tbuckley/cabot-search huggingface dataset:
Histopathology images-based deep learning prediction of prognosis and therapeutic response in small cell lung cancer
Authors: Yibo Zhang, Zijian Yang, Ruanqi Chen, Yanli Zhu, Li Liu, Jiyan Dong, Zicheng Zhang, Xujie Sun, Jianming Ying, Dongmei Lin, Lin Yang, Meng Zhou
Journal: npj Digital Medicine (2024)

Abstract Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer characterized by rapid tumor growth and early metastasis. Accurate prediction of prognosis and therapeutic response is crucial for optimizing treatment strategies and improving patient outcomes. In this study, we conducted a deep-learning analysis of Hematoxylin and Eosin (H&amp;E) stained histopathological images using contrastive clustering and identified 50 intricate histomorphological phenotype clusters (HPCs) as pathomic features. We identified two of 50 HPCs with significant prognostic value and then integrated them into a pathomics signature (PathoSig) using the Cox regression model. PathoSig showed significant risk stratification for overall survival and disease-free survival and successfully identified patients who may benefit from postoperative or preoperative chemoradiotherapy. The predictive power of PathoSig was validated in independent multicenter cohorts. Furthermore, PathoSig can provide comprehensive prognostic information beyond the current TNM staging system and molecular subtyping. Overall, our study highlights the significant potential of utilizing histopathology images-based deep learning in improving prognostic predictions and evaluating therapeutic response in SCLC. PathoSig represents an effective tool that aids clinicians in making informed decisions and selecting personalized treatment strategies for SCLC patients.
Clinical challenges in applying the new lung function test interpretive strategies: navigating pitfalls and possible solutions
Authors: Josuel Ora, Paola Rogliani
Journal: European Respiratory Journal (2024)

The European Respiratory Society (ERS)/ American Thoracic Society (ATS) recently released updated interpretive strategies for routine pulmonary function tests (PFTs) [1] building upon their previous standardization document [2]. Although some authors have already discussed the advantages and drawbacks of these new strategies [3], there remain several unclear points that require to be clarified. The published document proposes two interpretative flow charts and some tables [1], which lack integration and contradict each other at times, leading to confusion. For instance, a scenario in which the FEV1/FVC ratio falls below normal while the FEV1 value remains within normal limits. Such a case could be categorized as obstructive, as illustrated in the flow chart (Figure 8, ref. [1]) [1], or dysanaptic, as outlined in Table 4 of the same reference. The paradox becomes more pronounced when attempting to classify the obstruction since, based on the new recommendation, 'mild' is attributed to an FEV1 ranging between −1.65 and 2.5. Consequently, this scenario could be categorized as a dysanaptic pattern, considered as 'mild obstruction' for the sake of extrapolation, or even characterized as obstructed with a normal FEV1. Moreover, the interpretative flow chart, which starts from total lung capacity (TLC), introduces additional variables such as residual volume (RV)/TLC without seamless integration with the previous indices, further increasing the confusion. Likewise, the introduction of several patterns, such as the preserved ratio impaired spirometry (PRISm) [4], non-specific, and undefined patterns, lacks alignment with the interpretative flow charts. This inconsistency raises concerns about the overall clarity and usability of the flow chart. The paper delves into the revised PFT interpretive strategies proposed by ERS/ATS, shedding light on contradictions and identifying key areas for future attention. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: All authors have nothing to disclose.
In sarcoidosis trials, time also matters
Authors: Florence Jeny, Hilario Nunes, Dominique Valeyre
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Dhooria <i>et al</i>. present novel findings regarding glucocorticoid in sarcoidosis. Investigations are required to determine the optimal treatment duration and outcomes, with an emphasis on reducing severe adverse events and exploring alternatives therapies.</b>https://bit.ly/3SeIwS7
Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease
Authors: John A. Mackintosh, Daniel C. Chambers
Journal: European Respiratory Journal (2024)

