Immediate risk of cervical intraepithelial neoplasia and diagnostic value of colposcopy among cytology-negative women with oncogenic HPV: a retrospective study.

BACKGROUND: Cervical cancer screening results that are negative for cytology but positive for high-risk human papillomavirus (HR-HPV) are not uncommon. One-year follow-up is suggested for patients with no history of HPV positivity under the most recent American Society of Colposcopy and Cervical Pathology (ASCCP) guidelines (2019). The aim of this study was to evaluate the immediate risk of cervical intraepithelial neoplasia (CIN) among cytology-negative patients positive for HR-HPV. The diagnostic accuracy of colposcopy in these patients was investigated. METHODS: A retrospective study was conducted in patients who were cytology negative but HR-HPV positive and referred for colposcopy from January 2022 to August 2023. Patients were compared in terms of the immediate rate of CIN lesions among the HPV16-positive group, the HPV18-positive group and the non-16/18 HR-HPV-positive group. The distribution of CIN2 + lesions according to age was evaluated. The factors associated with the accuracy of colposcopy were evaluated using univariate and multivariate logistic regression. RESULTS: Among the 372 patients, 195 had chronic cervicitis, 131 had CIN1, 37 had CIN2/3, and nine had carcinoma. The immediate rates of CIN2 + lesions and CIN3 + lesions in patients who were not HR-HPV16/18-positive were comparable to those in patients who were HPV16/18-positive (P = 0.699). In addition, among patients diagnosed with CIN2 + lesions, 8 (17.39%) patients were women aged < 30 years. When pathological results were used as a reference, the consistency rate of colposcopy was 61.0% (227/372). Multivariate analyses revealed that age and the type of cervical transformation zone were independent factors affecting the accuracy of colposcopy (P < 0.001). CONCLUSIONS: In countries with limited resources, immediate colposcopy referral should be recommended for patients who are cytology negative but HR-HPV-positive (including non-16/18 HR-HPV-positive), and cervical cancer screening via cotesting should be suggested for women aged < 30 years. Colposcopy has moderate diagnostic value and can be affected by age and the type of cervical transformation zone.

Recombinant human thrombopoietin therapy for primary immune thrombocytopenia in pregnancy: a retrospective comparative cohort study.

BACKGROUND: Treatment options for pregnant women with immune thrombocytopenia (ITP) who do not respond to first-line treatment are limited. Few studies have reported the use of recombinant human thrombopoietin (rhTPO) for this subset of patients. AIMS: To investigate the efficacy and safety of rhTPO in ITP during pregnancy and determine obstetric outcomes and predictors of treatment response. METHODS: From July 2013 to October 2022, the data of 81 pregnant women with ITP and a platelet count < 30 × 109/L who did not respond to steroids and/or intravenous immunoglobulin were retrospectively analysed. Of these patients, 33 received rhTPO treatment (rhTPO group) while 48 did not (control group). Baseline characteristics, haematological disease outcomes before delivery, obstetric outcomes, and adverse events were compared between groups. In the rhTPO group, a generalised estimating equation (GEE) was used to investigate the factors influencing the response to rhTPO treatment. RESULTS: The baseline characteristics were comparable between both groups (P > 0.05, both). Compared with controls, rhTPO patients had higher platelet counts (median [interquartile range]: 42 [21.5-67.5] vs. 25 [19-29] × 109/L, P = 0.002), lower bleeding rate (6.1% vs. 25%, P = 0.027), and lower platelet transfusion rate before delivery (57.6% vs. 97.9%, P < 0.001). Gestational weeks of delivery (37.6 [37-38.4] vs 37.1 [37-37.2] weeks, P = 0.001) were longer in the rhTPO group than in the control group. The rates of caesarean section, postpartum haemorrhage, foetal or neonatal complications, and complication types in both groups were similar (all P > 0.05). No liver or renal function impairment or thrombosis cases were observed in the rhTPO group. GEE analysis revealed that the baseline mean platelet volume (MPV) (odds ratio [OR]: 0.522, P = 0.002) and platelet-to-lymphocyte ratio (PLR) (OR: 1.214, P = 0.025) were predictors of response to rhTPO treatment. CONCLUSION: rhTPO may be an effective and safe treatment option for pregnancies with ITP that do not respond to first-line treatment; it may have slightly prolonged the gestational age of delivery. Patients with a low baseline MPV and high baseline PLR may be more responsive to rhTPO treatment. The present study serves as a foundation for future research.

