tbuckley/cabot-search huggingface dataset:
Dementia with lewy bodies patients with high tau levels display unique proteome profiles
Authors: Sinead Greally, Mukesh Kumar, Christoph Schlaffner, Hanne van der Heijden, Elisabeth S. Lawton, Deeptarup Biswas, Sabina Berretta, Hanno Steen, Judith A. Steen
Journal: Molecular Neurodegeneration (2024)

Abstract Background Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer’s disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level. Methods Quantitative mass spectrometry analysis was used to measure protein abundance in the insoluble fraction from cortical brain tissue from pathologically diagnosed DLB subjects ( n = 30) and age-matched controls ( n = 29). Using tau abundance, we stratified the DLB subjects into two subgroups termed DLBTau + (higher abundance) and DLBTau − (lower abundance). We conducted proteomic analysis to characterize and compare the cortical proteome of DLB subjects exhibiting elevated tau, as well as the molecular modifications of tau and α-synuclein to explore the dynamic between tau and α-synuclein pathology in these patients. Results Proteomic analyses revealed distinct global protein dysregulations in DLBTau + and DLBTau − subjects when compared to controls. Notably, DLBTau + patients exhibited increased levels of tau, along with ubiquitin, and APOE, indicative of cortical proteome alterations associated with elevated tau. Comparing DLBTau + and DLBTau − groups, we observed significant upregulation of cytokine signaling and metabolic pathways in DLBTau − patients, while DLBTau + subjects showed increases in protein ubiquitination processes and regulation of vesicle-mediated transport. Additionally, we examined the post-translational modification patterns of tau and α-synuclein. Our analysis revealed distinct phosphorylation and ubiquitination sites on α-synuclein between groups. Moreover, we observed increased modifications on tau specifically within the DLBTau + subgroup. Conclusion This molecular-level data supports the idea of neurodegenerative disease as a continuum of diseases with distinct PTM profiles DLBTau + and DLBTau − patients in comparison to AD. These findings further emphasize the importance of identifying specific and tailored therapeutic approaches targeting the involved proteopathies in the neurodegenerative disease spectrum.
Mortality after high‐risk myocardial infarction over the last 20 years: Insights from the <scp>VALIANT</scp> and <scp>PARADISE</scp>‐<scp>MI</scp> trials
Authors: Alberto Foà, Maria A. Pabon, Eugene Braunwald, Karola Jering, Muthiah Vaduganathan, Brian L. Claggett, Lars Køber, Eldrin F. Lewis, Christopher B. Granger, Peter van der Meer, Jean L. Rouleau, Aldo P. Maggioni, John J.V. McMurray, Scott D. Solomon, Marc A. Pfeffer
Journal: European Journal of Heart Failure (2024)
Local glycolysis-modulating hydrogel microspheres for a combined anti-tumor and anti-metastasis strategy through metabolic trapping strategy
Authors: Huijie Han, Shiqi Wang, Mohammad-Ali Shahbazi, Yawei Du, Inge S Zuhorn, Jiachen Li, Jie Chen, Yu Chen, Raquel Bártolo, Wenguo Cui, Hélder A Santos
Journal: Journal of Controlled Release (2024)
Regulating tumor cells to awaken T cell antitumor function and enhance melanoma immunotherapy
Authors: Weihan Zhang, Shijun Yuan, Zipeng Zhang, Shunli Fu, Shujun Liu, Jinhu Liu, Qingping Ma, Zhenxing Xia, Panpan Gu, Shuying Gao, Zhiyue Zhang, Xinke Zhang, Yongjun Liu, Na Zhang
Journal: Biomaterials (2024)
Adenoviral-vectored neoantigen vaccine augments hyperexpanded CD8<sup>+</sup>T cell control of tumor challenge in mice
