tbuckley/cabot-search huggingface dataset:
Using the hospital frailty risk score to assess oesophago-gastric cancer patient outcomes: a retrospective cohort study
Authors: Alexander Harris, Towhid Imam, Rob Konstant-Hambling, Helene Flint, Simon Conroy, Sacheen Kumar, William Allum
Journal: International Journal of Surgery (2025)

The inclusion of clinical frailty in the assessment of patients planned for major surgery has proven to be an independent predictor of outcome. Since approximately half of all patients in the UK diagnosed with oesophagogastric (OG) cancer are over 75 years of age, assessment of frailty may be important in selection for surgery. This retrospective cohort study applied the Hospital Frailty Risk Score to data obtained from the NHS Secondary Uses Service electronic database for patients aged 75 years or older undergoing oesophagectomy and gastrectomy between April 2017 and March 2020. Descriptive statistics were performed to assess the effect of patient frailty on length of stay, 30-day readmission, and 30-day mortality rates. These outcomes were compared with those published by the National Oesophago-Gastric Cancer Audit. Over 90% of the 1775 patients identified according to the age and resection criteria exhibited some degree of frailty. The median length of stay and 30-day readmission rate increased as patient frailty increased following both oesophagectomy and gastrectomy, as did the 30-day mortality rate following gastrectomy. Frailty is a dynamic state and increasing age alone should not be a barrier to receiving the most appropriate treatment. Introducing standardized assessment of clinical frailty for patients with OG cancer to identify this cohort of patients earlier might enable targeted screening for frailty syndromes. This could facilitate the enhanced delivery of more holistic, frailty-attuned, approaches to person-centred care, and evidence-based treatment pathways for improved patient outcomes.
Vps4a Mediates a Unified Membrane Repair Machinery to Attenuate Ischemia/Reperfusion Injury
Authors: Xiaozhi Huang, Jiayin Zhang, Chen Xu, Ranran Cao, Peijun Jiang, Xue Ji, Wenyi Wang, Zhishan Huang, Peidong Han
Journal: Circulation Research (2025)

BACKGROUND: Cardiac ischemia/reperfusion disrupts plasma membrane integrity and induces various types of programmed cell death. The ESCRT (endosomal sorting complex required for transport) proteins, particularly AAA-ATPase Vps4a (vacuolar protein sorting 4a), play an essential role in the surveillance of membrane integrity. However, the role of ESCRT proteins in the context of cardiac injury remains unclear. METHODS: We simultaneously visualized the formation of membrane blebs and the subcellular translocation of Vps4a during a variety of cell death programs in primary cardiomyocytes. Vps4a cardiomyocyte-specific knockout and overexpression mice were generated and characterized. In vivo and ex vivo surgeries were performed to determine the effects of altered Vps4a expression levels on plasma membrane repair and cell survival. Given the role of Ripk3 (receptor-interacting kinase 3)-mediated pore formation in regulating cell membrane integrity, hearts from Ripk3 and Vps4a double-knockout mice were examined. The sequential recruitment of upstream ESCRT components that promote the translocation of Vps4a to injured sites was also assessed using genetic gain- and loss-of-function approaches. Finally, we overexpressed a mutated form of Vps4a with defective ATPase activity and investigated its function during cardiomyocyte membrane repair. RESULTS: Ischemia/reperfusion stimulation or forced induction of apoptosis, necroptosis, and pyroptosis in primary cardiomyocytes leads to membrane blebbing and the exposure of phosphatidylserine to the extracellular space. In response to injury, Vps4a promptly translocates to injured sites to reseal damaged membranes. Vps4a gain- and loss-of-function in the postnatal stage minimally affects cardiac structure formation and function. However, in the context of ischemia/reperfusion stimulation, overexpression of Vps4a protects cardiomyocytes against injury, whereas Vps4a -deficient hearts are more susceptible to cell damage. Additionally, Ripk3 deletion abrogates the detrimental effects of Vps4a deficiency during ischemia/reperfusion injury, and the Ca 2+ -Alix-Ist1 axis plays an essential role in recruiting Vps4a to the injured site. Mechanistically, Vps4a promotes the shedding of plasma membrane blebs to restrict permeability to the extracellular environment, and the surveillance of membrane integrity requires the ATPase activity of Vps4a. CONCLUSIONS: These results demonstrate that Vps4a-mediated plasma membrane repair is an intrinsic cell protection machinery that antagonizes cardiac ischemia/reperfusion injury, and our findings may contribute to the development of therapeutic strategies towards attenuating cardiac injury.
YAP1 mediates the dimensional and chemical coordination of immunoregulation and therapy in extensively passaged mesenchymal stem cells
Authors: Fang-Ying Du, Feng Zhou, Na Zhao, Lei Bao, Cheng-Biao Hu, Jing Lei, An-Qi Liu, Ying-Feng Gao, Li-Hui Bao, Hua Ni, Xiao-Rui Yu, Ji Chen, Bing-Dong Sui
Journal: Theranostics (2025)

