ZNF554 Inhibits Endometrial Cancer Progression via Regulating RBM5 and Inactivating WNT/ß-Catenin Signaling Pathway.

OBJECTIVE: Uterine corpus endometrial carcinoma (UCEC), a kind of gynecologic malignancy, poses a significant risk to women's health. The precise mechanism underlying the development of UCEC remains elusive. Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein superfamily, was reported to be dysregulated in various illnesses, including malignant tumors. This study aimed to examine the involvement of ZNF554 in the development of UCEC. METHODS: The expression of ZNF554 in UCEC tissues and cell lines were examined by qRT-PCR and Western blot assay. Cells with stably overexpressed or knocked-down ZNF554 were established through lentivirus infection. CCK-8, wound healing, and Transwell invasion assays were employed to assess cell proliferation, migration, and invasion. Propidium iodide (PI) staining combined with fluorescence-activated cell sorting (FACS) flow cytometer was utilized to detect cell cycle distribution. qRT-PCR and Western blotting were conducted to examine relative mRNA and protein levels. Chromatin immunoprecipitation assay and luciferase reporter assay were used to explore the regulatory role of ZNF554 in RNA binding motif 5 (RBM5). RESULTS: The expression of ZNF554 was found to be reduced in both UCEC samples and cell lines. Decreased expression of ZNF554 was associated with higher tumor stage, decreased overall survival, and reduced disease-free survival in UCEC. ZNF554 overexpression suppressed cell proliferation, migration, and invasion, while also inducing cell cycle arrest. In contrast, a decrease in ZNF554 expression resulted in the opposite effect. Mechanistically, ZNF554 transcriptionally regulated RBM5, leading to the deactivation of the Wingless (WNT)/ß-catenin signaling pathway. Moreover, the findings from rescue studies demonstrated that the inhibition of RBM5 negated the impact of ZNF554 overexpression on ß-catenin and p-glycogen synthase kinase-3ß (p-GSK-3ß). Similarly, the deliberate activation of RBM5 reduced the increase in ß-catenin and p-GSK-3ß caused by the suppression of ZNF554. In vitro experiments showed that ZNF554 overexpression-induced decreases in cell proliferation and migration were counteracted by RBM5 knockdown. Additionally, when RBM5 was overexpressed, it hindered the improvements in cell proliferation and migration caused by reducing the ZNF554 levels. CONCLUSION: ZNF554 functions as a tumor suppressor in UCEC. Furthermore, ZNF554 regulates UCEC progression through the RBM5/WNT/ß-catenin signaling pathway. ZNF554 shows a promise as both a prognostic biomarker and a therapeutic target for UCEC.

Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury.

Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.

WNT4 promotes macrophage polarization via granulosa cell M-CSF and reduces granulosa cell apoptosis in endometriosis.

BACKGROUND: WNT4 gene polymorphism are common in endometriosis and may functionally link estrogen and estrogen receptor signaling. Previous study confirmed estrogen and estrogen receptor signaling recruit macrophage to promote the pathogenesis of endometriosis. To investigate the effect of WNT4 in endometriosis involved in macrophage polarization and whether WNT4 could reduce the apoptosis of granulosa cells. METHODS: An observational study consisting of 8 cases of women with endometriosis (diagnosed by surgery and histology) and 22 mice of endometriosis animal model was conducted. Granulosa cells were isolated from 16 patients with endometriosis and co-cultured with macrophage under WNT4 treatment using TUNEL assay, quantitative reverse transcription PCR, flow cytometry and ELISA analysis. 22 mice of endometriosis animal model confirmed the WNT4 treatment effects using histology and immunohistochemistry, Western blot and flow cytometry. RESULTS: We observed that the apoptotic proportion of granulosa cells was significantly decreased and M2 macrophage was significantly increased after WNT4 treatment during the granulosa cell and macrophage co-culture system. To reveal the underlying mechanism for this, we conducted a series of experiments and found that high expression of granulosa cell M-CSF led to the M2 polarization of macrophages. The animal model also suggested that the anti-apoptotic effect of WNT4 on granulosa cells were conducted by the M2 polarized macrophage. CONCLUSIONS: WNT4 could reduce granulosa cell apoptosis and improve ovarian reserve by promoting macrophage polarization in endometriosis. M-CSF secreted by granulosa cell after WNT4 treatment was the main mediator of macrophage polarization.

