tbuckley/cabot-search huggingface dataset:
Combination Treatment with Verinurad and Allopurinol in CKD
Authors: Hiddo J.L. Heerspink, Austin G. Stack, Robert Terkeltaub, Niels Jongs, Lesley A. Inker, Magnus Bjursell, Noha Maklad, Shira Perl, Olof Eklund, Tord Rikte, C. David Sjöström, Vlado Perkovic
Journal: Journal of the American Society of Nephrology (2024)

Key Points The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD. Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia. Methods In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m 2 , and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60. Results Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m 2 , median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups. Conclusions Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo. Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.
Epithelial Malignant Pleural Mesothelioma Mimics Lymphoma on 18F-FDG PET/MRI
Authors: Tian Tian, Hangyu Xie, Meijuan Huang
Journal: Clinical Nuclear Medicine (2024)

Abstract Malignant pleural mesothelioma is a rare tumor with a poor prognosis. We describe a case of 55-year-old man without asbestos exposure history presenting with extensive lymph nodes with high 18 F-FDG uptake in PET/MRI but atypical pleural manifestations thereby being misdiagnosed for lymphoma. Pathological examination concludes for an epithelioid mesothelioma–associated lymph node metastasis. This case emphasizes that with the extensive lymph node abnormalities shown in PET imaging, in addition to the general consideration of lymphoma, it is still necessary to be vigilant about the possibility of mesothelioma and emphasizes the necessity of pathological examination.
Integrated electronic/fluidic microneedle system for glucose sensing and insulin delivery
Authors: Xinshuo Huang, Baoming Liang, Shuang Huang, Zhengjie Liu, Chuanjie Yao, Jingbo Yang, Shantao Zheng, Feifei Wu, Wan Yue, Ji Wang, Huijiuan Chen, Xi Xie
Journal: Theranostics (2024)

Background: Precise and dynamic blood glucose regulation is paramount for both diagnosing and managing diabetes.Continuous glucose monitoring (CGM) coupled with insulin pumps forms an artificial pancreas, enabling closed-loop control of blood glucose levels.Indeed, this integration necessitates advanced micro-nano fabrication techniques to miniaturize and combine sensing and delivery modules on a single electrode.While microneedle technology can mitigate discomfort, concerns remain regarding infection risk and potential sensitivity limitations due to their short needle length.Methods: This study presents the development of an integrated electronic/fluidic microneedle patch (IEFMN) designed for both glucose sensing and insulin delivery.The use of minimally invasive microneedles mitigates nerve contact and reduces infection risks.The incorporation of wired enzymes addresses the issue of "oxygen deprivation" during glucose detection by decreasing the reliance on oxygen.The glucose-sensing electrodes employ wired enzyme functionalization to achieve lower operating voltages and enhanced resilience to sensor interference.The hollow microneedles' inner channel facilitates precise drug delivery for blood glucose regulation.Results: Our IEFMN-based system demonstrated high sensitivity, selectivity, and a wide response range in glucose detection at relatively low voltages.This effectively reduced interference from both external and internal active substances.The microneedle array ensured painless and minimally invasive skin penetration, while wired enzyme functionalization not only lowered sensing potential but also improved glucose detection accuracy.In vivo, experiments conducted in rats showed that the device could track subcutaneous glucose fluctuations in real-time and deliver insulin to regulate blood glucose levels.Conclusions: Our work suggests that the IEFMN-based system, developed for glucose sensing and insulin delivery, exhibits good performance during in vivo glucose detection and drug delivery.It holds the potential to contribute to real-time, intelligent, and controllable diabetes management.
Diagnosis and Management of Paroxysmal Supraventricular Tachycardia
Authors: Gary Peng, Paul C. Zei
Journal: JAMA (2024)