Comprehensive Analysis of Alternative Polyadenylation Events Associated with the Tumor Immune Microenvironment in Colon Adenocarcinoma.

Objective: Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood. Methods: We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established. Results: A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells. Conclusion: Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.

Role and mechanism of the p-JAK2/p-STAT3 signaling pathway in follicular development in PCOS rats.

OBJECTIVE: To identify the association between the phosphorylated Janus kinase 2/phosphorylated signal transducer and activator of transcription (p-JAK2/p-STAT3) signaling pathway and follicular development in polycystic ovary syndrome (PCOS) rats, and explore the underlying mechanism. To evaluate the role of exogenous JAK2 inhibitor AG490 in the model and the associations among luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), cytochrome P450 17α (CYP17a), cytochrome P450 19 (CYP19), and PCOS. RESULTS: Rat models of PCOS was established. PCOS rats were intraperitoneally treated with double-distilled water (ddH2O)/DMSO/AG490. The rate of ovarian morphological recovery in the AG490 group was significantly higher compared with the DMSO group (83.3 % vs 9.1 %, X2 = 12.68, P < 0.001). Moreover, the short in the time the estrous cycle was resumed in the AG490 group (hazard ratio = 16.32, P < 0.001) compared with the DMSO group. Compared with the controls, p-JAK2, p-STAT3, LHCGR, and CYP17a expression levels were increased whereas that of FSHR and CYP19 were decreased in the ovaries of PCOS rats. However, an opposite trend was observed after treatment with AG490. Software prediction revealed that the p-STAT3 bound to the promoter regions of LHCGR, FSHR, CYP17a, and CYP19 genes. This finding was confirmed by results of correlation analysis (R = 0.834, -0.836, 0.875 and -0.712, respectively, all P < 0.001). CONCLUSION: This study demonstrated that the p-JAK2/p-STAT3 signaling pathway was involved in follicular development in PCOS rats by upregulating LHCGR and CYP17a expression, and downregulating that of FSHR and CYP19. AG490 treatment exerted beneficial effects. LHCGR, FSHR, CYP17a, and CYP19 are candidate genes associated with follicular development in PCOS rats.

Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity.

Flavonoids are a group of natural polyphenol substances abundant in vegetables, fruits, grains, and tea. As plant secondary metabolites, flavonoids play essential roles in many biological processes and responses to environmental factors in plants. Flavonoids are common in human diets and have antioxidant effects as well as other bioactivities (e.g., antimicrobial and anti-inflammatory properties), which reduce the risk of disease. Flavonoid bioactivity depends on structural substitution patterns in their C6-C3-C6 rings. However, reviews of plant flavonoid distribution and biosynthesis, as well as the health benefits of its bioactivity, remain scarce. Therefore, in the present review, we systematically summarize recent progress in the research of plant flavonoids, focusing on their biosynthesis (pathway and transcription factors) and bioactive mechanisms based on epidemic evidence, in vitro and in vivo research, and bioavailability in the human body. We also discuss future opportunities in flavonoid research, including biotechnology, therapeutic phytoproducts, and dietary flavonoids.

Value of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy to treat malignant peritoneal mesothelioma.

OBJECTIVE: To investigate the clinical efficacy of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for treating malignant peritoneal mesothelioma (MPM) and to assess the impact of this approach on patient prognosis. METHODS: A retrospective analysis of 44 patients with MPM was performed. The control group (CNG, N = 23) was treated with CRS combined with postoperative intraperitoneal (IP) chemotherapy, while the observation group (OG, N = 21) was treated with CRS combined with HIPEC. The treatment efficacy, volume of blood loss, operation time, postoperative length of stay, and 3-year survival rate (SR) were compared, and the factors affecting the prognosis of MPM patients were analyzed by multivariate analysis. RESULTS: The OG showed decreased volume of blood loss and operation time, while also showing increased overall treatment efficacy compared with the CNG. The SR in the OG was 65.22% compared with a rate of 33.33% in the CNG, and the 3-year SR in the OG was significantly higher than that in the CNG. Multivariate analysis revealed that tumor-node-metastasis (TNM) stage, Eastern Cooperative Oncology Group (ECOG) score, and treatment modality were independent risk factors for the prognosis of MPM patients. CONCLUSION: CRS combined with HIPEC for MPM has a favorable treatment efficacy and prolongs the survival of MPM patients. Additionally, TNM stage, ECOG score, and treatment modality are independent risk factors for the prognosis of MPM patients.

