tbuckley/cabot-search huggingface dataset:
Models for the marrow: A comprehensive review of AI‐based cell classification methods and malignancy detection in bone marrow aspirate smears
Authors: Tabita Ghete, Farina Kock, Martina Pontones, David Pfrang, Max Westphal, Henning Höfener, Markus Metzler
Journal: HemaSphere (2024)

Abstract Given the high prevalence of artificial intelligence (AI) research in medicine, the development of deep learning (DL) algorithms based on image recognition, such as the analysis of bone marrow aspirate (BMA) smears, is rapidly increasing in the field of hematology and oncology. The models are trained to identify the optimal regions of the BMA smear for differential cell count and subsequently detect and classify a number of cell types, which can ultimately be utilized for diagnostic purposes. Moreover, AI is capable of identifying genetic mutations phenotypically. This pipeline has the potential to offer an accurate and rapid preliminary analysis of the bone marrow in the clinical routine. However, the intrinsic complexity of hematological diseases presents several challenges for the automatic morphological assessment. To ensure general applicability across multiple medical centers and to deliver high accuracy on prospective clinical data, AI models would require highly heterogeneous training datasets. This review presents a systematic analysis of models for cell classification and detection of hematological malignancies published in the last 5 years (2019–2024). It provides insight into the challenges and opportunities of these DL‐assisted tasks.
Controversies and insights into PTBP1-related astrocyte-neuron transdifferentiation: neuronal regeneration strategies for Parkinson’s and Alzheimer’s disease
Authors: Simon McDowall, Vaishali Bagda, Stuart Hodgetts, Frank Mastaglia, Dunhui Li
Journal: Translational Neurodegeneration (2024)

Abstract Promising therapeutic strategies are being explored to replace or regenerate the neuronal populations that are lost in patients with neurodegenerative disorders. Several research groups have attempted direct reprogramming of astrocytes into neurons by manipulating the expression of polypyrimidine tract-binding protein 1 (PTBP1) and claimed putative converted neurons to be functional, which led to improved disease outcomes in animal models of several neurodegenerative disorders. However, a few other studies reported data that contradict these claims, raising doubt about whether PTBP1 suppression truly reprograms astrocytes into neurons and the therapeutic potential of this approach. This review discusses recent advances in regenerative therapeutics including stem cell transplantations for central nervous system disorders, with a particular focus on Parkinson’s and Alzheimer’s diseases. We also provide a perspective on this controversy by considering that astrocyte heterogeneity may be the key to understanding the discrepancy in published studies, and that certain subpopulations of these glial cells may be more readily converted into neurons.
Children exhibit a robust B-cell response to Omicron BA.2 after breakthrough infection with limited influence from the original antigenic sin
Authors: Zhiyang Ling, Zhangqian Zheng, Lingli Xu, Chunyan Yi, Xinran Dong, Xiaoqiong Gu, Xiaoyu Sun, Bingbing Wu, Bing Sun, Wenhao Zhou
Journal: Cellular and Molecular Immunology (2024)
Autologous non‐myeloablative hematopoietic stem cell transplantation for diffuse cutaneous systemic sclerosis: identifying disease risk factors for toxicity and long‐term outcomes in a prospective, single‐arm trial
Authors: George E Georges, Dinesh Khanna, Mark H Wener, Matthew G Mei, Maureen D Mayes, Robert W Simms, Vaishali Sanchorawala, Chitra Hosing, Suzanne Kafaja, Attaphol Pawarode, Leona A Holmberg, Jason Kolfenbach, Daniel E Furst, Keith M Sullivan, Suiyuan Huang, Ted Gooley, Richard A Nash
Journal: Arthritis & Rheumatology (2024)

