Additive Effects of Citrus Juice Flavonoid Naringenin and Statins on HERG Channels Expressed in Xenopus Oocytes.

OBJECTIVE: Naringenin, a major flavonoid found in citrus juice, has been shown to inhibit HERG channels and cause QT prolongation. Statins, the most commonly used class of cholesterol reducing drugs, have also been reported to inhibit HERG channels and prolong QT interval in patients using these drugs. However, the interaction between naringenin and statins on the function of HERG channels has not been studied. MATERIALS AND METHODS: In the present study, we expressed HERG channels in Xenopus oocytes and tested the effects of naringenin and statins separately and combined on HERG channels. RESULTS: When 30 µM naringenin was added to statins (1 µM rosuvastatin or 3 µM atorvastatin), significantly greater inhibition of HERG was demonstrated, compared to the inhibition caused by statins alone. CONCLUSIONS: The results indicate that an additive interaction occurs between naringenin and statins; this could pose an increased risk of arrhythmias by decreasing repolarization reserve.

Transient receptor potential vanilloid 1 (TRPV1)-independent actions of capsaicin on cellular excitability and ion transport.

Capsaicin is a naturally occurring alkaloid derived from chili pepper that is responsible for its hot pungent taste. Capsaicin is known to exert multiple pharmacological actions, including analgesia, anticancer, anti-inflammatory, antiobesity, and antioxidant effects. The transient receptor potential vanilloid subfamily member 1 (TRPV1) is the main receptor mediating the majority of the capsaicin effects. However, numerous studies suggest that the TRPV1 receptor is not the only target for capsaicin. An increasing number of studies indicates that capsaicin, at low to mid µM ranges, not only indirectly through TRPV1-mediated Ca2+ increases, but also directly modulates the functions of voltage-gated Na+ , K+ , and Ca2+ channels, as well as ligand-gated ion channels and other ion transporters and enzymes involved in cellular excitability. These TRPV1-independent effects are mediated by alterations of the biophysical properties of the lipid membrane and subsequent modulation of the functional properties of ion channels and by direct binding of capsaicin to the channels. The present study, for the first time, systematically categorizes this diverse range of non-TRPV1 targets and discusses cellular and molecular mechanisms mediating TRPV1-independent effects of capsaicin in excitable, as well as nonexcitable cells.

The prognostic value of squamous differentiation in endometrioid type endometrial cancer: a matched analysis.

We aimed to examine the effect of the squamous differentiation on survival outcomes of women with endometrioid adenocarcinoma. We retrospectively reviewed the patients with endometrioid adenocarcinoma who underwent primary surgical treatment in a tertiary referral hospital. Sixty-nine patients having squamous differentiation constituted the case group. Each woman in the case group was matched with two patients in the control group based on age, disease stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy. During the follow-up, the recurrence rates were similar between the case (5/69, 7.2%) and control (10/138, 7.2%) groups (p = 1.0). The 5-year disease-free survival rate was 90.2% for the case group and 88.6% for the control group (p = .51). The 5-year overall survival rate was 94.6% for the case group and 91.8% for the control group (p = .12). Squamous differentiation seems to have no impact on the prognosis of patients with endometrioid adenocarcinoma.IMPACT STATEMENTWhat is already known on this subject? A focus of squamous differentiation is recognised in 12.8-25% of women with endometrioid adenocarcinoma. The prognostic value of the squamous differentiation was evaluated in several previous studies. However, it could not be clarified due to the conflicting results of these studies.What do the results of this study add? The probable confounding effects of well-known prognostic factors including age at diagnosis, International Federation of Gynaecology and Obstetrics stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy were eliminated with the case-control study design in the current study. Our findings indicate that the presence of squamous differentiation does not have any prognostic effect in endometrioid type endometrial cancer.What are the implications of these findings for clinical practice and/or further research? The molecular prognosticators of endometrial cancer were extensively studied in recent years. It is likely that clinicopathological and molecular prognostic factors will be integrated for predicting prognosis as a part of routine clinical practice soon. In this context, the prognostic value of the squamous differentiation in endometrioid adenocarcinomas may further be clarified by larger and multicentric studies that utilise central pathology review.

