tbuckley/cabot-search huggingface dataset:
The Supporting Emerging Adults With Diabetes (SEAD) Program: An Adult-Based Real-World Clinical Model That Improves Hospitalizations, Diabetes Technology Uptake, and Glycemic Outcomes in Underserved Young Adults With Type 1 Diabetes
Authors: Shivani Agarwal, Priyanka Mathias, Clyde Schechter, Molly Finnan, Michael Greenberg, Stephanie L. Leung, Sharon Movsas, Judith A. Long
Journal: Diabetes Care (2024)

OBJECTIVE Underserved young adults (YA) with type 1 diabetes (T1D) experience the worst outcomes across the life span. We developed and integrated the Supporting Emerging Adults with Diabetes (SEAD) program into routine endocrinology care to address unmet social and medical challenges. RESEARCH DESIGN AND METHODS This study was designed as a longitudinal cohort study, with prospective data collection over 4 years on YA in SEAD compared with usual endocrine care. We used propensity-weighted analysis to account for differences in baseline characteristics, and multivariate regression and Cox proportional hazard models to evaluate change in outcomes over time. Primary outcomes included incidence of hospitalizations, diabetes technology uptake, and annual change in HbA1c levels. RESULTS We included 497 YA with T1D in SEAD (n = 332) and usual endocrine care (n = 165); mean age 25 years, 27% non-Hispanic Black, 46% Hispanic, 49% public insurance, mean HbA1c 9.2%. Comparing YA in SEAD versus usual care, 1) incidence of hospitalizations was reduced by 64% for baseline HbA1c &amp;gt;9% (HR 0.36 [0.13, 0.98]) and 74% for publicly insured (HR 0.26 [0.07, 0.90]); 2) automated insulin delivery uptake was 1.5-times higher (HR 1.51 [0.83, 2.77]); and 3) HbA1c improvement was greater (SEAD, −0.37% per year [−0.59, −0.15]; usual care, −0.26% per year [−0.58, 0.05]). CONCLUSIONS SEAD meaningfully improves clinical outcomes in underserved YA with T1D, especially for publicly insured and high baseline HbA1c levels. Early intervention for at-risk YA with T1D as they enter adult care could reduce inequity in short and long-term outcomes.
Activation of β3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue
Authors: Ze-Bei Zhang, Yu-Wen Cheng, Lian Xu, Jia-Qi Li, Xin Pan, Min Zhu, Xiao-Hui Chen, Ai-Jun Sun, Jing-Rong Lin, Ping-Jin Gao
Journal: Cardiovascular Research (2024)

Abstract Aims β3-AR (β3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate β3-AR activation-mediated PVAT function in AD/AA. Methods and Results Aortas from patients with thoracic aortic dissection (TAD) were collected to detect β3-AR expression in PVAT. ApoE-/- and β-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a β3-AR agonist. The results demonstrated an up-regulation of β3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of β3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. Conclusions Our findings illustrated the therapeutic potential of β3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.
HaploSweep: detecting and distinguishing recent soft and hard selective sweeps through haplotype structure
Authors: Shilei Zhao, Lianjiang Chi, Mincong Fu, Hua Chen
Journal: Molecular Biology and Evolution (2024)

Abstract Identifying soft selective sweeps using genomic data is a challenging yet crucial task in population genetics. In this study, we present HaploSweep, a novel method for detecting and categorizing soft and hard selective sweeps based on haplotype structure. Through simulations spanning a broad range of selection intensities, softness levels, and demographic histories, we demonstrate that HaploSweep outperforms iHS, nSL, and H12 in detecting soft sweeps. HaploSweep achieves high classification accuracy—0.9247 for CHB, 0.9484 for CEU, and 0.9829 YRI—when applied to simulations in line with the human Out-of-Africa demographic model. We also observe that the classification accuracy remains consistently robust across different demographic models. Additionally, we introduce a refined method to accurately distinguish soft shoulders adjacent to hard sweeps from soft sweeps. Application of HaploSweep to genomic data of CHB, CEU, and YRI populations from the 1000 genomes project has led to the discovery of several new genes that bear strong evidence of population-specific soft sweeps (HRNR, AMBRA1, BFA2T2, DYNC2H1, and RANBP2 etc), with prevalent associations to immune functions and metabolic processes. The validated performance of HaploSweep, demonstrated through both simulated and real data, underscores its potential as a valuable tool for detecting and comprehending the role of soft sweeps in adaptive evolution.
Global epidemiological trend of Klebsiella pneumoniae ST340: emergence of subclade KL15 co-producing K pneumoniae carbapenemase-2 and New Delhi metallo-β-lactamase-7 in the Americas
Authors: Felipe Vásquez-Ponce, Marco Vianello, Johana Becerra, Jesus G M Pariona, Karine Dantas, Gregory Melocco, Guilherme M Oliveira, Fernanda Esposito, Nilton Lincopan
Journal: The Lancet Microbe (2024)
Impact on beer sales of removing the pint serving size: An A-B-A reversal trial in pubs, bars, and restaurants in England
Authors: Eleni Mantzari, Gareth J Hollands, Martin Law, Dominique-Laurent Couturier, Theresa M Marteau
Journal: PLoS Medicine (2024)