Objective Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event‐free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSC) compared to monthly cyclophosphamide. We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of CD34+ selected graft, could provide comparable AHSCT outcomes. Methods 20 patients with high‐risk SSc were enrolled in a prospective, single‐arm trial with cyclophosphamide 200 mg/kg and horse anti‐thymocyte globulin (CY200/ATG), followed by unmanipulated autologous PBSC, then MMF maintenance starting at 2 months after AHSCT. Results Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% CI, 60.4%‐94.9%) and 75% (95% CI, 50%‐88.7%), respectively. Median follow‐up was 7.5 years (range, 5.6‐11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant‐related mortality occurred in 2 patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of 9 patients with anti‐RNA polymerase‐III antibody had both prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) upon study entry; all 4 patients developed prolonged organ failure/death early post‐transplant. Conclusion We observed favorable OS and EFS after AHSCT for SSc patients, using CY200/ATG, unmanipulated PBSC and MMF post‐transplant maintenance, that was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcome after AHSCT.
Efficacy of a TNF inhibitor in chronic low back pain with Modic changes type 1: The BackToBasic study A randomized controlled trial
Authors: Elisabeth Gjefsen, Lars C. Bråten, Erica Ponzi, Magnhild H. Dagestad, Gunn H. Marchand, Thomas Kadar, Gunnstein Bakland, Anne J. Haugen, Fredrik Granviken, Tonje W. Flørenes, Nils Vetti, Lars Grøvle, Aksel T. Nilsen, Astrid Lunestad, Thor E. Holmgard, Morten Valberg, Nils Bolstad, Ansgar Espeland, Jens I. Brox, Guro L. Goll, Kjersti Storheim, John‐Anker Zwart
Journal: Arthritis & Rheumatology (2024)

Objective The efficacy of TNF inhibitors for treating chronic low back pain with Modic changes is uncertain. This study investigated the superiority of infliximab over placebo in patients with Modic changes type 1. Methods In this multicenter, randomized, triple‐blind, placebo‐controlled trial, patients aged 18‐65 with moderate to severe chronic low back pain and Modic changes type 1 were enrolled from five Norwegian public hospitals between January 2019 and October 2022. Participants were randomly assigned to four intravenous infusions of 5 mg/kg infliximab or placebo. The primary outcome was difference in change in the Oswestry Disability Index (ODI) score from baseline to 5 months. Secondary outcomes included changes in low back pain intensity, disability, and health‐related quality of life. A linear mixed model was used for efficacy analyses. Results 128 patients (mean age 43 years, 65.6% women) participated (64 in each group). All patients who received at least one dose of the allocated infusion were included in the primary analyses. The average ODI score change was ‐7.0 (9.7) in the infliximab group and ‐6.4 (10.4) in the placebo group. The difference in the ODI change between the two groups was 1.3 ODI points (95% CI, ‐2.1 to 4.6; p= 0.45). Analyses showed no effect of infliximab compared to placebo on secondary outcomes. Adverse event rates were similar between groups. Conclusions Infliximab did not demonstrate superiority over placebo in reducing pain‐related disability in patients with moderate to severe chronic low back pain with Modic changes type 1 at 5 months. image
Development of Extra‐Musculoskeletal Manifestations in Upadacitinib‐Treated Patients With Psoriatic Arthritis or Axial Spondyloarthritis
Authors: Denis Poddubnyy, Bhumik Parikh, Dirk Elewaut, Victoria Navarro‐Compán, Stefan Siebert, Michael Paley, Derek Coombs, Ivan Lagunes, Ana Biljan, Priscila Nakasato, Peter Wung, Ennio Lubrano
Journal: Arthritis & Rheumatology (2024)

