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Jun-Qian Huang,1 Fang Wang,2 Long-Tao Wang,3 Yong-Mei Li,4 Jun-Li Lu,5 Jian-You Chen2 1Department of Respiratory and Critical Medicine, Qingdao Chengyang District People’s Hospital, Qingdao, Shandong, People’s Republic of China; 2Department of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of China; 3Department of Critical Care Medicine, Qingdao Chengyang District People’s Hospital, Qingdao, Shandong, People’s Republic of China; 4Department of Clinical Pharmacy, Qingdao Chengyang District People’s Hospital, Qingdao, Shandong, People’s Republic of China; 5Qingdao Chengyang District People’s Hospital, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Jian-You ChenDepartment of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of ChinaEmail youchanmou9834@163.comBackground: Asthma belongs to chronic inflammatory respiratory diseases characterized by airway inflammation and remodeling. Circular RNAs (circRNAs) are promising therapeutic targets for various diseases, including asthma. In this work, we aim to investigate the role of circular RNA Erb-B2 receptor tyrosine kinase 2 (circERBB2) during progression of asthma.Methods: Human airway smooth muscle cells (ASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) to mimic cell remodeling. The expression of circERBB2, microRNA-98-5p (miR-98-5p), and insulin-like growth factor 1 receptor (IGF1R) was measured by qRT-PCR. Cell proliferation, migration and apoptosis were determined by cell counting-8 (CCK-8), transwell, and flow cytometry. Protein levels of PCNA, MMP-9, IGF1R were evaluated using Western blotting. The levels of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 were detected by enzyme‐linked immunosorbent assay (ELISA). Luciferase reporter gene experiment was adopted to evaluate the targeting relationship between miR-98-5p with circERBB2 and IGF1R. Interaction between RNAs was determined by RNA pulldown and RIP assay.Results: The depletion of circERBB2 attenuated the proliferation, migration, and levels of inflammatory factors induced by PDGF-BB and cell apoptosis. CircERBB2 was identified to directly interact with miR-98-5p, and overexpression of miR-98-5p abolished the function of circERBB2 on PDGF-BB-stimulated ASMCs. IGF1R was identified as a target of miR-98-5p, and knockdown of IGF1R relieved the PDGF-BB-induced ASMCs proliferation and migration.Conclusion: Our work disclosed that knockdown of circERBB2 suppressed PDGF-BB-caused proliferation, migration and inflammatory response of ASMCs, through regulating miR-98-5p/IGF1R signaling, presented circERBB2 as a promising therapeutic target for asthma.Keywords: asthma, circERBB2, miR-98-5p, IGF1R, proliferation, migration

Xue Wang,&ast; Yue Zhang,&ast; Hong-Liang Sun, Li-Ting Wang, Xue-Feng Li, Fei Wang, Yan-Lin Wang, Qing-Chun Li Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, 256603, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing-Chun Li; Yan-Lin WangDepartment of Reproductive Medicine, Binzhou Medical University Hospital, No. 661 Huanghe 2nd Road, Binzhou, 256603, People’s Republic of ChinaTel +86 543 325 8715; +86 543 325 8713Fax +86 543 325 7792Email qingchunli_doc@163.com; docylwang2003@163.comObjective: The aim of the present study was to explore related clinical pregnancy outcome factors in intrauterine insemination (IUI).Materials and Methods: The clinical data of 3984 IUI cycles in 1862 couples experiencing infertility who attended the Reproductive Center of Binzhou Medical University Hospital between July 2006 and July 2017 were retrospectively analyzed. Female and male patient age, endometrial thickness (EMT), the post-wash total motile sperm count (PTMC), artificial insemination timing, insemination frequency, and ovarian stimulation protocols were compared between the study’s pregnant group and non-pregnant group in order to explore any correlation.Results: There were statistically significant differences in female and male age, EMT, artificial insemination timing, insemination frequency, and ovarian stimulation protocols between the two groups (p < 0.05). The clinical pregnancy rate was significantly higher in ovarian stimulation cycles than in natural cycles (21.2% and 11.6%, respectively; p < 0.01), the clinical pregnancy rate was significantly higher in double IUI than in single IUI (17.8% and 12.1%, respectively; p < 0.01), and EMT was significantly greater in the pregnant group than in the control group (p < 0.05). However, the differences in clinical pregnancy rates among the PTMC groups were not statistically significant (14.8%, 14.4%, 17.3%, and 17.3%, respectively; p > 0.05).Conclusion: The results of the present study demonstrate that the clinical IUI pregnancy rate is correlated with the factors of female age, male age, EMT, artificial insemination timing, insemination frequency, and ovarian stimulation protocols; the ovarian stimulation protocol can noticeably improve the patient pregnancy outcome. Furthermore, compared with single IUI, double IUI can significantly increase the clinical pregnancy rate.Keywords: intrauterine insemination, clinical pregnancy rate, post-wash total motile sperm count, ovarian stimulation cycle, timing of intrauterine insemination