The safety of major gynaecologic cancer surgery without routine preoperative COVID-19 testing in the COVID-19 era: a multicentre, retrospective, case-control study.

Our goal was to address the safety of major gynaecologic cancer surgery without routine preoperative COVID-19 testing in the COVID-19 era. The databases of seven gynaecologic cancer centres were searched in order to identify all consecutive gynaecologic cancer patients undergoing major surgery between March 11, 2020 and May 15, 2020 for this retrospective, case-control study. The case group consisted of patients with histopathologically confirmed gynaecologic cancers, and each case was matched with two counterparts who had undergone primary surgery before the COVID-19 pandemic. The case and the control groups were compared in terms of length of hospital stay, admission to the intensive care unit (ICU), intraoperative and postoperative complications.During the study period, 154 women with gynaecologic cancer undergoing major surgery were identified. Although the case group had more co-morbidities compared to the control group (103/154 vs. 178/308, respectively; p = .04), the median length of hospital stays, the rate of ICU admission, intraoperative complication rates and postoperative complication rates were similar in the two groups. Gynaecologic cancer surgery may be performed safely in the COVID-19 era with similar rates of ICU admission, intraoperative and postoperative complications compared to the patients operated before the COVID-19 pandemic.IMPACT STATEMENTWhat is already known on this subject? Many societies have announced their guidelines about the surgical management of gynaecologic cancer patients during the COVID-19 pandemic. However, most of them are not evidence-based and mostly on expert opinions.What do the results of this study add? The main findings of this retrospective, case-control study indicate that the short-term (30 day) outcomes of gynaecologic cancer patients undergoing major surgery in the COVID-19 era are similar to those who had been operated before the COVID-19 pandemic. The length of hospital stays, the rates of admission to the ICU, intraoperative and postoperative complications were comparable between women undergoing major gynaecologic cancer surgery in the COVID-19 era and the women who had been operated before the pandemic.What are the implications of these findings for clinical practice and/or further research? We can suggest that definitive surgery may be performed for gynaecologic cancer patients in the COVID-19 era if the resources permit and appropriate precautions such as social distancing, isolation and the use of personal protective equipment are taken.

Low-grade endometrial stromal sarcoma: A Turkish uterine sarcoma group study analyzing prognostic factors and disease outcomes.

OBJECTIVE: To investigate factors associated with refractory disease, recurrence, or death as well as disease-free survival (DFS) and overall survival (OS) in low-grade endometrial sarcoma (LGESS). METHODS: A multi-institutional, retrospective study was conducted in a total of 124 patients, who received a curative-intent surgery. The exclusion criteria were as follows: i) history of any other invasive disease; ii) neoadjuvant therapy; iii) fertility sparing surgery; iv) a different diagnosis after review of the slides. RESULTS: All patients underwent hysterectomy, 96% had bilateral salpingo-oophorectomy, and 65% had lymphadenectomy. Twelve (14.8%) of 81 patients undergoing lymphadenectomy had lymph node (LN) metastasis. Of those, 8 (9.8%) had pelvic LN metastasis whereas 4 (5.6%) had isolated paraaortic LN metastasis. Six of 8 (75%) patients with positive pelvic LNs had concurrent paraaortic LN metastasis. Among 124 patients, 3 patients (2.4%) had refractory disease following primary therapy. During a median follow-up of 45.5 months, 27 (22.3%) of 121 patients who achieved complete remission after primary therapy developed recurrence, and 10 patients (8.1%) died of disease. The 3-year DFS and OS were 76.9% and 93.8%, respectively. Stage was the sole independent prognostic factor in the whole cohort. When analyzing factors within subgroups of stage I and stage ≥II, there was no significant prognostic factor for stage I; however, lymphadenectomy and adjuvant chemotherapy were significantly associated with disease outcomes for stage ≥II. While lymphadenectomy was related with improved DFS, chemotherapy was associated with poor DFS and OS. CONCLUSION: The risk of LN metastasis at pelvic as well as paraaortic lymphatic basins is not negligible to omit lymphadenectomy in stage ≥II LGESS. Moreover, lymphadenectomy provides significant DFS advantage in patients with extrauterine disease.

