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Tao He,1,2,* Xiao-Yu Sun,1,2,* Meng-Han Tong,1,2 Ming-Jie Zhang,1,2 Zhi-Jun Duan1,2 1Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Dalian Central Laboratory of Integrative Neuro-Gastrointestinal Dynamics and Metabolism Related Diseases Prevention and Treatment, Dalian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhi-Jun Duan, Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, 161000, People’s Republic of China, Tel +86 83635963, Email cathydoctor@sina.comBackground and Aim: Obesity is association with elevated risks of erosive esophagitis (EE), and metabolic abnormalities play crucial roles in its development. The aim of the study was to assess the association between metabolic obesity phenotypes and the risk of EE.Methods: This retrospective study enrolled 11,599 subjects who had undergone upper gastrointestinal endoscopy at the First Affiliated Hospital of Dalian Medical University from January 1, 2008, to December 31, 2023. The enrolled individuals were grouped into four cohorts based on their metabolic health and obesity profiles, namely, metabolically healthy non-obesity (MHNO; n=2134, 18.4%), metabolically healthy obesity (MHO; n=1736, 15.0%), metabolically unhealthy non-obesity (MUNO; n=4290, 37.0%), and metabolically unhealthy obesity (MUO; n=3439, 29.6%). The relationships of the different phenotypes of metabolic obesity with the risks of developing EE in the different sexes and age groups were investigated by multivariate logistic regression analysis.Results: The MUNO, MHO, and MUO cohorts exhibited elevated risks of developing EE than the MHNO cohort. The confounding factors were adjusted for, and the findings revealed that the MUO cohort exhibited the greatest risk of EE, with odds ratios (ORs) of 5.473 (95% CI: 4.181– 7.165) and 7.566 (95% CI: 5.718– 10.010) for males and females, respectively. The frequency of occurrence of EE increased following an increase in proportion of metabolic risk factors. Subgroup analyses showed that the individuals under and over 60 years of age in the MHO, MUNO, and MUO cohorts exhibited elevated risks of developing EE. Further analysis suggested that obesity has a stronger influence on the risks of developing EE compared to metabolic disorders.Conclusion: Metabolic disorders and obesity are both related with an elevated risk of EE, in which obesity has a potentially stronger influence. Clinical interventions should target both obesity and metabolic disorders to reduce EE risk. Keywords: metabolic obesity phenotype, erosive esophagitis, metabolic disorders

Si Liu,1,2 Xiao-yun Xiong,2 Hua Chen,1 Meng-die Liu,1 Ying Wang,1 Ying Yang,1 Mei-jun Zhang,1 Qin Xiang1 1School of Nursing, Nan Chang University, Nan Chang, Jiang Xi, People’s Republic of China; 2Nursing Department, the Second Affiliated Hospital of Nan Chang University, Nan Chang, Jiang Xi, People’s Republic of ChinaCorrespondence: Xiao-yun Xiong, Nursing Department, the Second Affiliated Hospital of Nan Chang University, Min de Road #, Nan Chang, 330006, People’s Republic of China, Tel +86-791-8627-4550, Email 1028970010@qq.comObjective: The purpose of this study was to clarify the concept of transitional care in patients with heart failure.Background: Transitional care is increasingly being applied in patients with heart failure, but the concept of transitional care in heart failure patients is not uniform and confused with other definitions, which limits further research and practice on transitional care for these patients.Design: Rodgers’ evolutionary concept analysis.Methods: A comprehensive literature search was conducted using the PUBMED, EMBASE, EBSCO, Chinese Biological Medicine (CBM), CNKI, and WANFANG databases (up to January 26, 2023). We used Rodgers’ evolutionary concept analysis method to identify related concepts, attributes, antecedents, and consequences of transitional care in patients with heart failure.Results: A total of 33 articles were included. The following attributes belonging to transitional care in patients with heart failure were extracted from the literature: self-care, multidisciplinary collaboration, and information transmission. The antecedents were patients’ health status, the health literacy of patients and caregivers, the role functions of the main implementer and social and medical resources. Consequences were separated into two categories: patient-centered health outcomes (all-cause mortality, health-related quality of life, discharge preparedness, self-care behaviors, satisfaction of patients) and healthcare utilization outcomes (hospital readmission, length of hospital stay, emergency department visits).Conclusion: This study found that transitional care in heart failure patients is a systemic care process during a vulnerable period that improves patient self-management and coordination between hospital resources and social support systems for continuous management to promote smooth patient transitions between different locations. This concept analysis will inform healthcare providers in designing evidence-based interventions and quality improvement strategies to ensure that transition processes lead to desired outcomes. In addition, this study will also be helpful for developing specific assessment tools to identify patients with HF who need transitional care.Keywords: concept analysis, heart failure, transitional care, self care, collaboration

Biao Yang,1,* Tianhang Luo,1,* Meijing Zhang,2,* Zhengmao Lu,1 Xuchao Xue,1 Guoen Fang1 1Department of General Surgery, 2Department of Oncology, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Current evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in human cancers. The present study aims to assess differentially expressed lncRNAs related to diffuse-type gastric carcinoma (DGC). Next-generation RNA sequencing was carried out to detect aberrantly expressed lncRNAs in DGC. Real-time polymerase chain reaction (RT-PCR) was performed to evaluate RP11–357H14.17 gene expression levels in DGC cell lines/tissues comparatively with normal gastric epithelial cell lines and adjacent normal tissues. The associations of RP11–357H14.17 expression levels with the clinicopathological features were also analyzed. The regulatory effects of RP11–357H14.17 on the biological behaviors of DGC cells were evaluated by MTT, colony formation assays, flow cytometry for apoptosis, wound healing assay, and transwell migration and invasion assays. RP11–357H14.17 expression was remarkably increased in DGC tissues and cell lines compared with normal gastric epithelial cells and adjacent normal tissues. High levels of RP11–357H14.17 were associated with increased tumor size, deeper depth of invasion, lymphatic metastasis, and advanced pathological stage. Further experiments demonstrated that the DGC cells MGC-803 transfected with si-RP11–357H14.17 showed reduced cell proliferation, migration, invasion, enhanced G1 phase arrest and cell apoptosis. These findings suggest that the novel lncRNA RP11–357H14.17 is associated with poor prognosis, and may serve as a potential prognostic biomarker and target for new antineoplastic therapies in human DGC. Keywords: long noncoding RNA, RP11–357H14.17, diffuse-type gastric cancer, ­proliferation, invasion, metastasis

