Risk factors for methotrexate resistance in low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4).

The challenge of methotrexate (MTX) resistance among low-risk gestational trophoblastic neoplasia (GTN) patients has always been prominent. Despite the International Federation of Gynaecology and Obstetrics (FIGO) score of 0-4 patients comprising the majority of low-risk GTN patients, a comprehensive exploration of the prevalence and risk factors associated with MTX resistance has been limited. Therefore, we aimed to identify associated risk factors in GTN patients with a FIGO score of 0-4. Between January 2005 and December 2020, 310 low-risk GTN patients received primary MTX chemotherapy in two hospitals, with 265 having a FIGO score of 0-4. In the FIGO 0-4 subgroup, 94 (35.5%) were resistant to MTX chemotherapy, and 34 (12.8%) needed multi-agent chemotherapy. Clinicopathologic diagnosis of postmolar choriocarcinoma (OR = 17.18, 95% CI: 4.64-63.70, P < 0.001) and higher pretreatment human chorionic gonadotropin concentration on a logarithmic scale (log-hCG concentration) (OR = 18.11, 95% CI: 3.72-88.15, P < 0.001) were identified as independent risk factors associated with MTX resistance according to multivariable logistic regression. The decision tree model and regression model were developed to predict the risk of MTX resistance in GTN patients with a FIGO score of 0-4. Evaluation of model discrimination, calibration and net benefit revealed the superiority of the decision tree model, which comprised clinicopathologic diagnosis and pretreatment hCG concentration. The patients in the high- and medium-risk groups of the decision tree model had a higher probability of MTX resistance. This study represents the investigation into MTX resistance in GTN patients with a FIGO score of 0-4 and disclosed a remission rate of approximately 65% with MTX chemotherapy. Higher pretreatment hCG concentration and clinicopathologic diagnosis of postmolar choriocarcinoma were independent risk factors associated with resistance to MTX chemotherapy. The decision tree model demonstrated enhanced predictive capabilities regarding the risk of MTX resistance and can serve as a valuable tool to guide the clinical treatment decisions for GTN patients with a FIGO score of 0-4.

Exploring the role of disulfidptosis-related signatures in immune microenvironment, prognosis and therapeutic strategies of cervical cancer.

BACKGROUND: Cervical cancer is characterized by a complex immunosuppressive tumor microenvironment (TME). Disulfidptosis is a recently identified form of programmed cell death that has emerged as a crucial factor in tumorigenesis. However, the research on the specific involvement of disulfidptosis within the TME is still in its early stages. METHODS: Under glucose starvation, SiHa and HeLa cells underwent experiments employing diverse cell death inhibitors and SLC7A11 knockdown to observe their impact on cell survival. TCGA-CESC cohort was subjected to consensus clustering for disulfidptosis-related clusters. Prognosis, function, immune infiltration, and differentially expressed genes (DEGs) evaluations among clusters were compared. A prognostic model based on DEGs and disulfidptosis regulator genes (DRGs) was constructed and internally and externally validated. The correlation between YWHAG and clinicopathological characteristics in cervical cancer patients was investigated at both the mRNA and protein levels. Proliferation and migration assays were performed to uncover the roles of YWHAG in cervical cancer. RESULTS: Experimental validation confirmed disulfidptosis in cervical cancer cell lines. Cervical cancer patients were classified into three clusters based on DRGs, showing notably improved prognosis and increased immune infiltration in cluster B. The developed disulfidptosis-related prognostic model effectively stratified patients into high- and low-risk groups. Low-risk patients exhibited more favorable responses to immunotherapy and improved overall prognosis. Additionally, YWHAG, recognized as a tumor-promoting gene, demonstrated active roles in enhancing the growth, migration, and invasion of cervical cancer cells. CONCLUSION: Our research proposed a prognostic model for cervical cancer, probably contributing to tumor microenvironment traits and more potent immunotherapy strategy exploration.

