tbuckley/cabot-search huggingface dataset:
Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells
Authors: Qiong Wu, Chunjie Yu, Fang Yu, Yiran Guo, Yue Sheng, Liping Li, Yafang Li, Yutao Zhang, Chao Hu, Jue Wang, Tong-Chuan He, Yong Huang, Hongyu Ni, Zhiguang Huo, Wenshu Wu, Gang Greg Wang, Jianxin Lyu, Zhijian Qian
Journal: Journal of Clinical Investigation (2024)

Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.
ASSESSING THE QUALITY OF ARTIFICIAL INTELLIGENCE RESPONSES AND RESISTANCE TO SYCOPHANCY IN PROVIDING PATIENT-CENTERED MEDICAL ADVICE ON GASTROESOPHAGEAL REFLUX DISEASE
Authors: Benjamin Douglas Liu, Steve D'Souza, Melina Roy, MetroHealth Dietitians, Sherif Saleh, Ronnie Fass, Gengqing Song
Journal: Clinical Gastroenterology and Hepatology (2024)
Cationic conjugated polymers with tunable hydrophobicity for efficient treatment of multidrug-resistant wound biofilm infections
Authors: Ahmed Nabawy, Aritra Nath Chattopadhyay, Jessa Marie V Makabenta, Muhammad Aamir Hassan, Junwhee Yang, Jungmi Park, Mingdi Jiang, Taewon Jeon, Jungkyun Im, Vincent M Rotello
Journal: Biomaterials (2024)
HDAC6 mediates NLRP3 inflammasome activation in the pathogenesis of diabetic retinopathy
Authors: Jun-Sik Kim, Jae Hyun Jun, Jeongmi Lee, Sunyoung Park, Eunae Kim, Su Jung Hwang, Heesu Moon, Seung Hyun Baek, Hark Kyun Kim, Jinsu Park, Yoonsuk Cho, Jihoon Han, Chanhee Kim, Jongho Kim, Hyun-Mo Yang, Changsik Lee, Yeonseok Chung, Hyo-Jong Lee, Dong-Gyu Jo
Journal: Metabolism (2024)
Viral sepsis: diagnosis, clinical features, pathogenesis, and clinical considerations
Authors: Ji-Qian Xu, Wan-Ying Zhang, Jia-Ji Fu, Xiang-Zhi Fang, Cheng-Gang Gao, Chang Li, Lu Yao, Qi-Lan Li, Xiao-Bo Yang, Le-Hao Ren, Hua-Qing Shu, Ke Peng, Ying Wu, Ding-Yu Zhang, Yang Qiu, Xi Zhou, Yong-Ming Yao, You Shang
Journal: Military Medical Research (2024)

Abstract Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.
ATP-Gated P2X7-Ion Channel on Kidney-Resident Natural Killer T Cells and Memory T Cells in Intrarenal Inflammation
Authors: Marten Junge, Nastassia Liaukouskaya, Nicole Schwarz, Carolina Pinto-Espinoza, Alessa Z. Schaffrath, Björn Rissiek, Christian F. Krebs, Guido Rattay, Hans-Willi Mittrücker, Nicola M. Tomas, Annette Nicke, Friedrich Haag, Tobias B. Huber, Catherine Meyer-Schwesinger, Friedrich Koch-Nolte, Nicola Wanner
Journal: Journal of the American Society of Nephrology (2024)

