Copper-Catalyzed [4+1+1] Annulation of Ammonium Salts and Anthranils: Synthesis of 2,3-Diaroylquinolines.

A copper(I)-catalyzed protocol is developed for the synthesis of various 2,3-diaroylquinolines starting from achiral ammonium salts and anthranils through [4+1+1] annulation. Using copper(I) chloride as the sole catalyst, this reaction is featured with easily available starting materials, broad substrate scope, good yields and simple reaction conditions.

AP-1 and SP1 trans-activate the expression of hepatic CYP1A1 and CYP2A6 in the bioactivation of AFB1 in chicken.

Dietary exposure to aflatoxin B1 (AFB1) is harmful to the health and performance of domestic animals. The hepatic cytochrome P450s (CYPs), CYP1A1 and CYP2A6, are the primary enzymes responsible for the bioactivation of AFB1 to the highly toxic exo-AFB1-8,9-epoxide (AFBO) in chicks. However, the transcriptional regulation mechanism of these CYP genes in the liver of chicks in AFB1 metabolism remains unknown. Dual-luciferase reporter assay, bioinformatics and site-directed mutation results indicated that specificity protein 1 (SP1) and activator protein-1 (AP-1) motifs were located in the core region -1,063/-948, -606/-541 of the CYP1A1 promoter as well as -636/-595, -503/-462, -147/-1 of the CYP2A6 promoter. Furthermore, overexpression and decoy oligodeoxynucleotide technologies demonstrated that SP1 and AP-1 were pivotal transcriptional activators regulating the promoter activity of CYP1A1 and CYP2A6. Moreover, bioactivation of AFB1 to AFBO could be increased by upregulation of CYP1A1 and CYP2A6 expression, which was trans-activated owing to the upregulalion of AP-1, rather than SP1, stimulated by AFB1-induced reactive oxygen species. Additionally, nano-selenium could reduce ROS, downregulate AP-1 expression and then decrease the expression of CYP1A1 and CYP2A6, thus alleviating the toxicity of AFB1. In conclusion, AP-1 and SP1 played important roles in the transactivation of CYP1A1 and CYP2A6 expression and further bioactivated AFB1 to AFBO in chicken liver, which could provide novel targets for the remediation of aflatoxicosis in chicks.

Optimum Doses and Forms of Selenium Maintaining Reproductive Health via Regulating Homeostasis of Gut Microbiota and Testicular Redox, Inflammation, Cell Proliferation, and Apoptosis in Roosters.

BACKGROUND: There is a U-shaped relationship between dietary selenium (Se) ingestion and optimal sperm quality. OBJECTIVES: This study aimed to investigate the optimal dietary dose and forms of Se for sperm quality of breeder roosters and the relevant mechanisms. METHODS: In experiment 1, 18-wk-old Jingbai laying breeder roosters were fed a Se-deficient base diet (BD, 0.06 mg Se/kg), or the BD + 0.1, 0.2, 0.3, 0.4, 0.5, or 1.0 mg Se/kg for 9 wk. In experiment 2, the roosters were fed the BD or the BD + sodium selenite (SeNa), seleno-yeast (SeY), or Se-nanoparticles (SeNPs) at 0.2 mg Se/kg for 9 wk. RESULTS: In experiment 1, added dietary 0.2 and 0.3 mg Se/kg led to higher sperm motility and lower sperm mortality than the other groups at weeks 5, 7, and/or 9. Furthermore, added dietary 0.2-0.4 mg Se/kg produced better testicular histology and/or lower testicular 8-hydroxy-deoxyguanosine than the other groups. Moreover, integrated testicular transcriptomic and cecal microbiomic analysis revealed that inflammation, cell proliferation, and apoptosis-related genes and bacteria were dysregulated by Se deficiency or excess. In experiment 2, compared with SeNa, SeNPs slightly increased sperm motility throughout the experiment, whereas SeNPs slightly reduced sperm mortality compared with SeY at week 9. Both SeY and SeNPs decreased malondialdehyde in the serum than those of SeNa, and SeNPs led to higher glutathione peroxidase (GPX) and thioredoxin reductase activities and GPX1 and B-cell lymphoma 2 protein concentrations in the testis compared with SeY and SeNa. CONCLUSIONS: The optimal dietary Se dose for reproductive health of breeder roosters is 0.25-0.35 mg Se/kg, and SeNPs displayed better effects on reproductive health than SeNa and SeY in laying breeder roosters. The optimal doses and forms of Se maintain reproductive health of roosters associated with regulation intestinal microbiota homeostasis and/or testicular redox balance, inflammation, cell proliferation, and apoptosis.