Authors: Gabriel Dagotto, Alessandro Colarusso, Robert C Patio, David Li, Tochi Anioke, Victoria Giffin, Ruoran Guan, Trisha Anand, Esther Mbiwan, Malika Aid, Dan Barouch
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Neoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8 + T cell responses as vaccines against SARS-CoV-2, Ebola, and Zika, but their utility as neoantigen delivery vectors remains largely unexplored. In this study, we examine how an Ad-vectored neoantigen vaccine would impact tumor immunity compared with a peptide neoantigen vaccine. Methods We generated Ad serotype 26 (Ad26) vaccine candidates encoding B16-F10-ovalbumin (OVA) and MC38-specific neoantigens. Ad26 vaccines were compared with adjuvanted peptide delivery as prophylactic vaccines in B16-F10-OVA and MC38 challenge models. Immune responses induced by the best Ad26 vaccine (Ad26.VP22.7Epi) were compared with peptide vaccination systemically and within the tumor. Following vaccination with Ad26.VP22.7Epi, peptide, or sham, tumor-infiltrating CD45 + cells were analyzed using single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) to identify vaccine-induced differences in the tumor microenvironment. Results Single-shot Ad26 vaccines induced greater neoantigen-specific interferon-γ CD8 + T cell immune responses than two-shot adjuvanted peptide vaccines in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared with the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8 + T cell response against the Adpgk neoantigen, while the peptide vaccine-induced lower responses against both Adpgk and Reps1 neoantigens. scRNA-seq analysis of CD45 + tumor-infiltrating cells demonstrated that both Ad26.VP22.7Epi and peptide vaccine-induced similar numbers of infiltrating CD8 + T cells. However, Ad26.VP22.7Epi induced CD8 + T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared with peptide vaccine induced CD8 + T cells, suggesting improved functional T cell quality. TCR-seq of these tumor-infiltrating lymphocytes also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared with the peptide vaccine. Conclusions These results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8 + T cell responses and not only maximizing tumor infiltrating CD8 + T cell numbers.
Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn’s disease
Authors: Ju-Hyun Ahn, Marlus da Silva Pedrosa, Lacey R Lopez, Taylor N Tibbs, Joanna N Jeyachandran, Emily E Vignieri, Aaron Rothemich, Ian Cumming, Alexander D Irmscher, Corey J Haswell, William C Zamboni, Yen-Rei A Yu, Melissa Ellermann, Lee A Denson, Janelle C Arthur
Journal: Cell Host & Microbe (2024)
Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen
Authors: Esperanza Esquinas, Alvaro Moreno-Sanz, Victor Sandá, Damian Stodulski-Ciesla, Jennifer Borregón, Virginia Peña-Blanque, Javier Fernández-Calles, Narcis Fernandez-Fuentes, Juana Serrano-Lopez, Manel Juan, Pablo Engel, Pilar Llamas-Sillero, Laura Solán-Blanco, Beatriz Martin-Antonio
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results. Methods We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen’s expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)). Results We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19 − relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen. Conclusions Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.
Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics
Authors: Siyuan Wang, Fan Peng, Miao Dang, Huanmin Jiao, Huanqin Zhang, Kaixiang Zhou, Wenjie Guo, Zhiyun Gong, Lin Guo, Renquan Lu, Deliang Li, Bingrong Liu, Xu Guo, Jinliang Xing, Yang Liu
Journal: Gut (2024)

Early detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients.