Background: The P2X7 ion channel, a key sensor of sterile inflammation, has been implicated as a therapeutic target in glomerulonephritis, and P2X7-antagonistic nanobodies can attenuate experimental glomerulonephritis. However, little is known about the expression of P2X7 on renal immune cells. Methods: We used conventional immunofluorescence of kidney sections as well as intraperitoneal injection of nanobodies in mice followed by flow cytometry analysis of parenchymal T cells and RNA-sequencing to elucidate the expression and function of P2X7 on parenchymal and vascular immune cells in the mouse kidney. Results: Our study showed that parenchymal T cells, including a large subset of natural killer T cells and CD69 + tissue-resident memory T cells, display much higher cell surface levels of P2X7 than vascular T cells. After a single intraperitoneal injection of P2X7-blocking nanobodies, P2X7 on parenchymal T cells was fully occupied by the injected nanobodies within 30 min. This resulted in an effective protection of these cells from NAD-induced cell death during cell preparation. Conversely, systemic injection of NAD that mimics sterile inflammation results in the selective depletion of P2X7 hi CD69 hi T cells from the kidney parenchyma. Conclusions: Our study uncovered a novel purinergic regulatory mechanism affecting kidney-resident T cell populations.
Empagliflozin to prevent worsening of left ventricular volumes and systolic function after myocardial infarction (<scp>EMPRESS</scp>‐<scp>MI</scp>)
Authors: Jaclyn Carberry, Mark C. Petrie, Matthew M.Y. Lee, Bethany Stanley, Katriona J.M. Brooksbank, Ross T. Campbell, Richard Good, Pardeep S. Jhund, Peter Kellman, Ninian N. Lang, M. Mitchell Lindsay, Kenneth Mangion, Roy S. Gardner, Patrick B. Mark, Barbara Meyer, Joanne O'Donnell, Vanessa Orchard, Aadil Shaukat, Stuart Watkins, Alex McConnachie, John J.V. McMurray, Paul Welsh, Naveed Sattar, Colin Berry, Kieran F. Docherty
Journal: European Journal of Heart Failure (2024)
Effect of sacubitril/valsartan in heart failure with preserved ejection fraction across the age spectrum in <scp>PARAGON</scp>‐<scp>HF</scp>
Authors: Xiaowen Wang, Orly Vardeny, Brian Claggett, Muthiah Vaduganathan, Sheila M. Hegde, Hicham Skali, Maria A. Pabon, Alberto Foà, Safia Chatur, Annamaria Kosztin, Eileen O'Meara, Jean Rouleau, Margaret Redfield, Carolyn S.P. Lam, Michael Zile, Milton Packer, Amil M. Shah, Maja Cikes, Mauro Gori, Bela Merkely, Marc A. Pfeffer, John J.V. McMurray, Scott D. Solomon
Journal: European Journal of Heart Failure (2024)
The risk of death according to left ventricular ejection fraction and right ventricular dilatation in 17 321 adults with heart failure from 40 high‐, middle‐ and low‐income countries – A Global Congestive Heart Failure (G‐<scp>CHF</scp>) study
Authors: Darryl P. Leong, Philip G. Joseph, Hisham Dokainish, Stefan Störk, John V.V. McMurray, Lisa M. Mielniczuk, Sanjib Kumar Sharma, Andrés Orlandini, Kamilu M. Karaye, Antoni Bayes‐Genis, Tara McCready, Alex Grinvalds, Kumar Balasubramanian, Kelley R. Branch, Kristian Kragholm, Salim Yusuf
Journal: European Journal of Heart Failure (2024)