Objective Assess the development of extra‐musculoskeletal manifestations (EMMs) among patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) treated with upadacitinib 15 mg (UPA15). Methods Data (cutoff: 15August2022) from 5 clinical trials in PsA (2), radiographic axSpA (r‐axSpA; previously ankylosing spondylitis) (2), and non‐radiographic axSpA (nr‐axSpA) (1) were analyzed. Treatment‐emergent adverse events of EMMs including uveitis, inflammatory bowel disease (IBD), and psoriasis were assessed in patients treated with placebo (PBO), UPA15, or adalimumab (ADA; PsA only) and are reported as exposure‐adjusted event rates (events/100 patient‐years [E/100 PY]). Results Most patients (87.1%‐99.3%) did not have a history of EMMs at baseline. In PsA, development of uveitis and IBD were low regardless of treatment or prior EMM history; rates were similar with UPA15 and ADA. In r‐axSpA, development of uveitis was numerically lower (E/100 PY) in patients treated with UPA15 (2.8) versus PBO (7.5) and in patients with no history of uveitis (UPA15: 0.6; PBO: 1.2) versus a history (UPA15: 2.1; PBO: 6.2); occurrence of IBD and psoriasis were low regardless of treatment or prior history. In nr‐axSpA, development of uveitis was low regardless of history, but was numerically lower in patients treated with UPA15 (0.9) versus PBO (2.1); occurrence of IBD and psoriasis were low/absent. Conclusion In patients with spondyloarthritis, development of EMMs was generally low with UPA15. Uveitis was numerically lower in patients treated with UPA15 versus PBO, and particularly in r‐axSpA. Regardless of treatment in r‐axSpA, having a history of uveitis appeared to predispose patients for future uveitis events. image
CEA-Induced PI3K/AKT Pathway Activation through the Binding of CEA to KRT1 Contributes to Oxaliplatin Resistance in Gastric Cancer
Authors: Yifan Chen, Yulong Mi, Song Tan, Yizhen Chen, Shaolin Liu, Shengtao Lin, Changshun Yang, Weifeng Hong, Weihua Li
Journal: Drug Resistance Updates (2024)
Evaluating renal disease in pediatric‐onset anti‐neutrophil cytoplasmic antibody‐associated vasculitis: disease course, outcomes, and predictors of outcome
Authors: Kirandeep K. Toor, Audrea Chen, David A. Cabral, Cherry Mammen, Else S. Bosman, Ye Shen, Jeffrey N. Bone, Damien Noone, Eslam Al‐Abadi, Susanne Benseler, Roberta Berard, Marek Bohm, Sirirat Charuvanij, Kathryn Cook, Paul Dancey, Samundeeswari Deepak, Ciaran Duffy, Barbara Eberhard, Melissa Elder, Dirk Foell, Dana Gerstbacher, Merav Heshin‐Bekenstein, Adam Huber, Karen E. James, Susan Kim, Marisa Klein‐Gitelman, Neil Martin, Flora McErlane, L. Nandini Moorthy, Charlotte Myrup, Phil Riley, Susan Shenoi, Vidya Sivaraman, Tamara Tanner, Stacey Tarvin, Linda Wagner‐Weiner, Rae S. M. Yeung, Kelly L. Brown, Kimberly A. Morishita
Journal: Arthritis & Rheumatology (2024)