Perioperative SARS-CoV-2 infection among women undergoing major gynecologic cancer surgery in the COVID-19 era: A nationwide, cohort study from Turkey.

OBJECTIVE: The objective of this study was to determine the rate of perioperative SARS-CoV-2 infection among gynecologic cancer patients undergoing major surgery. METHODS: The database of the Turkish Ministry of Health was searched in order to identify all consecutive gynecologic cancer patients undergoing major surgery between March 11, 2020 and April 30, 2020 for this retrospective, nationwide, cohort study. The inclusion criteria were strictly founded on a final histopathological diagnosis of a malignant gynecologic tumor. COVID-19 cases were diagnosed by reverse transcriptase- polymerase chain reaction testing for SARS-CoV-2. The rate of perioperative SARS-CoV-2 infection and the 30-day mortality rate of COVID-19 patients were investigated. RESULTS: During the study period, 688 women with gynecologic cancer undergoing major surgery were identified nationwide. The median age of the patients was 59 years. Most of the surgeries were open (634/688, 92.2%). There were 410 (59.6%) women with endometrial cancer, 195 (28.3%) with ovarian cancer, 66 (9.6%) with cervical cancer, 14 (2.0%) with vulvar cancer and 3 (0.4%) with uterine sarcoma. The rate of SARS-CoV-2 infections confirmed within 7 days before or 30 days after surgery was 46/688 (6.7%). All but one woman was diagnosed postoperatively (45/46, 97.8%). The rates of intensive care unit admission and invasive mechanical ventilation were 4/46 (8.7%) and 2/46 (4.3%), respectively. The 30-day mortality rate was 0%. CONCLUSION: In the COVID-19 era, gynecologic cancer surgery may be performed with an acceptable rate of perioperative SARS-CoV-2 infection if the staff and the patients strictly adhere to the established infection control measures.

Is the extent of lymphadenectomy a prognostic factor in International Federation of Gynecology and Obstetrics stage II endometrioid endometrial cancer?

AIM: This study aimed to evaluate the prognostic significance of adequate lymph node dissection (LND) (≥10 pelvic lymph nodes (LNs) and ≥ 5 paraaortic LNs removed) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrioid endometrial cancer (EEC). METHODS: A multicenter department database review was performed to identify patients who had been operated and diagnosed with stage II EEC at seven centers in Turkey retrospectively. Demographic, clinicopathological, and survival data were collected and analyzed. RESULTS: We identified 284 women with stage II EEC. There were 170 (59.9%) patients in the adequate lymph node dissection (LND) group and 114 (40.1%) in the inadequate LND group. The 5-year overall survival (OS) rate of the inadequate LND group was significantly lower than that of the adequate LND group (84.1% vs. 89.1%, respectively; p = 0.028). In multivariate analysis, presence of lymphovascular space invasion (LVSI) (hazard ratio [HR]: 2.39, 95% confidence interval [CI]: 1.23-4.63; p = 0.009), age ≥ 60 (HR: 3.30, 95% CI: 1.65-6.57; p = 0.001], and absence of adjuvant therapy (HR: 2.74, 95% CI: 1.40-5.35; p = 0.003) remained as independent risk factors for decreased 5-year disease-free survival (DFS). Inadequate LND (HR: 2.34, 95% CI: 1.18-4.63; p < 0.001), age ≥ 60 (HR: 2.67, 95% CI: 1.25-5.72; p = 0.011), and absence of adjuvant therapy (HR: 4.95, 95% CI: 2.28-10.73; p < 0.001) were independent prognostic factors for decreased 5-year OS in multivariate analysis. CONCLUSION: Adequate LND and adjuvant therapy were significant for the improvement of outcomes in FIGO stage II EEC patients. Furthermore, LVSI was associated with worse 5-year DFS rate in stage II EEC.

CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells.

Tumor necrosis factor (TNF) is known to activate the epithelial Na+ channel (ENaC) in A549 cells. A549 cells are widely used model for ENaC research. The role of δ-ENaC subunit in TNF-induced activation has not been studied. In this study we hypothesized that δ-ENaC plays a major role in TNF-induced activation of ENaC channel in A549 cells which are widely used model for ENaC research. We used CRISPR/Cas 9 approach to knock down (KD) the δ-ENaC in A549 cells. Western blot and immunofluorescence assays were performed to analyze efficacy of δ-ENaC protein KD. Whole-cell patch clamp technique was used to analyze the TNF-induced activation of ENaC. Overexpression of wild type δ-ENaC in the δ-ENaC KD of A549 cells restored the TNF-induced activation of whole-cell Na+ current. Neither N-linked glycosylation sites nor carboxyl terminus domain of δ-ENaC was necessary for the TNF-induced activation of whole-cell Na+ current in δ-ENaC KD of A549 cells. Our data demonstrated that in A549 cells the δ-ENaC plays a major role in TNF-induced activation of ENaC.

Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice.

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.

Is It Possible to Develop a Prediction Model for Lymphovascular Space Invasion in Endometrioid Endometrial Cancer?

OBJECTIVE: The purpose of this retrospective study was to define a risk index that would serve as a surrogate marker of lymphovascular space invasion (LVSI) in women with endometrioid endometrial cancer (EC). MATERIALS AND METHODS: Final pathology reports of 498 women who underwent surgery with curative intent for endometrioid EC between January 2008 and June 2018 were retrospectively reviewed. Logistic regression was used to investigate clinicopathologic factors associated with positive LVSI status. Independent risk factors for LVSI were used to build a risk model and "risk of LVSI index" was defined as "tumor grade×primary tumor diameter×percentage of myometrium involved." The scores used in the "risk of LVSI index" were weighted according to the odds ratios assigned for each variable. The risk of LVSI index was noted for each patient. The diagnostic performance of the model was expressed as sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. RESULTS: According to the "risk of LVSI index," presence of LVSI was correctly estimated in 89 of 104 LVSI-positive women at a cutoff of 161.0 (sensitivity 85.5%, specificity 79.4%, negative predictive value 95.4%, positive predictive value 52.3%, positive likelihood ratio 4.15, negative likelihood ratio 0.18). The area under curve of the receiver-operating characteristics was 0.90 (95% confidence interval, 0.87-0.93) at this cutoff. CONCLUSIONS: It seems possible to predict the presence of LVSI in women with endometrioid EC when the "risk of LVSI index" is calculated. However, external validation of this model is warranted.

Neuroprotective Effect of Curcumin on the Nigrostriatal Pathway in a 6-Hydroxydopmine-Induced Rat Model of Parkinson's Disease is Mediated by α7-Nicotinic Receptors.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic nigrostriatal neurons. Most of the existing pharmacological approaches in PD consider replenishing striatal dopamine. It has been reported that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptor (α7-nAChR) stimulation may offer a potential therapeutic approach in PD. Our recent in-vitro studies demonstrated that curcumin causes significant potentiation of the function of α7-nAChRs expressed in Xenopus oocytes. In this study, we conducted in vivo experiments to assess the role of the α7-nAChR on the protective effects of curcumin in an animal model of PD. Intra-striatal injection of 6-hydroxydopmine (6-OHDA) was used to induce Parkinsonism in rats. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. The intraperitoneal administration of the α7-nAChR-selective antagonist methyllycaconitine (1 µg/kg) reversed the neuroprotective effects of curcumin in terms of both animal behavior and TH immunoreactivity. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism.

Pure large cell neuroendocrine carcinoma of ovary: A rare clinical entity.

OBJECTIVE: Large cell neuroendocrine carcinoma (LCNEC) of the ovary is a rare tumour. Its pure form without any associated surface epithelial stromal or germ cell component is more rarely seen. Its prognosis is generally very poor even when the diagnosis is made at an early stage. We report a case of pure large cell neuroendocrine tumour of ovary. The patient was a 73-year-old woman with symptom of pelvic pain. Ultrasonography detected an abdominal tumour larger than 10 cm. She underwent an exploratory laparotomy with resection of the pelvic mass. After the surgery six cycles of chemotherapy (Etoposide and Cisplatin) were administered to the woman. She is still healthy after the last chemotherapy. Due to the rarity of the disease, few number of reported cases and the lack of systematic population based studies or registry data, we reported this case.

Para-aortic lymph node involvement revisited in the light of the revised 2018 FIGO staging system for cervical cancer.

OBJECTIVE: This dual-institutional, retrospective study aimed to determine the clinicopathological risk factors for para-aortic lymph node (LN) metastasis among women who underwent radical hysterectomy with systematic pelvic and para-aortic lymphadenectomy for 2009 FIGO stage IB1-IIA2 cervical cancer. METHODS: Institutional cervical cancer databases of two high-volume gynecologic cancer centers in Ankara, Turkey were retrospectively analyzed. Women with 2009 FIGO stage IB1-IIA2 cervical cancer that had undergone radical hysterectomy with pelvic and para-aortic lymphadenectomy between January 2006 and December 2018 were included in the study. Patient data were analyzed with respect to para-aortic LN involvement and all potential clinicopathological risk factors for para-aortic LN metastasis were investigated. RESULTS: A total of 522 women met the inclusion criteria. Pelvic LN metastasis was detected in 190 patients (36.4%), para-aortic LN metastasis in 48 patients (9.2%), isolated para-aortic LN metastasis in 4 (0.8%), and both pelvic and para-aortic LN metastasis in 44 (8.4%) women, respectively. The independent risk factors identified for para-aortic LN involvement included parametrial invasion (odds ratio [OR]: 3.57, 95% confidence interval [CI]: 1.65-7.72; p = 0.001), metastasized pelvic LN size > 1 cm (OR: 4.51, 95% CI: 1.75-11.64; p = 0.002), multiple pelvic LN metastases (OR: 3.83, 95% CI: 1.46-10.01; p = 0.006), and common iliac LN metastasis (OR: 2.97, 95% CI: 1.01-8.68; p = 0.04). A total of 196 (37.5%) patients exhibited at least one risk factor for para-aortic nodal disease. CONCLUSION: Parametrial invasion, metastasized pelvic LN size > 1 cm, multiple pelvic LN metastases, and common iliac LN metastasis seem to be independent predictors of para-aortic LN involvement.

Curcumin Acts as a Positive Allosteric Modulator of α7-Nicotinic Acetylcholine Receptors and Reverses Nociception in Mouse Models of Inflammatory Pain.

Effects of curcumin, a major ingredient of turmeric, were tested on the function of the α7-subunit of the human nicotinic acetylcholine (α7-nACh) receptor expressed in Xenopus oocytes and on nociception in mouse models of tonic and visceral pain. Curcumin caused a significant potentiation of currents induced by acetylcholine (ACh; 100 µM) with an EC50 value of 0.2 µM. The effect of curcumin was not dependent on the activation of G-proteins and protein kinases and did not involve Ca2+-dependent Cl- channels expressed endogenously in oocytes. Importantly, the extent of curcumin potentiation was enhanced significantly by decreasing ACh concentrations. Curcumin did not alter specific binding of [125I]α-bungarotoxin. In addition, curcumin attenuated nociceptive behavior in both tonic and visceral pain models without affecting motor and locomotor activity and without producing tolerance. Pharmacological and genetic approaches revealed that the antinociceptive effect of curcumin was mediated by α7-nACh receptors. Curcumin potentiated the antinociceptive effects of the α7-nACh receptor agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU282987). Collectively, our results indicate that curcumin is a positive allosteric modulator of α7-nACh receptor and reverses nociception in mouse models of tonic and visceral pain.

