The Development of the Stress-Free Polishing System Based on the Positioning Error Analysis for the Deterministic Polishing of Jet Electrochemical Machining.

Deterministic polishing based on jet electrochemical machining (Jet-ECM) is a stress-free machining method for low-rigidity and ultra-precision workpieces. The nozzle is equivalent to a special tool in deterministic polishing, and the workpiece material is removed using the mechanism of electrochemical dissolution at the position where the nozzle passes. By precisely regulating the nozzle's movement speed and dwell time, the quantity of material removed from the workpiece at a designated position can be finely adjusted. With this mechanism, the improvement of the workpiece shape accuracy can be achieved by planning the nozzle trajectory and nozzle movement speed. However, due to the positioning errors of the polishing device, the actual position of the nozzle may deviate from the theoretical position, resulting in errors in material removal amount, which affects the accuracy and stability of the polishing process. This study established a mathematical model to analyze the influence of nozzle positioning errors in deterministic polishing based on Jet-ECM. This model has been used to design a specific deterministic polishing device based on Jet-ECM. With the proposed deterministic polishing device, the surface shape of the workpiece is converged. The surface peak-to-valley (PV) value of the φ 50 mm workpiece (valid dimensions = 90% of the central region) indicated that the shape error of the surface was reduced from 2.67 µm to 1.24 µm in 34 min. The power spectral density (PSD) method was used to evaluate the height distribution and height characteristics of the workpiece surface. The results show that the low frequency spatial error is reduced significantly after processing. This study improves the accuracy of the stress-free deterministic polishing methods and further expands the use of deterministic polishing in industry.

Diagnosis of leptospira by metagenomics next-generation sequencing with extracorporeal membrane oxygenation support: a case report.

BACKGROUND: Leptospirosis is an infectious disease caused by pathogenic Leptospira spp., which could result in severe illnesses. Indirect contact with these pathogens is more common. Individuals could contract this disease through contact with contaminated water or during floods. In this case, we present the details of a 40-year-old male pig farmer who suffered from severe pulmonary hemorrhagic leptospirosis and multiple organ failure. The diagnosis of leptospirosis was confirmed through metagenomics next-generation sequencing (mNGS) while the patient received extracorporeal membrane oxygenation (ECMO) support, and antibiotic treatment was adjusted accordingly. The patient underwent comprehensive treatment and rehabilitation in the intensive care unit. CONCLUSION: This case illustrates the importance of early diagnosis and treatment of leptospirosis. While obtaining the epidemiological history, second-generation metagenomics sequencing was utilized to confirm the etiology. The prompt initiation of ECMO therapy provided a crucial window of opportunity for addressing the underlying cause. This case report offers valuable insights for diagnosing patients with similar symptoms.

Dosimetric parameters and safety analysis of 3D-printing non-coplanar template-assisted interstitial brachytherapy for non-centrally recurrent cervical cancer.

Introduction: The prognosis of patients with non-central recurrent cervical cancer (NRCC) remains poor, and treatment options are limited. We aimed to explore the accuracy and safety of the 3D-printed non-coplanar template (3D-PNCT)-assisted 192Ir interstitial brachytherapy (ISBT) in the treatment of NRCC. Material and methods: A total of 36 patients with NRCC who received 3D-PNCT-guided 192Ir ISBT in the First Affiliated Hospital of Zhengzhou University from January 2021 to July 2022 were included in this study. There were 36 3D-PNCTs that were designed and printed. The prescribed dose was 30-36 Gy, divided into five to six times, once a week. To evaluate whether the actual parameters were consistent with the preoperative design, the dosimetric parameters of pre- and postoperative treatment plans were compared, including dose of 90% high-risk clinical target volume (HR-CTV D90), volume percentage of 100% and 150% prescribed dose V100% and V150%, homogeneity index (HI), conformal index (CI), external index (EI), and dose received by 2 cm3 (D2cm3) of the rectum, colon, bladder, and ileum. The safety parameters including occurrence of bleeding, infection, pain, radiation enteritis, and radiation cystitis within 3 months after operation were recorded. Results: All patients successfully completed the treatment and achieved the goals of the preoperative plan. There was no significant difference in the accuracy (HRCTVD90, V100%, EI, CI, and HI) and safety (D2cm3 of rectum, colon, bladder, and ileum) parameters of the postoperative plan compared with the preoperative plan (all p>0.05). Major side effects included bleeding at the puncture site (13.9%), postoperative pain (8.3%), acute radiation cystitis (13.9%), and radiation enteritis (19.4%). There were no serious perioperative complications and no grade 3-4 acute radiotherapy side effects. Conclusion: 3D-PNCT-assisted 192Ir ISBT can be accurately and safely applied in the treatment of patients with NRCC.

