tbuckley/cabot-search huggingface dataset:
Acetyl-CoA carboxylase 1 controls a lipid droplet–peroxisome axis and is a vulnerability of endocrine-resistant ER <sup>+</sup> breast cancer
Authors: Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Ludivine Morriset, Rania El Botty, Matteo Benelli, Joanna I. López-Velazco, Maria M. Caffarel, Ander Urruticoechea, George Sflomos, Luca Malorni, Michela Corsini, Luigi Ippolito, Elisa Giannoni, Icro Meattini, Vittoria Matafora, Kristina Havas, Angela Bachi, Paola Chiarugi, Elisabetta Marangoni, Andrea Morandi
Journal: Science Translational Medicine (2024)

Targeting aromatase deprives ER + breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER + breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long–chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor–treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER + breast cancers.
A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer
Authors: Aaron M. Miller, Zeynep Koşaloğlu-Yalçın, Luise Westernberg, Leslie Montero, Milad Bahmanof, Angela Frentzen, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Gregory Seumois, Jason Greenbaum, Spencer E. Brightman, Karla Soria Zavala, Rukman R. Thota, Martin S. Naradikian, Samir S. Makani, Scott M. Lippman, Alessandro Sette, Ezra E. W. Cohen, Bjoern Peters, Stephen P. Schoenberger
Journal: Science Translational Medicine (2024)

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4 + and CD8 + T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)–agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells.
Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition
Authors: Jonathan P. Sturgeon, Joice Tome, Cherlynn Dumbura, Florence D. Majo, Deophine Ngosa, Kuda Mutasa, Kanekwa Zyambo, Ellen Besa, Kanta Chandwe, Chanda Kapoma, Benjamin Mwapenya, Kusum J. Nathoo, Claire D. Bourke, Robert Ntozini, Bernard Chasekwa, Melanie Smuk, Mutsa Bwakura-Dangarembizi, Beatrice Amadi, Paul Kelly, Andrew J. Prendergast
Journal: Science Translational Medicine (2024)

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls ( n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children’s outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid–binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.
Author Correction: T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection
Authors: Matthias. T Stephan, Vladimir Ponomarev, Renier .J Brentjens, Alex. H Chang, Konstantin. V Dobrenkov, Glenn Heller, Michel Sadelain
Journal: Nature Medicine (2024)

In the originally published version of this article, the day 8, 19z1 + CD80 + 4-1BBL + , group of mice was inadvertently duplicated from a separate group of mice in Fig. 3a.The original data were located, and this error has now been corrected and can be seen as Fig. 1 below.
A Combination of Flexible Modified Plant Virus Nanoparticles Enables Additive Effects Resulting in Improved Osteogenesis
Authors: Juliane Schuphan, Natalija Stojanović, Ying‐Ying Lin, Eva Miriam Buhl, Sanja Aveic, Ulrich Commandeur, Stefan Schillberg, Horst Fischer
Journal: Advanced Healthcare Materials (2024)

Abstract Plant virus nanoparticles (VNPs) genetically engineered to present osteogenic cues provide a promising method for biofunctionalizing hydrogels in bone tissue engineering. Flexible Potato virus X (PVX) nanoparticles substantially enhance the attachment and differentiation of human mesenchymal stem cells (hMSCs) by presenting the RGD motif, hydroxyapatite‐binding peptide (HABP), or consecutive polyglutamates (E8) in a concentration‐dependent manner. Therefore, it is hypothesized that Tobacco mosaic virus nanoparticles, which present 1.6 times more functional peptides than PVX, will meliorate such an impact. This study hypothesizes that cultivating hMSCs on a surface coated with a combination of two VNPs presenting peptides for either cell attachment or mineralization can achieve additionally enhancing effects on osteogenesis. Calcium minerals deposited by differentiating hMSCs increases two to threefold for this combination, while the Alkaline Phosphatase activity of hMSCs grown on the PVX‐RGD/PVX‐HABP‐coated surface significantly surpasses any other VNP combination. Superior additive effects are observed for the first time by employing a combination of VNPs with varying functionalities. It is found that the flexible VNP geometry plays a more critical role than the concentration of functional peptides. In conclusion, various peptide‐presenting plant VNPs exhibit an additive enhancing effect offering significant potential for effectively functionalizing cell‐containing hydrogels in bone tissue engineering.
MASH Resolution Index: development and validation of a non-invasive score to detect histological resolution of MASH
Authors: Rohit Loomba, Maral Amangurbanova, Ricki Bettencourt, Egbert Madamba, Harris Siddiqi, Lisa Richards, Cynthia Behling, Claude B Sirlin, Mildred D Gottwald, Shibao Feng, Maya Margalit, Daniel Q Huang
Journal: Gut (2024)

