tbuckley/cabot-search huggingface dataset:
Deep Learning–Based 3D Single-Cell Imaging Analysis Pipeline Enables Quantification of Cell–Cell Interaction Dynamics in the Tumor Microenvironment
Authors: Bodong Liu, Yanting Zhu, Zhenye Yang, Helen H.N. Yan, Suet Yi Leung, Jue Shi
Journal: Cancer Research (2023)

The three-dimensional (3D) tumor microenvironment (TME) comprises multiple interacting cell types that critically impact tumor pathology and therapeutic response. Efficient 3D imaging assays and analysis tools could facilitate profiling and quantifying distinctive cell-cell interaction dynamics in the TMEs of a wide spectrum of human cancers. Here, we developed a 3D live-cell imaging assay using confocal microscopy of patient-derived tumor organoids and a software tool, SiQ-3D (single-cell image quantifier for 3D), that optimizes deep learning (DL)-based 3D image segmentation, single-cell phenotype classification, and tracking to automatically acquire multidimensional dynamic data for different interacting cell types in the TME. An organoid model of tumor cells interacting with natural killer cells was used to demonstrate the effectiveness of the 3D imaging assay to reveal immuno-oncology dynamics as well as the accuracy and efficiency of SiQ-3D to extract quantitative data from large 3D image datasets. SiQ-3D is Python-based, publicly available, and customizable to analyze data from both in vitro and in vivo 3D imaging. The DL-based 3D imaging analysis pipeline can be employed to study not only tumor interaction dynamics with diverse cell types in the TME but also various cell-cell interactions involved in other tissue/organ physiology and pathology.
Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice
Authors: Adriana Vasquez Ayala, Chia-Yun Hsu, Renee E. Oles, Kazuhiko Matsuo, Luke R. Loomis, Ekaterina Buzun, Marvic Carrillo Terrazas, Romana R. Gerner, Hsueh-Han Lu, Sohee Kim, Ziyue Zhang, Jong Hwee Park, Paul Rivaud, Matt Thomson, Li-Fan Lu, Booki Min, Hiutung Chu
Journal: The Journal of Experimental Medicine (2023)

Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders
Authors: C. Matthias Wilk, Flurin Cathomas, Orsolya Török, Jessica Le Berichel, Matthew D. Park, Camille Bigenwald, George R. Heaton, Pauline Hamon, Leanna Troncoso, Brooks P. Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Long Li, Antonio Aubry, Markus G. Manz, Julia K. Kofler, Zhenyu Yue, Sergio A. Lira, Florent Ginhoux, John F. Crary, Kenneth L. McClain, Jennifer L. Picarsic, Scott J. Russo, Carl E. Allen, Miriam Merad
Journal: Immunity (2023)
Sunak’s smoke-free generation: spare a thought for the tobacco industry
Authors: Greg Hartwell, Anna B Gilmore, May C I van Schalkwyk, Martin McKee
Journal: BMJ (2023)

The UK prime minister's call for a smoke-free generation, which follows similar measures in New Zealand, 1 would have been unimaginable for previous Conservative leaders.Rishi Sunak's two immediate predecessors, Liz Truss and Boris Johnson, have already argued against the plan. 2 3 Their comments are likely to be a precursor of a major campaign, led by the tobacco industry and the thinktanks it funds, to undermine this proposal.Such groups may well be feeling increasingly confident after the new coalition government scrapped New Zealand's smoke-free plans-a move causing widespread dismay among health experts and dubbed "catastrophic" for Māori communities. 4 prevent the UK legislation-which will progressively increase the age at which tobacco products can be bought-from being watered down or similarly abandoned, it is essential that politicians, the media, and the health community anticipate the arguments and tactics that will be used against the plans.These are easy to identify given evidence showing the tobacco industry has repeatedly used the same tactics and arguments to block, amend, or delay previous legislation. 5Drawing on this extensive literature, 5 6 we highlight three main arguments that will be used and explain why they are spurious.
Author Correction: CIS is a potent checkpoint in NK cell–mediated tumor immunity
Authors: Rebecca B. Delconte, Tatiana B. Kolesnik, Laura F. Dagley, Jai Rautela, Wei Shi, Eva M. Putz, Kimberley Stannard, Jian-Guo Zhang, Charis Teh, Matt Firth, Takashi Ushiki, Christopher E. Andoniou, Mariapia A. Degli-Esposti, Phillip P. Sharp, Caroline E. Sanvitale, Giuseppe Infusini, Nicholas P. D. Liau, Edmond M. Linossi, Christopher J. Burns, Sebastian Carotta, Daniel H. D. Gray, Cyril Seillet, Dana S. Hutchinson, Gabrielle T. Belz, Andrew I. Webb, Warren S. Alexander, Shawn S. Li, Alex N. Bullock, Jeffrey J. Babon, Mark J. Smyth, Sandra E. Nicholson, Nicholas D. Huntington
Journal: Nature Immunology (2023)
Enhancing Language-Conditioned Policy Generalization with Behavioral Information
Authors: Longhui Cao, Chao Wang, Juntong Qi, Yan Peng
Journal: Cyborg and Bionic Systems (2023)

