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Cong-Li Jia,1 Fu Yang,2 Rui-Ning Li3 1Weifang Medical College, Weifang, Shandong, People’s Republic of China; 2Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People’s Republic of ChinaCorrespondence: Fu YangDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xi Chang Road, Kunming, Yunnan, 650032, People’s Republic of ChinaTel +86 13888428338Email dediracy@163.comPurpose: To identify the potential differential genes between primary and metastatic melanoma, screen out immune-related genes in core genes and analyze their immune correlation, thus searching for the early diagnostic biomarkers of cutaneous malignant melanoma (CMM) and the targets of curbing metastasis.Materials and Methods: We analyzed two microarray datasets (GSE8401 and GSE46517) derived from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between primary and metastatic melanoma were screened out using the GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify the functions and pathways of DEGs. We analyzed protein–protein interaction of these DEGs based on the Search Tool for the Retrieval of Interacting Genes database and showed by Cytoscape software. In addition, the online Gene Expression Profiling Interactive Analysis tool (GEPIA) was used to analyze the prognostic value of hub genes expressed in metastatic melanoma patients. Immune-related genes in hub genes were screened and further analyzed.Results: A total of 178 upregulated DEGs and 4 downregulated DEGs were identified. 23 terms and 4 pathways were confirmed related to metastatic melanoma. Ten hub genes with a high degree of connectivity were found. Overexpression of three hub genes (DSG1, FLG, PKP1) (P< 0.01) was associated with metastasis and poor prognosis of CMM. Among them, the patients with overexpression of PKP1 suffered shorter survival. In addition, 2 immune-related genes (EGFR and CDH1) in hub genes were screened out and both of them were related to anti-tumor immunity, although their expression level did not affect the overall survival of CMM patients significantly.Conclusion: Our study suggests that DSG1, FLG and PKP1 were overexpressed in metastatic melanoma compared with primary melanoma, and overexpression of these three genes was an unfavorable prognostic factor ifor CMM patients, which may indicate that they are associated with promoting metastasis of malignant melanoma. EGFR and CDH1 play a crucial role in anti-tumor immunity for CMM. Further research is needed to explore the value of these genes in the inhibition of metastasis and treatment of CMM.Keywords: cutaneous malignant melanoma, metastasis, genes, PKP1, DSG1, FLG, CDH1, EGFR

Ammad Ahmad Farooqi,1 Jen-Yang Tang,2–4 Ruei-Nian Li,5 Muhammad Ismail,1 Yung-Ting Chang,6 Chih-Wen Shu,7 Shyng-Shiou F Yuan,8,9 Jing-Ru Liu,5 Qaisar Mansoor,1 Chih-Jen Huang,2,3,* Hsueh-Wei Chang5,9–11,*1Institute of Biomedical and Genetic Engineering (IBGE), KRL Hospital, Islamabad, Pakistan, 2Department of Radiation Oncology, Faculty of Medicine, College of Medicine, 3Department of Radiation Oncology, Kaohsiung Medical University Hospital, 4Department of Radiation Oncology, Kaohsiung Municipal Ta-Tung Hospital, 5Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan; 6Doctor Degree Program in Marine Biotechnology, National Sun Yat-sen University/Academia Sinica, 7Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 8Translational Research Center, 9Cancer Center, Kaohsiung Medical University Hospital, 10Institute of Medical Science and Technology, National Sun Yat-sen University, 11Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan*These authors contributed equally to this workAbstract: Research concerning the epigenome over the years has systematically and sequentially shown substantial development and we have moved from global inhibition of modifications of the epigenome toward identification and targeted therapy against tumor-specific epigenetic mechanisms. In accordance with this approach, several drugs with epigenetically modulating activity have received considerable attention and appreciation, and recently emerging scientific evidence is uncovering details of their mode of action. High-throughput technologies have considerably improved our existing understanding of tumor suppressors, oncogenes, and signaling pathways that are key drivers of cancer. In this review, we summarize the general epigenetic mechanisms in cancer, including: the post-translational modification of DNA methyltransferase and its mediated inactivation of Ras association domain family 1 isoform A, Sonic hedgehog signaling, Wnt signaling, Notch signaling, transforming growth factor signaling, and natural products with epigenetic modification ability. Moreover, we introduce the importance of nanomedicine for delivery of natural products with modulating ability to epigenetic machinery in cancer cells. Such in-depth and comprehensive knowledge regarding epigenetic dysregulation will be helpful in the upcoming era of molecular genomic pathology for both detection and treatment of cancer. Epigenetic information will also be helpful when nanotherapy is used for epigenetic modification.Keywords: epigenetic, modification, methylation, natural products, cancer

Introduction The medical staff involved in adverse events, referred to as second victims, usually suffer second victim syndrome endangering their health. Still, there are few organizational support projects in this area in China. Objective To explore the effect of mindfulness meditation on the level and needs of organizational support, and mindfulness awareness among nurses as second victims. Methods Forty-six nurses from a comprehensive tertiary hospital in Wuhan, China were selected to participate in the study. This study was conducted using a convenience sampling method for eight weeks of mindfulness meditation intervention. The Second Victim Experience and Support Tool and Mindfulness Attention Awareness Scale were used to assessing the need for support and mindfulness awareness of nurses prior to intervention, during the fourth and eighth weeks of intervention, and at the conclusion of the intervention course. Results The difference between the scores measured before the intervention, in the fourth week, and in the eighth week of intervention showed that the need for the second victim support from work-related organizations was significant ( F = 34.513, p = .000); there was no significant difference in the scores related to the need for nonwork-related support of the second victim in the participating nurses ( F = 1.373, p = .257); the scores of the level of mindfulness awareness were (64.85 ± 11.41), (68.63 ± 11.33), and (71.20 ± 8.41), a significant difference ( F = 18.848; p = .000) was found in terms of before and after the intervention; nurses’ second victim support needs gradually shifted from evasion to confronting problems appropriately. Conclusion Mindfulness meditation intervention is applicable to the second victim population of nurses. It is an effective way to support second victim nurses and can effectively improve their level of mindfulness and awareness.

Introduction During the pandemic, the nursing workforce is experiencing overwhelming workloads that carry a heavy psychological burden. A wide variety of psychological responses to the COVID-19 pandemic have been studied in nurses globally, but many are not studied or understudied in US nurses. Theoretical underpinnings of the current study are based on the disaster component of the Middle-Range Theory of Nurses' Psychological Trauma. Objective To explore the associations of psychological responses (life satisfaction, perceived stress, posttraumatic stress disorder [PTSD] symptomatology, attitude toward life, and compassion satisfaction), years of experience, and general health in US nurses during the COVID-19 pandemic using network analysis. Methods A cross-sectional study was conducted using an online survey from October to November 2020 in US nurses. Network analysis was used to model the data and analyze the centrality indices of betweenness, closeness, and strength. Data were reported according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist. Results In 128 nurses, 19.35% of nurses had probable PTSD. Network analysis showed strong significant correlations between life satisfaction and perceived stress (negative), between perceived stress and PTSD symptomatology (positive), and between attitude toward life and compassion satisfaction (positive). Conclusion Low life satisfaction, high perceived stress, and low attitude toward life are key inflection points that signal the need for psychological intervention in the US nursing workforce during the continued pandemic. Based on 2021 Tri-Council of Nursing COVID-19 Report and the 2022 International Council of Nurses guideline, healthcare should implement scalable, system-level interventions to reduce psychological burden during the pandemic. The current study suggests targets for such intervention, which may promote a healthier, more effective US nursing workforce.

