tbuckley/cabot-search huggingface dataset:
Inhibition of <i>de novo</i> ceramide synthesis by sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes
Authors: Srividya Velagapudi, Gergely Karsai, Maria Karsai, Shafeeq A Mohammed, Fabrizio Montecucco, Luca Liberale, Hwan Lee, Federico Carbone, Giovanni Francesco Adami, Kangmin Yang, Margot Crucet, Sokrates Stein, Franceso Paneni, Tetiana Lapikova-Bryhinska, Hyun-Duk Jang, Simon Kraler, Daria Vdovenko, Richard Arnold Züllig, Giovanni G Camici, Hyo-Soo Kim, Reijo Laaksonen, Philipp A Gerber, Thorsten Hornemann, Alexander Akhmedov, Thomas F Lüscher
Journal: Cardiovascular Research (2024)

Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular (CV) diseases. Dysregulated pro-apoptotic ceramide synthesis reduces β-cell insulin secretion, thereby promoting hyperglycaemic states that may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor CV outcomes. Sirtuin-1 (SIRT1) is a NAD + -dependent deacetylase that protects against pancreatic β-cell dysfunction; however, systemic levels are decreased in obese-T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycaemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice.
Suppressing FXR promotes antiviral effects of bile acids via enhancing the interferon transcription
Authors: Xue Liang, Kunpeng Liu, Xin Jia, Cuiqin Cheng, Meiqi Zhang, Lingdong Kong, Qiqi Li, Zhe Liu, Min Li, Junliang Li, Yao Wang, Anlong Xu
Journal: Acta Pharmaceutica Sinica B (2024)

Bile acids (BAs) are natural metabolites in mammals and have the potential to function as drugs against viral infection. However, the limited understanding of chenodeoxycholic acid (CDCA) receptors and downstream signaling, along with its lower suppression efficiency in inhibiting virus infection limits its clinical application. In this study, we demonstrate that farnesoid X receptor (FXR), the receptor of CDCA, negatively regulates interferon signaling, thereby contributing to the reduced effectiveness of CDCA against virus replication. FXR deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus infection. Mechanistically, FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3 (IRF3) through interaction. Reduced IRF3 transcriptional activity by FXR–IRF3 interaction significantly undermines the expression of Interferon Beta 1 (IFNB1) and the antiviral response of cells, especially upon the CDCA treatment. In FXR-deficient cells, or when combined with Z-guggulsterone (GUGG) treatment, CDCA exhibits a more potent ability to restrict virus infection. Thus, these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication, which can be attributed to the "signaling-brake" roles of FXR in interferon signaling. Targeting FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs.
Current status and trends in small nucleic acid drug development: Leading the future
Authors: Yuxi Miao, Chen Fu, Zhaojin Yu, Lifeng Yu, Yu Tang, Minjie Wei
Journal: Acta Pharmaceutica Sinica B (2024)

Small nucleic acid drugs, composed of nucleotides, represent a novel class of pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression and regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), microRNAs (miRNAs), and aptamers. The emergence of small nucleic acid drugs as a focal point in contemporary biopharmaceutical research is attributed to their remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, and prolonged activity. Overcoming challenges such as poor stability, immunogenicity, and permeability issues have been addressed through the integration of chemical modifications and the development of drug delivery systems. This review provides an overview of the current status and prospective trends in small nucleic acid drug development. Commencing with a historical context, we introduce the primary classifications and mechanisms of small nucleic acid drugs. Subsequently, we delve into the advantages of the U.S. Food and Drug Administration (FDA) approved drugs and mainly discuss the challenges encountered during their development. Apart from researching chemical modification and delivery system that efficiently deliver and enrich small nucleic acid drugs to target tissues, promoting endosomal escape is a critical scientific question and important research direction in siRNA drug development. Future directions in this field will prioritize addressing these challenges to facilitate the clinical transformation of small nucleic acid drugs.
Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases
Authors: Ao Wang, Yi Zhang, Xinting Lv, Guang Liang
Journal: Acta Pharmaceutica Sinica B (2024)