Importance Paroxysmal supraventricular tachycardia (PSVT), defined as tachyarrhythmias that originate from or conduct through the atria or atrioventricular node with abrupt onset, affects 168 to 332 per 100 000 individuals. Untreated PSVT is associated with adverse outcomes including high symptom burden and tachycardia-mediated cardiomyopathy. Observations Approximately 50% of patients with PSVT are aged 45 to 64 years and 67.5% are female. Most common symptoms include palpitations (86%), chest discomfort (47%), and dyspnea (38%). Patients may rarely develop tachycardia-mediated cardiomyopathy (1%) due to PSVT. Diagnosis is made on electrocardiogram during an arrhythmic event or using ambulatory monitoring. First-line acute therapy for hemodynamically stable patients includes vagal maneuvers such as the modified Valsalva maneuver (43% effective) and intravenous adenosine (91% effective). Emergent cardioversion is recommended for patients who are hemodynamically unstable. Catheter ablation is safe, highly effective, and recommended as first-line therapy to prevent recurrence of PSVT. Meta-analysis of observational studies shows single catheter ablation procedure success rates of 94.3% to 98.5%. Evidence is limited for the effectiveness of long-term pharmacotherapy to prevent PSVT. Nonetheless, guidelines recommend therapies including calcium channel blockers, β-blockers, and antiarrhythmic agents as management options. Conclusion and Relevance Paroxysmal SVT affects both adult and pediatric populations and is generally a benign condition. Catheter ablation is the most effective therapy to prevent recurrent PSVT. Pharmacotherapy is an important component of acute and long-term management of PSVT.
ASK1/p38 axis inhibition blocks the release of mitochondrial “danger signals” from hepatocytes and suppresses progression to cirrhosis and liver cancer
Authors: Zhenwei Peng, Guangyan Wei, Pinzhu Huang, Heansika Matta, Wen Gao, Ping An, Shuangshuang Zhao, Yi Lin, Li Tan, Kahini Vaid, Disha Skelton-Badlani, Imad Nasser, Grant Budas, David Lopez, Li Li, David Breckenridge, Rob Myers, John McHutchison, Ming Kuang, Yury V. Popov
Journal: Hepatology (2024)

Background and Aims: Apoptosis Signal–regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems. Approach and Results: Short-term (4–6 wk) and long-term (24–44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2−/− murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 − / − model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2−/− mice resulted in markedly reduced tumor number and size by ~50% compared to the control group. Conclusions: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2 −/− mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.
Enhanced SLC35B2/SAV1 sulfation axis promotes tumor growth by inhibiting Hippo signaling in HCC
Authors: Bo He, Zhao Huang, Siyuan Qin, Peilan Peng, Xirui Duan, Longqin Wang, Qin Ye, Kui Wang, Jingwen Jiang, Bowen Li, Rui Liu, Canhua Huang
Journal: Hepatology (2024)

Background and Aims: Protein tyrosine sulfation (PTS) is a common posttranslational modification that regulates a variety of physiological and pathological processes. However, the role of PTS in cancer remains poorly understood. The goal of this study was to determine whether and how PTS plays a role in HCC progression. Approach and Results: By mass spectrometry and bioinformatics analysis, we identified SAV1 as a novel substrate of PTS in HCC. Oxidative stress upregulates the transcription of SLC35B2, a Golgi-resident transporter of sulfate donor 3ʹ-phosphoadenosine 5ʹ-phosphosulfate, leading to increased sulfation of SAV1. Sulfation of SAV1 disrupts the formation of the SAV1-MST1 complex, resulting in a decrease of MST1 phosphorylation and subsequent inactivation of Hippo signaling. These molecular events ultimately foster the growth of HCC cells both in vivo and in vitro. Moreover, SLC35B2 is a novel transcription target gene of the Hippo pathway, constituting a positive feedback loop that facilitates HCC progression under oxidative stress. Conclusions: Our findings reveal a regulatory mechanism of the SLC35B2/SAV1 sulfation axis in response to oxidative stress, highlighting its potential as a promising therapeutic target for HCC.
Gsα Regulates Macrophage Foam Cell Formation During Atherosclerosis
Authors: Chang Ma, Yihui Li, Mi Tian, Qiming Deng, Xiaoteng Qin, Hanlin Lu, Jiangang Gao, Min Chen, Lee S. Weinstein, Mei Zhang, Peili Bu, Jianmin Yang, Yun Zhang, Cheng Zhang, Wencheng Zhang
Journal: Circulation Research (2024)