Background Smaller serving sizes could contribute towards reducing alcohol consumption across populations and thereby decrease the risk of 7 cancers and other diseases. To our knowledge, the current study is the first to assess the impact on beer, lager, and cider sales (hereafter, for ease, referred to just as “beer sales”) of removing the largest draught serving size (1 imperial pint) from the options available in licensed premises under real-word conditions. Methods and findings The study was conducted between February and May 2023, in 13 licensed premises in England. It used an A-B-A reversal design, set over 3 consecutive 4-weekly periods with “A” representing the nonintervention periods during which standard serving sizes were served, and “B” representing the intervention period when the largest serving size of draught beer (1 imperial pint (568 ml)) was removed from existing ranges so that the largest size available was two-thirds of a pint. Where two-third pints were not served, the intervention included introducing this serving size in conjunction with removing the pint serving size. The primary outcome was the mean daily volume of all beer sold, including draught, bottles, and cans (in ml), extracted from electronic sales data. Secondary outcomes were mean daily volume of wine sold (ml) and daily revenue (£). Thirteen premises completed the study, 12 of which did so per protocol and were included in the primary analysis. After adjusting for prespecified covariates, the intervention resulted in a mean daily change of −2,769 ml (95% CI [−4,188, −1,578] p &lt; 0.001) or −9.7% (95% CI [−13.5%, −6.1%] in beer sold. The daily volume of wine sold increased during the intervention period by 232 ml (95% CI [13, 487], p = 0.035) or 7.2% (95% CI [0.4%, 14.5%]). Daily revenues decreased by 5.0% (95% CI [9.6%, −0.3%], p = 0.038). Conclusions Removing the largest serving size (the imperial pint) for draught beer reduced the volume of beer sold. Given the potential of this intervention to reduce alcohol consumption, it merits consideration in alcohol control policies. Trial registration ISRCTN.com ISRCTN18365249 .
Precise In Situ Delivery of a Photo-enhanceable Inflammasome-Activating Nanovaccine Activates Anti-cancer Immunity
Authors: Yang Zhou, Li Pang, Tao Ding, Kang Chen, Jinzhao Liu, Meicen Wu, Weiping Wang, Kwan Man
Journal: Cancer Research (2024)

Abstract A variety of state-of-the-art nanovaccines (NVs) combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T cells infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the TME need to be explored to enhance the activity of NV. Here, we developed a photo-enhanceable inflammasome-activating NV (PIN) to achieve precise in situ delivery of a tumor antigen and a hydrophobic small molecule activating the NLRP3-inflammasome pathway. Near-infrared light irradiation promoted PIN accumulation in tumor sites through photo-triggered charge reversal of the nanocarrier. Systematic PIN administration facilitated intratumoral NLRP3 inflammasome activation and antigen cross-presentation in antigen-presenting cells upon light irradiation at tumor sites. Furthermore, PIN treatment triggered immune responses by promoting the production of proinflammatory cytokines and activated of anti-tumor immunity without significant systematic toxicity. Importantly, the PIN enhanced the efficacy of immune checkpoint blockade and supported the establishment of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Collectively, this study reports a safe and efficient photoresponsive system for co-delivery of antigens and immune modulators into tumor tissues with promising therapeutic potential.
Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer
Authors: Koki Oyama, Kohei Nakata, Chikanori Tsutsumi, Masataka Hayashi, Bo Zhang, Yuki Mochida, Tomohiko Shinkawa, Kento Hirotaka, Pingshan Zhong, Satomi Date, Haizhen Luo, Akihiro Kubo, Nobuhiro Higashijima, Yutaka Yamada, Toshiya Abe, Noboru Ideno, Kazuhiro Koikawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Hideya Onishi, Takashi Morisaki, Keiji Kuba, Yoshinao Oda, Masafumi Nakamura
Journal: Cancer Research (2024)