Kwei-Yan Liu,1 Li-Ting Wang,2 Hsueh-Chun Wang,3,4 Shen-Nien Wang,5– 7 Li-Wen Tseng,5 Chee-Yin Chai,8 Shyh-Shin Chiou,9,10 Shau-Ku Huang,1,11 Shih-Hsien Hsu5,12,13 1Department of Respirology & Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen, 518020, People’s Republic of China; 2Department of Life Science, National Taiwan Normal University, Taipei, Taiwan; 3Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; 4Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan; 5Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 6Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital; 7Department of Surgery, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 8Department of Pathology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 9Division of Hematology-Oncology Department of Pediatrics, Kaohsiung Medical University Hospital Kaohsiung Medical University, Kaohsiung, Taiwan; 10Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 11National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, Taiwan; 12Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 13Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Shih-Hsien Hsu; Shau-Ku Huang Email jackhsu@kmu.edu.tw; skhuang@nhri.org.twBackground: Club cells play an important role in maintaining lung homeostasis and aryl hydrocarbon receptor (AhR) is known to be important in xenobiotic metabolism, but its role in regulating club cells is currently unknown.Methods: To this end, mice with club cell-specific AhR deficiency were generated and evaluated in a model of antigen (ovalbumin, OVA)-induced airway inflammation for the number of infiltrating inflammatory cells, the levels of cytokines and CC10 and Notch signaling by standard methods.Results: After OVA sensitization and challenge, Scgb1a1-Cre; Ahrflox/flox mice showed aggravated levels of pulmonary inflammation with increased levels of inflammatory cells and cytokines 1 day after challenge as compared to those seen in their littermate controls, but in contrast to the littermate controls, no significant change in the levels of CC10 and SP-D was noted in Scgb1a1-Cre; Ahrflox/flox mice. Surprisingly, 7 days after the challenge, while, as expected, wild-type mice recovered from acute inflammation, significantly increased lymphocytic infiltration was noted in Scgb1a1-Cre; Ahrflox/flox mice, suggesting their defective mechanism of recovery. Mechanistically, this was due, in part, to the decreased Notch1 signaling and expression of its downstream gene, HES5, while AhR was shown to positively regulate Notch1 expression via its transactivating activity targeting the xenobiotic response element in the promoter region of Notch1 gene.Conclusion: Under the condition of pulmonary inflammation, AhR is critical in controlling lung club cell homeostasis via targeting Notch1 signaling and the generation of anti-inflammatory mediators.Keywords: AhR, club cells, CC10, Notch1, Hes5

Donggen Jiang,1,* Chutian Xiao,1,* Tuzeng Xian,1 Liantao Wang,2 Yunhua Mao,1 Junfu Zhang,1 Jun Pang1,3 1Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; 2Department of General Surgery, Shenzhen Shajing Affiliated Hospital of Guangzhou Medical University, Shenzhen, China; 3Department of Urology, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China *These authors contributed equally to this work Background: Doublecortin-like kinase 1 (DCLK1) has been proven to be involved in numerous tumors, while its role in prostate cancer (PCa) is still unclear. This study aimed at investigating the expression pattern and prognostic value of DCLK1 in PCa.Patients and methods: Real-time polymerase chain reaction and Western blot were employed to determine DCLK1 mRNA and protein levels in 25 paired fresh samples of PCa and benign prostatic hyperplasia (BPH) as well as in PCa cell lines. Immunohistochemistry (IHC) was also performed in 125 PCa and 65 BPH tissues to assess DCLK1 expression. Then, the association of DCLK1 expression with clinicopathological parameters and biochemical recurrence (BCR) after radical prostatectomy was statistically analyzed. In addition, the role of DCLK1 in PCa cell proliferation, migration, and invasion was evaluated by using MTT and transwell assays.Results: The mRNA and protein levels of DCLK1 were markedly higher in the fresh samples of PCa than that in BPH. Consistently, IHC revealed increased expression of DCLK1 in PCa paraffin-embedded tissues compared with BPH. Moreover, increased DCLK1 expression was significantly associated with postoperative Gleason grading (P=0.012), pathological T stage (P=0.001), seminal vesicle invasion (P=0.026), and lymph node involvement (P=0.017), respectively. The Kaplan–Meier curve analysis demonstrated that high DCLK1 expression was associated with lower postoperative BCR-free survival (bRFS). Furthermore, multivariate Cox analysis showed that postoperative Gleason grading (P=0.018), pathological T stage (P

Zhuo Wang,1,* Zun-Fu Ke,1,* Xiao-Fang Lu,1 Can-Jiao Luo,1 Yong-Dong Liu,1 Zhong-Wei Lin,2 Lian-Tang Wang1 1Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event. However, only a few of the causes of cases of HCC spontaneous regression are clear. More cases are ambiguous. We report on a patient who had a spontaneous regression of HCC as detected by histological and immunohistochemical exam, and compared this case to 20 cases of non-specific HCC. In our case, we found that the odd phenomenon is that CD163+ macrophages are overactivated in surviving HCC, which is spontaneously regressing. Concomitantly, we cannot find a similar phenomenon in peritumoral liver tissue or non-specific HCC. According to our microscopical morphology and immunohistochemical study, we considered that a clue of a possible etiology about HCC spontaneous regression is that CD163+ macrophages are overactivated. Keywords: hepatocellular carcinoma, spontaneous regression, macrophages, CD163, CD68

This document summarises the proposal of the LHC Dark Matter Working Group on how to present LHC results on s-channel simplified dark matter models and to compare them to direct (indirect) detection experiments.

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria., Competing Interests: Declaration of interests J.R.B., A.J.R.C., G.G., B.G.W., L.D.W.K., L.T.W., J.T., K. McHugh, and S.J.D. are inventors on patent applications relating to RH5 malaria vaccines and/or antibodies. A.M.M. and S.J.D. have consulted to GSK on malaria vaccines. A.M.M. has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and antibodies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines., Competing Interests: Declaration of interests J.T., L.T.W., and A.J.R.C. are co-inventors on a provisional patent filed on the mAbs described in this study. J.R.B., K.M., M.K.H., and S.J.D. are inventors on patent applications relating to RH5 malaria vaccines and/or antibodies. A.M.M. has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and antibodies. The content of this publication does not necessarily reflect the views or policies of the DHHS or of the institutions and companies with which the authors are affiliated., (Published by Elsevier Inc.)

Purpose: The innate immune response, particularly the reaction of polymorphonuclear neutrophils (PMNs), is crucial in shaping the outcomes of chronic inflammation, fibrosis, or osseointegration following biomaterial implantation. Peri-implantitis or peri-mucositis, inflammatory conditions linked to dental implants, pose a significant threat to implant success. We developed a single-cell analysis approach using a murine model to assess the immune response to implant materials, offering a practical screening tool for potential dental implants., Methods: We performed bioinformatics analysis and established a peri-implant inflammation model by inserting two titanium implants into the maxillary region, to examine the immune response., Results: Bioinformatics analysis revealed that titanium implants triggered a host immune response, primarily mediated by PMNs. In the in vivo experiments, we observed a rapid PMN-mediated response, with increased infiltration around the implants and on the implant surface by day 3. Remarkably, PMN attachment to the implants persisted for 7 days, resembling the immune profiles seen in human implant-mediated inflammation., Conclusions: Our findings indicate that persistent attachment of the short-living PMNs to titanium implants can serve as an indicator or traits of peri-implant inflammation. Therefore, analyzing gingival tissue at the single-cell level could be a useful tool for evaluating the biocompatibility of candidate dental implants.