Natural flavonoids disrupt bacterial iron homeostasis to potentiate colistin efficacy.

In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids-7,8-dihydroxyflavone, myricetin, and luteolin-prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system pmrA/pmrB, thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.

Changes in Nutritional Status of Cancer Patients Undergoing Proton Radiation Therapy Based on Real-World Data.

Methods: Observational study on 47 adult hospitalized cancer patients including 27 males and 20 females who received proton beam radiotherapy during December 2021 and August 2022. Nutritional assessments, 24 h dietary survey, handgrip strength (HGS) test, anthropometrical measurements, and hematological parameters were conducted or collected at the beginning and the completion of treatment. Results: The rate of nutritional risk and malnutrition among the total of 47 enrolled patients was 4.3% and 12.8% at the onset of proton radiation and raised up to 6.4% and 27.7% at the end of the treatment. 42.6% of patients experienced weight loss during the proton radiotherapy, and 1 of them had weight loss over 5%, and in general, the average body weight was stable over radiotherapy. The changes in patients' 24 h dietary intakes, HGS, and anthropometrical parameters, including triceps skinfold thickness (TSF), midupper arm circumference (MUAC), and midupper arm muscle circumference (MAMC), were statistically insignificant over the treatment (all p values > 0.05). The changes in patients' hematological parameters, including total protein (TP) and serum albumin (ALB), were not statistically significant over the treatment (all p values >0.05), and the level of hemoglobin (HGB) at the end of treatment was higher than that at the onset (p < 0.05). Conclusion: The results of this study demonstrated that proton radiotherapy might have a lighter effect on the nutritional status of cancer patients.

Bacterial Vaginosis Decreases the Risk of Cervical Cytological Abnormalities.

Genital tract infections, including vulvovaginal candidiasis and bacterial vaginosis, have emerged as potential modulators of persistent human papillomavirus (HPV) infections causing cervical cytologic abnormalities and cervical cancer. This study aimed to investigate whether vulvovaginal candidiasis or bacterial vaginosis had an additional effect on HPV infection and thus caused such abnormalities. ThinPrep cytologic tests were used to detect cytologic abnormalities, vulvovaginal candidiasis, and bacterial vaginosis in 14,679 women. Cytologic abnormalities included atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, atypical squamous cells-cannot exclude HSIL, and squamous cell carcinoma. Logistic regression Model 1 (univariate regression) and Model 2 (multivariate logistic regression analysis adjusted for age combined with HPV infection) were used to analyze the association between bacterial vaginosis and cytologic abnormalities, or vulvovaginal candidiasis and cytologic abnormalities, alone or in the presence of HPV infection. Bacterial vaginosis infection rates were found to be significantly higher in the cytology-negative group among all participants and those with HPV infection (P = 0.003, P < 0.001, respectively). Analyses using Model 1 and Model 2 both pointed to bacterial vaginosis as a protective factor against cytologic abnormalities for all participants (OR = 0.36, 0.17, respectively, P < 0.05) and for HPV-infected participants (OR = 0.17, 0.16, respectively, P < 0.05). Neither vulvovaginal candidiasis nor vulvovaginal candidiasis + HPV was significantly associated with the incidence of cytologic abnormalities based on Model 1 (OR = 0.94, 0.71, respectively, P > 0.05) and Model 2 (OR = 0.91, 0.74, respectively, P > 0.05). Furthermore, neither vulvovaginal candidiasis nor bacterial vaginosis increased the incidence of cytologic abnormalities regardless of HPV infection status, while bacterial vaginosis might possibly prevent cytologic abnormalities in women coinfected by HPV. PREVENTION RELEVANCE: Neither vulvovaginal candidiasis nor bacterial vaginosis was found to increase the incidence of cervical cytologic abnormalities with or without the presence of HPV. On the contrary, bacterial vaginosis may play a role in preventing cytologic abnormalities in women with HPV coinfection.

