Cu(II)-based complex loaded with drug paclitaxel hydrogels against thyroid cancer and optimizing novel derivatives.

This study introduces a novel approach for synthesizing a Cu(II)-based coordination polymer (CP), {[Cu(L)(4,4´-OBA)]·H2O}n (1), using a mixed ligand method. The CP was successfully prepared by reacting Cu(NO3)2·3H2O with the ligand 3,6-bis(benzimidazol-1-yl)pyridazine in the presence of 4,4´-H2OBA, demonstrating an innovative synthesis strategy. Furthermore, a novel hydrogel composed of hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) with a porous structure was developed for drug delivery purposes. This hydrogel facilitates the encapsulation of CP1, and enables the loading of paclitaxel onto the composite to form HA/CMCS-CP1@paclitaxel. In vitro cell experiments demonstrated the promising modulation of thyroid cancer biomarker genes S100A6 and ARID1A by HA/CMCS-CP1@paclitaxel. Finally, reinforcement learning simulations were employed to optimize novel metal-organic frameworks, underscoring the innovative contributions of this study.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Clinical characteristics and risk factors analysis of 505 cases of infusion reactions in a tertiary hospital.

Background: The clinical characteristics and risk factors of infusion reactions (IRs) are inadequately described in clinical practice due to underreported cases. In the present study, we reported the current status of IRs based on an in-hospital pharmacovigilance database of a tertiary care hospital. Methods: Our study conducted a retrospective analysis of drug-induced IRs recorded at an in-hospital pharmacovigilance center between January 2015 to December 2019. The descriptive statistical analysis encompassed main causative agents, clinical manifestations, organ/system involvement and outcome. The severity of IRs was assessed with reference to the CTCAE version 5.0 criteria and we investigated risk factors associated with severe IRs. Results: During the study period, a total of 505 cases of inpatient drug-induced IRs were detected, of which 79.2% (400 cases) were classified as general IRs and 20.8% (105 cases) were categorized as severe IRs. The primary drugs responsible for these reactions were antibiotics (23%, 116 cases), with piperacillin sodium-sulbactam sodium being the most prevalent, followed by antineoplastic agents (18.4%, 93 cases) and traditional Chinese medicine injections (TCMIs) (12.9%, 65 cases). The administration of cefoperazone - sulbactam, mannatide, Shenqi Fuzheng, elemene, and diterpene ginkgolides meglumine resulted in a higher incidence of critical IRs. Among all cases of IRs, 43.2%, 41.2%, and 23.4% showed signs and symptoms of circulation, skin mucosa, and respiratory organs/systems, respectively. 9.1% of cases experienced systemic damage, while 7.1% and 5.9% of cases reported neurological and gastrointestinal related adverse reactions, respectively. The multivariate analysis revealed that alcohol consumption (OR = 2.389%, 95% CI 1.141-5.002, p = 0.021), age over 65 (OR = 1.814%, 95% CI 1.052-3.127, p = 0.032) and the utilization of contrast media (OR = 4.072%, 95% CI 1.903-8.713, p < 0.001) were identified as risk factors for the development of severe IRs. Conclusion: Understanding the clinical characteristics of IRs helps to implement effective pharmaceutical monitoring and appropriate preventive measures for susceptible populations with risk factors.

Case Report: Leiomyosarcoma of the right external iliac artery: a diagnostic-based study on a rare case.

Leiomyosarcoma (LMS) is an uncommon and aggressive form of cancer that originates in the smooth muscles. It possesses the capacity for rapid growth and often manifests with general, nonspecific symptoms arising from the displacement of nearby structures rather than direct invasion. In this particular instance, an 81-year-old woman presented with right lower abdominal pain, leading to the discovery of a mass adjacent to the right external iliac artery. In this case, the patient was misdiagnosed initially because of her nonspecific and poorly distinguished clinical symptoms. The laboratory results were within normal ranges. A well-defined tumor was detected through laparoscopic operation and subsequently surgically excised. The histopathological analysis of the tumor revealed the presence of malignant spindle cells, nuclear pleomorphism, and tumor giant cells. Immunohistochemistry tests indicated positive results for CD34 and Desmin, while CD117 and DOG1 showed adverse effects. It is worth noting that LMS of the right external iliac artery is an infrequent occurrence, potentially resulting in delayed diagnosis and misidentification. To enhance our comprehension of this uncommon cancer, more cases with detailed information are essential.