Cell shortening and calcium dynamics in epicardial and endocardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

NEW FINDINGS: What is the central question of this study? To investigate haemodynamic dysfunction in the type 2 diabetic Goto-Kakizaki (GK) rat, we measured shortening and Ca2+ transport in ventricular myocytes from epicardial (EPI) and endocardial (ENDO) regions. What is the main finding and its importance? EPI and ENDO GK myocytes displayed similar hypertrophy. Time to peak (TPK) and time to half (THALF) relaxation were prolonged in EPI GK myocytes. TPK Ca2+ transient was prolonged and THALF decay of the Ca2+ transient was shortened in EPI GK myocytes. Amplitude of shortening, Ca2+ transient and sarcoplasmic reticulum Ca2+ were unaltered in EPI and ENDO myocytes from Goto-Kakizaki compared with control rats. We demostrated regional differences in shortening and Ca2+ transport in Goto-Kakizaki rats. ABSTRACT: Diabetic cardiomyopathy is considered to be one of the major diabetes-associated complications, and the pathogenesis of cardiac dysfunction is not well understood. The electromechanical properties of cardiac myocytes vary across the walls of the chambers. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the Goto-Kakizaki (GK) type 2 diabetic rat heart. Shortening and intracellular Ca2+ transients were measured by video edge detection and fluorescence photometry. Myocyte surface area was increased in EPI-GK and ENDO-GK compared with control EPI-CON and ENDO-CON myocytes. Time to peak shortening was prolonged in EPI-GK compared with EPI-CON and in ENDO-CON compared with EPI-CON myocytes. Time to half-relaxation of shortening and time to peak Ca2+ transient were prolonged in EPI-GK compared with EPI-CON myocytes. Time to half-decay of the Ca2+ transient was prolonged in EPI-CON compared with EPI-GK and in EPI-CON compared with ENDO-CON myocytes. The amplitude of shortening and the Ca2+ transient were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Sarcoplasmic reticulum Ca2+ and myofilament sensitivity to Ca2+ were unaltered in EPI-GK and ENDO-GK compared with their respective controls. Regional differences in Ca2+ signalling in healthy and diabetic myocytes might account for variation in the dynamics of myocyte shortening. Further studies will be required to clarify the mechanisms underlying regional differences in the time course of shortening and the Ca2+ transient in EPI and ENDO myocytes from diabetic and control hearts.

Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto-Kakizaki type 2 diabetic rats.

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca2+ homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca2+ in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca2+ transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca2+ currents and Ca2+ transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca2+ current was unaltered, the voltage dependence of the Ca2+ transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca2+ current and Ca2+ transient were unaltered. THALF decay of L-type Ca2+ current was unaltered; however, THALF decay of the Ca2+ transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca2+ current was unaltered; however, the voltage dependence of the Ca2+ transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca2+ transport in the GK diabetic rat hearts.

Prognostic factors and patterns of recurrence in lymphovascular space invasion positive women with stage IIIC endometriod endometrial cancer.

AIM: The purpose of this study was to determine the prognostic factors and patterns of failure in lymphovascular space invasion (LVSI)-positive women with stage IIIC endometrioid endometrial cancer (EC). METHODS: A multicenter, retrospective, department database review was performed to identify LVSI-positive patients with stage IIIC endometrioid EC at five gynecological oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. RESULTS: We identified 172 LVSI-positive women with stage IIIC endometrioid EC during the study period; 75 (43.6%) were classified as Stage IIIC1 and 97 (56.4%) as Stage IIIC2 . The median age at diagnosis was 59 years, and the median duration of follow up was 34.5 months. The total number of recurrences was 46 (26.7%). We observed 14 (8.1%) locoregional recurrences, 12 (7.0%) retroperitoneal failures and 20 (11.6%) distant relapses. For the entire study cohort, 5-year progression-free survival (PFS) was 67.4%, while the 5-year overall survival (OS) rate was 75.1%. Grade 3 histology (hazard ratio [HR] 2.62, 95% confidence interval [CI] 1.34-5.12; P = 0.005), cervical stromal invasion (HR 2.33, 95% CI 1.09-4.99; P = 0.028) and myometrial invasion (MMI) ≥50% (HR 4.0, 95% CI 1.16-13.69; P = 0.028) were found to be independent prognostic factors for decreased OS. CONCLUSION: Uterine factors such as grade 3 disease, cervical stromal invasion and deep MMI seem to be independently associated with decreased OS in LVSI-positive women with stage IIIC endometrioid EC. The high distant recurrence rate in this subgroup of patients warrants further studies in order to identify the most effective treatment strategy for those patients.