Generalizing policies learned by agents in known environments to unseen domains is an essential challenge in advancing the development of reinforcement learning. Lately, language-conditioned policies have underscored the pivotal role of linguistic information in the context of cross-environments. Integrating both environmental and textual information into the observation space enables agents to accomplish similar tasks across different scenarios. However, for entities with varying forms of motion but the same name present in observations (e.g., immovable mage and fleeing mage), existing methods are unable to learn the motion information the entities possess well. They face the problem of ambiguity caused by motion. In order to tackle this challenge, we propose the entity mapper with multi-modal attention based on behavior prediction (EMMA-BBP) framework, comprising modules for predicting motion behavior and text matching. The behavioral prediction module is used to determine the motion information of the entities present in the environment to eliminate the semantic ambiguity of the motion information. The role of the text-matching module is to match the text given in the environment with the information about the entity's behavior under observation, thus eliminating false textual information. EMMA-BBP has been tested in the demanding environment of MESSENGER, doubling the generalization ability of EMMA.
Development and characterization of NILK-2301, a novel CEACAM5xCD3 κλ bispecific antibody for immunotherapy of CEACAM5-expressing cancers
Authors: Anja Seckinger, Sara Majocchi, Valéry Moine, Lise Nouveau, Hoang Ngoc, Bruno Daubeuf, Ulla Ravn, Nicolas Pleche, Sebastien Calloud, Lucile Broyer, Laura Cons, Adeline Lesnier, Laurence Chatel, Anne Papaioannou, Susana Salgado-Pires, Sebastian Krämer, Ines Gockel, Florian Lordick, Krzysztof Masternak, Yves Poitevin, Giovanni Magistrelli, Pauline Malinge, Limin Shang, Sonja Kallendrusch, Klaus Strein, Dirk Hose
Journal: Journal of Hematology & Oncology (2023)

Abstract Background T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA). Methods We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). Results NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the “LALAPA” mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 ( E max = 89%), MKN-45 ( E max = 84%), and H2122 ( E max = 97%), with EC 50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice. Conclusions In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.
Benefits, harms and cost-effectiveness of cervical screening, triage and treatment strategies for women in the general population
Authors: Kate T. Simms, Adam Keane, Diep Thi Ngoc Nguyen, Michael Caruana, Michaela T. Hall, Gigi Lui, Cindy Gauvreau, Owen Demke, Marc Arbyn, Partha Basu, Nicolas Wentzensen, Beatrice Lauby-Secretan, Andre Ilbawi, Raymond Hutubessy, Maribel Almonte, Silvia De Sanjosé, Helen Kelly, Shona Dalal, Linda O. Eckert, Nancy Santesso, Nathalie Broutet, Karen Canfell
Journal: Nature Medicine (2023)

Abstract In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix , to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63–67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO’s updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.
Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy
Authors: Jae Kwang Yun, Sugyeong Kim, Hongyul An, Geun Dong Lee, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Sehoon Choi, Youngil Koh
Journal: Genome Medicine (2023)