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.

Preoperative prediction of clinical and pathological stages for patients with esophageal cancer using PET/CT radiomics.

BACKGROUND: Preoperative stratification is critical for the management of patients with esophageal cancer (EC). To investigate the feasibility and accuracy of PET-CT-based radiomics in preoperative prediction of clinical and pathological stages for patients with EC. METHODS: Histologically confirmed 100 EC patients with preoperative PET-CT images were enrolled retrospectively and randomly divided into training and validation cohorts at a ratio of 7:3. The maximum relevance minimum redundancy (mRMR) was applied to select optimal radiomics features from PET, CT, and fused PET-CT images, respectively. Logistic regression (LR) was applied to classify the T stage (T1,2 vs. T3,4), lymph node metastasis (LNM) (LNM(-) vs. LNM(+)), and pathological state (pstage) (I-II vs. III-IV) with features from CT (CT_LR_Score), PET (PET_LR_Score), fused PET/CT (Fused_LR_Score), and combined CT and PET features (CT + PET_LR_Score), respectively. RESULTS: Seven, 10, and 7 CT features; 7, 8, and 7 PET features; and 3, 6, and 3 fused PET/CT features were selected using mRMR for the prediction of T stage, LNM, and pstage, respectively. The area under curves (AUCs) for T stage, LNM, and pstage prediction in the validation cohorts were 0.846, 0.756, 0.665, and 0.815; 0.769, 0.760, 0.665, and 0.824; and 0.727, 0.785, 0.689, and 0.837 for models of CT_LR_Score, PET_ LR_Score, Fused_ LR_Score, and CT + PET_ LR_Score, respectively. CONCLUSIONS: Accurate prediction ability was observed with combined PET and CT radiomics in the prediction of T stage, LNM, and pstage for EC patients. CRITICAL RELEVANCE STATEMENT: PET/CT radiomics is feasible and promising to stratify stages for esophageal cancer preoperatively. KEY POINTS: • PET-CT radiomics achieved the best performance for Node and pathological stage prediction. • CT radiomics achieved the best AUC for T stage prediction. • PET-CT radiomics is feasible and promising to stratify stages for EC preoperatively.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia.

Clinically, arsenic trioxide (ATO) was applied to the treatment of acute promyelocytic leukemia (APL) as a reliable and effective frontline drug. However, the administration regimen of AsⅢ was limited due to its fast clearance, short therapeutic window and toxicity as well. Based on CD71 overexpressed on APL cells, in present study, a transferrin (Tf)-modified liposome (LP) was established firstly to encapsulate AsⅢ in arsenic-nickel complex by nickel acetate gradient method. The AsⅢ-loaded liposomes (AsLP) exhibited the feature of acid-sensitive release in vitro. Tf-modified AsLP (Tf-AsLP) were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢ which stimulated reactive oxygen species level and caspase-3 activity. Tf-AsLP prolonged half-life of AsⅢ in blood circulation, lowered systemic toxicity, and promoted apoptosis and induced cell differentiation at lesion site in vivo. Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect, accordingly, a Tf-modified RA liposome (Tf-RALP) was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy. As expected, the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model. Furthermore, APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection. The effect of co-administration (Tf-AsLP + Tf-RALP) was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells' apoptosis and differentiation in peripheral blood and bone marrow. Collectively, Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug. Moreover, Tf-AsLP combined with Tf-RALP could achieve better efficacy. Thus, transferrin-modified AsⅢ liposome would be a novel clinical strategy to improve patient compliance, with promising translation prospects.

Single-cell analysis reveals HBV-specific PD-1+CD8+ TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients.