Despite various public health strategies, malaria caused by Plasmodium falciparum parasites remains a major global health challenge that requires development of new interventions. Extended half-life human monoclonal antibodies targeting the P. falciparum circumsporozoite protein on sporozoites, the infective form of malaria parasites, prevent malaria in rodents and humans and have been advanced into clinical development. The protective epitopes on the circumsporozoite protein targeted by monoclonal antibodies have been defined. Cryogenic electron and multiphoton microscopy have enabled mechanistic structural and functional investigations of how antibodies bind to the circumsporozoite protein and neutralize sporozoites. Moreover, innovations in bioinformatics and antibody engineering have facilitated enhancement of antibody potency and durability. Here, we summarize the latest scientific advances in understanding how monoclonal antibodies to the circumsporozoite protein prevent malaria and highlight existing clinical data and future plans for how this emerging intervention can be used alone or alongside existing antimalarial interventions to control malaria across at-risk populations., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Radiation-induced lung injury (RILI) is a serious complication of radiation therapy, and it is mediated by long non-coding RNAs (lncRNAs)., Study Design and Methods: Mouse lung tissues were examined using RNA-Seq and RNA-Seq libraries 72 h after the administration of 6 Gy of X-ray irradiation. The target mRNAs were functionally annotated and the target lncRNA-based miRNAs and target miRNA-based mRNAs were predicted after irradiation to establish the lncRNA-miRNA-mRNA ceRNA axis., Results: The analyses showed that relative to unirradiated controls, 323 mRNAs, 114 miRNAs, and 472 lncRNAs were significantly up-regulated following irradiation, whereas 1907 mRNAs, 77 miRNAs, and 1572 lncRNAs were significantly down-regulated following irradiation. Voltage-gated ion channels, trans-membrane receptor protein tyrosine kinases, and vascular endothelial growth factor have all been associated with dysregulated miRNA-mRNA relationships. KEGG pathway analysis of the dysregulated miRNA-mRNA targets revealed involvement in pathways associated with the hedgehog signaling pathway-fly, ErbB signaling, VEGF signaling, axon guidance, and focal adhesion. KEGG analysis of differentially expressed showed enrichment of mRNAs in primary immunodeficiency, the intestinal immune axis for IgA production, hematopoietic cell lineages, systemic lupus erythematosus, and Th1 and Th2 cell differentiation. Finally, the ceRNA network revealed that BNIP1 was a critical mRNA modulated by the most significant upregulation of lncRNA E230013L22Rik., Conclusion: In summary, the lncRNA-miRNA-mRNA ceRNA axis of RILI was constructed following irradiation in a mouse model. RNA dysregulation in the early stage of RILI may lead to severe complications at a later stage, with BNIP1 contributing to radiation-induced cellular apoptosis in RILI., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Doxorubicin (DOX), a common chemotherapeutic agent in cancer therapy, is accompanied by pronounced cardiotoxicity. Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity (DIC). Asiatic acid (AA), a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica, displays antioxidant, anti-inflammatory, and antiapoptotic activities. In this study, we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms. A chronic DIC model was established by challenging mice with DOX (5 mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25 mg·kg -1 ·d -1 , i.g.). Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment. We showed that AA administration preserved cardiac function, significantly reduced cardiac injury, and improved cardiomyocyte contractile function in DIC mice. The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro. We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export, in a Nrf2-dependent manner. AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells. Moreover, AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385 (30 mg·kg-1·d-1, i.p.) administrated 30 min before AA in DIC mice. Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC, suggesting its therapeutic potential in the treatment of DIC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

N 6-methyladenosine (m6A) is the most abundant post-transcriptional dynamic RNA modification process in eukaryotes, extensively implicated in cellular growth, embryonic development and immune homeostasis. One of the most profound biological functions of m6A is to regulate RNA metabolism, thereby determining the fate of RNA. Notably, the regulation of m6A-mediated organized RNA metabolism critically relies on the assembly of membraneless organelles (MLOs) in both the nucleus and cytoplasm, such as nuclear speckles, stress granules and processing bodies. In addition, m6A-associated MLOs exert a pivotal role in governing diverse RNA metabolic processes encompassing transcription, splicing, transport, decay and translation. However, emerging evidence suggests that dysregulated m6A levels contribute to the formation of pathological condensates in a range of human diseases, including tumorigenesis, reproductive diseases, neurological diseases and respiratory diseases. To date, the molecular mechanism by which m6A regulates the aggregation of biomolecular condensates associated with RNA metabolism is unclear. In this review, we comprehensively summarize the updated biochemical processes of m6A-associated MLOs, particularly focusing on their impact on RNA metabolism and their pivotal role in disease development and related biological mechanisms. Furthermore, we propose that m6A-associated MLOs could serve as predictive markers for disease progression and potential drug targets in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment., Methods: HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues., Results: ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy., Conclusion: This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions., (© 2024. The Author(s).)

