Prognostic nomogram for bladder cancer with brain metastases: a National Cancer Database analysis.

BACKGROUND: This study aimed to establish and validate a nomogram for predicting brain metastasis in patients with bladder cancer (BCa) and assess various treatment modalities using a primary cohort comprising 234 patients with clinicopathologically-confirmed BCa from 2004 to 2015 in the National Cancer Database. METHODS: Machine learning method and Cox model were used for nomogram construction. For BCa patients with brain metastasis, surgery of the primary site, chemotherapy, radiation therapy, palliative care, brain confinement of metastatic sites, and the Charlson/Deyo Score were predictive features identified for building the nomogram. RESULTS: For the original 169 patients considered in the model, the areas under the receiver operating characteristic curve (AUC) were 0.823 (95% CI 0.758-0.889, P < 0.001) and 0.854 (95% CI 0.785-0.924, P < 0.001) for 0.5- and 1-year overall survival respectively. In the validation cohort, the nomogram displayed similar AUCs of 0.838 (95% CI 0.738-0.937, P < 0.001) and 0.809 (95% CI 0.680-0.939, P < 0.001), respectively. The high and low risk groups had median survivals of 1.91 and 5.09 months for the training cohort and 1.68 and 8.05 months for the validation set, respectively (both P < 0.0001). CONCLUSIONS: Our prognostic nomogram provides a useful tool for overall survival prediction as well as assessing the risk and optimal treatment for BCa patients with brain metastasis.

Estrogen inhibits autophagy and promotes growth of endometrial cancer by promoting glutamine metabolism.

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy.

Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs.

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion.

BACKGROUND/AIMS: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. METHODS: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. RESULTS: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor α (ERα) and ß (ERß) in UECC, blocking ERα or ERß resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. CONCLUSION: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER.

The role of the SDF-1/ CXCR7 axis on the growth and invasion ability of endometrial cancer cells.

PURPOSE: Stroma-derived factor-1 (SDF-1) and its receptor C-X-C chemokine receptor-4 (CXCR4) are involved in human endometrial carcinoma (EC) progression. CXCR7 is another important receptor of SDF-1 and has a higher affinity with SDF-1 compared with that of CXCR4. This paper aims to study the effects of the SDF-1/CXCR7 axis on the growth and invasion ability of EC cells. METHODS: CXCR7 expression was evaluated by quantitative RT-PCR, immunohistochemistry, immunocytochemistry and Western blotting in EC cell lines and 30 cases of primary EC tissue from patients. EC cell line proliferation and migration were assessed following knockdown of CXCR7 by MTT and transwell assays. RESULTS: The results showed that CXCR7 was highly expressed at both mRNA and protein levels in the EC cells and tissue. siCXCR7 effectively silenced CXCR7 in Ishikawa and AN3CA cells. Treatment with 17ß-oestradiol (17ß-E2) significantly increased the levels of CXCR7 and SDF-1 in Con, siCon and siCXCR7 treated Ishikawa. siCXCR7 persistently inhibited CXCR7 expression, even in cells treated with 17ß-E2. Moreover, in vitro functional analyses, silencing CXCR7 resulted in decreased proliferation in Ishikawa and AN3CA cells. Treatment with 17ß-E2 and SDF-1 significantly promoted the growth and migration in siCon treated Ishikawa and AN3CA. Interestingly, in response to 17ß-E2 and SDF-1 stimulation, siCXCR7 continuously inhibited the growth and invasion of Ishikawa and AN3CA cells. CONCLUSION: Our results indicate that SDF-1/CXCR7 plays a positive role in the proliferation and invasion of EC cells. CXCR7 inhibition treatment may provide a promising strategy for anti-tumour therapy for EC.

Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17ß-estradiol biosynthesis in endometrial carcinoma microenvironment.