Effects of Benzo[a]pyrene on Food Metabolism and Reproductive Endocrine and Ovarian Development in Female Scallop Chlamys farreri at Different Reproductive Stages.

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH) with the most carcinogenic effects of all the PAHs, has multiple toxic effects on marine bivalves. We investigated the interference mechanism of B[a]P on food metabolism (sugars, proteins, and sugars), and on reproductive endocrine and ovarian development in female scallops (Chlamys farreri). Scallops were exposed to different concentrations of B[a]P concentrations of 0, 0.38, 3.8, and 38 µg/L throughout gonadal development. Total cholesterol and triglyceride contents in the digestive glands were increased, and their synthesis genes were upregulated. The plasma glucose contents decreased with the inhibition of glycogen synthesis genes and the induction of glycolysis genes in the digestive gland. The results showed that B[a]P had endocrine-disrupting effects on scallops, that it negatively affected genes related to ovarian cell proliferation, sex differentiation, and egg development, and that it caused damage to ovarian tissue. Our findings supplement the information on B[a]P disruption in gonadal development of marine bivalves. Environ Toxicol Chem 2024;43:748-761. © 2023 SETAC.

Insights into mechanism of DNA damage and repair-apoptosis in digestive gland of female scallop Chlamys farreri under benzo[a]pyrene exposure during reproductive stage.

As one of the most carcinogenic persistent organic pollutants (POPs), benzo[a]pyrene (B [a]P) brings high toxicity to marine bivalves. Digestive gland is the most important metabolism-related organ of aquatic animals. This study conducted the digestive gland transcriptome of Chlamys farreri under B[a]P treatment at reproductive stages. And the reproductive-stage dependence metabolism-DNA repair-apoptosis process of scallops under 0, 0.04, 0.4 and 4 µg/L B[a]P was studied by qRT-PCR. The results demonstrated that the detoxification metabolism was disturbed after ovulation except for CYP3A4. In antioxidant system, antioxidant enzyme CAT and GPX, and GGT1 (one of the non-enzymatic antioxidants synthesis gene) continuously served the function of antioxidant defense. Three types of DNA repair were activated under B[a]P stress, however, DNA strand breaks were still serious. B[a]P exposure weakened death receptor pathway as well as enhanced mitochondrial pathway, surprisingly suppressing apoptosis in scallops. In addition, ten indicators were screened by Spearman correlation analysis. This study will provide sound theoretical basis for bivalve toxicology and contribute to the biomonitoring of marine POPs pollution.

Effects of ammonia exposure on anxiety behavior, oxidative stress and inflammation in guppy (Poecilia reticulate).

Ammonia is one of the most important aquatic environmental factors, which is of great concern. In order to evaluate the effect of ammonia on guppy (Poecilia reticulate), fish were exposed to increased concentrations (0, 12.50, 25.00, 41.67, 62.50 mg/L) of ammonia for 48 h. After exposure, we measured the anxiety behavior, antioxidant enzymes and pro-inflammation genes (TNF-α, IL-1ß and IL-6) of guppy. The results showed that ammonia stress induced fish anxiety, which was manifested by the increased latency to enter the upper half and decreased time spent in upper half compared with control fish. The guppy showed oxidative stress after 48 h of ammonia stress as evidenced by decreases in the activities of antioxidant enzymes and an increase in lipid hydroperoxide content. With prolonged ammonia stress, the expressions of HSP70, HSP90, TNF-α, IL-1ß and IL-6 mRNA at first had an increasing trend, and then decreased, all of which were significantly higher than the control levels at 12 h and 24 h after ammonia stress (P < 0.05). Ammonia significantly upregulated these genes mRNA levels after 48 h exposure, suggesting that heat shock proteins and innate immune system may try to protect cells from oxidative stress induced by ammonia stress. Our study showed that higher ammonia exposure induced oxidative stress in exposed fish, since inhibition of antioxidant enzymes activity and increases in lipid peroxidation, and inflammation occurred. Furthermore, the results will be helpful to understand the mechanism of ammonia toxicity in guppys.