Introduction: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting salivary and lacrimal glands, while endometriosis involves uterine-like tissue growth outside the uterus, causing pelvic pain and infertility. Investigating their intricate relationship using real-world data is crucial due to limited research on their connection., Material and Methods: This population-based cohort study included patients with endometriosis and controls without endometriosis. Propensity score matching was used to balance baseline differences in demographic and clinic characteristics between the two groups. Cox proportional hazards model were used to estimate the effect of endometriosis on the risk of new-onset pSS over time. A symmetrical cohort study, including patients with pSS and propensity score-matched controls without pSS, was conducted to investigate the effect of pSS on the risk of endometriosis over time. To elaborate on the mechanisms linking endometriosis and pSS, Ingenuity Pathway Analysis was performed to identify activated pathways in eutopic endometrium from patients with endometriosis and parotid tissues from patients with pSS., Results: A total of 15 947 patients with endometriosis and 15 947 propensity score-matched controls without endometriosis were included. Patients with endometriosis presented a significantly greater risk of pSS compared to non-endometriosis controls (adjusted hazard ratio, aHR = 1.57, 95% CI = 1.29-1.91, p < 0.001). In the symmetrical cohort study, which included 4906 pSS patients and 4,906 propensity score-matched controls without pSS, patients with pSS were found to be at a significantly higher risk of endometriosis compared to non-pSS controls (aHR = 1.51, 95% CI = 1.12-2.04, p = 0.012). Ingenuity Pathway Analysis showed that the underlying cellular mechanisms involved autoimmune-related pathways, including activation of dendritic cell maturation, and chronic inflammatory pathways, including the fibrosis signaling pathway., Conclusions: These findings support a bidirectional association between endometriosis and pSS, which may be driven by dendritic cell maturation and fibrosis signaling pathways., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Streptococcus spp. are important opportunistic pathogen of bacteremia in both immunocompetent and immunosuppressed patients. A streptococcal strain, designated ST2 T , was isolated from the blood specimen of a bacteremic patient. Comparative analyses of 16S rRNA, rpoB and groEL gene sequences demonstrated that the novel strain ST2 T is a member of the genus Streptococcus. Based on of 16S rRNA gene sequence similarities, the type strains of Streptococcus (S.) parasanguinis (99.2%), S. ilei (98.8%), S. oralis subsp. oralis (97.6%), S. australis (97.5%) and S. sanguinis (97.5%) were the closest neighbours to strain ST2 T . The housekeeping gene sequences (rpoB and groEL) similarities of strain ST2 T to these closely related type strains were 80.4-97.4%, respectively. The complete draft genome of strain ST2 T consisted of 2,155,906 bp with a G + C content of 42.0%. Strain ST2 T has an average nucleotide identity (ANI) value of 94.1 and 81.3% with S. parasanguinis ATCC 15912 T and S. ilei I-G2 T , respectively. The highest in silico DNA-DNA hybridization value with respect to the closest species S. parasanguinis was 55.6%, below the species cut-off of 70% hybridization. The primary cellular fatty acids of strain ST2 T were C 16:0 , C 18:1 ω9c, C 18:0 and C 14:0 . Based on biochemical criteria and molecular genetic evidence, it is proposed that strain ST2 T be assigned to a new species of the genus Streptococcus as Streptococcus taoyuanensis sp. nov. The type strain of Streptococcus taoyuanensis is ST2 T (=NBRC 115928 T  = BCRC 81374 T ) as the type strain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Influenza A virus can infect respiratory tracts and may cause severe illness in humans. Proteins encoded by influenza A virus can interact with cellular factors and dysregulate host biological processes to support viral replication and cause pathogenicity. The influenza viral PA protein is not only a subunit of influenza viral polymerase but also a virulence factor involved in pathogenicity during infection. To explore the role of the influenza virus PA protein in regulating host biological processes, we performed immunoprecipitation and LC‒MS/MS to globally identify cellular factors that interact with the PA proteins of the influenza A H1N1, 2009 pandemic H1N1, and H3N2 viruses. The results demonstrated that proteins located in the mitochondrion, proteasome, and nucleus are associated with the PA protein. We further discovered that the PA protein is partly located in mitochondria by immunofluorescence and mitochondrial fractionation and that overexpression of the PA protein reduces mitochondrial respiration. In addition, our results revealed the interaction between PA and the mitochondrial matrix protein PYCR2 and the antiviral role of PYCR2 during influenza A virus replication. Moreover, we found that the PA protein could also trigger autophagy and disrupt mitochondrial homeostasis. Overall, our research revealed the impacts of the influenza A virus PA protein on mitochondrial function and autophagy., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate macular microperimetry in patients with early primary open angle glaucoma (POAG) using a new custom-made pattern, and analyze the characteristics of macular sensitivity., Methods: This case-control study included 38 patients with POAG, who were divided into pre-perimetric glaucoma (18 eyes of 18 patients), early-stage (20 eyes of 20 patients), and control (20 eyes of 20 patients) groups. All subjects underwent standard 24-2 humphrey visual field test. An MP-3 microperimeter with a new custom-made pattern (28 testing points distributed in four quadrants, covering the central 10° of the retina) was used to evaluate macular sensitivity. Ganglion cell complex (GCC) thicknesses were examined using an RS-3000 Advance OCT system. The features of structure and function were analysed per quadrant., Results: The pre-perimetric glaucoma group had significantly lower inferior hemifield macular sensitivity compared to controls ( P <0.05). The early-stage POAG group had significantly lower average, inferior hemifield, inferonasal, and inferotemporal mean sensitivities compared to the pre-perimetric glaucoma group ( P <0.05), and lower macular sensitivity in all sectors compared to controls ( P <0.05). Regarding GCC thickness, all sectors in the early-stage POAG group became thinner compared to those in controls ( P <0.05); whereas all sectors in the early-stage POAG group, except the superonasal quadrant, became thinner compared to those in the pre-perimetric glaucoma group ( P <0.05). Macular sensitivity and GCC thickness were significantly associated in each sector. The inferotemporal quadrant had the highest correlation coefficients (0.840). The structure-function relationship for the inferonasal and inferotemporal sectors was stronger compared to the corresponding superior sectors., Conclusion: Microperimetry reveals variations in macular sensitivity in patients with early glaucoma earlier than conventional perimetry, particularly in pre-perimetric glaucoma cases in which it might be undetectable by conventional methods. The new custom-made pattern may improve the accuracy of microperimetry by enhancing point arrangement and reducing fatigue effects. Macular sensitivity measured by MP-3 with this pattern shows statistically significant structural and functional associations with the thicknesses of the GCC., Competing Interests: Conflicts of Interest: Liang S, None; Wang LT, None; Liu XL, None; Duan JL, None; Liu DY, None., (International Journal of Ophthalmology Press.)