Immune checkpoint blockade (ICB) treatment of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection may activate viral-specific T cells to attack HBV infected hepatocytes and thus induce immune-related liver injury. Therefore, it is important to deeply understand the impacts of HBV infection on HCC immune microenvironment in order to better design effective immunotherapies for HBV+ (HBV infected) HCC patients. Here, We performed cytometry by time-of-flight (CyTOF) analyses to characterize the distinct immune compositions of HCC tumors, tumor borders, and their associations with HCC/HBV related clinical characteristics. We identified 31 distinct immune clusters and found significant associations between immune signatures with clinicopathological features of HCC. We further revealed the HBV infection had more effects on shaping immune compositions in tumor borders than in tumors, with the significant enrichment of HBV-specific PD-1+CD8+ tissue-resident memory T (TRM) cells in tumor borders of HBV+ patients. We confirmed this subset with a more exhausted phenotype and respond more actively under anti-PD-L1 treatment, suggesting its involvement in immune-related liver injury induced by ICB treatment to HBV+ HCC patients. Our study shows it may be necessary to consider antiviral prophylaxis for HBV+ HCC patients receiving ICB treatment.

Left Atrial Appendage Volume Predicts Atrial Fibrillation Recurrence after Radiofrequency Catheter Ablation: A Meta-Analysis. / O Volume do Apêndice Atrial Esquerdo Prediz a Recorrência de Fibrilação Atrial após Ablação por Cateter de Radiofrequência: Uma Metanálise.

BACKGROUND: The influence of left atrial appendage volume (LAAV) on the recurrence of atrial fibrillation (AF) following radiofrequency catheter ablation remains unclear. OBJECTIVES: We performed a meta-analysis to assess whether LAAV is an independent predictor of AF recurrence following radiofrequency catheter ablation. METHODS: The PubMed and the Cochrane Library databases were searched until March 2022 to identify publications evaluating LAAV in association with AF recurrence after radiofrequency catheter ablation. Seven studies that fulfilled the specified criteria of our analysis were found. We used the Newcastle-Ottawa Scale to evaluate the quality of the studies. The pooled effects were evaluated depending on standardized mean differences (SMDs) or hazard ratios (HRs) with 95% confidence intervals (CIs). P values < 0.05 were considered statistically significant. RESULTS: A total of 1017 patients from 7 cohort studies with a mean follow-up 16.3 months were included in the meta-analysis. Data from 6 studies (943 subjects) comparing LAAV showed that the baseline LAAV was significantly higher in patients with AF recurrence compared to those without AF (SMD: -0.63; 95% CI: -0.89 to -0,37; all p values < 0.05; I2= 62.6%). Moreover, higher LAAV was independently associated with a significantly higher risk of AF recurrence after radiofrequency catheter ablation (HR: 1.10; 95% CI: 1.02 to 1.18). CONCLUSIONS: The meta-analysis showed that there is a significant correlation between LAAV and AF recurrence after radiofrequency catheter ablation, and the role of LAAV in AF patients should not be ignored in clinical practice.

