Comprehensive machine learning-based preoperative blood features predict the prognosis for ovarian cancer.

PURPOSE: Significant advancements in improving ovarian cancer (OC) outcomes have been limited over the past decade. To predict prognosis and improve outcomes of OC, we plan to develop and validate a robust prognosis signature based on blood features. METHODS: We screened age and 33 blood features from 331 OC patients. Using ten machine learning algorithms, 88 combinations were generated, from which one was selected to construct a blood risk score (BRS) according to the highest C-index in the test dataset. RESULTS: Stepcox (both) and Enet (alpha = 0.7) performed the best in the test dataset with a C-index of 0.711. Meanwhile, the low RBS group possessed observably prolonged survival in this model. Compared to traditional prognostic-related features such as age, stage, grade, and CA125, our combined model had the highest AUC values at 3, 5, and 7 years. According to the results of the model, BRS can provide accurate predictions of OC prognosis. BRS was also capable of identifying various prognostic stratifications in different stages and grades. Importantly, developing the nomogram may improve performance by combining BRS and stage. CONCLUSION: This study provides a valuable combined machine-learning model that can be used for predicting the individualized prognosis of OC patients.

Inflammatory markers are associated with infertility prevalence: a cross-sectional analysis of the NHANES 2013-2020.

BACKGROUND: Inflammation exerts a critical role in the pathogenesis of infertility. The relationship between inflammatory parameters from peripheral blood and infertility remains unclear. Aim of this study was to investigate the association between inflammatory markers and infertility among women of reproductive age in the United States. METHODS: Women aged 20-45 were included from the National Health and Nutrition Examination Survey (NHANES) 2013-2020 for the present cross-sectional study. Data of reproductive status was collected from the Reproductive Health Questionnaire. Six inflammatory markers, systemic immune inflammation index (SII), lymphocyte count (LC), product of platelet and neutrophil count (PPN), platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) were calculated from complete blood counts in mobile examination center. Survey-weighted multivariable logistic regression was employed to assess the association between inflammatory markers and infertility in four different models, then restricted cubic spline (RCS) plot was used to explore non-linearity association between inflammatory markers and infertility. Subgroup analyses were performed to further clarify effects of other covariates on association between inflammatory markers and infertility. RESULTS: A total of 3,105 women aged 20-45 was included in the final analysis, with 431 (13.88%) self-reported infertility. A negative association was found between log2-SII, log2-PLR and infertility, with an OR of 0.95 (95% CI: 0.78,1.15; p = 0.60), 0.80 (95% CI:0.60,1.05; p = 0.10), respectively. The results were similar in model 1, model 2, and model 3. Compared with the lowest quartile (Q1), the third quartile (Q3) of log2-SII was negatively correlation with infertility, with an OR (95% CI) of 0.56 (95% CI: 0.37,0.85; p = 0.01) in model 3. Similarly, the third quartile (Q3) of log2-PLR was negatively correlation with infertility, with an OR (95% CI) of 0.61 (95% CI: 0.43,0.88; p = 0.01) in model 3. No significant association was observed between log2-LC, log2-PPN, log2-NLR, log2-LMR and infertility in model 3. A similar U-shaped relationship between log2-SII and infertility was found (p for non-linear < 0.05). The results of subgroup analyses revealed that associations between the third quartile (Q3) of log2-SII, log2-PLR and infertility were nearly consistent. CONCLUSION: The findings showed that SII and PLR were negatively associated with infertility. Further studies are needed to explore their association better and the underlying mechanisms.

Graded diagnosis of Helicobacter pylori infection using hyperspectral images of gastric juice.