Abstract Background Clonal hematopoiesis (CH) frequently progresses after chemotherapy or radiotherapy. We evaluated the clinical impact of preoperative CH on the survival outcomes of patients with non-small cell lung cancer (NSCLC) who underwent surgical resection followed by adjuvant therapy. Methods A total of 415 consecutive patients with NSCLC who underwent surgery followed by adjuvant therapy from 2011 to 2017 were analyzed. CH status was evaluated using targeted deep sequencing of blood samples collected before surgery. To minimize the possible selection bias between the two groups according to CH status, a propensity score matching (PSM) was adopted. Early-stage patients were further analyzed with additional matched cohort of patients who did not receive adjuvant therapy. Results CH was detected in 21% (86/415) of patients with NSCLC before adjuvant therapy. Patients with CH mutations had worse overall survival (OS) than those without (hazard ratio [95% confidence interval] = 1.56 [1.07–2.28], p = 0.020), which remained significant after the multivariable analysis (1.58 [1.08–2.32], p = 0.019). Of note, the presence of CH was associated with non–cancer mortality ( p = 0.042) and mortality of unknown origin ( p = 0.018). In patients with stage IIB NSCLC, there was a significant interaction on OS between CH and adjuvant therapy after the adjustment with several cofactors through the multivariable analysis (HR 1.19, 95% CI 1.00–1.1.41, p = 0.041). Conclusions In resected NSCLC, existence of preoperative CH might amplify CH-related adverse outcomes through adjuvant treatments, resulting in poor survival results.
Prediction of atrial fibrillation from at-home single-lead ECG signals without arrhythmias
Authors: Matteo Gadaleta, Patrick Harrington, Eric Barnhill, Evangelos Hytopoulos, Mintu P. Turakhia, Steven R. Steinhubl, Giorgio Quer
Journal: npj Digital Medicine (2023)

Abstract Early identification of atrial fibrillation (AF) can reduce the risk of stroke, heart failure, and other serious cardiovascular outcomes. However, paroxysmal AF may not be detected even after a two-week continuous monitoring period. We developed a model to quantify the risk of near-term AF in a two-week period, based on AF-free ECG intervals of up to 24 h from 459,889 patch-based ambulatory single-lead ECG (modified lead II) recordings of up to 14 days. A deep learning model was used to integrate ECG morphology data with demographic and heart rhythm features toward AF prediction. Observing a 1-day AF-free ECG recording, the model with deep learning features produced the most accurate prediction of near-term AF with an area under the curve AUC = 0.80 (95% confidence interval, CI = 0.79–0.81), significantly improving discrimination compared to demographic metrics alone (AUC 0.67; CI = 0.66–0.68). Our model was able to predict incident AF over a two-week time frame with high discrimination, based on AF-free single-lead ECG recordings of various lengths. Application of the model may enable a digital strategy for improving diagnostic capture of AF by risk stratifying individuals with AF-negative ambulatory monitoring for prolonged or recurrent monitoring, potentially leading to more rapid initiation of treatment.
Macromolecular Complex Including MLL3, Carabin and Calcineurin Regulates Cardiac Remodeling
Authors: Roberto Pane, Loubna Laib, Karina Formoso, Maximin Détrait, Yannis Sainte-Marie, Florence Bourgailh, Nolan Ruffenach, Hanamée Faugeras, Ilias Simon, Emeline Lhuillier, Frank Lezoualc’h, Caroline Conte
Journal: Circulation Research (2023)

Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include extensive gene reprogramming, which is dependent on epigenetic regulation and chromatin remodeling. However, the chromatin remodelers and their regulatory functions involved in the pathogenesis of cardiac hypertrophy are not well characterized.
LncRNA <i>PSMB8-AS1</i> Instigates Vascular Inflammation to Aggravate Atherosclerosis
Authors: Shu Li, Run-Chao He, Shao-Guo Wu, Yu Song, Ke-Lan Zhang, Mao-Lin Tang, Yan-Rou Bei, Ting Zhang, Jin-Bo Lu, Xin Ma, Min Jiang, Liang-Jun Qin, Yudan Xu, Xian-Hui Dong, Jia Wu, Xiaoyan Dai, Yan-Wei Hu
Journal: Circulation Research (2023)

Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA,
Re-“Formate” T-cell Antitumor Responses
Authors: Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho
Journal: Cancer Discovery (2023)

Summary: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti–PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al., p. 2566 (8).
<i>Gelling</i>Bodies: Understanding the Mechanisms Underlying Arsenic Trioxide Action
Authors: Paolo Salomoni
Journal: Cancer Discovery (2023)

Summary: The study by Bercier and colleagues investigates the mechanisms of action of arsenic trioxide (ATO). The authors find that ATO promotes transition of PML nuclear bodies to a gel-like state via the PML trimerization domain and a critical cysteine residue. Overall, this work sheds new light onto how PML–RARα, the oncogene of APL, is targeted by ATO for disease eradication. See related article by Bercier et al., p. 2548 (6).
Cancer in 2023
Journal: Cancer Discovery (2023)

Summary: Excerpts from the 13th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to U.S. Congress and the public highlight current challenges in achieving the goal of the Cancer Moonshot to reduce the cancer death rate in the United States by 50% by 2047 and a call to action for robust, sustained support of medical research funding is issued.
Muscle and fat composition in patients with newly diagnosed multiple myeloma
Authors: Nadine H. Abdallah, Hiroki Nagayama, Naoki Takahashi, Wilson Gonsalves, Amie Fonder, Angela Dispenzieri, David Dingli, Francis K. Buadi, Martha Q. Lacy, Miriam Hobbs, Morie A. Gertz, Moritz Binder, Prashant Kapoor, Rahma Warsame, Suzanne R. Hayman, Taxiarchis Kourelis, Yi L. Hwa, Yi Lin, Robert A. Kyle, S. Vincent Rajkumar, Stephen M. Broski, Shaji K. Kumar
Journal: Blood Cancer Journal (2023)

Abstract Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010–2019 who had an 18 F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively ( P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively ( P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics.
Prognostic Models in Nephrology: Where Do We Stand and Where Do We Go from Here? Mapping Out the Evidence in a Scoping Review
Authors: Jet Milders, Chava L. Ramspek, Roemer J. Janse, Willem Jan W. Bos, Joris I. Rotmans, Friedo W. Dekker, Merel van Diepen
Journal: Journal of the American Society of Nephrology (2023)

Prognostic models can strongly support individualized care provision and well-informed shared decision making. There has been an upsurge of prognostic research in the field of nephrology, but the uptake of prognostic models in clinical practice remains limited. Therefore, we map out the research field of prognostic models for kidney patients and provide directions on how to proceed from here. We performed a scoping review of studies developing, validating, or updating a prognostic model for patients with CKD. We searched all published models in PubMed and Embase and report predicted outcomes, methodological quality, and validation and/or updating efforts. We found 602 studies, of which 30.1% concerned CKD populations, 31.6% dialysis populations, and 38.4% kidney transplantation populations. The most frequently predicted outcomes were mortality ( n =129), kidney disease progression ( n =75), and kidney graft survival ( n =54). Most studies provided discrimination measures (80.4%), but much less showed calibration results (43.4%). Of the 415 development studies, 28.0% did not perform any validation and 57.6% performed only internal validation. Moreover, only 111 models (26.7%) were externally validated either in the development study itself or in an independent external validation study. Finally, in 45.8% of development studies no useable version of the model was reported. To conclude, many prognostic models have been developed for patients with CKD, mainly for outcomes related to kidney disease progression and patient/graft survival. To bridge the gap between prediction research and kidney patient care, patient-reported outcomes, methodological rigor, complete reporting of prognostic models, external validation, updating, and impact assessment urgently need more attention.
Noninvasive and Multicancer Biomarkers: The Promise of LINE-1 Retrotransposons
Authors: Aurelien J. Doucet, Gael Cristofari
Journal: Cancer Discovery (2023)

LINE-1 retrotransposons are frequently active in epithelial tumors. In a new study, Taylor, Wu and colleagues now describe that one of the proteins encoded by LINE-1 elements, ORF1p, is detected in the bloodstream of patients with cancer, and can be used as a noninvasive and multicancer biomarker for diagnosis or treatment monitoring. See related article by Taylor, Wu et al., p. 2532 (7).