FUNDAMENTO: A influência do volume do apêndice atrial esquerdo (VAAE) na recorrência de fibrilação atrial (FA) após ablação por cateter de radiofrequência permanece obscura. OBJETIVOS: Realizamos uma metanálise para avaliar se o VAAE é um preditor independente de recorrência de FA após ablação por cateter de radiofrequência. MÉTODOS: Os bancos de dados PubMed e Cochrane Library foram pesquisados até março de 2022 para identificar publicações avaliando o VAAE em associação com a recorrência de FA após ablação por cateter por radiofrequência. Foram encontrados 7 estudos que preencheram os critérios especificados de nossa análise. Usamos a Escala de Newcastle-Ottawa para avaliar a qualidade dos estudos. Os efeitos agrupados foram avaliados dependendo das diferenças médias padronizadas (DMPs) ou hazard ratios (HRs) com intervalos de confiança (ICs) de 95%. Valores de p < 0,05 foram considerados estatisticamente significativos. RESULTADOS: Um total de 1.017 pacientes de 7 estudos de coorte com um seguimento médio de 16,3 meses foram incluídos na metanálise. Dados de 6 estudos (943 indivíduos) comparando VAAE mostraram que o VAAE basal foi significativamente maior em pacientes com recorrência de FA em comparação com aqueles sem FA (DMP: −0,63; IC de 95%: −0,89 a −0,37; todos os valores de p < 0,05; I 2 = 62,6%). Além disso, maior VAAE foi independentemente associado a um risco significativamente maior de recorrência de FA após ablação por cateter de radiofrequência (HR: 1,10; IC de 95%: 1,02 a 1,18). CONCLUSÕES: A metanálise mostrou que existe uma correlação significativa entre o VAAE e a recorrência de FA após ablação por cateter de radiofrequência, e o papel do VAAE em pacientes com FA não deve ser ignorado na prática clínica.

Salivary microbiome and metabolome analysis of severe early childhood caries.

BACKGROUND: Severe early childhood caries (SECC) is an inflammatory disease with complex pathology. Although changes in the oral microbiota and metabolic profile of patients with SECC have been identified, the salivary metabolites and the relationship between oral bacteria and biochemical metabolism remains unclear. We aimed to analyse alterations in the salivary microbiome and metabolome of children with SECC as well as their correlations. Accordingly, we aimed to explore potential salivary biomarkers in order to gain further insight into the pathophysiology of dental caries. METHODS: We collected 120 saliva samples from 30 children with SECC and 30 children without caries. The microbial community was identified through 16S ribosomal RNA (rRNA) gene high-throughput sequencing. Additionally, we conducted non-targeted metabolomic analysis through ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry to determine the relative metabolite levels and their correlation with the clinical caries status. RESULTS: There was a significant between-group difference in 8 phyla and 32 genera in the microbiome. Further, metabolomic and enrichment analyses revealed significantly altered 32 salivary metabolites in children with dental caries, which involved pathways such as amino acid metabolism, pyrimidine metabolism, purine metabolism, ATP-binding cassette transporters, and cyclic adenosine monophosphate signalling pathway. Moreover, four in vivo differential metabolites (2-benzylmalate, epinephrine, 2-formaminobenzoylacetate, and 3-Indoleacrylic acid) might be jointly applied as biomarkers (area under the curve = 0.734). Furthermore, the caries status was correlated with microorganisms and metabolites. Additionally, Spearman's correlation analysis of differential microorganisms and metabolites revealed that Veillonella, Staphylococcus, Neisseria, and Porphyromonas were closely associated with differential metabolites. CONCLUSION: This study identified different microbial communities and metabolic profiles in saliva, which may be closely related to caries status. Our findings could inform future strategies for personalized caries prevention, detection, and treatment.

Development of a predictive model for identifying previously undetected vertical root fractures.

This study aimed to develop a predictive model to screen for undetected vertical root fractures (VRFs) in root canal treated teeth. We included 95 root canal treated teeth with suspected VRFs; 77 for training and 18 for validation. Following clinical and cone-beam CT parameters were recorded: sex, tooth type, coronal restoration, time interval from completion of endodontic treatment to definitive diagnosis (TI), type of bone loss (BL), apical extent of root filling (AR) and the ratio of root filling diameter to the actual diameter in the coronal (1/3TA) and middle (2/3TA) root thirds. A predictive model p = 1/(1 - e-x ) was generated, where x = -7.433 + 1.977BL + 1.479 (2/3TA) + 1.102 AR; the sensitivity and specificity were 0.852 and 0.875 for training and 0.917 and 0.833 for validation. VRF teeth were more likely to have vertical bone loss and overfilled root canals. This model had a high diagnostic efficacy for VRFs.

