tbuckley/cabot-search huggingface dataset:
Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence
Authors: Zachary Strongin, Laurence Raymond Marchand, Claire Deleage, M. Betina Pampena, Maria Andrea Cardenas, Christian Michel Beusch, Timothy N. Hoang, Elizabeth A. Urban, Mael Gourves, Kevin Nguyen, Gregory K. Tharp, Stacey Lapp, Andrew R. Rahmberg, Justin Harper, Perla M. del Rio Estrada, Mauricio Gonzalez-Navarro, Fernanda Torres-Ruiz, Yara Andrea Luna-Villalobos, Santiago Avila-Rios, Gustavo Reyes-Teran, Rafick Sekaly, Guido Silvestri, Deanna A. Kulpa, Asier Saez-Cirion, Jason M. Brenchley, Steven E. Bosinger, David Ezra Gordon, Michael R. Betts, Haydn T. Kissick, Mirko Paiardini
Journal: Nature Immunology (2024)
Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety
Authors: Leonardo Tozzi, Xue Zhang, Adam Pines, Alisa M. Olmsted, Emily S. Zhai, Esther T. Anene, Megan Chesnut, Bailey Holt-Gosselin, Sarah Chang, Patrick C. Stetz, Carolina A. Ramirez, Laura M. Hack, Mayuresh S. Korgaonkar, Max Wintermark, Ian H. Gotlib, Jun Ma, Leanne M. Williams
Journal: Nature Medicine (2024)

Abstract There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or ‘biotypes’ to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free ( n = 801) and after randomization to pharmacotherapy or behavioral therapy ( n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.
Peripheral blood mononuclear cell respiratory function is associated with progressive glaucomatous vision loss
Authors: Bledi Petriti, Alessandro Rabiolo, Kai-Yin Chau, Pete A. Williams, Giovanni Montesano, Gerassimos Lascaratos, David F. Garway-Heath
Journal: Nature Medicine (2024)

Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma and all licensed treatments lower IOP. However, many patients continue to lose vision despite IOP-lowering treatment. Identifying biomarkers for progressive vision loss would have considerable clinical utility. We demonstrate that lower peripheral blood mononuclear cell (PBMC) oxygen consumption rate (OCR) is strongly associated with faster visual field (VF) progression in patients treated by lowering IOP (P < 0.001, 229 eyes of 139 participants), explaining 13% of variance in the rate of progression. In a separate reference cohort of untreated patients with glaucoma (213 eyes of 213 participants), IOP explained 16% of VF progression variance. OCR is lower in patients with glaucoma (n = 168) than in controls (n = 50; P < 0.001) and is lower in patients with low baseline IOP (n = 99) than those with high baseline IOP (n = 69; P < 0.01). PBMC nicotinamide adenine dinucleotide (NAD) levels are lower in patients with glaucoma (n = 29) compared to controls (n = 25; P < 0.001) and strongly associated with OCR (P < 0.001). Our results support PBMC OCR and NAD levels as new biomarkers for progressive glaucoma.
Enhancement of erythropoietic output by Cas9-mediated insertion of a natural variant in haematopoietic stem and progenitor cells
Authors: Sofia E. Luna, Joab Camarena, Jessica P. Hampton, Kiran R. Majeti, Carsten T. Charlesworth, Eric Soupene, Sridhar Selvaraj, Kun Jia, Vivien A. Sheehan, M. Kyle Cromer, Matthew H. Porteus
Journal: Nature Biomedical Engineering (2024)

Abstract Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis—the non-pathogenic hyper-production of red blood cells—that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34 + human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a β-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.
Roxadustat versus placebo for patients with lower‐risk myelodysplastic syndrome: MATTERHORN phase 3, double‐blind, randomized controlled trial
Authors: Moshe Mittelman, David H. Henry, John A. Glaspy, Anil Tombak, Rosemary Harrup, Inho Kim, Krzysztof Mądry, Barbara Grabowska, Tyson Lee, Katharina Modelska
Journal: American Journal of Hematology (2024)