Abstract The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.
CircRREB1 Mediates Metabolic Reprogramming and Stemness Maintenance to Facilitate Pancreatic Ductal Adenocarcinoma Progression
Authors: Zeyin Rong, Jin Xu, Jianhui Yang, Wei Wang, Rong Tang, Zifeng Zhang, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Chen Liang, Xianjun Yu, Si Shi
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with limited treatment options and poor patient survival. Circular RNAs (circRNAs) play crucial regulatory roles in the occurrence and development of various cancers, including PDAC. Here, using circRNA sequencing of diverse PDAC samples, we identified circRREB1 as an oncogenic circRNA that is significantly upregulated in PDAC and is correlated with an unfavorable patient prognosis. Functionally, loss of circRREB1 markedly inhibited glycolysis and stemness, while elevated circRREB1 elicited the opposite effects. Mechanistically, circRREB1 interacted with PGK1, disrupting the association between PTEN and PGK1 and increasing PGK1 phosphorylation to activate glycolytic flux. Moreover, circRREB1 promoted WNT7B transcription by directly interacting with YBX1 and facilitating its nuclear translocation, consequently activating the Wnt/β-catenin signaling pathway to maintain PDAC stemness. Overall, these results highlight circRREB1 as a key regulator of metabolic and stemness properties of PDAC.
CD24-Targeted NIR-II Fluorescence Imaging Enables Early Detection of Colorectal Neoplasia
Authors: Xiaoyong Guo, Shuangling Luo, Xiaofeng Wang, Yingying Cui, Miaomiao Li, Zeyu Zhang, Lidan Fu, Caiguang Cao, Xiaojing Shi, Haifeng Liu, Yawei Qu, Xiangyu Gao, Zhenhua Hu, Jie Tian
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting specific molecular characteristics of lesions. CD24 is upregulated during the adenoma-to-CRC transition, providing a potential target for FMI. Here, we developed a second near-infrared window (NIR-II) fluorescent probe with a high affinity for CD24 and evaluated its efficacy and targeting ability in cellular models, murine models, and clinical samples of CRC. CD24 expression was elevated in 76% of adenomas and 80% of CRCs. In a colitis-associated cancer mouse model, NIR-II imaging with the CD24-targeted probe achieved a significantly higher tumor-to-background ratio compared to conventional NIR-I imaging. The probe demonstrated exceptional sensitivity (92%) and specificity (92%) for detecting CRC, including small lesions less than 1 mm in size. This led to the identification of precancerous lesions missed by white-light detection and lesions missed by NIR-I imaging. Moreover, ex vivo human tissue incubation with the probe supported the potential for intraprocedural lesion identification via topical probe application during colonoscopy. In conclusion, this study successfully demonstrates the potential of CD24-targeted NIR-II imaging for identifying colorectal neoplasia, highlighting its significance for early CRC detection in the gastrointestinal tract.
Local TSH/TSHR signaling promotes CD8<sup>+</sup> T cell exhaustion and immune evasion in colorectal carcinoma
Authors: Sisi Zeng, Huiling Hu, Zhiyang Li, Qi Hu, Rong Shen, Mingzhou Li, Yunshi Liang, Zuokang Mao, Yandong Zhang, Wanqi Zhan, Qin Zhu, Feifei Wang, Jianbiao Xiao, Bohan Xu, Guanglong Liu, Yanan Wang, Bingsong Li, Shaowan Xu, Zhaowen Zhang, Ceng Zhang, Zhizhang Wang, Li Liang
Journal: Cancer Communications (2024)