Combined GSK-3ß and MEK inhibitors modulate the stemness and radiotherapy sensitivity of cervical cancer stem cells through the Wnt signaling pathway.

Cancer stem cells (CSCs) are the basis of cancer and lead to the recurrence and metastasis of cervical cancer. The aim of this study was to investigate the effects of antineoplastic agents on the stemness and radiotherapy sensitivity of cervical CSCs. Side population (SP) and non-side population (NSP) cells from the SiHa cervical cancer cell line were separated using flow cytometry. The cell spheroidization, proliferation, and subcutaneous tumor formation abilities of SP cells were stronger than those of NSP cells, and cervical CSC marker expressions increased in SP cells. The proliferation, anti-apoptosis and migration of SP cells under ionizing radiation were higher than those of SiHa cells. GSK-3ß and/or MEK inhibitors can increase the proliferation, migration and anti-apoptosis of SP cells, and CSC marker expressions. The Wnt pathway inhibitor decreased CSC stemness maintenance by combination of GSK-3ß and MEK inhibitors. Injection of GSK-3ß and MEK inhibitors under ionizing radiation promoted tumor growth and activated downstream factor expressions in the Wnt signaling pathway in vivo. This study demonstrated that combining GSK-3ß and MEK inhibitors can activate Wnt signaling pathway in cervical CSCs, thereby affecting their stemness maintenance and radiotherapy sensitivity.

[The phenotypes and genotypes of four patients with Dubin-Johnson syndrome].

OBJECTIVE: To explore the genetic etiology in four patients with hyperbilirubinemia, and discuss the correlation between clinical characteristics and molecular basis. METHODS: The data of clinical manifestation and auxiliary examinations were collected. Genomic DNA of the four patients was extracted and analyzed by next-generation sequencing using the panel including genes involved in hereditary metabolic liver diseases. Suspected variants were verified by Sanger sequencing. RESULTS: All of the four patients were males with normal liver enzymes. It was revealed that all the patients had heterozygous variants, among which c.3011C>T, c.2443C>T and c.2556del were the variants which have not been reported previously. CONCLUSION: All of the patients were diagnosed as Dubin-Johnson syndrome (DJS) caused by ABCC2 gene variants. The novel variants add to the spectrum of genetic variants of the disease. Because of the favorite prognosis, precise diagnosis can greatly reduce the psychological pressure of patients and avoid excessive treatments. At the same time, it could provide pertinent genetic counseling for the families.

Alterations of Gut Microbiome and Fecal Fatty Acids in Patients With Polycystic Ovary Syndrome in Central China.