Background Dynamic changes in non-invasive tests, such as changes in alanine aminotransferase (ALT) and MRI proton-density-fat-fraction (MRI-PDFF), may help to detect metabolic dysfunction-associated steatohepatitis (MASH) resolution, but a combination of non-invasive tests may be more accurate than either alone. We developed a novel non-invasive score, the MASH Resolution Index, to detect the histological resolution of MASH. Methods This study included a derivation cohort of 95 well-characterised adult participants (67% female) with biopsy-confirmed MASH who underwent contemporaneous laboratory testing, MRI-PDFF and liver biopsy at two time points. The primary objective was to develop a non-invasive score to detect MASH resolution with no worsening of fibrosis. The most predictive logistic regression model was selected based on the highest area under the receiver operating curve (AUC), and the lowest Akaike information criterion and Bayesian information criterion. The model was then externally validated in a distinct cohort of 163 participants with MASH from a clinical trial. Results The median (IQR) age and body mass index were 55 (45�62) years and 32.0 (30�37) kg/m 2 , respectively, in the derivation cohort. The most accurate model (MASH Resolution Index) included MRI-PDFF, ALT and aspartate aminotransferase. The index had an AUC of 0.81 (95% CI 0.69 to 0.93) for detecting MASH resolution in the derivation cohort. The score calibrated well and performed robustly in a distinct external validation cohort (AUC 0.83, 95% CI 0.76 to 0.91), and outperformed changes in ALT and MRI-PDFF. Conclusion The MASH Resolution Index may be a useful score to non-invasively identify MASH resolution.
Dual‐Responsive Nanogels with Cascaded Gentamicin Release and Lysosomal Escape to Combat Intracellular Small Colony Variants for Peritonitis and Sepsis Therapies
Authors: Shuang Xie, Yu Li, Wenxiong Cao, Jiawen Peng, Kun Huang, Jie Meng, Xiaohong Li
Journal: Advanced Healthcare Materials (2024)

Abstract Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn intracellular small colony variants (SCVs). Herein, the authors have developed nanogels (NGs) to destroy both planktonic bacteria and SCVs and eliminate excessive inflammations for peritonitis and sepsis therapies. Free gentamicin (GEN) and hydroxyapatite nanoparticles (NPs) with GEN loading and mannose grafts (mHA G ) are inoculated into ε‐polylysine NGs to obtain NG@G1‐mHA G2 through crosslinking with phenylboronic acid and tannic acid. The H 2 O 2 consumption after reaction with phenylboronic esters and the elimination of free radicals by tannic acid alleviates the escalated inflammatory status to promote sepsis therapy. After mannose‐mediated uptake into macrophages, the acid‐triggered degradation of mHA G NPs generates Ca 2+ to destabilize lysosomes and the efficient lysosomal escape leads to reversion of hypometabolic SCVs into normal phenotype and their sensitivity to GEN. In a peritonitis mouse model, NG@G1‐mHA G2 treatment provides strong and persistent bactericidal effects against both extracellular bacteria and intracellular SCVs and extends survival of peritonitis mice without apparent hepatomegaly, splenomegaly, pulmonary edema, and inflammatory cell infiltration. Thus, this study demonstrates a concise and versatile strategy to eliminate SCVs and relieve inflammatory storms for peritonitis and sepsis therapies without infection recurrence.
Accelerometer-derived physical activity and the risk of death, heart failure, and stroke in patients with atrial fibrillation: a prospective study from UK Biobank
Authors: Hyo-Jeong Ahn, Eue-Keun Choi, Tae-Min Rhee, JungMin Choi, Kyung-Yeon Lee, Soonil Kwon, So-Ryoung Lee, Seil Oh, Gregory Y H Lip
Journal: British Journal of Sports Medicine (2024)