Polymorphonuclear neutrophils (PMNs), the predominant immune cell type in humans, have long been known as first-line effector cells against bacterial infections mainly through phagocytosis and production of reactive oxygen species (ROS). However, recent research has unveiled novel and pivotal roles of these abundant but short-lived granulocytes in health and disease. Human mesenchymal stromal/stem cells (MSCs), renowned for their regenerative properties and modulation of T lymphocytes from effector to regulatory phenotypes, exhibit complex and context-dependent interactions with PMNs. Regardless of species or source, MSCs strongly abrogate PMN apoptosis, a critical determinant of PMN function, except if PMNs are highly stimulated. MSCs also have the capacity to fine-tune PMN activation, particularly in terms of CD11b expression and phagocytosis. Moreover, MSCs can modulate numerous other PMN functions, spanning migration, ROS production, and neutrophil extracellular trap (NET) formation/NETosis, but directionality is remarkably dependent on the underlying context: in normal nondiseased conditions, MSCs enhance PMN migration and ROS production, whereas in inflammatory conditions, MSCs reduce both these functions and NETosis. Furthermore, the state of the MSCs themselves, whether isolated from diseased or healthy donors, and the specific secreted products and molecules, can impact interactions with PMNs; while healthy MSCs prevent PMN infiltration and NETosis, MSCs isolated from patients with cancer promote these functions. This comprehensive analysis highlights the intricate interplay between PMNs and MSCs and its profound relevance in healthy and pathological conditions, shedding light on how to best strategize the use of MSCs in the expanding list of diseases with PMN involvement., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation., Methods: Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45 - MSCs., Results: Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD + ), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD + , with oral NAD + precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days., Conclusions: We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD + -a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars., (© 2024. The Author(s).)

Background: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known., Methods: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment., Results: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy., Conclusions: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: The association of migraine with the risk of certain cancer has been reported. The aim of this pilot study was to examine the associations between migraine and the onset of head and neck cancers (HNC)., Materials and Methods: A total of 1755 individuals were identified through a nationwide population-based cohort registry in Taiwan between 2000 and 2013. The primary end point variable was new-onset head and neck cancers in patients with migraine versus non-migraine controls. Cox proportional hazard regression was used to derive the risk of HNC. Subgroup analyses were performed to determine subpopulations at risk of migraine-associated HNC. Sub-outcome analyses were carried out to provide the subtypes of migraine-associated HNC. Propensity score matching was utilized to validate the findings., Results: A total of four patients out of 351 patients with migraine and seven out of 1404 non-migraine controls developed HNC. The incidence of HNC was higher in patients with migraine than that in non-migraine controls (108.93 vs. 48.77 per 100,000 person-years) (adjusted hazard ratio, aHR = 2.908, 95% CI = 0.808-10.469; p = 0.102). The risk of HNC in patients with migraine with aura (aHR = 5.454, 95% CI = 0.948-26.875; p = 0.264) and without aura (aHR = 2.777, 95% CI = 0.755-8.473; p = 0.118) was revealed. The incidence of non-nasopharyngeal HNC secondary to migraine (112.79 per 100,000 person-years) was higher than that of nasopharyngeal cancer secondary to migraine (105.33 per 100,000 person-years)., Conclusion: A higher incidence of HNC was observed in a small sample of patients with migraine, especially in those with migraine with aura. Migraine-associated HNC included non-nasopharyngeal HNC. Studies with a larger sample are needed to confirm the finding of the high risk of HNC in people with migraine., (© 2023 Wiley Periodicals LLC.)

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration., Competing Interests: The authors declare no conflict of interest., (© 2024, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.

Diclofenac (DCF) is a widely-used nonsteroidal anti-inflammatory drug that is routinely found in surface water bodies. While ozonation and ultraviolet (UV) radiation are commonly employed as disinfection methods in water treatment processes, the degradation of DCF in these processes occurs due to the strong oxidizing activity of the reactive oxygen species produced during both ozonation and UV radiation. Despite extensive studies reporting the removal and transformation of DCF through ozone and UV treatments, the potential hidden hazards of toxicity arising from these processes as well as the identification of the toxic transformation products have often been overlooked. In this study, various toxicities including microtoxicity, genotoxicity and antiestrogenicity were evaluated using multiple in-vitro bioassays. The transformation products were identified via ultra-performance liquid chromatography equipped with mass spectrometry (UPLC-MS). Correlation analysis was employed to gain deeper insight into the contributions of degradation products to overall toxicity. The results revealed that DCF possessed significant genotoxic and antiestrogenic effects, but displayed minimal microtoxicity. Microtoxic products such as those containing carbazole were generated during DCF degradation with ozone, UVA and UVC. Antiestrogenic products with dichloroaniline structures were observed in DCF ozonation but not in photodegradation by UVA and UVC. These findings highlighted the hidden risks associated with the disinfection of water containing micropollutants such as DCF., 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 Ltd. All rights reserved.)