Objective: The purpose of this study was to elucidate the characteristics of the gut microbiome in patients with Polycystic ovary syndrome (PCOS) and analyze the alterations of fecal fatty acid metabolism, so as to further provide the pathogenesis of PCOS. Methods: Fecal samples from the PCOS group (n = 31) and healthy control group (n = 27) were analyzed by 16S rRNA gene sequencing and untargeted metabolomics. Peripheral venous blood was collected to measure serum inflammation and intestinal permeability. Finally, the correlation analysis of intestinal flora, fecal metabolites, and laboratory indicators was carried out. Results: Serum D-lactate content in the PCOS group was higher than that in the control group. There was no significant difference in microbial α diversity and ß diversity between PCOS patients and healthy controls. Peptostreptococcaceae and Bacteroidales S24-7 group existed significant differences between PCOS patients and healthy controls. Based on linear discriminant analysis selection, 14 genera including Klebsiella, Enterobacteriaceae, and Gammaproteobacteria were dominant in patients with PCOS, while 4 genera, including rumenococcus (Ruminocaccaceae UCG 013), prewortella (Prevotellaceae UCG 001), and erysipelas (Erysipelatoclostridium), were dominant in healthy controls. Compared with PCOS with Body mass index (BMI) < 24, patients with BMI ≥ 24 have multiple dominant genera including Abiotrophia and Peptostreptococcaceae. Moreover, serum levels of free testosterone and androstenedione were positively correlated with Megamonas, while total testosterone was negatively correlated with Alistipes. Additionally, fecal contents of acetic acid and propionic acid in patients with PCOS were significantly higher than those in healthy controls. Eubacterium_coprostanoligenes_group and Alistipes were positively correlated with 6 kinds of fatty acids. Conclusion: Specific intestinal flora fecal fatty acids and serum metabolites may mediate the occurrence and development of PCOS. PCOS patients with different body sizes have specific intestinal flora.

Transcriptome Analysis Reveals the Immune Infiltration Profiles in Cervical Cancer and Identifies KRT23 as an Immunotherapeutic Target.

Cervical cancer (CC) is one of the most common malignancies in women worldwide. Dismal prognosis rates have been associated with conventional therapeutic approaches, emphasizing the need for new strategies. Recently, immunotherapy has been used to treat various types of solid tumors, and different subtypes of the tumor microenvironment (TME) are associated with diverse responses to immunotherapy. Accordingly, understanding the complexity of the TME is pivotal for immunotherapy. Herein, we used two methods, "ssGSEA" and "xCell," to identify the immune profiles in CC and comprehensively assess the relationship between immune cell infiltration and genomic alterations. We found that more adaptive immune cells were found infiltrated in tumor tissues than in normal tissues, whereas the opposite was true for innate cells. Consensus clustering of CC samples based on the number of immune cells identified four clusters with different survival and immune statuses. Then, we subdivided the above four clusters into "hot" and "cold" tumors, where hot tumors exhibited higher immune infiltration and longer survival time. Enrichment analyses of differentially expressed genes (DEGs) revealed that the number of activated immune signaling pathways was higher in hot tumors than that in cold tumors. Keratin, type I cytoskeletal 23 (KRT23), was upregulated in cold tumors and negatively correlated with immune cell infiltration. In vitro experiments, real-time reverse transcription-quantitative polymerase chain reaction, cytometric bead arrays, and ELISA revealed that knockdown of KRT23 expression could promote the secretion of C-C motif chemokine ligand-5 and promote the recruitment of CD8+ T cells. We also constructed a model based on DEGs that exhibited a high predictive power for the survival of CC patients. Overall, our study provides deep insights into the immune cell infiltration patterns of CC. Moreover, KRT23 has huge prospects for application as an immunotherapeutic target. Finally, our model demonstrated a good predictive power for the prognosis of CC patients and may guide clinicians during immunotherapy.

A novel mutation of KCNJ1 identified in an affected child with nephrolithiasis.