Helicobacter pylori is a potential underlying cause of many diseases. Although the Carbon 13 breath test is considered the gold standard for detection, it is high cost and low public accessibility in certain areas limit its widespread use. In this study, we sought to use machine learning and deep learning algorithm models to classify and diagnose H. pylori infection status. We used hyperspectral imaging system to gather gastric juice images and then retrieved spectral feature information between 400 and 1000 nm. Two different data processing methods were employed, resulting in the establishment of one-dimensional (1D) and two-dimensional (2D) datasets. In the binary classification task, the random forest model achieved a prediction accuracy of 83.27% when learning features from 1D data, with a specificity of 84.56% and a sensitivity of 92.31%. In the ternary classification task, the ResNet model learned from 2D data and achieved a classification accuracy of 91.48%.

A qualitative study on the clinical safety and user experiences of female condoms for anal intercourse among men who have sex with men in Shanghai, China.

Objective: This qualitative study aimed to understand the clinical safety, efficacy, and receptiveness of using the female condom (FC) during anal intercourse among men who have sex with men (MSM). Methods: Subjects for this study were recruited from a two-group crossover trial among MSM in Shanghai. The trial consisted of two phases, each including the use of condoms (FC vs. male condom), questionnaires, and in-depth one-on-one interviews. The two phases were separated by a washout period of 4 weeks. The minimum sample size for this study was determined in accordance with the principle of "information saturation." The qualitative data were organized and analyzed using ATLAS.ti version 7. Results: A total of 26 participants from the MSM population were recruited for this study, with 10 assuming the insertive role (i.e., "1"), 8 assuming the receptive role (i.e., "0"), and 8 being versatile (i.e., "0.5"). Each participant completed the crossover trial comprising two phases. The cumulative usage of FCs and male condoms (MCs) amounted to 115 and 127 times, respectively. During the reported sexual encounters, no participants reported incidents of condom rupture, slippage, or other malfunctions. A few participants reported experiencing slight chafing pain, primarily put forward by "0" participants. Apart from those reports, no instances of bleeding, swelling, or allergic reactions were reported. The efficiency of FC in disease prevention, the sexual partner's willingness to use FC, the freshness of FC, and positive sexual experiences were the main reasons for the consistent use of FC for anal sex. Discomfort and pain during sexual activity, the loose design and thick material of FCs, and difficulties in placing FCs were the major obstacles to FC use among MSM. The elements referring to the forehead exhibited varied in importance among "1,", "0," and "0.5" participants. Regarding the willingness to use the FC in the future anal intercourse, 61.54% of participants expressed a positive inclination, 23.08% were uncertain, and 15.38% stated that they would not. "A better sense of security during anal sex" was the main factor affecting willingness among "0" participants and "the sexual pleasure that the FC brought" among "1" participants. Improving the design and technology of FCs and increasing the frequency of use and practice might improve the use skills, which will favor the willingness to use FCs among the MSM population. Conclusion: FCs received positive user feedback from study participants, but distinctions were found in individuals in different sexual roles. Large-scale quantitative studies are needed to evaluate the clinical safety of the FC and its effectiveness in preventing the transmission of STDs during anal intercourse.

CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1.

PURPOSE: Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain. METHODS: The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2. RESULTS: We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy. CONCLUSION: As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.

Effect of aspirin, warfarin, and proton-pump inhibitors on performance of fecal immunochemical test in colorectal cancer screening: a systematic review and meta-analysis.