Tumor-stroma interactions contribute greatly to intratumoral estrogen biosynthesis in endometrial carcinoma, but the mechanisms involved remain largely unknown. Previous study demonstrated that intratumoral aromatase upregulation in stromal cells participated in this process, but the specific aromatase-regulators have not been reported. In the present study, we found that aromatase expression in intratumoral stroma, but not in tumor epithelium, correlated positively with interleukin 6 (IL-6) expression in cancer epithelial cells by immunohistochemistry, which was confirmed using laser capture microdissection/real-time reverse transcription-PCR. With stimulation by exogenous IL-6, aromarase expression was increased in stromal cells not but not in cancer cells. Aromatase mRNA levels in endometrial cancer cells were not influenced by cocultivation with intratumoral stromal cells. When cocultured with 17ß-estradiol (E2 )-treated cancer cells, aromatase mRNA in stromal cells was significantly elevated and increased IL-6 protein levels were detected in E2 -treated culture medium. Next, we demonstrated that E2 -induced IL-6 production was through cooperation between estrogen receptor α and nuclear factor-kappa B. Furthermore, an IL-6 receptor blocking antibody could attenuate the upregulation of aromatase expression in stromal cells and the E2 concentration in coculture systems of cancer and stromal cells. The results were confirmed by an orthotopic nude endometrial carcinoma model in vivo. These studies elucidated the activation of a positive feedback loop, that is, IL-6 stimulated by E2 in endometrial cancer cells induced aromatase expression in stromal cells, promoting enhanced intratumoral E2 synthesis. Blocking of this tumor-stroma interaction may be a therapeutic strategy to overcome in situ estrogen biosynthesis in endometrial carcinoma.

Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK-NF-κB signaling pathway.

Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK-NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.

[Construction of a predictive model for in-hospital mortality of sepsis patients in intensive care unit based on machine learning].

OBJECTIVE: To analyze the risk factors of in-hospital death in patients with sepsis in the intensive care unit (ICU) based on machine learning, and to construct a predictive model, and to explore the predictive value of the predictive model. METHODS: The clinical data of patients with sepsis who were hospitalized in the ICU of the Affiliated Hospital of Jining Medical University from April 2015 to April 2021 were retrospectively analyzed,including demographic information, vital signs, complications, laboratory examination indicators, diagnosis, treatment, etc. Patients were divided into death group and survival group according to whether in-hospital death occurred. The cases in the dataset (70%) were randomly selected as the training set for building the model, and the remaining 30% of the cases were used as the validation set. Based on seven machine learning models including logistic regression (LR), K-nearest neighbor (KNN), support vector machine (SVM), decision tree (DT), random forest (RF), extreme gradient boosting (XGBoost) and artificial neural network (ANN), a prediction model for in-hospital mortality of sepsis patients was constructed. The receiver operator characteristic curve (ROC curve), calibration curve and decision curve analysis (DCA) were used to evaluate the predictive performance of the seven models from the aspects of identification, calibration and clinical application, respectively. In addition, the predictive model based on machine learning was compared with the sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE II) models. RESULTS: A total of 741 patients with sepsis were included, of which 390 were discharged after improvement, 351 died in hospital, and the in-hospital mortality was 47.4%. There were significant differences in gender, age, APACHE II score, SOFA score, Glasgow coma score (GCS), heart rate, oxygen index (PaO2/FiO2), mechanical ventilation ratio, mechanical ventilation time, proportion of norepinephrine (NE) used, maximum NE, lactic acid (Lac), activated partial thromboplastin time (APTT), albumin (ALB), serum creatinine (SCr), blood urea nitrogen (BUN), blood uric acid (BUA), pH value, base excess (BE), and K+ between the death group and the survival group. ROC curve analysis showed that the area under the curve (AUC) of RF, XGBoost, LR, ANN, DT, SVM, KNN models, SOFA score, and APACHE II score for predicting in-hospital mortality of sepsis patients were 0.871, 0.846, 0.751, 0.747, 0.677, 0.657, 0.555, 0.749 and 0.760, respectively. Among all the models, the RF model had the highest precision (0.750), accuracy (0.785), recall (0.773), and F1 score (0.761), and best discrimination. The calibration curve showed that the RF model performed best among the seven machine learning models. DCA curve showed that the RF model exhibited greater net benefit as well as threshold probability compared to other models, indicating that the RF model was the best model with good clinical utility. CONCLUSIONS: The machine learning model can be used as a reliable tool for predicting in-hospital mortality in sepsis patients. RF models has the best predictive performance, which is helpful for clinicians to identify high-risk patients and implement early intervention to reduce mortality.

