Pan-cancer analyses reveal genomics and clinical outcome association of the fatty acid oxidation regulators in cancer.

Background: Fatty acid oxidation (FAO) is considered to play a vital part in tumor metabolic reprogramming. But the comprehensive description of FAO dysregulation in tumors has not been unknown. Methods: We obtained FAO genes, RNA-seq data and clinical information from the Msigdb, TCGA and GTEx databases. We assessed their prognosis value using univariate cox analysis, survival analysis and Kaplan-Meier curve. We determined the function of FAO genes using gene set variation analysis. The correlation analysis was calculated by corrplot R package. Immunotherapy response was assessed through TIDE scores. The protein expression levels of FAO genes were validated using immunohistochemistry (IHC). Results: The FAO scores were highest in COAD but lowest in PCPG. FAO scores were significantly associated with the prognosis of some cancers in OS, DSS, DFI and PFI. Besides, gene set variation analysis identified that FAO scores were related to immune-related pathways, and immune infiltration analysis showed FAO scores were positively related to cancer-associated fibroblasts and various immune-related genes. TIDE scores were significantly decreased in ACC, CHOL, ESCA, GBM, LAML, SARC, SKCM and THCA compared with normal samples, while it was significantly increased in BLCA, LUAD, LUSC, PCPG, PRAD and STAD. Besides, most FAO genes were downregulated in pan-cancer compared with normal samples. Moreover, we found copy number variation (CNV) of FAO genes played a positive role in their mRNA expression, while methylation was negative. We determined FAO genes were closely related to some drugs in pan-cancer. Conclusions: FAO score is a novel and promising factor for predicting outcomes.

TRIM28 recruits E2F1 to regulate CBX8-mediated cell proliferation and tumor metastasis of ovarian cancer.

Chromobox protein homolog 8 (CBX8) is a transcriptional suppressor participated in various cancers. However, the function and mechanism of CBX8 in the progression of ovarian cancer (OC) are unclear. In this study, we found that CBX8 was upregulated in OC tissues originating from GEPIA and TNM databases, OC patients' samples from hospital, and OC cell lines. Furthermore, CBX8 knockdown by short hairpin RNA (shRNA) technology markedly inhibited proliferation and invasion, induced migration, cell cycle arrest, and apoptosis in vitro. Mechanistically, CBX8 activated PI3K/AKT/mTOR signaling pathway to take effect. In addition, TRIM28 and E2F1 were enriched in OC tissues from the TNM database and OC patients' samples similar to the results of CBX8. Correlation analysis indicated positive correlations among TRIM28, E2F1, and CBX8. E2F1 was proved to bind to the promoter regions of CBX8 and TRIM28, while TRIM28 recruited E2F1 to increase the expression of CBX8 to further increase cell viability, proliferation, and invasion, and decrease migration, apoptosis, and cell cycle progression. Finally, CBX8 or TRIM28 knockdown repressed tumor growth and metastasis of OC in vivo. Therefore, our study showed that the promoting effect of CBX8 on tumor growth and metastasis of OC was participated in the PI3K/AKT/mTOR signaling, TRIM28 and E2F1. Our findings suggested that CBX8 could serve as a potential marker and therapeutic target for OC patients.

Identifying Immune Cell Infiltration and Hub Genes Related to M2 Macrophages in Endometriosis by Bioinformatics Analysis.

Endometriosis (EM) is a chronic, estrogen-dependent inflammatory disease. Presently, the pathophysiology of EM is still unclear, and numerous studies have established that the immune system plays a major role in the pathophysiology of EM. Six microarray datasets were downloaded from the GEO public database. A total of 151 endometrial samples (72 ectopic endometria and 79 controls) were included in this study. CIBERSORT and ssGSEA were applied to calculate the immune infiltration of EM and control samples. Moreover, we validated four different correlation analyses to explore immune microenvironment of EM and finally identified M2 macrophage-related hub genes and further conducted the specific immunologic signaling pathway analysis by GSEA. The logistic regression model was investigated by ROC and further validated by two external datasets. From the results of the two immune infiltration assays, we concluded that M2 macrophages, regulatory T cells (Tregs), M1 macrophages, activated B cells, T follicular helper cells, activated dendritic cells, and resting NK cells have a significant difference between control and EM tissues. Through multidimensional correlation analysis, we found that macrophages play an important central role in cell-to-cell interactions, especially M2 macrophages. Four immune-related hub genes, namely FN1, CCL2, ESR1, and OCLN, are closely related to M2 macrophages and play a crucial role in the occurrence and immune microenvironment of endometriosis. The combined AUC of ROC prediction model in test and validation sets were 0.9815 and 0.8206, respectively. We conclude that M2 macrophages play a central role in the immune-infiltrating microenvironment of EM.