Abstract Aims The aim of this study was to describe the prognostic importance of left ventricular ejection fraction (LVEF) versus right ventricular (RV) dilatation and dysfunction in patients with heart failure (HF) from countries of different income levels. Methods and results We enrolled 17 321 participants with HF from 40 countries. Participants were followed for a median (25th–75th percentile) of 2.1 (2.0–4.6) years. Cox proportional hazards models were performed with adjustment for age, sex, HF aetiology, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, tobacco and alcohol use, functional class, and the use of HF medications, blood pressure, serum creatinine and HF duration. During follow‐up, 5738 (33%) participants died and 3569 (21%) were hospitalized for HF. Compared with LVEF ≥50%, the hazard ratios (HR) for death were 0.88 (95% confidence interval [CI] 0.80–0.97, p = 0.009) in patients with LVEF 40–49%, 0.96 (95% CI 0.88–1.05, p = 0.40) for LVEF 30–39%, and 1.18 (95% CI 1.08–1.29, p &lt; 0.0001) for LVEF &lt;30%. RV enlargement was associated with an increased risk of death (HR 1.35, 95% CI 1.26–1.44, p &lt; 0.0001). The relationship between LVEF and death differed according to HF aetiology (interaction p = 0.0010). In ischaemic HF and idiopathic dilated cardiomyopathy, there was a continuous inverse association between LVEF and the risk of death, but in hypertensive, valvular and other HF types, there was no association between LVEF and the risk of mortality. Conclusion Reduced LVEF was associated with worse prognosis in ischaemic and idiopathic dilated cardiomyopathy but not in HF of other causes. RV enlargement was associated with a more marked increase in the risk of death.
Spatial patterns and MRI-based radiomic prediction of high peritumoral tertiary lymphoid structure density in hepatocellular carcinoma: a multicenter study
Authors: Shichao Long, Mengsi Li, Juan Chen, Linhui Zhong, Aerzuguli Abudulimu, Lan Zhou, Wenguang Liu, Deng Pan, Ganmian Dai, Kai Fu, Xiong Chen, Yigang Pei, Wenzheng Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Tertiary lymphoid structures (TLS) within the tumor microenvironment have been associated with cancer prognosis and therapeutic response. However, the immunological pattern of a high peritumoral TLS (pTLS) density and its clinical potential in hepatocellular carcinoma (HCC) remain poor. This study aimed to elucidate biological differences related to pTLS density and develop a radiomic classifier for predicting pTLS density in HCC, offering new insights for clinical diagnosis and treatment. Spatial transcriptomics (n=4) and RNA sequencing data (n=952) were used to identify critical regulators of pTLS density and evaluate their prognostic significance in HCC. Baseline MRI images from 660 patients with HCC who had undergone surgery treatment between October 2015 and January 2023 were retrospectively recruited for model development and validation. This included training (n=307) and temporal validation (n=76) cohorts from Xiangya Hospital, and external validation cohorts from three independent hospitals (n=277). Radiomic features were extracted from intratumoral and peritumoral regions of interest and analyzed using machine learning algorithms to develop a predictive classifier. The classifier's performance was evaluated using the area under the curve (AUC), with prognostic and predictive value assessed across four independent cohorts and in a dual-center outcome cohort of 41 patients who received immunotherapy. Patients with HCC and a high pTLS density experienced prolonged median overall survival (p<0.05) and favorable immunotherapy response (p=0.03). Moreover, immune infiltration by mature B cells was observed in the high pTLS density region. Spatial pseudotime analysis and immunohistochemistry staining revealed that expansion of pTLS in HCC was associated with elevated CXCL9 and CXCL10 co-expression. We developed an optimal radiomic-based classifier with excellent discrimination for predicting pTLS density, achieving an AUC of 0.91 (95% CI 0.87, 0.94) in the external validation cohort. This classifier also exhibited promising stratification ability in terms of overall survival (p<0.01), relapse-free survival (p<0.05), and immunotherapy response (p<0.05). We identified key regulators of pTLS density in patients with HCC and proposed a non-invasive radiomic classifier capable of assisting in stratification for prognosis and treatment.
Correction: International Alliance of Urolithiasis (IAU) consensus on miniaturized percutaneous nephrolithotomy
Authors: Guo-Hua Zeng, Wen Zhong, Giorgio Mazzon, Wei Zhu, Sven Lahme, Sanjay Khadgi, Janak Desai, Madhu Agrawal, David Schulsinger, Mantu Gupta, Emanuele Montanari, Juan Manuel Lopez Martinez, Shabir Almousawi, Vincent Emanuel F. Malonzo, Seshadri Sriprasad, Otas Durutovic, Vimoshan Arumuham, Stefania Ferretti, Wissam Kamal, Ke-Wei Xu, Fan Cheng, Xiao-Feng Gao, Ji-Wen Cheng, Bhaskar Somani, Mordechai Duvdevani, Kah Ann Git, Christian Seitz, Norberto Bernardo, Tarek Ahmed Amin Ibrahim, Albert Aquino, Takahiro Yasui, Cristian Fiori, Thomas Knoll, Athanasios Papatsoris, Nariman Gadzhiev, Ulanbek Zhanbyrbekuly, Oriol Angerri, Hugo Lopez Ramos, Iliya Saltirov, Mohamad Moussa, Guido Giusti, Fabio Vicentini, Edgar Beltran Suarez, Margaret Pearle, Glenn M. Preminger, Qing-Hui Wu, Chu Ann Chai, Khurshid Ghani, Marcus Maroccolo, Marianne Brehmer, Palle J. Osther, Marek Zawadzki, Azimdjon Tursunkulov, Monolov Nurbek Kytaibekovich, Abdusamad Abdukakhorovich Abuvohidov, Cesar Antonio Recalde Lara, Zamari Noori, Stefano Paolo Zanetti, Sunil Shrestha, Jean de la Rosette, John Denstedt, Zhang-Qun Ye, Kemal Sarica, Simon Choong
Journal: Military Medical Research (2024)
Apoptotic extracellular vesicles: mechanisms, applications, and therapeutic potential
Authors: Dongjian Han, Zhe Li, Fuhang Wang, Ke Cheng, Deliang Shen
Journal: Med-X (2024)