Associations of multiple plasma metals with chronic kidney disease in patients with diabetes.

As common contaminants, metals are non-negligible risk factors for diabetes and chronic kidney disease. However, whether there is an association between multiple metals exposure and incident chronic kidney disease (CKD) risk in patients with diabetes is unclear. We conducted a prospective study to evaluate these associations. In total, 3071 diabetics with baseline estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 from the Dongfeng-Tongji cohort were included. We measured baseline plasma concentrations of 23 metals and investigated the associations between plasma metal concentrations and CKD in diabetics using logistic regression, the least absolute shrinkage and selection operator (LASSO), and the Bayesian Kernel Machine Regression (BKMR) models. During average 4.6 years of follow-up, 457 diabetics developed CKD (14.9 %). The three models consistently found plasma levels of zinc, arsenic, and rubidium had a positive association with incident CKD risk in patients with diabetes, while titanium, cadmium, and lead had an inverse correlation. The results of BKMR showed a significant and positive overall effect of 23 metals on the risk of CKD, when all of the metals were above the 50th percentile as compared to the median value. In addition, potential interactions of zinc and arsenic, zinc and cadmium, zinc and lead, titanium and arsenic, and cadmium and lead on CKD risk were observed. In summary, we found significant associations of plasma titanium, zinc, arsenic, rubidium, cadmium, and lead with CKD in diabetes and interactions between these metals except for rubidium. Co-exposure to multiple metals was associated with increased CKD risk in diabetics.

Anlotinib improved the reactive cutaneous capillary endothelial proliferation induced by camrelizumab: a case report.

Background: Programmed cell death protein-1 (PD-1) or its ligand PD-L1 monoclonal antibodies, opening a new era of tumor immunotherapy, and they have significantly improved the overall survival of many patients with advanced solid tumors. However, in addition to its effectiveness, we should also pay attention to its adverse effects. The instructions of the PD-1 inhibitor camrelizumab clearly indicate that reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse reaction; it is common for many immune checkpoint inhibitors (ICIs). Here we describe a case that anlotinib improved RCCEP induced by anti-PD-1 blockade camrelizumab with some focus on further management of this symptoms. Case Description: A 57-year-old man with squamous cell carcinoma of the upper lobe of the left lung, and with mediastinal lymphocyte and liver metastasis, received the fifth cycle of chemotherapy and immunotherapy with camrelizumab (200 mg, every 3 weeks). Four days after treatment with camrelizumab, the patient's face, head, neck, and chest skin had multiple scattered bright red round papules, which were diagnosed as RCCEP. The patient was treated with oral anlotinib (8 mg, once a day). After 5 days of treatment, the symptoms of RCCEP gradually eased, and the patient was discharged. Conclusions: In conclusion, we have reported a case of RCCEP induced by anti-PD-1 blockade camrelizumab. The patient was given oral anlotinib to relieve the symptoms of RCCEP. Suggesting that anlotinib could be a potential management to reduce the adverse reactions who are treated with camrelizumab. The risk for RCCEP should always be kept in mind during camrelizumab treatment.

