Shao, Huan Xi
Journal: BMJ (2024)

<b>Huan Xi and colleagues</b> argue that tailored strategies are needed to seamlessly integrate frailty assessment into multimorbidity management, thereby promoting a shift towards a health oriented management approach
Phase 1b Study of the Immunocytokine Simlukafusp alfa (FAP-IL2v), in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Aaron R. Hansen, Carlos A. Gomez-Roca, Debbie G. J. Robbrecht, Loic Verlingue, Antoine Italiano, Julie E. Bauman, Neeltje Steeghs, Hans Prenen, Jérôme Fayette, James Spicer, Jiaxin Niu, Christin Habigt, Meike Schneider, Stefan Evers, Nassim Sleiman, David Dejardin, Caroline Ardeshir, Daniela Schmid, Christophe Boetsch, Jehad Charo, Anton Kraxner, Volker Teichgräber, Nino Keshelava, Marcelo R. Bonomi
Journal: Clinical Cancer Research (2024)

Abstract Purpose: This phase Ib trial evaluated fibroblast activation protein-α–targeted IL2 variant (FAP-IL2v), a novel immunocytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Patients received FAP-IL2v either on a continuous weekly (QW) schedule or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses. Results: A total of 58 patients were enrolled, 19 patients into the dose-escalation part, and 39 patients into the expansion part. The maximum tolerated dose of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v–related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, and the objective response rate was 7% (95% confidence interval, 3.2–14.7). Conclusions: The safety profile of FAP-IL2v in combination with cetuximab was acceptable, and pharmacodynamic markers support the proposed mode of action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).]
Cross-Sectional Examination of Thyroid Hormones and Environmental Exposure to Multiclass Pesticides in Women of Reproductive Age in China
Authors: Feng-Jiao Peng, Paul Palazzi, Sakina Mezzache, Emilie Adelin, Nasrine Bourokba, Philippe Bastien, Brice M.R. Appenzeller
Journal: Environmental Health Perspectives (2024)

Some pesticides have been shown to interfere with thyroid functions through changes in thyroid hormone (TH) levels. However, few human studies have explored associations between TH levels and environmental exposure to currently used pesticides, including neonicotinoids, phenylpyrazoles, phenoxy acids, and azoles. Moreover, such studies often measure biomarkers of exposure in urine or blood, and thus reveal only recent exposure. In contrast, hair has been demonstrated to be a suitable matrix for assessing chronic exposure to both persistent and nonpersistent organic pollutants.
Reverse Selection Designs for Accommodating Multiple Control Arms
Authors: Sarah Samorodnitsky, Megan Othus, Michael LeBlanc, Michael C. Wu
Journal: Clinical Cancer Research (2024)

Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.
First-In-Human Dose-Escalation Study of Fianlimab, an Anti–Lymphocyte Activation Gene-3 Antibody, with Cemiplimab in patients with advanced malignancies
Authors: Nehal J. Lakhani, Kyriakos P. Papadopoulos, Melissa Lynne Johnson, Haeseong Park, Ding Wang, Timothy A. Yap, Afshin Dowlati, Robert G. Maki, Susanna Ulahannan, Filipa Lynce, Karen Kelly, Stephen Williamson, Jyoti Malhotra, Shuquan Chen, Ana Gonzalez Ortiz, Vladimir Jankovic, Anne Paccaly, Sheila Masinde, Jayakumar Mani, Israel Lowy, Giuseppe Gullo, Tasha Sims, Glenn Kroog
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti–PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. Patients and Methods: Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were the rate of dose-limiting toxicities, adverse events (including immune mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. Results: Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, in 87% of patients with fianlimab + cemiplimab, and in 87% of patients who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose proportional and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response, three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1,600 mg Q3W (20 mg/kg in an 80-kg individual) is the selected dose for phase 2 and phase 3 studies. Conclusions: Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.