Nephrolithiasis is not common in children, but the incidence is gradually increased in these years. Urinary tract malformations, urinary infection, dietary habits, geographic region and genetic factor are involved in the etiology of nephrolithiasis. For the affected child, it is especially important to elucidate the etiology, which may provide an accurate diagnosis, a personalized therapy and effective follow-up strategy. Here to seek the etiology of a ten-year-old boy incidentally found with nephrolithiasis, next generation sequencing (NGS) including a panel with 248 genes involved in hereditary kidney diseases was performed for the boy and identified two mutations of KCNJ1, c.89G > A (p.C30Y) and c.65G > T (p.R22M), and the later was a novel missense mutation originated from his father. The child was confirmed with type II Bartter syndrome (BS) caused by KCNJ1 mutations. Our study suggests that BS may be difficult to get diagnosed at an early stage based on clinical manifestations or biochemical laboratory tests, and NGS is an efficient way to determine the etiology and provide further treatment and guide fertility counseling for the affected family.

[Prenatal diagnosis and genetic counselling for a pedigree carrying a large fragment deletion of 13q].

OBJECTIVE: To carry out prenatal diagnosis for a fetus with normal ultrasonographic finding at 20 weeks' gestation but a copy number variant(CNV) of 13q indicated by non-invasive prenatal test (NIPT). METHODS: Karyotyping analysis and chromosomal CNV assay were carried out on the amniotic fluid sample. Parental peripheral blood sample was collected for chromosomal analysis. Detailed fetal ultrasound scan was carried out to rule out structural abnormalities of the fetus. RESULTS: The fetus was detected with a heterozygous 10.14 Mb deletion at 13q21.1q21.32, which has originated from the phenotypically normal mother. No apparent karyotypic abnormality was detected in the fetus and its parents. No ultrasonic abnormality was found in the fetus. CONCLUSION: Both the fetus and its mother have carried a heterozygous 10.14 Mb deletion at 13q21.1q21.32 and presented normal phenotypes.Combined with literature review, the segmental deletion was judged to be a benign variant.

A de novo and novel nonsense variants in ASXL2 gene is associated with Shashi-Pena syndrome.

This ASXL2 gene encodes a member of a family of epigenetic regulators that bind various histone-modifying enzymes and are involved in the assembly of transcription factors at specific genomic loci. Recent research has found that pathogenic variants in ASXL2 gene can lead to Shashi-Pena syndrome. However, clinical reports of individuals with damaging ASXL2 variants were limited and clinical phenotypic information may also be incomplete at present. Here, we reported a patient from Chinese family presenting with Shashi-Pena syndrome duo to a nonsense variant c.2485C > T; p. (Gln829*) in ASXL2 and analyzed the clinical phenotypes of the patient. In addition to the typical facial appearance, feeding difficulty, cardiac dysfunction and developmental delay, the patient also demonstrated multiple clinical problems not reported in other published cases, including granulocytopenia, thrombocytopenia and "single transverse palmar crease". Additionally, this is also the first case of premature death associated to Shashi-Pena syndrome induced by ASXL2 variants in a Chinese population. Our results provided important information for genetic counseling of the family and broaden the spectrum of phenotypes and genetic variations of the syndrome.

Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study.

BACKGROUND: Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients with platinum-resistant ROC were enrolled to receive camrelizumab (200 mg every 3 weeks by intravenous infusion) and oral famitinib (20 mg once daily). All patients had disease progression during or <6 months after their most recent platinum-based chemotherapy. Primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 based on investigator's assessment. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), 12-month OS rate and safety profile. RESULTS: Of the 37 women enrolled, 11 (29.7%) patients had primary platinum resistant, 15 (40.5%) patients had secondary platinum resistant and 11 (29.7%) patients had primary platinum refractory disease. As the cut-off date of April 9, 2021, nine (24.3%) patients had achieved a confirmed objective response, the ORR was 24.3% (95% CI, 11.8 to 41.2) and the DCR was 54.1% (95% CI, 36.9 to 70.5). Patients with this combination regimen showed a median TTR of 2.1 months (range, 1.8-4.1) and a median DoR of 4.1 months (95% CI, 1.9 to 6.3). Median PFS was 4.1 months (95% CI, 2.1 to 5.7), and median OS was 18.9 months (95% CI, 10.8 to not reached), with the median follow-up duration of 22.0 months (range, 12.0-23.7). The estimated 12-month OS rate was 67.2% (95% CI, 49.4 to 79.9). The most common ≥grade 3 treatment-related adverse events were hypertension (32.4%), decreased neutrophil count (29.7%) and decreased platelet count (13.5%). One (2.7%) patient died of grade 5 hemorrhage that was judged possibly related to study treatment by investigator. CONCLUSION: The camrelizumab with famitinib combination appeared to show antitumor activity in heavily pretreated patients with platinum-resistant ROC with an acceptable safety profile. This combination might provide a novel alternative treatment strategy in platinum-resistant ROC setting and warranted further exploration. TRIAL REGISTRATION NUMBER: NCT03827837.