Association between neutrophil percentage-to-albumin ratio and 28-day mortality in Chinese patients with sepsis.

OBJECTIVE: To assess the association between neutrophil percentage-to-albumin ratio (NPAR) and 28-day mortality in severely ill Chinese patients with sepsis. METHODS: In this retrospective, single-centre study, sepsis patients admitted to the ICU of the Affiliated Hospital of Jining Medical University between May 2015 and December 2021 were retrospectively analysed. The relationship between NPAR and 28-day mortality was examined using Cox proportional-hazards model. RESULTS: In total, 741 patients with sepsis were included. Multivariate analysis, adjusted for age, sex, body mass index (BMI), smoking and alcohol drinking history, showed an association between elevated NPAR and a high risk of 28-day mortality. After removal of additional confounders, moderate and high NPAR values remained significantly associated with 28-day mortality in comparison with low NPAR values (tertile 2 vs 1: HR, 95% CI: 1.42, 1.06-1.90; tertile 3 vs 1: HR, 95% CI: 1.35, 1.00-1.82). Survival curves stratified by NPAR groups showed that high NPAR levels had lower survival probabilities than lower NPAR levels. Subgroup analysis did not show any significant interactions between NPAR and 28-day mortality. CONCLUSIONS: Elevated NPAR values were linked to increased 28-day mortality in severely ill Chinese patients with sepsis. The findings require verification by large, prospective, multi-centre studies.

Stem cells implanted with nanofibrous mats for injured endometrial regeneration and immune-microenvironment remodeling.

Severe endometrial injury caused by invasive uterine operation and/or endometritis often results in intrauterine adhesions (IUAs), which are named Asherman's syndrome (AS), further leading to menstrual disorders, infertility and severe complications during pregnancy and delivery. IUAs or AS has been a challenging medical problem. Stem cells are a promising therapeutic modality for endometrial regeneration in patients with refractory AS. Here, we developed a new system of adipose-derived mesenchymal stem cells (ADMSCs) implantation on silk fibroin/polycaprolactone (SF/PCL) electrospun nanofibers (ADMSCs-SF/PCL) and used it in the damaged endometrium of a rat model. After SF/PCL enhanced the proliferation of transplanted ADMSCs, the results showed that the ADMSCs-SF/PCL system could recover morphology, promote regeneration of the glands and angiogenesis by increasing CD31 expression, and reverse endometrial fibrosis by decreasing TGF-ß/Smad expression. In addition, the ADMSCs-SF/PCL system also increased the expression of differentiation and decidualization markers, including HOXA11, HAND2 and FOXO1. Most importantly, the ADMSCs-SF/PCL system could remodel the special immune microenvironment, resulting in dominant NK infiltration and a normal Th1/Th2 bias in the endometrium. Moreover, this treatment had a lower but more persistent effect than estrogen. Thus, the ADMSCs-SF/PCL system enhanced endometrial restoration, suggesting a promising strategy for damaged endometrial regeneration and immune microenvironment remodeling.

The decidual stromal cells-secreted CCL2 induces and maintains decidual leukocytes into Th2 bias in human early pregnancy.