Jie Zhang,1 Dan Liu,1 Mengjun Zhang,1 Yuqi Sun,1,2 Xiaojun Zhang,1 Guannan Guan,1 Xiuli Zhao,1 Mingxi Qiao,1 Dawei Chen,1 Haiyang Hu1 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2Department of Pharmaceutics, School of Pharmacy, Liaoning Medical University, Jinzhou, Liaoning Province, People’s Republic of China Abstract: Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells. Keywords: PAMAM dendrimers, multidrug resistance, endocytosis, intracellular transportation, exocytosis

Junhui Su,1–3,* Cui Chang,3,* Qi Xiang,1,2 Zhi-Wei Zhou,4 Rong Luo,5 Lun Yang,6 Zhi-Xu He,7 Hongtu Yang,2,3 Jianan Li,1 Yu Bei,1 Jinmei Xu,1,2 Minjing Zhang,1 Qihao Zhang,1 Zhijian Su,1 Yadong Huang,1 Jiyan Pang,5 Shu-Feng Zhou4,7 1Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, 2Department of Pharmacy, Jinan University, Guangzhou, 3The People’s Hospital of Shenzhen City, Shenzhen, People’s Republic of China; 4Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA; 5School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 6Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 7Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People’s Republic of China *These two authors contributed equally to this work Abstract: Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug–drug interactions via the chemical–protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1'-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1'-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members. Keywords: Xyloketal B, molecular target, cytochrome P450 3A, DDI-CPI tool, DAVID, midazolam, pharmacokinetics, rat, bioinformatics

Ming-jun Zhang,1 Sheng-nan Liu,1 Ge Xu,2 Ya-nan Guo,1 Jian-nan Fu,3 De-chun Zhang11Molecular Medicine and Tumor Research Center, Chongqing Medical University, 2Electron Microscopy Group, Department of Life Science, Chongqing Medical University, Chongqing, People's Republic of China; 3First People's Hospital of Jiulongpo District, Chongqing, People's Republic of ChinaBackground: The existing evidence that nanobacteria (NB) are closely associated with human disease is overwhelming. However, their potential toxicity against cancer cells has not yet been reported. The objective of this study was to investigate the cytotoxic effects of NB and nanohydroxyapatites (nHAPs) against human breast cancer cells and to elucidate the mechanisms of action underlying their cytotoxicity.Methodology/principal findings: NB were isolated from calcified placental tissue, and nHAPs were artificially synthesized. The viability of the MDA-MB-231 human breast cancer cell line was tested by using the Kit-8 cell counting kit assay. Apoptosis was examined by transmission electron microscopy and flow cytometry. The endocytosis of NB and nHAPs by MDA-MB-231 cells was initially confirmed by microscopy. Although both NB and nHAPs significantly decreased MDA-MB-231 cell viability and increased the population of apoptotic cells, NB were more potent than nHAPs. After 72 hours, NB also caused ultrastructural changes typical of apoptosis, such as chromatin condensation, nuclear fragmentation, nuclear dissolution, mitochondrial swelling, and the formation of apoptotic bodies.Conclusion/significance: In MDA-MB-231 human breast cancer cells, NB and nHAPs exerted cytotoxic effects that were associated with the induction of apoptosis. The effects exerted by NB were more potent than those induced by nHAPs. NB cytotoxicity probably emerged from toxic metabolites or protein components, rather than merely the hydroxyapatite shells. NB divided during culturing, and similar to cells undergoing binary fission, many NB particles were observed in culture by transmission electron microscopy, suggesting they are live microorganisms.Keywords: nanobacteria, nanohydroxyapatites, human breast cancer MDA-MB-231 cells, cytotoxicity, apoptosis

Zheng-mao Zhang,1 Xue-mei Yang,1 Chao Zhang,2 Min-jie Zhang,1 Xia Li,1 Feng-hua Zhang,3 Shan Kang,1 Shi-jie Wang,4 Bao-en Shan21Department of Gynecology and Obstetrics, Fourth Hospital of Hebei Medical University, 2Research Center, Fourth Hospital of Hebei Medical University, 3Department of General Surgery, Hebei General Hospital, 4Department of Gastroscopy, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of ChinaObjective: This study aimed to examine the expression of immune suppression factors and the mechanisms of antitumor effects of cord blood dendritic cells (DCs) stimulated by soluble cluster of differentiation 40 ligand (sCD40L) and cytokines in vitro in ovarian cancer patients.Methods: The expression levels of interleukin (IL)-10 and transforming growth factor (TGF)-β messenger RNA in peripheral blood were detected by reverse transcription polymerase chain reaction; expression levels of CD80 and CD86 in DCs stimulated by sCD40L were detected using flow cytometry and confocal laser scanning microscopy.Results: Expression levels of IL-10 and TGF-β genes in the peripheral blood of ovarian cancer patients were significantly increased compared with patients with benign ovarian tumors (P < 0.05). The expression levels of CD80 and CD86 in DCs cultured in the granulocyte-macrophage colony-stimulating factor + IL-4 + stem cell factor + Flt-3 ligand + sCD40L group were significantly increased compared with those in the control group, as assessed by flow cytometry and confocal laser scanning microscopy (P < 0.05).Conclusion: A variety of cytokines in combination with sCD40L can promote the proliferation of cord blood-derived DCs and induce their maturation as well as stimulating a specific antitumor response.Keywords: antitumor response, cytokine, immunotherapy, cord blood, IL-10, TGF-β