Extreme weather raises the prices of regional emission allowances in China.

Extreme weather is an unexpected shock to the socioeconomic, which is likely to create climate risks in the process of global warming mitigation. The aim of this study is to investigate the impact of extreme weather on prices of China's regional emission allowances, by using the panel data of four representative pilots in China (Beijing, Guangdong, Hubei, and Shanghai) from April 2014 to December 2020. The overall findings reveal that extreme weather, especially extreme heat, has a short-term lagged positive impact on carbon prices. In particular, the specific performance of extreme weather under different conditions is as follows: (i) carbon prices in tertiary-dominated markets are more sensitive to extreme weather, (ii) extreme heat has a positive effect on carbon prices while extreme cold does not, and (iii) the positive impact of extreme weather on carbon market is significantly stronger during compliance periods. This study provides the decision-making basis for emission traders to avoid losses caused by market fluctuations.

A novel CDKN1A-JAZF1 gene fusion in low-grade endometrial stromal sarcoma arising from endometriosis in abdominal wall cesarean section scar: A case report and literature review.

OBJECTIVE: We report a low-grade endometrial stromal sarcoma (ESS) with a novel CDKN1A-JAZF1 fusion gene arising from abdominal wall endometrioma. CASE REPORT: A 40-year-old woman presented with a 5.5-cm abdominal wall mass juxtaposed to the postoperative scar of two cesarean sections. Histologically, the tumor exhibited obvious tongue-like protrusions into the surrounding tissue, showed spindle cells with multinodular growth pattern that occasionally rotate around small arteries. Immunohistochemically, the tumor cells were positive for CD10, estrogen receptor (ER), progesterone receptor (PR), negatively stained for smooth muscle actin (SMA), CD117, CyclinD1. In addition, a previously undescribed gene fusion between CDNK1A 5' end of exon 1(NM_000389.5) and JAZF1 3' end of exon 5 (NM_175,061,3) was reported in this case. CONCLUSION: This report of ESS suggesting that rapidly growing abdominal wall masses without menstruation-related should be promptly evaluated and treated aggressively. In addition, we have expanded the molecular landscape of low-grade ESS.

Is there different prognosis between cervical endometrioid adenocarcinoma and ordinary cervical adenocarcinoma in a propensity score matching study based on the surveillance, epidemiology, and end results (SEER) database?

Background: There has been lack of guidance for stratify treatment between cervical endometrioid adenocarcinoma (EC) and ordinary cervical adenocarcinoma (AC), therefore understanding the difference of prognosis between EC and AC is important for individualized therapy for these patients. Methods: In this study, we compare the survival outcomes between cervical EC and AC patients from the SEER database. we analyzed 2,554 patients for overall survival (OS) and 2,527 patients for disease-specific survival (DSS), Cox regression and Kaplan-Meier analyses were conducted to analyze the survival outcomes of the AC and EC patients, a 1:1 propensity score matching (PSM) method was used to match patients and balance various factors, OS and DSS were analyzed among the subgroups before and after 1:1 PSM. Results: In the unmatched cohort, in the multivariate analysis, no statistically significant difference was found in terms of OS (P=0.24) and DSS (P=0.20) between the EC and AC patients, The 3- and 5-year OS rates were 77.89% and 72.65% for the AC patients, and 83.38% and 75.64% for the EC patients respectively. The 3- and 5-year DSS rates were 84.93% and 79.69% for the EC patients, 83.97% and 76.78% for the AC patients, respectively. In the PSM cohort, 280 AC patients and 280 EC patients were included in the analysis of OS. 273 AC patients and 275 EC patients were included in the analysis of DSS, the Kaplan-Meier analysis and the multivariate analysis also produced similar results for the unmatched groups. Conclusions: There were no statistically significant differences in OS and DSS between the cervical EC and AC patients.

Mast cell stabilizer ketotifen reduces hyperalgesia in a rodent model of surgically induced endometriosis.

