tbuckley/cabot-search huggingface dataset:
Natural product mediated mesenchymal–epithelial remodeling by covalently binding ENO1 to degrade m6A modified β-catenin mRNA
Authors: Tianyang Chen, Guangju Liu, Sisi Chen, Fengyuan Zhang, Shuoqian Ma, Yongping Bai, Quan Zhang, Yahui Ding
Journal: Acta Pharmaceutica Sinica B (2024)

The transition of cancer cells from epithelial state to mesenchymal state awarded hepatocellular carcinoma (HCC) stem cell properties and induced tumorigenicity, drug resistance, and high recurrence rate. Reversing the mesenchymal state to epithelial state by inducing mesenchymal-epithelial remodeling could inhibit the progression of HCC. Using high-throughput screening, chrysin was selected from natural products to reverse epithelial-mesenchymal transition (EMT) by selectively increasing CDH1 expression. The target identification suggested chrysin exerted its anti-HCC effect through covalently and specifically binding threonine 205 (Thr205) of alpha-enolase (ENO1). For the first time, we revealed that ENO1 bound β-catenin mRNA, and recruited YTHDF2 to identify the m6A modified β-catenin in the 3'-UTR region to degrade β-catenin mRNA. Eventually, the CDH1 gene expression was improved through the regulation of β-catenin mRNA. ENO1/β-catenin mRNA interaction might be a promising target for cellular plasticity reprogramming. Moreover, chrysin could mediate mesenchymal‒epithelial remodeling through increasing degradation of β-catenin mRNA by promoting the binding of ENO1 and β-catenin mRNA. To the best of our knowledge, chrysin is the first reported small molecule inducing β-catenin mRNA degradation through binding to ENO1. The water-soluble derivative of chrysin may be a natural product-derived lead compound for circumventing metastasis, recurrence, and drug resistance of HCC by mediating mesenchymal‒epithelial remodeling.
Multi-degradation-adaptation network for fundus image enhancement with degradation representation learning
Authors: Ruoyu Guo, Yiwen Xu, Anthony Tompkins, Maurice Pagnucco, Yang Song
Journal: Medical Image Analysis (2024)

Fundus image quality serves a crucial asset for medical diagnosis and applications. However, such images often suffer degradation during image acquisition where multiple types of degradation can occur in each image. Although recent deep learning based methods have shown promising results in image enhancement, they tend to focus on restoring one aspect of degradation and lack generalisability to multiple modes of degradation. We propose an adaptive image enhancement network that can simultaneously handle a mixture of different degradations. The main contribution of this work is to introduce our Multi-Degradation-Adaptive module which dynamically generates filters for different types of degradation. Moreover, we explore degradation representation learning and propose the degradation representation network and Multi-Degradation-Adaptive discriminator for our accompanying image enhancement network. Experimental results demonstrate that our method outperforms several existing state-of-the-art methods in fundus image enhancement. Code will be available at https://github.com/RuoyuGuo/MDA-Net.
Patient-reported outcomes in chronic hepatitis delta: An exploratory analysis of the Phase III MYR301 trial of bulevirtide
Authors: Maria Buti, Heiner Wedemeyer, Soo Aleman, Vladimir Chulanov, Viacheslav Morozov, Olga Sagalova, Tatiana Stepanova, Robert G. Gish, Andrew Lloyd, Ankita M. Kaushik, Vithika Suri, Dmitry Manuilov, Anu O. Osinusi, John F. Flaherty, Pietro Lampertico
Journal: Journal of Hepatology (2024)

Background & AimsOnce-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD.MethodsIn an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS).ResultsPatient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale.ConclusionPROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD.Impact and implicationsBulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group).Clinical trial registrationClinicalTrials.gov Identifier, NCT03852719
PHF6 suppresses self-renewal of leukemic stem cells in AML
Authors: Sapana S. Jalnapurkar, Aishwarya S. Pawar, Subin S. George, Charles Antony, Patrick Somers, Jason Grana, Victoria K. Feist, Sandeep Gurbuxani, Vikram R. Paralkar
Journal: Leukemia (2024)

Abstract Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9 -driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9 -driven AML and identify a population that we term the “LIC-e” (leukemia initiating cells enriched) population. We find that Phf6 loss expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.
Systemic interindividual DNA methylation variants in cattle share major hallmarks with those in humans
Authors: Wen-Jou Chang, Maria S. Baker, Eleonora Laritsky, Chathura J. Gunasekara, Uditha Maduranga, Justine C. Galliou, Joseph W. McFadden, Jessica R. Waltemyer, Bruce Berggren-Thomas, Brianna N. Tate, Hanxue Zhang, Benjamin D. Rosen, Curtis P. Van Tassell, George E. Liu, Cristian Coarfa, Yi Athena Ren, Robert A. Waterland
Journal: Genome biology (2024)

We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle.
BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality
Authors: Xin Li, Lee Zou
Journal: Journal of Clinical Investigation (2024)