Protein tyrosine phosphorylation is a post-translational modification that regulates protein structure to modulate demic organisms' homeostasis and function. This physiological process is regulated by two enzyme families, protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). As an important regulator of protein function, PTPs are indispensable for maintaining cell intrinsic physiology in different systems, as well as liver physiological and pathological processes. Dysregulation of PTPs has been implicated in multiple liver-related diseases, including chronic liver diseases (CLDs), hepatocellular carcinoma (HCC), and liver injury, and several PTPs are being studied as drug therapeutic targets. Therefore, given the regulatory role of PTPs in diverse liver diseases, a collated review of their function and mechanism is necessary. Moreover, based on the current research status of targeted therapy, we emphasize the inclusion of several PTP members that are clinically significant in the development and progression of liver diseases. As an emerging breakthrough direction in the treatment of liver diseases, this review summarizes the research status of PTP-targeting compounds in liver diseases to illustrate their potential in clinical treatment. Overall, this review aims to support the development of novel PTP-based treatment pathways for liver diseases.
Representation of internal speech by single neurons in human supramarginal gyrus
Authors: Sarah K Wandelt, David A Bjånes, Kelsie Pejsa, Brian Lee, Charles Liu, Richard A Andersen
Journal: Nature Human Behaviour (2024)

Abstract Speech brain–machine interfaces (BMIs) translate brain signals into words or audio outputs, enabling communication for people having lost their speech abilities due to diseases or injury. While important advances in vocalized, attempted and mimed speech decoding have been achieved, results for internal speech decoding are sparse and have yet to achieve high functionality. Notably, it is still unclear from which brain areas internal speech can be decoded. Here two participants with tetraplegia with implanted microelectrode arrays located in the supramarginal gyrus (SMG) and primary somatosensory cortex (S1) performed internal and vocalized speech of six words and two pseudowords. In both participants, we found significant neural representation of internal and vocalized speech, at the single neuron and population level in the SMG. From recorded population activity in the SMG, the internally spoken and vocalized words were significantly decodable. In an offline analysis, we achieved average decoding accuracies of 55% and 24% for each participant, respectively (chance level 12.5%), and during an online internal speech BMI task, we averaged 79% and 23% accuracy, respectively. Evidence of shared neural representations between internal speech, word reading and vocalized speech processes was found in participant 1. SMG represented words as well as pseudowords, providing evidence for phonetic encoding. Furthermore, our decoder achieved high classification with multiple internal speech strategies (auditory imagination/visual imagination). Activity in S1 was modulated by vocalized but not internal speech in both participants, suggesting no articulator movements of the vocal tract occurred during internal speech production. This work represents a proof-of-concept for a high-performance internal speech BMI.
Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction
Authors: Guochong Jia, Jie Ping, Xingyi Guo, Yaohua Yang, Ran Tao, Bingshan Li, Stefan Ambs, Mollie E Barnard, Yu Chen, Montserrat Garcia-Closas, Jian Gu, Jennifer J Hu, Dezheng Huo, Esther M John, Christopher I Li, James L Li, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Tuya Pal, Michael F Press, Maureen Sanderson, Dale P Sandler, Xiao-Ou Shu, Melissa A Troester, Song Yao, Prisca O Adejumo, Thomas Ahearn, Abenaa M Brewster, Anselm J M Hennis, Timothy Makumbi, Paul Ndom, Katie M O'Brien, Andrew F Olshan, Mojisola M Oluwasanu, Sonya Reid, Ebonee N Butler, Maosheng Huang, Atara Ntekim, Huijun Qian, Haoyu Zhang, Christine B Ambrosone, Qiuyin Cai, Jirong Long, Julie R Palmer, Christopher A Haiman, Wei Zheng
Journal: Nature Genetics (2024)
Prognostic Value of a 6-Minute Walk Test in Patients With Transthyretin Cardiac Amyloidosis
Authors: Adam Ioannou, Carlo Fumagalli, Yousuf Razvi, Aldostefano Porcari, Muhammad U. Rauf, Ana Martinez-Naharro, Lucia Venneri, William Moody, Richard P. Steeds, Aviva Petrie, Carol Whelan, Ashutosh Wechalekar, Helen Lachmann, Philip N. Hawkins, Scott D. Solomon, Julian D. Gillmore, Marianna Fontana
Journal: Journal of the American College of Cardiology (2024)