Rationale: Mesenchymal stem cells (MSCs) possess potent immunomodulatory capability, but occasionally, clinical application of MSCs is hindered by compromised cell functionality and insufficient therapeutic efficacy. Methods: Here, well-established mouse models of dextran sulfate sodium (DSS)-induced colitis and streptozotocin (STZ)-induced type 1 diabetes (T1D) were used to evaluate therapeutic immunomodulatory effects of human umbilical cord-derived MSCs. MSCs were examined at the fifth (P5) and the fifteenth (P15) passages, and three-dimensional (3D) culture was conducted by Matrigel incorporation. A series of biochemical, histopathological and cellular assays were performed to investigate the MSC function and therapeutic performance, and immunoregulation was evaluated by in vitro co-culture with T cells and in vivo analyses of T-cell infiltration into target tissues. RNA sequencing (RNA-seq) analysis followed by immunofluorescence staining, gene expression analyses and chemical regulation were used to investigate the molecular targets. Results: MSCs lose therapeutic immunomodulatory effects after extensive expansion to P15 when cell senescence occurs. Intriguingly, 3D preconditioning of MSCs in Matrigel promotes diminished immunoregulatory capability despite extensive passages, which benefits function of P15-MSCs to modulate T-cell subsets in co-culture, suppress infiltration of pro-inflammatory T cells in the colon and pancreas tissues after infusion, ameliorate systemic inflammation, and alleviate colitis and T1D in mice. Mechanistically, 3D culture provokes transcriptomic reprogramming of MSCs toward a Yes-associated protein 1 (YAP1)-marked, Hippo signaling pathway-upregulated state with promoted release of the anti-inflammatory cytokine, transforming growth factor-beta1 (TGF-β1). Moreover, chemical regulation of YAP1 by clinically relevant drugs, verteporfin (VP) and prostaglandin E2 (PGE2), affects TGF-β1 expression and the immunomodulatory capability of MSCs during dimensional culture. Conclusions: Taken together, these findings unravel YAP1-based dimensional and chemical coordination of expanded MSC immunoregulation, which will shed light on precisely controlled translational application.
Chronic stress induces depression through MDGA1-Neuroligin2 mediated suppression of inhibitory synapses in the lateral habenula
Authors: Xuehui Wang, Hao Wei, Zhe Hu, Jie Jiang, Xinyan Dong, Jinpiao Zhu, Haiyan Chen, Nils Brose, Noa Lipstein, Tonghui Xu, Steven A. Connor, Daqing Ma, Yicheng Xie
Journal: Theranostics (2025)

Rationale: The hyperactivity of lateral habenula (LHb) has been implicated in the pathophysiology of depression, but the regulatory mechanisms of inhibitory synapses in this context remains unclear. MDGA1 and neuroligin2 (Nlgn2), both regulators of inhibitory synapses, selectively interact in the LHb. We aimed to investigate if their interaction contributes to chronic restrained stress (CRS)-induced depression by modulating inhibitory synapses. Methods: Transgenic mouse models were established to conditional knockout/recover of MDGA1 expression or knockin Nlgn2 variant incapable of binding MDGA1 in the LHb, using viral Cre-recombinase expression. Synaptic function and density were assessed through electrophysiology and immunostaining, respectively. An acute restrained stress (ARS) model and chemogenetic activation of the lateral hypothalamus (LH) were used to stimulate the LHb. Behavioral tests related to depression were conducted following CRS. Results: MDGA1 and Nlgn2 selectively interacted in the LHb, which was elevated following CRS. Germline knockout of MDGA1 increased inhibitory transmission and GABAergic synapse density in the LHb, effects that were reversed by adult re-expression of MDGA1. Introduction of the Nlgn2 variant incapable of binding MDGA1 similarly enhanced inhibitory transmission and increased GABAergic synapse density in the LHb. Both germline MDGA1 deficiency and introduction of the Nlgn2 variant mitigated ARS- and LH activation-induced LHb neuron hyperactivation. MDGA1 deficiency in the LHb during adulthood increased inhibitory synaptic strength and conferred significant resistance to CRS-induced depressive behaviors, similar to the effects of introducing the Nlgn2 variant in the LHb. Conclusions: Our findings suggests that MDGA1-mediated suppression of Nlgn2 facilitates depression onset through limiting GABAergic synapse formation within the LHb. Targeting MDGA1/Nlgn2 complexes residing at GABAergic synapses within the lateral habenula may be viable for alleviating core behavioral symptoms of major depression.
Current status, challenges, and prospects of artificial intelligence applications in wound repair theranostics
Authors: Huazhen Liu, Wenbin Sun, Weihuang Cai, Kaidi Luo, Chunxiang Lu, Aoxiang Jin, Jiantao Zhang, Yuanyuan Liu
Journal: Theranostics (2025)