O Volume do Apêndice Atrial Esquerdo Prediz a Recorrência de Fibrilação Atrial após Ablação por Cateter de Radiofrequência: Uma Metanálise / Left Atrial Appendage Volume Predicts Atrial Fibrillation Recurrence after Radiofrequency Catheter Ablation: A Meta-Analysis

Resumo Fundamento A influência do volume do apêndice atrial esquerdo (VAAE) na recorrência de fibrilação atrial (FA) após ablação por cateter de radiofrequência permanece obscura. Objetivos Realizamos uma metanálise para avaliar se o VAAE é um preditor independente de recorrência de FA após ablação por cateter de radiofrequência. Métodos Os bancos de dados PubMed e Cochrane Library foram pesquisados até março de 2022 para identificar publicações avaliando o VAAE em associação com a recorrência de FA após ablação por cateter por radiofrequência. Foram encontrados 7 estudos que preencheram os critérios especificados de nossa análise. Usamos a Escala de Newcastle-Ottawa para avaliar a qualidade dos estudos. Os efeitos agrupados foram avaliados dependendo das diferenças médias padronizadas (DMPs) ou hazard ratios (HRs) com intervalos de confiança (ICs) de 95%. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados Um total de 1.017 pacientes de 7 estudos de coorte com um seguimento médio de 16,3 meses foram incluídos na metanálise. Dados de 6 estudos (943 indivíduos) comparando VAAE mostraram que o VAAE basal foi significativamente maior em pacientes com recorrência de FA em comparação com aqueles sem FA (DMP: −0,63; IC de 95%: −0,89 a −0,37; todos os valores de p < 0,05; I 2 = 62,6%). Além disso, maior VAAE foi independentemente associado a um risco significativamente maior de recorrência de FA após ablação por cateter de radiofrequência (HR: 1,10; IC de 95%: 1,02 a 1,18). Conclusões A metanálise mostrou que existe uma correlação significativa entre o VAAE e a recorrência de FA após ablação por cateter de radiofrequência, e o papel do VAAE em pacientes com FA não deve ser ignorado na prática clínica.

Abstract Background The influence of left atrial appendage volume (LAAV) on the recurrence of atrial fibrillation (AF) following radiofrequency catheter ablation remains unclear. Objectives We performed a meta-analysis to assess whether LAAV is an independent predictor of AF recurrence following radiofrequency catheter ablation. Methods The PubMed and the Cochrane Library databases were searched until March 2022 to identify publications evaluating LAAV in association with AF recurrence after radiofrequency catheter ablation. Seven studies that fulfilled the specified criteria of our analysis were found. We used the Newcastle-Ottawa Scale to evaluate the quality of the studies. The pooled effects were evaluated depending on standardized mean differences (SMDs) or hazard ratios (HRs) with 95% confidence intervals (CIs). P values < 0.05 were considered statistically significant. Results A total of 1017 patients from 7 cohort studies with a mean follow-up 16.3 months were included in the meta-analysis. Data from 6 studies (943 subjects) comparing LAAV showed that the baseline LAAV was significantly higher in patients with AF recurrence compared to those without AF (SMD: −0.63; 95% CI: −0.89 to −0,37; all p values < 0.05; I2= 62.6%). Moreover, higher LAAV was independently associated with a significantly higher risk of AF recurrence after radiofrequency catheter ablation (HR: 1.10; 95% CI: 1.02 to 1.18). Conclusions The meta-analysis showed that there is a significant correlation between LAAV and AF recurrence after radiofrequency catheter ablation, and the role of LAAV in AF patients should not be ignored in clinical practice.

[The impact of anxiety levels in male soldiers with infertility on stress coping strategies and the quality of fertility life].