Summary: Purpose: Self-management is critical to improve health outcomes of elderly patients with coronary heart disease (CHD). Sense of coherence (SOC) is found to be linked with self-management behaviors. However, their deeper relationship is not clear. The purposes of this study were to investigate the association between SOC and self-management behaviors among elderly CHD patients in China, and whether confrontation mediates this association. Methods: A cross-sectional design was used. A total of 275 elderly patients with CHD recruited from the cardiology department in a general hospital in North China were surveyed from October 2015 to April 2016. SOC, confrontation, and self-management behaviors were measured using the Chinese version of the SOC scale, subscale of Medical Coping Modes Questionnaire—Confrontation, and the CHD self-management scale, respectively. Correlation analysis and path analysis were conducted to analyze the data. Results: The mean (±standard deviation) scores of SOC, confrontation, and self-management behaviors were 62.20 (±9.61), 19.55 (±3.15), and 76.17 (±10.63), respectively. Correlation analysis showed that SOC, confrontation, and self-management behaviors were significantly correlated with each other. Path analysis indicated that SOC exerted a direct effect on self-management behaviors, whereas could affect self-management indirectly via confrontation. Bootstrap test result showed that confrontation played a mediating role (β = .20, p

Objectives: Engaging, enhancing and embedding clinical audit improvement activities into everyday practice to develop capacity, capability and culture in continuous improvement. Method: Through the implementation of an electronic quality management system called Governance, Evidence, Knowledge and Outcome (GEKO), the key aspects of governance, evidence knowledge and outcomes were able to be applied to quality initiatives. Implementation of the GEKO system incorporated the principles of total quality control and management to include strategic management control and marketing in parallel with leadership strategies. The vision was to motivate staff to enable ownership of the quality cycle of continuous improvement of patient care to incorporate underlying systems and processes that impact on patient care. Results: A continuous improvement pathway was successfully established 4 months post hospital commissioning. Over 890 (approximately 16% workforce) multidisciplinary and multi-professional staff received training and support for QIs in 12 months; over 535 quality proposals were received on GEKO. Submissions by profession: nursing and midwifery 46% (246), medical 33% (177), allied health 9% (48), pharmacy 5% (27), and non-clinical staff 7% (37). Average new submissions per month were 42. Reviews demonstrated the application of a rapid cycle approach to develop, test, modify and refine improvements and enhanced clinical care. Conclusion: Appropriate governance structure, processes, extensive education and training together with collaborative relationships are the keys to embed clinical audit improvement into everyday practice. The availability of a quality management system like GEKO is very useful to make QI accessible to all staff.

Purpose: The purpose of this study was to test the reliability and validity of the Behavior Assessment for Children (BAC) in a community of school-aged children in Taiwan. Method: A school-based sample comprising third grade and fourth grade students was recruited from Taichung City in Taiwan. The parents (n = 248) and teachers (n = 15) of these students completed structured questionnaires, including the Child Behavior Checklist (CBCL) and the proposed BAC. Content validity, concurrent validity, construct validity, internal consistency, and inter-rater reliability of the BAC were assessed. Results: The BAC comprised three subscales (attention, emotion, and self-control) that included 17 items. The content validity index (CVI) score was 0.98. The result of the confirmatory factor analysis (goodness of fit = .90, root mean square of residual = .03, root mean square error of approximation = .06, and comparative fit index = .94) supported the construct validity of the three BAC subscales. The concurrent validity of the BAC subscales significantly correlated with the compatible CBCL subscales (r = .59–.78, p

The aim of the study was to assess the prevalence, knowledge and behavior about reproductive tract infections (RTIs) among rural Chinese women in Hunchun, China. Methods: The study employed a cross-sectional research design with a convenience sample of 190 participants who had received microfinancing. Data were collected by trained research staff, utilizing face to face interviews and physical examinations. Results: About 1 in 5 participants (20.3%) had had more than 5 pregnancies and 26.7% had had 3 or more abortions. More than half (57.3%) of study participants had an RTI at the time of examination, and 92.3% reported having had at least one RTI symptom. Nearly half (49.6%) of the women who exhibited RTI symptoms reported no utilization of any healthcare services. Age, number of pregnancies, RTI knowledge, and behavior were found to be significant correlates in the sample. Conclusions: The prevalence of RTI among low-income rural Chinese women were extremely high, indicating the urgent need for effective and culturally sensitive health education, particularly targeted to the poor rural population.

In order to explore the rational use of nursing resources in the epidemic situation of COVID-19, we optimized the shift arrangement in COVID-19 isolation area and constructed a reasonable nursing schedule under the condition of limited human resources. Seventy-eight nurses were arranged in COVID-19 isolation area to work for 1 week according to 3 different shifts: 4 + 4 h, 6 h and 6 h (overlapping by 1 h). Through the form of questionnaire, the comprehensive job satisfaction of 3 different models were compared, and the nursing quality and the consumption of protective equipment under 3 different modes were analyzed. The results showed that the comprehensive job satisfaction and nursing quality of nurses in 6 h (overlapping by 1 h) shift mode were better than those in other shift modes, and the consumption of protective equipment was lower.

Background Chronic musculoskeletal pain (CMP) is the most common self-reported chronic pain condition. Current treatment for CMP is limited. Methods This was a two-phase study. In Phase 1, three auricular point acupressure (APA)-naïve participants were recruited to explore their experiences of APA and a smartphone app was developed based on their feedback. In Phase 2, a prospective longitudinal study was used to examine the effectiveness of the smartphone app to self-manage CMP. Results Phase 1 resulted in the successful development of the APA smartphone app. In Phase 2, after four weeks of APA, participants reported reduced pain intensity (30%), pain interference (35%), and disability (40%), as well as improved physical function (47%). The mean score for the participants’ perception of treatment efficacy was 4.94 (SD = 2.08, scale of 0–7) indicating that approximately 70% of participants rated global improvements with noticeable changes. The majority (88%, n = 22) of the participants were satisfied with the treatment: 32% [8] were very satisfied and 56% [n = 14] were somewhat satisfied. The average frequency of pressing APA seeds per day was 2.93 times (SD = 2.27, range 0–10) and 1.60 minutes per time (SD = 2.64, range 0–10); the participants were able to adhere to the suggested pressing time per day, although they only pressed the ear points about 53% of the suggested time. Conclusion It is feasible for individuals to learn APA from the smartphone app and successfully self-administer APA to manage their pain. Participants found the app useful and were satisfied with the information provided through the app.

Purpose: This study examined breast cancer screening practice and health promoting behaviors and the predicting factors of breast cancer screening practice in Chinese women. Methods: A correlational research design was used to recruit a convenience sample of 770 women living in four cities (Beijing, Shanghai, Guangzhou, and Xi’an) in China. Participants completed self-report questionnaire consisting of general characteristics, breast cancer screening, health promoting behaviors, perceived benefits and perceived barriers. Results: The participants were mostly 36−55 years old (51.3%), married (86.8%), premenopause (77.7%), had children (83.4%), and breastfed (73%). About 60% of Chinese women participated in some type of breast cancer screening practices, among them only 60 (7.8%) women used mammography, ultrasonogram and breast self-examination. The main reason for doing breast cancer screening was "feeling necessary for the screening". About 36% of the participants reported they did not perform any of screening practices, because they "don’t feel it necessary". The women who had breast cancer screening regularly reported better health promoting behavior and perceived benefits and less perceived barriers than those who did not (F=10.45, p