We write to congratulate Zhang et al. [1] on another fascinating manuscript which expands the narrative on telomeres and their relevance to fibrotic interstitial lung disease (ILD). Yet again, telomere length is shown to be fundamental to a person's outcome and their response to treatment, albeit an adverse response to immunosuppression, mirroring the authors' previous post hoc analysis of the PANTHER-IPF data [2]. However, as in previous manuscripts [3, 4], the authors consider telomere length as a variable that modulates outcome in an individual with a correctly diagnosed ILD, rather than a parameter which might instead inform the diagnosis. It is now time to include telomere length as a fundamental component of interstitial lung disease taxonomy <https://bit.ly/3GcUPaJ>
Treatment of dyspnoea
Authors: Nausherwan K. Burki
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>The mechanisms of respiratory sensations and dyspnoea and how they relate to an article in the <i>ERJ</i> examining direct methods to ameliorate dyspnoea in patients on mechanical ventilation</b>https://bit.ly/41kLneV
Early-life airway microbiome and childhood asthma development
Authors: Zhaozhong Zhu
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Neonatal airway colonisation by bacteria was associated with a four-fold increased risk of persistent wheeze/asthma by age 7 years. However, neonatal airway colonisation was not associated with asthma development from age 7 to 18 years.</b>https://bit.ly/487Ov0b
Reply: A suggested classification of disease behaviour and treatment response in sarcoidosis trials
Authors: Sahajal Dhooria, Inderpaul Singh Sehgal, Ritesh Agarwal
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>A uniform system must be used to classify disease severity, disease evolution, treatment response and other treatment-related behaviour in pulmonary sarcoidosis</b>https://bit.ly/3Rravwa
Reshaping the fabric of health: a call for improving the respiratory health of textile workers in low- and middle-income countries
Authors: Tara Ballav Adhikari, Torben Sigsgaard, Per Kallestrup, Om Kurmi
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Textile workers in LMICs face health risks due to cotton dust and substandard working conditions. Simple and affordable interventions can improve their respiratory health, but systemic changes and collective action are essential for a healthier future.</b>https://bit.ly/3GQ18kL
Reply: Telomere length and immunosuppression in non-idiopathic pulmonary fibrosis interstitial lung disease
Authors: David Zhang, Ayodeji Adegunsoye, Justin M. Oldham, Paul J. Wolters, Christine Kim Garcia, Chad A. Newton
Journal: European Respiratory Journal (2024)

We thank J.A. Mackintosh and D.C. Chambers for their thoughtful discussions following our work detailing the pharmacogenetic interaction between telomere shortening and immunosuppression leading to harm in patients with non-idiopathic pulmonary fibrosis interstitial lung disease (ILD) patients [1]. Our findings suggest that shared genetic vulnerability to pulmonary fibrosis from telomere attrition may also inform a personalised approach to treatment. As J.A. Mackintosh and D.C. Chambers astutely point out, this study presumed an accurate ILD diagnostic categorisation through multidisciplinary discussions. Limitations notwithstanding, this classification schema remains the current standard for ILD diagnosis and treatment. While we agree with the prospect of genomics-informed ILD taxonomy as a successor to a purely phenotype-driven classification, we believe that the transition must be pursued carefully and systematically. As such, our findings of genomic marker associations with outcomes across ILD diagnostic subtypes is a rational next step towards incorporating genetic information into ILD decision-making. Refining ILD taxonomy through the lens of common molecular endotypes may inform personalised ILD management https://bit.ly/3RyRKrX
Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review
Authors: Peter Galle, Richard S Finn, Catherine Ruth Mitchell, Kerigo Ndirangu, Zahra Ramji, Gabrielle Sophie Redhead, David J Pinato
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes. Methods Embase ® , Medline ® , and EBM Reviews were searched via the OVID ® platform on February 15, 2022. Conference proceedings, clinical trial registries, and global regulatory and reimbursement body websites were also searched. Eligible publications included clinical trials enrolling patients receiving cancer treatment with either PD-1, PD-L1, or CTLA-4 reporting outcomes including incidence or prevalence of ADAs and the impact of immunogenicity on treatment safety and efficacy. Reference lists of eligible publications were also searched. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and evidence quality assessment was conducted using the appropriate Joanna Briggs Institute Critical Appraisal tool. Results After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics. Conclusions Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes.
Early time-restricted eating improves markers of cardiometabolic health but has no impact on intestinal nutrient absorption in healthy adults
Authors: M. Alan Dawson, Susan N. Cheung, Michael R. La Frano, Ravinder Nagpal, Claire E. Berryman
Journal: Cell Reports Medicine (2024)