miR-497-5p/SALL4 axis promotes stemness phenotype of choriocarcinoma and forms a feedback loop with DNMT-mediated epigenetic regulation.

Choriocarcinoma stem-like cells (CSLCs) might be at the origin of choriocarcinoma development associated with drug resistance or relapse. Spalt-like transcription factor 4 (SALL4), which is considered to be a stemness-related gene, can be regulated by miRNAs. In this study, SALL4 result is associated with progression-free survival of choriocarcinoma patients and CSLC's stemness characteristics. In addition, it could be downregulated by miR-497-5p by direct binding. miR-497-5p silencing by hypermethylation promoted malignant CSLC phenotype in vitro and in vivo. Furthermore, increased DNA methyltransferases (DNMTs) by SALL4 upregulation inhibited miR-497-5p expression via hypermethylation promotion. SALL4 appeared to be a key factor in promoting stemness phenotype of choriocarcinoma. Silencing miR-497-5p and SALL4 promotes choriocarcinoma progression and forms a feedback loop with DNMT-mediated epigenetic regulation, playing a crucial role in stemness maintenance in choriocarcinoma.

Disregulations of PURPL and MiR-338-3p Could Serve As Prognosis Biomarkers for Epithelial Ovarian Cancer.

Objective: The present study aimed to explore the expressions of long noncoding RNA (lncRNA) p53 upregulated regulator of p53 levels (PURPL) in different ovarian tissues, and to evaluate the significance of disregulations of PURPL and microRNA-338-3p (miR-338-3p) in epithelial ovarian cancer (EOC). Methods: The expressions of PURPL in ovarian cancer, the relations between PURPL and the prognosis of ovarian cancer, and the relation between PURPL and miR-338-3p were queried in multiple biomedical databases. Real-time PCR was performed to detect the expressions of PURPL in different ovarian tissues. Logistic regression analysis was used to analyze the risk factors of recurrence and death. Kaplan-Meier analysis was implemented to evaluate the relations between PURPL and miR-338-3p expressions and the survival of ovarian cancer. Results: PURPL could target miR-338-3p, PURPL were upregulated in ovarian cancer tissues, upregulation of PURPL in ovarian cancer was negatively related with the recurrence free survival (RFS) and overall survival (OS), which were indicated by biomedical databases query. Our data showed upregulations of PURPL were noted in ovarian cancer tissues. Higher expressions of PURPL were associated with more advanced FIGO stage and developed lymph node metastasis in epithelial ovarian cancer. Upregulation of PURPL was related with the recurrence (P=0.002, OR=21.482, 95%CI: 3.457~94.251) and death (P=0.004, OR=35.643, 95%CI: 2.453~84.359) of ovarian cancer patient. PURPL expressions were negatively correlated to miR-338-3p expressions in different ovarian tissues (r = -0.968, P<0.0001). Poor RFS (χ2=19.410, P=0.0002) and OS (χ2=17.600, P=0.0005) were found in patients with high level PURPL and low level miR-338-3p expressions. Conclusions: Upregulation of PURPL and downregulation of miR-338-3p were related with the poor RFS and OS of ovarian cancer, which indicated disregulations of PURPL and miR-338-3p could serve as prognosis biomarkers for epithelial ovarian cancer.