Background: The purpose of the current study was to determine whether the use of hematopoietic stem cell transplantation (HCT) to treat leukemia, lymphoma, or multiple myeloma (MM) differs by race and sex.Methods: The annual incidence of leukemia, lymphoma, and MM was estimated in the United States in people aged <70 years by race and sex using the Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1997 and 2002 and US census reports for the year 2000. The annual incidence of autologous, human leukocyte antigen (HLA) identical sibling, and unrelated HCT performed in these groups was estimated using Center for International Blood and Marrow Transplant Research data from 1997 through 2002. Logistic regression analysis was used to calculate the age-adjusted odds ratio (OR) of receiving HCT for Caucasians versus African Americans and for men versus women.Results: The likelihood of undergoing HCT was found to be higher for Caucasians than for African Americans (OR, 1.40; 95% confidence interval [95% CI], 1.34-1.46). This difference existed for each type of HCT: autologous (OR, 1.24; 95% CI, 1.19-1.30), HLA identical sibling (OR, 1.59; 95% CI, 1.46-1.74), and unrelated donor (OR, 2.02; 95% CI, 1.75-2.33). Overall, men were more likely than women to receive HCT (OR, 1.07; 95% CI, 1.05-1.1 [P<.0001]); however, this difference was found to be significant only for autologous HCT (OR, 1.10; 95% CI, 1.07-1.13 [P<.0001]).Conclusions: HCT is more frequently used to treat leukemia, lymphoma, and MM in Caucasians than in African American individuals. African Americans have lower rates of both autologous and allogeneic HCT, indicating that donor availability cannot fully explain the differences. Women are less likely than men to receive autologous HCT for reasons unexplained by age or disease status. [ABSTRACT FROM AUTHOR]

Background: The relationships between alcohol marketing exposure, alcohol use, and purchase have been widely studied. However, prospective studies examining the causal relationships in real-world settings using mobile health tools are limited., Objective: We used ecological momentary assessment (EMA) to examine both the within-person- and between-person-level effects of alcohol marketing exposure on any alcohol use, amount of alcohol use, any alcohol purchase, and frequency of alcohol purchase among university students., Methods: From January to June 2020, we conducted a prospective cohort study via EMA among university students in Hong Kong who reported current drinking. Over 14 consecutive days, each participant completed 5 fixed-interval, signal-contingent EMAs daily via a smartphone app. Each EMA asked about the number and types of alcohol marketing exposures, the amount and types of alcohol used, and whether any alcohol was purchased, all within the past 3 hours. We used 2-part models, including multilevel logistic regressions and multilevel gamma regressions, to examine if the number of alcohol marketing exposure was associated with subsequent alcohol use and alcohol purchase., Results: A total of 49 students participated, with 33% (16/49) being male. The mean age was 22.6 (SD 2.6) years. They completed 2360 EMAs (completion rate: 2360/3430, 68.8%). Participants reported exposure to alcohol marketing in 5.9% (140/2360), alcohol use in 6.1% (145/2360), and alcohol purchase in 2.4% (56/2360) of all the EMAs. At the between-person level, exposure to more alcohol marketing predicted a higher likelihood of alcohol use (adjusted odd ratio [AOR]=3.51, 95% CI 1.29-9.54) and a higher likelihood of alcohol purchase (AOR=4.59, 95% CI 1.46-14.49) the following day. Exposure to more alcohol marketing did not increase the amount of alcohol use or frequency of alcohol purchases the following day in participants who used or purchased alcohol. At the within-person level, exposure to more alcohol marketing was not associated with a higher likelihood of alcohol use, amount of alcohol use, higher likelihood of alcohol purchase, or frequency of alcohol purchases the following day (all P s >.05). Each additional exposure to alcohol marketing within 1 week predicted an increase of 0.85 alcoholic drinks consumed in the following week (adjusted B=0.85, 95% CI 0.09-1.61). On days of reporting alcohol use, the 3 measures for alcohol marketing receptivity were not associated with more alcohol use or purchase (all P s >.05)., Conclusions: By using EMA, we provided the first evidence for the effect of alcohol marketing exposure on initiating alcohol use and purchase in current-drinking university students. Our findings provide evidence of the regulation of alcohol marketing for the reduction of alcohol use and purchase among young adults., (©Min Jin Zhang, Tzu Tsun Luk, Sai Yin Ho, Man Ping Wang, Tai Hing Lam, Yee Tak Derek Cheung. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 03.09.2024.)