Abstract Apoptotic extracellular vesicles (ApoEVs) are membrane-bound vesicles released during apoptosis, crucial for intercellular communication by delivering bioactive molecules to recipient cells. These vesicles are increasingly recognized for their potential in tumor therapy, immune modulation, and tissue regeneration. Recent studies reveal that ApoEVs play diverse roles in the medical fields. In tumor therapy, they enhance targeted drug delivery and antitumor immunity. Immune modulation is achieved by presenting antigens to immune cells, fostering specific responses. ApoEVs also aid in tissue regeneration, promoting wound healing and tissue repair. Advances in isolation and engineering techniques have improved the purity and functionality of ApoEVs, enabling their use as therapeutic delivery platforms. ApoEVs hold significant clinical potential by transferring genetic material, proteins, and other bioactive molecules. However, challenges such as standardizing production, ensuring safety, and addressing heterogeneity must be overcome. Future research should optimize isolation methods, elucidate ApoEV mechanisms, and develop strategies to enhance therapeutic efficacy. ApoEVs offer promising applications in cancer treatment, immune regulation, and tissue regeneration. This review summarizes the latest research and potential clinical applications of ApoEVs, highlighting their therapeutic promise and the challenges ahead. Graphical Abstract
Astrocytes contribute to toll-like receptor 2-mediated neurodegeneration and alpha-synuclein pathology in a human midbrain Parkinson’s model
Authors: Fiona Weiss, Laura Hughes, Yuhong Fu, Cedric Bardy, Glenda M. Halliday, Nicolas Dzamko
Journal: Translational Neurodegeneration (2024)

Abstract Background Parkinson’s disease (PD) is characterised by degeneration of ventral midbrain dopaminergic (DA) neurons and abnormal deposition of α-synuclein (α-syn) in neurons. Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of α-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of α-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological α-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD. Methods Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and α-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and α-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation. Results TLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated α-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated α-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons. Conclusions Taken together, these results support a role for astrocyte dysfunction in α-syn accumulation and DA neuronal loss following TLR2 activation in PD.
Plasma lipidomics and fungal peptide-based community analysis identifies distinct signatures of early mortality in acute liver failure
Authors: Neha Sharma, Sushmita Pandey, Gaurav Tripathi, Manisha Yadav, Nupur Sharma, Babu Mathew, Abhishak Gupta, Vasundhra Bindal, Sadam H. Bhat, Yash magar, Rimsha Saif, Sanju Yadav, Amritpal Kaur, Rakhi Maiwall, Shvetank Sharma, Shiv Kumar Sarin, Jaswinder Singh Maras
Journal: Clinical and Molecular Hepatology (2024)