FTO-stabilized lncRNA HOXC13-AS epigenetically upregulated FZD6 and activated Wnt/ß-catenin signaling to drive cervical cancer proliferation, invasion, and EMT.

PURPOSE: Cervical cancer (CC) is the third most prevalent malignancy in women. Frizzled class receptor 6 (FZD6) is demonstrated to either activate or repress the activity of Wnt/ß-catenin pathway, a crucial signaling involved in cancer development. However, the role of FZD6 in CC is unknown. The present study explored the function of FZD6 and its mechanism in CC. METHODS: The levels of FZD6, HOXC13-AS were detected in CC specimens and CC cell lines via qRT-PCR. Cell proliferation and invasion was explored via CCK-8 assay, colony formation assay and transwell assay. Luciferase reporter analysis, FISH, subcellular fractionation, chromatin immunoprecipitation and RNA immunoprecipitation were performed for investigating the molecular mechanism. RESULTS: FZD6 was up-regulated in CC. FZD6 silence retarded proliferation, invasion, and epithelial-to-mesenchymal transition (EMT), and inactivated Wnt/ß-catenin. HOXC13 antisense RNA (HOXC13-AS) was up-regulated in CC and positively correlated with FZD6. Mechanistically, HOCX13-AS1 augmented FZD through cAMP-response element binding protein-binding protein (CBP)-modulated histone H3 on lysine 27 acetylation (H3K27ac). Additionally, fat mass and obesity-associated protein (FTO) reduced N6-methyladenosine (m6A) and stabilized HOXC13-AS in CC. CONCLUSIONS: In conclusion, this study firstly showed that FTO-stabilized HOXC13-AS epigenetically up-regulated FZD6 and activated Wnt/ß-catenin signaling to drive CC proliferation, invasion, and EMT, suggesting HOXC13-AS as a potential target for CC treatment.

Dysregulation of exosomal miR-192 and miR-194 expression in lung adenocarcinoma patients.

Non-small cell lung cancer (NSCLC) is the main reason of cancer linked mortality and around 80% of cases diagnosed in advanced stage. Therefore current study designed to evaluate the deregulation of miRNA-194 and miRNA-192 in different body fluid of Non small cell lung cancer participants. Present study recruited newly diagnosed histopathologically confirmed. It was observed that the 40% NSCLC participants showed elevated miR-194 expression and 60% NSCLC participants showed reduced miR-194 expression in serum sample while in Bronchial wash, only 20% NSCLC participants showed elevated miR-194 expression while 80% showed reduced miR-194 expression (p = 0.003). It was found that the 54% NSCLC participants showed elevated miR-192 expression and 55% NSCLC participants showed reduced miR-192 expression in serum sample while In Bronchial wash sample, only 25% NSCLC participants showed high miR-192 expression while 75% showed low miR-192 expression (P = 0.0004). Expression of miR-194 was significantly associated with TNM stages (p < 0.0001, p < 0.0001), distant organ metastases (p < 0.0001, p < 0.0001), pathological grade (p = 0.0009, p = 0.0005) among serum sample and bronchial wash sample. Same observation was found with expression of miR-192 and it was significantly associated with TNM stages (p < 0.0001, p < 0.0001), distant organ metastases (p < 0.0001, p < 0.0001), pathological grade (p = 0.006, p = 0.001) among serum sample and bronchial wash sample. It was observed that the NSCLC participants who had high serum based miR-194 expression showed 22 months of overall median survival while low expression of serum based miR-194 expression showed 18 months of overall median survival. Present study suggests that decreased expression of miR-194 and miR-192 was significantly associated with different clinical features of NSCLC cases. However, significantly higher number of NSCLC cases showed low expression of miR-194 and miR-192 in bronchial lavage sample. Decreased poor overall survival was found to be associated with bronchial wash sample with respect to low miR-194 and miR-192 expression while NSCLC participants showed better overall survival with high miR-194 and miR-192 expression. This suggested decreased expression of miR-192 and miR-194 expression could be the potential prognostic marker among NSCLC participants.

Low-dose aspirin improves endometrial receptivity in the midluteal phase in unexplained recurrent pregnancy loss.

