tbuckley/cabot-search huggingface dataset:
The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy
Authors: Hongtu Hu, Weiwei Li, Yiqun Hao, Zhuan Peng, Zhengping Zou, Jiali Wei, Ying Zhou, Wei Liang, Yun Cao
Journal: Cell Reports Medicine (2024)

Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
Affinity-independent memory B cell origin of the early antibody-secreting cell response in naive individuals upon SARS-CoV-2 vaccination
Authors: Zhe Li, Anna Obraztsova, Fuwei Shang, Opeyemi Ernest Oludada, Joshua Malapit, Katrin Busch, Monique van Straaten, Erec Stebbins, Rajagopal Murugan, Hedda Wardemann
Journal: Immunity (2024)

Highlights•SARS-CoV-2 mRNA vaccination activates naive and pre-existing MBCs in naive individuals•S-reactive naive, but not pre-existing, MBCs show signs of strong affinity maturation•Despite low S reactivity, pre-existing MBCs dominate the early ASC response•High-affinity anti-S MBCs and ASCs develop from naive, not MBC, precursorsSummaryMemory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the circulating B cell repertoire in humans. These pre-existing MBCs dominate recall responses to their cognate antigens, but how they respond to recognition of novel antigens is not well understood. Here, we tracked the origin and followed the differentiation paths of MBCs in the early anti-spike (S) response to mRNA vaccination in SARS-CoV-2-naive individuals on single-cell and monoclonal antibody levels. Pre-existing, highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody-secreting cells (ASCs). By contrast, and despite similar levels of S reactivity, naive B cells showed strong signs of antibody affinity maturation before differentiating into MBCs and ASCs. Thus, pre-existing human MBCs differentiate into ASCs in response to novel antigens, but the quality of the humoral and cellular anti-S response improved through the clonal selection and affinity maturation of naive precursors.Graphical abstract
Efficiency and Safety of Targeted Alpha Therapy in Metastatic Neuroendocrine Tumors
Authors: Dong Yun Lee, Yong-il Kim
Journal: Clinical Nuclear Medicine (2024)

Despite the effectiveness of 177 Lu-based peptide receptor radionuclide therapy in treating metastatic neuroendocrine tumors (NETs), disease progression posttreatment remains a significant challenge. Targeted alpha therapy (TAT) has emerged as a promising option for patients experiencing such progression. This study aims to assess the therapeutic efficiency and toxicity of TAT in patients with metastatic NET through a meta-analysis.
Relationship between serum urate and changes in dual-energy CT monosodium urate crystal volume over 1 year in people with gout: an individual participant data analysis
Authors: Brooke Kelly, Greg D. Gamble, Anne Horne, Anthony J. Doyle, Jill Drake, Opetaia Aati, Chang-Nam Son, Ramanamma Kalluru, Kieran Latto, Lisa Stamp, Nicola Dalbeth
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Objectives</h3> The dynamics of monosodium urate (MSU) crystal changes across a range of serum urate concentrations in people with gout are unknown. This study aimed to systematically examine the relationship between serum urate and changes in dual-energy CT (DECT) urate volume in people with gout and stable serum urate concentrations. <h3>Methods</h3> Individual participant data were analysed from three studies of people with gout. The time periods for the analysis were selected to identify study participants with serial DECT scans of both feet over a 12-month epoch of stable urate-lowering therapy and serum urate concentrations. Data from 251 study participants were analysed using a mixed models analysis of covariance approach according to mean serum urate cut-points and mean serum urate bands. <h3>Results</h3> For all mean serum urate cut-points assessed (0.24, 0.30, 0.36, 0.42 and 0.48 mmol/L), reductions in DECT urate volumes were observed below the cut-point. Increased DECT urate volumes were observed at or above the 0.48 mmol/L mean serum urate cut-point. Differences in the change in DECT volume were observed for the 0.42 mmol/L cut-point (p=0.0044) and the 0.48 mmol/L cut-point (p&lt;0.0001). Significantly reduced DECT urate volumes were observed for the mean serum urate bands&lt;0.24 mmol/L and 0.24–0.29 mmol/L and increased DECT urate volume was observed for the mean serum urate band≥0.48 mmol/L. <h3>Conclusions</h3> Over 1 year, MSU crystal dissolution, as measured by DECT, occurs with mean serum urate bands of&lt;0.24 mmol/L and 0.24–0.29 mmol/L while MSU crystal formation occurs with mean serum urate≥0.48 mmol/L.
FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis
Authors: Maheedhar Kodali, Leelavathi N. Madhu, Venkata Sai Vashishta Kolla, Sahithi Attaluri, Charles Huard, Yogish Somayaji, Bing Shuai, Chase Jordan, Xiaolan Rao, Sanath Shetty, Ashok K. Shetty
Journal: Military Medical Research (2024)