This study aims to investigate the impact of antithrombotic agents and proton-pump inhibitors (PPIs) on fecal immunochemical test (FIT). PubMed, EMBASE, Web of Science, Cochrane Central, and Google Scholar were searched from inception until September 3, 2023. Studies comparing the diagnostic performance of FIT between medicine users and non-users in average-risk colorectal cancer screening populations were included. Pooled sensitivity, specificity, and positive predictive values (PPVs) for advanced neoplasia (AN) of FIT were compared by reporting pooled odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model. Twenty-two studies enrolling 5,572,367 individuals were included. For aspirin, pooled sensitivity and specificity for AN were 57.2% and 88.4% in users versus 60.2% and 93.2% in non-users; while pooled ORs were 1.49 (95% CI 0.89-2.48, P = 0.13) and 0.72 (95% CI 0.62-0.83, P < 0.001), respectively. In subgroup analysis, there was no difference in sensitivity and specificity between the two groups at the cutoff of 20 µg Hb/g (P = 0.57 and 0.29, respectively) but a significantly lower specificity in users compared with non-users at lower cutoffs (P < 0.001). Moreover, a significantly lower PPVAN in users compared with non-users was observed after matching age and sex confounders (P = 0.001). Warfarin had no significant influence on PPVAN of FIT (P = 0.43). PPIs were associated with a significantly lower PPVAN in users (P < 0.001). Aspirin use was associated with lower specificity and PPV of FIT. Aspirin discontinuation before FIT to reduce false-positive results should be interpreted with caution given concerns about cardiovascular events. Increasing cutoff values of FIT in aspirin users may be another possible approach. Additionally, warfarin withdrawal before FIT is unnecessary but PPIs withdrawal before FIT is recommended to reduce false-positive results.

Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides.

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.

Construction of 131I-RGDyC-PEG-PAMAM-DTX targeted drug delivery system and study of its physicochemical properties and biological activity.

OBJECTIVE: To construct a novel targeted drug delivery nanoprobe: iodine-131-arginine-glycine-aspartate-tyrosine-cysteine peptide-polyethylene glycol-fifth generation polyamide-amine-docetaxel (131I-RGDyC-PEG-PAMAM-DTX) and to investigate its physicochemical properties and biological activity. MATERIALS AND METHODS: Docetaxel was wrapped by solvent volatilization method, and the regression curve of DTX was constructed by high-performance liquid chromatography to determine its drug loading. The particle size of RGDyC-PEG-PAMAM-DTX was detected by dynamic light scattering. The 131I labeling was performed by a chloramine-T method and purified by Sephadex-G50 column chromatography, and it is in vitro stability and lipid-water partition coefficient was investigated. The cytotoxicity of RGDyC-PEG-PAMAM-DTX and 131I-RGDyC-PEG-PAMAM-DTX on A549 cells in vitro was detected by Cell Counting Kit-8 assay. RESULTS: Arginine-glycine-aspartate-tyrosine-cysteine peptide-PEG-PAMAM-DTX was successfully prepared by solvent volatilization with a loading capacity of about 44µg/mg. The average particle size of RGDyC-PEG-PAMAM-DTX was 57.8nm; the labeling rate of 131I-RGDyC-PEG-PAMAM-DTX by the chloramine-T method was 74.09%-76.09%, and the radiochemical purity was 88.9%-92.6% after purification. The in vitro stability showed that the radiochemical purity was above 80% after 72h in fetal bovine serum and PBS buffer (25oC and 37oC).CCK-8 assay showed that RGDyC-PEG-PAMAM-DTX and 131I-RGDyC-PEG-PAMAM-DTX had more pronounced cytotoxic effects than free DTX and 131I. CONCLUSION: Iodine-131-RGDyC-PEG-PAMAM-DTX has good physicochemical properties and apparent cytotoxic effectsandis expected to be used in treating tumors.

Mitigation of heat stress in wheat (Triticum aestivum L.) via regulation of physiological attributes using sodium nitroprusside and gibberellic acid.