Megestrol acetate drives endometrial carcinoma cell senescence via interacting with progesterone receptor B/FOXO1 axis.

Megestrol acetate is a common and efficient anticancer progesterone. To explore the activity and the therapeutic mechanisms of megestrol acetate in endometrial cancer, human endometrial cancer cell lines Ishikawa and HHUA overexpressing progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were treated with megestrol acetate. Cell viability, apoptosis, cycle arrest, and senescence, as well as the expressions of p21 and p16, two hallmarks of cellular senescence, were evaluated. Compared with the control, >10 nmol/L megestrol acetate treatment could significantly reduce endometrial cancer cell growth, and induce the irreversible G1 arrest and cell senescence. The expression of cyclin D1 in megestrol acetate treated cells was downregulated, while the expressions of p21 and p16 were upregulated via PR-B isoform. FOXO1 inhibitor AS1842856 could significantly abrogate megestrol acetate-induced cell senescence, suggesting that FOXO1 was involved in megestrol acetate/PR-B axis. These findings may provide a new understanding for the treatment of human endometrial cancer.

Pegylated liposomal doxorubicin in patients with epithelial ovarian cancer.

OBJECTIVE: To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. METHODS: This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. RESULTS: Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2-6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4-46.4%), and the DCR was 65.2% (95% CI, 56.4-74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. CONCLUSIONS: For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Targeting of KDM5A by miR-421 in Human Ovarian Cancer Suppresses the Progression of Ovarian Cancer Cells.

PURPOSE: The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes cell growth in many human cancers. A series of functional experiments were conducted to explore the role of miR-421/KDM5A in ovarian cancer cells and their underlying molecular mechanisms. MATERIALS AND METHODS: Public microarray databases were analyzed to assess KDM5A and miR-421 expression in ovarian cancer. KDM5A was predicted to be a target of miR-421 using software analysis. The expression of the miR-421/KDM5A regulatory axis in ovarian cancer and the mechanisms of its effects on proliferation, migration, and invasion of ovarian cancer cell lines were investigated. RESULTS: Compared with normal ovarian tissues, the expression of KDM5A mRNA and protein was elevated (P<0.05), and miR-421 expression was reduced in ovarian cancer tissue (P<0.05). miR-421 was found to bind specifically to the KDM5A gene. Silencing KDM5A or overexpressing miR-421 significantly inhibited proliferation, migration, and invasion of OVCAR-8 and SKOV-3 cells. Similarly, compared with nude mice injected with cells transfected with empty capsids, the in vivo proliferation rate of OVCAR-8 cells after miR-421 overexpression was reduced significantly. CONCLUSION: The miR-421/KDM5A regulatory axis plays an important role in the development and progression of ovarian cancer cells.

Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.

BACKGROUND: Ovarian cancer (OvCa) is the leading cause of death of gynecological malignancies worldwide. Vascular endothelial growth factor A (VEGFA), the most potent angiogenic factor, is responsible for tumor growth and angiogenesis, but its role in OvCa chemotherapy resistance remains unclear. METHODS: RT-PCR and Western blot were used to detect VEGFA expression in tumor cells and normal ovarian surface epithelial cells. Gene Ontology (GO) enrichment analysis was used to analyze GO terms correlated with VEGFA. In in vitro experiments, we knockdown VEGFA in tumor cells and detected the tumor cell viability and apoptosis after chemotherapy drug treatment by MTT assay and flow cytometry. Western blot was used to detect autophagy and apoptosis related proteins. RESULTS: We proved that VEGFA was highly expressed in tumor cells comparted with normal ovarian surface epithelial cells, and enriched GO analysis of VEGFA showed that VEGFA was involved in anti-apoptotic process. Further in vitro experiments confirmed that expression of VEGFA was correlated with chemotherapy resistance and this effect was mediated by autophagy. Meanwhile tumor cells treated with chemotherapy drugs also promoted the expression of VEGFA. Knockdown VEGFA inhibited autophagy of tumor cells and thus potents the killing efficiency in DDP resistant tumor cells and this effect could be reversed by the addition of recombinant VEGFA. CONCLUSION: Taken together, our study demonstrates that VEGFA is involved in anti-apoptosis of tumor cells to chemotherapy, killing partly through autophagy, indicating that VEGFA may serve as a potential target to improve chemotherapy treatment.