OBJECTIVE: To explore and analyze the correlation between anxiety levels, coping strategies, and fertility quality of life in male soldiers with infertility. METHODS: A questionnaire survey was conducted on 480 male soldiers with infertility who visited the Reproductive Medicine Department of the Eastern Theater Command General Hospital from June 2022 to February 2023, analyze the impact of anxiety levels on stress coping strategies and fertility quality of life in male officers and soldiers with infertility. RESULTS: Self evaluation scale score is (43.06 ± 15.02), Fertility Quality of Life Scale score is （52.11 ± 36.68）, Trait Coping Style Questionnaire score is (48.45 ± 23.15). The relevant analysis results show that there is a negative correlation between the scores of the Self Rating Anxiety Scale and the Reproductive Quality of Life Scale, a positive correlation between the scores of the Self Rating Anxiety Scale and the Trait Coping Style Questionnaire, and a positive correlation between the scores of the Reproductive Quality of Life Scale and the Trait Coping Style Questionnaire. The results of multiple regression analysis showed that years of infertility, history of childbirth, anxiety level, and coping strategies entered the regression equation. The anxiety level of male officers and soldiers with infertility has a mediating effect on the relationship between stress coping styles and quality of life during childbirth. CONCLUSION: The mental health status of male officers and soldiers with infertility is poor, and their coping strategies and quality of life during childbirth are at a moderate to low level. This indicates that more attention should be paid to the special group of male officers and soldiers with infertility, and psychological intervention should be strengthened in routine treatment. Provide support from different perspectives to address concerns and enhance the combat effectiveness of the military.

Three-dimensional ultrasound assessment of risk factors for cystocele and Green classification in primipara.

Background and aims: The present study aimed to analyze the effects of factors on cystocele and the Green classification. Materials and methods: We conducted a cross-sectional study on 357 primiparous women examined at our hospital from January 2019 to May 2021. The following data were recorded: maternal characteristics, neonatal characteristics, and factors of childbirth. It was added to the multivariate logistic regression model to determine the independent predictors of the cystocele and the Green classification. Results: A total of 242 women had cystocele, including 71 women with Green type I cystocele, 134 women with Green type II cystocele, and 37 women with Green type III cystocele. In multivariate logistic regression analysis, body mass index (BMI) at delivery was associated with cystocele, while BMI at delivery and the second stage of labor (SSL) > 1 h were independently with the distance from the symphysis pubis to the bladder neck (SPBN) abnormal (P < 0.05). BMI at examination was associated with the large retrovesical angle (RVA) (P < 0.05). BMI at delivery and the fetal right occiput anterior position (ROA) were independently associated with the distance from the symphysis pubis to the posterior wall of the bladder (SPBP) abnormal (P < 0.05), while epidural anesthesia (EDA) was the protective factor (P < 0.05). Conclusion: Primipara women should strive to avoid exposure to modifiable risk factors such as controlling weight during pregnancy, reducing weight after delivery, and shortening SSL to reduce the occurrence of cystocele.

Prediction of tumor recurrence by distinct immunoprofiles in liver transplant patients based on mass cytometry.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is a marker of poor prognosis. However, the reliable biomarkers of post-LT HCC recurrence remain to be identified. In this study, serial peripheral blood samples from the LT recipients with and without HCC recurrence were collected at five time points. Single-cell mass cytomertry (CyTOF) was utilized for the in-depth analysis of peripheral blood monocellular cells (PBMCs). CyTOF analysis showed that at 3 weeks post-LT, the activated immune cell population was increased, while the fraction of immune cells with suppressive functions (myeloid-derived suppressive cells) was reduced. The post-LT immune composition in patients with LT for HCC was enormously different from that in patients with LT for causes other than HCC. Furthermore, at 3 weeks after LT, compared with patients without recurrence, the patients with HCC recurrences were high in two subsets of T cells: CD57+ HLA-DR+ CD8+ and CD28+γδ. The CD57+ HLA-DR+ CD8+ T cells presented high levels of perforin, granzyme B, and Ki-67 and displayed a highly cytotoxic and proliferative phenotype, while the CD28+γδ T cells had reduced levels of IFN-γ and, hence, were less activated compared to CD28- cells. Based on these findings, we concluded that analyzing the PBMCs of LT recipients by CyTOF can predict the post-LT HCC recurrence. The distinct immune features can stratify patients with the risk of HCC recurrence at 3 weeks after LT, which will help clinician in further management plan and improve the prognosis of patients.

