Characteristics and functions of memory regulatory T cells in normal pregnancy cycle and pregnancy complications.

Regulatory T cells (Tregs) are activated and expanded after exposure to fetal-specific (paternal) antigens. A proportion of Tregs differentiate into memory Tregs (mTregs), exhibiting immune memory function and exerting more potent immunosuppression than naive Tregs (nTregs). However, it is unclear how mTregs are regulated during normal and pathological pregnancies (e.g., gestational diabetes mellitus (GDM) and preeclampsia (PE)). In this study, PD-1, HLA-G, and HLA-DR expressions on memory CD4+ T cells, naive CD4+ T cells, Tregs, mTregs, and nTregs in healthy non-pregnant women (n=20), healthy first (n=20), second (n=20), and third-trimester women (n=20), postpartum women (n=20), GDM (n=20), and PE patients (n=20) were analyzed. The proportion of mTregs out of Tregs was increased (P<0.05) in the first trimester compared with that in non-pregnancy and reduced in the second and third trimesters. The proportions of PD-1+ Tregs and mTregs were significantly increased during the first trimester compared to those of non-pregnancy (P<0.01), reached their maximum in the second trimester. Moreover, the proportions of HLA-G+ memory CD4+ T cells, Tregs, and mTregs were increased in the first and second trimesters (P<0.01), reached their maximum in the third trimester. GDM patients were characterized by significantly lower percentages of PD-1+ and HLA-G+ mTregs (P<0.01), while PE patients were characterized by significantly lower percentages of HLA-G+ mTregs (P<0.01), compared with the healthy third-trimester women. In general, as demonstrated by this study, mTregs increase in number and enhance maternal-fetal immunoregulation during pregnancy, and their dysfunction can result in pregnancy complications such as GMD or PE.

Memory regulatory T cells in pregnancy.

Pregnancy requires the process of maternal immune tolerance to semi-allogeneic embryos. In contrast, an overreactive maternal immune system to embryo-specific antigens is likely to result in the rejection of embryos while damaging the invading placenta, such that the likelihood of adverse pregnancy outcomes can be increased. Regulatory T cells (Tregs) are capable of suppressing excessive immune responses and regulating immune homeostasis. When stimulating Tregs, specific antigens will differentiate into memory Tregs with long-term survival and rapid and powerful immune regulatory ability. Immunomodulatory effects mediated by memory Tregs at the maternal-fetal interface take on critical significance in a successful pregnancy. The impaired function of memory Tregs shows a correlation with various pregnancy complications (e.g., preeclampsia, gestational diabetes mellitus, and recurrent pregnancy losses). However, the differentiation process and characteristics of memory Tregs, especially their role in pregnancy, remain unclear. In this study, a review is presented in terms of memory Tregs differentiation and activation, the characteristics of memory Tregs and their role in pregnancy, and the correlation between memory Tregs and pregnancy complications. Furthermore, several potential therapeutic methods are investigated to restore the function of memory Tregs in accordance with immunopathologies arising from memory Tregs abnormalities and provide novel targets for diagnosing and treating pregnancy-associated diseases.

Evaluation of the quality and reliability of anal cancer and its precancerous lesions-related content on YouTube: a cross-sectional study.

OBJECTIVES: This research aims at evaluating the quality of anal cancer and its precancerous lesions-related videos on YouTube. DESIGN: Cross-sectional survey design. SETTING: USA. PARTICIPANTS: The top 150 videos on YouTube were selected for analysis based on three search terms. The duplicate, irrelevant, commercial, operation-related and audio-free videos were excluded. Finally, 105 relevant videos were included. METHODS: We assessed the completeness of video content from six dimensions and marked the men having sex with men (MSM)-related videos. To measure the video quality, DISCERN, Journal of the American Medical Association (JAMA) Benchmark Criteria, Patient Education Materials Assessment Tool (PEMAT) and Global Quality Scale (GQS) were used. The correlation between DISCERN classification and duration, JAMA, PEMAT and GQS scores were recorded. RESULTS: The video content was mainly about the management of the disease (mean score 1.086). Overall, the quality of videos uploaded by the non-profit organisation was relatively high. A correlation existed between each other of the JAMA, DISCERN and GQS scores (p<0.001). Moreover, they were positively correlated with video duration and PEMAT scores (p<0.001). CONCLUSIONS: Although the overall quality of information about anal cancer and its precancerous lesions videos on YouTube is acceptable, it might not fully meet the health information needs of patients. Therefore, they should exercise caution when using YouTube as a source of anal cancer-related information, especially the MSM population.

Immune checkpoint inhibitors and reproductive failures.

