The effects of the combination of temozolomide and Eribulin on T98G human glioblastoma cell line: an ultrastructural study.

Glioblastoma tumors are the most aggressive primary brain tumors that develop resistance to temozolomide (TMZ). Eribulin (ERB) exhibits a unique mechanism of action by inhibiting microtubule dynamics during the G2/M cell cycle phase. We utilized the T98G human glioma cell line to investigate the effects of ERB and TMZ, both individually and in combination. The experimental groups were established as follows: control, E5 (5 nM ERB), T0.75 (0.75 mM TMZ), T1 (1.0 mM TMZ), and combination groups (E5+T0.75 and E5+T1). All groups showed a significant decrease in cell proliferation. Apoptotic markers revealed a time-dependent increase in annexin-V expression, across all treatment groups at the 48-hour time point. Caspase-3, exhibited an increase in the combination treatment groups at the 48-hour mark. Transmission electron microscopy (TEM) revealed normal ultrastructural features in the glioma cells of the control group. However, treatments induced ultrastructural changes within the spheroid glioblastoma model, particularly in the combination groups. These changes included a dose-dependent increase in autophagic vacuoles and apoptotic morphology of the cells. In conclusion, the similarity in the mechanism of action between ERB and TMZ suggests the potential for synergistic effects when combined. Our results highlight that this combination induced severe damage and autophagy in glioma spheroids after 48 hours.

Investigation of doxorubicin combined with ciprofloxacin-induced cardiotoxicity: from molecular mechanism to fundamental heart function.

This study was designed to investigate the impacts of Doxo alone and in combination with Cipro on the hepatic and cardiac CYP1A2, CYP2J3, and CYP3A1 mRNA levels. We also aimed to analyze the cardiac function by perfusing isolated rat hearts. Rats were given Doxo and/or Cipro in chronic (3-week) and acute (single-day) dosing schedules. Cardiac CYP2J3, CYP3A1, and CYP1A2 gene expression levels were measured by quantitative reverse transcription PCR. Cardiac functions of the isolated hearts were evaluated by using the Langendorff technique. Doxo alone (2.5 mg/kg) and Doxo + Cipro (2.5 mg + 20 mg/kg) significantly decreased hepatic CYP1A2 expression compared to saline, whereas Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 mg + 20 mg/kg) showed significantly higher cardiac CYP1A2 expression in comparison to control. In the liver tissue, Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg) decreased the CYP2J3 expression than the control group. The Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg)-treated group had significantly higher cardiac CYP2J3 expression compared to control. Doxo (2.5 mg/kg; cumulative dose 15 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg) showed significantly higher cardiac CYP3A1 expressions than the control. Rate-pressure product (HR × LVDP)/1000) showed an overall decrease in cardiac functions of Doxo (2.5 mg/kg) and Doxo + Cipro (2.5 + 20 mg/kg)-treated group. We found considerable effects in chronic protocol; Doxo alone high dose and plus Cipro decreased hepatic CYP1A2 and CYP2J3 mRNA. On the other hand, these treatment groups exhibited an increase in the cardiac CYP1A2, CYP2J3, and CYP3A1 expression and likewise deteriorated the overall hemodynamic parameters.

Influence of Selective Dopamine Agonist Ropinirole on Conditioned Place Preference and Somatic Signs of Morphine Withdrawal in Rats.

The underlying mechanism of dependence and rewarding effects of morphine is imperative to understand. The primary aim of this study was to investigate whether ropinirole D2/3 agonist affects the rewarding and reinforcing properties of morphine-induced conditioned place preference (CPP) and withdrawal syndromes in rats. On day one, the animals were randomly divided to conduct the pre-test. The morphine (10 mg/kg, i.p.) and/or saline was administered on alternate days in an 8-day CPP session. On day 10, 15 min prior to the post-conditioning test (expression), a single dose of ropinirole (1, 2, and 5 mg/kg, i.p.) was given to rats. In extinction session, ropinirole was injected daily, and CPP was extinguished by repeated testing, with intervals of 3 days. Finally, reinstatement was assessed by administering ropinirole (1, 2, and 5 mg/kg) 15 min before the morphine injection. Morphine dependence was developed by administering increasing doses of morphine (10-50 mg/kg, i.p.). To assess withdrawal symptoms, ropinirole (1, 2, and 5 mg/kg) was injected 15 min before naloxone (2 mg/kg, s.c.) administration. The present study confirms that ropinirole attenuates expression and reinstatement of CPP, while it precipitates the extinction of morphine-induced CPP. Naloxone-precipitated morphine withdrawal symptoms, including wet dog shakes and weight loss, were attenuated although jumping was increased by a single ropinirole injection. Thus, ropinirole was influential in attenuating expression, reducing drug seeking and weakening reinstatement via the dopaminergic system. These findings show that ropinirole might affect neuro-adaptive changes related to dependence.