Abstract In patients with lower‐risk myelodysplastic syndromes/neoplasms (MDS), response to first‐line therapy is limited and transient. The MATTERHORN randomized, double‐blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion‐dependent, lower‐risk MDS. Eligible patients had very low‐, low‐, or intermediate‐risk MDS with or without prior erythropoiesis‐stimulating agent treatment, and a transfusion burden of 1–4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders ( p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p ‐nominal = .047). The seven on‐study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.
Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy
Authors: Gregory A. Wyant, Qinqin Jiang, Madhu Singh, Shariq Qayyum, Clara Levrero, Bradley A. Maron, William G. Kaelin
Journal: Circulation (2024)

BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
Deep Learning for Echo Analysis, Tracking, and Evaluation of Mitral Regurgitation (DELINEATE-MR)
Authors: Aaron Long, Christopher M. Haggerty, Joshua Finer, Dustin Hartzel, Linyuan Jing, Azadeh Keivani, Christopher Kelsey, Daniel Rocha, Jeffrey Ruhl, David vanMaanen, Gil Metser, Eamon Duffy, Thomas Mawson, Mathew Maurer, Andrew J. Einstein, Ashley Beecy, Deepa Kumaraiah, Shunichi Homma, Qi Liu, Vratika Agarwal, Mark Lebehn, Martin Leon, Rebecca Hahn, Pierre Elias, Timothy J. Poterucha
Journal: Circulation (2024)

BACKGROUND: Artificial intelligence, particularly deep learning (DL), has immense potential to improve the interpretation of transthoracic echocardiography (TTE). Mitral regurgitation (MR) is the most common valvular heart disease and presents unique challenges for DL, including the integration of multiple video-level assessments into a final study-level classification. METHODS: A novel DL system was developed to intake complete TTEs, identify color MR Doppler videos, and determine MR severity on a 4-step ordinal scale (none/trace, mild, moderate, and severe) using the reading cardiologist as a reference standard. This DL system was tested in internal and external test sets with performance assessed by agreement with the reading cardiologist, weighted κ, and area under the receiver-operating characteristic curve for binary classification of both moderate or greater and severe MR. In addition to the primary 4-step model, a 6-step MR assessment model was studied with the addition of the intermediate MR classes of mild-moderate and moderate-severe with performance assessed by both exact agreement and ±1 step agreement with the clinical MR interpretation. RESULTS: A total of 61 689 TTEs were split into train (n=43 811), validation (n=8891), and internal test (n=8987) sets with an additional external test set of 8208 TTEs. The model had high performance in MR classification in internal (exact accuracy, 82%; κ=0.84; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR) and external test sets (exact accuracy, 79%; κ=0.80; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR). Most (63% internal and 66% external) misclassification disagreements were between none/trace and mild MR. MR classification accuracy was slightly higher using multiple TTE views (accuracy, 82%) than with only apical 4-chamber views (accuracy, 80%). In subset analyses, the model was accurate in the classification of both primary and secondary MR with slightly lower performance in cases of eccentric MR. In the analysis of the 6-step classification system, the exact accuracy was 80% and 76% with a ±1 step agreement of 99% and 98% in the internal and external test set, respectively. CONCLUSIONS: This end-to-end DL system can intake entire echocardiogram studies to accurately classify MR severity and may be useful in helping clinicians refine MR assessments.
Author Correction: The state of the art in secondary pharmacology and its impact on the safety of new medicines
Authors: Richard J. Brennan, Stephen Jenkinson, Andrew Brown, Annie Delaunois, Bérengère Dumotier, Malar Pannirselvam, Mohan Rao, Lyn Rosenbrier Ribeiro, Friedemann Schmidt, Alicia Sibony, Yoav Timsit, Vicencia Toledo Sales, Duncan Armstrong, Armando Lagrutta, Scott W. Mittlestadt, Russell Naven, Ravikumar Peri, Sonia Roberts, James M. Vergis, Jean-Pierre Valentin
Journal: Nature Reviews Drug Discovery (2024)
Integrative single-cell and bulk transcriptomes analyses reveals heterogeneity of serine-glycine-one-carbon metabolism with distinct prognoses and therapeutic vulnerabilities in HNSCC
Authors: Lixuan Wang, Rongchun Yang, Yue Kong, Jing Zhou, Yingyao Chen, Rui Li, Chuwen Chen, Xinran Tang, Xiaobing Chen, Juan Xia, Xijuan Chen, Bin Cheng, Xianyue Ren
Journal: International Journal of Oral Science (2024)