High-dimensional Single-cell Analysis Delineates Peripheral Immune Signature of Coronary Atherosclerosis in Human Blood.

Rationale: Pathogenesis of human coronary atherosclerosis is tightly associated with the imbalance of inflammation and resolution in the local immune microenvironment of AS plaques. However, how the peripheral immune system dynamically changes along with disease progression in humans remains unclear. As a result, the minimally-invasive clinical biomarkers that can sensitively distinguish different stages of human coronary atherosclerosis are still lacking. Methods: We performed single-cell Cytometry by Time-Of-Flight (CyTOF) analyses to comprehensively profile the compositions and phenotypes of CD45+ cells derived from 83 human peripheral blood samples with two independent antibody-staining panels (T cell panel and myeloid cell panel). Clinical associations between the frequencies of peripheral immune cell subsets with AS plaque burdens of coronary arteries (Gensini score) and serum lipids were also examined. By integrating immune and clinical features, we established novel CVD risk prediction models to stratify patients in different disease stages. Results: We revealed the disease stage-associated peripheral immune features for patients with coronary atherosclerosis (CAS) and atherosclerotic cardiovascular disease (ASCVD), and also identified the specific peripheral immune cell subsets that were tightly associated with the disease severity of coronary arteries (Gensini score). By integrating these peripheral immune signatures with clinical features, we have established a disease progression prediction (DPP) model that could precisely discriminate CAS patients from ASCVD patients with high prediction accuracy (ROC-AUC = 0.88). Conclusion: The progression of coronary atherosclerosis is accompanied by significant alterations of the peripheral immune system, including the changes in the distributions as well as phenotypic functions of specific immune cell subsets. The indicated stage-specific peripheral immune signatures thus become promising minimally-invasive liquid biomarkers that could help to potentially diagnose and monitor the CVD progression in humans.

The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis.

OBJECTIVE: The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin (MET), Gonadotropin-releasing hormone agonist (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET). METHODS: Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. The extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis. RESULTS: After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD = -1.43, 95% CI: -2.05 to -0.80, P < 0.00001). After MET treatment, the serum AMH decreased in polycystic ovary syndrome (PCOS) patients (WMD = -1.79, 95% CI: -2.32 to -1.26, P < 0.00001), in both obese and non-obese patients. GnRH-a treatment in endometriosis patients led to dynamic changes in the serum AMH levels, that is, ascent at 1 month (P = 0.05), and descent at 3 months (P = 0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD = 0.18, 95% CI: 0.09 to 0.27, P < 0.0001). After VD treatment the serum AMH increased, and it was obvious in non-PCOS patients (WMD = 0.78, 95% CI: 0.34 to 1.21, P = 0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD = -1.24, 95% CI: -1.87 to -0.61, P = 0.0001). CONCLUSIONS: Serum AMH levels may be affected in the short term after drug application. Specifically, OC, MET and CC lead to decreased AMH level, DHEA and VD lead to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medications should be taken into consideration when AMH is used as a marker of ovarian reserve.

NOD2 is involved in regulating odontogenic differentiation of DPSCs suppressed by MDP through NF-κB/p65 signaling.

Dental pulp stem cells (DPSCs) are well known for their capable of both self-renewal and multilineage differentiation. Dental tissue diseases, include caries, are often accompanied by inflammatory microenvironment, and muramyl dipeptide (MDP) is involved in the inflammatory stimuli to influence the differentiation of DPSCs. Nucleotide-binding oligomerization domain 2 (NOD2), a member of the cytosolic Nod-like receptor (NLR) family, plays a key role in inflammatory homeostasis regulation, but the role of NOD2 in DPSCs differentiation under inflammatory is still unclear. In this study, we identified that MDP suppressed odontogenic differentiation of DPSCs via NOD2/ NF-κB/p65 signaling pathway. Alizarin red staining and ALP activity showed the odontogenic differentiation was suppressed by MDP in a concentration-dependent manner, and the expression of dentin differentiation marker protein dentin matrix protein 1 (DMP-1) and dentin Sialophosphoprotein (DSPP) also indicated the same results. The expression of NOD2 increased gradually with the concentration of MDP as well as the phosphorylation and nuclear translocation of p65, which meant NF-κB signaling pathway was activated. Further, the interference of NOD2 inhibited the phosphorylation and nuclear translocation of p65 and reversed the MDP-mediated decrease of odontoblast differentiation of DPSCs. Our study showed that MDP can inhibit the odontoblast differentiation of DPSCs in a concentration-dependent manner. The NF-κB signaling pathway was activated by increasing expression of NOD2. Interference of NOD2 reversed the negative ability odontoblast differentiation of DPSCs in the inflammatory environment. Our study might provide a theoretical basis for the clinical treatment for dentinogenesis of DPSCs.

