Objective To investigate the effects of Echinococcus multilocularis infection on levels of memory T (Tm) cells and their subsets in lymph nodes of mice at different stages of infection, so as to provide new insights into immunotherapy for alveolarechinococcosis. MethodsTwenty-four C57BL/6J mice aged 6 to 9 weeks were randomly divided into the infection group and the control group, of 12 mice in each group. Mice in the infection group were administered with 3 000 E. multilocularis protoscoleces via portal venous injection, while animals in the control group were administered with an equal volume of physiological saline. Three mice from each group were sacrificed 4, 12 weeks and 24 weeks post-infection, and lymph nodes were sampled and stained with hematoxylin and eosin (HE) to investigate the histopathological changes of mouse lymph nodes in the infection group. The expression and localization of T lymphocyte surface markers CD3, CD4, and CD8 were observed in mouse lymph nodes using immunohistochemical staining. In addition, lymphocyte suspensions were prepared from mouse lymph nodes in both groups at different time points post-infection, and the levels of Tm cell subsets and their secreted cytokines were detected using flow cytometry. Results HE staining showed diffuse structural alterations in the subcapsular cortical and paracortical regions of mouse lymph nodes in the infection group 4 weeks post-infection with E. multilocularis. Immunohistochemical staining detected CD3, CD4 and CD8 expression in mouse lymph nodes in both groups. Flow cytometry revealed higher proportions of CD4⁺ Tm cells [(55.3 ± 4.8)% vs. (38.8 ± 6.1)%; t = -4.259, P < 0.05] and CD4⁺ tissue-resident Tm (Trm) cells [(57.7 ± 3.7)% vs. (34.1 ± 11.2)%; t = -3.990, P < 0.05] in mouse lymph nodes in the infection group than in the control group 4 weeks post-infection, and higher proportions of CD4⁺ Tm cells [(34.6 ± 3.2)% vs. (23.3 ± 7.5)%; t = -2.764, P < 0.05] and CD4⁺ Trm cells [(44.0 ± 1.9)% vs. (31.2 ± 1.5)%; t = -4.039, P < 0.05] in mouse lymph nodes in the infection group than in the control group 24 weeks post-infection. The proportions of CD8⁺ Tm cells were higher in the infection group than in the control group 4 weeks [(56.8 ± 2.7)% vs. (43.9 ± 5.2)%; t = -4.416, P < 0.01] and 12 weeks post-infection [(25.4 ± 2.7)% vs. (12.0 ± 2.6)%; t = -2.552, P < 0.05], while the proportions of tumor necrosis factor (TNF)-α⁺ CD4⁺ T cells [(15.7 ± 5.0)% vs. (49.4 ± 6.4)%; t = 7.150, P < 0.01], TNF-α⁺CD8⁺ T cells [(20.7 ± 5.5)% vs. (57.5 ± 8.4)%; t = -6.694, P < 0.01], and TNF-α⁺ CD8⁺ Tm cells [7.0% (1.0%) vs. 31.0% (11.0%); Z = -2.236, P < 0.05] were lower in the infection group than in the control group 24 weeks post-infection. Conclusions Tm cells levels are consistently increased in lymph nodes of mice at different stages of E. multilocularis infection, with Trm cells as the predominantly elevated subset. The impaired capacity of CD8⁺ Tm cells to secrete the effector molecule TNF-α in mouse lymph nodes at the late-stage infection may facilitate chronic parasitism of E. multilocularis.

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators. Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),anti-infective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group. Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-α and IL-6 may partake the inflammatory process of DILI.

Objective:Renal involvement in primary Sjogren′s syndrome (pSS) has been considered rare, and recent studies have shown that there was a large difference in the prevalence of the disease, which has been reported to range from 0.03% to 67%. The meta-analysis was to determine the prevalence of renal involvement in pSS patients.Methods:The study on pSS renal involvement was conducted in Pubmed, Embase and Cochrane Library from January 2002 to May 2019. After logarithmic conversion of the prevalence rate, meta-analysis of random effect model was carried out to explore the prevalence of pSS renal involvement. Subgroup analysis and meta regression analysis were used to explore the source of heterogeneity. We also performed sensitivity analysis and assessments of publication bias by Begger′s test.Results:The meta-analysis included eighteen observational studies of 8 888 participants. The result in random effects model showed that the combined prevalence was 9.0% (95% CI: 6.0%-12.0%), with significant heterogeneity between these studies ( I2=97%, P<0.01). The source of heterogeneity was explained by a stratified analysis of region, type of study, and the diagnostic criteria for renal involvement. Sensitivity analysis showed that the result was robust and Begger′s test did not detect the presence of publication bias. Conclusions:The prevalence of renal involvement in pSS is 9.0%. Due to huge heterogeneity, large multicenter prospective studies will be needed to determine its prevalence and the relationship between pSS and kidney.