BACKGROUND: Many cardiovascular pathologies are induced by signaling through G-protein-coupled receptors via Gsα (G protein stimulatory α subunit) proteins. However, the specific cellular mechanisms that are driven by Gsα and contribute to the development of atherosclerosis remain unclear. METHODS: High-throughput screening involving data from single-cell and bulk sequencing were used to explore the expression of Gsα in atherosclerosis. The differentially expression and activity of Gsα were analyzed by immunofluorescence and cAMP measurements. Macrophage-specific Gsα knockout (Mac-Gsα KO ) mice were generated to study the effect on atherosclerosis. The role of Gsα was determined by transplanting bone marrow and performing assays for foam cell formation, Dil-ox-LDL (oxidized low-density lipoprotein) uptake, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: ScRNA-seq showed elevated Gnas in atherosclerotic mouse aorta’s cholesterol metabolism macrophage cluster, while bulk sequencing confirmed increased GNAS expression in human plaque macrophage content. A significant upregulation of Gsα and active Gsα occurred in macrophages from human and mouse plaques. Ox-LDL could translocate Gsα from macrophage lipid rafts in short-term and promote Gnas transcription through ERK1/2 activation and C/EBPβ phosphorylation via oxidative stress in long-term. Atherosclerotic lesions from Mac-Gsα KO mice displayed decreased lipid deposition compared with those from control mice. Additionally, Gsα deficiency alleviated lipid uptake and foam cell formation. Mechanistically, Gsα increased the levels of cAMP and transcriptional activity of the cAMP response element binding protein, which resulted in increased expression of CD36 and SR-A1. In the translational experiments, inhibiting Gsα activation with suramin or cpGN13 reduced lipid uptake, foam cell formation, and the progression of atherosclerotic plaques in mice in vivo. CONCLUSIONS: Gsα activation is enhanced during atherosclerotic progression and increases lipid uptake and foam cell formation. The genetic or chemical inactivation of Gsα inhibit the development of atherosclerosis in mice, suggesting that drugs targeting Gsα may be useful in the treatment of atherosclerosis.
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases
Authors: Chan Rim, Min-Jung You, Minyeop Nahm, Min-Soo Kwon
Journal: Translational Neurodegeneration (2024)

Abstract Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.
A genomic variation map provides insights into peanut diversity in China and associations with 28 agronomic traits
Authors: Qing Lu, Lu Huang, Hao Liu, Vanika Garg, Sunil S. Gangurde, Haifen Li, Annapurna Chitikineni, Dandan Guo, Manish K. Pandey, Shaoxiong Li, Haiyan Liu, Runfeng Wang, Quanqing Deng, Puxuan Du, Rajeev K. Varshney, Xuanqiang Liang, Yanbin Hong, Xiaoping Chen
Journal: Nature Genetics (2024)
Intense 18F–Prostate-Specific Membrane Antigen Uptake and Mild 18F-FDG Uptake in a Biopsy-Proven Pulmonary Hemangioma
Authors: Feng Xu, Frank Liu
Journal: Clinical Nuclear Medicine (2024)

Abstract We present intense radiotracer activity in a soft tissue density abutting the aortic arch of the left lung on 18 F–prostate-specific membrane antigen PET/CT scan in a patient with prostate cancer, mimicking metastatic disease from prostate cancer versus primary lung malignancy. 18 F-FDG PET/CT scan, however, shows no elevated FDG activity. The results of pathology examination from resected specimen are consistent with pulmonary hemangioma.
Early Metformin Treatment for Gestational Diabetes—Reply
Authors: Fidelma Dunne, Christine Newman, Andrew Smyth
Journal: JAMA (2024)

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Artificial intelligence and open science in discovery of disease-modifying medicines for Alzheimer’s disease
Authors: Feixiong Cheng, Fei Wang, Jian Tang, Yadi Zhou, Zhimin Fu, Pengyue Zhang, Jonathan L. Haines, James B. Leverenz, Li Gan, Jianying Hu, Michal Rosen-Zvi, Andrew A. Pieper, Jeffrey Cummings
Journal: Cell Reports Medicine (2024)