The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA).
Insights into therapeutic peptides in the cancer-immunity cycle: Update and challenges
Authors: Xiaokun Zhang, Ye Wu, Jiayi Lin, Shengxin Lu, Xinchen Lu, Aoyu Cheng, Hongzhuan Chen, Weidong Zhang, Xin Luan
Journal: Acta Pharmaceutica Sinica B (2024)

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.
Mitophagy and cGAS–STING crosstalk in neuroinflammation
Authors: Xiaogang Zhou, Jing Wang, Lu Yu, Gan Qiao, Dalian Qin, Betty Yuen-Kwan Law, Fang Ren, Jianming Wu, Anguo Wu
Journal: Acta Pharmaceutica Sinica B (2024)

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS–STING pathway. We critically evaluated the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, activating the cGAS–STING pathway. This activation prompts the production of proinflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS–STING pathway. Effective mitophagy might suppress the cGAS–STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS–STING pathway, potentially leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy–cGAS–STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, which could lead to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues in neurodegenerative disease research.
Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke
Authors: Ru Li, Riqing Wei, Chenxin Liu, Keying Zhang, Sixiao He, Zhifeng Liu, Junhao Huang, Youyong Tang, Qiyuan An, Ligen Lin, Lishe Gan, Liying Zhao, Xiaoming Zou, Fudi Wang, Yuan Ping, Qiang Ma
Journal: Acta Pharmaceutica Sinica B (2024)

With the escalating prevalence of global heat waves, heat stroke has become a prominent health concern, leading to substantial liver damage. Unlike other forms of liver injury, heat stroke-induced damage is characterized by heat cytotoxicity and heightened inflammation, directly contributing to elevated mortality rates. While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction, their specific correlation with heat stroke liver injury remains unclear. Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke, initiating IL-1
Engineered nanoparticles for precise targeted drug delivery and enhanced therapeutic efficacy in cancer immunotherapy
Authors: Xueqiang Peng, Jianjun Fang, Chuyuan Lou, Liang Yang, Shaobo Shan, Zixian Wang, Yutong Chen, Hangyu Li, Xuexin Li
Journal: Acta Pharmaceutica Sinica B (2024)

The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system. However, the challenge of practical and precise targeting of malignant cells persists. To address this, engineered nanoparticles (NPs) have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions, owing to their small size, low immunogenicity, and ease of surface modification. This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy, encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness. Moreover, it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities. Finally, the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy, which could shape the path for future advancements in this promising field.
Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis
Authors: Hiroki Sato, Evan S. Dellon, Seema S. Aceves, Nicoleta C. Arva, Mirna Chehade, Margaret H. Collins, Carla M. Davis, Gary W. Falk, Glenn T. Furuta, Nirmala P. Gonsalves, Sandeep K. Gupta, Ikuo Hirano, Girish Hiremath, David A. Katzka, Paneez Khoury, John Leung, Paul Menard-Katcher, Robbie Pesek, Kathryn A. Peterson, Maria A. Pletneva, Jonathan M. Spergel, Joshua B. Wechsler, Guang-Yu Yang, Marc E. Rothenberg, Tetsuo Shoda
Journal: Journal of Allergy and Clinical Immunology (2024)
GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3
Authors: Siping Liang, Jinyu Zhou, Can Cao, Yiting Liu, Siqi Ming, Xi Liu, Yuqi Shang, Juanfeng Lao, Qin Peng, Jiahui Yang, Minhao Wu
Journal: Cellular and Molecular Immunology (2024)
Newborn Screening for 6 Lysosomal Storage Disorders in China
Authors: Siyu Chang, Xia Zhan, Yuchao Liu, Huanlei Song, Zizhen Gong, Lianshu Han, Gustavo H. B. Maegawa, Xuefan Gu, Huiwen Zhang
Journal: JAMA Network Open (2024)