Surgery with hyperthermic intraperitoneal chemotherapy after response to induction chemotherapy in patients with peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC) with peritoneal metastases (PM) has a dismal prognosis and to date only a few management options have been reported. Of those, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after induction bidirectional intraperitoneal and systemic chemotherapy (BIPSC) appear as a promising treatment option for these patients. Outcome data including safety and efficacy of CRS with radical Gastrectomy and HIPEC after response to combination of laparoscopic HIPEC (LHIPEC) with BIPSC as an induction therapy in patients with PM of GC was evaluated in this retrospective observational study. METHODS: Diagnostic Laparoscopy was performed in 53 patients with PM of GC who admitted to the Center for Treatment of Peritoneal Surface Malignancies, Istanbul, between 2013 and 2016. Peritoneal cancer index (PCI), ascites status and cytology were determined. The patients underwent LHIPEC and then, BIPSC induction chemotherapy using intraperitoneal docetaxel (30 mg/m2) and cisplatin (30 mg/m2) and intravenous Docetaxel/Cisplatin/5-Fluorouracil (DCF) for 3 cycles. In selected patients, CRS with radical gastrectomy and HIPEC were performed after the response to induction therapy. BIPSC was continued for 3 more cycles with a dose reduction in an adjuvant setting. RESULTS: All LHIPEC procedures were uneventful with Grade 1-2 side effects (11/53, 20,8%). As a response to induction chemotherapy PCI was reduced from 19.6±8 (range, 6-39) to 13.6±9.8 (range, 1-39) (P<0.001). Ascites was detected in 55% (29 out of 53) and cytology was positive in 51% (27 out of 53) of the patients before induction chemotherapy. Ascites was completely abolished and all cytology became negative. Then, 34 of 53 (64.15%) patients underwent CRS with radical gastrectomy and HIPEC. CC0/1 resection was achieved in 22 (64.70%) of patients (P<0.05). The median survival time was 18.9±13.4 (95% CI: 15.2-22.6 months. Combined surgery and HIPEC related mortality occurred in 1 out of 34 patients (2.9%) due to developed diffuse intravascular coagulation at postoperative day 2. Grade 2 operative complications included biliary fistula in one, and duodenal stump leakage in two patients (8.7%). All of the fistula closed with conservative management. The median survival time was 18.9±13.4 months and the median progression-free survival time was 15.6±12.9 with 1-, 2-, and 5-year survival rates of 82.4%, 59% and 17.6% in patients with PM of GC. Multivariate analysis identified high peritoneal cancer index (P=0.000) and complete resection (P<0.05) as independent predictors for better progression-free and overall survival. CONCLUSIONS: The best outcomes can be expected with optimal cytoreduction and limited peritoneal dissemination in response to induction chemotherapy. Knowledgeable selection of patients with PM of GC is essential to perform surgery with HIPEC safely with acceptable mortality and morbidity.

Therapeutic potential of cyclooxygenase-3 inhibitors in the management of glioblastoma.

In this study we investigated the expression of COX-1, COX-2 and COX-3 mRNA in C6 glioblastoma and normal brain tissues and the effects of acetaminophen, indomethacin or metamizole treatments on the development of C6 glioblastoma in relation with COX inhibition. Glioblastoma cells were inoculated intracerebrally into frontal lobe of adult male Wistar albino rats. 10 days after inoculation, rats were treated with 150 mg/kg acetaminophen, 10 mg/kg indomethacin or 150 mg/kg metamizole. The tumor size was measured histologically and total RNA was isolated from tumor or normal brain tissue and mRNA levels of COX isoforms were determined by qRT-PCR. Our results showed the presence of COX-1, COX-2 and COX-3 expressions in both C6 glioblastoma and normal brain tissues. In tumor tissues COX-3 expression was significantly higher than normal brain tissue (p < 0.05) while there was no significant difference in COX-1 and COX-2 expressions. Acetaminophen and indomethacin decreased the tumor size by 71 and 43 % by inhibiting COX-3 mRNA expression around 87 and 91 % respectively. For the first time our study proposes a possible relationship between COX-3 mRNA expression and C6 glioblastoma development. We also suggested that the inhibition of COX-3 enzyme may be responsible for decrease in tumor size in part, the mechanism by which acetaminophen and indomethacin decreased rat C6 glioblastoma growth. However, the molecular events responsible for COX-3 effects on tumor development are still unresolved as these drugs exert their anti-cancer effect via both COX-3 dependent and independent mechanisms.

Evaluation of demographic characteristics, and general disease state of patients affliated with home health care unit of Malatya State Hospital.

