tbuckley/cabot-search huggingface dataset:
Proteomic Profiling of Serum Extracellular Vesicles Identifies Diagnostic Signatures and Therapeutic Targets in Breast Cancer
Authors: Ganfei Xu, Rui Huang, Reziya Wumaier, Jiacheng Lyu, Minjing Huang, Yaya Zhang, Qingjian Chen, Wenting Liu, Mengyu Tao, Junjian Li, Zhonghua Tao, Bo Yu, Erxiang Xu, Lingfeng Wang, Guoying Yu, Olivier Gires, Lei Zhou, Wei Zhu, Chen Ding, Hongxia Wang
Journal: Cancer Research (2024)

Analysis of extracellular vesicles (EV) is a promising noninvasive liquid biopsy approach for breast cancer detection, prognosis, and therapeutic monitoring. A comprehensive understanding of the characteristics and proteomic composition of breast cancer-specific EVs from human samples is required to realize the potential of this strategy. In this study, we applied a mass spectrometry-based, data-independent acquisition proteomic approach to characterize human serum EVs derived from patients with breast cancer (n = 126) and healthy donors (n = 70) in a discovery cohort and validated the findings in five independent cohorts. Examination of the EV proteomes enabled the construction of specific EV protein classifiers for diagnosing breast cancer and distinguishing patients with metastatic disease. Of note, TALDO1 was found to be an EV biomarker of distant metastasis of breast cancer. In vitro and in vivo analysis confirmed the role of TALDO1 in stimulating breast cancer invasion and metastasis. Finally, high-throughput molecular docking and virtual screening of a library consisting of 271,380 small molecules identified a potent TALDO1 allosteric inhibitor, AO-022, which could inhibit breast cancer migration in vitro and tumor progression in vivo. Together, this work elucidates the proteomic alterations in the serum EVs of breast cancer patients to guide the development of improved diagnosis, monitoring, and treatment strategies. Significance: Characterization of the proteomic composition of circulating extracellar vesicles in breast cancer patients identifies signatures for diagnosing primary and metastatic tumors and reveals tumor-promoting cargo that can be targeted to improve outcomes.
An Endocellulase‐Triggered NO Targeted‐Release Enzyme‐Prodrug Therapy System and Its Application in Ischemia Injury
Authors: Bo He, Yating Zhang, Huaping Liu, Manuel Tang, Ke Yang, Silian Cheng, Jie Shen, Yongzhen Wei, Weiliang Deng, Qiang Zhao, Guang‐Yu Yang
Journal: Advanced Healthcare Materials (2024)

Nitric oxide (NO) is a crucial gaseous signaling molecules in regulating cardiovascular, immune, and nervous systems. Controlled and targeted NO delivery is imperative for treating cancer, inflammation, and cardiovascular diseases. Despite various enzyme-prodrug therapy (EPT) systems facilitating controlled NO release, their clinical utility is hindered by nonspecific NO release and undesired metabolic consequence. In this study, a novel EPT system is presented utilizing a cellobioside-diazeniumdiolate (Cel2-NO) prodrug, activated by an endocellulase (Cel5A-h38) derived from the rumen uncultured bacterium of Hu sheep. This system demonstrates nearly complete orthogonality, wherein Cel2-NO prodrug maintains excellent stability under endogenous enzymes. Importantly, Cel5A-h38 efficiently processes the prodrug without recognizing endogenous glycosides. The targeted drug release capability of the system is vividly illustrated through an in vivo near-infrared imaging assay. The precise NO release by this EPT system exhibits significant therapeutic potential in a mouse hindlimb ischemia model, showcasing reductions in ischemic damage, ambulatory impairment, and modulation of inflammatory responses. Concurrently, the system enhances tissue repair and promotes function recovery efficacy. The novel EPT system holds broad applicability for the controlled and targeted delivery of essential drug molecules, providing a potent tool for treating cardiovascular diseases, tumors, and inflammation-related disorders.
International study on prevalence of itch: examining the role of itch as a major global public health problem
Authors: Gil Yosipovitch, Charbel Skayem, Marketa Saint Aroman, Charles Taieb, Medhi Inane, Yaron Ben Hayoun, Nuria Perez Cullel, Catherine Baissac, Bruno Halioua, Marie Aleth Richard, Laurent Misery
Journal: British Journal of Dermatology (2024)