Evaluation of immune checkpoint inhibitor efficacy for solid tumors with<i>CD274</i>(PD-L1 gene) amplification identified by comprehensive genomic profiling: retrospective study based on a nationwide database
Authors: Tomohiro Nakayama, Takayuki Takahama, Yasutaka Chiba, Naoki Shiraishi, Hisato Kawakami, Kimio Yonesaka, Kazuhiko Nakagawa, Hidetoshi Hayashi
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Amplification of the programmed cell death-ligand 1 gene ( CD274 ) is highly prevalent and associated with a high response rate to immune checkpoint inhibitors (ICIs) in lymphomas, and is also a potential biomarker for ICI treatment of solid tumors. However, the efficacy of ICIs for solid tumors with CD274 amplification identified by comprehensive genomic profiling (CGP) has been unclear. We here examined ICI efficacy for solid tumors with CD274 amplification identified by CGP in a national database. Methods We retrospectively analyzed data from the Center for Cancer Genomics and Advanced Therapeutics database containing 60,155 CGP test results for individuals with solid tumors. Only clinical data from patients treated with ICIs alone (not those undergoing concomitant therapy with molecularly targeted or cytotoxic chemotherapeutic agents) were evaluated. We matched 48 patients in the CD274 amplification-positive group with 170 patients in the CD274 amplification-negative group in a 1:4 ratio based on tumor type, histology, treatment, and age. Overall survival (OS), time to next treatment (TTNT), and response rate were evaluated as treatment outcomes in the two groups. Results OS was similar in the CD274 -amplified and matched CD274 -non-amplified groups (median of 22.1 vs 26.3 months, respectively; HR of 0.92 with a 95% CI of 0.55 to 1.54; p=0.075). TTNT tended to be longer in the CD274 -amplified group than in the matched CD274 -non-amplified group (median of 16.5 vs 14.0 months; HR of 0.63 with a 95% CI of 0.37 to 1.08; p=0.091). The objective response rate was 33.3% and 18.4% (difference of 14.9%, with a 95% CI of –0.2% to 31.6%), and the disease control rate was 63.9% and 41.1% (difference of 22.8%, with a 95% CI of 5.1% to 40.4%), in the CD274 -amplified and matched CD274 -non-amplified groups, respectively. Conclusions The number of patients with solid tumors positive for CD274 amplification in this analysis is the largest to date, and our results suggest that such gene amplification may be associated with the outcome of ICI treatment in such individuals. CD274 amplification identified by CGP may therefore be a predictor of ICI efficacy for solid tumors. Trial registration number UMIN000029779.
Association of cardiorespiratory fitness with the incidence and progression trajectory of cardiometabolic multimorbidity
Authors: Yanchun Chen, Hongxi Yang, Dun Li, Lihui Zhou, Jing Lin, Xin Yin, Weiling Yang, Ying Gao, Qing Zhang, Sean X Leng, Yaogang Wang
Journal: British Journal of Sports Medicine (2024)

Objectives This study examined the relationship of cardiorespiratory fitness (CRF) in the transition from healthy status to first cardiometabolic disease, subsequent cardiometabolic multimorbidity and further to death. Methods We used data from the UK Biobank of 47 484 participants without cardiometabolic diseases at baseline. CRF was assessed via a 6 min incremental ramp cycle ergometer test and expressed in metabolic equivalent of tasks (METs, 1 MET=3.5 mL/kg/min). Cardiometabolic multimorbidity was defined as at least two diseases among diabetes, hypertension, coronary heart disease and stroke. Results Over 12.5 years median follow-up, 8123 participants developed first cardiometabolic disease, 1958 developed cardiometabolic multimorbidity and 2177 died. CRF was associated with different transition stages in cardiometabolic multimorbidity development. The HRs (95% CIs) per MET increase in CRF were 0.94 (0.93 to 0.95) and 0.97 (0.96 to 0.99) for transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity. Per MET increase in CRF was associated with reduced risk of transition from healthy baseline to death (HR: 0.97, 95% CI 0.95 to 0.99), but not for the transition from first cardiometabolic disease and cardiometabolic multimorbidity to death. When first cardiometabolic disease was divided into specific cardiometabolic diseases, there were comparable trends of CRF on the disease-specific transitions from healthy baseline to first cardiometabolic disease and subsequent cardiometabolic multimorbidity. Conclusion Higher CRF was associated with a lower risk of progression from a healthy state to first cardiometabolic disease and subsequently to cardiometabolic multimorbidity. These findings suggest that improving CRF is a potential strategy for preventing cardiometabolic multimorbidity development.