Sonosensitizer nanoplatform-mediated sonodynamic therapy induced immunogenic cell death and tumor immune microenvironment variation.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies, and effective treatments are still lacking due to drug tolerance and tumor recurrence. In this study, we aimed to investigate the effects of sonodynamic therapy (SDT) on ovarian cancer and its potential mechanism. Folate receptor-targeted and ultrasound-responsive nanoparticles (NPs) were constructed using PLGA-PEG-FA (PLGA: poly (lactic-co-glycolic) acid, polyethylene glycol (PEG), FA: folate), the reactive oxygen species (ROS)-generating sonosensitizer IR780 and the oxygen-carrying material perfluorohexane (PFH), termed IRO@FA NPs. The antitumor effect of NPs triggered by ultrasound (US) was measured by an apoptosis assay in a C57/BL6 mouse model. Immunochemistry and flow cytometry were used to detect the proportion of CD3+ T, CD4+ T, CD8+ T cells and activated dendritic cells (DCs) in spleens and tumor tissues to assess variation in the immune response. Moreover, endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) markers (high mobility group protein box-1, ATP and calreticulin) were detected to identify potential mechanisms. The results showed that IRO@FA NP-mediated SDT promoted ID8 cell apoptosis both in vitro and in vivo. The densities of CD3+ and CD8+ T lymphocytes and inflammatory markers were upregulated in tumor tissues. IRO@FA NP-mediated SDT prompted DC maturation and T lymphocyte infiltration by inducing ID8 cell ICD.

Tumor-associated macrophages induced spheroid formation by CCL18-ZEB1-M-CSF feedback loop to promote transcoelomic metastasis of ovarian cancer.

BACKGROUND: Ovarian cancer (OvCa)-tumor-associated macrophages (TAMs) spheroids are abundantly present within ascites of high malignant patients. This study investigated the mutual interaction of OvCa cells and TAMs in the spheroids. METHODS: Three-dimensional coculture system and transwell coculture system were created to mimic the OvCa and TAMs in spheroids and in disassociated state. Transwell-migration assay and scratch wound healing assay were used to measure the invasive and migratory capacity. Western blot, quantitative reverse transcription-PCR and immunostaining were used to measure the mesenchymal and epithelial markers. Flow cytometry was used to assess the polarization of TAMs. Also, the differential gene expression profile of OvCa cells and OvCa cells from spheroids were tested by RNA-sequence. Finally, the ovarian mice models were constructed by intraperitoneal injection of ID8 or OvCa-TAMs spheroids. RESULTS: Our results indicated that the formation of OvCa-TAMs spheroids was positive related to the malignancy of OvCa cells. M2-TAMs induced the epithelial-mesenchymal transition of OvCa cells by releasing chemokine (C-C motif) ligand 18 (CCL18) in the spheroids. While, CCL18 induced macrophage colony-stimulating factor (M-CSF) transcription in OvCa cells through zinc finger E-box-binding homeobox 1 (ZEB1). This study further indicated that M-CSF secreted by OvCa cells drived the polarization of M2-TAMs. Therefore, a CCL18-ZEB1-M-CSF interacting loop between OvCa cells and TAMs in the spheroids was identified. Moreover, with blocking the expression of ZEB1 in the OvCa cell, the formation of OvCa-TAMs spheroids was impeded. In the ovarian mice models, the formation of OvCa-TAMs spheroids in the ascites was promoted by overexpressing of ZEB1 in OvCa cells, which resulted in faster and earlier transcoelomic metastasis. CONCLUSION: These findings suggested that the formation of OvCa-TAMs spheroids resulted in aggressive phenotype of OvCa cells, as a specific feedback loop CCL18-ZEB1-M-CSF in it. Inhibition of ZEB1 reduced OvCa-TAMs spheroids in the ascites, impeding the transcoelomic metastasis and improving the outcome of ovarian patients.

Protective Effects of Reduced Glutathione and Ulinastatin on Xeno-transplanted Human Ovarian Tissue Against Ischemia and Reperfusion Injury.

