Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P < 0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P < 0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB.     

Níveis de Tiol Sérico e Homeostase Tiol/Dissulfeto em Pacientes com Doença Valvar Mitral Reumatismal e em Sujeitos Saudáveis

BackgroundRheumatic mitral valve disease (RMVD) is the most common presentation of rheumatic heart disease (RHD). Inflammation and fibrosis processes also play significant roles in its pathogenesis. Recent studies showed that thiols and thiol-disulfide are promising novel oxidative stress markers.ObjectivesThe present study aimed to evaluate differences in the serum thiol and thiol-disulfide levels in patients with RMVD and the control group.MethodsNinety-two patients with RMVD were enrolled in the study. Fifty-four healthy subjects, age, and gender-matched with the study group, were also included in the study as a control group. This study investigated thiol levels in patients with RMVD and the control group. P-values lower than 0.05 were considered statistically significant.ResultsThe patients with RMVD presented higher systolic pulmonary artery pressure (SPAP) and left atrial (LA) diameter levels than the control group. Native thiol (407±83 μmol/L vs. 297±65 μmol/L, p<0.001) and total thiol (442±82 μmol/L vs. 329±65 μmol/L, p<0.001) levels were higher in the control group. Disulfide (16.7±4.9 μmol/L vs. 14.8±3.7 μmol/L, p=0.011) levels were higher in the group of patients with RMVD. A positive correlation was found between disulfide/native and disulfide/total thiols ratio with SPAP, LA diameter, and MS severity. Disulfide/total thiols ratio was significantly higher in patients with severe MS than with mild to moderate MS patients.ConclusionsTo the best of our knowledge, this is the only study of its kind that has evaluated thiol/disulfide homeostasis as a novel predictor, which was more closely related to RMVD and the severity of MS.     

Effect of Pilates Training on People With Fibromyalgia Syndrome: A Pilot Study

Altan L, Korkmaz N, Bingol Ü, Gunay B. Effect of Pilates training on people with fibromyalgia syndrome: a pilot study.ObjectiveTo investigate the effects of Pilates on pain, functional status, and quality of life in fibromyalgia, which is known to be a chronic musculoskeletal disorder.DesignRandomized, prospective, controlled, and single-blind trial.SettingPhysical medicine and rehabilitation department.ParticipantsWomen (N=50) who had a diagnosis of fibromyalgia syndrome (FMS) according to the American College of Rheumatology criteria.InterventionThe participants were randomly assigned into 2 groups. In group 1, a Pilates exercise program of 1 hour was given by a certified trainer to 25 participants 3 times a week for 12 weeks. In group 2, which was designed as the control group, 25 participants were given a home exercise (relaxation/stretching) program. In both groups, pre- (week 0) and posttreatment (week 12 and week 24) evaluation was performed by one of the authors, who was blind to the group allocation.Main Outcome MeasuresPrimary outcome measures were pain (visual analog scale) and Fibromyalgia Impact Questionnaire (FIQ). Exploratory outcome measures were number of tender points, algometric score, chair test, and Nottingham Health Profile.ResultsTwenty-five Pilates exercise and 24 relaxation/stretching exercise participants completed the study. In group 1, significant improvement was observed in both pain and FIQ at week 12 but only in FIQ at 24 weeks. In group 2, no significant improvement was obtained in pain and FIQ at week 12 and week 24. Comparison of the 2 groups showed significantly superior improvement in pain and FIQ in group 1 at week 12 but no difference between the 2 groups at week 24.ConclusionsWe suggest Pilates as an effective and safe method for people with FMS. Our study is the first clinical study designed to investigate the role of the Pilates method in FMS treatment. We believe that further research with more participants and longer follow-up periods could help assess the therapeutic value of this popular physical exercise method.     

Serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women.

AIMS: The aims of the present study were to determine the serum concentrations of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin and insulin resistance in benign and malignant epithelial ovarian tumors, and to discuss the use of these markers in benign-malignant tumor differentiation. METHODS: Forty-seven postmenopausal women with ovarian tumor and 31 age-matched, postmenopausal, healthy controls were included in this study. Insulin resistance index by homeostasis model assessment (HOMA score) and fasting blood glucose (FBG), serum IGF-I, IGFBP-3, leptin and CA-125 concentrations were determined in all patients preoperatively. The results were evaluated according to postoperative histopathology results. RESULTS: According to postoperative histopathology results, the patients were divided into malignant (n = 23), benign (n = 24) and control (n = 31) groups. There were no differences among the groups in relation to age, body mass index, FBG and HOMA score (p > 0.05). Serum concentrations of CA-125 were elevated in the malignant group compared with the benign ovarian tumor and control groups (p < 0.05). In contrast, serum IGF-I concentrations were significantly decreased in patients with malignant and benign ovarian tumors compared with controls (p < 0.05). Serum IGFBP-3 concentrations were also found to be lower in women with malignant ovarian tumors than in women with benign tumors (p < 0.05). Serum leptin did not differ among patients with malignant-benign tumors and controls (p > 0.05). CONCLUSION: Serum leptin and HOMA score have not been found to be valid indicators in ovarian tumors. However, the present data suggest that low concentrations of IGF-I and IGFBP-3 could be a reliable marker to differentiate benign from malignant ovarian tumors. Further experimental studies are warranted to understand the impact of the IGF-I system in ovarian carcinogenesis.     