Abstract Background Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex ® , a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI. Methods Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N -diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests. Results GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus. Conclusions The use of an FDA-approved CBD (Epidiolex ® ) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
Intra-Ethnic and Geographic Disparities in Stage at Diagnosis for Non-Small Cell Lung Cancer
Authors: Qinran Liu, Heidy N Medina, Tulay Koru-Sengul, Estelamari Rodriguez, Gilberto Lopes, Frank J Penedo, Farhad Islami, Paulo S Pinheiro
Journal: JNCI Journal of the National Cancer Institute (2024)

Despite the importance of early detection for lung cancer outcomes, staging disparities among the growing US Hispanic population remain underexplored. This population-based study aimed to identify racial/ethnic disparities among non-Hispanic White, non-Hispanic Black, and Hispanic (including specific subgroups) patients in stage at diagnosis for potentially curable non-small cell lung cancer (NSCLC).
Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females
Authors: Brendan Cordeiro, Jeeyoon Jennifer Ahn, Saurabh Gawde, Carmen Ucciferri, Nuria Alvarez-Sanchez, Xavier S Revelo, Natalie Stickle, Kaylea Massey, David G Brooks, Joel M Guthridge, Gabriel Pardo, Daniel A Winer, Robert C Axtell, Shannon E Dunn
Journal: Cell Metabolism (2024)

Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-α and potentiated STAT1 expression and IFN-γ production by naive CD4
On RNA-programmable gene modulation as a versatile set of principles targeting muscular dystrophies
Authors: Sabrina Capelletti, Sofía C García Soto, Manuel A F V Gonçalves
Journal: Molecular Therapy (2024)

The repurposing of RNA-programmable CRISPR systems from genome editing into epigenome editing tools is gaining pace, including in research and development efforts directed at tackling human disorders. This momentum stems from the increasing knowledge regarding the epigenetic factors and networks underlying cell physiology and disease etiology and from the growing realization that genome editing principles involving chromosomal breaks generated by programmable nucleases are prone to unpredictable genetic changes and outcomes. Hence, engineered CRISPR systems are serving as versatile DNA-targeting scaffolds for heterologous and synthetic effector domains that, via locally recruiting transcription factors and chromatin remodeling complexes, seek interfering with loss-of-function and gain-of-function processes underlying recessive and dominant disorders, respectively. Here, after providing an overview about epigenetic drugs and CRISPR-Cas-based activation and interference platforms, we cover the testing of these platforms in the context of molecular therapies for muscular dystrophies. Finally, we examine attributes, obstacles, and deployment opportunities for CRISPR-based epigenetic modulating technologies.Graphical abstract
Clinical features and surgical strategy of retroperitoneal liposarcoma involving the kidney capsule: A retrospective comparative cohort study
Authors: Yiyuan Li, Jichun Zhao, Bin Huang, Qiang Guo
Journal: International Journal of Surgery (2024)