Recently, transplantation of cryopreserved ovarian tissue is the method for fertility preservation for oncologic and nononcologic reasons. The main challenge of ovarian cryopreservation followed by transplantation is that ischemia reperfusion injury (IRI) induced the loss of follicles. The aim of this study was to evaluate the effects of glutathione (GSH), ulinastatin (UTI) or both (GSH+UTI) on preventing ischemia reperfusion-induced follicles depletion in ovarian grafts.Ovarian fragments were collected from 20 women aged 29±6 years. Frozen-thawed human ovarian tissue was xenografted into SCID mice, at the same time GSH, UTI and GSH+UTI was administrated respectively. The ovarian grafts were collected at the 1st, 3rd, 7th, 14th, 28th, 56th, and 85th day after xenotransplantation. Follicle survival rate was measured by H&E staining and Live/Dead staining. Angiogenic activity and macrophage recruitment was evidenced by immunohistochemical staining. The oxidative stress and inflammatory cytokines in human ovarian xenografts were measured by real-time PCR. The results indicated that after the treatments of GSH, UTI and GSH+UTI in the hosts, follicular survival in ovarian grafts were improved. The level of VEGF, CD31, and antioxidant enzymes superoxide dismutase 1 and superoxide dismutase 2 in ovarian grafts were increased. Accumulation of macrophages, level of IL6 and TNF-α, as well as malondialdehyde was decreased in ovarian grafts from treated groups. In conclusion, administration of GSH, UTI and GSH+UTI decreased the depletion of follicles in human grafts post-transplantation by inhibiting IRI-induced antiangiogenesis, oxidative stress and inflammation.

Risk Factors for Urinary Incontinence in Chinese Women: A Cross-sectional Survey.

OBJECTIVE: Urinary incontinence is highly prevalent among women, with a substantial effect on health-related quality of life. This article aimed to investigate the independent factors for urinary incontinence (UI) and the relative importance of each factor. METHODS: This study was a cross-sectional survey of Chinese women in Guangzhou. Female 20 years and older were invited to participate. The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form was used to determine whether respondents are experiencing UI. Univariate and multivariate unconditional logistic regression analyses were performed to determine the significant risk factors associated with UI. RESULTS: A total of 2626 women were invited to participate in the survey. The response rate was 80.5% (2114/2626). The prevalence of UI among the study population was 31.2%. Old age, increased body mass index, childbirth, family history of any female pelvic floor disorders, symptoms of chronic cough or rhinitis, wearing a corset, and often drinking were independent risk factors for UI. CONCLUSIONS: Urinary incontinence is common among Chinese women in Guangzhou. Among the factors that we are concerned with, old age and vaginal delivery are the two with greatest impact. Moreover, wearing a corset and drinking are the 2 lifestyle factors associated with UI.

Severe cervical inflammation and high-grade squamous intraepithelial lesions: a cross-sectional study.

PURPOSE: Inflammation has been reported as a facilitator in cervical oncogenesis, but the correlation between inflammation and cytological abnormality remains uncertain. The aim of this study was to investigate the correlation between inflammation and cytological abnormality. METHODS: ThinPrep cytological test (TCT) was used to detect cervical cytological abnormalities and inflammation degrees of 46,255 women in this prospective cross-sectional study. Histopathological examination was used to define the cervical intraepithelial neoplasia (CIN) in patients with cervical cytological abnormalities. RESULTS: The study revealed that 8.87% (4102/46,255) of TCT results had cytological abnormalities. The 4102 included cases were classified as the case group, including atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Women with negative intraepithelial lesion or malignancy (NILM) were classified as the control group. About 88.83% (3644/4102) of women with cytological abnormalities showed inflammations. The rate of severe inflammation was significantly higher in the case group than the control group (23.86% vs. 2.0%, P = 0.000). Our results also showed that patients with severe inflammation had a significantly increasing incidence of cytological abnormality by 12.598 times and elevated the risk of HSIL by 756.47 times, compared to the inflammation negative group. CONCLUSION: Severe inflammation was positively related to HSIL. Patients with severe cervical inflammation should be given more follow-ups and regular examinations and treated more carefully than those with mild or no inflammation.