Purpose: This study aimed to investigate the effect of oral treatment with ketotifen, a mast cell (MC) stabilizer, in a rat model of surgically induced endometriosis. Methods: At 14 days after Sprague-Dawley rats had surgery, they were treated with ketotifen (1 or 10 mg/kg/day). Pain behaviors were evaluated 3 days prior to surgery and then at 7, 14, 21, and 28 days after surgery. At day 28, rats were sacrificed and all samples were then processed for biochemical studies. Results: We found that ketotifen-treated rats showed significantly shorter duration of hyperalgesia (p<0.05); smaller cyst diameter (p<0.05) and lower histopathologic score (p<0.001); significantly lower MC number and degranulation (p<0.001), blood vessel number (p<0.001), lower expression levels of nerve growth factor (p<0.001), cyclooxygenase-2 (p<0.001), intercellular cell adhesion molecule-1 (p<0.001), and vascular endothelial growth factor (p<0.05) in cysts, and nerve growth factor (p<0.001) and transient receptor potential cation channel, subfamily V, member 1 (p<0.001) in dorsal root ganglia; and lower histamine (p<0.05) and tumor necrosis factor-alpha (p<0.05) concentrations in serum compared with placebo-treated animal subjects. Conclusion: Oral treatment with ketotifen significantly suppressed the development of hyperalgesia, probably by modulating MC activity in cysts, thereby reducing peripheral sensitization due to noxious signals from endometriotic lesions. Our results suggest that ketotifen may inhibit the development of endometriotic lesions and hyperalgesia in rats.

Is there a correlation between inflammatory markers and coagulation parameters in women with advanced ovarian endometriosis?

BACKGROUND: Endometriosis is defined as a chronic inflammatory disease. Recent studies have shown that increased coagulation parameters including fibrinogen and platelets are associated with endometriosis. The objective of this study was to determine the levels of inflammatory markers and coagulation parameters and their correlations in women with endometriomas compared to those with benign ovarian cysts or normal pelvic anatomy. METHODS: Between June 2015 and June 2017, a total of 548 women who underwent laparoscopic/laparotomic surgery for ovarian endometriomas (OMA group, n = 226), non-endometriosis benign ovarian cysts (Cyst group, n = 210) and tubal reanastomosis (Control group, n = 112) were recruited in this study. Inflammatory markers including c-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and coagulation parameters including platelet count, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time, and plasma fibrinogen as well as CA-125 were determined. RESULTS: Compared with Cyst group and Control group, TT and PT in OMA group were significantly shorter and plasma fibrinogen levels were significantly higher (P < 0.05). Moreover, the levels of plasma fibrinogen were positively correlated with CRP, NLR and PLR (P < 0.05). In addition, the confidence intervals for the area under the curve (AUC) for CA-125 × fibrinogen were significantly higher than those for CA-125 (0.904-0.952 vs. 0.899-0.949) in the diagnosis of endometrioma. CONCLUSIONS: These results indicate that women with endometriomas demonstrate a hypercoagulable status due to the inflammatory nature of endometriosis. The combined determination for CA-125 and fibrinogen demonstrate a higher area under the curve than the single detection of CA-125 in those with endometriomas compared to these with benign ovarian cysts. TRIAL REGISTRATION: This study was approved by the Human Ethics Committee of the Women's Hospital, School of Medicine, Zhejiang University (No.20170174) and all women provided written informed consent.

Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain.

Brain-derived neurotrophic factor (BDNF) is a regulator for the formation and maintenance of chronic pain in various chronic disorders and has been shown to increase in the serum of women with endometriosis. However, BDNF expression in the peritoneal fluid (PF) and ectopic lesions and its role in endometriosis pain remain unclear. Thus, this study aims to determine the BDNF concentrations in serum and PFs and BDNF expression levels in ectopic lesions and endometriotic stromal cells (ESCs) of women with endometriosis (n = 60). The obtained results were then compared with those of women without endometriosis (n = 38). Brain-derived neurotrophic factor concentrations in serum and PF, as well as the BDNF expression levels in ectopic lesions and endometriotic cells, were evaluated through enzyme-linked immunosorbent assay, immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. As a result, BDNF concentrations in serum and PF were significantly higher in women with endometriosis with pain (2284.3 ± 51.5 pg/mL, n = 23; 58.8 ± 6.4 pg/mL, n = 16) than in women with endometriosis without pain (1999.8 ± 61.1 pg/mL, n = 37; 31.7 ± 2.9 pg/mL, n = 25; P < .01). Moreover, BDNF messenger RNA (mRNA) expression levels in ectopic lesions (8.97 ± 1.44, n = 29) were significantly higher than eutopic (0.97 ± 0.14, n = 16; P < .01) and control endometrium (1.23 ± 0.19, n = 18; P < .01) and were correlated with endometriosis pain ( P < .05). Furthermore, increased BDNF mRNA and protein expression levels in ESCs induced by estradiol or interleukin 1ß were removed using a phosphorylated extracellular-regulated protein kinase 1/2 inhibitor. These results suggest that BDNF may play an important role in the pathogenesis of endometriosis pain.