Objectives We aimed to study the disease course, outcomes, and predictors of outcome in pediatric‐onset anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) affecting the kidneys. Methods Patients eligible for this study had a diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or ANCA positive pauci‐immune glomerulonephritis, were ≤ 18 years at diagnosis, had renal disease defined by biopsy or dialysis dependence, and had clinical data at diagnosis and either 12‐ or 24‐months. Ambispective data from the ARChiVE/PedVas Registry was used. The primary outcome was inactive renal disease (PVAS = 0 or 1) at 12‐months. Secondary outcomes included rates of improved renal function and damage within 24‐months. Renal function, defined by estimated glomerular filtration rate (eGFR), was categorized into KDIGO (Kidney Disease Improving Global Outcomes) stages at diagnosis and tested as a predictor of outcome using a proportional odds logistic regression model. Results 145 patients were included. 68% were female, 78% had GPA. At 12‐months, 83% of patients achieved inactive renal disease; however, 42% had evidence of permanent renal damage. Compared to patients with normal renal function at diagnosis, patients with moderate‐to‐severely reduced renal function, or kidney failure at diagnosis had an odds ratio of 8.62 ( p= 0.002, 95% CI: 2.31, 32.1) and 26.3 (p &lt;0.001, 95% CI: 6.32, 109), respectively, for being in a worse KDIGO category at 12‐months. Conclusion The majority of pediatric‐AAV patients achieve inactive renal disease by 12‐months; however, almost half have evidence of damage. Renal function at diagnosis is a strong predictor of renal function at 12‐months. image
Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development
Authors: Bong Chan Jeon, Yu-Ji Kim, Ae Kyung Park, Mi-Ran Song, Ki Myeong Na, Juwon Lee, Dasom An, Yeseul Park, Heeyoun Hwang, Tae-Don Kim, Junghyun Lim, Sung-Kyun Park
Journal: Cellular and Molecular Immunology (2024)
Cost-effectiveness and return on investment of hepatitis C virus elimination in China: A modelling study
Authors: Meiyu Wu, Jing Ma, Xuehong Wang, Sini Li, Chongqing Tan, Ouyang Xie, Andong Li, Aaron G Lim, Xiaomin Wan
Journal: Clinical and Molecular Hepatology (2024)

The WHO set the goal of eliminating hepatitis C virus (HCV) by 2030, with 80% and 65% reductions in HCV incidence and mortality rates, respectively. We aimed to evaluate the health benefits, cost-effectiveness and return on investment (ROI) of HCV elimination. Using an HCV transmission compartmental model, we evaluated the benefits and costs of different strategies combining screening and treatment for Chinese populations. We identified strategies to achieve HCV elimination and calculated the incremental cost-effectiveness ratios (ICERs) per disability-adjusted life year (DALY) averted for 2022-2030 to identify the optimal elimination strategy. Furthermore, we estimated the ROI by 2050 by comparing the required investment with the economic productivity gains from reduced HCV incidence and deaths. The strategy that results in the most significant health benefits involves conducting annual primary screening at a rate of 14%, re-screening people who inject drugs (PWID) annually and the general population every five years, and treating 95% of those diagnosed (P14-R4-T95), preventing approximately 5.75 and 0.44 million HCV infections and deaths, respectively, during 2022-2030. At a willingness-to-pay threshold of $12,615, the P14-R4-T95 strategy is the most cost-effective, with an ICER of $5,449/DALY. By 2050, this strategy would have a net benefit of $120,997 million (ROI=0.868). Achieving HCV elimination in China by 2030 will require significant investment in large-scale universal screening and treatment, but it will yield substantial health and economic benefits and is cost effective.
Constructing a Metal–Organic Frameworks‐Based Long‐Acting Sequential Release System for the Treatment of Alzheimer's Disease
Authors: Qi Ding, Yun Zhao, Enpeng Xi, Kangning Liu, Nan Gao, Guangshan Zhu
Journal: Advanced Healthcare Materials (2024)

Abstract Due to the unclear pathogenesis of Alzheimer's disease (AD) and the lack of a completely cured medication, AD patients need to take medication in order and on time every day all one's life, which is difficult for severe memory impairment patients to strictly follow on time. Traditional AD drug carriers, such as sugar coating and capsules, rely on dissolution or fragmentation to achieve drug release, which lacks the interaction between drug molecules and carriers, thus they cannot achieve sufficient long‐acting and sequential drug release. Herein, Mn‐MOF‐74, which ligand structure is similar to two antioxidants dihydroquercetin (DHQ) and resveratrol (Res) is chosen as the carrier. Due to the differences in adsorption energy between DHQ/MOF and Res/MOF, the release speed of DHQ is much faster than Res. Therefore, Mn‐MOF‐74 loaded with DHQ and Res (DR@MOF) showed sequential drug release and a long‐term antioxidant effect for ≈72 h, with an efficacy time six times longer than that of vitamin E. In 5×FAD transgenic mice, DR@MOF exhibited excellent capacity in maintaining oxidative balance in the brain, ameliorating spatial learning and memory deficits, and showed the potential of an AD agent for long‐acting and sequential treatment.
Acute Three‐Dimensional Hypoxia Regulates Angiogenesis
Authors: Dimitris Ntekoumes, Jiyeon Song, Haohao Liu, Connor Amelung, Ya Guan, Sharon Gerecht
Journal: Advanced Healthcare Materials (2024)