Heat stress poses a threat to plants in arid and semiarid regions, leading to soil salinization and plant mortality. Researchers are exploring remedies to alleviate these effects, including using gibberellic acid (GA3) to regulate plant enzymes and antioxidants. Additionally, sodium nitroprusside (SNP) is gaining attention, but its combined effect with GA3 requires further research. To address this gap, we investigated the effects of GA3 and SNP on plants under heat stress conditions. For that, wheat plants were cultivated under 40 °C for 6 h per day (15 days). Sodium nitroprusside (donor of NO and SNP) and gibberellic acid (GA3), respectively, with 100 µM and 5 µg/ml concentrations, were applied as foliar sprays at 10 days after sowing (DAS). Results showed that SNP + GA3 treatment had the highest plant height (4.48% increase), plant fresh weight (29.7%), plant dry weight (87%), photosynthetic rate (39.76%) and stomatal conductance (38.10%), and Rubisco (54.2%) compared to the control. Our findings indicate a significant increase in NO, H2O2, TBARS, SOD, POD, APX, proline, GR, and GB that greatly scavenged reactive oxygen species (ROS) for decreasing the adverse effect of stress. Such findings confirmed the efficacy of the combined treatment of SNP + GA3 under high-temperature stress compared to the solitary application of GA3, SNP, and control. In conclusion, using SNP + GA3 is a better strategy for mitigating heat stress in wheat than individual applications. Further research is recommended to validate the effectiveness of SNP + GA3 in other cereal crops.

Risk control of host cell proteins in one therapeutic antibody produced by concentrated fed-batch (CFB) mode.

Multiple control strategies, including a downstream purification process with well-controlled parameters and a comprehensive release or characterization for intermediates or drug substances, were implemented to mitigate the potential risk of host cell proteins (HCPs) in one concentrated fed-batch (CFB) mode manufactured product. A host cell process specific enzyme-linked immunosorbent assay (ELISA) method was developed for the quantitation of HCPs. The method was fully validated and showed good performance including high antibody coverage. This was confirmed by 2D Gel-Western Blot analysis. Furthermore, a LC-MS/MS method with non-denaturing digestion and a long gradient chromatographic separation coupled with data dependent acquisition (DDA) on a Thermo/QE-HF-X mass spectrometer was developed as an orthogonal method to help identify the specific types of HCPs in this CFB product. Because of the high sensitivity, selectivity and adaptability of the new developed LC-MS/MS method, significantly more species of HCP contaminants were able to be identified. Even though high levels of HCPs were observed in the harvest bulk of this CFB product, the development of multiple processes and analytical control strategies may greatly mitigate potential risks and reduce HCPs contaminants to a very low level. No high-risk HCP was identified and the total amount of HCPs was very low in the CFB final product.

A case report of lymphangioleiomyomatosis with retroperitoneal masses in pregnancy.

Background: Lymphangioleiomyomatosis (LAM) is a rare, gradually advancing tumor of unknown origin. It is distinguished by the anomalous proliferation of pulmonary smooth muscle cells and predominantly manifests in women of childbearing age. In this study, we aim to present a noteworthy case of LAM accompanied by lymphangioleiomyoma in the retroperitoneal space during pregnancy, a scenario susceptible to misdiagnosis. Case presentation: A 31-year-old woman, facing an unintended pregnancy, presented during the 13th week with a cystic-solid mass exhibiting abundant blood signals in the pelvic cavity, as revealed by routine obstetrical ultrasound. Concurrently, her chest CT disclosed diffuse thin-walled cavities in both lungs. Despite the absence of clinical symptoms, the patient abandoned pregnancy and underwent a complete curettage. However, 24 days post-operation, she was readmitted for further assessment, revealing an enlargement of the mass encompassing the abdominal aorta and inferior vena cava, along with compression on the middle and lower segments of the ureter. After a multi-disciplinary discussion and patient explanation, an exploratory laparotomy was performed, resulting in the complete removal of the tumor. Intraoperative pathological examination and immunohistochemical staining indicated a retroperitoneal mass devoid of malignant evidence. The comprehensive morphologic and immunophenotypic features substantiated the diagnosis of lymphangioleiomyomatosis. The postoperative course was uneventful, culminating in the patient's discharge. Conclusion: The consideration of Lymphangioleiomyomatosis (LAM) with a retroperitoneal tumor is crucial in the differential diagnosis of pelvic and abdominal masses. The preoperative diagnosis of this tumor poses a challenge, as ultrasound or CT scans may not yield definitive results. Accurate diagnosis necessitates not only a pathological examination of the retroperitoneal mass but also the correlation with the patient's chest High-Resolution Computed Tomography (HRCT) findings and corresponding clinical manifestations. Optimal management involves radical surgery, with surgeons comprehensively factoring in both fetal and maternal conditions when formulating a treatment plan.