Importance Newborn screening (NBS) for lysosomal storage disorders (LSDs) is becoming an increasing concern in public health. However, the birth prevalence of these disorders is rarely reported in the Chinese population, and subclinical forms of diseases among patients identified by NBS have not been evaluated. Objective To evaluate the birth prevalence of the 6 LSDs in the Shanghai population and determine subclinical forms based on clinical, biochemical, and genetic characteristics. Design, Setting, and Participants This cohort study included 50 108 newborns recruited from 41 hospitals in Shanghai between January and December 2021 who were screened for 6 LSDs using tandem mass spectrometry (MS/MS). Participants with screen-positive results underwent molecular and biochemical tests and clinical assessments. Data were analyzed from January 2021 through October 2022. Exposures All participants were screened for Gaucher, acid sphingomyelinase deficiency (ASMD), Krabbe, mucopolysaccharidosis type I, Fabry, and Pompe diseases using dried blood spots. Main Outcomes and Measures Primary outcomes were the birth prevalence and subclinical forms of the 6 LSDs in the Shanghai population. Disease biomarker measurements, genetic testing, and clinical analysis were used to assess clinical forms of LSDs screened. Results Among 50 108 newborns (26 036 male [52.0%]; mean [SD] gestational age, 38.8 [1.6] weeks), the mean (SD) birth weight was 3257 (487) g. The MS/MS-based NBS identified 353 newborns who were positive. Of these, 27 newborns (7.7%) were diagnosed with 1 of 6 LSDs screened, including 2 newborns with Gaucher, 5 newborns with ASMD, 9 newborns with Krabbe, 8 newborns with Fabry, and 3 newborns with Pompe disease. The combined birth prevalence of LSDs in Shanghai was 1 diagnosis in 1856 live births, with Krabbe disease the most common (1 diagnosis/5568 live births), followed by Fabry disease (1 diagnosis/6264 live births), and ASMD (1 diagnosis/10 022 live births). Biochemical, molecular, and clinical analysis showed that early-onset clinical forms accounted for 3 newborns with positive results (11.1%), while later-onset forms represented nearly 90% of diagnoses (24 newborns [88.9%]). Conclusions and Relevance In this study, the combined birth prevalence of the 6 LSDs in Shanghai was remarkably high. MS/MS-based newborn screening, combined with biochemical and molecular genetic analysis, successfully identified and characterized newborns who were screen-positive, which may assist with parental counseling and management decisions.
Patent Portfolios Protecting 10 Top-Selling Prescription Drugs
Authors: Caroline Horrow, Sarah M.E. Gabriele, S. Sean Tu, Ameet Sarpatwari, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2024)

Importance Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years. Objective To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval. Design and Setting This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023. Main Outcomes and Measures Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time). Results The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval. Conclusions and Relevance This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.
Opioid-Induced Adrenal Insufficiency
Authors: Douglas Rice, Hirofumi Yoshida
Journal: JAMA Internal Medicine (2024)

This case report describes a woman in her 40s with opioid use disorder receiving methadone who was admitted for extended antibiotic treatment for methicillin-resistant Staphylococcus aureus bacteremia and was subesequently diagnosed with opioid-induced adrenal insufficiency.
Health Service Use and Costs During Pregnancy Among Privately Insured Individuals With Congenital Heart Disease
Authors: Anushree Agarwal, Rong Duan, Nasim C. Sobhani, Aarthi Sabanayagam, Gregory M. Marcus, Michelle Gurvitz
Journal: JAMA Network Open (2024)

Individuals with congenital heart disease (CHD) are increasingly reaching childbearing age, are more prone to adverse pregnancy events, and uncommonly undergo recommended cardiac evaluations. Data to better understand resource allocation and financial planning are lacking.
Physicians and Specialties in the Veterans Health Administration’s Community Care Network
Authors: Yevgeniy Feyman, Kevin N. Griffith, Allison Dorneo, Sandra F. Simmons, Christianne L. Roumie, Kristin M. Mattocks
Journal: JAMA Network Open (2024)

This cross-sectional study of data from the US Veterans Health Administration examines the availability of services provided through community care networks by specialty and clinical characteristics.