Early time-restricted eating (eTRE) improves aspects of cardiometabolic health. Although the circadian system appears to regulate nutrient absorption, little is known about the effects of eTRE on intestinal absorption. In this randomized crossover trial, 16 healthy adults follow a controlled, weight maintenance diet for 9 days, consuming all calories between 0800 and 1400 (eTRE schedule) or 0800 and 2000 (control schedule). We measure the energy content of the diet, stool, and urine with bomb calorimetry and calculate intestinal energy absorption. The eTRE schedule is more effective than the control eating schedule for improving markers of cardiometabolic health, including 24-h mean glucose concentrations and glycemic variability, assessed as the mean amplitude of glycemic excursions. However, eTRE has no effect on intestinal energy and macronutrient absorption, gastrointestinal transit time, colonic hydrogen gas production, or stool microbial composition, suggesting eTRE does not impact gastrointestinal function. This trial is registered (ClinicalTrials.gov: NCT04877262).
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Authors: Luyen Tien Vu, Faraz Ahmed, Hongya Zhu, David Shing Huk Iu, Elizabeth A. Fogarty, Yeonui Kwak, Weizhong Chen, Carl J. Franconi, Paul R. Munn, Ann E. Tate, Susan M. Levine, Jared Stevens, Xiangling Mao, Dikoma C. Shungu, Geoffrey E. Moore, Betsy A. Keller, Maureen R. Hanson, Jennifer K. Grenier, Andrew Grimson
Journal: Cell Reports Medicine (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we use single-cell RNA sequencing (scRNA-seq) to examine immune cells in patient and control cohorts. Postexertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. To detect changes coincident with PEM, we applied scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients display classical monocyte dysregulation suggestive of inappropriate differentiation and migration to tissue. We identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlates with disease severity. Comparing the transcriptome at baseline and postexercise challenge, we discover patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation in platelets.
Discovery of galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors
Authors: Yiting Wang, Yufan Sun, Shouyan Deng, Jiayang Liu, Jianghong Yu, Hao Chi, Xue Han, Yuan Zhang, Jiawei Shi, Yungang Wang, Yingfei Quan, Hai Li, Jie Xu
Journal: Cell Reports Medicine (2024)

LILRB4 is an immunosuppressive receptor, and its targeting drugs are undergoing multiple preclinical and clinical trials. Currently, the absence of a functional LILRB4 ligand in solid tumors not only limits the strategy of early antibody screening but also leads to the lack of companion diagnostic (CDx) criteria, which is critical to the objective response rate in early-stage clinical trials. Here, we show that galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4, and its ligation induces M-MDSC by activating STAT3 and inhibiting NF-κB. Significantly, Gal-8, but not APOE, can induce MDSC, and both ligands bind LILRB4 noncompetitively. Gal-8 expression promotes in vivo tumor growth in mice, and the knockout of LILRB4 attenuates tumor growth in this context. Antibodies capable of functionally blocking Gal-8 are able to suppress tumor growth in vivo. These results identify Gal-8 as an MDSC-driving ligand of LILRB4, and they redefine a class of antibodies for solid tumors.
Acute rehabilitation following traumatic anterior shoulder dislocation (ARTISAN): pragmatic, multicentre, randomised controlled trial
Authors: Rebecca S Kearney, David R Ellard, Helen Parsons, Aminul Haque, James Mason, Henry Nwankwo, Helen Bradley, Stephen Drew, Chetan Modi, Howard Bush, David Torgerson, Martin Underwood
Journal: BMJ (2024)

Abstract Objective To assess the effects of an additional programme of physiotherapy in adults with a first-time traumatic shoulder dislocation compared with single session of advice, supporting materials, and option to self-refer to physiotherapy. Design Pragmatic, multicentre, randomised controlled trial (ARTISAN). Setting and participants Trauma research teams at 41 UK NHS Trust sites screened adults with a first time traumatic anterior shoulder dislocation confirmed radiologically, being managed non-operatively. People were excluded if they presented with both shoulders dislocated, had a neurovascular complication, or were considered for surgical management. Interventions One session of advice, supporting materials, and option to self-refer to physiotherapy (n=240) was assessed against the same advice and supporting materials and an additional programme of physiotherapy (n=242). Analyses were on an intention-to-treat basis with secondary per protocol analyses. Main outcome measures The primary outcome was the Oxford shoulder instability score (a single composite measure of shoulder function), measured six months after treatment allocation. Secondary outcomes included the QuickDASH, EQ-5D-5L, and complications. Results 482 participants were recruited from 40 sites in the UK. 354 (73%) participants completed the primary outcome score (n=180 allocated to advice only, n=174 allocated to advice and physiotherapy). Participants were mostly male (66%), with a mean age of 45 years. No significant difference was noted between advice compared with advice and a programme of physiotherapy at six months for the primary intention-to-treat adjusted analysis (between group difference favouring physiotherapy 1.5 (95% confidence interval −0.3 to 3.5)) or at earlier three month and six week timepoints. Complication profiles were similar across the two groups (P&gt;0.05). Conclusions An additional programme of current physiotherapy is not superior to advice, supporting materials, and the option to self-refer to physiotherapy. Trial registration Current Controlled Trials isrctn63184243 .
Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity
Authors: Maria Chondronikola, Jun Yoshino, Raja Ramaswamy, Joseph Daniel Giardina, Richard Laforest, Richard L. Wahl, Bruce W. Patterson, Bettina Mittendorfer, Samuel Klein
Journal: Cell Reports Medicine (2024)

