tbuckley/cabot-search huggingface dataset:
Therapeutic Inhibition of <i>LincRNA-p21</i> Protects Against Cardiac Hypertrophy
Authors: Yi Wang, Mingming Zhang, Rong Wang, Jing Lin, Qing Ma, Haipeng Guo, Huihui Huang, Zhuomin Liang, Yangpo Cao, Xiaoran Zhang, Yao Wei Lu, Jianming Liu, Feng Xiao, Hualin Yan, Nadya Dimitrova, Zhan-Peng Huang, John D. Mably, William T. Pu, Da-Zhi Wang
Journal: Circulation Research (2024)

Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood.
Hyperexpression of tumor necrosis factor receptor 2 inhibits differentiation of myeloid‐derived suppressor cells by instigating apolarity during ageing
Authors: Ming Wang, Yijie Han, Xiaohan Yao, Xixi Duan, Jiajia Wan, Xiaohan Lou, Yan Yan, Peiguo Zheng, Fazhan Wang, Linyu Zhu, Chen Ni, Zhenzhen Pan, Zihao Wang, Lin Chen, Zhaoqing Wang, Zhihai Qin
Journal: MedComm (2024)

Abstract During the ageing process, TNF‐α can promote the expansion of myeloid‐derived suppressor cells (MDSCs). However, it remains unclear which receptor(s) of TNF‐α are involved in and how they modulate this process. Here, we report that TNFR2 hyperexpression induced by either TNF‐α or IL‐6, two proinflammatory factors of senescence‐associated secretory phenotype (SASP), causes cellular apolarity and differentiation inhibition in aged MDSCs. Ex vivo overexpression of TNFR2 in young MDSCs inhibited their polarity and differentiation, whereas in vivo depletion of Tnfr2 in aged MDSCs promotes their differentiation. Consequently, the age‐dependent increase of TNFR2 versus unaltered TNFR1 expression in aged MDSCs significantly shifts the balance of TNF‐α signaling toward the TNFR2–JNK axis, which accounts for JNK‐induced impairment of cell polarity and differentiation failure of aged MDSCs. Consistently, inhibiting JNK attenuates apolarity and partially restores the differentiation capacity of aged MDSCs, suggesting that upregulated TNFR2/JNK signaling is a key factor limiting MDSC differentiation during organismal ageing. Therefore, abnormal hyperexpression of TNFR2 represents a general mechanism by which extrinsic SASP signals disrupt intrinsic cell polarity behavior, thereby arresting mature differentiation of MDSCs with ageing, suggesting that TNFR2 could be a potential therapeutic target for intervention of ageing through rejuvenation of aged MDSCs.
Myricanol prevents aging‐related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5
Authors: Shengnan Shen, Qiwen Liao, Peng Lyu, Jigang Wang, Ligen Lin
Journal: MedComm (2024)

Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall-related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage-induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage-induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging.
Multi‐omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation
Authors: Zhengtao Liu, Hai Zhu, Junsheng Zhao, Lu Yu, Shuping Que, Jun Xu, Lei Geng, Lin Zhou, Luca Valenti, Shusen Zheng
Journal: MedComm (2024)

Abstract To identify the mechanism underlying macrosteatosis (MaS)‐related graft failure (GF) in liver transplantation (LT) by multi‐omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery ( n = 68) and validation ( n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS‐related inferior post‐transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome‐related pathways. Core features of MaS‐related GF were presented on decreased transferrin and impaired anti‐oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia‐inducible factor 1A (HIF1A). Furthermore, miR‐362‐3p and miR‐299‐5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS‐related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi‐omics data depicted a panorama of biological pathways deregulated in MaS‐related GF. Transcriptional regulatory networks centered on transferrin and anti‐oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.
Perianal fistulizing Crohn’s disease-associated anorectal and fistula cancers: systematic review and expert consensus
Authors: Serre-Yu Wong, Cathy Rowan, Elvira Diaz Brockmans, Cindy C Y Law, Elisabeth Giselbrecht, Celina Ang, Sergey Khaitov, David Sachar, Alexandros D Polydorides, Leon Shin-Han Winata, Bram Verstockt, Antonino Spinelli, David T Rubin, Parakkal Deepak, Dermot P B McGovern, Benjamin D McDonald, Phillip Lung, Lilli Lundby, Amy L Lightner, Stefan D Holubar, Luke Hanna, Carla Hamarth, Jeroen Geldof, Anders Dige, Benjamin L Cohen, Michele Carvello, Cristiana Bonifacio, Gabriele Bislenghi, Corina Behrenbruch, David H Ballard, Emre Altinmakas, Shaji Sebastian, Phil Tozer, Ailsa Hart, Jean-Frederic Colombel
Journal: Clinical Gastroenterology and Hepatology (2024)

Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium.
Allergic inflammation triggers dyslipidemia via IgG signalling
Authors: Nieves Fernández‐Gallego, Raquel Castillo‐González, Lucía Moreno‐Serna, Antonio J. García‐Cívico, Elisa Sánchez‐Martínez, Celia López‐Sanz, Ana Luiza Fontes, Lígia L. Pimentel, Ana Gradillas, David Obeso, René Neuhaus, Marta Ramírez‐Huesca, Ignacio Ruiz‐Fernández, Emilio Nuñez‐Borque, Yolanda R. Carrasco, Borja Ibáñez, Pilar Martín, Carlos Blanco, Coral Barbas, Domingo Barber, Luis M. Rodríguez‐Alcalá, Alma Villaseñor, Vanesa Esteban, Francisco Sánchez‐Madrid, Rodrigo Jiménez‐Saiz
Journal: Allergy (2024)

Abstract Background Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Methods We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell‐depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post‐allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction. Results We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T‐cell‐driven late phase inflammation. On the contrary, the IgG‐mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction. Conclusion Overall, this study reveals that IgG‐mediated allergic inflammation regulates lipid metabolism.
We are not in a Woody Allen film yet
Authors: Lorenzo Fuccio
Journal: Endoscopy (2024)

The ability to repeat the famous scene from Woody Allen's Annie Hall film (1977), in which the main character begins a heated discussion about Marshall McLuhan's theories with a particularly annoying neighbor, and Marshall McLuhan himself comes out from behind a display board to clarify exactly how things are [1], would be very nice every time we are unsure about how to manage or what to suggest to a patient.
Molecular and transcriptional basis of bidirectional CD4<sup>+</sup> T cell exhaustion in oropharyngeal squamous cell carcinoma
Authors: Danni Cheng, Ke Qiu, Daibo Li, Minzi Mao, Yufang Rao, Yao Song, Lan Feng, Xiuli Shao, Chuanhuan Jiang, Yan Wang, Li Li, Xuemei Chen, Sisi Wu, Haiyang Wang, Jun Liu, Haopeng Yu, Wei Zhang, Fei Chen, Yu Zhao, Jianjun Ren
Journal: MedComm (2024)

Abstract Tumor‐infiltrating CD4 + T cells orchestrate the adaptive immune response through remarkable plasticity, and the expression patterns of exhaustion‐related inhibitory receptors in these cells differ significantly from those of CD8 + T cells. Thus, a better understanding of the molecular basis of CD4 + T cell exhaustion and their responses to immune checkpoint blockade (ICB) is required. Here, we integrated multiomics approaches to define the phenotypic and molecular profiles of exhausted CD4 + T cells in oropharyngeal squamous cell carcinoma (OPSCC). Two distinct immune‐promoting (Module 1) and immunosuppressive (Module 2) functional modules in tumor‐infiltrating CD4 + T cells were identified, and both the immune‐promoting function of Module 1 cells and immunosuppressive function of Module 2 cells were positively associated with their corresponding exhaustion states. Furthermore, the application of ICBs targeting effector CD4 + T cells in Module 1 (αPD‐1) and Treg cells in Module 2 (αCTLA‐4) in mouse models could help reinvigorate the effector function of Module 1‐exhausted CD4 + T cells and reduce the immunosuppressive function of Module 2‐exhausted CD4 + T cells, ultimately promoting OPSCC tumor regression. Taken together, our study provides a crucial cellular basis for the selection of optimal ICB in treating OPSCC.
Effectiveness of a nurse-led one-to-one education programme in addition to standard care in children with atopic dermatitis: a multicentre randomized control trial
Authors: Sebastien Barbarot, Helene Aubert, Marie-Anne Vibet, Maëlle Leray, Aurore Foureau, Francoise Elan, Laëtitia Menneron, Jean-Francois Stalder, Juliette Mazereeuw-Hautier, Alice Phan, Catherine Droitcourt, Anne-Claire Bursztejn, Franck Boralevi, Christine Chiaverini, Nadia Raison-Peyron, Audrey Lasek, Laurent Misery, Claire Abasq, Stephanie Mallet
Journal: British Journal of Dermatology (2024)