The intestinal histopathology, innate immune response and antioxidant capacity of blunt snout bream (Megalobrama amblycephala) in response to Aeromonas hydrophila.

The present study was performed to determine the effects of Aeromonas hydrophila infection on intestinal -histopathology, innate immune response and changes in antioxidant capacity of blunt snout bream (Megalobrama amblycephala). A series of histopathological changes, innate immune enzyme activities, antioxidant enzyme activities, and the corresponding mRNA relative genes expressions in intestines were measured at 0, 1, 2, and 3 weeks post-treatment of Aeromonas hydrophila (1✕107 CFU mL-1) infection. The results showed that Aeromonas hydrophila induced changes in intestinal morphology, including the decreased muscularis thickness, the proliferated goblet cells, and the atrophied intestine villi height. Moreover, the innate immune enzymes activities in serum such as acid phosphatase, alkaline phosphatase, lysozyme activities and immunoglobulin M were significantly reduced after infection at 1week, 2week and 3week. The contents of complement 3 and complement 4 were significantly decreased after infection as well. In addition, the antioxidant enzymes activities, including superoxide dismutase, catalase and glutathione peroxidase in the experimental groups were significantly decreased compared with the control group, whereas the content of malondialdehyde was significantly increased after infection at 1week, 2week and 3week. Furthermore, the mRNA relative expressions of the inflammatory cytokines such as tumor necrosis factor-α, interleukins-1ß, interferon-γ, and interleukins-6 were significantly increased after infection with Aeromonas hydrophila. The TJ-related gene expressions in the intestine of zonula occluden-1, occludin, occludin-1, occludin-2 were significantly reduced throughout the infection period. The mRNA relative expressions of signal transducers and activators of transcription 4 and janus kinase-3 in the intestine were significantly ascended compared with the non-infected group. Overall, the results elucidated that the intestine tissue injury and innate immune response reduction, as well as antioxidant capacity attenuation were occurred against Aeromonas hydrophila infection of the blunt snout bream.

Reproductive toxicity induced by benzo[a]pyrene exposure: first exploration highlighting the multi-stage molecular mechanism in female scallop Chlamys farreri.

Reproductive toxicity induced by benzo[a]pyrene (B[a]P) exposure has received great ecotoxicological concerns. However, huge gaps on the molecular mechanism still exist in bivalves. In this study, reproduction-related indicators were investigated in female scallops Chlamys farreri during life cycle of proliferative, growth, mature, and spawn stages, under gradient concentrations of B[a]P at 0, 0.04, 0.4, and 4 µg/L. Meanwhile, a multi-stage ovarian transcriptome analysis under 4 µg/L B[a]P exposure was also conducted to elucidate the potential molecular mechanisms. The results indicated that life-cycle exposure to 0.4 and 4 µg/L B[a]P significantly decreased GSI and sex steroid levels. Even 0.04 µg/L B[a]P could play the adverse role in DNA integrity at the mature and spawn stages. Ovarian histological sections showed that B[a]P inhibited the maturation and release of oocytes. Through the functional enrichment analysis of differentially expressed genes (DEGs) from transcriptome data, 18 genes involved in endocrine disruption effects, DNA damage and repair, and oogenesis were selected and further determined by qRT-PCR. The downregulation of genes involved in steroidogenic and estrogen signaling pathways indicated that B[a]P could cause endocrine disruption through both receptor-dependent and receptor-independent pathways. The variations of gene expressions involved in DNA single-strand break and repair implied the presence of toxic mechanisms similar with vertebrates. Additionally, the changes of gene expressions of cell cycle, apoptosis, and cell adhesion suggested that exposure to B[a]P possibly caused the reproductive toxicity effects by affecting oogenesis. Taken together, this study was a pioneer in combining genome-wide transcriptomic analysis with its corresponding reproductive indicators (GSI, sex steroid levels, DNA single-strand break, and histological sections) to explore the bivalves' toxic mechanisms under B[a]P exposure. Meanwhile, some genes involved in estrogen signaling pathway and DNA damage were firstly analyzed in bivalves, and the expression data might be useful in establishing new hypotheses and discovering new biomarkers for marine biomonitoring.