Characterization of light chain c-terminal extension sequence variant in one bispecific antibody.

Protein modifications such as post-translational modifications (PTMs) and sequence variants (SVs) occur frequently during protein biosynthesis and have received great attention by biopharma industry and regulatory agencies. In this study, an aberrant peak near light chain (LC) was observed in the non-reduced capillary electrophoresis sodium dodecyl sulfate (nrCE-SDS) electrophoretogram during cell line development of one bispecific antibody (BsAb) product, and the detected mass was about 944 Da higher than LC. The corresponding peak was then enriched by denaturing size-exclusion chromatography (SEC-HPLC) and further characterized by nrCE-SDS and peptide mapping analyses. De novo mass spectra/mass spectra (MS/MS) analysis revealed that the aberrant peak was LC related sequence variant, with the truncated C-terminal sequence "SFNR" ("GEC"deleted) linked with downstream SV40 promotor sequence "EAEAASASELFQ". The unusual sequence was further confirmed by comparing with the direct synthetic peptide "SFNREAEAASASELFQ". It was demonstrated by mRNA sequencing of the cell pool that the sequence variant was caused by aberrant splicing at the transcription step. The prepared product containing this extension variant maintained well-folded structure and good functional properties though the LC/Heavy chain (HC) inter-chain disulfide was not formed. Several control strategies to mitigate the risk of this LC related sequence variant were also proposed.

Application of deep learning in the real-time diagnosis of gastric lesion based on magnifying optical enhancement videos.

Background and aim: Magnifying image-enhanced endoscopy was demonstrated to have higher diagnostic accuracy than white-light endoscopy. However, differentiating early gastric cancers (EGCs) from benign lesions is difficult for beginners. We aimed to determine whether the computer-aided model for the diagnosis of gastric lesions can be applied to videos rather than still images. Methods: A total of 719 magnifying optical enhancement images of EGCs, 1,490 optical enhancement images of the benign gastric lesions, and 1,514 images of background mucosa were retrospectively collected to train and develop a computer-aided diagnostic model. Subsequently, 101 video segments and 671 independent images were used for validation, and error frames were labeled to retrain the model. Finally, a total of 117 unaltered full-length videos were utilized to test the model and compared with those diagnostic results made by independent endoscopists. Results: Except for atrophy combined with intestinal metaplasia (IM) and low-grade neoplasia, the diagnostic accuracy was 0.90 (85/94). The sensitivity, specificity, PLR, NLR, and overall accuracy of the model to distinguish EGC from non-cancerous lesions were 0.91 (48/53), 0.78 (50/64), 4.14, 0.12, and 0.84 (98/117), respectively. No significant difference was observed in the overall diagnostic accuracy between the computer-aided model and experts. A good level of kappa values was found between the model and experts, which meant that the kappa value was 0.63. Conclusions: The performance of the computer-aided model for the diagnosis of EGC is comparable to that of experts. Magnifying the optical enhancement model alone may not be able to deal with all lesions in the stomach, especially when near the focus on severe atrophy with IM. These results warrant further validation in prospective studies with more patients. A ClinicalTrials.gov registration was obtained (identifier number: NCT04563416). Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04563416.

A novel IgG Fc by computer-aided design enhances heavy-chain heterodimerization in bi- or trispecific antibodies.