Abstract Hypoxia elicits a multitude of tissue responses depending on the severity and duration of the exposure. While chronic hypoxia is shown to impact development, regeneration, and cancer, the understanding of the threats of acute (i.e., short‐term) hypoxia is limited mainly due to its transient nature. Here, a novel gelatin‐dextran (Gel‐Dex) hydrogel is established that decouples hydrogel formation and oxygen consumption and thus facilitates 3D sprouting from endothelial spheroids and, subsequently, induces hypoxia “on‐demand.” The Gel‐Dex platform rapidly achieves acute moderate hypoxic conditions without compromising its mechanical properties. Acute exposure to hypoxia leads to increased endothelial cell migration and proliferation, promoting the total length and number of vascular sprouts. This work finds that the enhanced angiogenic response is mediated by reactive oxygen species, independently of hypoxia‐inducible factors. Reactive oxygen species‐dependent matrix metalloproteinases activity mediated angiogenic sprouting is observed following acute hypoxia. Overall, the Gel‐Dex hydrogel offers a novel platform to study how “on‐demand” acute moderate hypoxia impacts angiogenesis, with broad applicability to the development of novel sensing technologies.
Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies
Authors: Zhongfei Tao, Zuzana Chyra, Jana Kotulová, Piotr Celichowski, Jana Mihályová, Sandra Charvátová, Roman Hájek
Journal: Blood Cancer Journal (2024)

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.
Nicotinamide N‐methyltransferase negatively regulates metastasis‐promoting property of cancer‐associated fibroblasts in lung adenocarcinoma
Authors: Peiyu Wang, Guangxi Wang, Haoran Li, Yuyao Yuan, Haiming Chen, Shaodong Wang, Zewen Sun, Fanjie Meng, Yun Li, Fan Yang, Jun Wang, Kezhong Chen, Mantang Qiu
Journal: Cancer Communications (2024)

Abstract Background Recurrence and metastasis remain significant challenges in lung adenocarcinoma (LUAD) after radical resection. The mechanisms behind the recurrence and metastasis of LUAD remain elusive, and deregulated cellular metabolism is suspected to play a significant role. This study explores the metabolic and epigenetic regulation mediated by nicotinamide N‐methyl transferase (NNMT) in LUAD. Methods Untargeted metabolomic analyses were performed to detect metabolism irregularities. Single‐cell RNA sequencing (RNA‐seq) databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment. The biological functions of NNMT were investigated both in vitro and in vivo, with RNA‐seq and chromatin immunoprecipitation‐PCR providing insights into underlying mechanisms. Finally, single‐cell RNA‐seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings. Results Untargeted metabolomic analyses revealed metabolic aberrations in amino acids, organic acids, lipids, and nicotinamide pathways, which are linked to metastasis of non‐small cell lung cancer. NNMT is a key enzyme in nicotinamide metabolism, and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis. NNMT was proved to be predominantly expressed in cancer‐associated fibroblasts (CAFs) within the stromal regions of LUAD, and a low stromal NNMT expression was identified as a predictor of poor disease‐free survival following radical resection of LUAD. The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments, which confirmed that NNMT negatively regulated the metastasis‐promoting properties of CAFs in LUAD. Mechanistically, the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle, resulting in heightened methylation at H3K4me3. This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs, including those encoding collagens, integrins, laminins, and matrix metalloproteinases, thereby facilitating cancer cell invasion and metastasis. Reanalysis of single‐cell RNA‐seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT's negative regulation of these genes in CAFs. Conclusions This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs, expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.