Intravenous theophylline decreases post-dural puncture headaches

Post-dural puncture headache (PDPH) is a common complication of lumbar puncture. As invasive treatments for PDPH have known complications, pharmacologic management may be preferable. The aim of this study was to evaluate and to compare the efficacy of intravenous theophylline treatment for PDPH, in comparison with a placebo. We found that intravenous theophylline infusion was effective for decreasing the painfulness of PDPH compared with the control group. The mean visual analogue scale (VAS) value was 7.05+/-1.47 before the theophylline infusion and 2.88+/-2.31 after infusion. An average of 59.1% relief of pain was obtained in the group treated with theophylline infusion. The improvement in VAS in the study group was significant (p<0.001), whereas that in the control group was not (p=0.15). The mean VAS decrease after theophylline infusion was 4.17+/-2.03 in the study group and 0.41+/-0.71 in the control group; the difference in improvement between the groups was significant (p<0.001). Intravenous theophylline infusion is an easy, rapid, minimally invasive, an effective treatment for PDPH. It may be attempted in PDPH patients before invasive techniques are used. To the best of our knowledge, this is the first report on the effect of intravenous infusion of theophylline compared with a placebo in the treatment of PDPH.     

Endovascular repair in management of thoracic aortic aneurysms

Objective Aneurysms of the thoracic aorta are still potentially life-threatening situations. The conventional operation is still associated with morbidity. Endovascular stent graft repair offers an alternative to conventional operation for management of aortic diseases. Our aim was to report our experience with endovascular stent graft repair of thoracic aortic aneurysms. Patients and Methods Between November 2002 and October 2005, endovascular stent graft repair was performed in 26 patients: post-traumatic aortic aneurysm (n = 4), Type B dissection (n = 3) and descending thoracic aortic aneurysm (n = 19). The deployed stent graft systems were Talent-Medtronic (n = 14) and Excluder-Gore (n=12). Results Successful deployment of the stent grafts in the appropriate position was achieved in all patients. There was neither hospital mortality nor paraplegia. Late and non-procedure related death occurred in only one patient (3.8%). An average of 40% shrinkage of the aneurysmal space was observed. There was no early mortality and endoleaks. The median intensive care unit and hospital stay times were 1 and 7 days (range 4–13 days), respectively. Post-operative computed tomography scans were obtained in all patients and complete thrombosis was observed in the false lumen of dissecan aneurysms (n = 3) and sac of saccular aneurysms in 25 patients. Mean follow up time was 17.1 ± 5.4 months. Conclusions Endovascular stent graft treatment for treatment of thoracic aorta aneurysm, Type B dissection and traumatic disease of the thoracic aorta is technically feasible. Although the short and mid-term results are encouraging the long term results will determine the future of this treatment. This study was presented as an oral presentation in the 17th Annual Meeting of the Mediterranean Association of Cardiology and Cardiac Surgery, in Portorož, Slovenia, September 22–24, 2005.     

Long term effect of vagus nerve stimulation in pediatric intractable epilepsy: an extended follow-up

Purpose

Over the past two decades, vagus nerve stimulation (VNS) has become an accepted and viable treatment modality for intractable epilepsy both in children and adults. Earlier studies have demonstrated short-term seizure outcomes, usually for up to 5 years; so far, none have reported an extended outcome in children. We aimed to assess long term seizure outcome in children with intractable epilepsy for more than 5 years.

Methods

We identified patients who had VNS implantation for treatment of intractable epilepsy from March 2000 to March 2015 at our Epilepsy Center and collected data including demographic, age at epilepsy onset and VNS implantation, duration of epilepsy, seizure type, number of antiepilepsy drugs (AEDs), and monthly seizure frequency before VNS implantation and at the last clinic visit. Phone surveys were conducted with patients without recent clinic follow-up.