Single-cell immune signature for detecting early-stage HCC and early assessing anti-PD-1 immunotherapy efficacy.

BACKGROUND: The early diagnosis of hepatocellular carcinoma (HCC) can greatly improve patients' 5-year survival rate, and the early efficacy assessment is important for oncologists to harness the anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced HCC. The lack of effective predicting biomarkers not only leads to delayed detection of the disease but also results in ineffective immunotherapy and limited clinical survival benefit. METHODS: We exploited the single-cell approach (cytometry by time of flight (CyTOF)) to analyze peripheral blood mononuclear cells from multicohorts of human samples. Immune signatures for different stages of patients with HCC were systematically profiled and statistically compared. Furthermore, the dynamic changes of peripheral immune compositions for both first-line and second-line patients with HCC after anti-PD-1 monotherapy were also evaluated and systematically compared. RESULTS: We identified stage-specific immune signatures for HCC and constructed a logistic AdaBoost-SVM classifier based on these signatures. The classifier provided superior performance in predicting early-stage HCC over the commonly used serum alpha-fetoprotein level. We also revealed the treatment stage-specific immune signatures from peripheral blood and their dynamical changing patterns, all of which were integrated to achieve early discrimination of patients with non-durable benefit for both first-line and second-line anti-PD-1 monotherapies. CONCLUSIONS: Our newly identified single-cell peripheral immune signatures provide promising non-invasive biomarkers for early detection of HCC and early assessment for anti-PD-1 immunotherapy efficacy in patients with advanced HCC. These new findings can potentially facilitate early diagnosis and novel immunotherapy for patients with HCC in future practice and further guide the utility of CyTOF in clinical translation of cancer research. TRIAL REGISTRATION NUMBERS: NCT02576509 and NCT02989922.

Tumor-permeable smart liposomes by modulating the tumor microenvironment to improve the chemotherapy.

Low levels of accumulation and permeability in tumors are two primary reasons for the limited efficacy of conventional antineoplastic nanodrugs. In the present study, based on an original corosolic acid liposome (CALP) carrier with the functions of cell penetration, tumor permeability and anti-inflammation developed by our previous work, a versatile PTX/CALP was achieved by CALP loading paclitaxel (PTX). Compared to conventional PTX liposomes (PTX/LP) prepared by cholesterol and phospholipid, PTX/CALP exhibited extremely increasing cellular uptake and cytotoxicity in vitro, and in vivo enhancing the accumulation and permeability of tumor, thus significantly improving the antitumor efficacy. Further evidence indicated that PTX/CALP conspicuously promoted the recruitment of CD8+ T cells as well as reduced the infiltration of regulatory T cells and M2 macrophages into tumor by inducing enhanced immunogenic cell death (ICD) and down-regulating the inflammation level. Therefore, the improvement of efficacy was also attributed to the superiorities of PTX/CALP in modulating the inflammatory and immunosuppressive tumor microenvironment. Overall, the smart PTX liposomes based on the multi-functional CALP carrier without any modification could overcome the harsh tumor biological barriers, enhance the induction of ICD and then achieve satisfactory efficacy, suggesting its promising potentials in industrial transfer and clinical application.