Skin injuries caused by physical, pathological, and chemical factors not only compromise appearance and barrier function but can also lead to life-threatening microbial infections, posing significant challenges for patients and healthcare systems. Artificial intelligence (AI) technology has demonstrated substantial advantages in processing and analyzing image information. Recently, AI-based methods and algorithms, including machine learning, deep learning, and neural networks, have been extensively explored in wound care and research, providing effective clinical decision support for wound diagnosis, treatment, prognosis, and rehabilitation. However, challenges remain in achieving a closed-loop care system for the comprehensive application of AI in wound management, encompassing wound diagnosis, monitoring, and treatment. This review comprehensively summarizes recent advancements in AI applications in wound repair. Specifically, it discusses AI's role in injury type classification, wound measurement (including area and depth), wound tissue type classification, wound monitoring and prediction, and personalized treatment. Additionally, the review addresses the challenges and limitations AI faces in wound management. Finally, recommendations for the application of AI in wound repair are proposed, along with an outlook on future research directions, aiming to provide scientific evidence and technological support for further advancements in AI-driven wound repair theranostics.
LAT1-specific PET radiotracers: Development and clinical experiences of a new class of cancer-specific radiopharmaceuticals
Authors: Arifudin Achmad, Hirofumi Hanaoka, Holis Abdul Holik, Keigo Endo, Yoshito Tsushima, Achmad Hussein S. Kartamihardja
Journal: Theranostics (2025)

The quest for a cancer-specific positron emission tomography (PET) tracer has been ongoing for decades. Current evidence shows that targeting amino acid metabolism dysregulation is a valid alternative cancer detection method and can complement the conventional approach, which relies on targeting increased glucose metabolism. The rate of amino acid metabolism in all major organs is mostly equally low and does not change in any physiological dynamics. The amino acid metabolism rate only spikes in malignant tissues. PET imaging targeting LAT1 (L-type amino acid transporter 1) demonstrated accurate cancer imaging of various cancer types with nearly negligible background uptake. LAT1 is a pan-cancer biomarker of amino acid metabolism dysregulation. The upregulated LAT1 expression in cancer cells depicts their dynamic behavior and aggressiveness. This review discussed PET radiotracers developed as a LAT1-specific agent and how this new class of cancer-specific radiopharmaceuticals could deliver PET images with clinical properties we yearn for, such as high specificity toward various malignancies, robust non-cancer exclusion (mainly inflammatory reactions), accurate malignant lesion delineation, representative therapeutic monitoring, and long-term prognostication.
Artificial Intelligence Predicts Multiclass Molecular Signatures and Subtypes Directly From Breast Cancer Histology: a Multicenter Retrospective Study
Authors: Xiangyang Zhang, Yang Chen, Changjing Cai, Yifeng Wang, Jun Tan, Zijie Fang, Le Wei, Zhuchen Shao, Liwen Wang, Tiezheng Qi, Yihan Liu, Zhaohui Jiang, Yin Li, Ying Han, Tibera Kagemulo Rugambwa, Shan Zeng, Haoqian Wang, Hong Shen, Yongbing Zhang
Journal: International Journal of Surgery (2025)