Metabolic Molecule PLA2G2D Is a Potential Prognostic Biomarker Correlating With Immune Cell Infiltration and the Expression of Immune Checkpoint Genes in Cervical Squamous Cell Carcinoma.

Cervical squamous cell carcinoma (CSCC) is the major pathological type of cervical cancer (CC), the second most prevalent reproductive system malignant tumor threatening the health of women worldwide. The prognosis of CSCC patients is largely affected by the tumor immune microenvironment (TIME); however, the biomarker landscape related to the immune microenvironment of CSCC and patient prognosis is less characterized. Here, we analyzed RNA-seq data of CSCC patients from The Cancer Genome Atlas (TCGA) database by dividing it into high- and low-immune infiltration groups with the MCP-counter and ESTIMATE R packages. After combining weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis, we found that PLA2G2D, a metabolism-associated gene, is the top gene positively associated with immune infiltration and patient survival. This finding was validated using data from The Cancer Genome Characterization Initiative (CGCI) database and further confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, multiplex immunohistochemistry (mIHC) was performed to confirm the differential infiltration of immune cells between PLA2G2D-high and PLA2G2D-low tumors at the protein level. Our results demonstrated that PLA2G2D expression was significantly correlated with the infiltration of immune cells, especially T cells and macrophages. More importantly, PLA2G2D-high tumors also exhibited higher infiltration of CD8+ T cells inside the tumor region than PLA2G2D-low tumors. In addition, PLA2G2D expression was found to be positively correlated with the expression of multiple immune checkpoint genes (ICPs). Moreover, based on other immunotherapy cohort data, PLA2G2D high expression is correlated with increased cytotoxicity and favorable response to immune checkpoint blockade (ICB) therapy. Hence, PLA2G2D could be a novel potential biomarker for immune cell infiltration, patient survival, and the response to ICB therapy in CSCC and may represent a promising target for the treatment of CSCC patients.

Temporal transcriptome analysis in female scallop Chlamys farreri: First molecular insights into the disturbing mechanism on lipid metabolism of reproductive-stage dependence under benzo[a]pyrene exposure.

Polycyclic aromatic hydrocarbons (PAHs) are one of the most widespread persistent organic pollutants (POPs) in marine environment. Benzo[a]pyrene (B[a]P), the most toxic carcinogen of PAHs, is widely studied as a representative that interferes with lipid metabolism. However, the underlying molecular mechanisms of lipid metabolism by B[a]P interference towards bivalve, one of the marine-pollution bio-indicators have not been elucidated yet, especially during gonadal development which is closely associated with lipids. In this study, female scallops Chlamys farreri were cultured with natural and 4 µg/L B[a]P exposed seawater, respectively, and a multi-stage (proliferative, growth, mature, and spawn stage) ovarian transcriptome profiling was performed to decipher the reproductive stage-dependence disturbing mechanisms on lipid metabolism caused by B[a]P in bivalves. The results revealed the potential molecular mechanism of B[a]P-induced triglycerides (TGs) accumulation, which probably resulted from the collaboration of promoting synthesis and inhibiting metabolization of TGs, notably, this mechanism also occurred at spawn stage. Correspondingly, B[a]P and TGs contents measured in ovary offered direct biochemical evidences for the interference effects and stage-dependent accumulation patterns of B[a]P. Moreover, the gene expressions of fatty acids synthesis related enzymes were down-regulated cooperatively, illustrating the molecular compensatory mechanism that reduced susceptibility from oxidative damage. And these results further emphasized the important role of prostaglandins (PGs) in immune response mediated by arachidonic acid metabolism. In addition, this study explored the underlying molecular mechanism affected by B[a]P on sterol metabolism, which possibly posed a threat to normal reproductive functions in bivalves. Taken together, our findings filled the gap of the stage-dependent interference molecular mechanisms on lipid metabolism behind bivalves, and provided a new perspective for investigating the adaptive mechanisms of bivalves under POPs stress.