Plasma metals and cancer incidence in patients with type 2 diabetes.

There is limited evidence on the relationships between plasma levels of multiple metals and risk of incident cancer in patients with type 2 diabetes mellitus (T2DM). We examined the associations between plasma levels of 12 metals (iron, copper, zinc, selenium, chromium, manganese, molybdenum, cobalt, nickel, arsenic, cadmium, and lead) and cancer risk in 4573 T2DM patients using Cox proportional hazards models. With a median follow-up of 10.2 years, 541 incident cancers were identified. The multiple-metals model revealed that each 1-SD increase in ln-transformed plasma copper (HR: 1.14; 95%CI: 1.02, 1.27) and lead (HR:1.20; 95%CI:1.03, 1.39) were significantly associated with increased cancer incidence while each 1-SD increase in ln-transformed plasma zinc (HR: 0.82; 95%CI: 0.71, 0.96) and chromium (HR: 0.88; 95%CI: 0.82, 0.94) were significantly associated with decreased cancer incidence. When all participants were further stratified into four subgroups by the quartile levels (Q1-4) of plasma metals, manganese showed significant positive associations with cancer incidence in the upper two quartiles (P trend = 0.003) while nickel showed significant negative associations with cancer incidence in Q2 and 4 groups (P trend = 0.033) compared with participants in Q1 group. Collectively, monitoring of metal levels in diabetic patients needs to be strengthened, which is of great significance for the prevention of incident cancer.

Ultrasound-Mediated Long-Circulating Nanopolymer Delivery of Therapeutic siRNA and Antisense MicroRNAs Leads to Enhanced Paclitaxel Sensitivity in Epithelial Ovarian Cancer Chemotherapy.

Epithelial ovarian cancer (EOC) is one of the leading malignant tumors that seriously threaten women's health. The development of new drugs or increasing the sensitivities of current chemotherapy drugs is critically needed. The purpose of this study was to assess the synergistic effects of two silencing RNAs [salt-inducible kinase 2 (SIK2) siRNA and antisense-microRNA21 (anti-miR21)] encapsulated in long-circulating folate-lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanopolymers (FaLPHNPs) administered using an ultrasound- and microbubble (US-MB)-mediated approach to sensitize human EOC xenografts to paclitaxel (PTX). In the in vitro assays, this lipid-PLGA hybrid nanopolymer exhibited an extended circulation profile (t1/2: ∼8.5 h); US-MB-mediated complementary delivery of FaLPHNPs resulted in a significant reduction in EOC cell (OVCR3, A2780, and SKOV3) proliferation. In vivo, there was a 2.5-fold increase (p < 0.05) in RNA delivery in EOC xenografts, which resulted in a notable inhibition of tumor growth compared with that in the non-ultrasound-mediated and PTX alone-treated controls. We validated the therapeutic roles of SIK2, the target gene in treating advanced ovarian cancer, and anti-miR21 by evaluating the significant inhibition of tumor growth upon SIK2 silencing and inhibition of endogenous miR21 function. In summary, the results of this study revealed that US-MB-mediated codelivery of SIK2 siRNA, and anti-miR21 encapsulated in a folate-lipid-PLGA hybrid polymer nanoparticle could significantly improve the sensitivity of EOC tumors to PTX and is a highly effective approach for treating EOC in complementary experiments. Further research of this strategy could lead to better treatment results for patients with EOC.

SPOP Regulates The Biological Mechanism Of Ovarian Cancer Cells Through The Hh Signaling Pathway.