Detection of biomarkers of breast cancer incurs additional costs and tissue burden. We propose a deep learning-based algorithm (BBMIL) to predict classical biomarkers, immunotherapy-associated gene signatures, and prognosis-associated subtypes directly from hematoxylin and eosin stained histopathology images. BBMIL showed the best performance among comparative algorithms on the prediction of classical biomarkers, immunotherapy related gene signatures, and subtypes.
Lactylation in health and disease: physiological or pathological?
Authors: Lijun Zhao, Haonan Qi, Huiying Lv, Wenyue Liu, Rui Zhang, Angang Yang
Journal: Theranostics (2025)

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles in different aspects of energy metabolism and signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as a novel posttranslational modification (PTM). Research indicates that Kla is an essential balancing mechanism in a variety of organisms and is involved in many key cellular biological processes through different pathways. Kla is closely related to disease development and represents a potential and important new drug target. In line with existing reports, we searched for newly discovered Kla sites on histone and nonhistone proteins; reviewed the regulatory mechanisms of Kla (particularly focusing on the enzymes directly involved in the reversible regulation of Kla, including "writers" (modifying enzymes), "readers" (modification-binding enzymes), and "erasers" (demodifying enzymes); and summarized the crosstalk between different PTMs to help researchers better understand the widespread distribution of Kla and its diverse functions. Furthermore, considering the "double-edged sword" role of Kla in both physiological and pathological contexts, this review highlights the "beneficial" biological functions of Kla in physiological states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) and its "detrimental" pathogenic or inducive effects on pathological processes, particularly malignant tumors and complex nontumor diseases. We also clarify the molecular mechanisms of Kla in health and disease, and discuss its feasibility as a therapeutic target. Finally, we describe the detection technologies for Kla and their potential applications in diagnosis and clinical settings, aiming to provide new insights for the treatment of various diseases and to accelerate translation from laboratory research to clinical practice.
Exercise ameliorates osteopenia in mice via intestinal microbial-mediated bile acid metabolism pathway
Authors: Congcong Yu, Rongtai Sun, Wentao Yang, Tianyuan Gu, Xiaozhang Ying, Lin Ye, Yang Zheng, Shunwu Fan, Xiangjun Zeng, Shasha Yao
Journal: Theranostics (2025)

Rationale: Physical exercise is essential for skeletal integrity and bone health. The gut microbiome, as a pivotal modulator of overall physiologic states, is closely associated with skeletal homeostasis and bone metabolism. However, the potential role of intestinal microbiota in the exercise-mediated bone gain remains unclear. Methods: We conducted microbiota depletion and fecal microbiota transplantation (FMT) in ovariectomy (OVX) mice and aged mice to investigate whether the transfer of gut ecological traits could confer the exercise-induced bone protective effects. The study analyzed the gut microbiota and metabolic profiles via 16S rRNA gene sequencing and LC-MS untargeted metabolomics to identify key microbial communities and metabolites responsible for bone protection. Transcriptome sequencing and RNA interference were employed to explore the molecular mechanisms. Results: We found that gut microbiota depletion hindered the osteogenic benefits of exercise, and FMT from exercised osteoporotic mice effectively mitigated osteopenia. Comprehensive profiling of the microbiome and metabolome revealed that the exercise-matched FMT reshaped intestinal microecology and metabolic landscape. Notably, alterations in bile acid metabolism, specifically the enrichment of taurine and ursodeoxycholic acid, mediated the protective effects on bone mass. Mechanistically, FMT from exercised mice activated the apelin signaling pathway and restored the bone-fat balance in recipient MSCs. Conclusion: Our study underscored the important role of the microbiota-metabolic axis in the exercise-mediated bone gain, heralding a potential breakthrough in the treatment of osteoporosis.
Metabolism of hepatic stellate cells in chronic liver diseases: emerging molecular and therapeutic interventions
Authors: Mengyao Yan, Yimin Cui, Qian Xiang
Journal: Theranostics (2025)

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and metabolic dysfunction-associated alcoholic liver disease (MetALD), and viral hepatitis, can lead to liver fibrosis, cirrhosis, and cancer. Hepatic stellate cell (HSC) activation plays a central role in the development of myofibroblasts and fibrogenesis in chronic liver diseases. However, HSC activation is influenced by the complex microenvironments within the liver, which are largely shaped by the interactions between HSCs and various other cell types. Changes in HSC phenotypes and metabolic mechanisms involve glucose, lipid, and cholesterol metabolism, oxidative stress, activation of the unfolded protein response (UPR), autophagy, ferroptosis, senescence, and nuclear receptors. Clinical interventions targeting these pathways have shown promising results in addressing liver inflammation and fibrosis, as well as in modulating glucose and lipid metabolism and metabolic stress responses. Therefore, a comprehensive understanding of HSC phenotypes and metabolic mechanisms presents opportunities for novel therapeutic approaches aimed at halting or even reversing chronic liver diseases.
Glutamatergic pathways from medial prefrontal cortex to paraventricular nucleus of thalamus contribute to the methamphetamine-induced conditioned place preference without affecting wakefulness
Authors: Xiang Li, Xing Xu, Quying Feng, Ning Zhou, Yuhong He, Ying Liu, Haoqing Tai, Hee Young Kim, Yu Fan, Xiaowei Guan
Journal: Theranostics (2025)