Background: B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide is the only blood biomarker in established risk calculators for pulmonary arterial hypertension (PAH). Profiling systemic-originated plasma immunoglobulin G (IgG) N-glycans, which reflect different components of the pathophysiology of PAH including immune dysregulation and inflammation, may improve PAH risk assessment., Objectives: This study sought to identify plasma IgG N-glycan biomarkers that predict survival in PAH to improve risk assessment., Methods: This cohort study examined 622 PAH patients from 2 national centers (Beijing [discovery] cohort: n = 273; Shanghai [validation] cohort: n = 349). Plasma IgG N-glycomes were profiled by a robust mass spectrometry-based method. Prognostic IgG N-glycan traits were identified and validated in the 2 cohorts using Cox regression and Kaplan-Meier survival analyses. The added value of IgG N-glycan traits to previously established risk models was assessed using Harrell C-indexes and survival analysis., Results: Plasma IgG fucosylation was found to predict survival independent of age and sex in the discovery cohort (HR: 0.377; 95% CI: 0.168-0.845; P = 0.018) with confirmation in the validation cohort (HR: 0.445; 95% CI: 0.264-0.751; P = 0.005). IgG fucosylation remained a robust predictor of mortality in combined cohorts after full adjustment and in subgroup analyses. Integrating IgG fucosylation into previously established risk models improved their predictive capacity, marked by an overall elevation in Harrell C-indexes. IgG fucosylation was useful in further stratifying the intermediate-risk patients classified by a previously established model., Conclusions: Plasma IgG fucosylation informs PAH prognosis independent of established factors, offering additional value for predicting PAH outcomes., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the National Key Research and Development Program of China (2022YFC2703902 and 2022YFC2703901), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-018), National Natural Science Foundation of China (82241020 and 32371506), Natural Science Foundation of Shanghai (22ZR1452400), Pujiang Talent Program (22PJD064), and National High-Level Hospital Clinical Research Funding (2022-PUMCH-A-200 and 2022-PUMCH-B-099). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We developed and experimentally realized a scheme of optical nonreciprocity (ONR) by using degenerate two-level atoms embedded in an optical ring cavity. For the degenerate transition F g = 4 ↔ F e = 3, we first studied the cavity-transmission property in different coupling field configurations and verified that under the strong-coupling regime, the single-dark-state peak formed by electromagnetically induced transparency (EIT) showed ONR. The stable ground-state Zeeman coherence for Λ-chains involved in the degenerate two-level system was found to be important in the formation of intracavity EIT. However, different from the three-level atom-cavity system, in the degenerate two-level system, the ONR effect based on intracavity EIT occurred only at a low probe intensity, because the cavity-atom coupling strength was weakened in the counter-propagating probe and coupling field configuration. Furthermore, ONR transmission with a high contrast and linewidth-narrowing was experimentally demonstrated.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a considerable health risk. Nevertheless, its risk factors are not thoroughly comprehended, and the association between the reticulocyte count and MASLD remains uncertain. This study aimed to explore the relationship between reticulocyte count and MASLD. Methods: A total of 310,091 individuals from the UK Biobank were included in this cross-sectional study, and 7,316 individuals were included in this prospective study. The cross-sectional analysis categorized reticulocyte count into quartiles, considering the sample distribution. Logistic regression models examined the connection between reticulocyte count and MASLD. In the prospective analysis, Cox analysis was utilized to investigate the association. Results: Our study findings indicate a significant association between higher reticulocyte count and an elevated risk of MASLD in both the cross-sectional and prospective analyses. In the cross-sectional analysis, the adjusted odds ratios (ORs) of MASLD increased stepwise over reticulocyte count quartiles (quartile 2: OR 1.22, 95% CI 1.17-1.28, p < 0.001; quartile 3: OR 1.44; 95% CI 1.38-1.51, p < 0.001; quartile 4: OR 1.66, 95% CI 1.59-1.74, p < 0.001). The results of prospective analyses were similar. Conclusion: Increased reticulocyte count was independently associated with a higher risk of MASLD. This discovery offers new insights into the potential of reticulocytes as biomarkers for MASLD., 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 Ma, Li, Li, Hong, Cui, Zhang, Li, Xiao, Zhu, Zeng, Xu, Lai and Liu.)

As global climate change persists, ongoing warming exposes plants, including kiwifruit, to repeated cycles of drought stress and rewatering, necessitating the identification of drought-resistant genotypes for breeding purposes. To better understand the physiological mechanisms underlying drought resistance and recovery in kiwifruit, moderate (40-45% field capacity) and severe (25-30% field capacity) drought stresses were applied, followed by rewatering (80-85% field capacity) to eight kiwifruit rootstocks in this study. We then conducted a multivariate analysis of 20 indices for the assessment of drought resistance and recovery capabilities. Additionally, we identified four principal components, each playing a vital role in coping with diverse water conditions. Three optimal indicator groups were pinpointed, enhancing precision in kiwifruit drought resistance and recovery assessment and simplifying the evaluation system. Finally, MX-1 and HW were identified as representative rootstocks for future research on kiwifruit's responses to moderate and severe drought stresses. This study not only enhances our understanding of the response mechanisms of kiwifruit rootstocks to progressive drought stress and recovery but also provides theoretical guidance for reliable screening of drought-adaptive kiwifruit genotypes., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Plutella xylostella (Linnaeus) is a destructive pest of cruciferous crops due to its strong reproductive capacity and extensive resistance to pesticides. Seminal fluid proteins (SFPs) are the main effective factors that determine the reproductive physiology and behaviour of both sexes. Although an increasing number of SFPs have been identified, the effects of astacins in SFPs on agricultural pests have not yet been reported. Here, we elucidated the mechanisms by which Sast1 (seminal astacin 1) regulates the fertility of Plutella xylostella (L.)., Results: PxSast1 was specifically expressed in the testis and accesssory gland. CRISPR/Cas9-induced PxSast1 knockout successfully constructed two homozygous mutant strains. Sast1 impaired the fertility of P. xylostella by separately regulating the reproductive capacity of males and females. Loss of PxSast1, on the one hand, significantly decreased the ability of males to mate and fertilize, mainly manifested as shortened mating duration, reduced mating competitiveness and decreased eupyrene sperm production; on the other hand, it significantly inhibited the expression of chorion genes in females, resulting in oogenesis deficits. Simultaneously, for mated females, the differentially expressed genes in signalling pathways related to oogenesis and chorion formation were significantly enriched after PxSast1 knockout., Conclusion: These analyses of the functions of PxSast1 as the regulator of spermatogenesis and oogenesis establish its importance in the fertility process of P. xylostella, as well as its potential as a promising target for genetic regulation-based pest control. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the pulmonary vasculature and elevated pulmonary arterial pressure, ultimately leading to right heart failure and death. Despite its clinical significance, the precise molecular mechanisms driving PAH pathogenesis warrant confirmation. Compelling evidence indicates that during the development of PAH, pulmonary vascular cells exhibit a preference for energy generation through aerobic glycolysis, known as the "Warburg effect", even in well-oxygenated conditions. This metabolic shift results in imbalanced metabolism, increased proliferation, and severe pulmonary vascular remodeling. Exploring the Warburg effect and its interplay with glycolytic enzymes in the context of PAH has yielded current insights into emerging drug candidates targeting enzymes and intermediates involved in glucose metabolism. This sheds light on both opportunities and challenges in the realm of antiglycolytic therapy for PAH., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cross-coupling reactions represent an indispensable tool in chemical synthesis. An intriguing challenge in this field is to achieve selective cross-coupling between two precursors with similar reactivity or, to the limit, the identical molecules. Here we report an unexpected dehydrobrominative cross-coupling between 1,3,5-tris(2-bromophenyl)benzene molecules on silver surfaces. Using scanning tunneling microscopy, we examine the reaction process at the single-molecular level, quantify the selectivity of the dehydrobrominative cross-coupling, and reveal the modulation of selectivity by substrate lattice-related catalytic activity or molecular assembly effect. Theoretical calculations indicate that the dehydrobrominative cross-coupling proceeds via regioselective C-H bond activation of debrominated TBPB and subsequent highly selective C-C coupling of the radical-based intermediates. The reaction kinetics plays an important role in the selectivity for the cross-coupling. This work not only expands the toolbox for chemical synthesis but also provides important mechanistic insights into the selectivity of coupling reactions on the surface.