BACKGROUND: Ovarian cancer is characterized by high metastatic potential and high mortality. More than 80% of primary ovarian malignancies are epithelial ovarian cancers. There is increasing evidence that Speckle-type POZ protein (SPOP) is highly correlated with the development of various types of cancer. However, the effects of SPOP on epithelial ovarian cancer and the associated molecular mechanisms remain unclear. MATERIALS AND METHODS: We compared SPOP expression between epithelial ovarian cancer tissues and normal ovarian tissues by using immunohistochemical staining. To determine the role of SPOP in epithelial ovarian cancer cells, we overexpressed or knocked down SPOP in the epithelial ovarian cancer cell line OVCAR-3 using lentiviral vectors. RESULTS: Our results from the present study indicated that SPOP expression was significantly downregulated in human epithelial ovarian cancer and was associated with the FIGO stage and the histopathologic grading of the tumor. The overexpression and knockdown experiments revealed that SPOP inhibited proliferation while promoting apoptosis in ovarian cancer cells. Inhibition of SPOP mis-activated the Hedgehog (Hh) signaling pathway, thereby inhibiting apoptosis in ovarian cancer cells. CONCLUSION: SPOP suppresses proliferation and promotes apoptosis in human ovarian cancer cells by inhibiting the Hh signaling pathway, offering the possibility of new approaches for the treatment of ovarian cancer.

Association between exposure to arsenic, nickel, cadmium, selenium, and zinc and fasting blood glucose levels.

Associations between single metal and fasting blood glucose (FBG) levels have been reported in previous studies. However, the association between multi-metals exposure and FBG level are little known. To assess the joints of arsenic (As), nickel (Ni), cadmium (Cd), selenium (Se), and zinc (Zn) co-exposure on FBG levels, Bayesian kernel machine regression (BKMR) statistical method was used to estimate the potential joint associations between As, Ni, Cd, Se, and Zn co-exposure and FBG levels among 1478 community-based Chinese adults from two counties, Shimen (n = 696) and Huayuan (n = 782), with different exposure profiles in Hunan province of China. The metals levels were measured in spot urine (As, Ni, and Cd) and plasma (Se and Zn) using inductively coupled plasma-mass spectrometry, respectively. The exposure levels of all the five metals were significantly higher in Shimen area (median: As = 57.76 µg/L, Cd = 2.75 µg/L, Ni = 2.73 µg/L, Se = 112.67 µg/L, Zn = 905.68 µg/L) than those in Huayuan area (As = 41.14 µg/L, Cd = 2.22 µg/L, Ni = 1.88 µg/L, Se = 65.59 µg/L, Zn = 819.18 µg/L). The BKMR analyses showed a significantly positive over-all effect of the five metals on FBG levels when metals concentrations were all above the 50th percentile while a statistically negative over-all effect when metals concentrations were all under the 50th percentile in Shimen area. However, a totally opposite over-all effect of the mixture of the five metals on FBG levels was found in Huayuan area. BKMR also revealed a non-linear exposure-effect of Zn on FBG levels in Huayuan area. In addition, interaction effects of As and Se on FBG level were observed. The relationship between single or combined metals exposure and FBG was different against different exposure profiles. Potential interaction effects of As and Se on FBG levels may exist.

Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling.

BACKGROUND: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. This study demonstrates the antiangiogenic effects of scutellarin (SCU) on high glucose- and hypoxia-stimulated human retinal endothelial cells (HRECs) and on a diabetic rat model by oral administration. The antiangiogenic mechanisms of SCU in vitro and in vivo were investigated. METHOD: HRECs were cultured in high glucose- (30 mM D-glucose) and hypoxia (cobalt chloride-treated)-stimulated diabetic condition to evaluate the antiangiogenic effects of SCU by CCK-8 test, cell migration experiment (wound healing and transwell), and tube formation experiment. A streptozotocin-induced type II diabetic rat model was established to measure the effects of oral administration of SCU on protecting retinal microvascular dysfunction by Doppler waveforms and HE staining. We further used western blot, luciferase reporter assay, and immunofluorescence staining to study the antiangiogenic mechanism of SCU. The protein levels of phospho-ERK, phospho-FAK, phospho-Src, VEGF, and PEDF were examined in HRECs and retina of diabetic rats. RESULT: Our results indicated that SCU attenuated diabetes-induced HREC proliferation, migration, and tube formation and decreased neovascularization and resistive index in the retina of diabetic rats by oral administration. SCU suppressed the crosstalk of phospho-ERK, phospho-FAK, phospho-Src, and VEGF in vivo and in vitro. CONCLUSIONS: These results suggested that SCU can be an oral drug to alleviate microvascular dysfunction of DR and exerts its antiangiogenic effects by inhibiting the expression of the crosstalk of VEGF, p-ERK, p-FAK, and p-Src.