Methamphetamine (METH) is a commonly abused psychostimulant with a high addictive nature. The paraventricular nucleus of thalamus (PVT), a key nucleus for arousal, has attracted much attention in the reward process of substance use. However, at which stage dose the PVT encode the reward process? How to reduce the side-effects of modulating PVT on wakefulness during the treatment of substance use? These issues remain unclear. The goal of the current study is to explore the role of the PVT and the glutamatergic projections from medial prefrontal cortex (mPFC) to PVT in the reward process of METH. Methods: Here, the conditioned place preference (CPP) was used to assess the reward process of METH in male mice, combined with methods of c-Fos mapping, virus-based neural tracing, patch-clamp recording, EEG-EMG recordings, optogenetics and designer receptor exclusively activated by designer drugs (DREADDs). Results: The glutamatergic neurons in PVT (PVTGlu) were triggered during METH CPP-Test, rather than by METH CPP-Training. Suppressing either PVTGlu or glutamatergic projection from mPFC to PVT efficiently disrupted the acquisition of METH CPP in male mice, mainly mediated by the GluN2A subunit of NMDA receptor. Further, inhibition of PVTGlu affected the rhythm of EEG-EMG, whereas inhibition of glutamatergic projection from mPFC to PVT did not. Conclusion: PVTGlu is involved in the reward process of METH at the retrieval stage of METH-conditioned context, rather than at the stage of encoding association between METH and context. The glutamatergic projections from mPFC to PVT, especially the GluN2A molecule, may be a promising therapeutic target for reducing METH reward, as there are no significant side effects on wakefulness.
Interaction of the Gut-Liver-Brain Axis and the sterolbiome with sexual dysfunction in patients with cirrhosis
Authors: Spencer C. Harris, Jasmohan S. Bajaj
Journal: Gut Microbes (2025)

There is a complex interplay between the gut microbes, liver, and central nervous system, a gut-liver-brain axis, where the brain impacts intestinal and hepatic function while the gut and liver can impact cognition and mental status. Dysregulation of this axis can be seen in numerous diseases. Hepatic encephalopathy, a consequence of cirrhosis, is perhaps the best studied perturbation of this system. However, patients with cirrhosis have been shown to have increased incidence of other disorders of mental health which may be otherwise less clinically identifiable. Sexual dysfunction affects a large proportion of patients with cirrhosis and is associated with decreased quality of life. Screening for sexual dysfunction in patients with cirrhosis is often overlooked, and even when identified, treatment options are limited, particularly in patients with advanced liver disease. The mechanism by which patients with cirrhosis develop sexual dysfunction is multifactorial, but a key driver of this clinical manifestation is alterations in circulating sex hormones. In patients with cirrhosis, low serum sex hormones have been shown to be associated with higher mortality regardless of MELD score. The gut microbiome has been shown to have an immense metabolic capacity to metabolize steroid hormones. This "sterolbiome" has already been implicated in other disease processes and has been linked to low circulating sex hormones, suggesting a new mechanism by which sex hormones may be altered in disease states where the gut-liver-brain axis is disrupted. The aim of this review is to cover sex hormone changes and sexual dysfunction in cirrhosis, examine the gut microbiome and its metabolic capacity, particularly for steroid hormones, and consider how microbial changes using fecal microbiota transplant could modulate sexual dysfunction.
Vaccination against measles-mumps-rubella and rates of non-targeted infectious disease hospitalisations: Nationwide register-based cohort studies in Denmark, Finland, Norway, and Sweden
Authors: Lise Gehrt, Sören Möller, Hélène Englund, Ida Laake, Heta Nieminen, Berit Feiring, Mika Lahdenkari, Arto A Palmu, Lill Trogstad, Christine Stabell Benn, Signe Sørup
Journal: Journal of Infection (2025)