Inducing tertiary lymphoid structure (TLS) formation can fuel antitumor immunity. It is necessary to create mouse models containing TLS to explore strategies of TLS formation. Oncolytic herpes simplex virus-1 (oHSV) exhibited intense effects in preclinical and clinical trials. However, the role of oHSV in TLS formation remains to be elucidated. Here, we observed the presence of TLS in 4MOSC1 and MC38 subcutaneous tumour models. Interestingly, oHSV evoked TLS formation, and increased infiltration of B cells and stem-like TCF1 + CD8 + T cells proliferation. Mechanistically, oHSV increased the expression of TLS-related chemokines, along with upregulated CXCL10/CXCR3 to facilitate TLS formation. Notably, CXCL10 and CXCR3 were favourable prognostic factors for cancer patients, and closely related with immune cells infiltration. Inhibiting CXCL10/CXCR3 reduced TCF1 + CD8 + T cells and granzyme B expression, and impaired oHSV-mediated TLS formation. Furthermore, oHSV-mediated TLS formation revealed superior response and survival rate when combined with αPD-1 treatment. Collectively, these findings indicate that oHSV recruits stem-like TCF1 + CD8 + T cells through CXCL10/CXCR3 pathway to propagate TLS formation, and warrants future antitumor immunity development., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate the combined effect of handgrip strength (HGS) and obesity phenotype on the risk of stroke in Chinese middle-aged and elderly people., Methods: The data was used from the China Health and Retirement Longitudinal Study (CHARLS). Middle-aged and older adults who participated in surveys between 2011 and 2018 were included in the study. They were divided into 4 different types of obesity phenotypes based on obesity and metabolic status: metabolically healthy non-overweight/obesity (MHNO), metabolically healthy overweight/obesity (MHO), metabolically abnormal non-overweight/obesity (MANO), and metabolically abnormal overweight/obesity (MAO). The HGS level was divided into low and high groups according to the median values. Cox proportional risk regression model was used to analyze the joint effect of HGS and obesity phenotype on the risk of stroke among participants., Results: A total of 7904 participants aged 58.89±9.08 years were included in this study. After adjusting for potential confounders, high HGS&MHO (HR=1.86, 95 % CI=1.12-3.09), high HGS&MANO (HR=2.01, 95 %CI=1.42-2.86), high HGS&MAO (HR=2.01, 95 % CI=1.37-2.93), low HGS&MHNO (HR=1.57, 95 % CI=1.00-2.46), low HGS&MHO (HR=2.09, 95 % CI=1.29-3.38), low HGS&MANO (HR=2.02, 95 % CI=1.35-3.03), and low HGS&MAO (HR=2.48, 95 % CI=1.72-3.58) group had significantly higher risks of stroke than the high HGS&MHNO group., Conclusion: The coexistence of metabolically unhealthy and low HGS can synergistically increase the risk of stroke in Chinese middle-aged and elderly people., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Myasthenia gravis (MG) is etiologically associated with thymus abnormalities, but its pathology in the thymus remains unclear. In this study, we attempt to narrow down the features associated with MG using spatial transcriptome analysis of thymoma and thymic hyperplasia samples. We find that the majority of thymomas are constituted by the cortical region. However, the small medullary region is enlarged in seropositive thymomas and contains polygenic enrichment and MG-specific germinal center structures. Neuromuscular medullary thymic epithelial cells, previously identified as MG-specific autoantigen-producing cells, are enriched in the cortico-medullary junction. The medulla is characterized by a specific chemokine pattern and immune cell composition, including migratory dendritic cells and effector regulatory T cells. Similar germinal center structures and immune microenvironments are also observed in the thymic hyperplasia medulla. This study shows that the medulla and junction areas are linked to MG pathology and provides insights into future MG research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Atrial myopathy-defined as abnormal left atrial (LA) size and function-is associated with an increased risk of atrial fibrillation, heart failure, and dementia. Central arterial stiffness is associated with increased atrial afterload and fibrosis and may be a risk factor for atrial myopathy. We examined the association of carotid-femoral pulse wave velocity (cfPWV) with LA function and assessed potential causal relationships. We included 2825 Atherosclerosis Risk in Communities (ARIC) study participants from Visit 5 (2011-2013). cfPWV was related to echocardiographic LA function continuously per 1-SD and categorically in quartiles. Mendelian randomization (MR) analysis was performed using U.K. Biobank-derived genetic variants associated with arterial stiffness index and cardiac magnetic resonance measures of LA function. When analyzed per SD increment (297.6 cm/s), higher cfPWV was significantly associated with lower LA reservoir and conduit strain (β = -0.53%, 95% CI [-0.81, -0.25] and β = -0.46%, 95% CI [-0.68, -0.25], respectively) after adjusting for demographics, clinical characteristics, systolic blood pressure, and left ventricular (LV) morphology and function. In MR analyses there was a non-significant inverse association of arterial stiffness index with LA total, passive, and active emptying fractions. Higher cfPWV is associated with lower LA reservoir and conduit strain, independent of systolic blood pressure and LV morphology and function. No evidence for a causal relationship between arterial stiffness index and alterations in LA function was found. Future studies should examine the prospective association of central arterial stiffness with LA function alterations., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Flight safety in helicopters is a critical aspect of overall aircraft operational safety management, particularly during engine failures requiring autorotative glide, which makes it extremely challenging for the pilot to land the helicopter successfully. In this study, we evaluated the workload and attention allocation of helicopter pilots under such circumstances. In the experiment, a helicopter flight simulator was used to simulate level flight followed by autorotative glide, with the two phases divided into time segments for data collection. First, the data were visualized using heat maps and saccade sequence diagrams, while changes in eye movement metrics (such as peak value and standard deviation) were statistically analyzed. Finally, the criteria through the inter-criteria correlation (CRITIC) method was used to calculate the weight coefficient for each area of interest. This evaluation system was further applied to analyze and compare the changes in eye-movement data and attention to areas of interest during the two phases. The results revealed a shorter fixation duration, but a greater fixation number during the autorotative glide phase. Further, the mean pupil diameter changed over a larger range than during level flight (in level flight, the mean was 5.229 mm, while the standard deviation was 0.059 mm; in autorotative glide the corresponding values were 5.326 mm and 0.126 mm, respectively). For the tachometer, the weight coefficient matched the color of the heat map (2.7 % and colorless during level flight, but 23.8 % and red during autorotative glide), while those for the airspeed indicator and forward view differed significantly between the two phases. This discrepancy stemmed from the fact that during autorotative glide, the pilots prioritized monitoring aircraft rotation speed and attitude, with a particular focus on the forward view, rotor speed, and airspeed, resulting in a more concentrated attention distribution compared to that achieved during level flight. These results confirmed a significant increase in pilot workload during autorotative glide landing, while a shift was observed from low-frequency long gaze time during level flight to high-frequency short gaze time during autorotative glide. Furthermore, the pilots allocated 81 % of their attention to the tachometer, airspeed indicator, and forward views. Adopting this strategy can improve pilots' landing success and provide flight students with valuable training advice to prevent landing failures when helicopters lose power., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

This study aims to enhance the effectiveness of high resolution manometry (HRM) and pH-impedance monitoring metrics in distinguishing between gastro-esophageal reflux disease (GERD) and non-GERD. A retrospective propensity score matching (PSM) study was conducted on 643 patients with GERD symptoms. PSM matched 134 GERD patients with 134 non-GERD controls. Body mass index (BMI), intra-esophageal pressure (IEP) and intra-gastric pressure (IGP) were significantly higher in the GERD group compared to the non-GERD group. BMI was correlated with IEP and IGP positively. IGP was positively correlated with esophagogastric (EGJ) pressure (EGJ-P) in participants with EGJ type 1 and 2, but not in participants with EGJ type 3. BMI was correlated with distal MNBI negatively. Logistic regression showed BMI as an independent risk factor for GERD. Receiver operating characteristic curve (ROC) and decision curve analysis (DCA) showed that BMI adjusted EGJ contractile integral (EGJ-CI) and BMI adjusted MNBI were superior to the corresponding original ones in predicting GERD susceptibility. According to the findings, BMI and IGP are the main factors contributing to the development of GERD. BMI affects IEP through the adaptive response of EGJ-P to IGP. Incorporating BMI into the calculations of EGJ-CI and MNBI can improve their ability in predicting GERD susceptibility., (© 2024. The Author(s).)