The human conceptus is a semi-allograft, which is antigenically foreign to the mother. Hence, the implantation process needs mechanisms to prevent allograft rejection during successful pregnancy. Immune checkpoints are a group of inhibitory pathways expressed on the surface of various immune cells in the form of ligand receptors. Immune cells possess these pathways to regulate the magnitude of immune responses and induce maternal-fetal tolerance. Briefly, 1) CTLA-4 can weaken T cell receptor (TCR) signals and inhibit T cell response; 2) The PD-1/PD-L1 pathway can reduce T cell proliferation, enhance T cell anergy and fatigue, reduce cytokine production, and increase T regulatory cell activity to complete the immunosuppression; 3) TIM3 interacts with T cells by binding Gal-9, weakening Th1 cell-mediated immunity and T cell apoptosis; 4) The LAG-3 binding to MHC II can inhibit T cell activation by interfering with the binding of CD4 to MHC II, and; 5) TIGIT can release inhibitory signals to NK and T cells through the ITIM structure of its cytoplasmic tail. Therefore, dysregulated immune checkpoints or the application of immune checkpoint inhibitors may impair human reproduction. This review intends to deliver a comprehensive overview of immune checkpoints in pregnancy, including CTLA-4, PD-1/PD-L1, TIM-3, LAG-3, TIGIT, and their inhibitors, reviewing their roles in normal and pathological human pregnancies.

The Clinical Characteristics and Prognostic Factors of Primary Extramammary Paget's Disease Treated with Surgery in Anogenital Regions: A Large Population Study from the SEER Database and Our Centre.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant cutaneous tumour that is commonly located in anogenital regions. The diagnosis of the disease is always delayed, and treatment is usually troublesome. This study aims to summarise the clinicopathological characteristics and the risk factors of prognosis for EMPD in anogenital regions, potentially providing evidence for the diagnosis and treatment of anogenital EMPD. METHODS: 688 patients were sourced from the Surveillance, Epidemiology and End Results (SEER) program between 1992 and 2021. In total, 176 participants from our centre from between 2011 and 2021 were included to investigate the characteristics and prognosis for EMPD in anogenital regions. RESULTS: From the SEER program data, patient age of 65 years or older, metastasis of lymph nodes, Spanish-Hispanic-Latino race, diameter exceeding 10cm and lesions located anally were revealed as independent risk factors for shorter cancer-specific survival (CSS). However, the data from our centre highlighted that metastasis of lymph nodes and tumours extending through the epidermis are independent risk factors of shortened progression-free survival (PFS) and CSS of anogenital EMPD. CONCLUSION: This synthesised study revealed that some characteristics are regarded as risk factors for poor clinical prognosis, which have potential value in formulating more normative and effective strategies for patients with EMPD in anogenital regions.

Incidence of and risk factors for post-intensive care syndrome among Chinese respiratory intensive care unit patients: A cross-sectional, prospective study.

BACKGROUND: Patients transferred from the respiratory intensive care unit (ICU) can experience post-intensive care syndrome (PICS), which comprises cognitive, psychological, and physical disorders that seriously affect the quality of life. Therefore, it was necessary to explore the incidence of and the risk factors for PICS among respiratory ICU patients. OBJECTIVES: This study evaluated PICS among respiratory ICU patients and explored the risk factors for PICS. METHODS: This cross-sectional, prospective study was performed at one hospital in China. Using convenience sampling, 125 respiratory ICU patients from August 2018 to June 2019 were recruited for the study. The Mini-Mental State Examination, Confusion Assessment Method for the Intensive Care Unit, Hospital Anxiety and Depression Scale, Medical Research Council Scale, activities of daily living scale, Pittsburgh Sleep Quality Index, and the 14-item fatigue scale were used to comprehensively assess the patients' cognitive status, psychological status, and physiological status when entering the ICU and 2 weeks after leaving the ICU. Factors affecting PICS were measured using researcher-created questionnaires of patients' general information and disease-related information. RESULTS: Fifteen patients were lost to follow-up. Fifty-nine patients had PICS (incidence rate, 53.6%). Logistic regression showed that risk factors for PICS were age, invasive mechanical ventilation, noninvasive ventilator-assisted ventilation, and coronary heart disease (P < 0.05). CONCLUSION: The PICS incidence was high. Older age, longer invasive mechanical ventilation times, longer noninvasive ventilator times, and coronary heart disease were risk factors for PICS. ICU medical workers in China should pay more attention on PICS, know the risk factors, and implement preventive measures.

Fourth generation cryogenic neutral cluster beam apparatus for studying fundamental properties of metallic clusters.