Urethral plate (UP)-preserving urethroplasty is simple and has few complications, but it may affect the development of penis in the long term and lead to recurrent chordee. In this study, we used obliquely cut UP to repair hypospadias with mild chordee after degloving (15°-30°) and compared the results with onlay urethroplasty to explore its rationality and feasibility. Between April 2018 and October 2020, 108 hypospadias patients underwent onlay urethroplasty or modified onlay urethroplasty. Clinical data were prospectively collected, and medium-term outcomes were assessed at follow-up. The complications were compared between the two groups. Forty-four patients underwent the modified onlay procedure (Group I), with follow-up time (mean ± standard deviation [s.d.]) of 23.2 ± 4.5 (range: 17-31) months. Sixty-four patients underwent a standard onlay procedure (Group II), with follow-up time (mean ± s.d.) of 39.7 ± 3.9 (range: 32-46) months. There was no difference in age at surgery. The urethral defect length and operative time were longer in Group I. Six cases of fistula and one case each of stricture and diverticulum were reported in Group I. In Group II, 11 cases of fistula and one case each of stricture and diverticulum were reported. The complication rates were 18.2% and 20.3% in Group I and Group II, respectively (P > 0.05). These medium-term follow-up results demonstrate that the modified onlay procedure (oblique cut UP urethroplasty) is a safe and feasible technique for hypospadias with mild chordee after degloving. Compared with standard onlay urethroplasty, this modified procedure is conducive to the complete removal of scar tissue underlying the UP without increasing the risk of surgical complications.
Male ; Humans ; Infant ; Hypospadias/surgery* ; Cicatrix/surgery* ; Constriction, Pathologic/surgery* ; Urethra/surgery* ; Diverticulum ; Urologic Surgical Procedures, Male/methods* ; Treatment Outcome

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gαq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting Gαq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gαq/11 inhibitors, and identified GQ262 with improved Gαq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase (ERK), and yes-associated protein (YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gαq/11 directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gαq/11 may be an efficient strategy against uveal melanoma.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by thrombotic or obstetrical events and persistent antiphospholipid antibodies (aPLs). Chemokine-like factor-like MARVEL transmembrane domain-containing family (CMTM) is widely expressed in the immune system and may closely related to APS. This review aimed to systematically summarize the possible effects of CMTM on APS. Publications were collected from PubMed and Web of Science databases up to August 2020. CKLF, CKLFSF, CMTM, antiphospholipid syndrome, immune cells, and immune molecules were used as search criteria. Immune cells, including neutrophil, dendritic cells (DCs), T-cells, B-cells, and inflammatory cytokines, play an important role in the development of APS. Chemokine-like factor 1 (CKLF1) has a chemotactic effect on many cells and can affect the expression of inflammatory cytokines and adhesion molecules through the nuclear factor- kB (NF- kB) pathway or mitogen-activated protein kinase (MARK) pathway. CKLF1 can participate in the maturation of DCs, T lymphocyte activation, and the activation of neutrophils through the MAPK pathway. CMTM1 may act on Annexin A2 by regulating Ca 2+ signaling. CMTM2 and CMTM6 are up-regulated in neutrophils of APS patients. Some CMTM family members influence the activation and accumulation of platelets. CMTM3 and CMTM7 are binding partners of B-cell linker protein (BLNK), thereby linking B cell receptor (BCR) and activating BLNK-mediated signal transduction in B cells. Moreover, CMTM3 and CMTM7 can act on DCs and B-1a cell development, respectively. CMTM may have potential effects on the development of APS by acting on immune cells and immune molecules. Thus, CMTM may act as a novel prognostic factor or immunomodulatory treatment option of APS.

Objective To evaluate the survival and prognostic factors of esophageal cancer treated with definitive ( chemo ) radiotherapy by applying novel radiation techniques including three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT). Methods Clinical data of 2762 patients with non-operated esophageal squamous cell carcinoma who underwent definitive ( chemo ) radiotherapy from 2002 to 2016 in 10 hospitals were retrospectively analyzed.The prognostic factors were also identified and analyzed. Results The median follow-up time was 60. 8 months. The 1-, 2-, 3-and 5-year overall survival (OS) of all patients was 71. 4％,48. 9％,39. 3％,and 30. 9％,respectively.The 1-,2-,3-and 5-year progression-free survival (PFS) was 59.5％,41.5％,35.2％,and 30％,respectively.The median survival was 23 months.The median time to progression was 17. 2 months.Multivariate analysis demonstrated that age, primary tumor location, clinical stage, tumor target volume, EQD2 and treatment mode were the independent prognostic factors for OS.Primary tumor location,clinical stage,tumor target volume and EQD2 were the independent prognostic factors for PFS. Conclusions In this first large-scale multi-center retrospective analysis of definitive ( chemo) radiotherapy for esophageal squamous cell carcinoma in China, the 5-year OS of patients with esophageal squamous cell carcinoma is significantly improved by 3DCRT, IMRT combined with chemotherapy drugs. However, the findings remain to be validated by prospective clinical trials with high-level medical evidence.

Sperm DNA damage is recognized as an important biomarker of male infertility. To investigate this, sperm DNA damage was assessed by the sperm chromatin dispersion (SCD) test in semen and motile spermatozoa harvested by combined density gradient centrifugation (DGC) and swim-up in 161 couples undergoing in vitro fertilization (IVF). Semen analysis and sperm DNA damage results were compared between couples who did or did not achieve pregnancy. The sperm DNA damage level was significantly different between the two groups (P < 0.05) and was negatively correlated with IVF outcomes. Logistic regression analysis confirmed that it was an independent predictor for achieving clinical pregnancy. The effects of different levels of sperm DNA damage on IVF outcomes were also compared. There were significant differences in day 3 embryo quality, blastocyst formation rate, and implantation and pregnancy rates (P < 0.05), but not in the basic fertilization rate between the two groups. Thus, sperm DNA damage as measured by the SCD appears useful for predicting the clinical pregnancy rate following IVF.
Adult ; Chromatin/chemistry* ; DNA Damage ; Embryo Implantation ; Embryonic Development ; Female ; Fertilization in Vitro ; Humans ; Male ; Predictive Value of Tests ; Pregnancy ; Pregnancy Outcome ; Pregnancy Rate ; Semen Analysis ; Sperm Injections, Intracytoplasmic ; Sperm Motility ; Spermatozoa/ultrastructure*