New daily persistent headache (NDPH) is a kind of persistent headache that patients can identify the exact date of the sudden onset.It is one of the rare primary headaches difficult to be cured and may lead to disability,seriously affecting the daily life and work.The exact pathogenesis of NDPH remains unclear,which makes the treatment difficult.Here we report a case of refractory NDPH treated by intravenous injection of esketamine at a sub-anesthetic dose.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC 50 value of 4.16 μM for Hela cells and 3.78 μM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer., (© 2024 Wiley Periodicals LLC.)

Introduction: Kinesiophobia denotes an excessive and irrational apprehension towards physical activity or exercise among patients, stemming from a perception of susceptibility to painful injury or re-injury. Cardiac rehabilitation stands pivotal in the secondary prevention spectrum for individuals with cardiovascular ailments, with exercise constituting a cornerstone of this regimen. However, the emergence of kinesiophobia poses a formidable challenge, diminishing patient adherence to cardiac rehabilitation protocols, particularly among those grappling with chronic heart failure. To bolster exercise-based rehabilitation initiatives in this cohort, a thorough comprehension of the multifaceted factors precipitating kinesiophobia is imperative. This review endeavors to delineate prevailing evidence and prevalence concerning kinesiophobia triggers in chronic heart failure patients, while pinpointing research lacunae for future exploration., Methods: Employing a scoping review methodology, our investigation culled data from diverse scholarly databases, including Embase, PubMed, Scopus, CINAHL, Web of Science, Medline, Sinomed, CNKI, Wangfan, and VIP., Results: After thorough evaluation, 9 studies that met the inclusion criteria were ultimately incorporated., Discussion: Our findings underscore a notable prevalence of kinesiophobia in chronic heart failure patients, predominantly influenced by socio-demographic factors, psychological and cognitive factors, disease and treatment factors, as well as lifestyle and behavior. Armed with these insights, future interventions can be tailored to mitigate kinesiophobia levels, fostering enhanced engagement in exercise-centric cardiac rehabilitation endeavors among patients grappling with chronic heart failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiang, Xiong, Zhang, Liu, Chen, Liu, Wang and Yang.)

Cancer immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA methyltransferase inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of immune checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for cancer immunotherapy.

Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first FDA-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). We investigated its impact in URD-HCT patients using Center for International Blood and Marrow Transplant Research data for 7/8-human leukocyte antigen (HLA)-mismatched (MMUD) or 8/8-HLA-matched (MUD) URD-HCT recipients between 2011-2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept+CNI/MTX vs CNI/MTX, CNI/MTX+antithymocyte globulin (ATG), and post-transplant cyclophosphamide-based prophylaxis (PT-Cy); other outcomes included aGVHD, chronic GVHD, non-relapse mortality, and relapse. For 7/8-MMUDs, day-180 OS (primary endpoint supporting FDA approval) was significantly higher for abatacept+CNI/MTX vs CNI/MTX (98%vs75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (83%vs55%; p=0.0036), CNI/MTX+ATG (83%vs46%; p=0.0005) and similar to PT-Cy (80%vs68%; p=0.2325). Two-year RFS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (74%vs49%; p=0.0098) and CNI/MTX+ATG (77%vs35%; p=0.0002), and similar vs PT-Cy (72%vs56%; p=0.1058). For 8/8-MUDs, 2-year OS was similar with abatacept+CNI/MTX vs CNI/MTX (70%vs62%; p=0.2569), CNI/MTX+ATG (75%vs64%; p=0.1048), and PT-Cy (74%vs69%; p=0.5543). Two-year RFS for abatacept+CNI/MTX was numerically higher vs CNI/MTX (63%vs52%; p=0.1497) with an improved hazard ratio (HR: 0.46 [0.25-0.86]), and vs CNI/MTX+ATG (66%vs55%; p=0.1193; HR: 0.39 [0.21-0.73]). Two-year RFS was similar vs PT-Cy (68%vs57%; p=0.2356; HR: 0.54 [0.26-1.11]). For both 7/8-MMUD and 8/8-MUD recipients, abatacept+CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX+ATG; outcomes were similar to PT-Cy-based regimens. Abatacept+CNI/MTX has potential to facilitate unrelated donor pool expansion for HCT., (Copyright © 2024 American Society of Hematology.)

Objectives: The aim of this study was to explore inflammation of soft tissue around the upper third molar as a prevalent cause of limited mouth opening, identify the clinical and radiographic features, and summarize the therapeutic effectiveness of tooth extraction., Materials and Methods: A retrospective analysis of data from 264 patients with limited mouth opening over the last five years was performed., Results: Among the 264 patients, 24 (9.1%) had inflammation of the soft tissue around the upper third molar, which was the second most common cause of limited mouth opening. Twenty-one of the twenty-four affected patients, with an average mouth opening of 19.1 ± 7.6 mm, underwent upper third molar extraction. Gingival tenderness around the upper third molar or maxillary tuberosity mucosa was a characteristic clinical manifestation (p < 0.05). The characteristic features on maxillofacial CT included soft tissue swelling around the upper third molar and gap narrowing between the maxillary nodules and the mandibular ascending branch. Post extraction, the average mouth opening increased to 31.4 ± 4.9 mm (p < 0.05), and follow-up CT demonstrated regression of the inflammatory soft tissue around the upper third molar., Conclusions: Inflammation of soft tissue around the upper third molar is a common cause of limited mouth opening. Symptoms of pain associated with the upper third molar and distinctive findings on enhanced maxillofacial CT scans are crucial for diagnosis. Upper third molar extraction yields favorable therapeutic outcomes., Clinical Relevance: Inflammation of the soft tissue around the maxillary third molar commonly causes limited mouth opening, but this phenomenon has long been overlooked. Clarifying this etiology can reduce the number of misdiagnosed patients with restricted mouth opening and enable more efficient treatment for patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/β-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/β-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/β-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the β-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/β-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/β-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

A total of 82 patients and healthy subjects in the First Affiliated Hospital of Sun Yat-sen University from March to August 2023 were recruited. The cohort consisted of 43 patients with head and neck squamous cell carcinoma (HNSCC) and 39 non-cancer patients or healthy subjects. There were 63 males and 19 females, with a median age of 62 (46, 67) years. The levels of folate receptor-positive circulating tumor cells (FR + CTCs) in the blood of HNSCC patients and non-cancer/healthy subjects were 12.4 (8.5, 17.8) floate unit (FU)/3 ml and 5.0 (3.8, 6.6) FU/3 ml, respectively, with a statistically significant difference ( P <0.001). The area under the receiver operating characteristic (ROC) curve for FR + CTCs levels was 0.937 (95% CI : 0.888-0.986, P <0.001), with a cut-off value of 7.4 FU/3 ml determined by the maximum Youden index. At this cut-off value, the sensitivity and specificity of FR + CTCs for diagnosing HNSCC were 90.70% and 89.74%, respectively. The current study suggests that FR + CTCs could be used as a liquid biopsy marker for the screening and diagnosis of HNSCC.