Background: Valid and generalizable data on the clinical features and surgical strategies for retroperitoneal liposarcoma (LPS) involving the kidney capsule remain scarce. This study aimed to investigate the clinical characteristics, morbidity, mortality, and long-term survival of patients with retroperitoneal LPS involving the kidney capsule. Methods: The authors analyzed a prospectively maintained database of patients who underwent surgical resection for retroperitoneal LPS between 2015 and 2020. The patients were categorized into kidney capsule or no kidney capsule groups based on the presence or absence of kidney capsule involvement. A kidney-sparing strategy for retroperitoneal LPS involving the kidney capsule was developed. The primary outcome measure was overall survival (OS). The cumulative event probability curve was estimated using the Kaplan–Meier, and differences between groups using the Log-Rank. Results: The study population consisted of 128 patients—54 with and 74 without kidney capsule involvement. Of these patients, 70 were female (54.7%) and 58 were male (45.3%), with a median age of 55. The median follow-up duration was 35 months. Postoperative morbidity, mortality, length of hospital stay, length of ICU stay, OS, and recurrence-free survival (RFS) did not differ significantly between the groups. Eleven patients developed postoperative acute kidney injury (AKI), and one patient required dialysis during the follow-up period. In multivariable logistic regression analysis, only nephrectomy was independently associated with postoperative AKI. Subgroup analysis of patients with kidney capsule involvement showed that nephrectomy did not improve OS or RFS but significantly decreased postoperative estimated glomerular filtration rate. Conclusion: Nephrectomy was associated with an increased risk of postoperative AKI after retroperitoneal LPS resection. A kidney-sparing strategy for retroperitoneal LPS involving the kidney capsule achieved optimal clinical outcomes.
Accuracy of cell-free Mycobacterium tuberculosis DNA testing in pleural effusion for diagnosing tuberculous pleurisy: a multicenter cross-sectional study
Authors: Wei-Li Du, Jian-Qin Liang, Xin-Ting Yang, Cheng-Jun Li, Qing-Feng Wang, Wen-Ge Han, Ye Li, Zhi-Hui Li, Dong-Mei Zhao, Fu-Dong Xu, Yan-Xiao Rong, Xiao-Jing Cui, Hui-Min Li, Feng Wang, Peng-Chong Liu, Dong-Lin Guo, Hai-Bin Wang, Xu-Ya Xing, Jia-Lu Che, Zi-Chen Liu, Na-Na Zhang, Kun Li, Yi Liu, Li Wang, Hai-Bo Wang, Nan-Ying Che
Journal: Military Medical Research (2024)

Abstract Background The diagnosis of tuberculous pleurisy (TP) presents a significant challenge due to the low bacterial load in pleural effusion (PE) samples. Cell-free Mycobacterium tuberculosis DNA (cf-TB) in PE samples is considered an optimal biomarker for diagnosing TP. This study aimed to evaluate the applicability of cf-TB testing across diverse research sites with a relatively large sample size. Methods Patients suspected of TP and presenting with clinical symptoms and radiological evidence of PE were consecutively enrolled by treating physicians from 11 research sites across 6 provinces in China between April 2020 and August 2022. Following centrifugation, sediments obtained from PE were used for Xpert MTB/RIF (Xpert) and mycobacterial culture, while the supernatants were subjected to cf-TB testing. This study employed a composite reference standard to definite TP, which was characterized by any positive result for Mycobacterium tuberculosis (MTB) through either PE culture, PE Xpert, or pleural biopsy. Results A total of 1412 participants underwent screening, and 1344 (95.2%) were subsequently enrolled in this study. Data from 1241 (92.3%) participants were included, comprising 284 with definite TP, 677 with clinically diagnosed TP, and 280 without TP. The sensitivity of cf-TB testing in definite TP was 73.6% (95% CI 68.2–78.4), significantly higher than both Xpert (40.8%, 95% CI 35.3–46.7, P &lt; 0.001) and mycobacterial culture (54.2%, 95% CI 48.4–59.9, P &lt; 0.001). When clinically diagnosed TP was incorporated into the composite reference standard for sensitivity analysis, cf-TB testing showed a sensitivity of 46.8% (450/961, 95% CI 43.7–50.0), significantly higher than both Xpert (116/961, 12.1%, 95% CI 10.2–14.3, P &lt; 0.001) and mycobacterial culture (154/961, 16.0%, 95% CI 13.8–18.5, P &lt; 0.001). The specificities of cf-TB testing, Xpert, and mycobacterial culture were all 100.0%. Conclusions The performance of cf-TB testing is significantly superior to that of Xpert and mycobacterial culture methods, indicating that it can be considered as the primary diagnostic approach for improving TP detection. Trial registration The trial was registered on Chictr.org.cn (ChiCTR2000031680, https://www.chictr.org.cn/showproj.html?proj=49316 ).
HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy and enzalutamide: ARCHES
Authors: Nima Sharifi, Arun A Azad, Mona Patel, Jason W D Hearn, Michele Wozniak, Fabian Zohren, Jennifer Sugg, Gabriel P Haas, Arnulf Stenzl, Andrew J Armstrong
Journal: Cell Reports Medicine (2024)
Disease activity of rheumatoid arthritis and kidney function decline: a large prospective registry study
Authors: Sho Fukui, Wolfgang C. Winkelmayer, Sara K. Tedeschi, Javier Marrugo, Hongshu Guan, Leslie Harrold, Heather J. Litman, Tomohiro Shinozaki, Daniel H. Solomon
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Introduction</h3> Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain. <h3>Method</h3> We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR&lt;60 mL/min/1.73 m<sup>2</sup>) and stage G3b (eGFR&lt;45 mL/min/1.73 m<sup>2</sup>). Results were adjusted for relevant time-fixed and time-varying covariates. <h3>Results</h3> 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m<sup>2</sup>) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of −0.83 mL/min/1.73 m<sup>2</sup> and estimated additional annual declines (95% CI) of –0.09 (–0.15 to –0.03) in low, –0.17 (−0.23 to –0.10) in moderate and −0.18 (–0.27 to –0.08) mL/min/1.73 m<sup>2</sup> in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity. <h3>Conclusions</h3> Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR.
Response to “No increased risk of breast or gynecologic malignancies in women exposed to spironolactone for dermatologic conditions: A retrospective cohort study”
Authors: Deesha Desai, Michelle Sikora, Ambika Nohria, Avrom S Caplan, Mario Lacouture, Jerry Shapiro, Kristen I Lo Sicco
Journal: Journal of the American Academy of Dermatology (2024)
Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells
Authors: Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong
Journal: Molecular Therapy (2024)

Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor erythroid 2-related 2 (Nrf2) is the ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8
Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency
Authors: Vi Pham, Lucas Tricoli, Xinying Hong, Parith Wongkittichote, Carlo Castruccio Castracani, Amaliris Guerra, Lars Schlotawa, Laura A Adang, Amanda Kuhs, Margaret M Cassidy, Owen Kane, Emily Tsai, Maximiliano Presa, Cathleen Lutz, Stefano B Rivella, Rebecca C Ahrens-Nicklas
Journal: Molecular Therapy (2024)
The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data
Authors: Jie Zheng, Jieli Lu, Jiying Qi, Qian Yang, Huiling Zhao, Haoyu Liu, Zhihe Chen, Lanhui Huang, Youqiong Ye, Min Xu, Yu Xu, Tiange Wang, Mian Li, Zhiyun Zhao, Ruizhi Zheng, Shuangyuan Wang, Hong Lin, Chunyan Hu, Celine Sze Ling Chui, Shiu Lun Au Yeung, Shan Luo, Olympia Dimopoulou, Padraig Dixon, Sean Harrison, Yi Liu, Jamie Robinson, James Yarmolinsky, Philip Haycock, Jinqiu Yuan, Sarah Lewis, Zhongshang Yuan, Tom R Gaunt, George Davey Smith, Guang Ning, Richard M Martin, Bin Cui, Weiqing Wang, Yufang Bi
Journal: Cell Reports Medicine (2024)

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (n
Long-term effects of flexible visitation in the intensive care unit on family members’ mental health: 12-month results from a randomized clinical trial
Authors: Jennifer Menna Barreto de Souza, Aline Paula Miozzo, Rosa da Rosa Minho dos Santos, Duane Mocellin, Gabriela Soares Rech, Geraldine Trott, Gabriel Pozza Müller Estivalete, Daniel Sganzerla, Denise de Souza, Regis Goulart Rosa, Cassiano Teixeira
Journal: Intensive Care Medicine (2024)
Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance
Authors: Chaojia Chen, Fangcheng Zhao, Jiali Peng, Di Zhao, Liyun Xu, Huayu Li, Shuaiya Ma, Xueqi Peng, Xue Sheng, Yang Sun, Tixiao Wang, Haoqing Dong, Yuming Ding, Zhuanchang Wu, Xiaohong Liang, Lifen Gao, Hongyan Wang, Chunhong Ma, Chunyang Li
Journal: Cell Reports Medicine (2024)

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8