A cryogenic beam apparatus for studying neutral clusters has been built and tested. The lowest beam temperature reaches less than 9 K at a repetition rate of 20 Hz. Mechanical decoupling from the refrigerator avoids misalignment during temperature ramping. Adopting a permanent magnet based magnetic deflector eliminates the hysteresis and electric noise of the traditional electromagnet and offers excellent reproducibility of the applied magnetic field. The mass spectrometer can operate in either Mass Spectroscopy Time-Of-Flight mode or Position-Sensitive Time-Of-Flight mode with spatial resolution better than 7 µm. Its performance is demonstrated with niobium and cobalt clusters.

TikTok and YouTube as sources of information on anal fissure: A comparative analysis.

Introduction: Anal fissure is a common colorectal disease impacting patients' life quality with high incidence. Social media platforms are becoming a kind of health information source nowadays. This study aims to evaluate and compare the quality of anal fissure-related videos on TikTok and YouTube. Materials and methods: One hundred videos were sourced from TikTok and YouTube, respectively and videos were screened further. The completeness of six types of content within the videos is assessed, including the definition of disease, symptoms, risk factors, evaluation, management and outcomes. Finally, the DISCERN instrument, Patient Education Materials Assessment Tool and Global Quality scale are used to assess video display quality and content. A correlation analysis is undertaken considering the video features, DISCERN, PEMAT and GQS scores. Results: Physicians and non-profit organizations contributed almost all video content among selected videos. A statistically significant correlation between DISCERN classification and duration, PEMAT understandability, PEMAT actionability and GQS scores is recorded. DISCERN total scores were significantly positively correlated with video duration, PEMAT understandability, PEMAT actionability and GQS scores. GQS scores were significantly positively correlated with duration, PEMAT understandability and PEMAT actionability scores. For content, the videos mainly described management and symptoms while containing limited information on the disease evaluation, and outcomes. Conclusions: The sources of uploaders on YouTube are more diverse than TikTok, and the quality of videos is also relatively higher on YouTube. Even so, the video quality of the two platforms still needs to be further improved. Health information without integrity, reliability and practicability impacts patients' disease perception and health-seeking behavior, leading to serious consequences. Much effort must be taken to improve the quality of videos regarding anal fissures on the two platforms, which will facilitate the development of public health education on this issue.

The characteristics of antigenic specificity of memory regulatory t cells in women with unexplained recurrent pregnancy loss.

Regulatory T cells (Tregs) proliferate after encountering the fetal antigen, which plays an important role in maintaining maternal-fetal tolerance. Activated Tregs increase number and function after antigen encounter and develop memory. Upon subsequent antigen exposure, Treg cells re-expand more rapidly. However, the characteristics of memory regulatory T cells (mTregs) during normal pregnancy and unexplained recurrent pregnancy loss (URPL) have not been elucidated well. In this study, we analyzed the proportion of Tregs and mTregs in the peripheral blood and their surface expression of PD-1, CCR6, and HLA-G in normal non-pregnant (n = 20) and pregnant (n = 20) women, and non-pregnant (n = 20) and pregnant URPL (n = 20) women. We found that the proportions of mTregs in lymphocytes, CD3+ T cells, CD4+ T cells, and Tregs were lower in pregnant URPL patients than in normal pregnant women. The proportions of CD4+CD45RO+ Th cells in lymphocytes, CD3+ T, and CD4+ T cells in the pregnant URPL group were the highest among the four groups (P < 0.05). There were no significant differences among the other three groups (P > 0.05). The proportions of CD4+/CCR6+/mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were significantly lower in the non-pregnant normal group and non-pregnant URPL group than in normal pregnant group and pregnant URPL group (P < 0.05, respectively). The proportions of CD4+/CCR6+ mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were lower in pregnant URPL group than in normal pregnant group (P < 0.05, respectively). These findings indicate that fetal antigen-specific mTregs play an important role in pregnancy maintenance, and the dysregulation of mTreg may contribute to URPL.

Comparison of Treatment Efficacy and Survival Outcomes Between Asian and Western Patients With Unresectable Gastric or Gastro-Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis.