Abstract Background Very few studies have evaluated the global prevalence of pruritus. Objectives To assess its prevalence according to age, sex, ethnicity and geographic region. Methods An international cross-sectional study was conducted in 20 countries from January to April 2023. Participants were asked to complete a questionnaire on sociodemographics, and to confirm the presence or absence of a skin disease in the last 12 months and the presence or absence of pruritus in the last 7 days. Results The studied sample included 50 552 individuals. The worldwide prevalence of pruritus was 39.8%. The age group ≥ 65 years had the highest prevalence (43.3%). The prevalence was 40.7% among women and 38.9% among men (P &amp;lt; 0.001). There was no significant difference between ethnicities (P = 0.14). Compared with North America (41.2%), the prevalence of pruritus was significantly lower in Europe (35.9%, P &amp;lt; 0.001), Australia (38.4%, P = 0.017), East Asia (40.2%, P = 0.04) and Latin America (36.5%, P &amp;lt; 0.001), and higher in Africa (45.7%, P = 0.007). No significant difference was found with the Middle East (40.2%, P = 0.36). The prevalence of pruritus in BRICS countries (40.3%) was significantly higher than that in developed countries (38.7%) (P &amp;lt; 10–3). Conclusions Out analysis is limited because there is no information about the severity or type (acute, chronic) of pruritus. The global prevalence of pruritus revealed age, sex and geographic region differences, with no ethnic differences.
Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model
Authors: John A. Hey, Jeremy Y. Yu, Susan Abushakra, Jean F. Schaefer, Aidan Power, Patrick Kesslak, Martin Tolar
Journal: Drugs (2024)

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.
Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer’s Disease
Authors: John A. Hey, Susan Abushakra, Kaj Blennow, Eric M. Reiman, Jakub Hort, Niels D. Prins, Katerina Sheardova, Patrick Kesslak, Larry Shen, Xinyi Zhu, Adem Albayrak, Jijo Paul, Jean F. Schaefer, Aidan Power, Martin Tolar
Journal: Drugs (2024)

ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.
Unveiling the reliability of Left Atrial Strain measurement: A dedicated Speckle Tracking Software perspective in controls and cases
Authors: G E Mandoli, M C Pastore, M C Procopio, A Pica, M Vigna, G Benfari, E E Diviggiano, L Martini, S Lunghetti, M Focardi, M Y Henein, M Cameli
Journal:  (2024)

Speckle tracking echocardiography increasingly supports left atrial (LA) strain (LAS) analysis for diagnosis and prognosis of various clinical conditions. Prior limitations, such as the absence of dedicated software, have been overcome by validated ventricular-based software. A newly automated real-time and offline LA-specific software have now become available on echocardiographs and dedicated workstations. This study aimed at comparing LA strain measures obtained from new fully automated software vs. traditional semi-automated ventricular-based methods in different groups of patients.
Intraplatelet miRNA-126 regulates thrombosis and its reduction contributes to platelet inhibition
Authors: Lu-Jun Zhang, Yang-Xi Hu, Rong-Zhong Huang, Yan-Yan Xu, Shao-Hua Dong, Fang-Hao Guo, Jun-Jun Guo, Jing-Jing Qiu, Zi-Yun Cao, Li-Jiang Wei, Jia-Hao Mao, Ankang Lyu, Jun-Ling Liu, Xian-Xian Zhao, Zhi-Fu Guo, Qing Jing
Journal: Cardiovascular Research (2024)

MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear. Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading, and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the phosphoinositide 3-kinase/protein kinase B pathway, enhancing platelet activation through activating the integrin αIIbβ3-mediated outside-in signalling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease in platelet activity. Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy.
G Protein-Coupled Receptors: A Century of Research and Discovery
Authors: Samuel Liu, Preston J. Anderson, Sudarshan Rajagopal, Robert J. Lefkowitz, Howard A. Rockman
Journal: Circulation Research (2024)

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.
Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases
Authors: Yufeng Hu, Wei Li, Xu Cheng, Hailong Yang, Zhi-Gang She, Jingjing Cai, Hongliang Li, Xiao-Jing Zhang
Journal: Circulation Research (2024)

Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway–mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.
The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy
Authors: Alin Rai, Bethany Claridge, Jonathan Lozano, David W. Greening
Journal: Circulation Research (2024)

From their humble discovery as cellular debris to cementing their natural capacity to transfer functional molecules between cells, the long-winded journey of extracellular vesicles (EVs) now stands at the precipice as a next-generation cell-free therapeutic tool to revolutionize modern-day medicine. This perspective provides a snapshot of the discovery of EVs to their emergence as a vibrant field of biology and the renaissance they usher in the field of biomedical sciences as therapeutic agents for cardiovascular pathologies. Rapid development of bioengineered EVs is providing innovative opportunities to overcome biological challenges of natural EVs such as potency, cargo loading and enhanced secretion, targeting and circulation half-life, localized and sustained delivery strategies, approaches to enhance systemic circulation, uptake and lysosomal escape, and logistical hurdles encompassing scalability, cost, and time. A multidisciplinary collaboration beyond the field of biology now extends to chemistry, physics, biomaterials, and nanotechnology, allowing rapid development of designer therapeutic EVs that are now entering late-stage human clinical trials.
Recent advances to address challenges in extracellular vesicle-based applications for lung cancer
Authors: Gaigai Huang, Wenshu Zheng, Yu Zhou, Meihua Wan, Tony Hu
Journal: Acta Pharmaceutica Sinica B (2024)