Metabolic heterogeneity plays a central role in sustaining uncontrolled cancer cell proliferation and shaping the tumor microenvironment (TME), which significantly compromises the clinical outcomes and responses to therapy in head and neck squamous cell carcinoma (HNSCC) patients. This highlights the urgent need to delineate the intrinsic heterogeneity and biological roles of metabolic vulnerabilities to advance precision oncology. The metabolic heterogeneity of malignant cells was identified using single-cell RNA sequencing (scRNA-seq) profiles and validated through bulk transcriptomes. Serine-glycine-one-carbon (SGOC) metabolism was screened out to be responsible for the aggressive malignant properties and poor prognosis in HNSCC patients. A 4-SGOC gene prognostic signature, constructed by LASSO-COX regression analysis, demonstrated good predictive performance for overall survival and therapeutic responses. Patients in the low-risk group exhibited greater infiltration of exhausted CD8+ T cells, and demonstrated better clinical outcomes after receiving immunotherapy and chemotherapy. Conversely, high-risk patients exhibited characteristics of cold tumors, with enhanced IMPDH1-mediated purine biosynthesis, resulting in poor responses to current therapies. IMPDH1 emerged as a potential therapeutic metabolic target. Treatment with IMPDH inhibitors effectively suppressed HNSCC cell proliferation and metastasis and induced apoptosis in vitro and in vivo by triggering GTP-exhaustion nucleolar stress. Our findings underscore the metabolic vulnerabilities of HNSCC in facilitating accurate patient stratification and individualized precise metabolic-targeted treatment.
Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition
Authors: Sohel Shamsuzzaman, Rebecca A. Deaton, Anita Salamon, Heather Doviak, Vlad Serbulea, Victoria M. Milosek, Megan A. Evans, Santosh Karnewar, Subhi Saibaba, Gabriel F. Alencar, Laura S. Shankman, Kenneth Walsh, Stefan Bekiranov, Olivier Kocher, Monty Krieger, Bengt Kull, Marie Persson, Erik Michaëlsson, Nils Bergenhem, Sepideh Heydarkhan-Hagvall, Gary K. Owens
Journal: Circulation (2024)

Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke.
Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association
Authors: Aeron M. Small, Katherine E. Yutzey, Bryce A. Binstadt, Kaitlin Voigts Key, Nabila Bouatia-Naji, David Milan, Elena Aikawa, Catherine M. Otto, Cynthia St. Hilaire
Journal: Circulation (2024)

Valvular heart disease is a common cause of morbidity and mortality worldwide and has no effective medical therapy. Severe disease is managed with valve replacement procedures, which entail high health care-related costs and postprocedural morbidity and mortality. Robust ongoing research programs have elucidated many important molecular pathways contributing to primary valvular heart disease. However, there remain several key challenges inherent in translating research on valvular heart disease to viable molecular targets that can progress through the clinical trials pathway and effectively prevent or modify the course of these common conditions. In this scientific statement, we review the basic cellular structures of the human heart valves and discuss how these structures change in primary valvular heart disease. We focus on the most common primary valvular heart diseases, including calcific aortic stenosis, bicuspid aortic valves, mitral valve prolapse, and rheumatic heart disease, and outline the fundamental molecular discoveries contributing to each. We further outline potential therapeutic molecular targets for primary valvular heart disease and discuss key knowledge gaps that might serve as future research priorities.
Expert consensus on endodontic therapy for patients with systemic conditions
Authors: Xin Xu, Xin Zheng, Fei Lin, Qing Yu, Benxiang Hou, Zhi Chen, Xi Wei, Lihong Qiu, Chen Wenxia, Jiyao Li, Lili Chen, Zuomin Wang, Hongkun Wu, Zhiyue Lu, Jizhi Zhao, Yuhong Liang, Jin Zhao, Yihuai Pan, Shuang Pan, Xiaoyan Wang, Deqin Yang, Yanfang Ren, Lin Yue, Xuedong Zhou
Journal: International Journal of Oral Science (2024)