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).
Corrigendum to “Microbe-based therapies for colorectal cancer: Advantages and limitations” [Semin. Cancer Biol. 86 (2022) 652–665]
Authors: M. Saeed, A. Shoaib, R. Kandimalla, S. Javed, A. Almatroudi, R. Gupta, F. Aqil
Journal: Seminars in Cancer Biology (2024)
Separate gut-brain circuits for fat and sugar reinforcement combine to promote overeating
Authors: Molly McDougle, Alan de Araujo, Arashdeep Singh, Mingxin Yang, Isadora Braga, Vincent Paille, Rebeca Mendez-Hernandez, Macarena Vergara, Lauren N. Woodie, Abhishek Gour, Abhisheak Sharma, Nikhil Urs, Brandon Warren, Guillaume de Lartigue
Journal: Cell Metabolism (2024)

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.
Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors
Authors: Francesca Pettinella, Barbara Mariotti, Chiara Lattanzi, Kirsten Bruderek, Marta Donini, Sara Costa, Olivia Marini, Giulia Iannoto, Sara Gasperini, Elena Caveggion, Monica Castellucci, Federica Calzetti, Francisco Bianchetto-Aguilera, Elisa Gardiman, Matteo Giani, Stefano Dusi, Maurizio Cantini, Aurora Vassanelli, Denise Pavone, Michele Milella, Sara Pilotto, Pamela Biondani, Benedikt Höing, Marie Carolin Schleupner, Timon Hussain, Boris Hadaschik, Cordelia Kaspar, Carlo Visco, Cristina Tecchio, Leo Koenderman, Flavia Bazzoni, Nicola Tamassia, Sven Brandau, Marco A. Cassatella, Patrizia Scapini
Journal: Cell Reports Medicine (2024)

Precise molecular characterization of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is hampered by their mixed composition of mature and immature cells and lack of specific markers. Here, we focus on mature CD66b+CD10+CD16+CD11b+ PMN-MDSCs (mPMN-MDSCs) from either cancer patients or healthy donors receiving G-CSF for stem cell mobilization (GDs). By RNA sequencing (RNA-seq) experiments, we report the identification of a distinct gene signature shared by the different mPMN-MDSC populations under investigation, also validated in mPMN-MDSCs from GDs and tumor-associated neutrophils (TANs) by single-cell RNA-seq (scRNA-seq) experiments. Analysis of such a gene signature uncovers a specific transcriptional program associated with mPMN-MDSC differentiation and allows us to identify that, in patients with either solid or hematologic tumors and in GDs, CD52, CD84, and prostaglandin E receptor 2 (PTGER2) represent potential mPMN-MDSC-associated markers. Altogether, our findings indicate that mature PMN-MDSCs distinctively undergo specific reprogramming during differentiation and lay the groundwork for selective immunomonitoring, and eventually targeting, of mature PMN-MDSCs.
Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss
Authors: Clara Mendia, Thibault Peineau, Mina Zamani, Chloé Felgerolle, Nawal Yahiaoui, Nele Christophersen, Samantha Papal, Audrey Maudoux, Reza Maroofian, Pranav Patni, Sylvie Nouaille, Michael R. Bowl, Sedigheh Delmaghani, Hamid Galehdari, Barbara Vona, Didier Dulon, Sandrine Vitry, Aziz El-Amraoui
Journal: Molecular Therapy (2024)

Hearing loss is a major health concern affecting millions of people worldwide with currently limited treatment options. In clarin-2-deficient Clrn2