SznF, a member of the emerging family of heme-oxygenase-like (HO-like) di-iron oxidases and oxygenases, employs two distinct domains to catalyze the conversion of N ω -methyl-L-arginine (L-NMA) into N-nitroso-containing product, which can subsequently be transformed into streptozotocin. Using unrestricted density functional theory (UDFT) with the hybrid functional B3LYP, we have mechanistically investigated the two sequential hydroxylations of L-NMA catalyzed by SznF's binuclear iron central domain. Mechanism B primarily involves the O-O bond dissociation, forming Fe(IV)=O, induced by the H + /e - introduction to the Fe A side of μ-1,2-peroxo-Fe 2 (III/III), the substrate hydrogen abstraction by Fe(IV)=O, and the hydroxyl rebound to the substrate N radical. The stochastic addition of H + /e - to the Fe B side (mechanism C) can transition to mechanism B, thereby preventing enzyme deactivation. Two other competing mechanisms, involving the direct O-O bond dissociation (mechanism A) and the addition of H 2 O as a co-substrate (mechanism D), have been ruled out., (© 2024 Wiley‐VCH GmbH.)

Background: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear., Methods: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined., Results: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A , TET2 , RUNX1 , and ASXL1 . During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively ( P <0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P =0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1β and interleukin-6 and lower interleukin-4 and IgG galactosylation levels., Conclusions: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up., Competing Interests: Disclosures None.

Objective: Reviews have shown that mindfulness-based interventions (MBIs) were effective in improving cardiovascular risk factors (CVRFs), but the results were contradictory. This umbrella review aimed to summarize and grade the existing reviews on CVRFs associated with MBIs., Methods: The protocol of this umbrella review had been registered in PROSPERO (CRD42022356812). PubMed, Web of science, Embase, The Cochrane Library, Scopus, Medline, PsycINFO and CINAHL were searched from database inception to 20 July 2022. The quality of evidence was assessed through GRADE., Results: Twenty-seven reviews with 14,923 participants were included. Overall, 45% of reviews had low heterogeneity (I 2  < 25%). For the quality of evidence, 31% were rated very low, 42% were rated low, 17% were rated moderate and 10% were rated high. MBIs significantly improved systolic blood pressure [SMD -5.53 mmHg (95% CI -7.81, -3.25)], diastolic blood pressure [SMD -2.13 mmHg (95% CI -2.97, -1.30)], smoking [Cohen's d 0.42 (95% CI 0.20, 0.64)], glycosylated hemoglobin [MD 0.01 (95% CI -0.43, -0.07)], binge eating behavior [SMD -6.49 (95% CI -10.80, -2.18)], depression [SMD -0.72 (95% CI -1.23, -0.21)] and stress [SMD -0.67 (95% CI -1.00, -0.34)]., Conclusions: In conclusion, this umbrella review provided evidence for the role of MBIs in the improvement of CVRFs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2 , as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.

Hepatocellular carcinoma (HCC) is the most widespread histological form of primary liver cancer, and it faces great diagnostic and therapeutic difficulties owing to its tumor diversity. Herein, we aim to establish a unique prognostic molecular subtype (MST) and based on this to find potential therapeutic targets to develop new immunotherapeutic strategies. Using calcium channel molecules expression-based consensus clustering, we screened 371 HCC patients from The Cancer Genome Atlas to screen for possible MSTs. We distinguished core differential gene modules between varying MSTs, and Tumor Immune Dysfunction and Exclusion scores were employed for the reliable assessment of HCC patient immunotherapeutic response rate. Immunohistochemistry and Immunofluorescence staining were used for validation of predicted immunotherapy outcomes and underlying biological mechanisms, respectively. We identified two MSTs with different clinical characteristics and prognoses. Based on the significant differences between the two MSTs, we further identified Follistatin-like 3 (FSTL3) as a potential indicator of immunotherapy resistance and validated this result in our own cohort. Finally, we found that FSTL3 is predominantly expressed in HCC stromal components and that it is a factor in enhancing fibroblast-M2 macrophage signaling crosstalk, the function of which is relevant to the pathogenesis of HCC. The presence of two MSTs associated with the calcium channel phenotype in HCC patients may provide promising directions for overcoming immunotherapy resistance in HCC, and the promotion of FSTL3 expressed in stromal components for HCC hyperfibrosis may be responsible for the poor response rate to immunotherapy in Cluster 2 (C2) patients., (© 2023. The Author(s).)

Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by pulmonary arterial remodeling. Despite that current combination therapy has shown improvement in morbidity and mortality, a better deciphering of the underlying pathological mechanisms and novel therapeutic targets is urgently needed to combat PAH. MicroRNA, the critical element in post-transcription mechanisms, mediates cellular functions mainly by tuning downstream target gene expression. Meanwhile, upstream regulators can regulate miRNAs in synthesis, transcription, and function. In vivo and in vitro studies have suggested that miRNAs and their regulators are involved in PAH. However, the miRNA-related regulatory mechanisms governing pulmonary vascular remodeling and right ventricular dysfunction remain elusive. Hence, this review summarized the controversial roles of miRNAs in PAH pathogenesis, focused on different miRNA-upstream regulators, including transcription factors, regulatory networks, and environmental stimuli, and finally proposed the prospects and challenges for the therapeutic application of miRNAs and their regulators in PAH treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the study's design, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023. Published by Elsevier Inc.)