Abstract The overall health condition of patients significantly affects the diagnosis, treatment, and prognosis of endodontic diseases. A systemic consideration of the patient’s overall health along with oral conditions holds the utmost importance in determining the necessity and feasibility of endodontic therapy, as well as selecting appropriate therapeutic approaches. This expert consensus is a collaborative effort by specialists from endodontics and clinical physicians across the nation based on the current clinical evidence, aiming to provide general guidance on clinical procedures, improve patient safety and enhance clinical outcomes of endodontic therapy in patients with compromised overall health.
3D electronic implants in subretinal space: Long-term follow-up in rodents
Authors: Mohajeet B. Bhuckory, Bing-Yi Wang, Zhijie C. Chen, Andrew Shin, Davis Pham-Howard, Sarthak Shah, Nicharee Monkongpitukkul, Ludwig Galambos, Theodore Kamins, Keith Mathieson, Daniel Palanker
Journal: Biomaterials (2024)
Community MRSA outbreaks in areas of low prevalence
Authors: Katherine L. Bellis, Oshani M. Dissanayake, Ewan M. Harrison, Dinesh Aggarwal
Journal: Clinical Microbiology and Infection (2024)

Community-acquired (CA), community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) infection presents a significant public health challenge, even where MRSA rates are historically lower. Despite successes in reducing hospital-onset MRSA, CO-MRSA rates are increasing globally, with a need to understand this trend, and the potential risk factors for re-emergence.
Reply to correspondence: Correspondence to “the impact of indoor pollution on asthma‐related outcomes: A systematic review for the <scp>EAACI</scp> guidelines on environmental science for allergic diseases and asthma”
Authors: Carlos Canelo‐Aybar, Wendy Nieto‐Gutierrez, L. Yesenia Rodriguez‐Tanta, Yahveth Cantero‐Forti, Pablo Alonso‐Coello, Marek Jutel, Cezmi A. Akdis, Ioana Agache
Journal: Allergy (2024)

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1low/CAMSAP3low, emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer
Authors: Xiaodan Mao, Xiaoyue Tang, Jingxuan Ye, Shuxia Xu, Yue Wang, Xianhua Liu, Qibin Wu, Xite Lin, Maotong Zhang, Jiangfeng Liu, Juntao Yang, Pengming Sun
Journal: Molecular Cancer (2024)

Abstract The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1 low /CAMSAP3 low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1 low /CAMSAP3 low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
Safety of non-replicative and oncolytic replication-selective HSV vectors
Authors: Alberto L. Epstein, Samuel D. Rabkin
Journal: Trends in Molecular Medicine (2024)

Herpes simplex virus type 1 (HSV-1) is a DNA virus and human pathogen used to construct promising therapeutic vectors. HSV-1 vectors fall into two classes: replication-selective oncolytic vectors for cancer therapy and defective non-replicative vectors for gene therapy. Vectors from each class can accommodate ≥30 kb of inserts, have been approved clinically, and demonstrate a relatively benign safety profile. Despite oncolytic HSV (oHSV) replication in tumors and elicited immune responses, the virus is well tolerated in cancer patients. Current non-replicative vectors elicit only limited immune responses. Seropositivity and immune responses against HSV-1 do not eliminate either the vector or infected cells, and the vectors can therefore be re-administered. In this review we highlight vectors that have been translated to the clinic and host–virus immune interactions that impact on the safety and efficacy of HSVs.