Objective: This study aimed to examine the effects of semi-immersive virtual reality (VR)-based exercise on the quality of life of older adults., Methods: It used a randomized controlled trial design. Older adults (mean age: 72.16 ± 4.9 years) were randomly assigned to experimental ( n  = 48) and control ( n  = 50) groups. The experimental group engaged in semi-immersive VR exercise for 75-90 min, twice a week, for 12 weeks and partook in no other intervention between the end of the exercise intervention and follow-up. Control group members did not participate in any similar program during the intervention or follow-up periods. Both groups completed three assessments: at baseline (pre-test), post-intervention (post-test), and 3 months later (follow-up). Quality of life was assessed using the World Health Organization Quality of Life Instrument-Older Adults Module., Results: Generalized estimating equation analyses indicated that the experimental group exhibited significant post-intervention improvements in quality of life in terms of sensory ability, autonomy, social participation/isolation, death and dying domain, and overall quality of life scores. However, none of these significant effects were maintained 3 months after exercise intervention cessation., Conclusions: Semi-immersive VR exercise may be a feasible strategy toward enhancing the quality of life of older adults. However, the participants' quality of life was not maintained upon exercise cessation, indicating that older adults need to be encouraged to exercise regularly to maintain a good quality of life. VR may need to be combined with other modes of intervention in the future to facilitate long-term quality-of-life improvement in older adults., Competing Interests: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Hepatitis B virus (HBV) infection significantly impacts Asian populations. The influences of continuous HBV antigen and inflammatory stimulation to T cells in chronic hepatitis B (CHB) remain unclear. In this study, we first conducted bioinformatics analysis to assess T-cell signaling pathways in CHB patients. In a Taiwanese cohort, we examined the phenotypic features of HBV core -specific T cells and their correlation with clinical parameters. We used core protein overlapping peptides from the Taiwan prevalent genotype B HBV to investigate the antiviral response and the functional implication of HBV-specific T cells. In line with Taiwanese dominant HLA-alleles, we also evaluated ex vivo HBV core -specific T cells by pMHC-tetramers targeting epitopes within HBV core protein. Compared to healthy subjects, we disclosed CD8 T cells from CHB patients had higher activation marker CD38 levels but showed an upregulation in the inhibitory receptor PD-1. Our parallel study showed HBV-specific CD8 T cells were more activated with greater PD-1 expression than CMV-specific subset and bulk CD8 T cells. Moreover, our longitudinal study demonstrated a correlation between the PD-1 fluctuation pattern of HBV core -specific CD8 T cells and liver inflammation in CHB patients. Our research reveals the HBV core antigen-mediated immunopathologic profile of CD8 T cells in chronic HBV infection. Our findings suggest the PD-1 levels of HBV core -specific CD8 T cells can be used as a valuable indicator of personal immune response for clinical application in hepatitis management., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Incarceration of the appendix within a femoral hernia is a rare condition of abdominal wall hernia about 0.1 to 0.5% in reported femoral hernia [1]. We report a case of a 56-year-old female whose appendix was trapped in the right femoral canal. There are few reports in the literature on entrapment of the appendix within a femoral hernia. The management of this condition includes antibiotics, drainage appendectomy, hernioplasty and mesh repair., (© 2024. The Author(s).)

Ubiquitination is a type of post-translational modification that covalently links ubiquitin to a target protein, which plays a critical role in modulating protein activity, stability, and localization. In contrast, this process is reversed by deubiquitinases (DUBs), which remove ubiquitin from ubiquitinated substrates. Dysregulation of DUBs is associated with several human diseases, such as cancer, inflammation, neurodegenerative disorders, and autoimmune diseases. Thus, DUBs have become promising targets for drug development. Although the physiological and pathological effects of DUBs are increasingly well understood, the clinical drug discovery of selective DUB inhibitors has been challenging. Herein, we summarize the structures and functions of main classes of DUBs and discuss the recent progress in developing selective small-molecule DUB inhibitors as antitumor agents., 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 Masson SAS. All rights reserved.)

The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47. Genetic ablation of FILIP1L in FAPs abolishes the effects of exercise or Musclin on FAPs and the benefits on the reduction of fibrosis and fatty infiltration. Overall, exercise forms a microenvironment of myokines in muscle and prevents the abnormal accumulation of FAPs in a Musclin/FILIP1L-dependent manner. The administration of exogenous Musclin exerts a therapeutic effect, demonstrating a potential therapeutic approach for muscle atrophy or acute muscle injury., Competing Interests: Declaration of interests The authors declare competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interests There are no competing interests to disclose.

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Extreme heat exposure is a growing health problem, and the effects of heat on the gastrointestinal (GI) tract is unknown. This study aimed to assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes., Aim: To assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes., Methods: Patients admitted to the intensive care unit (ICU) due to heatstroke were included from 83 centres. Patient history, laboratory results, and clinically relevant outcomes were recorded at ICU admission and daily until up to day 15, ICU discharge, or death. GI symptoms, including nausea/vomiting, diarrhoea, flatulence, and bloody stools, were recorded. The characteristics of patients with heatstroke concomitant with GI symptoms were described. Multivariable regression analyses were performed to determine significant predictors of GI symptoms., Results: A total of 713 patients were included in the final analysis, of whom 132 (18.5%) patients had at least one GI symptom during their ICU stay, while 26 (3.6%) suffered from more than one symptom. Patients with GI symptoms had a significantly higher ICU stay compared with those without. The mortality of patients who had two or more GI symptoms simultaneously was significantly higher than that in those with one GI symptom. Multivariable logistic regression analysis revealed that older patients with a lower GCS score on admission were more likely to experience GI symptoms., Conclusion: The GI manifestations of heatstroke are common and appear to impact clinically relevant hospitalization outcomes., 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.)

To investigate the characteristics, source apportionment, and potential source areas of carbonaceous aerosols in Chongqing during winter, PM 2.5 samples were collected from January 2021 to February 2021 in the urban areas of Wanzhou (WZ), Yubei (YB), and Shuangqiao (SQ). The results showed that the average mass concentrations of PM 2.5 , OC, and EC in SQ were (72.6 ±33.3), (18.2 ±8.2), and (4.4 ±1.7) μg·m -3 , respectively, higher than those in WZ[(67.2 ±30.3), (17.2 ±7.4), and (5.1 ±2.4) μg·m -3 ] and YB[(63.4 ±25.7), (15.4 ±6.3), and (4.2 ±1.9) μg·m -3 ]. Compared with that during the clear period, the concentration and fraction of EC in total carbon increased by 103.0% and 8.1%, respectively, in WZ compared to that in other areas during pollution period, whereas the OC/EC ratio was decreased significantly (-10.5%), indicating that the primary emission of carbonaceous aerosols increased significantly during the pollution period. The average mass concentrations of secondary organic carbon (SOC) in SQ and YB were (7.7 ±4.8) μg·m -3 and (6.9 ±2.8) μg·m -3 significantly higher, respectively, than that in WZ[(4.5 ±1.9) μg·m -3 ] during the campaign. This indicated that the secondary transformation had a greater influence on the carbonaceous aerosols in SQ and YB than that in WZ. Furthermore, in contrast to that in WZ, the ratios of SOC/OC were increased with the increase in PM 2.5 concentrations, and significant correlations between SOC concentration and aerosol water content, NO 2 concentration, and the value of NOR were observed in SQ and YB ( P &lt; 0.01), indicating that the increasing of carbonaceous aerosol concentrations might be mainly driven by the SOC with -NO 2 groups produced by aqueous chemical reactions during winter in SQ and YB. The positive definite matrix factor (PMF) results in these urban areas showed that the contribution of biomass/coal combustion source in WZ (47.4%) was significantly higher than that in YB (34.2%) and SQ (38.1%), whereas the gasoline motor vehicle emission and secondary transformation impacts were more significant in YB. The results of the concentration weighted trajectory (CWT) showed that the potential sources of carbonaceous aerosols were mainly the local and northeastern parts of these urban areas (such as Changshou).

Pulmonary infection is highly prevalent in patients with acute myocardial infarction undergoing percutaneous coronary intervention. However, the potential mechanism is not well characterized. Myocardial ischemia-reperfusion injury (MIRI) induces acute lung injury (ALI) related to pulmonary infection and inflammation. Recent studies have shown that pyroptosis mediates ALI in several human respiratory diseases. It is not known whether MIRI induces pyroptosis in the lungs. Furthermore, ticagrelor is a clinically approved anti-platelet drug that reduces ALI and inhibits the expression levels of several pyroptosis-associated proteins, but the effects of ticagrelor on MIRI-induced ALI have not been reported. Therefore, we investigated whether ticagrelor alleviated ALI in the rat MIRI model, and its effects on pyroptosis in the lungs. Sprague-Dawley rats were randomly divided into four groups: control, MIRI, MIRI plus low ticagrelor (30 mg/kg), and MIRI plus high ticagrelor (100 mg/kg). Hematoxylin and Eosin (HE) staining was performed on the lung sections, and the HE scores were calculated to determine the extent of lung pathology. The wet-to-dry ratio of the lung tissues were also determined. The expression levels of pyroptosis-related proteins such as NLRP3, ASC, and Cleaved caspase-1 were estimated in the lung tissues using the western blot. ELISA was used to estimate the IL-1β levels in the lungs. Immunohistochemistry was performed to determine the levels of MPO-positive neutrophils as well as the total NLRP3-positive and Cleaved caspase-1-positive areas in the lung tissues. The lung tissues from the MIRI group rats showed significantly higher HE score, wet-to-dry ratio, and the MPO-positive area compared to the control group, but these effects were attenuated by pre-treatment with ticagrelor. Furthermore, lung tissues of the MIRI group rats showed significantly higher expression levels of pyroptosis-associated proteins, including NLRP3 (2.1-fold, P < 0.05), ASC (3.0-fold, P < 0.01), and Cleaved caspase-1 (9.0-fold, P < 0.01). Pre-treatment with the high-dose of ticagrelor suppressed MIRI-induced upregulation of NLRP3 (0.46-fold, P < 0.05), ASC (0.64-fold, P < 0.01), and Cleaved caspase-1 (0.80-fold, P < 0.01). Immunohistochemistry results also confirmed that pre-treatment with ticagrelor suppressed MIRI-induced upregulation of pyroptosis in the lungs. In summary, our data demonstrated that MIRI induced ALI and upregulated pyroptosis in the rat lung tissues. Pre-treatment with ticagrelor attenuated these effects., Competing Interests: The authors declare that they have no competing interests., (© 2024 Dai et al.)

Purpose: Hepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence., Methods: This is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model., Results: Among the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival., Conclusion: Combined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Although great progress has been made in anti-cancer therapy, the prognosis of laryngeal squamous cell carcinoma (LSCC) patients remains unsatisfied. Quantities of studies demonstrate that glycolytic reprograming is essential for the progression of cancers, where triosephosphate isomerase 1 (TPI1) serves as a catalytic enzyme. However, the clinicopathological significance and potential biological functions of TPI1 underlying LSCC remains obscure., Methods: We collected in-house 82 LSCC tissue specimens and 56 non-tumor tissue specimens. Tissue microarrays (TMA) and immunohistochemical (IHC) experiments were performed. External LSCC microarrays and bulk RNA sequencing data were integrated to evaluate the expression of TPI1. We used a log-rank test and the CIBERSORT algorithm to assess the prognostic value of TPI1 and its association with the LSCC microenvironment. Malignant laryngeal epithelial cells and immune-stromal cells were identified using inferCNV and CellTypist. We conducted a comprehensive analysis to elucidate the molecular functions of TPI1 in LSCC tissue and single cells using Pearson correlation analysis, high dimensional weighted gene co-expression analysis, gene set enrichment analysis, and clustered regularly interspaced short palindromic repeats (CRISPR) screen. We explored intercellular communication patterns between LSCC single cells and immune-stromal cells and predicted several therapeutic agents targeting TPI1., Results: Based on the in-house TMA and IHC analysis, TPI1 protein was found to have a strong positive expression in the nucleus of LSCC cells but only weakly positive activity in the cytoplasm of normal laryngeal cells (p < 0.0001). Further confirmation of elevated TPI1 mRNA expression was obtained from external datasets, comparing 251 LSCC tissue samples to 136 non-LSCC tissue samples (standardized mean difference = 1.06). The upregulated TPI1 mRNA demonstrated a high discriminative ability between LSCC and non-LSCC tissue (area under the curve = 0.91; sensitivity = 0.87; specificity = 0.79), suggesting its potential as a predictive marker for poor prognosis (p = 0.037). Lower infiltration abundance was found for plasma cells, naïve B cells, monocytes, and neutrophils in TPI-high expression LSCC tissue. Glycolysis and cell cycle were significantly enriched pathways for both LSCC tissue and single cells, where heat shock protein family B member 1, TPI1, and enolase 1 occupied a central position. Four outgoing communication patterns and two incoming communication patterns were identified from the intercellular communication networks. TPI1 was predicted as an oncogene in LSCC, with CRISPR scores less than -1 across 71.43% of the LSCC cell lines. TPI1 was positively correlated with the half maximal inhibitory concentration of gemcitabine and cladribine., Conclusions: TPI1 is dramatically overexpressed in LSCC than in normal tissue, and the high expression of TPI1 may promote LSCC deterioration through its metabolic and non-metabolic functions. This study contributes to advancing our knowledge of LSCC pathogenesis and may have implications for the development of targeted therapies in the future., (© 2023. The Author(s).)