Background: Colorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment., Methods: A retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival., Results: The blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma., Conclusions: Our study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Assessment of cardiac structure and function improves risk prediction of new-onset atrial fibrillation (AF) in different populations. We aimed to comprehensively compare standard and newer measures of cardiac structure and function in improving prediction of AF in a cohort of older adults without history of AF and stroke., Methods: We included 5050 participants without prevalent AF and stroke (mean age 75 ± 5 years, 59% women and 22% Black) from the Atherosclerosis Risk in Communities (ARIC) study who underwent complete 2-dimensional echocardiography, including speckle-tracking analysis of the left ventricle (LV) and left atrium (LA). We assessed the association of cardiac measures with incident AF (including atrial flutter) and quantified the extent to which these measures improved model discrimination and risk classification of AF compared with the CHARGE-AF score., Results: Over a median follow-up time of 7 years, 676 participants developed AF (incidence rate, 2.13 per 100 person-years). LV mass index and wall thickness, E/e' and measures of LA structure and function, but not LV systolic function, were associated with incident AF, after accounting for confounders. Above all, LA reservoir strain, contraction strain, and LA minimal volume index (C-statistics [95%Confidence interval]: 0.73 [0.70,0.75], 0.72 [0.70,0.75] and 0.72 [0.69,0.75], respectively) significantly improved the risk discrimination of the CHARGE-AF score (baseline C-statistic: 0.68 [0.65,0.70]) and achieved the highest category-based net reclassification improvement (29%, 24% and 20%, respectively)., Conclusions: In a large cohort of older adults without prevalent AF and stroke, measures of LA function improved the prediction of AF more than other conventional cardiac measures., (Published by Oxford University Press on behalf of the European Society of Cardiology 2024.)

This research aims to understand why both low and high subordinate performance can induce abusive supervision. Drawing on the framework of affective events theory and research on anger and envy, we posit that low performance incurs abuse due to supervisor anger, whereas high performance elicits abuse due to supervisor envy. More specifically, subordinate performance has a decreasing curvilinear relationship with supervisor anger (i.e., a negative effect that gradually dissipates) and an increasing curvilinear relationship with supervisor envy (i.e., a positive effect that gradually emerges). Through supervisor anger and envy, subordinate performance therefore presents different curvilinear indirect relationships with abusive supervision. The results from two vignette-based experiments and a multiwave, multisource field study support these hypotheses. We further find that supervisor comparison orientation augments the curvilinear emergence of supervisor envy and ensuing abuse in response to higher subordinate performance. However, regardless of their level of performance orientation, supervisors are prone to higher anger and subsequent abusive supervision in response to lower subordinate performance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Very brief advice (VBA; ≤ 3 min) on quitting is practical and scalable during brief medical interactions with patients who smoke. This study aims to synthesize the effectiveness of VBA for smoking cessation and summarize the implementation strategies., Methods: We searched randomized controlled trials aiming at tobacco abstinence and comparing VBA versus no smoking advice or no contact from Medline, Embase, CINAHL, Cochrane Library, PsycInfo databases, six Chinese databases, two trial registries ClinicalTrials.gov and WHO-ICTRP from inception to September 30, 2023. Grading of Recommendations, Assessment, Development, and Evaluations framework was used to assess the certainty of the evidence of the meta-analytic findings. The outcomes were self-reported long-term tobacco abstinence at least 6 months after treatment initiation, earlier than 6 months after treatment initiation, and quit attempts. Effect sizes were computed as risk ratio (RR) with 95% CI using frequentist random-effect models., Data Synthesis: Thirteen randomized controlled trials from 15 articles (n = 26,437) were included. There was moderate-certainty evidence that VBA significantly increased self-reported tobacco abstinence at ≥ 6 months in the adjusted model (adjusted risk ratio ARR 1.17, 95% CI: 1.07-1.27) compared with controls. The sensitivity analysis showed similar results when abstinence was verified by biochemical validation (n = 6 studies, RR 1.53, 95% CI 0.98-2.40). There was high-certainty evidence that VBA significantly increased abstinence at < 6 months (ARR 1.22, 95% CI: 1.01-1.47). Evidence of effect on quit attempts (ARR 1.03, 95% CI 0.97-1.08) was of very low certainty., Discussion: VBA delivered in a clinical setting is effective in increasing self-reported tobacco abstinence, which provides support for wider adoption in clinical practice., (© 2024. The Author(s).)

Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithms. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis (PCA). A diagnostic model was developed using random forest algorithm (ntree=400) and validated by ROC curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by qRT-PCR. We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P<0.0001) and interleukins pathway (R=0.79, P<0.0001). Furtherer, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes., (© Crown copyright 2024.)