OBJECTIVE: To evaluate differences in Doppler parameters and pregnancy outcomes, if any, and to determine the predictive accuracy of such indices, as well as the effects of low-dose aspirin (LDA) in unexplained recurrent pregnancy loss (URPL). METHODS: An observational study was conducted at Ren Ji Hospital, Shanghai, China, from May 2015 to December 2016. The endometrial thickness, and the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) values of endometrial and uterine artery blood flow were collected. Receiver operating characteristic (ROC) curve analysis was used to analyze data from URPL patients (three or more first-trimester spontaneous abortions with unknown etiology) and patients with normal fertility. A second ultrasonography examination was performed in URPL patients who had received daily LDA for 2 months. RESULTS: There were 190 URPL patients and 35 control patients. Endometrial thickness was significantly thinner in URPL patients than control patients (P=0.005). The PI, RI, and S/D values for endometrial blood flow and the mean PI, RI, and S/D values for uterine arteries were significantly higher in URPL patients (P<0.001). The predictive accuracy of the indices mentioned above were 0.660, 0.802, 0.852, 0.837, 0.784, 0.929, and 0.929, respectively. Following LDA supplementation, URPL patients showed a significant reduction in resistance to endometrial and uterine artery blood flow (P<0.001). CONCLUSION: URPL patients had impaired uterine perfusion. Doppler parameters are valuable in predicting women at high risk of URPL. LDA could be effective in improving endometrial receptivity.

MicroRNA-203 promotes the progression of non-small cell lung cancer via surviving.

PURPOSE: MicroRNAs are involved in the occurrence and progression of tumors. Previous studies have confirmed that microRNA-203 serves as an oncogene. The specific role of microRNA-203 in non-small cell lung cancer (NSCLC) is rarely reported. This study aimed to explore the regulatory effect of microRNA-203 on NSCLC and its underlying mechanism. METHODS: MicroRNA-203 expression in 96 pairs of NSCLC tissues and paracancer tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Correlation between microRNA-203 expression and prognosis of NSCLC was further analyzed. Proliferative, migratory and invasive abilities of NSCLC cells after transfection with si-microRNA-203 or si-negative control (NC) were assessed by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), colony formation and Transwell assay, respectively. Rescue experiments were conducted to investigate the interaction between microRNA-203 and survivin in regulating NSCLC progression. RESULTS: MicroRNA-203 was highly expressed in NSCLC tissues than in paracancer tissues. Correlation analyses showed that microRNA-203 expression was positively correlated to tumor stage, lymph node metastasis and distant metastasis, whereas it was not correlated to age and sex of NSCLC patients. MicroRNA-203 knockdown inhibited proliferative, migratory and invasive abilities of NSCLC cells. Rescue experiments confirmed that microRNA-203 promotes the progression of NSCLC via targeting survivin. CONCLUSIONS: MicroRNA-203 is highly expressed in NSCLC, and is closely related to tumor stage, lymph node metastasis, distant metastasis and poor prognosis of NSCLC patients. It is concluded that microRNA-203 promotes the progression of NSCLC via regulating survivin expression.

Prediction of thrombophilia in patients with unexplained recurrent pregnancy loss using a statistical model.

OBJECTIVE: To establish a statistical model to predict thrombophilia in patients with unexplained recurrent pregnancy loss (URPL). METHODS: A retrospective case-control study was conducted at Ren Ji Hospital, Shanghai, China, from March 2014 to October 2016. The levels of D-dimer (DD), fibrinogen degradation products (FDP), activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), and platelet aggregation in response to arachidonic acid (AA) and adenosine diphosphate (ADP) were collected. Receiver operating characteristic curve analysis was used to analyze data from 158 UPRL patients (≥3 previous first trimester pregnancy losses with unexplained etiology) and 131 non-RPL patients (no history of recurrent pregnancy loss). A logistic regression model (LRM) was built and the model was externally validated in another group of patients. RESULTS: The LRM included AA, DD, FDP, TT, APTT, and PT. The overall accuracy of the LRM was 80.9%, with sensitivity and specificity of 78.5% and 78.3%, respectively. The diagnostic threshold of the possibility of the LRM was 0.6492, with a sensitivity of 78.5% and a specificity of 78.3%. Subsequently, the LRM was validated with an overall accuracy of 83.6%. CONCLUSION: The LRM is a valuable model for prediction of thrombophilia in URPL patients.

The Biological Effects of Dickkopf1 on Small Cell Lung Cancer Cells and Bone Metastasis.