Therapeutic patient education (TPE) is recommended for children with atopic dermatitis (AD), but no consensus has been reached on the optimal tailoring of delivery. While repeated multidisciplinary group education sessions have shown effectiveness, the benefits of one-on-one educational interventions led by nurses for children with AD have not yet been assessed.
Bone-organ axes: bidirectional crosstalk
Authors: An-Fu Deng, Fu-Xiao Wang, Si-Cheng Wang, Ying-Ze Zhang, Long Bai, Jia-Can Su
Journal: Military Medical Research (2024)

Abstract In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.
Integration of Clinical Trial Spatial Multiomics Analysis and Virtual Clinical Trials Enables Immunotherapy Response Prediction and Biomarker Discovery
Authors: Shuming Zhang, Atul Deshpande, Babita K. Verma, Hanwen Wang, Haoyang Mi, Long Yuan, Won Jin Ho, Elizabeth M. Jaffee, Qingfeng Zhu, Robert A. Anders, Mark Yarchoan, Luciane T. Kagohara, Elana J. Fertig, Aleksander S. Popel
Journal: Cancer Research (2024)

Due to the lack of treatment options, there remains a need to advance new therapeutics in hepatocellular carcinoma (HCC). The traditional approach moves from initial molecular discovery through animal models to human trials to advance novel systemic therapies that improve treatment outcomes for patients with cancer. Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential biomarkers for immunotherapy, we developed a new computational model to track tumor progression at the organ scale while capturing the spatial heterogeneity of the tumor in HCC. This computational model of spatial quantitative systems pharmacology was designed to simulate the effects of combination immunotherapy. The model was initiated using literature-derived parameter values and fitted to the specifics of HCC. Model validation was done through comparison with spatial multiomics data from a neoadjuvant HCC clinical trial combining anti-PD1 immunotherapy and a multitargeted tyrosine kinase inhibitor cabozantinib. Validation using spatial proteomics data from imaging mass cytometry demonstrated that closer proximity between CD8 T cells and macrophages correlated with nonresponse. We also compared the model output with Visium spatial transcriptomics profiling of samples from posttreatment tumor resections in the clinical trial and from another independent study of anti-PD1 monotherapy. Spatial transcriptomics data confirmed simulation results, suggesting the importance of spatial patterns of tumor vasculature and TGFβ in tumor and immune cell interactions. Our findings demonstrate that incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides a novel approach for patient outcome prediction and biomarker discovery. Significance: Incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides an effective approach for patient outcome prediction and biomarker discovery.
Super-enhancer-driven IRF2BP2 enhances ALK activity and promotes neuroblastoma cell proliferation
Authors: Yanling Chen, Ran Zhuo, Lichao Sun, Yanfang Tao, Gen Li, Frank Zhu, Yunyun Xu, Jianwei Wang, Zhiheng Li, Juanjuan Yu, Hongli Yin, Di Wu, Xiaolu Li, Fang Fang, Yi Xie, Yizhou Hu, Hairong Wang, Chun Yang, Lei Shi, Xiaodong Wang, Zimu Zhang, Jian Pan
Journal: Neuro-Oncology (2024)