Heat Stress Impairs Male Reproductive System with Potential Disruption of Retinol Metabolism and Microbial Balance in the Testis of Mice.

BACKGROUND: Heat stress (HS) has a harmful impact on the male reproductive system, primarily by reducing the sperm quality. The testicular microenvironment plays an important role in sperm quality. OBJECTIVES: This study aimed to explore the underlying mechanism by which HS impairs the male reproductive system through the testicular microenvironment. METHODS: Ten-week-old male mice (n = 8 mice/group) were maintained at a normal temperature (25°C, control) or subjected to HS (38°C for 2 h each day, HS) for 2 wk. The epididymides and testes were collected at week 2 to determine sperm quality, histopathology, retinol concentration, the expression of retinol metabolism-related genes, and the testicular microbiome. The testicular microbiome profiles were analyzed using biostatistics and bioinformatics; other data were analyzed using a 2-sided Student's t test. RESULTS: Compared with the control, HS reduced (P < 0.05) sperm count (42.4%) and motility (97.7%) and disrupted the integrity of the blood-testis barrier. Testicular microbial profiling analysis revealed that HS increased the abundance of the genera Asticcacaulis, Enhydrobacter, and Stenotrophomonas (P < 0.05) and decreased the abundance of the genera Enterococcus and Pleomorphomonas (P < 0.05). Notably, the abundance of Asticcacaulis spp. showed a significant negative correlation with sperm count (P < 0.001) and sperm motility (P < 0.001). Moreover, Asticcacaulis spp. correlated significantly with most blood differential metabolites, particularly retinol (P < 0.05). Compared with the control, HS increased serum retinol concentrations (25.3%) but decreased the testis retinol concentration by 23.7%. Meanwhile, HS downregulated (P < 0.05) the expression of 2 genes (STRA6 and RDH10) and a protein (RDH10) involved in retinol metabolism by 27.3%-36.6% in the testis compared with the control. CONCLUSIONS: HS reduced sperm quality, mainly because of an imbalance in the testicular microenvironment potentially caused by an increase in Asticcacaulis spp. and disturbed retinol metabolism. These findings may offer new strategies for improving male reproductive capacity under HS.

Translocation of gut microbes to epididymal white adipose tissue drives lipid metabolism disorder under heat stress.

Heat stress induces multi-organ damage and serious physiological dysfunction in mammals, and gut bacteria may translocate to extra-intestinal tissues under heat stress pathology. However, whether gut bacteria translocate to the key metabolic organs and impair function as a result of heat stress remains unknown. Using a heat stress-induced mouse model, heat stress inhibited epididymal white adipose tissue (eWAT) expansion and induced lipid metabolic disorder but did not damage other organs, such as the heart, liver, spleen, or muscle. Microbial profiling analysis revealed that heat stress shifted the bacterial community in the cecum and eWAT but not in the inguinal white adipose tissue, blood, heart, liver, spleen, or muscle. Notably, gut-vascular barrier function was impaired, and the levels of some bacteria, particularly Lactobacillus, were higher in the eWAT, as confirmed by catalyzed reporter deposition fluorescence in situ hybridization (CARD-FISH) staining when mice were under heat stress. Moreover, integrated multi-omics analysis showed that the eWAT microbiota was associated with host lipid metabolism, and the expression of genes involved in the lipid metabolism in eWAT was upregulated under heat stress. A follow-up microbial supplementation study after introducing Lactobacillus plantarum to heat-stressed mice revealed that the probiotic ameliorated heat stress-induced loss of eWAT and dyslipidemia and reduced gut bacterial translocation to the eWAT by improving gut barrier function. Overall, our findings suggest that gut bacteria, particularly Lactobacillus spp., play a crucial role in heat stress-induced lipid metabolism disorder and that there is therapeutic potential for using probiotics, such as Lactobacillus plantarum.

YAP inhibitor verteporfin suppresses tumor angiogenesis and overcomes chemoresistance in esophageal squamous cell carcinoma.