The bone is among the most common sites of metastasis in patients with lung cancer. Over 30%-40% of lung cancers can develop bone metastasis, and no effective therapeutic methods exist in clinic cases. Wnt/ß-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferentially metastasizes to the skeleton. However, the role of DKK1 in osteotropism of small cell lung cancer (SCLC) remains to be elucidated. This study aimed to define the role of DKK1 in SCLC bone metastasis and investigate the underlying mechanisms. Our results demonstrated that the expression level of DKK1 was dramatically higher in bone metastatic SCLC cells (SBC-5 cell line) compared with that in cells without bone metastatic ability (SBC-3 cell line). Therefore, we hypothesized that DKK1 was involved in the bone metastasis of SCLC. We then suppressed the DKK1 expression in SBC-5 cells by RNAi and found that downregulation of DKK1 can inhibit cell proliferation, colony formation, cell migration, and invasion, but increase the apoptosis rate. Downregulation of DKK1 did not affect the cell cycle progression of SBC-5 cells in vitro. In vivo, downregulated DKK1 in SBC-5 cells resulted in attenuated bone metastasis. These results indicated that DKK1 may be an important regulator in bone metastases of SCLC, and targeting DKK1 may be an effective method to prevent and treat skeleton metastases in SCLC cases.

CXCR2-Mediated Granulocytic Myeloid-Derived Suppressor Cells' Functional Characterization and Their Role in Maternal Fetal Interface.

To investigate CXC chemokine receptor 2 (CXCR2)-mediated granulocytic myeloid-derived suppressor cells' (MDSCs) (G-MDSCs) functional characterization and their role in maternal-fetal interface. Proportions of CXCR2(+) MDSCs and CXCR2 protein levels in total MDSCs were lower in abortion-prone CBA/J×DBA/2 mice than in CBA/J×BALB/c mice with normal pregnancy. Treatment with CXCR2 neutralizing antibody in vivo at early stage of pregnancy significantly increased the embryo resorption rates and reduced MDSCs abundance in mice from CBA/J×BALB/c matings. Adoptive transfer of MDSCs improved pregnancy outcomes in anti-CXCR2-pretreated CBA/J mice in CBA/J×BALB/C matings. CXCR2 was capable of enhancing the migration of G-MDSCs efficiently instead of monocytic MDSCs (M-MDSCs). In addition to preferential G-MDSC accumulation, arginase I expression as well as arginase I activity of G-MDSCs were regulated by CXCR2. CXCL1, as one of CXCR2 ligands, correlated well with CXCR2-mediated G-MDSCs migration and arginase I activity. CXCR2/CXCL1 axis promotes G-MDSC recruitment and facilitates arginase I expression and activity of these cells at maternal-fetal interface. These findings provide comprehensive insights into how G-MDSCs are recruited to decidual tissues and how local G-MDSCs maintain pregnancy tolerance.

Granulocytic myeloid-derived suppressor cells maintain feto-maternal tolerance by inducing Foxp3 expression in CD4+CD25-T cells by activation of the TGF-ß/ß-catenin pathway.

STUDY HYPOTHESIS: The transforming growth factor (TGF)-ß/ß-catenin pathway is involved in granulocytic myeloid-derived suppressor cell (G-MDSCs)-induced Foxp3 expression in CD4(+)CD25(-)T cells, which plays an essential role in maintaining feto-maternal tolerance. STUDY FINDING: Decidual G-MDSCs play an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, which is dependent on TGF-ß/ß-catenin pathway. WHAT IS KNOWN ALREADY: MDSCs contribute to the observed increase in regulatory T cells in animal cancer models. The TGF-ß/ß-catenin pathway is required for T cell development and survival. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: MDSC levels in deciduas from patients undergoing elective termination of pregnancy or spontaneous abortion were assessed by flow-cytometric analysis. The best characterized markers of G-MDSCs cells were examined by immunocytochemistry and flow-cytometric analysis. In vivo, fetus resorption and proportion of decidual immune cells were evaluated after depletion of G-MDSCs. In vitro, we established an antigen-non-specific (CD3/CD28) CD4(+)CD25(-)T and G-MDSC co-culture system and added TGF-ß, anti-TGFß, TGF-ß plus anti-TGFß or ß-catenin inhibitor ICG001 to the system. Protein levels were measured by western blot. MAIN RESULTS AND THE ROLE OF CHANCE: G-MDSCs showed a significant decrease in spontaneous abortion compared with elective abortion in women with normal pregnancy (P < 0.01), whereas the numbers of monocytic MDSCs remained unchanged. The dynamics of G-MDSCs in mice revealed that few G-MDSCs were present in non-pregnant uteri. G-MDSCs expanded rapidly in CBA/J×BALB/c mice with normal pregnancy and decreased in CBA/J×DBA/2 mice with abortion-prone pregnancy. G-MDSCs were characterized by the expression of CD115, CD117, CD135, CD62L, CCR2, MHCII, CD80, Arginase I and iNOS, and a lack of F4/80 or CD11c expression. Specifically, depletion of G-MDSCs-induced severe embryo resorption and decreased the percentage of CD4(+)CD25(+)Foxp3(+)T cells. In vitro, G-MDSCs had an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, dependent on TGF-ß/ß-catenin pathway. LIMITATIONS, REASONS FOR CAUTION: It is not sufficient to examine the role of G-MDSCs in the maintenance of maternal-fetal tolerance by depleting G-MDSCs using neutralizing antibody. Further studies are needed to establish an animal model of G-MDSCs in order to elucidate their exact role at the maternal-fetal tolerance. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide novel insights into a new function and mechanism of action for G-MDSCs in mediating feto-maternal immune tolerance. LARGE-SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This research was supported by the National Natural Science Foundation of China (Grant No. 81270715; 91442113). The authors have nothing to disclose.