Objective Data on cardiovascular outcomes according to objectively measured physical activity (PA) in patients with atrial fibrillation (AF) are scarce. This study explored the associations between PA derived from wrist-worn accelerometers and the risk of death, incident heart failure (HF), and incident stroke in patients with AF. Methods From 37 990 patients with AF in UK Biobank, 2324 patients with accelerometer data were included. Weekly moderate-to-vigorous PA (MVPA) duration was computed from accelerometer data. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality, incident HF, and incident stroke. Restricted cubic splines estimated the dose–response associations between MVPA duration and the outcomes. The adjusted HRs (aHRs) of the outcomes according to adherence to PA standard guidelines (performing MVPA≥150 min/week) were also evaluated. Results The mean age was 66.9±6.2 years and 64.9% were male. During a median follow-up of 6.7 years, there were 181 all-cause deaths, 62 cardiovascular deaths, 225 cases of incident HF, and 91 cases of incident stroke; the overall incidence rate per 1000 patient-years was 11.76, 4.03, 15.16 and 5.99, respectively. There was a linear inverse dose–response relationship between MVPA (≥108 min/week) and all-cause mortality. Performing MVPA for 105–590 min/week was associated with a lower risk of HF than those with no measurable MVPA. The risk of stroke and cardiovascular mortality was not associated with MVPA. Performing guideline-adherent MVPA was related to a 30% lower risk of all-cause mortality (aHR: 0.70 (0.50–0.98), p=0.04) and 33% lower risk of HF (aHR 0.67 (0.49–0.93), p=0.02). Conclusion In patients with AF, accelerometer-derived PA data supports lower risks of all-cause mortality and HF according to a greater level of MVPA and adherence to PA guidelines. Regular MVPA should be encouraged in patients with AF as a part of integrated management.
Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes
Authors: Mathilde Ruggiu, Marion V. Guérin, Béatrice Corre, Margot Bardou, Ruby Alonso, Erica Russo, Zacarias Garcia, Lea Feldmann, Fabrice Lemaître, Mathilde Dusseaux, Capucine L. Grandjean, Philippe Bousso
Journal: The Journal of Experimental Medicine (2024)

Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh). In two different models, anti-PD-1 mAb increased the activation and proliferation of tumor-specific T cells in lymph nodes. Surprisingly, anti-PD-1 mAb did not primarily target CD8+ T cells but instead stimulated IL-4 production by Tfh cells, the major population bound by anti-PD-1 mAb. Blocking IL-4 or inhibiting the Tfh master transcription factor BCL6 abrogated anti-PD-1 mAb activity in lymph nodes while injection of IL-4 complexes was sufficient to recapitulate anti-PD-1 mAb activity. A similar mechanism was observed in a vaccine model. Finally, nivolumab also boosted human Tfh cells in humanized mice. We propose that Tfh cells and IL-4 play a key role in the peripheral activity of anti-PD-1 mAb.
Effects of testosterone and sex hormone binding globulin on lung function in males and females: a multivariable Mendelian Randomisation study
Authors: Diana A van der Plaat, Alexandra Lenoir, Shyamali Dharmage, James Potts, Francisco Gómez Real, Seif O Shaheen, Debbie Jarvis, Cosetta Minelli, Bénédicte Leynaert
Journal: Thorax (2024)

Background Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. Methods We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. Findings In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV 1 in both males and females, but a moderate detrimental effect of SHBG on FEV 1 and FEV 1 /FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. Interpretation These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.
Cognitive Function and Variability in Antipsychotic Drug–Naive Patients With First-Episode Psychosis
Authors: Maria Lee, Martin Cernvall, Jacqueline Borg, Pontus Plavén-Sigray, Cornelia Larsson, Sophie Erhardt, Carl M. Sellgren, Helena Fatouros-Bergman, Simon Cervenka
Journal: JAMA Psychiatry (2024)

Importance Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated. Objective To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls. Data Sources In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022. Study Selection Original studies reporting data on cognitive function in antipsychotic drug–naive patients with first-episode psychosis (FEP) were included. Data Extraction and Synthesis Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias. Main Outcomes and Measures The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability. Results Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = −1.16; 95% CI, −1.35 to −0.98; verbal learning: Hedges g = −1.08; 95% CI, −1.28 to −0.88; visual learning: Hedges g = −1.05; 95% CI, −1.27 to −0.82; working memory: Hedges g = −1.04; 95% CI, −1.35 to −0.73; attention: Hedges g = −1.03; 95% CI, −1.24 to −0.82; reasoning/problem solving: Hedges g = −0.90; 95% CI, −1.12 to −0.68; executive function: Hedges g = −0.88; 95% CI, −1.07 to −0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92). Conclusions and Relevance Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.
Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru
Authors: Letizia Trevisi, Meredith B. Brooks, Mercedes C Becerra, Roger I. Calderón, Carmen C. Contreras, Jerome T. Galea, Judith Jimenez, Leonid W. Lecca, Rosa M. Yataco, Ximena Tovar, Zibiao Zhang, Megan Murray, Chuan-Chin Huang
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority.