Ion channels as therapeutic targets in high grade gliomas

Abstract: Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14-15 months with maximal treatment. High grade gliomas (HGG) form a leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies

The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line.

The voltage gated potassium (K+) channels Eag and HERG have been implicated in the pathogenesis of various cancers, through association with cell cycle changes and programmed cell death. The role of these channels in the onset and progression of ovarian cancer is unknown. An understanding of mechanism by which Eag and HERG channels affect cell proliferation in ovarian cancer cells is required and therefore we investigated their role in cell proliferation and their effect on the cell cycle and apoptosis of ovarian cancer cells

Probing the link between oestrogen receptors and oesophageal cancer

<p>Abstract</p> <p>Background</p> <p>Human oesophageal carcinoma is considered to be one of the most aggressive malignancies and has a very poor prognosis. The incidence of oesophageal cancer shows a gender bias and is higher in males compared with females, the ratio between males and females varying from 3:1 to 7:1. This sex ratio is not entirely attributable to differences in the prevalence of known risk factors between the sexes. The potential role of oestrogen receptors (ER) in oesophageal cancer has been debated for several years but the significance of the receptors in this cancer remains unknown. Most of the work has been based on immunohistochemistry and has not been validated with other available techniques. The inconsistencies in the published literature on the link between ER expression and oesophageal cancer warrant a thorough evaluation of the potential role of ERs in this malignancy. Even the expression of the two ER isoforms, ERα and ERβ, and its implications for outcome of treatments in histological subtypes of oesophageal tumours is ill defined. The aim of this article is to provide updated information from the available literature on the current status of ER expression in oesophageal cancer and to discuss its potential therapeutic role.</p> <p>Methods and Results</p> <p>We performed a comprehensive literature search and analysed the results regarding ER expression in oesophageal tumours with special emphasis on expression of different oestrogen receptors and the role of sex hormones in oesophageal cancer. This article also focuses on the significance of the two main ER subtypes and mechanisms underlying the presumed male predominance of this disease.</p> <p>Conclusion</p> <p>We postulate that differential oestrogen receptor status may be considered a biomarker of poor clinical outcome based on tissue dedifferentiation or advanced stage of the disease. Further, if we can establish the importance of oestrogen and its receptors in the context of oesophageal cancer, then this may lead to a new future direction in the management of this malignancy.</p

Identifying the problems, solutions, and challenges in referral writing: A Scoping Review

Abstract Background Both primary care physicians and other specialists are not satisfied with the quality and content of written communication between colleagues(1). &nbsp;There is need of identifying the factors that lead to this dissatisfaction. Many of these are discussed in literature such as communication skills, teaching and assessment of referral writings to undergraduates, and lack of validated tool for evaluation of referral(2). This article is scoping review of literature for finding the problems, solutions, and challenges in referral writing. Methods The databases utilized for finding various referral systems are PubMed, ERIC, Pakmedinet and Google scholar. The article included in the study was 12 which were identified through PRISMA. These 12 articles were reviewed by two authors. (FA and TA) The first step was the application of Qualsyst criteria and then the two authors analyzed the final 12 articles for thematic analysis independently. Results The problems, solutions and challenges in referral writing were found after the thematic analysis by two authors. The multiple challenges regarding referral writing include the fact that details about the inadequate data written in referral letters, lack of teaching and learning strategies and lack of proper communication between physicians. There are many solutions like teaching and assessing the referral writing skills, introducing reflection and feedback to improve the skill among young doctors. Moreover, teaching the art of referral writing should include in the medical curriculum. Conclusion Referral writing is an important part of medical communication. A good quality referral will save time in management of patients. It will also enhance the outcome of patient management. There is need of teachings about communication skills in undergraduates and postgraduates students

The role of oxidative stress in antipsychotics induced ovarian toxicity

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1 μM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P < 0.0001, < 0.0001 and < 0.01, respectively). All APs at IC50s significantly (P < 0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5 mM) or quercetin (50 mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity

Excess androgen production in subcutaneous adipose tissue of women with polycystic ovarian syndrome

© 2019 Society for Endocrinology Published by Bioscientifica Ltd. The purpose of this study was to investigate androgen production and the role of insulin and LH in its regulation in subcutaneous adipose tissue (SAT) of women with polycystic ovarian syndrome (PCOS). Protein and mRNA expression of androgen synthesis enzymes (cytochrome P450 17A1 (CYP17A1) and aldo-keto reductase 1C3 (AKR1C3)) were measured in SAT biopsies from women with PCOS, diagnosed according to the Rotterdam criteria (n = 15) and healthy controls (n = 15). Cultured mature adipocytes (differentiated from SAT biopsies) were treated with insulin ± phosphoinositol-3-kinase inhibitor (LY294002) or LH ± insulin. CYP17A1 and AKR1C3 mRNA expression and testosterone concentrations were measured in treated and untreated adipocyte cultures. AKR1C3 mRNA was significantly (P < 0.001) greater in PCOS vs non-PCOS SAT, but CYP17A1 was not significantly different between the two groups. AKR1C3 and CYP17A1 protein expression was not significantly different in PCOS vs non-PCOS SAT. In untreated adipocyte cultures, CYP17A1, AKR1C3 and testosterone levels were significantly higher in the PCOS vs the non-PCOS groups. Addition of insulin increased AKR1C3 mRNA and testosterone levels, but not CYP17A1 mRNA in non-PCOS with no effect on PCOS adipocytes. The stimulatory effects of insulin were not inhibited by LY294002. Addition of LH increased CYP17A1, AKR1C3 and testosterone in non-PCOS adipocytes with no effect in PCOS adipocytes. In conclusion, SAT of women with PCOS produces excess androgen, which may contribute to PCOS-related hyperandrogenaemia. This SAT androgen excess is independent of obesity and is not directly stimulated by inulin or LH

Patient attitudes towards physician nonverbal behaviors during consultancy: result from a developing country

Background. Nonverbal behaviors have a significant impact on patients during consultations. This study was undertaken to find out the attitudes and preferences of the patients regarding nonverbal communication during consultations with physicians, in a tertiary care hospital. Methods. A questionnaire based cross-sectional study was carried out at the Aga Khan University Hospital, Karachi, Pakistan, during the months of January to March 2012. All patients (\u3e18 years of age) coming for consultancy in the family medicine clinics were approached; out of 133, 120 agreed to participate. The subjects were asked questions regarding physician’s comforting touch and eye contact and their responses were noted. The data were analyzed using SPSS and chi-square test was used to identify corelations. Results. Overall, 120 patients were enrolled. About 58.3% were men and 41.7% were women with a mean age of 34.9 ± 10.9 years. 95.8% were Muslims and 57.6% had more than 12 years of education. Among females 74% wanted supportive touch from doctors, used to comfort the patient (45%) or to show respect (27.5%) or as healing (30%). 86.1% of the respondents believe that establishing eye contact with the patient shows that the doctor is attentive towards his/her patient. The eye contact should be brief but regular (54.1%) and prolonged staring (36.7%) makes them uncomfortable.Conclusion. Nonverbal communication helps to strengthen the doctor-patient relation as patients do appreciate positive touch and eye contact from their physicians

Isolation and culture of dental pulp stem cells from permanent and deciduous teeth

OBJECTIVE: To isolate dental pulp mesenchymal stem cells (MSCs) from non-infected human permanent and deciduous teeth. METHODS: It was an in-vitro experimental study. Human teeth were collected from 13 apparently healthy subjects including nine adults and four children. After decoronation dental pulps were extirpated from teeth and cultured via explant method in a stem cell defined media. Data was analyzed by descriptive statistics. RESULTS: As above MSCs emerged exhibiting fibroblast-like morphology. In vitro culture was positive for 100% (9/9) and 75% (3/4) of the permanent and deciduous teeth respectively. First cell appeared from deciduous teeth pulp in 10±6.2 days while permanent teeth pulp took 12.4±3.7 days. Together, 26.6±3.6 and 24.5±3.5 days were required for permanent and deciduous tooth pulp stem cells to be ready for further assays. CONCLUSIONS: The protocol we developed is easy and consistent and can be used to generate reliable source of MScs for engineering of calcified and non-calcified tissue for regenerative medicine approaches.

The Impact of High BMI on Pregnancy Outcomes and Complications in Women with PCOS Undergoing IVF - A Systematic Review and Meta-Analysis

(1) Background: Current evidence indicates that women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization (IVF) have an increased likelihood of adverse pregnancy outcomes. The objective of this systematic review was to clarify the role of a PCOS-related high body mass index (BMI) in these unfavourable pregnancy outcomes. (2) Methods: A comprehensive search of electronic databases was conducted to identify studies investigating the impact of high BMI on pregnancy outcomes in women with PCOS undergoing IVF. RevMan software (v5.4) was used to calculate the odds ratio (OR) and 95% confidence interval (CI). (3) Results: Nineteen eligible studies (n = 7680) were identified, including 16 retrospective cohort studies (n = 6934), two prospective cohort studies (n = 525), and one cross-sectional study (n = 221). Pooled analysis showed significantly higher odds of clinical pregnancy (OR, 1.16 [95% CI, 1.04–1.29]; z = 2.73; p = 0.006; I2 = 30%) and livebirths (OR, 1.88 [95% CI, 1.56–2.27]; z = 6.54; p < 0.0001; I2 = 55%) in women with PCOS with a normal versus a high BMI. Meta-analysis showed significantly increased odds of miscarriages in women with PCOS with a high versus a normal BMI (OR, 0.76 [95% CI, 0.60–0.95]; z = 2.42; p = 0.02; I2 = 53%). Pooled analysis of three studies (n = 993) showed significantly higher ORs of gestational diabetes mellitus (OR 3.96 [95% CI 1.62–9.68]; z = 3.01; p = 0.003; I2 = 58%) and gestational hypertension (OR 2.16 [95% CI 1.32–3.54]; z = 3.05; p = 0.002; I2 = 68%) in women with PCOS with a high versus a normal BMI. Meta-analysis of three studies reported significantly greater odds of a caesarean section for women with PCOS with a high versus a normal BMI (OR 0.45 [95% CI 0.29–0.69]; z = 3.66; p = 0.0003; I2 = 0%). (4) Conclusions: The increased likelihood of adverse pregnancy outcomes observed in women with PCOS undergoing IVF seems to be attributable to a PCOS-related high BMI