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting in BRCA1/2 deficiency are frequently identified in breast, ovarian, prostate, pancreatic, and other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted cancer therapy. However, a substantial fraction of cancer patients carrying BRCA1/2 mutations do not respond to PARPis, and most patients develop resistance to PARPis over time, highlighting a major obstacle to PARPi therapy in the clinic. Recent studies have revealed that changes of specific functional defects of BRCA1/2-deficient cells, particularly their defects in suppressing and protecting single-stranded DNA gaps, contribute to the gain or loss of PARPi-induced synthetic lethality. These findings not only shed light on the mechanism of action of PARPis, but also lead to revised models that explain how PARPis selectively kill BRCA-deficient cancer cells. Furthermore, new mechanistic principles of PARPi sensitivity and resistance have emerged from these studies, generating potentially useful guidelines for predicting the PARPi response and design therapies for overcoming PARPi resistance. In this Review, we will discuss these recent studies and put them in context with the classic views of PARPi-induced synthetic lethality, aiming to stimulate the development of new therapeutic strategies to overcome PARPi resistance and improve PARPi therapy.
Targeting apoptotic pathways for cancer therapy
Authors: Xiaobing Tian, Praveen R. Srinivasan, Vida Tajiknia, Ashley F. Sanchez Sevilla Uruchurtu, Attila A. Seyhan, Benedito A. Carneiro, Arielle De La Cruz, Maximilian Pinho-Schwermann, Andrew George, Shuai Zhao, Jillian Strandberg, Francesca Di Cristofano, Shengliang Zhang, Lanlan Zhou, Alexander G. Raufi, Arunasalam Navaraj, Yiqun Zhang, Nataliia Verovkina, Maryam Ghandali, Dinara Ryspayeva, Wafik S. El-Deiry
Journal: Journal of Clinical Investigation (2024)

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.
Multiscale modeling uncovers 7q11.23 copy number variation–dependent changes in ribosomal biogenesis and neuronal maturation and excitability
Authors: Marija Mihailovich, Pierre-Luc Germain, Reinald Shyti, Davide Pozzi, Roberta Noberini, Yansheng Liu, Davide Aprile, Erika Tenderini, Flavia Troglio, Sebastiano Trattaro, Sonia Fabris, Ummi Ciptasari, Marco Tullio Rigoli, Nicolò Caporale, Giuseppe D’Agostino, Filippo Mirabella, Alessandro Vitriolo, Daniele Capocefalo, Adrianos Skaros, Agnese Virginia Franchini, Sara Ricciardi, Ida Biunno, Antonino Neri, Nael Nadif Kasri, Tiziana Bonaldi, Rudolf Aebersold, Michela Matteoli, Giuseppe Testa
Journal: Journal of Clinical Investigation (2024)

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs.
Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice
Authors: Naima S. Dahir, Yijun Gui, Yanan Wu, Patrick R. Sweeney, Alix A.J. Rouault, Savannah Y. Williams, Luis E. Gimenez, Tomi K. Sawyer, Stephen T. Joy, Anna K. Mapp, Roger D. Cone
Journal: Journal of Clinical Investigation (2024)

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.
In vitro and ex vivo models of microbial keratitis: Present and future
Authors: Kelvin Kah Wai Cheng, Leonie Fingerhut, Sheelagh Duncan, N. Venkatesh Prajna, Adriano G. Rossi, Bethany Mills
Journal: Progress in Retinal and Eye Research (2024)

Microbial keratitis (MK) is an infection of the cornea, caused by bacteria, fungi, parasites, or viruses. MK leads to significant morbidity, being the fifth leading cause of blindness worldwide. There is an urgent requirement to better understand pathogenesis in order to develop novel diagnostic and therapeutic approaches to improve patient outcomes. Many in vitro, ex vivo and in vivo MK models have been developed and implemented to meet this aim. Here, we present current in vitro and ex vivo MK model systems, examining their varied design, outputs, reporting standards, and strengths and limitations. Major limitations include their relative simplicity and the perceived inability to study the immune response in these MK models, an aspect widely accepted to play a significant role in MK pathogenesis. Consequently, there remains a dependence on in vivo models to study this aspect of MK. However, looking to the future, we draw from the broader field of corneal disease modelling, which utilises, for example, three-dimensional co-culture models and dynamic environments observed in bioreactors and organ-on-a-chip scenarios. These remain unexplored in MK research, but incorporation of these approaches will offer further advances in the field of MK corneal modelling, in particular with the focus of incorporation of immune components which we anticipate will better recapitulate pathogenesis and yield novel findings, therefore contributing to the enhancement of MK outcomes.
Performance of various pneumonia severity models for predicting adverse outcomes in elderly inpatients with community-acquired pneumonia
Authors: Lixue Huang, Bingxuan Weng, Xiaoying Gu, Yuanqi Wang, Mengyuan Wang, Jianzhen Weng, Yang Ju, Xuefeng Zhong, Xunliang Tong, Yanming Li
Journal: Clinical Microbiology and Infection (2024)
Point Mutation P174L of the penA Gene Endowing Ceftazidime resistance to Burkholderia pseudomallei in China
Authors: Shen Tian, Xingyong Wu, Lin Liu, Anyang Li, Xuemiao Li, Hua Pei, Yanshuang Wang, David A B Dance, Hai Chen, Qianfeng Xia
Journal: Drug Resistance Updates (2024)
Rectal organoid morphology analysis (ROMA) as a novel physiological assay for diagnostic classification in cystic fibrosis
Authors: Senne Cuyx, Anabela Santo Ramalho, Steffen Fieuws, Nikky Corthout, Marijke Proesmans, Mieke Boon, Kaline Arnauts, Marianne S Carlon, Sebastian Munck, Lieven Dupont, Kris De Boeck, François Vermeulen
Journal: Thorax (2024)

Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing
DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke
Authors: Tian‐Jie Lyu, Xin Qiu, Yubo Wang, Ling Zhang, Yalun Dai, Xuechun Wang, Shunying Zhao, Meilin Xiang, Lu Cui, Si Cheng, Yang Liu, Hongqiu Gu, Yong Jiang, Xia Meng, Yilong Wang, Xingquan Zhao, Xianwei Wang, Qian Li, Meng Wang, Yingyu Jiang, Zhe Xu, Xinying Huang, Hao Li, Yongjun Wang, Zixiao Li
Journal: MedComm (2024)

Abstract Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A , the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A ‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.
Pyroptosis, gasdermins and allergic diseases
Authors: Ronald Allan Panganiban, Kari C. Nadeau, Quan Lu
Journal: Allergy (2024)

Pyroptosis is an inflammatory form of programmed cell death that is distinct from necrosis and apoptosis. Pyroptosis is primarily mediated by the gasdermin family of proteins (GSDMA-E and PVJK), which, when activated by proteolytic cleavage, form pores in the plasma membrane, leading to cell death. While much of the past research on pyroptosis has focused on its role in cancer, metabolic disorders, and infectious diseases, recent experimental and observational studies have begun to implicate pyroptosis in allergic diseases. These studies suggest that gasdermin-mediated pyroptosis contributes to the development of allergic conditions and could offer novel targets for therapy. Here, we review our current understanding of pyroptosis with an emphasis on the role of gasdermins as executioners of pyroptosis and potential mediators to allergic disease. We highlight new discoveries that establish a mechanistic link between the biochemical actions of gasdermins and the onset of allergic diseases. Additionally, we discuss how pyroptosis and gasdermins might contribute to the dysfunction of epithelial barrier, a key factor believed to initiate the progression of various allergic diseases.
Risk of pulmonary embolism and deep vein thrombosis following COVID‐19: a nationwide cohort study
Authors: Hye Jun Kim, Seogsong Jeong, Jihun Song, Sun Jae Park, Young Jun Park, Yun Hwan Oh, Jaehun Jung, Sang Min Park
Journal: MedComm (2024)

Recent studies elucidate that coronavirus disease 2019 (COVID-19) patients may face a higher risk of cardiovascular complications. This study aimed to evaluate association of COVID-19 with the risk of pulmonary embolism (PE) or deep vein thrombosis (DVT). This nationwide population-based retrospective cohort study included Korean adult citizens between January 2021 and March 2022 from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort. The Fine and Gray's regression with all-cause death as a competing event was adopted to evaluate PE and DVT risks after COVID-19. This study included a total of 1,601,835 COVID-19 patients and 14,011,285 matched individuals without COVID-19. The risk of PE (adjusted hazard ratio [aHR], 6.25; 95% confidence interval [CI], 3.67-10.66;
Differential decline of SARS‐CoV‐2‐specific antibody levels, innate and adaptive immune cells, and shift of Th1/inflammatory to Th2 serum cytokine levels long after first COVID‐19
Authors: Bernhard Kratzer, Pia Gattinger, Doris Trapin, Paul Ettel, Ulrike Körmöczi, Arno Rottal, Robert B. Stieger, Al Nasar Ahmed Sehgal, Melanie Feichter, Kristina Borochova, Inna Tulaeva, Katharina Grabmeier‐Pfistershammer, Peter A. Tauber, Thomas Perkmann, Ingrid Fae, Sabine Wenda, Michael Kundi, Gottfried F. Fischer, Rudolf Valenta, Winfried F. Pickl
Journal: Allergy (2024)

SARS-CoV-2 has triggered a pandemic and contributes to long-lasting morbidity. Several studies have investigated immediate cellular and humoral immune responses during acute infection. However, little is known about long-term effects of COVID-19 on the immune system.
Improved sleep parallels improvements in atopic dermatitis signs, symptoms, and quality of life in adult patients treated with dupilumab: 24-week results from the DUPISTAD study
Authors: Joseph F. Merola, Albert S. Chiou, Emmanuel During, Peter Foley, Jiangming Wu, Marius Ardeleanu, Zafer E. Ozturk
Journal: Journal of the American Academy of Dermatology (2024)