Estrogen is an important mediator of mast cell activation in ovarian endometriomas.

Endometriosis is an estrogen-dependent disease. Previous research has shown that abnormal enzymes associated with estrogen (E2) metabolism and an increased number of mast cells (MCs) in endometriomas are implicated in the pathogenesis of endometriosis. However, it remains unclear how MCs mediate the role of E2 in endometriosis. Accordingly, we investigated whether E2 was associated with the number of MCs, and the rate of degranulation, in local ovarian endometriomas, as well as the role of E2 on MCs during the pathogenesis of endometriosis. Using enzyme-linked immunosorbent assay and immunohistochemistry, we found that concentrations of E2, and the number and activity of MCs, were significantly higher in ovarian endometriomas than in controls, and that these parameters were correlated with the severity of endometriosis-associated dysmenorrhea. By measuring the release of hexosaminidase, we found that the rate of RBL2H3 cell degranulation increased after E2 treatment. Furthermore, activation of RBL2H3 cells by E2 was found to trigger the release of biologically active nerve growth factor, which promotes neurite outgrowth in PC12 cells and also sensitizes dorsal root ganglion cells via upregulation of Nav1.8 and transient receptor potential cation channel (subfamily V member 1) expression levels. When treated with E2, endometriotic cells could promote RBL2H3 cell recruitment by upregulating expression levels of stem cell factor, transforming growth factor-ß and monocyte chemoattractant protein-1; these observations were not evident with control endometrial cells. Thus, elevated E2 concentrations may be a key factor for degranulation and recruitment of MCs in ovarian endometriomas, which play a key role in endometriosis-associated dysmenorrhea.

P2X3 receptor involvement in endometriosis pain via ERK signaling pathway.

The purinergic receptor P2X ligand-gated ion channel 3 (P2X3) is crucially involved in peripheral nociceptive processes of somatic and visceral pain. Endometriosis pain is considered as a kind of inflammatory and neuropathic pain. However, whether P2X3 is involved in endometriosis pain has not been reported up to date. Here, we aimed to determine whether P2X3 expression in endometriotic lesions is involved in endometriosis pain, which is regulated by inflammatory mediators through extracellular regulated protein kinases (ERK) signalling pathway. We found that P2X3 expressions in endometriosis endometrium and endometriotic lesions were both significantly higher as compared with control endometrium (P<0.05), and both positively correlated with pain (P<0.05). The expression levels of phosphorylated -ERK (p-ERK), phosphorylated-cAMP-response element binding protein (p-CREB), and P2X3 in endometriotic stromal cells (ESCs) were all significantly increased in comparison to the initial levels after treated with interleukin (IL)-1ß (P<0.05) or adenosine triphosphate (ATP) (P<0.05), respectively, and did not increase after the ESCs were pre-treated with ERK1/2 inhibitor. Additionally, P2X3 and calcitonin gene related peptide (CGRP) were co-expressed in endometriotic lesions. These obtained results suggest that P2X3 might be involved in endometriosis pain signal transduction via ERK signal pathway.

[Research progress on the role of epithelial-mesenchymal transition in pathogenesis of endometriosis].

Epithelial-mesenchymal transition plays an important role in the development and progression of endometriosis. Mesenchymal-epithelial transition is involved in forming localized lesions of endometriosis, while EMT is involved in the injury, repair and fibrosis induced by local inflammation of endometriosis and the process of cell invasion and metastasis. The studies of signal transduction pathway and related proteins of epithelial-mesenchymal transition in the process of endometriosis may provide new targets for diagnosis and treatment of endometriosis.