The high failure rate of clinical trials in Alzheimer's disease (AD) and AD-related dementia (ADRD) is due to a lack of understanding of the pathophysiology of disease, and this deficit may be addressed by applying artificial intelligence (AI) to "big data" to rapidly and effectively expand therapeutic development efforts. Recent accelerations in computing power and availability of big data, including electronic health records and multi-omics profiles, have converged to provide opportunities for scientific discovery and treatment development. Here, we review the potential utility of applying AI approaches to big data for discovery of disease-modifying medicines for AD/ADRD. We illustrate how AI tools can be applied to the AD/ADRD drug development pipeline through collaborative efforts among neurologists, gerontologists, geneticists, pharmacologists, medicinal chemists, and computational scientists. AI and open data science expedite drug discovery and development of disease-modifying therapeutics for AD/ADRD and other neurodegenerative diseases.
Combination of 68Ga-FAPI-04 and Dedicated Breast PET (MAMMI PET) Outperformed Breast MRI and 18F-FDG PET/CT by Revealing Nipple and Skin Involvement of Breast Cancer
Authors: Duygu Has Simsek, Melis Oflas, Ravza Yilmaz, Mustafa Tukenmez, Serkan Kuyumcu
Journal: Clinical Nuclear Medicine (2024)

Abstract A 41-year-old woman with newly diagnosed breast cancer had suspicious clinical findings of skin involvement on physical examination. The primary tumor had no FDG uptake in 18 F-FDG PET/CT. Nipple and skin had no pathologic enhancement for invasion in breast MRI. Because the T stage was unclear, the patient underwent 68 Ga-FAPI-04 PET/CT for further evaluation. Combination of 68 Ga-FAPI-04 with dedicated breast PET (MAMMI PET) showed nipple and skin involvement of breast cancer with intense FAPI uptake. Consequently, a skin-sparing mastectomy was performed. Histopathological examination confirmed invasive lobular carcinoma infiltration of the deep dermis in the nipple and skin tissue.
Germline CHEK2 mutations in patients with myeloid neoplasms
Authors: Lucie Freiman, Lise Larcher, Giulia Tueur, Nadia Vasquez, Mélanie Da Costa, Matthieu Duchmann, Emmanuel Raffoux, Lionel Adès, Pierre Fenaux, Jean Soulier, Nicolas Duployez, Emmanuelle Clappier, Marie Sébert
Journal: Leukemia (2024)
Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation
Authors: Valeria Lo Faro, Arjun Bhattacharya, Wei Zhou, Dan Zhou, Ying Wang, Kristi Läll, Masahiro Kanai, Esteban Lopera-Maya, Peter Straub, Priyanka Pawar, Ran Tao, Xue Zhong, Shinichi Namba, Serena Sanna, Ilja M. Nolte, Yukinori Okada, Nathan Ingold, Stuart MacGregor, Harold Snieder, Ida Surakka, Jonathan Shortt, Chris Gignoux, Nicholas Rafaels, Kristy Crooks, Anurag Verma, Shefali S. Verma, Lindsay Guare, Daniel J. Rader, Cristen Willer, Alicia R. Martin, Milam A. Brantley, Eric R. Gamazon, Nomdo M. Jansonius, Karen Joos, Nancy J. Cox, Jibril Hirbo
Journal: Cell Reports Medicine (2024)

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.
Deregulation of the p19/CDK4/CDK6 axis in Jak2V617F megakaryocytes accelerates the development of myelofibrosis
Authors: Hélène Duparc, Delphine Muller, Laure Gilles, Agathe L. Chédeville, Mira El Khoury, Rose Guignard, Najet Debili, Monika Wittner, Alexandre Kauskot, Florence Pasquier, Iléana Antony-Debré, Caroline Marty, William Vainchenker, Isabelle Plo, Hana Raslova
Journal: Leukemia (2024)