Benzo[a]pyrene exposure induced reproductive endocrine-disrupting effects via the steroidogenic pathway and estrogen signaling pathway in female scallop Chlamys farreri.

Benzo[a]pyrene (B[a]P), as one of the typical polycyclic aromatic hydrocarbons and environmental contaminants, may cause endocrine disrupting effects and reproductive impairments in bivalves. However, the molecular mechanisms are still not fully understood. In this study, three reproductive stages (proliferative stage, growing stage and mature stage) of female scallops Chlamys farreri were exposed to B[a]P at 0, 0.38 and 3.8 µg/L. The present study determined the adverse effects of B[a]P on gonadosomatic index, circulating hormone concentrations, endocrine-associated gene expression and ovarian histology. Significant decrease in sex hormones including progesterone (P), testosterone (T) and 17ß-estradiol (E2), was observed in B[a]P-treated C. farreri at growing stage and mature stage. These effects were associated with down-regulated expression of steroidogenic enzymes, including 3ß-HSD, CYP17 and 17ß-HSD, which were regulated by the upstream adenylate cyclase (Adcy) - protein kinase (PKA) signaling pathway. Ovarian transcript levels of estrogen receptor (ER) and caveolin-1 (cav-1) were decreased in B[a]P-treated C. farreri. Vitellogenin (Vtg), an estrogen-mediated gene involved in ovarian development, was down-regulated by B[a]P. Furthermore, ovarian histology was investigated to clarify the impairment of B[a]P on ovaries at growing stage and mature stage. Overall, the present results elucidated the anti-estrogenic mechanisms along the steroidogenic pathway and estrogen signaling pathway for the stage-dependent endocrine-disrupting effects of B[a]P. This finding provides important information regarding to the underlying molecular mechanisms of B[a]P-induced endocrine disruption in different reproductive stages of bivalves. In addition, the adverse effects should be taken into concertation during protection of bivalves germplasm resources and comprehensive evaluation of ecological risks.

Effect of Right Heart Systolic Function on Outcomes in Patients with Constrictive Pericarditis Undergoing Pericardiectomy.

BACKGROUND: To determine the influence of right ventricular function in patients with constrictive pericarditis (CP) undergoing surgery and to compare the outcomes of patients who received surgery with those managed medically. METHODS: Patients with the diagnosis of CP and healthy volunteers were recruited from January 2006 to November 2011. Patients with CP chose to either receive pericardiectomy or medical management. Echocardiographic measurements were performed to evaluate heart function, and survival was recorded. RESULTS: A total of 58 patients with CP (36 received pericardiectomy, 22 managed medically), and 43 healthy volunteers were included. CP patients who received surgery had a higher survival rate than those managed medically (P = 0.003), and higher survival was also seen in the subgroup of CP patients with severely impaired right systolic function. Albumin level, left ventricular end-diastolic dimension, and tricuspid regurgitation velocity were associated with survival in CP patients who received surgery. CONCLUSIONS: Preoperative right heart function does not affect surgical outcomes. Patients with severely impaired preoperative right systolic function obtain a greater survival advantage with surgery than with medical treatment.