The classical `knob-into-holes' (KIH) strategy (knob(T366Y)/hole (Y407T)) has successfully enhanced the heterodimerization of a bispecific antibody (BsAb) resulting in heterodimer formation up to 92% of protein A (ProA)-purified protein pool. However, it does not show high efficiency for every BsAb. KIH was initially applied to a CD20/CD3 BsAb. After in silico modeling, two additional new mutations, S354Y in knob-heavy chain (HC) and Q347E in hole-HC, together with KIH named `ETYY', were introduced in the Fc. The CD20/CD3 BsAb hybrid only represented ~ 50% of the ProA-purified protein pool when KIH was applied. With ETYY, the percentage of CD20/CD3 hybrid increased to 93.8%. CD20/CD3-v4b (containing ETYY) retains the original activity of the BsAb at both Fab and Fc regions, and also shows good developability. These results indicate that the computer-aided novel ETYY design has the potential to improve the development of next-generation BsAbs with higher yields and simpler purification.

The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer.

Cervical cancer is the most frequently diagnosed malignancy in the female reproductive system. Conventional stratification of patients based on clinicopathological characters has gradually been outpaced by a molecular profiling strategy. Our study aimed to identify a reliable metabolism-related predictive signature for the prognosis and anti-tumor immunity in cervical cancer. In this study, we extracted five metabolism-related hub genes, including ALOX12B, CA9, FAR2, F5 and TDO2, for the establishment of the risk score model. The Kaplan-Meier curve suggested that patients with a high-risk score apparently had a worse prognosis in the cervical cancer training cohort (TCGA, n = 304, p < 0.0001), validation cohort (GSE44001, n = 300, p = 0.0059) and pan-cancer cohorts (including nine TCGA tumors). Using a gene set enrichment analysis (GSEA), we observed that the model was correlated with various immune-regulation-related pathways. Furthermore, pan-cancer cohorts and immunohistochemical analysis showed that the infiltration of tumor infiltrating lymphocytes (TILs) was lower in the high-score group. Additionally, the model could also predict the prognosis of patients with cervical cancer based on the expression of immune checkpoints (ICPs) in both the discovery and validation cohorts. Our study established and validated a metabolism-related prognostic model, which might improve the accuracy of predicting the clinical outcome of patients with cervical cancer and provide guidance for personalized treatment.

Copper enhances genotoxic drug resistance via ATOX1 activated DNA damage repair.

Copper is involved in various biochemical and physiological processes. The absorbed copper ions are transported to the intracellular destination via copper chaperones, such as ATOX1. Previous studies have demonstrated that neoplastic cells have a high demand for copper; however, its role in cancer cells has not been fully elucidated. Here, we reveal that the high level of copper contributes to drug resistance and repair of damaged DNA in cancer cells at least partially via ATOX1-induced expression of MDC1, a crucial protein involved in double-strand DNA damage repair. Specifically, ATOX1 enters into nuclear to target MDC1 promoter after treatments of various genotoxic agents, thus promoting the transcription of MDC1 in a copper-dependent manner. Therefore, knockout or blockage of ATOX1 conferred sensitivity to Gemcitabine in transplanted tumor mouse models. Together, our findings gain new insight into the role of copper in DNA damage repair and provide a novel strategy for clinical cancer therapy of drug-resistance cancers.

The distribution and pathogenic risk of non-9-valent vaccine covered HPV subtypes in cervical lesions.

Human papillomavirus (HPV) infection is the main cause of female precancerous lesions and cervical cancer. The development and application of HPV prophylactic vaccines have been recognized as a major effective intervention for the control of cervical lesions. However, the infection rate and clinical characters of non-9-valent vaccine covered HPV subtypes are still worth studying. In this retrospective study, we included patients diagnosed and treated in the Department of Gynecology of Shanghai General Hospital between January 2017 and February 2021. The clinical features of non-9-valent vaccine covered HPV subtypes were explored in 2179 patients who have normal results, 338 patients with cervical intraepithelial neoplasia 1 (CIN1), and 153 patients with ≥CIN2. Univariate analysis showed that compared to the normal cervix group, age ≥50, pregnancy ≥5, delivery ≥3, menopause, no condom use, and cervical transformation zone type III were risk factors for CIN1 or ≥CIN2 (p < 0.05). Thirty-one percent of CIN1 and 26% of ≥CIN2 were attributed to HPV51, HPV53, HPV56, and HPV68. Multivariate analysis revealed that HPV53, HPV81, age, menopause, cervical transformation area and involved glands were independent risk factors for ≥CIN2 group compared to the CIN1 group (p < 0.05). Additionally, among the 14 non-9-valent vaccine covered HPV subtypes, the infection rates of HPV53, 56, 51, and 68 were higher in this study. In conclusion, our study demonstrated the distribution and pathogenic risk of non-9-valent vaccine covered HPV subtypes in cervical lesions. These findings might supply a foundation for optimizing cervical cancer prevention in the post-vaccine era.