The precise mechanism of characteristic Th2 predominance at maternal-fetal interface remains unresolved. In the present study, we investigated roles of the decidua-derived CCL2 in Th2 predominance at maternal-fetal interface. FCM shows that 55% CD56(+)CD16(-)CD3(-) decidual NK, 52% CD4(+) T cells and 75% CD14(+) monocytes express CCR2. Recombinant human CCL2 (rhCCL2) and the decidual stromal cells (DSCs)-derived supernatant can enhance proliferation and inhibit apoptosis of these decidual leukocytes (DLCs), and promote Th2 cytokines production, IL-4 and IL-10, with an increase in GATA-3 transcription. They also inhibit the secretion of Th1 cytokines, TNF-α and IFN-γ, with a decrease in T-bet transcription It is concluded that the secreted CCL2 by decidual stromal cells increases GATA-3 transcription and decreases T-bet transcription in the decidual leukocytes, which contributes to Th2 polarization at maternal-fetal interface. Furthermore, the Th2 cytokines, IL-4 and IL-10, rather than Th1 cytokines, was shown to increase CCL2 secretion of DSC.

The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells.

The selective ER modulator tamoxifen (TAM(1)) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G-protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17ß-estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus.

Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition.

Recurrent spontaneous abortion (RSA) is the most common complication of pregnancy where reduced invasion of trophoblasts plays a major role. This work aimed to explore the effect of abnormally expressed long non-coding RNA (lncRNA) ZEB2-AS1 on the occurrence of RSA. Differentially expressed lncRNAs in trophoblast cells between healthy controls and patients with RSA were screened using the GEO database. Female CBA/J mice were allowed to mate with male DBA/2 mice to establish inbred mice with RSA. ZEB2-AS1 was poorly expressed in placental tissues and trophoblast cells in the condition of RSA. ZEB2-AS1 upregulation augmented proliferation, migration, and invasion of trophoblast cells in vitro. ZEB2-AS1 negatively regulated cystatin C (CST3) expression. Further overexpression of CST3 blocked the activity of trophoblast cells. ZEB2-AS1 recruited enhancer of EZH2 to the promoter region of CST3, which increased H3K27me3 modification to suppress CST3 expression. In vivo, overexpression of ZEB2-AS1 reduced embryo resorption rate and increased the weights of fetuses and placentas in mice with RSA. However, the protective roles of ZEB2-AS1 were blocked upon artificial silencing of EZH2 or upregulation of CST3. Taken together, this study demonstrates that ZEB2-AS1 enhances activity of trophoblast cells and prevents RSA development through reducing CST3 expression in an EZH2-dependent manner.

Chitosan/silk fibroin biomimic scaffolds reinforced by cellulose acetate nanofibers for smooth muscle tissue engineering.

Reconstruction of multilayered and functional smooth muscle tissues remains a challenge nowadays. Cryogels possess great advantages in three-dimensional tissue regeneration owing to the interconnected macroporous structure, but their applications have been hindered because of limited mechanical properties. Inspired by the natural extracellular matrix, cellulose acetate electrospun nanofibers (NFs) were incorporated to chitosan/silk fibroin (CS/SF) cryogel scaffolds to address this problem in this work. Compared with pure CS/SF scaffolds, CS/SF/NFs composite scaffolds showed roughened surface and enlarged pore size (216.2 ± 65.3 µm vs. 263.1 ± 75.7 µm) allowing for cell adhesion and proliferation. Incorporation of nanofibers upgraded the mechanical properties of scaffolds with a six-fold increase in compressive modulus. The proliferation and infiltration of smooth muscle cells (SMCs) were remarkably improved with the existence of nanofibers. Besides, SMCs cultured on CS/SF/NFs scaffolds displayed higher expression of contraction-related genes, verifying their potential for smooth muscle tissue engineering.

Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes.