Tackling algorithmic bias and promoting transparency in health datasets: the STANDING Together consensus recommendations
Authors: Joseph E Alderman, Joanne Palmer, Elinor Laws, Melissa D McCradden, Johan Ordish, Marzyeh Ghassemi, Stephen R Pfohl, Negar Rostamzadeh, Heather Cole-Lewis, Ben Glocker, Melanie Calvert, Tom J Pollard, Jaspret Gill, Jacqui Gath, Adewale Adebajo, Jude Beng, Cassandra H Leung, Stephanie Kuku, Lesley-Anne Farmer, Rubeta N Matin, Bilal A Mateen, Francis McKay, Katherine Heller, Alan Karthikesalingam, Darren Treanor, Maxine Mackintosh, Lauren Oakden-Rayner, Russell Pearson, Arjun K Manrai, Puja Myles, Judit Kumuthini, Zoher Kapacee, Neil J Sebire, Lama H Nazer, Jarrel Seah, Ashley Akbari, Lew Berman, Judy W Gichoya, Lorenzo Righetto, Diana Samuel, William Wasswa, Maria Charalambides, Anmol Arora, Sameer Pujari, Charlotte Summers, Elizabeth Sapey, Sharon Wilkinson, Vishal Thakker, Alastair Denniston, Xiaoxuan Liu
Journal: The Lancet Digital Health (2024)
Personalized neoantigen hydrogel vaccine combined with PD-1 and CTLA-4 double blockade elicits antitumor response in liver metastases by activating intratumoral CD8<sup>+</sup>CD69<sup>+</sup>T cells
Authors: Shichuan Tang, Ruijing Tang, Geng Chen, Da Zhang, Kongying Lin, Huan Yang, Jun Fu, Yutong Guo, Fangzhou Lin, Xiuqing Dong, Tingfeng Huang, Jie Kong, Xiaowei Yin, Aimin Ge, Qizhu Lin, Ming Wu, Xiaolong Liu, Yongyi Zeng, Zhixiong Cai
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Liver metastasis is highly aggressive and immune tolerant, and lacks effective treatment strategies. This study aimed to develop a neoantigen hydrogel vaccine (NPT-gels) with high clinical feasibility and further investigate its efficacy and antitumor molecular mechanisms in combination with immune checkpoint inhibitors (ICIs) for the treatment of liver metastases. Methods The effects of liver metastasis on survival and intratumor T-cell subpopulation infiltration in patients with advanced tumors were investigated using the Surveillance, Epidemiology, and End Results Program (SEER) database and immunofluorescence staining, respectively. NPT-gels were prepared using hyaluronic acid, screened neoantigen peptides, and dual clinical adjuvants [Poly(I:C) and thymosin α-1]. Then, the efficacy and corresponding antitumor molecular mechanisms of NPT-gels combined with programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 double blockade (PCDB) for the treatment of liver metastases were investigated using various preclinical liver metastasis models. Results Liver metastases are associated with poorer 5-year overall survival, characterized by low infiltration of cytotoxic CD8 + T cells and high infiltration of regulatory T cells (Tregs). NPT-gels overcame the challenges faced by conventional neoantigen peptide vaccines by sustaining a durable, high-intensity immune response with a single injection and significantly improving the infiltration of neoantigen-specific T-cell subpopulations in different mice subcutaneous tumor models. Importantly, NPT-gels further combined with PCDB could enhance neoantigen-specific T-cell infiltration and effectively unlock the immunosuppressive microenvironment of liver metastases, showing superior antitumor efficacy and inducing long-term immune memory in various preclinical liver metastasis models without obvious toxicity. Mechanistically, the combined strategy can inhibit Tregs, induce the production and infiltration of neoantigen-specific CD8 + CD69 + T cells to enhance the immune response, and potentially elicit antigen-presenting effects in Naïve B_Ighd + cells and M1-type macrophages. Conclusions This study demonstrated that NPT-gels combined with PCDB could exert a durable and powerful antitumor immunity by enhancing the recruitment and activation of CD8 + CD69 + T cells, which supports the rationale and clinical translation of this combination strategy and provides important evidence for further improving the immunotherapy efficacy of liver metastases in the future.