Heritable diseases often manifest in a highly tissue-specific manner, with different disease loci mediated by genes in distinct tissues or cell types. We propose Tissue-Gene Fine-Mapping (TGFM), a fine-mapping method that infers the posterior probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing GWAS summary statistics (and in-sample LD) and leveraging eQTL data from diverse tissues to build cis-predicted expression models; TGFM also assigns PIPs to causal variants that are not mediated by gene expression in assayed genes and tissues. TGFM accounts for both co-regulation across genes and tissues and LD between SNPs (generalizing existing fine-mapping methods), and incorporates genome-wide estimates of each tissue's contribution to disease as tissue-level priors. TGFM was well-calibrated and moderately well-powered in simulations; unlike previous methods, TGFM was able to attain correct calibration by modeling uncertainty in cis-predicted expression models. We applied TGFM to 45 UK Biobank diseases/traits (average N = 316K) using eQTL data from 38 GTEx tissues. TGFM identified an average of 147 PIP > 0.5 causal genetic elements per disease/trait, of which 11% were gene-tissue pairs. Implicated gene-tissue pairs were concentrated in known disease-critical tissues, and causal genes were strongly enriched in disease-relevant gene sets. Causal gene-tissue pairs identified by TGFM recapitulated known biology (e.g., TPO -thyroid for Hypothyroidism), but also included biologically plausible novel findings (e.g., SLC20A2 -artery aorta for Diastolic blood pressure). Further application of TGFM to single-cell eQTL data from 9 cell types in peripheral blood mononuclear cells (PBMC), analyzed jointly with GTEx tissues, identified 30 additional causal gene-PBMC cell type pairs at PIP > 0.5-primarily for autoimmune disease and blood cell traits, including the biologically plausible example of CD52 in classical monocyte cells for Monocyte count. In conclusion, TGFM is a robust and powerful method for fine-mapping causal tissues and genes at disease-associated loci.

Inositol hexaphosphate (InsP 6 ) is the major storage form of phosphorus in seeds. Reducing seed InsP 6 content is a breeding objective in agriculture, as InsP 6 negatively impacts animal nutrition and the environment. Nevertheless, how InsP 6 accumulation is regulated remains largely unknown. Here, we identify a clade of receptor-like cytoplasmic kinases (RLCKs), named Inositol Polyphosphate-related Cytoplasmic Kinases 1-6 (IPCK1-IPCK6), deeply involved in InsP 6 accumulation. The InsP 6 concentration is dramatically reduced in seeds of ipck quadruple (T-4m/C-4m) and quintuple (C-5m) mutants, accompanied with the obviously increase of phosphate (Pi) concentration. The plasma membrane-localized IPCKs recruit IPK1 involved in InsP 6 synthesis, and facilitate its binding and activity via phosphorylation of GRF 14-3-3 proteins. IPCKs also recruit IPK2s and PI-PLCs required for InsP 4 /InsP 5 and InsP 3 biosynthesis respectively, to form a potential IPCK-GRF-PLC-IPK2-IPK1 complex. Our findings therefore uncover a regulatory mechanism of InsP 6 accumulation governed by IPCKs, shedding light on the mechanisms of InsP biosynthesis in eukaryotes., (© 2024. The Author(s).)

Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy owing to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from patients with AD. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and ROS production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the risk factors affecting regional lymph node metastasis in salivary gland mucoepidermoid carcinoma (MEC) and to establish a nomogram model for individually predicting lymph node metastasis in salivary gland MEC. Methods: The clinical data of 2 152 patients with salivary gland MEC from 1975 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The collected data were divided into training cohort (1 506 cases) and validation cohort (646 cases) according to the ratio of 7∶3. Single-factor regression and multi-factor logistic regression were used to screen factors related to local lymph node metastasis in salivary gland MEC, with constructing of a nomogram. Calibration curve, receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) and decision curve analysis were used to evaluate model performance in the validation cohort and the total cohort. Statistical tests were performed using SPSS (26.0) and R (4.3.0) software. Results: Multivariate logistic regression results showed that M stage [ OR (95% CI ):12.360(3.295-46.365), P =0.014], pathological grade Ⅱ、Ⅲ、Ⅳ[ OR (95% CI ): 1.956(1.329-2.879), 9.654(6.309-14.772), 9.298(6.072-14.238), P <0.001], T staging T2, T3, T4[ OR (95% CI ): 1.706(0.932-3.124), 3.021(1.790-5.096), 3.311(1.925-5.695), P <0.001], and gender [ OR (95% CI ):0.759(0.593-0.972), P =0.029] were independent factors affecting local lymph node metastasis in salivary gland MEC. Through verification in the validation cohort and the total cohort, the AUC values were greater than 0.8, and the calibration curve was close to the perfect reference line, proving that the constructed nomogram model had good specificity and sensitivity for predicting local lymph node metastasis in salivary gland MEC. Conclusion: M stage, pathological grade, T stage, and gender are risk factors for predicting regional lymph node metastasis and the established-nomogram has good predictive performance for local lymph node metastasis in salivary gland MEC.

Background: The regulatory effects of KIF26B on gastric cancer (GC) have been confirmed, but the specific mechanism still needs further exploration. Pan-cancer analysis shows that the KIF26B expression is highly related to immune infiltration of cancer-associated fibroblasts (CAFs), and CAFs promote macrophage M2 polarization and affect cancers' progression., Aim: To investigate the regulatory functions of KIF26B on immune and metastasis of GC., Methods: We analyzed genes' mRNA levels by quantitative real-time polymerase chain reaction. Expression levels of target proteins were detected by immunohistochemistry, ELISA, and Western blotting. We injected AGS cells into nude mice for the establishment of a xenograft tumor model and observed the occurrence and metastasis of GC. The degree of inflammatory infiltration in pulmonary nodes was observed through hematoxylin-eosin staining. Transwell and wound healing assays were performed for the evaluation of cell invasion and migration ability. Tube formation assay was used for detecting angiogenesis. M2-polarized macrophages were estimated by immunofluorescence and flow cytometry., Results: KIF26B was significantly overexpressed in cells and tissues of GC, and the higher expression of KIF26B was related to GC metastasis and prognosis. According to in vivo experiments, KIF26B promoted tumor formation and metastasis of GC. KIF26B expression was positively associated with CAFs' degree of infiltration. Moreover, CAFs could regulate M2-type polarization of macrophages, affecting GC cells' migration, angiogenesis, invasion, and epithelial-mesenchymal transition process., Conclusion: KIF26B regulated M2 polarization of macrophage through activating CAFs, regulating the occurrence and metastasis of GC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Withdrawal symptoms lead to smoking relapse and reduce the intention to quit. The present pilot RCT examined the effect of simple and very brief handgrip and isometric exercises on reducing withdrawal symptoms, measured by the strength of tobacco craving, Questionnaire of Smoking Urges-Brief (QSU-B), Mood and Physical Symptoms Scale (MPSS), and Positive and Negative Affect Schedule (PANAS)., Methods: In this 2-arm, open-labeled pilot RCT, 30 current smokers who had abstained from tobacco for at least 9 hours were randomly assigned (allocation ratio 1:1) to either the intervention group that watched a 5-minute video and did 5-minute handgrip and isometric exercises (pulling and pushing) or control group that watched 10-minute healthy-diet videos. Measurements were taken before, immediately after, and 10 minutes post-intervention. Outcomes were self-reported strength of tobacco craving, QSU-B, MPSS, and PANAS scores. The effect size for group-by-time interaction was assessed using Cohen's f 2 (small=0.02, medium=0.15, large=0.35)., Results: Group-by-time interactions showed that the intervention group showed larger reductions than the control group in the strength of tobacco craving (Cohen's f 2 =0.54, 95% CI: 0.52-0.57), QSU-B (Cohen's f 2 =0.77; 95% CI: 0.74-0.80), and MPSS (Cohen's f 2 =0.51; 95% CI: 0.46-0.56) over the three measurement points., Conclusions: This RCT showed that simple and brief handgrip and isometric exercises could immediately reduce withdrawal symptoms and up to 10 minutes., Clinical Trial Registration: in https://clinicaltrials.gov/., Identifier: NCT04059497., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2024 Zhang M.J. et al.)