Awareness and Knowledge Levels of Turkish College Students about Human Papilloma Virus Infection and Vaccine Acceptance.

Awareness of HPV by the target population is an important determinant of vaccine acceptance. The aim of this study is to evaluate the awareness of HPV infection and acceptability of the HPV vaccines among Turkish college students. College students aged 18-30 who were attending a large public university in Ankara participated in this study. The participants were asked to complete a questionnaire to elicit demographic characteristics, awareness level of HPV and HPV vaccine, and willingness to be vaccinated. One thousand one hundred sixty students responded to the invitation email and completed the questionnaire. The mean scores of female students about HPV and HPV vaccine were 7.1/15 and 3.6/9, respectively, while these scores were 7.9/15 and 3.4/9 among male students, respectively. While 51 % percent of female and 33.5 % of male students had heard of HPV and 32.8 % and 18 % of them had heard of HPV vaccine, respectively, only 1.5 % of female and 0.4 % of male students had been vaccinated against HPV. A total of 507 students (43.7 %) had previously heard of HPV. Only 309 (26.6 %) of the participants had previously heard of the HPV vaccine, and 45.1 % of the students were willing to receive HPV vaccination. The main predictors for willingness to be vaccinated were the following: sexual experience, sexual behavior, past history of sexually transmitted infection (STI), and knowledge about HPV and HPV vaccine. Higher awareness levels of HPV and HPV vaccine are significantly related to greater willingness to be vaccinated, and the main reasons for rejecting the vaccine were insufficient information about the vaccine and possible unknown side effects.

Natural Negative Allosteric Modulators of 5-HT3 Receptors.

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.

Is Tumor Size Really Important for Prediction of Lymphatic Dissemination in Grade 1 Endometrial Carcinoma With Superficial Myometrial Invasion?

OBJECTIVES: Selection of patients with endometrioid endometrial cancer (EEC), in whom systematic lymph node dissection (LND) is indicated, is an important part of management to maintain optimal oncological outcomes, while avoiding unnecessary morbidities. According to the current approach, LND is recommended for the patients with International Federation of Gynecology and Obstetrics (FIGO) grade 1 to 2 tumors and a primary tumor diameter (PTD) greater than 2 cm, even with myometrial invasion (MMI) of less than 50%. We aimed to determine incidence of LN metastasis in this particular group of patients with grade 1 tumors, superficial MMI, and a PTD greater than 2 cm. MATERIALS AND METHODS: This study only focused on women with FIGO grade 1 EEC having less than 50% MMI. Therefore, women with grade 2 or 3 tumors were excluded, as well as patients with 50% or greater MMI. We also excluded women with macroscopic extrauterine disease, as well as patients with cervical stromal involvement. Patients were divided into subgroups with regard to PTD; group 1 was composed of patients with PTD of 20 mm or less, whereas group 2 was composed of patients with PTD greater than 20 mm. All clinical and pathological variables were compared between the groups. RESULTS: Final pathology reports of 484 women with EEC who underwent surgical staging were analyzed. Among these women, there were 123 women in group 1 (PTD ≤ 20 mm) and 120 women in group 2 (PTD > 20 mm), with FIGO grade 1 tumors and superficial MMI. The median number of total LNs removed was 54 (range, 20-151). There were no women with pelvic and/or para-aortic LN metastasis in group 2, as well as in group 1. CONCLUSIONS: Our results suggest that lymphadenectomy may be omitted in women with FIGO grade 1 EEC having superficial MMI regardless of PTD. Deferral of systematic LND in this subgroup of patients may lead to reductions in costs and surgical morbidity.