Attenuated macrophage cholesterol efflux function in patients with obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with premature atherosclerosis. However, the associated mechanism remains unknown. This study investigates the expression of adenosine triphosphate (ATP)-binding cassette transporter protein A1 (ABCA1) and cellular cholesterol efflux in cultured macrophages from OSAHS patients. METHODS: Of the 18 subjects enrolled in this study, six subjects with apnea-hypopnea index (AHI) <5 were placed into the control group, and 12 subjects with AHI ≥5 were placed into the OSAHS group. Peripheral blood mononuclear cells (PBMCs) from each subject were isolated, purified, cultured, and differentiated into macrophages in vitro. ABCA1 mRNA and protein expression were evaluated by reverse transcription PCR and Western Blot, respectively. Both ABCA1-mediated and autologous serum induced cholesterol efflux were measured by isotopic cholesterol efflux assays. RESULTS: The levels of AHI and high sensitivity C-reactive protein (hsCRP) were significantly higher in the OSAHS group than in the control group. ABCA1 mRNA and protein expressions in PBMCs-derived macrophages were significantly reduced in patients with OSAHS compared to that in controls (p < 0.05). Both ABCA1-mediated and autologous serum-induced cholesterol efflux were significantly lower in the OSAHS group than that in the control group (p = 0.033 and p = 0.01, respectively). Pearson's correlation analysis revealed a negative correlation between AHI and the mRNA (r = -0.7726, p = 0.0007) and protein (r = -0.8112, p = 0.0044) expression of ABCA1, a positive correlation between ABCA1-mediated cholesterol efflux and the minimum oxygen saturation (r = 0.7954, p < 0.0001), and a negative correlation between AHI and autologous serum induced cholesterol efflux (r = -0.7756, p = 0.0002). CONCLUSION: ABCA1 expression and cellular cholesterol efflux in macrophages were significantly decreased in OSAHS patients, which closely correlated with the severity of disease. Our findings provide meaningful insights into the mechanism of atherogenesis in OSAHS patients.

[Cardiovascular manifestations in Chinese patients with hypereosinophilic syndrome].

OBJECTIVE: To evaluate the cardiovascular involvements in Chinese patients with hypereosinophilic syndrome. METHOD: We respectively reviewed 149 inpatients with hypereosinophilic syndrome admitted to Peking Union Medical College Hospital and analyzed the cardiovascular involvements in these patients. RESULTS: Cardiac abnormalities was evidenced in 32.9% patients (49/149). The ratio of male vs female was 34:15. The average age of the patients was (41.3 ± 16.9) years and course of disease was (26.4 ± 72.3) months. Cardiovascular involvements included ST segment and/or T wave (ST-T) ischemic changes, arrhythmia, myocardial injury, cardiac thrombosis, pericardial effusion, pulmonary hypertension, valve disorder, vein or artery thrombosis. After glucocorticoid and/or chemotherapeutic agents and treatment for symptoms, 11 (22.4%) patients achieved remission but have recurrent attacks and 3 (6.1%) patients died from failure in treatment. The prognosis in patients with echocardiogram abnormalities were poorer than those only with electrocardiogram abnormalities (P < 0.05). CONCLUSIONS: Cardiovascular involvements are common in patients with hypereosinophilic syndrome and the manifestation of these involvement is various. Cardiovascular complications of HES are a major source of morbidity and mortality in these disorders.

[Comparison of radiography and magnetic resonance imaging in detecting arthropathies in patients with hemophilia].

OBJECTIVE: To compare magnetic resonance imaging (MRI) and radiography in detecting arthropathies in patients with hemophilia. METHODS: Of 41 symptomatic joint images in the 14 patients with hemophilia, each joint was examined with both radiography and MRI within the same day. Imaging findings with both two modes were compared. RESULTS: Soft tissue swelling or joint effusion was observed in 33 joints by radiographs and in 34 joints by MRI. Joint erosions were demonstrated in 34 joints by MRI and in 20 joints by radiographs. Joint cysts were shown in 21 joints by MRI and in 9 joints by radiographs. Significant differences in the detection of erosion and cyst were found between radiography and MRI (P < 0. 05). MRI showed improvement for detecting more foci of both erosion and cyst than radiography. Bone marrow edema in 14 joints, hemorrhage in 34 joints, and synovial hypertrophy in 27 joints were revealed only by MRI. CONCLUSION: MRI is superior to conventional radiography in detecting the abnormal changes, and should be considered as the imaging mode of choice in evaluating hemophilic arthropathies.