Background: Gastric cancer and gastro-esophageal adenocarcinoma are geographically heterogeneous diseases. Previous studies suggested that Asian and Western patients with late-stage gastric or gastro-esophageal adenocarcinoma possess distinct survival outcomes. However, the interregional differences of multiple systemic therapies in unresectable diseases have not been comprehensively described. Materials and Methods: We searched PubMed-MEDLINE, Embase, Web of Science and Cochrane Library from inception to 31 October 2021 and reviewed major conference abstracts for controlled trials of systemic therapies in unresectable gastric or gastro-esophageal adenocarcinoma that reported hazard ratios stratified by geographical region. The primary measurements were overall survival and progression-free survival. The pooled hazard ratios and 95% confidence intervals for overall survival and progression-free survival in Asian and Western populations were calculated using a random effect model. A linear regression model was adopted to compare the overall survival and progression-free survival between Asian and Western patients. Results: A total of 9033 patients from 20 studies were included for analysis. Immunotherapy was associated with an improvement in the overall survival for both Asian (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) and Western (hazard ratio, 0.90; 95% confidence interval, 0.81-1.00) patients, with no significant difference between the two groups (P = 0.32). Trends of survival benefit with anti-HER2 therapy and anti-angiogenic therapy versus control were observed in both Asian and Western patients, although statistical significance was not denoted. Subgroup analyses yielded a statistically superior overall survival of Asian versus Western patients in trials that investigated first-line immunotherapy (P = 0.04). Due to the linear regression analyses with scatter plot graphs, Asian patients showed a higher overall survival, but not progression-free survival, than Western patients irrespective of treatment type. Conclusion: Asian and Western patients with unresectable gastric or gastro-esophageal adenocarcinoma show similar responses to systemic therapies with limited interregional differences. Exceptionally, first-line immunotherapy could elicit superior survival among Asian populations. In addition, Asian patients with gastric or gastro-esophageal adenocarcinoma display a superior OS compared with Western counterparts.

Overexpression of CBS/H2S inhibits proliferation and metastasis of colon cancer cells through downregulation of CD44.

BACKGROUND: The role of hydrogen sulfide (H2S) in cancer biology is controversial, including colorectal cancer. The bell-shaped effect of H2S refers to pro-cancer action at lower doses and anti-cancer effect at higher concentrations. We hypothesized that overexpression of cystathionine-beta-synthase (CBS)/H2S exerts an inhibitory effect on colon cancer cell proliferation and metastasis. METHODS: Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), clone-formation and sphere formation assay. Cell migration was evaluated by transwell migration assay. Intracellular H2S was detected by H2S probe. Chromatin immunoprecipitation (ChIP) analysis was carried out to examine DNA-protein interaction. Cell experiments also included western blotting, flow cytometry, immunohistochemistry (IHC) and immunofluorescence analysis. We further conducted in vivo experiments to confirm our conclusions. RESULTS: Overexpression of CBS and exogenous H2S inhibited colon cancer cell proliferation and migration in vitro. In addition, overexpression of CBS attenuated tumor growth and liver metastasis in vivo. Furthermore, CD44 and the transcription factor SP-1 was probably involved in the inhibitory effect of CBS/H2S axis on colon cancer cells. CONCLUSIONS: Overexpression of CBS and exogenous provision of H2S inhibited colon cancer cell proliferation and migration both in vivo and in vitro. Molecular mechanisms might involve the participation of CD44 and the transcription factor SP-1.

KLRK1 as a prognostic biomarker for lung adenocarcinoma cancer.

Lung cancer is one of the most common malignancy worldwide and causes estimated 1.6 million deaths each year. Cancer immunosurveillance has been found to play an important role in lung cancer and may be related with its prognosis. KLRK1, encoding NKG2D, is a homodimeric lectin-like receptor. However, there has not been one research of KLRK1 as a biomarker in lung cancer. Data including patients` clinical characteristics and RNAseq information of KLRK1 from TCGA were downloaded. A total of 1019 patients with lung cancer were included in this study, among which 407 patients were female and 611 patients were male. Evaluations of mRNA expression, diagnostic value by ROC (receiver operating characteristic) curves and prognostic value by survival curve, Cox model and subgroup analysis were performed. The level of KLRK1 expression in lung adenocarcinoma cancer tissues and normal lung tissues was detected by qRT-PCR. The CCK-8 assay investigated the proliferation rate and the wound healing assay assessed the migratory ability in vitro. The expression of KLRK1 in tumor was lower than that in normal tissue. KLRK1 expression was associated with gender, histologic grade, stage, T classification and vital status. Patients with high KLRK1 expression presented an improved overall survival (P = 0.0036) and relapse free survival (P = 0.0031). KLRK1 was found to have significant prognostic value in lung adenocarcinoma (P = 0.015), stage I/II (P = 0.03), older patients (P = 0.0052), and male (P = 0.0047) by subgroup overall survival analysis, and in lung adenocarcinoma (P = 0.0094), stage I/II (P = 0.0076), older patients (P = 0.0072), and male (P = 0.0033) by subgroup relapse free survival analysis. Lung adenocarcinoma cancer patients with high KLRK1 expression presented an improved overall survival (P = 0.015) and relapse free survival (P = 0.0094). In vitro studies indicated that KLRK1 inhibited tumor cell proliferation and migration. KLRK1 was an independent prognostic factor and high KLRK1 expression indicated a better overall and relapse free survival. KLRK1 may be a prognostic biomarker for lung adenocarcinoma cancer.