NS: non-survivors associated enzymes (FC>1.5;Kennedy cycle).This contributed to phosphatidic acidmediated hyper-inflammation in ALF-non-survivors. Conclusion:In ALF plasma lipidome and mycobiome are dysregulated.Increase circulating phosphatidylcholine could stratify ALF predisposed to early-mortality or require emergency liver transplantation.
5‐Fluorouracil Loaded Prebiotic–Probiotic Liposomes Modulating Gut Microbiota for Improving Colorectal Cancer Chemotherapy
Authors: Xujie Sun, Xiaoting Shan, Binyu Zhu, Ying Cai, Zongyan He, Lingli Zhou, Lixuan Yin, Yiran Liu, Kaiyue Liu, Tian Zhang, Ning Yang, Yaping Li, Tianqun Lang
Journal: Advanced Healthcare Materials (2024)

Abstract The gut microbiota exerts inhibitory effects on the occurrence and progression of colorectal cancer (CRC) through various mechanisms. Compared to traditional microbiota regulation methods, prebiotics and probiotics demonstrate significant advantages in terms of safety and patient adaptability. Their synergy not only improves the intestinal environment but also enhances the host's anti‐tumor immune response. 5‐Fluorouracil (5‐FU) is a first‐line chemotherapy drug that has a short half‐life and low bioavailability. However, if administered in an untargeted manner, 5‐FU also causes adverse reactions. Liposomes can improve the pharmacokinetic profile of drugs and provide targeted delivery to the tumor site, thereby reducing side effects. In this work, a 5‐FU‐loaded liposome is modified with the prebiotic xylan derivative Sxy and the probiotic Akkermansia muciniphila active phospholipid homolog 1,2‐dipalmitoylphosphatidy‐lethanolamine (DPPE) to construct FLSK. The latter effectively prolongs the intestinal transport and release of 5‐FU, maintaining high drug concentrations at the tumor site. FLSK is found to inhibit tumor growth and significantly extends the survival period of mice. In addition, FLSK promotes anti‐tumor immunity and regulation of the gut microbiota. Combining the merits of prebiotics and probiotics, FLSK provides a potential strategy for integrating chemotherapy with gut microbiota regulation therapy for the treatment of CRC.
Tuning Helical Peptide Nanofibers as a Sublingual Vaccine Platform for a Variety of Peptide Epitopes
Authors: Emily F Roe, Helena Freire Haddad, Kat M Lazar, Peiying Liu, Joel H Collier
Journal: Advanced Healthcare Materials (2024)

Abstract Mucosal immune responses to vaccination are essential for achieving full protection against pathogens entering their host at mucosal sites. However, traditional parenteral immunization routes commonly fail to raise significant mucosal immunity. Sublingual immunization is a promising alternative delivery route to raise robust immune responses both systemically and at mucosal sites, and nanomaterial‐based subunit vaccine platforms offer opportunities for raising epitope‐specific responses. Here, sublingual immunization is reported using the Coil29 platform of coiled‐coil self‐assembling peptide nanofibers. The successful immunization with epitopes of varying physicochemical properties by including mucus‐modulating components – namely sequences of proline, alanine, and serine (PAS) is demonstrated. PASylation is shown to decrease mucin complexation and increase epithelial penetration in vitro, enabling sublingual immunization against a variety of selected peptide epitopes in vivo. Coil29 fibers are also readily formed into tablets for solid‐state dosing formulations and maintain their immunogenicity in this state. Previous sublingual peptide nanofiber immunotherapies have been based on different structures, such as highly stable β‐sheets. The present work demonstrates that alternatively folded structures such as α‐helical nanofibers can also be rendered sublingually immunogenic, enabling immunization with a variety of peptide epitopes and offering additional ways to specify mucus interactions, delivery state, dosing, and formulation.