PURPOSE: Targeting angiogenesis is an attractive strategy for the effective treatment of cancer. This study aimed to investigate the anti-cancer activities of YAP inhibitor verteporfin (VP) in esophageal squamous cell carcinoma (ESCC) cells through its inhibitory effect on tumor angiogenesis. METHODS: Cell proliferation, apoptosis, migration and invasion abilities were estimated by MTT, colony formation, DAPI staining, wound healing and transwell assays, respectively. Human umbilical vein endothelial cell (HUVEC) tube formation assay and chick embryo chorioallantoic membrane (CAM) model were used to observe angiogenesis in vitro and in vivo. The interactions between ESCC cells and HUVECs were assessed by cell chemotactic migration and adhesion assays. The expression levels of angiogenesis-related molecules were detected by Western blot. RESULTS: We found that VP was potential to inhibit ESCC cell proliferation, migration, invasion and induce apoptosis in the dose-dependent fashion. VP also significantly suppressed proliferation, migration, and tube formation of HUVECs and promoted apoptosis of HUVECs, and reduced angiogenesis in CAM. Moreover, VP inhibited ESCC cell-induced angiogenesis in vitro by decreasing HUVEC chemotactic migration, adhesion and tube formation, and also reduced ESCC cell-induced neovascularization of the CAM in vivo. In addition, VP suppressed the expression of pro-angiogenic molecules such as VEGFA, MMP-2 and ß-catenin in ESCC cells. Furtherly, VP increased the chemosensitivity of ESCC-resistant cells to paclitaxel (PTX). The combination of VP and PTX attenuated the resistant cell-mediated angiogenesis in vitro and in vivo. CONCLUSION: These results reveal for the first time that VP potently inhibits malignant progression and overcomes chemoresistance of ESCC cells via inhibition of tumor angiogenesis. It provides insight into a new strategy for the treatment of ESCC that VP could be a potential drug candidate for targeting tumor angiogenesis.

Selenium Deficiency Dysregulates One-Carbon Metabolism in Nutritional Muscular Dystrophy of Chicks.

BACKGROUND: Nutritional muscular dystrophy (NMD) in animals is induced by dietary selenium (Se) deficiency. OBJECTIVES: This study was conducted to explore the underlying mechanism of Se deficiency-induced NMD in broilers. METHODS: One-day-old male Cobb broilers (n = 6 cages/diet, 6 birds/cage) were fed a Se-deficient diet (Se-Def, 47 µg Se/kg) or the Se-Def supplemented with 0.3 mg Se/kg (control) for 6 wk. Thigh muscles of broilers were collected at week 6 for measuring Se concentration, histopathology, and transcriptome and metabolome assays. The transcriptome and metabolome data were analyzed with bioinformatics tools and other data were analyzed with Student's t tests. RESULTS: Compared with the control, Se-Def induced NMD in broilers, including reduced (P < 0.05) final body weight (30.7%) and thigh muscle size, reduced number and cross-sectional area of fibers, and loose organization of muscle fibers. Compared with the control, Se-Def decreased (P < 0.05) the Se concentration in the thigh muscle by 52.4%. It also downregulated (P < 0.05) GPX1, SELENOW, TXNRD1-3, DIO1, SELENOF, H, I, K, M, and U by 23.4-80.3% in the thigh muscle compared with the control. Multi-omics analyses indicated that the levels of 320 transcripts and 33 metabolites were significantly altered (P < 0.05) in response to dietary Se deficiency. Integrated transcriptomics and metabolomics analysis revealed that one-carbon metabolism, including the folate and methionine cycle, was primarily dysregulated by Se deficiency in the thigh muscles of broilers. CONCLUSIONS: Dietary Se deficiency induced NMD in broiler chicks, potentially with the dysregulation of one-carbon metabolism. These findings may provide novel treatment strategies for muscle disease.

Selenium deficiency-induced multiple tissue damage with dysregulation of immune and redox homeostasis in broiler chicks under heat stress.