The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can provide valuable visualization information on the expression, occupancy and bio-distribution of target protein. Herein, we reported a series of diarylsulfonylurea NLRP3 fluorescent inhibitors bearing an amino benzodiazole fluorophore. Compared to the previously reported NLRP3 fluorescent probes, these inhibitors are more structurally concise and membrane permeable due to no additionally appended fluorophore via a linker. Among this series, compound 13a exhibited the most potent cellular NLRP3 inhibitory effect with an IC50 value of 49 nM, and significantly suppressed LPS/Nigericin-induced secretion of active caspase-1 and mature IL-1ß in a dose-dependent manner to block the activation of NLRP3 inflammasome. Meanwhile, this new probe exhibited promising fluorescent properties for specifically detecting and imaging the LPS-induced or constitutively expressed NLRP3 proteins in RAW264.7 cells. Collectively, probe 13a is a potent NLRP3 fluorescent inhibitor with cellular NLRP3 imaging ability, which is useful for NLRP3 inhibitor screening and related mechanism study.

MiR-125b promotes proliferation and migration of type II endometrial carcinoma cells through targeting TP53INP1 tumor suppressor in vitro and in vivo.

BACKGROUND: Our previous studies have identified that miR-125b was overexpressed in type II endometrial carcinoma (EC) cells compared with type I using microRNAs microarray. Although recent studies have shown the important role of miR-125b in several tumors and overexpression of miR-125b in advanced EC, its function in this disease has not yet been defined. In the present study, we tried to confirm the result of microRNAs microarray and further investigated the functions of miR-125b in EC, and tried to find new downstream targets of miR-125b. METHODS: Differential expression of miR-125b was detected between type II EC cells (KLE, AN3CA) with ER negative and type I EC cells (ishikawa, RL95-2) with ER positive by qRT-PCR and northern blotting. The effects of miR-125b of on proliferation, migration, and target protein expression were evaluated by CCK8 assay, wound healing assay, transwell migration assay, western blotting, and Tumorigenicity assays in nude mice. In addition, luciferase reporter plasmid was constructed to demonstrate the direct target of miR-125b. RESULTS: MiR-125b was overexpressed in type II EC cells compared with type I. Exogenous miR-125b expression increased proliferation and migration of ishikawa cells and abrogating expression of miR-125b suppressed proliferation, and migration of AN3CA cells in vitro. In addition, in vivo tumor formation assay confirmed that forced miR-125b expression promoted proliferation potential of ishikawa cells, and tumor suppressor gene Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) was identified to be the direct target of miR-125b. CONCLUSIONS: TP53INP1 was newly identified to be the direct downstream target of miR-125b. MiR-125b, which was overexpressed in type II EC cells compared with type I, contributes to malignancy of type II EC possibly through down-regulating TP53INP1.

Solvothermal synthesis of nanoporous polymer chalk for painting superhydrophobic surfaces.

Reported here is a facile synthesis of nanoporous polymer chalk for painting superhydrophobic surfaces. Taking this nanoporous polymer as a media, superhydrophobicity is rapidly imparted onto three typical kinds of substrates, including paper, transparent polydimethylsiloxane (PDMS), and finger skin. Quantitative characterization showed that the adhesion between the water droplet and polymer-coated substrates decreased significantly compared to that on the original surface, further indicating the effective wetting mode transformation. The nanoporous polymer coating would open a new door for facile, rapid, safe, and larger scale fabrication of superhydrophobic surfaces on general substrates.

Crosstalk between estrogen receptor and mitogen-activated protein kinase signaling in the development and progression of endometrial cancer.