Zinc regulates primary ovarian tumor growth and metastasis through the epithelial to mesenchymal transition.

BACKGROUND: The trace element zinc plays an indispensable role in human health and diseases including cancer due to its antioxidant properties. While zinc supplements have been used for cancer prevention, zinc is also a risk factor for cancer development. It is still unclear how zinc plays a role in ovarian cancer. METHODS: To understand how zinc contributes to ovarian tumor growth and metastasis, we examined whether zinc contributes to tumor metastasis by regulating epithelial to mesenchymal transition (EMT) using ovarian cancer cells in vitro. Cell migration and invasion were examined using transwell plates and EMT markers were examined using Western blot. Primary ovarian tumor growth and metastasis were assessed using orthotopic ovarian cancer mouse models in vivo. RESULTS: Zinc promoted EMT, while TPEN (N, N, N', N'-tetrakis-(2-pyridylmethyl)-ethylenediamine), a membrane-permeable selective zinc chelator, inhibited EMT in a dose dependent manner in ovarian cancer cells. Moreover, zinc promoted ovarian cancer cell migration and invasion, while TPEN inhibited cell migration and invasion. Zinc activated expression of the metal response transcriptional factor-1 (MTF-1), while TPEN inhibited MTF-1 expression in a dose dependent manner. Knockout of MTF-1 inhibited zinc-induced cell migration, invasion and augmented the inhibitory effect of TPEN on cell migration and invasion. Loss of MTF-1 attenuated zinc-induced ERK1/2 and AKT activation and augmented the effect of TPEN in attenuating the ERK1/2 and AKT pathways. TPEN effectively inhibited primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse model by suppressing EMT. CONCLUSION: zinc contributes to ovarian tumor metastasis by promoting EMT through a MTF-1 dependent pathway. Zinc depletion by TPEN may be a novel approach for ovarian cancer therapy by inhibiting EMT and attenuating the ERK1/2 and AKT pathways.

CircRNA circ_POLA2 Promotes Cervical Squamous Cell Carcinoma Progression via Regulating miR-326/GNB1.

Circular RNAs (circRNAs) are a group of non-coding RNAs that have an essential function in the development and progression of various cancers. The expression pattern and function of circRNA in cervical squamous cell carcinoma (CESC) are not fully understood. In the present study, we aimed to investigate the expression profiles and regulation mechanism of circRNA circ_POLA2 in CESC. Circ_POLA2 was highly expressed in CESC tissues and positively correlated with poor prognosis in CESC patients. Knockdown of circ_POLA2 using shRNA inhibited cervical cancer cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, circ_POLA2 could sponge endogenous microRNA-326 (miR-326) and inhibit its expression. Furthermore, miR-326 negatively regulated G protein subunit beta 1 (GNB1) by targeting its 3'-UTR. Intriguingly, we found that GNB1 was overexpressed and associated with poor prognosis in CESC patients. Overexpression of GNB1 could antagonize the inhibitory effect of miR-326 on cervical cancer cell proliferation, migration, and invasion. In addition, we demonstrated that circ_POLA2/miR-326/GNB1 axis regulated ERK signaling. In conclusion, circ_POLA2 promotes cervical squamous cell carcinoma development and progression via regulating the miR-326/GNB1 axis, which might serve as a novel therapeutic target for CESC patients.