The impact of robustness of deformable image registration on contour propagation and dose accumulation for head and neck adaptive radiotherapy.

Deformable image registration (DIR) is the key process for contour propagation and dose accumulation in adaptive radiation therapy (ART). However, currently, ART suffers from a lack of understanding of "robustness" of the process involving the image contour based on DIR and subsequent dose variations caused by algorithm itself and the presetting parameters. The purpose of this research is to evaluate the DIR caused variations for contour propagation and dose accumulation during ART using the RayStation treatment planning system. Ten head and neck cancer patients were selected for retrospective studies. Contours were performed by a single radiation oncologist and new treatment plans were generated on the weekly CT scans for all patients. For each DIR process, four deformation vector fields (DVFs) were generated to propagate contours and accumulate weekly dose by the following algorithms: (a) ANACONDA with simple presetting parameters, (b) ANACONDA with detailed presetting parameters, (c) MORFEUS with simple presetting parameters, and (d) MORFEUS with detailed presetting parameters. The geometric evaluation considered DICE coefficient and Hausdorff distance. The dosimetric evaluation included D95 , Dmax , Dmean , Dmin , and Homogeneity Index. For geometric evaluation, the DICE coefficient variations of the GTV were found to be 0.78 ± 0.11, 0.96 ± 0.02, 0.64 ± 0.15, and 0.91 ± 0.03 for simple ANACONDA, detailed ANACONDA, simple MORFEUS, and detailed MORFEUS, respectively. For dosimetric evaluation, the corresponding Homogeneity Index variations were found to be 0.137 ± 0.115, 0.006 ± 0.032, 0.197 ± 0.096, and 0.006 ± 0.033, respectively. The coherent geometric and dosimetric variations also consisted in large organs and small organs. Overall, the results demonstrated that the contour propagation and dose accumulation in clinical ART were influenced by the DIR algorithm, and to a greater extent by the presetting parameters. A quality assurance procedure should be established for the proper use of a commercial DIR for adaptive radiation therapy.

Anti-inflammatory effect of Mongolian drug Naru-3 on traumatic spinal cord injury and its mechanism of action.

Objective This study was performed to confirm the anti-inflammatory effect of the Mongolian drug Naru-3 on traumatic spinal cord injury (TSCI) and its possible mechanism of action. Methods We prepared a TSCI model using Sprague-Dawley rats. The rats were divided into a Naru-3 group and a methylprednisolone group. Real-time polymerase chain reaction and western blotting were performed to measure the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß. Enzyme-linked immunosorbent assay kits were employed to detect serum inflammatory cytokine levels. The localization and expression of monocyte chemotactic protein-1 (MCP-1) in spinal cord tissue was determined by immunohistochemical analysis. Flow cytometry was performed to analyze the ratio of M1- and M2-phenotype macrophages. The locomotor function recovery was evaluated by the Basso, Beattie, and Bresnahan score. Results Naru-3 significantly inhibited the inflammatory response and reduced the expression of TNF-α, IL-6, and IL-1ß in both spinal cord and blood in a time- and concentration-dependent manner. Immunohistochemical analysis indicated that Naru-3 significantly reduced MCP-1 expression in spinal cord and promoted M2-phenotype macrophage differentiation. Conclusions Naru-3 is an effective treatment for impact-induced TSCI in rats. Naru-3 treatment affects inflammatory cytokine levels and macrophage differentiation, which play a role in TSCI remission.