The ameliorative effect of melatonin on LPS-induced Sertoli cells inflammatory and tight junctions damage via suppression of the TLR4/MyD88/NF-κB signaling pathway in newborn calf.

The blood-testicular barrier (BTB) is involved in spermatogenesis, protects sperm development, and plays a crucial role in the reproductive process. Tight junctions (TJs) between Sertoli cells (SCs) are the key structure of (BTB), and if its structure is damaged, BTB function is affected. The cellular inflammation caused by Gram-negative bacteria affects the structural integrity of TJs. Melatonin (MT) has anti-inflammatory effects; however, the effect of MT in newborn calf SCs is unknown. Therefore, this experiment studied the protective effect of MT. The results showed that LPS upregulated TLR4, MyD88, and NF-κB expressions, in turn, activated the TLR4/MyD88/NF-κB signaling pathway, produced a large amount of IL-6 and IL-1ß, downregulated the expression of ZO-1 and Occludin, and reduced the viability of SCs, which resulted in the inflammatory response of SCs and damage of TJs. The addition of MT decreased TLR4, MyD88, and NF-κB expressions, it then inhibited the activation of TLR4/MyD88/NF-κB signaling pathway, downregulated the expression of IL-6 and IL-1ß, upregulated the expression of ZO-1 and Occludin, and increased the cell viability, thereby alleviating the inflammatory response of SCs, and restored the TJs structure. Overall, our results reveal that MT can alleviate LPS-induced in newborn calf SCs Inflammation and TJs injury through TLR4/MyD88/NF-κB signaling pathway.

The alleviative effect of thyroid hormone on cold stress-induced apotosis via HSP70 and mitochondrial apoptosis signal pathway in bovine Sertoli cells.

Thyroid hormone was involved in gene expression and functional regulation in various signal pathways. Cold stress can increase triiodothyronine (T3) level in the blood. The aim of this study was to investigate the effect of T3 on HSP70 expression and apoptosis in Sertoli cells (SCs) under cold stress in vitro culture at 26 °C, and provide a theoretical and practical basis for improving the reproductive efficiency of bulls in cold areas. SCs were treated with different cold stress duration and different T3 concentrations for pre-screening. HSP70 inhibitor was added later, and the apoptotic rate was measured using flow cytometry. The expression of HSP70 and the main genes of mitochondrial apoptosis pathway were determined by means of real-time PCR and western-blot, respectively. The localization of HSP70 was assessed by immunofluorescence. The results showed that cold stress (26 °C, 6 h) played an inductive role in SCs apoptotic rate (P < 0.01) and the transfer of HSP70 into the nucleus. 100 nM T3 further promoted HSP70 expression and its transfer into the nucleus, which significantly inhibited the expression of vital genes (cyt-c, Caspase-9 and Caspase-3) in mitochondrial pathway (P < 0.05). Subsequently, higher survival and lower apoptotic rates of SCs (P < 0.01) were observed. When T3 and HSP70 inhibitor were added together, the expression of cyt-c, Caspase-9 and Caspase-3 were inhibited (P < 0.05), and then the declining apoptotic rate increased again (P < 0.01). In conclusion, T3 can regulate HSP70 expression and translocation to mediate mitochondrial apoptosis pathway to inhibit SCs apoptosis induced by cold stress.