Enhancing access to prostheses in sports: a call to action for the future of Paralympic athletes
Authors: Ashley Iain Simpson
Journal: British Journal of Sports Medicine (2024)

<h3>ABSTRACT</h3> Conjugative plasmids from the IncHI incompatibility group are relevant vectors for multidrug resistance. In this study, a comparison of the similarities and differences in the 44 publicly available sequences of IncHI plasmids from Enterobacteriaceae (1961-2013), revealed extensive conservation of their coding sequences. However, each genome had accessory regions with features of degradation or resistance to antibacterial agents. This article elucidates the IncHI1, IncHI2 and IncHI3 subgroup plasmids from the evolutive line based on multiple drug-resistant modules, explains the origin of the IncHI1 pAKU1-like composite transposon lineage, typifies the subgroup IncHI3, which is distantly related to IncHI1 and IncHI2 in phylogenetic analyses, confirms the relations within the transfer regions of H-group plasmids, and points to the divergence time of evolution with phylogenetic trees. Homology between subgroups, as measured by the molecular clock test, indicated that the contemporary IncHI1 and IncHI2 transfer region lineages diverged from an ancestral clone approximately 8,000 years ago (17,000 years ago if the divergent IncHI3 plasmids are included), although the IncH backbone was older. The uniformity of the composite transposon shared by most IncHI1 subgroup plasmids might be functionally equivalent to the heavy metal resistance that is mediated by some operons in the IncHI2 subgroup plasmids. A comparison of the DNA among these closely related plasmids provided insights on the horizontal and vertical transfers that were involved in their development.
Impact of postpartum exercise on pelvic floor disorders and diastasis recti abdominis: a systematic review and meta-analysis
Authors: Nicole F Beamish, Margie H Davenport, Muhammad Usman Ali, Matthew J Gervais, Talia Noel Sjwed, Gyanjot Bains, Allison Sivak, Rita E Deering, Stephanie-May Ruchat
Journal: British Journal of Sports Medicine (2024)

Objective To examine the effect of exercise during the first year postpartum on pelvic floor disorders and diastasis recti abdominis. Design Systematic review with random effects meta-analysis. Data sources: MEDLINE, EMBASE, CINAHL, SPORTDiscuss, Evidence-Based Medicine Reviews (Ovid), Scopus, Web of Science and ClinicalTrials.gov were searched until 12 January 2024. Eligibility criteria for selecting studies Studies of all designs (except case studies) and languages were included if they contained information on the Population (individuals in the first year postpartum), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise alone (‘exercise-only’) or in combination with other intervention (eg, biofeedback; ‘exercise+co-intervention’)), Comparator (no exercise or different exercise measures) and Outcome (symptom severity and risk of urinary incontinence, anal incontinence, pelvic organ prolapse, diastasis recti abdominis and sexual function). Results 65 studies (n=21 334 participants) from 24 countries were included. ‘Moderate’ certainty of evidence revealed that pelvic floor muscle training reduced the odds of urinary incontinence by 37% (seven randomised controlled trials (RCTs), n=1930; OR 0.63, 95% CI 0.41 to 0.97, I 2 72%) and pelvic organ prolapse by 56% (one RCT, n=123; OR 0.44, 95% CI 0.21 to 0.91) compared with control groups. ‘Low’ certainty of evidence showed a greater reduction in inter-rectus distance measured at rest and during a head lift following abdominal muscle training compared with no exercise. Evidence on the effect of exercise on the risk of anal incontinence and diastasis recti abdominis, as well as the severity of anal incontinence, urinary incontinence, pelvic organ prolapse and sexual function, is limited. Conclusion Evidence supports the effectiveness of postpartum pelvic floor muscle training in reducing the odds of urinary incontinence and pelvic organ prolapse and postpartum abdominal exercise training in reducing inter-rectus distance. PROSPERO registration number CRD42022359282.