Fluorene was previously reported to have anticancer activity against human cancer cells. In this study, we examined the in vitro function of 9-methanesulfonylmethylene-2, 3-dimethoxy-9 H -fluorene (MSDF), a novel fluorene derivative, its anticancer potential in human hepatocellular carcinoma (HCC) cells and its underlying molecular mechanism. The disruption of cellular homeostasis caused by MSDF was found to promote reactive oxygen species (ROS) generation, leading to the activation of cellular apoptosis. As a survival strategy, cells undergo autophagy during oxidative stress. MSDF-induced apoptosis occurred through both receptor-mediated extrinsic and mitochondrial-mediated intrinsic routes. The development of acidic vesicular organelles and the accumulation of LC3-II protein suggest an increase in the autophagic process. Apoptosis was detected by double staining. The MAPK/ERK and PI3K/Akt signaling pathways were indeed suppressed during treatment. Along with elevated ROS generation and apoptosis, MSDF also caused anoikis and cell death by causing cells to lose contact with their extracellular matrix. ROS production was induced by MSDF and sustained by an NAC scavenger. MSDF-induced apoptosis led to increased autophagy, as shown by the suppression of apoptosis by Z-VAD-FMK. However, inhibition of autophagy by inhibitor 3-MA increased MSDF-induced apoptosis. More evidence shows that MSDF downregulated the expression of immune checkpoint proteins, suggesting that MSDF could be used in the future as an adjuvant to improve the effectiveness of HCC immunotherapy. Altogether, our results highlight the potential of MSDF as a multitarget drug for the treatment of HCC., Competing Interests: Declaration of competing interest We declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The development of nonapoptotic programmed cell death inducers as anticancer agents has emerged as a cancer therapy field. Ferroptosis, ferrous ion-driven programmed cell death that is induced by redox imbalance and dysfunctional reactive oxygen species (ROS) clearance, is triggered during sorafenib and PD-1/PD-L1 immunotherapy. DFIQ, a quinoline derivative, promotes apoptosis by disrupting autophagic flux and promoting ROS accumulation. Our pilot experiments suggest that DFIQ participates in ferroptosis sensitization. Thus, in this study, we aimed to reveal the mechanisms of DFIQ in ferroptosis sensitization and evaluate the clinical potential of DFIQ., Methods: We treated the non-small cell lung cancer (NSCLC) cell lines H1299, A549, and H460 with the ferroptosis inducer (FI) DFIQ and analyzed viability, protein expression, ROS generation, and fluorescence staining at different time points. Colocalization analysis was performed with ImageJ., Results: DFIQ sensitized cells to FIs such as erastin and RSL3, resulting in a decrease in IC 50 of at least 0.5-fold. Measurement of ROS accumulation to explore the underlying mechanism indicated that DFIQ and FIs treatment promoted ROS accumulation and SOD1/SOD2 switching. Mitochondria, known ROS sources, produced high ROS levels during DFIQ/FI treatment. RSL3 treatment promoted mitochondrial damage and mitophagy, an autophagy-associated mitochondrial recycling system, and cotreatment with DFIQ induced accumulation of mitochondrial proteins, which indicated disruption of mitophagic flux. Thus, autophagic flux was measured in cells cotreated with DFIQ. DFIQ treatment was found to disrupt autophagic flux, leading to accumulation of damaged mitochondria and eventually inducing ferroptosis. Furthermore, the influence of DFIQ on the effects of clinical FIs, such as sorafenib, was evaluated, and DFIQ was discovered to sensitize NSCLC cells to sorafenib and promote ferroptosis., Conclusions: This study indicates that DFIQ not only promotes NSCLC apoptosis but also sensitizes cells to ferroptosis by disrupting autophagic flux, leading to accumulation of dysfunctional mitochondria and thus to ferroptosis. Ferroptosis is a novel therapeutic target in cancer therapy. DFIQ shows the potential to enhance the effects of FIs in NSCLC and act as a potential therapeutic adjuvant in ferroptosis-mediated therapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To evaluate the efficacy and safety of high-intensity focused ultrasound (HIFU) combined with the levonorgestrel intrauterine system (LNG-IUS) for adenomyosis., Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, SinoMed, Wanfang, and VIP databases from their inception to Nov 20, 2021 for relevant articles that compared HIFU combined with LNG-IUS vs. HIFU alone in patients with adenomyosis. RevMan5.4 software was used for the data analysis. The primary outcome was changes in volume of the uterine. Secondary outcomes included visual analog scale (VAS) scores for dysmenorrhea, serum CA125 level, recurrence rate, changes in volume of the adenomyotic lesion, menstrual volume scores, and adverse reactions. Data synthesis was conducted using a random-effects model with significant heterogeneity (I 2  > 50%), and using a fixed-effects model otherwise. This study is registered on the PROSPERO platform (CRD42021295214)., Results: The final analysis included 13 studies, with a total of 1861 patients. Results of analysis revealed that there was no significant difference in uterine volume reduction between the HIFU control group and the HIFU/LNG-IUS group at 3 months after procedure (MD:30.63). Compared with the HIFU control group, the HIFU/LNG-IUS group had more pronounced reduction in uterine volume at 6 (MD:29.04) and 12 months (MD:22.10) after procedure. The HIFU/LNG-IUS group has lower VAS scores for dysmenorrhea than the HIFU control group at 3 (MD:1.68), 6 (MD:1.69), and 12 months (MD:1.30) after procedure. Serum CA125 level in the HIFU/LNG-IUS group decreased more significantly than the HIFU control group at 6 (MD:18.34) and 12 months (MD:18.49) after procedure. The recurrence rate in the HIFU/LNG-IUS group was lower than that in the HIFU control group (RR:0.20)., Conclusions: Compared to HIFU control group, HIFU/LNG-IUS group for the management of adenomyosis had more advantages in alleviating symptoms and decreasing the volumes of the uterine and adenomyotic lesions. However, since the number of the included studies was too small and some of them were not RCT, this conclusion needs to be referenced with caution., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immune checkpoint inhibitors (ICIs) are safe and efficacious treatments for advanced primary liver cancer (PLC). The efficacy of different ICIs in the treatment of liver cancer remains unclear. The purpose of this study was to explore whether there is a difference in the efficacy and safety of various programmed cell death protein 1 (PD-1) inhibitors in combination with lenvatinib in the treatment of unresectable PLC. Patients with PLC treated with lenvatinib in combination with PD-1 inhibitors (camrelizumab, tislelizumab, sintilimab, or pembrolizumab) between January 2018 and December 2021 were retrospectively enrolled. Tumor response, adverse events, and grades were evaluated. Kaplan-Meier analysis and log-rank test were used to compare the overall survival and progression-free survival of patients treated with different PD-1 inhibitors. Cox regression analysis was used for univariate and multivariate analyses to identify clinical variables related to treatment efficacy. This study included a total of 176 patients who received a combination of lenvatinib and PD-1 inhibitors. Of these, 103 patients received camrelizumab, 44 received tislelizumab, 20 received sintilimab, and 9 received pembrolizumab. There was no significant difference in the pairwise comparison of camrelizumab, tislelizumab, sintilimab, and pembrolizumab using Kaplan-Meier survival analysis. Adverse events occurred in 40 (22.7%) patients (grade ≥ 3, 2.3%). The incidence of grade 3 adverse events among the four PD-1 inhibitor groups was below 5%. Camrelizumab, tislelizumab, sintilimab, and pembrolizumab are viable options for patients with unresectable PLC. These PD-1 inhibitors in combination with lenvatinib showed good safety profiles. The results guide selecting treatment for patients with unresectable PLC., (© 2023. The Author(s).)

Several randomized controlled trials (RCTs) have investigated the effects of fermented foods on metabolic outcomes in adult patients suffering from diabetes and prediabetes. However, the results of these RCTs are conflicting. This systematic review and meta-analysis was carried out on data from RCTs to evaluate the effects of fermented foods in patients with diabetes and prediabetes. The PubMed, Web of Science, Embase, the Cochrane Library and Scopus databases were searched up to 21 June, 2022. English-language RCTs of fermented foods consumption were included which gave metabolic outcomes on body composition, glucose control, insulin sensitivity, lipid profile, as well as blood pressure. Eighteen RCTs met the inclusion criteria and 843 participants were included in the final analysis. The pooled results showed a significant reduction of fasting blood glucose (FBG), the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), low density lipid cholesterol (LDL-C) and diastolic blood pressure (DBP) in the intervention group versus the control group. The results of this research showed that fermented foods have the potential to improve some metabolic outcomes, including FBG, HOMA-IR, TC, LDL-C, and DBP in patients with diabetes and prediabetes.

Aim: The activation of NLRP3 inflammasome leads to the stimulation of cytokines and is significantly involved in the pathogenesis and progression of autoimmune diseases. The purpose of this study is to examine the associations of NLRP3 gene polymorphisms with rheumatoid arthritis (RA) and primary Sjogren's syndrome (SS) patients. Methods: A total of 239 patients with RA, 285 patients with primary SS, and 170 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood mononuclear cells, and gene polymorphisms were genotyped through the TaqMan assay. Antinuclear antibody (ANA), anti-Ro, and anti-CCP antibodies were detected using immunofluorescence immunoassay. Results: The T allele of rs4612666 CT elevated the susceptibility to RA disease. The RF titer during diagnosis of RA was significantly high in RA patients with the A allele of rs12079994 G/A polymorphism. The titer of anti-CCP during diagnosis of RA was high in the absence of the C allele of rs10754558 C/G polymorphisms in RA patients. Antinuclear antibody and anti-CCP were positively associated with the A allele of rs12079994 G/A polymorphism in primary SS. The C allele of rs4612666 C/T was negatively associated with ANA in primary SS. Conclusions: The results have shown that NLRP3 gene polymorphisms may play a role in the pathogenesis of RA and primary SS., Competing Interests: The authors declare no conflict of interest.

Background: Immune checkpoint inhibitors (ICIs) have improved survival outcomes and resulted in long-term responses in primary liver cancer in some patients. Nevertheless, not all patients with PLC could benefit from immunotherapy. Therefore, it is necessary to identify patients suitable for such therapy., Methods: 215 patients with primary liver cancer with immunotherapy from Nanfang Hospital were screened between August 2018 and October 2020 as a training set and our validation set included 71 patients of hepatocellular carcinoma from Jiangxi Cancer Hospital from May 2019 to July 2021. The primary endpoint was the disease control rate (DCR), and the secondary endpoints were overall survival (OS) and progression-free survival., Results: In the training set, neutrophil-lymphocyte ratio (NLR) ≥3 and alpha-fetoprotein (AFP) level ≥20 ng/mL were independently associated with non-DCR in the training set after adjusting for distant metastasis at baseline and targeted therapy combination. Furthermore, a hepatic immune predictive index (HIPI) based on NLR and AFP level was developed and patients with poor HIPI associated with worse clinical outcomes. In validation set, high HIPI was associated with poor OS., Conclusion: HIPI, based on NLR and AFP level, is an effective indicator in ICI-treated patients with primary liver cancer. Our findings may help guide the selection and on-treatment strategies for immunotherapies for primary liver cancer patients., (© 2022 S. Karger AG, Basel.)