Does temporary transfer to preoperative hemodialysis influence postoperative outcomes in patients on peritoneal dialysis? A retrospective cohort study.

Background: The associations between preoperative transfer to hemodialysis (HD) and postoperative outcomes in patients on chronic peritoneal dialysis (PD) remain unknown. We conducted this retrospective cohort study to investigate whether preoperative HD could influence surgical outcomes in PD patients undergoing major surgeries. Methods: All chronic PD patients who underwent major surgeries from January 1, 2007, to December 31, 2020, at Peking University First Hospital were screened. Major surgery was defined as surgical procedures under general, lumbar or epidural anesthesia, with more than an overnight hospital stay. Patients under the age of 18, with a dialysis duration of less than 3 months, and those who underwent renal implantation surgeries and procedures exclusively aimed at placing or removing PD catheters were excluded. Patients involved were divided into either HD or PD group based on their preoperative dialysis status for further analysis. Results: Of 105 PD patients enrolled, 65 continued PD, and 40 switched to HD preoperatively. Patients with preoperative HD were significantly more likely to develop postoperative hyperkalemia. The total complication rates were numerically higher in patients undergoing preoperative HD. After adjustment, the incidence of postoperative hyperkalemia or any other postoperative complication rates were similar between groups. There were no differences in long-term survival between the two groups. Conclusions: It does not seem indispensable for PD patients to switch to temporary HD before major surgeries.

The Value of the Systemic Immune-Inflammation Index in Predicting Survival Outcomes in Patients with Brain Metastases of Non-Small-Cell Lung Cancer Treated with Stereotactic Radiotherapy.

BACKGROUND: As a parameter integrating platelet (P), neutrophil (N), and lymphocyte (L) levels, the systemic immune-inflammation index (SII) has been used as a prognostic marker for patient survival in various types of solid malignant tumors. However, there is no in-depth study in non-small-cell lung cancer (NSCLC) patients with brain metastases after stereotactic radiotherapy. Therefore, we performed a retrospective analysis to determine the clinical and prognostic value of the SII in NSCLC patients with brain metastases who underwent stereotactic radiotherapy. MATERIALS AND METHODS: We enrolled 124 NSCLC patients with brain metastases treated with stereotactic radiotherapy in our hospital between May 2015 and June 2018. We obtained all baseline blood samples within one week prior to stereotactic radiotherapy. The SII was calculated by the following formula: neutrophil counts × platelet counts/lymphocyte counts. The optimal cutoff value of the SII for predicting prognosis was assessed by receiver operating characteristic (ROC) curves with the maximum log-rank values. The discriminative ability of predicting prognosis was calculated and compared using the Kaplan-Meier method and log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were combined to evaluate the prognostic impact of the blood index on overall survival (OS) and progression-free survival (PFS). Only those parameters that proved to be associated with statistically significant differences in clinical outcomes were compared in multivariate analysis using a multiple Cox proportional hazard regression model to identify independent prognostic factors. RESULTS: Of the total enrolled patients, 53.2% and 46.8% have high SII and low SII, respectively. In this study, Kaplan-Meier curve analysis revealed that the median PFS was 9 months (range: 2-22 months) and the median OS was 18 months (range: 4-37 months). Applying an optimal cutoff of 480 (SII), the median PFS was better in the low SII group patients (11.5 vs. 9 months), and the median OS was significantly longer in the low SII group patients (20 vs. 18 months). A SII > 480 was significantly associated with worse OS (HR: 2.196; 95% CI 1.259-3.832; P = 0.006) and PFS (HR: 2.471; 95% CI 1.488-4.104; P < 0.001) according to univariate analysis. In multivariate analysis, only age (HR: 2.159; 95% CI 1.205-3.869; P = 0.010), KPS (HR: 1.887; 95% CI 1.114-3.198; P = 0.018), and SII (HR: 1.938; 95% CI 1.046-3.589; P = 0.035) were independently correlated with OS, and SII (HR: 2.224; 95% CI 1.298-3.810; P = 0.004) was an independent prognostic predictor of PFS, whereas we found that other inflammation-based indices lost their independent value. CONCLUSIONS: The SII, which is an integrated blood parameter based on platelet, neutrophil, and lymphocyte counts, may be an independent prognostic indicator and may be useful for the identification of NSCLC patients with brain metastases after stereotactic radiotherapy at high risk for recurrence.