Broiler chicks are fast-growing and susceptible to dietary selenium (Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male chicks (n=6 cages/diet, 6 chicks/cage) were fed with a Se-deficient diet (Se-Def, 0.047 mg Se/kg) or the Se-Def+0.3 mg Se/kg (Control, 0.345 mg Se/kg) for 6 weeks. The serum, liver, pancreas, spleen, heart, and pectoral muscle of the broilers were collected at week 6 to assay for Se concentration, histopathology, serum metabolome, and tissue transcriptome. Compared with the Control group, Se deficiency induced growth retardation and histopathological lesions and reduced Se concentration in the five organs. Integrated transcriptomics and metabolomics analysis revealed that dysregulation of immune and redox homeostasis related biological processes and pathways contributed to Se deficiency-induced multiple tissue damage in the broilers. Meanwhile, four metabolites in the serum, daidzein, epinephrine, L-aspartic acid and 5-hydroxyindoleacetic acid, interacted with differentially expressed genes with antioxidative effects and immunity among all the five organs, which contributed to the metabolic diseases induced by Se deficiency. Overall, this study systematically elucidated the underlying molecular mechanisms in the pathogenesis of Se deficiency-related diseases, which provides a better understanding of the significance of Se-mediated heath in animals.

Novel ultralong and photoactive Bi2Ti4O11/TiO2 heterojunction nanofibers toward efficient textile wastewater treatment.

The elimination of dyes from textile wastewater with a lower carbon footprint is highly contingent on the design of green catalysts. Here, we innovatively developed ultralong one-dimensional Bi2Ti4O11/TiO2 heterojunction nanofibers via electrospinning so as to photocatalytically degrade dyes efficiently and sustainably through the utilisation of renewable solar irradiation. The heterostructured Bi2Ti4O11/TiO2 nanofibers exhibited desirable activity in the visible light region through the slight shift of the absorption edge to a longer wavelength. The Bi2Ti4O11/TiO2 nanofibers calcined at 550 °C had a lower optical band gap (3.08 eV) than that of the pure TiO2 (3.32 eV), as evidenced by their higher photocatalytic degradation kinetics of a model dye (Acid Orange 7) (2.5 times greater than those of pure TiO2). The enhanced visible light photocatalytic performance arose from the formation of both the Bi2Ti4O11/TiO2 heterojunction and the effective separation of photogenerated holes and electrons. The employment of ultralong Bi2Ti4O11/TiO2 heterojunction nanofibers for dye removal/decolourisation under visible light is an efficient, cost effective and sustainable solution, which will provide significant insights for practical textile wastewater treatment in view of practical engineering applications.

[Effect of Gegen Qinlian Decoction on methylation and expression of Scd1gene in adipose tissue of insulin resistant rats and correlations between methylation and physiological and biochemical parameters].

This study aimed to explore the effect of Gegen Qinlian Decoction(GQD) on the methylation and mRNA expression level of stearoyl CoA desaturase(SCD) gene in the adipose tissue of rats with insulin resistance(IR) induced by high-fat diet as well as the correlations between methylation and physiological and biochemical indicators. The animals were divided into seven groups, namely, blank control(C) group, IR model group, low-(1.65 g·kg~(-1)), medium-(4.95 g·kg~(-1)), and high(14.85 g·kg~(-1))-dose GQD(GQDL, GQDM, and GQDH) groups, rosiglitazone(RGN, 5 mg·kg~(-1)) group, and simvastatin(SVT, 10 mg·kg~(-1)) group. The rat epididymal adipose tissue was collected for detecting all the cytosine methylation levels in two fragments of Scd1 gene by bisulfite sequencing PCR(BSP). Scd1-1 was located in CG shores and Scd1-2 in CG islands, including the transcriptional start site(TSS). The Scd1 mRNA level was determined by quantitative real-time PCR(q-PCR). Spearman correlation coefficient was used to analyze the correlations between amplified fragment C methylation and physiological and biochemical indicators. The results showed that GQDM remarkably reversed the elevated CG7 methylation in the TSS upstream region of Scd1-2 triggered by high-fat diet. GQDL significantly reversed the lowered total CG methylation in the downstream region of Scd1-2 induced by the high-fat diet. GQD did not significantly improve the decreased Scd1 mRNA expression caused by high-fat diet. Changes in methylation of the total CG, CG5 and CT11 of Scd1-1 in CG shores exhibited significant negative correlations with the serum triglyceride(TG) but positive correlation with the Scd1 mRNA level. The methylation of several C sites in the TSS upstream region of Scd1-2 was positively correlated with physiological and biochemical parameters. The methylation of several CG sites in the TSS downstream region of Scd1-2 was negatively associated with physiological and biochemical parameters. Besides, the methylation of several CH sites in the downstream fragment was positively correlated with physiological and biochemical parameters. All these have demonstrated that GQD may exert the therapeutic effect by regulating the methylation of CG7 in the TSS upstream region and total CG site in the TSS downstream region of Scd1 gene. The methylation of total CG, CG5 and CT11 sites in CG shores of Scd1 gene may be important targets for regulating Scd1 mRNA level and affecting serum TG.