Background & Aims: Immune checkpoint inhibitors (ICIs) play an increasingly important role in the treatment of primary liver cancer (PLC). Some patients with PLC experience symptoms of splenomegaly. Splenomegaly may affect the efficacy of ICIs due to an imbalance of the immune microenvironment. Currently, there is a lack of evidence on the relationship between splenomegaly and prognosis in patients with PLC treated with ICIs. This study analyzed the relationship between splenomegaly and prognosis in patients with PLC treated with ICIs., Methods: In this retrospective cohort study of 161 patients with PLC treated with ICIs, splenomegaly was diagnosed using computed tomography or magnetic resonance imaging and the impact of splenomegaly on patient survival was analyzed., Results: Through univariate and multivariate Cox regression analyses, we determined that splenomegaly was associated with shortened overall survival (p = 0.002) and progression-free survival (p = 0.013) in patients with PLC treated with ICIs. Kaplan-Meier analysis further validated our results. The overall survival and progression-free survival of patients with splenomegaly were significantly shorter than those of patients without splenomegaly (p < 0.01 and p = 0.02, respectively)., Conclusions: We concluded that splenomegaly was a predictor of prognosis in patients with PLC treated with ICIs. This is the first study to report this important finding., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

(1) Background: It is widely accepted that aberrant methylation patterns contribute to the development of systemic lupus erythematosus (SLE). Ten-eleven translocation (TET) methylcytosine dioxygenase is an essential enzyme of which there are three members, TET1, 2, and 3, involved in hydroxymethylation, a newly uncovered mechanism of active DNA methylation. The epigenomes of gene transcription are regulated by 5-hydroxymethylcytocine (5-hmC) and TETs, leading to dysregulation of the immune system in SLE. The purpose of this study was to investigate the global hydroxymethylation status in SLE peripheral blood mononuclear cells (PBMCs) and to explore the role of TETs in changing the patterns of methylation. (2) Methods: We collected PBMCs from 101 SLE patients and 100 healthy donors. TaqMan real-time polymerase chain-reaction assay was performed for the detection of 5-methylcytosine (5-mC), 5-hmC, and TET2 mRNA expression and single-nucleotide polymorphism genotyping. The methylation rates in different CpG sites of TET2 promoters were examined using next-generation sequencing-based deep bisulfite sequencing. Putative transcription factors were investigated using the UCSC Genome Browser on the Human Dec. 2013 (GRCh38/hg38) Assembly. (3) Results: 5-mC and 5-hmC were both decreased in SLE. The mRNA expression level of TET2 was notably high and found to be correlated with the levels of immunologic biomarkers that are indicative of SLE disease activity. The analysis of methylation rates in the TET2 promoter revealed that SLE patients had significantly higher and lower rates of methylation in TET2 105146072-154 and TET2 105146218-331, respectively. (4) Conclusions: TET2 may play an important role in 5-mC/5-hmC dynamics in the PBMCs of SLE patients. The epigenetic modification of TET2 promoters could contribute to the pathogenesis of SLE and the intensity of the immunologic reaction.

Aim: To assess the impact of the obesity epidemic on type 2 diabetes (T2D), prediabetes and glycometabolic indices in children and adolescents., Methods: We searched four electronic databases (PubMed, Embase, Cochrane and Web of Science). Cross-sectional or cohort studies that reported on obesity and the prevalence of T2D or prediabetes in children and adolescents were reviewed. The study design, sample size and clinical outcomes were extracted from each study. The prevalence of T2D and prediabetes from the studies were pooled using meta-analysis methods., Results: Meta-analysis of 228184 participants showed that the prevalence of T2D was 1.3% (95% confidence interval (CI), 0.6-2.1%) in obese subjects, which was 13 times that in normal weight subjects (0.1%, 95% CI, 0.01-0.2%). The prevalence of prediabetes in obese subjects was 3 times that in normal subjects at 17.0% (13.0-22.0%) vs. 6.0% (0.01-11.0%). Moreover, BMI was positively correlated with the prevalence of T2D, prediabetes and glycometabolic indices in obese children and adolescents., Conclusion: The pooled results confirm that obesity in children and adolescents leads to statistically significant increases in the prevalence of T2D and prediabetes and in glycometabolic indicator levels., Competing Interests: Declarations of interest None., (Copyright © 2022 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Selective halogenation is important in synthetic chemistry. BesD, a new member of the non-heme Fe(II)/α-ketoglutarate (αKG)-dependent halogenase family, can activate the sp 3 C-H bond and halogenate lysine, in particular without a carrier protein. Using the density functional calculations, a chlorination mechanism in BesD has been proposed, mainly including the formation of Cl-Fe(IV)=O through the αKG decarboxylation, the isomerization of Cl-Fe(IV)=O, the substrate hydrogen abstraction by Fe(IV)=O, and the rebound of chloro to the substrate carbon radical. The hydrogen abstraction is rate-limiting. The isomerization of Cl-Fe(IV)=O is essential for the hydrogen abstraction and the chiral selectivity. The BesD-catalyzed bromination and azidation of lysine adopt the same mechanism as the chlorination. The hardly-changed overall barriers indicate that the introduced ligands (X) do not affect the reaction rate significantly, implying that the X-introduced reactions catalyzed by BesD may be extended to other X anions., (© 2022 Wiley-VCH GmbH.)

Aromatic ring fusion to porphyrins and their derivatives represents an attractive route to tune the molecular conjugation and thus expand their functionalities. Here, we report the expansion of the aromatic π-system of palladium tetraphenyltetrabenzoporphyrins (Pd-TPTBP) via surface-assisted γ- ortho cyclodehydrogenation on Ag(111). The chemical transformation of Pd-TPTBP into different products at an elevated temperature of 600 K was revealed at the single-molecule level using bond-resolved scanning tunneling microscopy with a CO-functionalized tip. We captured a series of γ -ortho cyclodehydrogenation products, wherein the maximum extent to which the reaction can progress is associated with 7-fold C-C formation to afford nearly planar γ- ortho fused porphyrins with 66 conjugated π-electrons. In addition, a small number of molecules undergo C-C bond dissociation of meso -phenyl at elevated temperature, producing fully planar γ- ortho fused products lacking one or two phenyl moieties. Scanning tunneling spectroscopy measurements and DFT calculations suggest the electronic gap of the γ -ortho fused porphyrin decreases compared to that of the precursor. The HOMO and LUMO of the planar γ- ortho fused products are localized on the partially fused benzo moieties and the meso -position, respectively.