Abstract Background Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB). Methods The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing. Results The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2, and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB. Conclusions Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of the NB susceptibility gene ALK.
Effectiveness of ferritin-guided donation intervals in whole-blood donors in the Netherlands (FIND'EM): a stepped-wedge cluster-randomised trial
Authors: Amber Meulenbeld, Steven Ramondt, Maike G Sweegers, Franke A Quee, Femmeke J Prinsze, Emiel O Hoogendijk, Dorine W Swinkels, Katja van den Hurk
Journal: The Lancet (2024)
Cognitive performance in functional seizures compared with epilepsy and healthy controls: a systematic review and meta analysis
Authors: Ryan Van Patten, Tara A Austin, Erica Cotton, Lawrence Chan, John A Bellone, Kristen Mordecai, Hamada Altalib, Stephen Correia, Elizabeth W Twamley, Richard N Jones, Kelsey Sawyer, W Curt LaFrance
Journal: The Lancet Psychiatry (2024)
Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial
Authors: Christopher Burton, Cara Mooney, Laura Sutton, David White, Jeremy Dawson, Aileen R Neilson, Gillian Rowlands, Steve Thomas, Michelle Horspool, Kate Fryer, Monica Greco, Tom Sanders, Ruth E Thomas, Cindy Cooper, Emily Turton, Waquas Waheed, Jonathan Woodward, Ellen Mallender, Vincent Deary
Journal: The Lancet (2024)
Correlation of baseline ENPP1 and cGAS expression in advanced solid tumors with intratumoral immune activation and clinical outcomes after treatment with the first-in-class oral ENPP1 inhibitor RBS2418, alone or in combination with pembrolizumab.
Authors: Thomas Urban Marron, Zev A. Wainberg, Alexander I. Spira, Michael S. Gordon, Christopher Chen, Jennifer Margaret Segar, Ralph V. Boccia, Jordan Berlin, Ildiko Csiki, Juergen Schanzer, Ningwu Huang, Jeffrey Glen, Klaus Klumpp, Jamal Ghazi Misleh
Journal: Journal of Clinical Oncology (2024)

2597 Background: ENPP1 is a nucleotide pyrophosphatase and phosphodiesterase. Its expression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis and reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting anticancer immunity. RBS2418, a first-in-class, potent ENPP1 inhibitor, is evaluated as monotherapy and combination with pembrolizumab in advanced/metastatic solid tumors. Methods: Phase 1 dose escalation with 100, 200, 400 and 800 mg BID dose and selected expansion cohorts of RBS2418 alone or in combination with pembrolizumab (200 mg IV q3w) in patients who have failed all approved treatments including immunotherapy. Primary outcome measures are safety and PK. Tumor biopsy, and blood samples are collected to determine PK/PD and immune profiles using LC/MS, ENPP1 inhibition, immunofluorescence, IHC, flow cytometry, and TCR/RNAseq analysis. Results: All dose levels evaluated to date were safe and well tolerated with no DLTs. Median plasma concentrations of RBS2418 increased in a dose-dependent manner. Plasma and tumor concentrations of RBS2418 were above the ENPP1 inhibition EC90 level in all patients at all-time points tested. Preliminary analyses support the premise that ENPP1 and cGAS co-expression (EG+ phenotype) in tumors correlates with RBS2418 treatment associated immune activation and clinical benefit. Analysis of all currently available paired pre- and on-treatment biopsies showed on-treatment immune activation profiles in 100% (n=6) with EG+ phenotype and 0% (0/6) with EG- phenotype at baseline. Immune activation profiles include an increase in tumor-infiltrating T-cells and M2 to M1 macrophage switch, consistent with the mechanism of action. EG +/- phenotype and immune activation profile also correlated with observed clinical outcomes. Conclusions: Oral RBS2418 alone or with pembrolizumab has been safe, well tolerated with no DLTs at all dose levels evaluated to date in the ongoing Ph1 dose escalation and expansion study. The robust PK profile shows plasma levels enabling complete ENPP1 inhibition at all time points. Immune activation and observed clinical benefit of treatment in late line treatment of refractory metastatic solid tumors such as CRC and HCC was associated with baseline ENPP1 and cGAS protein expression in tumors. These results warrant further development of RBS2418 in advanced tumors and enrollment continues in expansion cohorts on this phase 1 study. Clinical trial information: NCT05270213 .