EAG2 potassium channel with evolutionarily conserved function as a brain tumor target.

Over 20% of the drugs for treating human diseases target ion channels, but no cancer drug approved by the US Food and Drug Administration (FDA) is intended to target an ion channel. We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis, delineate downstream pathways, and uncover a mechanism for different potassium channels to functionally cooperate and regulate mitotic cell volume and tumor progression. EAG2 potassium channel was enriched at the trailing edge of migrating medulloblastoma (MB) cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment.

Circadian rhythm of redox state regulates excitability in suprachiasmatic nucleus neurons.

Daily rhythms of mammalian physiology, metabolism, and behavior parallel the day-night cycle. They are orchestrated by a central circadian clock in the brain, the suprachiasmatic nucleus (SCN). Transcription of clock genes is sensitive to metabolic changes in reduction and oxidation (redox); however, circadian cycles in protein oxidation have been reported in anucleate cells, where no transcription occurs. We investigated whether the SCN also expresses redox cycles and how such metabolic oscillations might affect neuronal physiology. We detected self-sustained circadian rhythms of SCN redox state that required the molecular clockwork. The redox oscillation could determine the excitability of SCN neurons through nontranscriptional modulation of multiple potassium (K(+)) channels. Thus, dynamic regulation of SCN excitability appears to be closely tied to metabolism that engages the clockwork machinery.

Cellular mechanism for spontaneous calcium oscillations in astrocytes.

AIM: To determine the Ca2+ source and cellular mechanisms of spontaneous Ca2+ oscillations in hippocampal astrocytes. METHODS: The cultured cells were loaded with Fluo-4 AM, the indicator of intracellular Ca2+, and the dynamic Ca2+ transients were visualized with confocal laser-scanning microscopy. RESULTS: The spontaneous Ca2+ oscillations in astrocytes were observed first in co-cultured hippocampal neurons and astrocytes. These oscillations were not affected by tetrodotoxin (TTX) treatment and kept up in purity cultured astrocytes. The spontaneous Ca2+ oscillations were not impacted after blocking the voltage-gated Ca2+ channels or ethylenediamine tetraacetic acid (EDTA) bathing, indicating that intracellular Ca2+ elevation was not the result of extracellular Ca2+ influx. Furthermore, the correlation between the spontaneous Ca2+ oscillations and the Ca2+ store in endoplasmic reticulum (ER) were investigated with pharmacological experiments. The oscillations were: 1) enhanced when cells were exposed to both low Na+ (70 mmol/L) and high Ca2+ (5 mmol/L) solution, and eliminated completely by 2 micromol/L thapsigargin, a blocker of sarcoplasmic reticulum Ca2+-ATPase; and 2) still robust after the application with either 50 micromol/L ryanodine or 400 micromol/L tetracaine, two specific antagonists of ryanodine receptors, but depressed in a dose-dependent manner by 2-APB, an InsP3 receptors (InsP3R) blocker. CONCLUSION: InsP3R-induced ER Ca2+ release is an important cellular mechanism for the initiation of spontaneous Ca2+ oscillation in hippocampal astrocytes.