Background/purpose: Recent studies showed that Histone deacetylases 6 (HDAC6) inhibitors could improve arthritis in rheumatoid arthritis (RA) rodent models, whereas lower HDAC6 expression was observed in RA patients' synovial fibroblasts, raising the concerns to use HDAC6 inhibitors to treat RA patients. In the present study, we investigated the involvement of HDAC6 mRNA expression and promoter methylation in RA., Methods: The DNA and RNAs were extracted from the peripheral blood mononuclear cells (PBMCs) from 138 RA patients and 102 healthy controls. The pyrosequencing technique was used for promoter methylation analysis. The quantitative real-time polymerase chain reaction was used to determine the HDAC6 mRNA expression. The patients' clinical characteristics and disease biomarkers were recorded when blood sampling., Results: The HDAC6 mRNA expression was lower in the RA patients than controls (p = 0.001). The RA patients had significant hypomethylation of the HDAC6 promoter (p < 0.001). The HDAC6 promoter was hypo-methylated in the -229, -225, -144, and -142 CpG sites in RA patients (p < 0.05). Unexpectedly, promoter methylation and mRNA expression of the HDAC6 gene were positively associated (p < 0.001). The HDAC6 mRNA expression and promoter methylation status were associated with the risk of RA (p = 0.006 and 0.002, respectively). The inflammatory cytokines, TNF-α and IL-6, were significantly increased after HDAC6 knockdown in PMA-stimulated THP1 cells and SW982 cells (p < 0.05)., Conclusion: The HDAC6 mRNA expression and promoter methylation were lower in RA patients. Both HDAC6 mRNA expression level and promoter hypomethylation were associated the susceptibility of RA. HDAC6 inhibitors seem not proper for RA patients' treatment., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To explore the dynamic changes of donor derived T cells at different time points in the aplastic anemia mouse model. Methods: The aplastic anemia mouse model was induced and then the proportion of infiltrated donor derived T cells in spleen and bone marrow, expression of activation molecular markers, cell cycle and functional subsets were measured by flow cytometry at different time points to evaluate the functional status of T cells in different periods. Results: ①T cell immune-mediated aplastic anemia mouse model was successfully established by half lethal dose irradiation combined with major histocompatibility antigen (MHC) haploidentical lymph node cells infusion. ②The donor derived T cells began to infiltrate significantly in the spleen of aplastic anemia mouse from the 3rd day after transplantation and the ratio of CD4(+)/CD8(+) gradually inverted. After the 5th day, they gradually entered the bone marrow, predominated by CD8(+) cells. ③The expression peak of CD69 in donor CD4(+) cells was later than that in CD8(+) cells. The trend of CD25 expression in CD4(+) cells was the same as that in CD8(+) cells, but the expression level in CD8(+) cells was higher than CD4(+) cells. ④The proportion of donor CD4(+) cells in S/G(2)/M phase reached the peak in spleen, about 12%, within 3 days after transplantation, while a higher level in CD8(+) cells, which was about 20%. And the proportion of both CD4(+) and CD8(+) cells in S/G(2)/M phase increased again after entering bone marrow, which was continued to be higher in CD8(+) cells than that in CD4(+) cells after 3 days of transplantation. ⑤Immune activated T cells in the spleen rapidly differentiated into effector memory T cells (T(EM)) after a short central memory T cell (T(CM)) stage. After entering the bone marrow, some T(EM) differentiated into effector cells to further function. Conclusion: In the aplastic anemia mouse model, donor derived T cells activated rapidly after entering the allogenic recipient, reached its proliferation booming period and differentiated into T(EM) cells within 5 days. After 5 days, they began to enter the bone marrow to continue proliferate and damage hematopoiesis.

Background: Immune checkpoint inhibitors (ICIs) have been used to successfully treat primary liver cancer (PLC); however, identifying modifiable patient factors associated with therapeutic benefits is challenging. Obesity is known to be associated with increased survival after ICI treatment; however, the relationship between body composition (muscle, fat) and outcomes is unclear. This study aimed to evaluate the association between sarcopenia and CT-derived fat content and the prognosis of ICIs for the treatment of PLC., Methods: In this retrospective cohort study of 172 patients with PLC, we measured the skeletal muscle index (SMI), skeletal muscle density, visceral adipose tissue index, subcutaneous adipose tissue index, total adipose tissue index (TATI), and visceral-to-subcutaneous adipose tissue area ratio using CT. In addition, we analyzed the impact of body composition on the prognosis of the patients. Multivariate Cox regression analysis was used to screen for influencing factors., Results: Among the seven body composition components, low SMI (sarcopenia) and low TATI were significantly associated with poor clinical outcomes. Multivariate analysis revealed that sarcopenia (hazard ratio [HR], 5.39; 95% confidence interval [CI], 1.74-16.74; p = 0.004) was a significant predictor of overall survival (OS). Kaplan-Meier curves showed that sarcopenia and TATI were significant predictors of OS. Body mass index was not associated with survival outcomes., Conclusions: Sarcopenia and fat tissue content appear to be independently associated with reduced survival rates in patients with PLC treated with ICIs., (© 2022. The Author(s).)

Purpose: To explore the utility of CTE in the evaluation of bowel invasion in patients with primary ovarian, fallopian tube, and peritoneal cancer., Methods: This observational study included 73 patients who received CTE before operation between September 2019 and December 2021. Two radiologists reviewed CTE images, focusing on the sites and depth of bowel involvement. Based on the findings during surgical exploration, we evaluated the diagnostic power, like sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+ LR), and negative likelihood ratio (- LR) of CTE. Additionally, the characteristic images of bowel involvement on CTE corresponding to surgical findings were shown in the study., Results: The rate of macroscopic bowel invasion in this cohort was 49.31% (36/73), of which eight patients had small bowel involvement, 17 patients had colon involvement and 27 patients had sigmoid-rectum involvement. CTE detected bowel invasion in the small intestine with a sensitivity, specificity, PPV, NPV, and accuracy of 87.50%, 92.31%, 58.33%, 98.36%, 91.78%; for colon, the statistics were 58.82%, 96.43%, 83.33%, 88.52%, 87.67% and for sigmoid-rectum 62.96%, 82.61%, 68.00%, 79.17%, 75.34%, respectively., Conclusion: CTE appeared a preferable diagnostic power on the small bowel and colon invasion in patients with primary ovarian, fallopian tube, and peritoneal cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Primary fallopian tube cancer (PFTC) shares the same diagnostic and management guidelines with epithelial ovarian cancer (EOC). The LION trail raised concerns regarding the role of systematic pelvic and para-aortic lymphadenectomy during debulking surgery. We aimed to evaluate the significance of lymphadenectomy in PFTC survival., Methods: This retrospective study analyzed the clinical features and survival of patients with PFTC who underwent primary surgery in our center between January 2013 and October 2020., Results: Sixty-one patients diagnosed with PFTC were included in the study. Twenty-five (41.0%, 25/61) were diagnosed with FIGO (International Federation of Gynecology and Obstetrics) stages I/II and 36 (59.0%, 36/61) were diagnosed with stage III/IV. Twenty-nine (47.5%, 29/61) underwent pelvic lymphadenectomy with or without para-aortic lymphadenectomy, among which 12 (41.4%, 12/29) had lymph node metastasis confirmed by postoperative pathology. The mean progression-free survival was 60.4 months in the lymphadenectomy group and 37.8 months in the no-lymphadenectomy group ( p  = 0.042, HR 0.374, 95% CI 0.145-0.966)., Conclusions: PFTC is often diagnosed earlier and has a better prognosis than EOC. Most patients with PFTC would benefit from lymphadenectomy. However, the extent to which this association translates to a more diverse population needs to be further identified.