Spatially isolated CoNx quantum dots on carbon nanotubes enable a robust radical-free Fenton-like process.

We unprecedentedly report spatially separated CoNx nanodots on carbon nanotubes (CNTs) via a facile formamide condensation reaction. To our knowledge, CoNx-CNTs outperform the activities of current catalysts in peroxymonosulfate activation. CoNx-CNT-oriented radical-free degradation of contaminants shows robust anti-interference capacity toward environmental conditions. Our work will stimulate general interest in designing cost-effective and versatile quantum-/atom-sized catalysts with fully exposed active sites for water purification and beyond.

Magnetic CoFe2O4 nanocrystals derived from MIL-101 (Fe/Co) for peroxymonosulfate activation toward degradation of chloramphenicol.

In this study, porous magnetic CoFe2O4 nanocrystals (NCs) were successfully synthesized by using bimetal-organic framework (MOF) as a precursor, and used as catalysts to activate peroxymonosulfate (PMS) for the removal of chloramphenicol (CAP) in the solution. The structure and physicochemical properties of CoFe2O4 NCs were thoroughly examined by a series of characterization techniques. The results revealed as-synthesized CoFe2O4 had a nanorod-shaped structure with high specific surface area (83.00 m2 g-1) and pore volume (0.31 cm3 g-1). Furthermore, the degradation efficiency (100%) and the removal of total organic carbon (68.09%) were achieved after 120 min with 0.1 g/L CoFe2O4 NCs, 2 mM PMS and 10 mg/L CAP at pH of 8.20. In addition, effects of catalyst dosage, PMS dosage, initial pH values, CAP concentration and co-existing anions as well as natural organic matters in the solution on the degradation efficiencies were studied and all the removal can be well fitted with pseudo-first-order kinetic model (R2 > 0.96). Sulfate radicals (SO4•-) and hydroxyl radicals (HO•) were proved to be two main reactive species for CAP removal in CoFe2O4/PMS system based on quenching experiments. CAP was degraded by the main pathways of dichlorination, denitration, decarboxylation, hydroxylation, ring cleavage and chain cleavage on CoFe2O4/PMS system through high performance liquid chromatograph-mass spectrometry analysis. We believe that this study would be very meaningful to promote the applications of MOFs-derived catalysts on the SO4•- based advanced oxidation processes (SR-AOPs) for the environmental remediation.

Effect of a Multi-Carbohydrase and Phytase Complex on the Ileal and Total Tract Digestibility of Nutrients in Cannulated Growing Pigs.

The current study evaluated the influence of a multi-carbohydrase and phytase complex (MCPC) on the ileal and total tract digestibility of nutrients in growing pigs. A total of eight barrows (initial BW = 30.7 ± 1.1 kg) were surgically fitted with a T-cannula at the distal ileum and randomly allotted to four groups. The experiment was conducted according to a 4 × 4 Latin square design, each period lasting 10 days. Pigs were fed four experimental diets, which consisted of two basal diets (BD1, low phytate; BD2, high phytate) with or without MCPC containing at least 1800 U xylanase, 6600 U α-arabinofuranosidase, 1244 U ß-glucanase, and 1000 U phytase per/kg corn-soybean meal with 15% corn distillers based diet. The high phytate diet reduced (p < 0.05) the apparent ileal digestibility (AID) of crude protein by 1.4% and the apparent total tract digestibility (ATTD) of organic matter, crude protein, and gross energy by 1.7, 2.3, and 1.9%, respectively, and tended to decrease (p = 0.10) the ATTD of Ca by 17.3%, relative to the low phytate diet. The dietary supplementation of the MCPC increased (p < 0.05) the AID of phosphorus (P) and calcium (Ca) by 34.2% and 31.1% for BD1 and 26.7% and 41.3% for BD2, respectively, and increased (p < 0.05) ATTD of crude fat, P, and Ca by 1.4%, 45.6%, and 9.6% for BD1 and 3.1%, 66.0%, and 52.7% for BD2, respectively. The MCPC supplementation did not significantly increase the AID and (or) ATTD of crude protein, organic matter, and starch. In conclusion, the dietary supplementation of the MCPC could improve the AID of P and Ca and the ATTD of crude fat, P, and Ca.