Lung cancer, highly prevalent and the leading cause of cancer-related death globally, persists as a significant challenge due to the lack of definitive tumor markers for early diagnosis and personalized therapeutic interventions. Recently, extracellular vesicles (EVs), functioning as natural carriers for intercellular communication, have received increasing attention due to their ability to traverse biological barriers and deliver diverse biological cargoes, including cytosolic proteins, cell surface proteins, microRNA, lncRNA, circRNA, DNA, and lipids. EVs are increasingly recognized as a valuable resource for non-invasive liquid biopsy, as well as drug delivery platforms, and anticancer vaccines for precision medicine in lung cancer. Herein, given the diagnostic and therapeutic potential of tumor-associated EVs for lung cancer, we discuss this topic from a translational standpoint. We delve into the specific roles that EVs play in lung cancer carcinogenesis and offer a particular perspective on how advanced engineering technologies can overcome the current challenges and expedite and/or enhance the translation of EVs from laboratory research to clinical settings.
Pathological autoantibody internalisation in myositis
Authors: Iago Pinal-Fernandez, Sandra Muñoz-Braceras, Maria Casal-Dominguez, Katherine Pak, Jiram Torres-Ruiz, Jon Musai, Stefania Dell'Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Maria Dolores Cano, Ana Matas-Garcia, Joan Padrosa, Ester Tobias-Baraja, Gloria Garrabou, Iban Aldecoa, Gerard Espinosa, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Albert Gil-Vila, Ernesto Trallero-Araguás, Lisa Christopher-Stine, Thomas E Lloyd, Teerin Liewluck, Elie Naddaf, Werner Stenzel, Steven A Greenberg, Josep Maria Grau, Albert Selva-O'Callaghan, Jose Cesar Milisenda, Andrew Lee Mammen
Journal: Annals of the Rheumatic Diseases (2024)

Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption.
Is radial extracorporeal shock wave therapy (rESWT), sham-rESWT or a standardised exercise programme in combination with advice plus customised foot orthoses more effective than advice plus customised foot orthoses alone in the treatment of plantar fasciopathy? A double-blind, randomised, sham-controlled trial
Authors: Marte Heide, Cecilie Røe, Marianne Mørk, Kjersti Myhre, Cathrine Brunborg, Jens Ivar Brox, Aasne Fenne Hoksrud
Journal: British Journal of Sports Medicine (2024)

To assess whether radial extracorporeal shock wave therapy (rESWT), sham-rESWT or a standardised exercise programme in combination with advice plus customised foot orthoses is more effective than advice plus customised foot orthoses alone in alleviating heel pain in patients with plantar fasciopathy.
PatchSorter: a high throughput deep learning digital pathology tool for object labeling
Authors: Cédric Walker, Tasneem Talawalla, Robert Toth, Akhil Ambekar, Kien Rea, Oswin Chamian, Fan Fan, Sabina Berezowska, Sven Rottenberg, Anant Madabhushi, Marie Maillard, Laura Barisoni, Hugo Mark Horlings, Andrew Janowczyk
Journal: npj Digital Medicine (2024)

Abstract The discovery of patterns associated with diagnosis, prognosis, and therapy response in digital pathology images often requires intractable labeling of large quantities of histological objects. Here we release an open-source labeling tool, PatchSorter, which integrates deep learning with an intuitive web interface. Using &gt;100,000 objects, we demonstrate a &gt;7x improvement in labels per second over unaided labeling, with minimal impact on labeling accuracy, thus enabling high-throughput labeling of large datasets.
Development of an effective predictive screening tool for prostate cancer using the ClarityDX machine learning platform
Authors: M. Eric Hyndman, Robert J. Paproski, Adam Kinnaird, Adrian Fairey, Leonard Marks, Christian P. Pavlovich, Sean A. Fletcher, Roman Zachoval, Vanda Adamcova, Jiri Stejskal, Armen Aprikian, Christopher J. D. Wallis, Desmond Pink, Catalina Vasquez, Perrin H. Beatty, John D. Lewis
Journal: npj Digital Medicine (2024)

Abstract The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients’ risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.
Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation
Authors: Vlad Taru, Gyongyi Szabo, Wajahat Mehal, Thomas Reiberger
Journal: Journal of Hepatology (2024)

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.
Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein
Authors: Laura García-Pupo, Lucie Crouzier, Alberto Bencomo-Martínez, Johann Meunier, Axelle Morilleau, Benjamin Delprat, Marquiza Sablón Carrazana, Roberto Menéndez Soto del Valle, Tangui Maurice, Chryslaine Rodríguez-Tanty
Journal: Acta Pharmaceutica Sinica B (2024)

The aggregation of Amyloid-