Objective: To analyze the clinical characteristics of Wilson's disease (WD) with onset of acute liver failure (ALF) in children. Methods: Clinical data of 19 children diagnosed with WD presented with ALF in Xi'an Children's Hospital from January 2016 to April 2021 were retrospectively analyzed, including general condition, clinical manifestation, laboratory examination, and gene detection. The children were divided into the death group and survival group according to the clinical outcome. The children who had hepatic WD with non-ALF onset during the same period were selected as the control. The general conditions and laboratory indexes were compared between death group and survival group, ALF group and non-ALF group. T-test, Mann Whitney U test or χ 2 test were used to compare the differences between the two groups. Results: Of the 19 WD children with ALF onset, 10 were females and 9 were males. The age of admission was (10.1±2.6) years and time to onset of first visit was 9 (4, 15) days. Among the WD children with ALF onset, 4 children were lost to follow-up, 5 cases death (death group) and 10 cases survived (survival group). The ceruloplasmin in the death group was higher than that in the survival group (0.078 (0.055, 0.105) vs. 0.033 (0.027, 0.058) g/L, Z =-2.33, P =0.020). There were 95 children who had hepatic WD with non-ALF onset. The WD patients with ALF onset were older at admission (9.9 (8.0, 11.1) vs. 5.4 (3.7, 6.9) years, Z =-5.25, P <0.001), had higher ceruloplasmin (0.060 (0.030, 0.078) vs. 0.024 (0.006, 0.060) g/L, Z =-3.11, P =0.002), 24 h urinary copper (674 (205, 1 803) vs . 149 (108, 206) μg, Z =-4.25, P <0.001), and positive rate of K-F ring [17/19 vs. 7%(7/95), χ 2 =50.17, P <0.001] while shorter onset time at initial visit (0.3 (0.1, 0.5) vs. 1.0 (0.7, 6.0) months, Z =-4.28, P <0.001). There was no gender difference between the two groups [9/19 vs. 61%(58/95), χ 2 =1.22, P =0.269]. Of the 19 WD children with ALF onset, 13 had the ATP7B gene tested, and 15 reported variants were detected. The main variations were c.2333G>T (p. Arg778Leu), c.2621C>T (p. Ala874Val) and c.2975C>T (p. Pro992Leu). The allele frequencies were 6/26(23%), 4/26(15%) and 3/26(12%), respectively. Conclusions: Children of WD onset with ALF are school-aged and above. They have an acute onset, a short course of the disease, and poor prognosis. The positive rate of K-F ring, ceruloplasmin and urinary copper are higher than those of the hepatic WD children with non-ALF onset.

Background: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune-mediated inflammatory processes, although it remains unknown whether CREM is involved in RA., Methods: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real-time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t-tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression., Results: Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001)., Conclusions: Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Crohn's disease (CD) is a chronic nonspecific intestinal inflammatory disease. The aetiology and pathogenesis of CD are still unclear. Anal fistula is the main complication of CD and is a difficult problem to solve at present. The main limitation of developing new therapies is bound up with the short of preclinical security and effectiveness data. Therefore, an ideal animal model is needed to establish persistent anal fistula and an inflamed rectal mucosa., Aim: To improve the induction method of colitis and establish a reliable and reproducible perianal fistulizing Crohn's disease animal model to evaluate new treatment strategies., Methods: Twenty male New Zealand rabbits underwent rectal enema with different doses of 2,4,6-trinitrobenzene sulfonic acid to induce proctitis. Group A was treated with an improved equal interval small dose increasing method. The dosage of group B was constant. Seven days later, the rabbits underwent surgical creation of a transsphincteric fistula. Then, three rabbits were randomly selected from each group every 7 d to remove the seton from the fistula. The rabbits were examined by endoscopy every 7 days, and biopsy forceps were used to obtain tissue samples from the obvious colon lesions for histological analysis. The disease activity index (DAI), colonoscopy and histological scores were recorded. Perianal endoscopic ultrasonography (EUS) was used to evaluate the healing of fistulas., Results: Except for the DAI score, the colonoscopy and histological scores in group A were significantly higher than those in group B ( P < 0.05). In the ideal model rabbit group, on the 7 th day after the removal of the seton, all animals had persistent lumens on EUS imaging, showing continuous full-thickness high signals. Histological inspection of the fistula showed acute and chronic inflammation, fibrosis, epithelialization and peripheral proctitis of the adjoining rectum., Conclusion: The improved method of CD colitis induction successfully established a rabbit perianal fistula CD preclinical model, which was confirmed by endoscopy and pathology., Competing Interests: Conflict-of-interest statement: The authors have nothing to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Dyslipidemia is a significant contributor to cardiovascular and cerebrovascular diseases. Research on the relationship between breakfast consumption frequency and dyslipidemia in the working population is lacking. Therefore, we aimed to investigate this relationship based on a retrospective cohort study of a large working population in China., Methods: This retrospective cohort study used data from the physical examinations and questionnaire survey of working participants at Nanfang Hospital from January 20, 2015 to October 16, 2020. Univariate and multivariate analyses were conducted to explore the relationship between breakfast consumption frequency and dyslipidemia in this working population (n = 7644)., Results: The prevalence of dyslipidemia among the participants was 26.4%. The univariate logistic regression test showed that the breakfast consumption frequency was inversely correlated with dyslipidemia. After adjusting for multiple factors, such as sex, age, body mass index, hypertension, hyperuricaemia, diabetes, smoking status, alcohol consumption, education level, marital status, long-term exposure to kitchen oil fumes, attending business dinners, and sleep time, it was found that breakfast consumption remained inversely associated with dyslipidaemia. The odds ratio for daily breakfast consumption was 0.466 (95% confidence interval 0.283-0.770, P = 0.003). After adjusting for confounding factors, we found that the higher the frequency of breakfast consumption, the lower the odds ratios for hypertriglyceridaemia., Conclusions: This study demonstrated that breakfast consumption frequency was inversely correlated with dyslipidemia. The higher the frequency of breakfast, the lower the risk of hypertriglyceridaemia. This study provides a basis on which dietary suggestions for the working population and lifestyle guidance for patients with a clinical need to prevent dyslipidemia can be made., (© 2022. The Author(s).)

Background: At present, some cancer patients experience hyperprogressive disease (HPD) after receiving immunotherapy. This study used the Response Evaluation Criteria in Solid Tumors 1.1 to evaluate the incidence of HPD in patients receiving immune checkpoint inhibitors (ICIs) for treating primary liver cancer (PLC) and to explore the risk factors for HPD., Methods: This retrospective, single-center study included patients with PLC who were treated with ICIs. The RECIST 1.1 was used to determine patients with HPD. Univariate and multivariate regression analyses were performed to explore the risk factors for HPD, and clinical variables with prognostic significance for HPD were included to establish a risk model., Results: Among 129 patients with PLC treated with ICIs, HPD occurred in 13 patients (10.1%). In the multivariate regression analysis, lymph node metastasis and lung metastasis were risk factors for HPD. The area under the curve of the risk model, established by including lymph node metastasis, lung metastasis, neutrophil-lymphocyte ratio, albumin, and performance status, was 0.801 (P<0.001). The progression-free survival of HPD patients was significantly worse than that of non-HPD patients (P<0.001)., Conclusions: In this study, 10.1% of patients with PLC had HPD. Compared with the non-HPD patients, lung metastasis and lymph node metastasis were independent risk factors of HPD.

Grafting is a technique that provides a substantial way to enhance nutrient utilization thereby improves plant growth and yield quality. Although it is commonly practised in horticultural crops, the impact of scion-rootstock interaction on nutrient distribution is still unclear. Here, 'Newhall' navel orange plants grafted on Trifoliate orange (T) as the original rootstock were inarched with trifoliate orange (N/Tt combination) or carrizo citrange (N/Tc combination) rootstock seedlings. The experimental plants were treated with isotope 10 B solution for 7 weeks to investigate the effect of different inarched rootstocks on B distribution and translocation by using a two-root system. From this study, the original rootstock played a more dominant role in B distribution to scion tissues than the inarching rootstock either in N/Tt or N/Tc combination. From inarched combinations, the carrizo citrange in the N/Tc combination had a higher ability to distribute B to new leaves, new twigs and old twigs than trifoliate orange in the N/Tt combination. However, the original rootstock of N/Tt distributed more B to scion tissues than N/Tc and the B concentration in old leaves and new leaves of N/Tt plants was significantly higher than that of N/Tc plants. These results suggest that scion B status is influenced by the B distribution of two inarching rootstocks in an inarching plant, as well as the affinity between the inarching rootstock and grafted plant. In addition, by either adding 10 B to the inarching rootstock or original rootstock, we could detect 10 B in the other rootstock root in both N/Tt and N/Tc combinations. The results further suggest that B can translocate from rootstock to leaves and then, re-translocate from scion to rootstock through the cycling of B transportation., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)