OBJECTIVE: Home Health Care Unit a unit provides health services for elderly, bedridden and individuals with chronic diseases at home along within the frame of the diagnosis, and treatments of the relevant experts. Therefore, it is intended to reduce the probable physical and emotional burden related to the patient that arise by commuting to the hospital, to increase the number of empty beds for other patients and to improve the living standard by reducing the risk of hospital infection. In this study, the demographic characteristics of housebound patients, their general disease and its relationship with age and gender was investigated. METHODS: The following study was performed on 626 active patients of Malatya State Hospital Home Health Care Unit from January to November 2014. Data were analyzed using Microsoft Excel Program. RESULTS: The study included 60.5% (n=379) female and 39.5% (n=247) male patients. The highest group consisted of patients with 80 years or above 37.7% (n=236). Cerebrovascular disease (CVD) (n=95; 25.0%), senility (n=56; 14.8%) and Alzheimer's disease (n=50; 13.2%) were commonly observed in women. Male patients had CVD (n=54; 21.8%), femur fracture or gonarthrosis which required surgery (n=28; 11.3%), and fracture due to trauma or traffc accidents (n=28; 11.3%), senility and Alzheimer's disease (n=218.5%). CONCLUSION: In recent years home health care units became even more important after the gradual increase in the elderly population and injuries due to accidents. This study can help to provide home health care units in a more effcient manner by educating the staff and relatives who take care of the patients.

Mediastinal adipose tissue expresses a pathogenic profile of 11 ß-hydroxysteroid dehydrogenase Type 1, glucocorticoid receptor, and CD68 in patients with coronary artery disease.

OBJECTIVE: Cardiac visceral fat is accepted to be a new marker for cardiometabolic risk due to its association with increased cardiovascular risk factors. This study aimed to compare the expression of 11 beta hydroxysteroid dehydrogenases (11ß-HSD)-1, glucocorticoid receptor (GCR), and CD68 in mediastinal and subcutaneous adipose tissues (MAT, and SAT, respectively) and to assess their possible relationships with the development of coronary artery disease (CAD). METHODS AND RESULTS: Expression of 11ß-HSD-1, GCR, and CD68 mRNA levels were measured by quantitative real-time polymerase chain reaction in MAT and SAT tissues of 37 patients undergoing coronary artery bypass grafting due to CAD (CAD group) and 19 non-CAD patients (controls) undergoing heart valve surgery. 11ß-HSD-1 in MAT and SAT and GCR expression in MAT and SAT were found to be significantly increased in CAD group when compared with controls (P<.05, respectively). In CAD group, 11ß-HSD-1 mRNA levels were found to be significantly higher in MAT compared to SAT (P<.05). CD68 mRNA levels were significantly higher in MAT of CAD group compared to controls (P<.05). Immunohistochemical analyses demonstrated the presence of CD68+ cells and increased 11ß-HSD-1 expression in MAT of CAD group compared to SAT. CONCLUSION: The present study demonstrate that the mediastinal fat exhibits a pathogenic mRNA profile of 11ß-HSD-1, GCR, and CD68. The identification of 11ß-HSD-1 expression within the mediastinal fat, along with increased GCR expressions and the presence of CD68+ cells highlight that MAT potentially contributes to the pathogenesis of CAD.

The role of mediastinal adipose tissue 11ß-hydroxysteroid d ehydrogenase type 1 and glucocorticoid expression in the development of coronary atherosclerosis in obese patients with ischemic heart disease.

BACKGROUND: Visceral fat deposition and its associated atherogenic complications are mediated by glucocorticoids. Cardiac visceral fat comprises mediastinal adipose tissue (MAT) and epicardial adipose tissue (EAT), and MAT is a potential biomarker of risk for obese patients. AIM: Our objective was to evaluate the role of EAT and MAT 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) and glucocorticoid receptor (GCR) expression in comparison with subcutaneous adipose tissue (SAT) in the development of coronary atherosclerosis in obese patients with coronary artery disease (CAD), and to assess their correlations with CD68 and fatty acids from these tissues. METHODS AND RESULTS: Expression of 11ß-HSD-1 and GCR was measured by qRT-PCR in EAT, MAT and SAT of thirty-one obese patients undergoing coronary artery bypass grafting due to CAD (obese CAD group) and sixteen obese patients without CAD undergoing heart valve surgery (controls). 11ß-HSD-1 and GCR expression in MAT were found to be significantly increased in the obese CAD group compared with controls (p < 0.05). In the obese CAD group, 11ß-HSD-1 and GCR mRNA levels were strongly correlated in MAT. Stearidonic acid was significantly increased in EAT and MAT of the obese CAD group and arachidonic acid was significantly expressed in MAT of the obese male CAD group (p < 0.05). CONCLUSIONS: We report for the first time the increased expression of 11ß-HSD-1 and GCR in MAT compared with EAT and SAT, and also describe the interrelated effects of stearidonic acid, HOMA-IR, plasma cortisol and GCR mRNA levels, explaining 40.2% of the variance in 11ß-HSD-1 mRNA levels in MAT of obese CAD patients. These findings support the hypothesis that MAT contributes locally to the development of coronary atherosclerosis via glucocorticoid action.