Current HIV vaccines designed to stimulate CD8 + T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8 + T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8 + T cell response may require a vaccination strategy that drives further TCR clonal selection.

The protective roles of extracellular vesicles derived from human umbilical cord mesenchymal stem cells against oxazolone-induced damage in the immortalized human keratinocyte cell line HaCaT were investigated. The cells were pretreated with or without UCMSC-derived extracellular vesicles 24 h before oxazolone exposure. The pretreated UVMSC-EVs showed protective activity, elevating cell viability, reducing intracellular ROS, and reducing the changes in the mitochondrial membrane potential compared to the cells with a direct oxazolone treatment alone. The UCMSC-EVs exhibited anti-inflammatory activity via reducing the inflammatory cytokines IL-1β and TNF-α. A mechanism study showed that the UCMSC-EVs increased the protein expression levels of SIRT1 and P53 and reduced P65 protein expression. It was concluded that UVMSC-EVs can induce the antioxidant defense systems of HaCaT cells and that they may have potential as functional ingredients in anti-aging cosmetics for skin care.

Introduction: This study aimed to explore the impact of gonadotropin-releasing hormone agonists (GnRHa) on final adult height (FAH) in girls with early and fast puberty., Methods: A retrospective study was conducted by reviewing data from the medical records of the Pediatric Endocrinology Clinics between January 1, 2010, and December 31, 2020, at MacKay Children's Hospital. The treatment group included 109 patients who received 3.75 mg monthly for at least 1 year, whereas the control group consisted of 95 girls who received no treatment., Results: The treatment group was significantly older at the time of inclusion(chronological age (CA1), treatment vs. control, 8.7 vs. 8.4 years, p < 0.001), had a more advanced bone age (BA) (BA1, 11.5 vs. 10.8 years, p < 0.001), BA1-CA1 (2.7 vs. 2.2 years, p < 0.001), and shorter predicted adult height (PAH1) (153.3 vs. 157.1 cm, p = 0.005) that was significantly lower than their target height (Tht)(PAH1-Tht, -3.9 vs. -1.3 cm, p = 0.039). The FAHs of the GnRHa and the control group were similar (157.0 vs. 156.7 cm, p = 0.357) and were not significantly different from their Tht (FAH vs. Tht in the GnRHa group, 157.0 vs. 157.0 cm; control group, 156.7 vs. 157.0 cm). In the subgroup analysis, FAH was significantly higher after GnRHa treatment in those with PAH1 less than 153 cm and Tht (154.0 vs. 152.0 cm, p = 0.041), and those whose CA1 was between 8 and 9 years (158.0 vs. 155.4 cm, p = 0.004). We defined satisfactory FAH outcome as FAH-PAH1≥5 cm and significant factors were GnRHa therapy, PAH1 shorter than their Tht, age younger than 9 years, and faster growth velocity during the first year., Discussion: GnRHa is effective in restoring the Tht in some early and fast pubertal girls, especially in those with poorly PAH (PAH lower than 153 cm and shorter than their target height). A younger age at initiation of treatment and a faster growth velocity during treatment are associated with a better height gain., 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 © 2023 Tseng, Lee, Huang, Wu, Wang, Lin, Cheng, Lo, Chang and Ting.)

Background: RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown., Methods: A phase 1b, single-center, dose-escalation, age-de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania (NCT03435874). Between 12 th April and 25 th October 2018, 63 healthy adults (18-35 years), young children (1-6 years), and infants (6-11 months) received a priming dose of viral-vectored ChAd63 RH5 or rabies control vaccine. Sixty participants were boosted with modified vaccinia virus Ankara (MVA) RH5 or rabies control vaccine 8 weeks later and completed 6 months of follow-up post priming. Primary outcomes were the number of solicited and unsolicited adverse events post vaccination and the number of serious adverse events over the study period. Secondary outcomes included measures of the anti-RH5 immune response., Findings: Vaccinations were well tolerated, with profiles comparable across groups. No serious adverse events were reported. Vaccination induced RH5-specific cellular and humoral responses. Higher anti-RH5 serum immunoglobulin G (IgG) responses were observed post boost in young children and infants compared to adults. Vaccine-induced antibodies showed growth inhibition activity (GIA) in vitro against P. falciparum blood-stage parasites; their highest levels were observed in infants., Conclusions: The ChAd63-MVA RH5 vaccine shows acceptable safety and reactogenicity and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in RH5-vaccinated infants are the highest reported to date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines to protect against clinical malaria in young African infants., Funding: Medical Research Council, London, UK., Competing Interests: Declaration of interests S.J.D. is a named inventor on patent applications relating to RH5 malaria vaccines and adenovirus-based vaccines, is an inventor on intellectual property licensed by Oxford University Innovation to AstraZeneca, and has been a consultant to GSK on malaria vaccines. A.M.M. has been a consultant to GSK on malaria vaccines, has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and adenovirus-based vaccines, and is an inventor on intellectual property licensed by Oxford University Innovation to AstraZeneca., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Declaration of competing interests There are no competing interests to disclose.