Results

Fifty-six patients (aged 4–17 at the time of implant) are the subjects of the study. Seizure reduction of >50 % was achieved in 9.8 % (6th month), 24 % (2nd year), 46.4 % (3rd year), and 54 %(5th year), and overall 35 (62.5 %) of the 56 subjects had a greater than 50 % reduction in seizure frequency at the last follow-up. Eleven patients became seizure free. The results, once obtained, were maintained steadily or even improved over time without any loss of efficacy during the follow-up. The only parameter, significantly related with clinical response, was age at seizure onset. The most frequent adverse events were hoarseness, cough, sore throat, and anorexia, experienced by 13 patients. Two patients had local wound infections and lead to the removal of the stimulator. An improvement in alertness, attention, and psychomotor activity, independent of the efficacy of vagal nerve stimulation, was observed in 8 patients.

Conclusion

To our knowledge, this is the first pediatric study evaluating seizure outcome over more than 5 years of follow-up, and demonstrates a favorable seizure outcome of >50 % seizure frequency in 62.5 % of patients and seizure freedom in 11 patients. It is well tolerated over an extended period of time.

     

PRAME mRNA levels in cases with acute leukemia: clinical importance and future prospects

The PRAME (preferentially expressed antigen of melanoma) gene has been shown to be expressed in high levels in some solid tumors and hemopoietic neoplasias but not or only weakly expressed in normal tissues. It encodes an antigen recognized by autologous cytolytic T lymphocytes. PRAME is a good candidate for tumor immunotherapy and is a useful marker gene for detection of minimal residual disease (MRD). In this study, PRAME mRNA using real-time RT-PCR was studied in 74 adult cases with acute leukemia-68 had de-novo acute leukemia, 3 had chronic myeloid leukemia-blastic crisis (CML-BC), and 3 had myelodysplastic/myeloproliferative syndrome-blastic transformation (MDS/MPD-BT)-and the results were compared with 30 age-matched healthy volunteers. Nineteen of 74 cases with leukemia expressed PRAME, while only 2 controls showed weak expression. The prevalence of PRAME expression in AML and ALL cases was 30% and 17%, respectively. We did not find any important correlation between PRAME expression and clinical characteristics, such as age, sex, organomegaly/lymphadenopathy, Hb, WBC count, platelet count, LDH level, alkaline phosphatase, albumin, cell-surface antigens, response to therapy, or progression-free and overall survival. PRAME was monitored in 15 cases during remission and/or relapse. There was a good correlation between PRAME mRNA and hematological remission and/or relapse. Interestingly, PRAME was very high in one case with AML but was not found 3 months after allogeneic transplantation. PRAME mRNA is observed in about one-third of AML cases; it may be a useful marker to detect MRD, and it may also be a good predictor for the timing of donor lymphocyte infusions (DLI) in the post-transplant period in cases of molecular relapse.     

Multicenter evaluation of AYC.2.2 agar for the isolation of mycobacteria from clinical samples

PurposeThe aim of this multicenter study is to evaluate AYC.2.2 agar for the isolation of mycobacteria from clinical samples.MethodsTotally 5559 media were tested in 7 centers. AYC.2.2 agar media for the study were prepared by C1 and sent to other centers under appropriate conditions. Other media except AYC.2.2 agar were purchased commercially.The media were subjected to routine laboratory operations in the center where they were sent. After the samples received for routine processing (in all centers, samples were processed with the same method (NALC-NaOH)), they were cultivated on routine media and AYC.2.2 agar afterward.ResultsC1: Average growth time was determined as 12.74±3.74 days with MGIT 960 system; 24.42±4.75 days with LJ and 24.37±4.96 days with AYC.2.2 agar. C2: Average growth time was determined as 18.25±9.32 days with TK-Medium, 28.73±7.44 days with LJ, and 31.72±6.35 days with AYC.2.2 agar. C3: Average growth time was determined as 20.48±7.24 days with Ogawa medium, 20.74±7.12 days with LJ, and 20.26±7.43 days with AYC.2.2 agar. C4: Average growth time was determined as 15.27±6.37 days with MGIT 960 system, 22.14±9.1 days with LJ, and 22±8.45 days with AYC.2.2 agar. C5: Average growth time was determined as 13±4.24 days with MGIT 960 system, 32.16±6.23 days with LJ, and 33±5.73 days with AYC.2.2 agar. C6: Average growth time was determined as 9±3.11 days with MGIT 960 system, 18.68±5.32 days with LJ, and 18.34±4.63 days AYC.2.2 agar. C7: Average growth time was determined as 14.74±7.65 with MGIT 960 system, 26.01±8.21 days with LJ, and 26.24±7.88 days with AYC.2.2 agar.ConclusionsIn conclusion, similar results were obtained with LJ and Ogawa media and AYC.2.2 agar. Furthermore, more studies should be conducted for isolation of M. tuberculosis and performing antibiotic susceptibility tests using AYC.2.2 agar before it can be used as a routine media in the laboratories.