To investigate the impact of four single nucleotide polymorphisms (SNPs) of the HIF1α gene and its interaction with Helicobacter pylori (H. pylori) infection on susceptibility to gastric cancer (GC).Logistic regression was used to test the relationship between four SNPs of HIF1α gene and the susceptibility of GC. A generalized multifactor dimensionality reduction (GMDR) model was used to assess the HIF1α gene-H. pylori infection interaction.Logistic regression analysis indicated that both the rs11549465-CT genotype and the T allele were associated with an increased risk of GC, adjusted OR (95% CI) were 1.63 (1.09-2.20) (CT vs. CC) and 1.70 (1.13-2.36) (T vs. C), respectively. We also found that both the rs11549467-A allele and rs11549467-GA genotype were associated with an increased risk of GC, and adjusted OR (95% CI) were 2.21 (1.61-2.86) (GA vs. GG), 2.13 (1.65-2.65) (A vs. G), respectively. However, no statistically significant impact of rs2057482 or rs1957757 on risk of GC was found. The GMDR model indicated a statistically significant two-dimensional model combination (including rs11549467 and H. pylori infection). The selected model had testing balanced accuracy of 0.60 and the best cross-validation consistencies of 10/10 (p = 0.0107). Compared with H. pylori infection negative participants with rs11549467-GG genotype, H. pylori positive participants with the rs11549467-GA genotype had the highest GC risk, the OR (95% CI) was 3.04 (1.98-4.12).The rs11549467-A allele and rs11549467-GA genotype was associated with increased GC risk. Additionally, the gene-environment interaction between HIF-1α-rs11549467 and H. pylori infection was also correlated with an increased risk of GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cysteine conjugation is widely used to constrain phage displayed peptides for the selection of cyclic peptides against specific targets. In this study, the nontoxic Bi 3+ ion was used as a cysteine conjugation reagent to cross-link peptide libraries without compromising phage infectivity. We constructed a randomized 3-cysteine peptide library and cyclized it with Bi 3+ , followed by a selection against the maltose-binding protein as a model target. Next-generation sequencing of selection samples revealed the enrichment of peptides containing clear consensus sequences. Chemically synthesized linear and Bi 3+ cyclized peptides were used for affinity validation. The cyclized peptide showed a hundred-fold better affinity (0.31 ± 0.04 μM) than the linear form (39 ± 6 μM). Overall, our study proved the feasibility of developing Bi 3+ constrained bicyclic peptides against a specific target using phage display, which would potentially accelerate the development of new peptide-bismuth bicycles for therapeutic or diagnostic applications.

Objectives: This study established the diagnostic accuracy of the Fonseca Anamnestic Index (FAI) in relation to the Diagnostic Criteria for TMD (DC/TMD) standard. Methods: A total of 866 TMD patients and 57 TMD-free controls were instructed to answer the FAI and DC/TMD Symptom Questionnaire (SQ). Participants were subsequently categorized into no (NT), pain-related (PT), and/or intra-articular (IT) TMDs using the DC/TMD protocolized examination/algorithms. Receiver operating characteristics (ROC) curves, best cut-off points, and accuracy measures were determined. Results: The FAI demonstrated high accuracy for detecting all TMDs, PT, and IT (AUC = 0.96-0.98). The best cut-off points were 22.50 for all TMDs/IT and 27.50 for PT. Sensitivity of the FAI was high (94.23-98.21%), but specificity was moderate (87.72%) for all diagnostic categories. Discussion: The diagnostic accuracy of the FAI for identifying pain-related and intra-articular TMDs was high. FAI scores ≥25 points should be used to screen for TMDs.

Objectives: To develop a deep learning-based system for precise, robust, and fully automated segmentation of the mandibular canal on cone beam computed tomography (CBCT) images., Methods: The system was developed on 536 CBCT scans (training set: 376, validation set: 80, testing set: 80) from one center and validated on an external dataset of 89 CBCT scans from 3 centers. Each scan was annotated using a multi-stage annotation method and refined by oral and maxillofacial radiologists. We proposed a three-step strategy for the mandibular canal segmentation: extraction of the region of interest based on 2D U-Net, global segmentation of the mandibular canal, and segmentation refinement based on 3D U-Net., Results: The system consistently achieved accurate mandibular canal segmentation in the internal set (Dice similarity coefficient [DSC], 0.952; intersection over union [IoU], 0.912; average symmetric surface distance [ASSD], 0.046 mm; 95% Hausdorff distance [HD95], 0.325 mm) and the external set (DSC, 0.960; IoU, 0.924; ASSD, 0.040 mm; HD95, 0.288 mm)., Conclusions: These results demonstrated the potential clinical application of this AI system in facilitating clinical workflows related to mandibular canal localization., Clinical Significance: Accurate delineation of the mandibular canal on CBCT images is critical for implant placement, mandibular third molar extraction, and orthognathic surgery. This AI system enables accurate segmentation across different models, which could contribute to more efficient and precise dental automation systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZX, HB and PD are associated with DeepCare, a company focuses on artificial intelligence applications in dentistry. This study and its findings were unrelated to their affiliation. The authors are solely responsible for the content of this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)