Nanocrystalline ferrihydrite activated peroxymonosulfate for butyl-4-hydroxybenzoate oxidation: Performance and mechanism.

Heterogeneous catalysts activated peroxymonosulfate (PMS) for degradation of refractory organic contaminants has been recognized as a promising removal technology for the environmental remediation. In this study, nanocrystalline ferrihydrite (NFH) was prepared to activate PMS for the degradation of butyl-4-hydroxybenzoate (BHB). XPS analysis indicates that calcination process played a key role in regulating the surface oxygen species of NFH, thus control its activation ability toward PMS. NFH exhibits excellent stability (the released concentration of Fe ions < 0.13 mg/L) and desirable reusability. Increasing solution temperature and NFH dosage exerted a positive role in PMS activation for BHB removal, while such positive correlation was not found in the case of increasing initial pH. Increasing the static solution dissolved oxygen remarkably enhanced BHB oxidation kinetics. However, continuous N2 and air blowing caused a significant decline in BHB removal. Reaction mechanism study showed that SO4‒, OH, O2‒, and 1O2 were the main reactive oxygen species for degrading BHB by NFH/PMS. LC/MS analysis indicated BHB was degraded by the pathways of hydroxylation, carboxylation, decarboxylation, dehydrogenation, ring cleavage and chain cleavage reaction. This work suggests the ferrihydrite might be a promising catalyst to activate PMS to destroy refractory organic pollutants in the environmental remediation.

One-step fabrication of recycled Ag nanoparticles/graphene aerogel with high mechanical property for disinfection and catalytic reduction of 4-nitrophonel.

Fabrication of smart composites with expected removal property and excellent recycle performance for micro-pollutants including microbes and organic contaminants without formation of second-pollutants is highly desired. In this work, Ag nanoparticles (Ag NPs) homogenously loaded on graphene aerogel (GA) as Ag NPs/GA was facilely fabricated by a one-step process and the composite was characterized in detail. The bactericidal performance of the composite towards escherichia coli (E. coli) was evaluated and the catalytic activity was probed for the reduction of 4-nitrophenol (4-NP). Results showed that the composite contains about 44.4 wt% of well-dispersed Ag NPs with diameters ranging from 10 to 100 nm. Compared with the bare Ag particles or GA, Ag NPs/GA exhibited an enhanced bactericidal performance for 8-lg of E. coli cells with 100% inactivation rate and catalytic activity for 4-NP with 96.6% degradation rate, respectively. Impressively, the 100% inactivation rates for 8-lg of E. coli remained after 7 recycles and the releasing silver was negligible compared with the loaded Ag NPs. Moreover, the used Ag NPs/GA for the catalytic reduction of 4-NP can be regenerated easily by calcination in inert atmosphere. Hence, Ag NPs/GA can be regarded as a promising and cost-efficient composite for environmental remediation.

Association of tRNA methyltransferase NSUN2/IGF-II molecular signature with ovarian cancer survival.

AIM: To investigate the association between NSUN2/IGF-II signature and ovarian cancer survival. METHODS: Using a publicly accessible dataset of RNA sequencing and clinical follow-up data, we performed Classification and Regression Tree and survival analyses. RESULTS: Patients with NSUN2 high IGF-II low had significantly superior overall and disease progression-free survival, followed by NSUN2 low IGF-II low, NSUN2 high IGF-II high and NSUN2 low IGF-II high (p < 0.0001 for overall, p = 0.0024 for progression-free survival, respectively). The associations of NSUN2/IGF-II signature with the risks of death and relapse remained significant in multivariate Cox regression models. Random-effects meta-analyses show the upregulated NSUN2 and IGF-II expression in ovarian cancer versus normal tissues. CONCLUSION: The NSUN2/IGF-II signature associates with heterogeneous outcome and may have clinical implications in managing ovarian cancer.