Abstract Background Dysfunction of CD8 + T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid‐stimulating hormone (TSH)/thyroid‐stimulating hormone receptor (TSHR) signaling in CD8 + T cell exhaustion and tumor immune evasion remain poorly understood. This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8 + T cells and immune evasion in colorectal cancer (CRC). Methods TSHR expression levels in CD8 + T cells were assessed with immunofluorescence and flow cytometry. Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8 + T cells. Mechanistic insights were mainly gained through RNA‐sequencing, Western blotting, chromatin immunoprecipitation and luciferase activity assay. Immunofluorescence, flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues. Results TSHR was highly expressed in cancer cells and CD8 + T cells in CRC tissues. TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8 + T cell exhaustion. Conditional deletion of TSHR in CD8 + tumor‐infiltrating lymphocytes (TILs) improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1 (PD‐1) and hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3) through the protein kinase A (PKA)/cAMP‐response element binding protein (CREB) signaling pathway. CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8 + T cells, resulting in immunosuppression in the TME. Myeloid‐derived suppressor cells (MDSCs) was the main source of TSH within the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response. Conclusions The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8 + T cell exhaustion and immune evasion in CRC. TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.
<scp>HLA</scp>‐<scp>DR</scp><sup>+</sup> regulatory T cells and <scp>IL</scp>‐10 are associated with success or failure of desensitization outcomes
Authors: Xiaoying Zhou, Diane Dunham, Sayantani B. Sindher, Andrew Long, Andrea Fernandes, Iris Chang, Amal Assa'ad, Jacqueline Pongracic, Jonathan M. Spergel, Jonathan Tam, Stephen Tilles, Julie Wang, Scott D. Boyd, R. Sharon Chinthrajah, Kari C. Nadeau
Journal: Allergy (2024)

Abstract Background Omalizumab (XOLAIR®)‐assisted multi‐food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab‐assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab‐assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab‐assisted mOIT. Methods Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high‐dimensional cytometry‐based single‐cell data and high‐throughput multiplex cytokine data. Results Our results demonstrated that the frequency of HLA‐DR + Treg cells, and the production of Th2 cytokines (IL‐4, IL‐5, IL‐13, and IL‐9) as well as the immunoregulatory cytokine IL‐10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA‐DR + Treg cells and enhanced production of IL‐10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab‐assisted mOIT inducing a significant reduction in the production of Th2 cytokines. Conclusions We demonstrated that the frequency of HLA‐DR + Treg cells and IL‐10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab‐assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.
Comorbidity and Disease Activity in Multiple Sclerosis
Authors: Amber Salter, Samantha Lancia, Kaarina Kowalec, Kathryn C. Fitzgerald, Ruth Ann Marrie
Journal: JAMA Neurology (2024)

Multiple studies suggest that comorbidity worsens clinically relevant outcomes in multiple sclerosis (MS), including the severity of disability at diagnosis and rate of disability worsening after diagnosis. However, less is known regarding the association of comorbidity with measures of disease activity, such as relapse rate and magnetic resonance imaging lesion accrual, which are relevant to clinicians and clinical trialists.
Synergistic effect of FMS-like tyrosine kinase-3 (FLT3) inhibitors combined with a CDK7 inhibitor in FLT3-ITD-mutated acute myeloid leukemia
Authors: Bon-Kwan Koo, Eun-Ji Choi, Ju Hyun Moon, Ji Yun Kim, Hyunkyung Park, Han-Seung Park, Yunsuk Choi, Jung-Hee Lee, Kyoo-Hyung Lee, Eun Kyung Choi, Eunji Kim, Je-Hwan Lee, Eun-Hye Hur
Journal: Blood Cancer Journal (2024)
Unraveling the extracellular vesicle network: insights into ovarian cancer metastasis and chemoresistance
Authors: Wei Dai, Jianwei Zhou, Ting Chen
Journal: Molecular Cancer (2024)

Ovarian cancer (OC) is one of the most prevalent and lethal gynecological malignancies, with high mortality primarily due to its aggressive nature, frequent metastasis, and resistance to standard therapies. Recent research has highlighted the critical role of extracellular vesicles (EVs) in these processes. EVs, secreted by living organisms and carrying versatile and bioactive cargoes, play a vital role in intercellular communication. Functionally, the transfer of cargoes orchestrates multiple processes that actively affect not only the primary tumor but also local and distant pre-metastatic niche. Furthermore, their unique biological properties position EVs as novel therapeutic targets and promising drug delivery systems, with potential profound implications for cancer patients.This review summarizes recent progress in EV biology, delving into the intricate mechanisms by which EVs contribute to OC metastasis and drug resistance. It also explores the latest advances and therapeutic potential of EVs in the clinical context of OC. Despite the progress made, EV research in OC remains in its nascent stages. Consequently, this review presents existing research limitations and suggests avenues for future investigation. Altogether, the review aims to elucidate the critical roles of EVs in OC and spotlight their promising potential in this field.