OBJECTIVE: The objectives of the study were to evaluate the role of mitogen-activated protein kinase (MAPK) signaling in normal, hyperplastic, and neoplastic endometrium in relation to estrogen receptor (ER) status and to investigate whether 17ß-estradiol (E2) and tamoxifen (TAM) mediate the proliferation and apoptosis of endometrial cancer cells through the MAPK pathway. METHODS: The expressions of phosphorylated and total extracellular signal-regulated kinases 1/2 (phosphorylated extracellular signal-regulated kinase 1/2 [p-ERK1/2] and total ERK1/2 [t-ERK1/2]) were analyzed with immunohistochemistry in normal, hyperplastic, and neoplastic endometrium. The expression levels of p-ERK1/2 and t-ERK1/2 in RL95-2 and KLE after stimulation by E2, progesterone (P), and TAM were detected by Western blotting. The effects of E2 and TAM in combination with MAPK pathway inhibitors on the growth and apoptosis of endometrial cancer cells were examined by the MTS assay and flow cytometry analysis. RESULTS: The expression level of p-ERK1/2 was significantly associated with the International Federation of Gynecology and Obstetrics stage (P = 0.0072). The ratio of phosphorylated/total ERK1/2 was higher in ER-positive endometrial cancer tissues and cells (P < 0.05). 17ß-Estradiol increased ERK1/2 phosphorylation, and TAM decreased ERK1/2 phosphorylation in endometrial cancer cell lines within 30 minutes (P < 0.05). The MEK1/2 inhibitor, U0126, and the stress-activated protein kinase/c-Jun NH2-terminal kinase inhibitor, SP600125, significantly suppressed the proliferation of human endometrial cancer cell lines RL95-2 and KLE induced by E2 (P < 0.05). The level of TAM-induced apoptosis was greater in KLE than in RL95-2 cells, and the p38 cascade was involved in the TAM-induced apoptosis of both cell lines (P < 0.05). CONCLUSIONS: The cross-talk between MAPK signaling and ER status might exert a key role in progression of endometrial cancer. Furthermore, the effects of E2 or TAM on the proliferation or apoptosis of ER-positive and ER-negative endometrial cancer cells were mediated through distinct MAPK pathways. These mechanisms might contribute to ER-specific differences in MAPK activation for molecular-target therapies in endometrial carcinoma.

Research progress on the association between environmental pollutants and the resistance mechanism of PARP inhibitors in ovarian cancer.

The occurrence and progression of ovarian cancer are closely related to genetics and environmental pollutants. Poly(ADP-ribose) polymerase (PARP) inhibitors have been a major breakthrough in the history of ovarian cancer treatment. PARP is an enzyme responsible for post-translational modification of proteins and repair of single-stranded DNA damage. PARP inhibitors can selectively inhibit PARP function, resulting in a synthetic lethal effect on tumor cells defective in homologous recombination repair. However, with large-scale application, drug resistance also inevitably appears. For PARP inhibitors, the diversity and complexity of drug resistance mechanisms have always been difficult problems in clinical treatment. Herein, we mainly summarized the research progress of DNA damage repair and drug resistance mechanisms related to PARP inhibitors and the impact of environmental pollutants on DNA damage repair to aid the development prospects and highlight urgent problems to be solved.

LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells.

Ovarian cancer is one of the most lethal gynecologic malignancies. It has been shown that PARP inhibitors can selectively target BRCA-mutated ovarian cancer and exert some effects on ovarian cancer without BRCA mutations. However, the mechanism is still unclear. In this study, wild-type BRCA ovarian cancer cells (A2780 and SKOV3) were used. Our results showed that using a PARP inhibitor (olaparib or AG14361) alone significantly inhibited the proliferation of A2780 cells but negligibly inhibited the proliferation of SKOV3 cells. We used RNA sequencing to explore differentially expressed genes and found that PARP inhibitors increased LDH-A in SKOV3 cells, which was confirmed by RT-PCR. Oxamate (a specific inhibitor of LDH-A) was used to investigate whether LDH-A inhibition enhances the suppressive effects of PARP inhibitors on ovarian cancer without BRCA mutations. CCK-8 assays, scratch assays and Transwell assays were used to determine cell proliferation, cell migration ability and invasion ability, respectively. Both olaparib and AG14361 significantly inhibited the proliferation/invasion ability of A2780 cells but not SKOV3 cells. Inhibition of LDH-A can remarkably promote the inhibitory effects of PARP inhibitors on both A2780 and SKOV3 cells. Thus, high expression level of LDH-A influenced the suppressive effects of PARP inhibitors on ovarian cancer with wild-type BRCA, and LDH-A inhibition notably enhanced this effect.