The effect of alpha-lipoic acid on oxidative parameters, SCUBE-1 and SCUBE-2 in hepatic ischemia-reperfusion injury in cholestatic rats.

OBJECTIVE: The aim of the study was to evaluate the protective effects of alpha-lipoic acid (ALA) on the liver, oxidative parameters, and signal peptide-CUB-epidermal growth factor-like domain-containing proteins 1 and 2 (SCUBE-1 and -2) in an experimental cholestatic hepatic ischemia-reperfusion (IR) model. MATERIALS AND METHODS: Twenty-four female rats were included in the study and divided into four groups of six rats each. Group 1 was the control group, in which only laparotomy was performed; Group 2 underwent laparotomy and received alpha-lipoic acid (ALA) on a daily basis; bile duct ligation was performed in Group 3; bile duct ligation was performed, and ALA was administered to Group 4. All rats underwent relaparotomy on the seventh day, followed by 30 minutes of hepatic ischemia and 60 minutes of reperfusion in Groups 3 and 4. Liver tissue and blood samples were taken for histopathological and biochemical examinations. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), albumin, ischemia modified albumin (IMA), SCUBE-1, SCUBE-2, total antioxidant status (TAS) and total oxidant status (TOS) levels were also examined. RESULTS: The SCUBE-1 and SCUBE-2 values in Group 4 were lower than in Group 3, but no significant difference was observed between all the groups. The AST, TBIL, and DBIL levels were significantly higher in Groups 3 and 4 than in Groups 1 and 2 (p<0.0001). Although TOS was the highest in Group 3, the measurements were similar across the groups (p=0.464). IMA and TAS were similar between Groups 3 and 4 but significantly higher in these groups than in Groups 1 and 2 (p=0.001). The hepatic injury observed in Groups 3 and 4 was significantly higher than that observed in Groups 1 and 2 (p<0.0001). In the histopathological examination, neutrophilic infiltration and bile duct proliferation were less commonly detected in the portal areas in Group 4 than in Group 3, and necrotic foci were not observed due to the administration of ALA. CONCLUSIONS: The promising effects of ALA, known for its powerful antioxidant properties, on the IR injury of the liver can allow it to enter clinical practice in the future.

A novel homozygous nonsense mutation in CAST associated with PLACK syndrome.

Peeling skin syndrome is a heterogeneous group of rare disorders. Peeling skin, leukonychia, acral punctate keratoses, cheilitis and knuckle pads (PLACK syndrome, OMIM616295) is a newly described form of PSS with an autosomal recessive mode of inheritance. We report a 5.5-year-old boy with features of PLACK syndrome. Additionally, he had mild cerebral atrophy and mild muscle involvements. Whole exome sequencing was performed in genomic DNA of this individual and subsequent analysis revealed a homozygous c.544G > T (p.Glu182*) nonsense mutation in the CAST gene encoding calpastatin. Sanger sequencing confirmed this variant and demonstrated that his affected aunt was also homozygous. Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals. This study further supports a key role for calpastatin in the tight regulation of proteolytic pathways within the skin.

Differentiation between idiopathic granulomatous mastitis and malignant breast lesions using strain ratio on ultrasonic elastography.

PURPOSE: The goal of this study was to investigate the strain elastography imaging characteristics of idiopathic granulomatous mastitis (IGM) and compare strain ratio values of IGM with those of breast cancer. MATERIAL AND METHODS: Twenty-three consecutive women with IGM (mean age, 37.9±6.6 [SD] years; range: 26-52 years) and 45 women with malignant breast tumor (mean age, 52.8±12.0 [SD], range, 32-77 years) who had been scheduled for ultrasound-guided core biopsy were recruited to the study. All had ultrasonography with elastography before biopsy. The strain ratios of lesions were calculated using surrounding normal breast tissue as the reference in both groups and compared between the two groups. Receiver-operating-characteristics (ROC) curves were formed. Sensitivity, specificity, cut-off, and area under curve (AUC) values were calculated. RESULTS: The mean strain ratio on sonoelastography was 1.5±0.8 (SD) (range: 0.2-4.0) for IGM and 5.3±5.2 (SD) (range: 1.4-33) for malignant lesions. Strain ratio values in IGM lesions were significantly lower than in malignant lesions (P˂0.05). ROC test yielded an AUC value of 0.939 (95% confidence interval, 0.882-0.995; P<0.0001). Optimal cut-off value for strain ratio value was 2.5 yielding 87% sensitivity and 96% specificity for the diagnosis of IGM. CONCLUSION: Sonoelastographic strain ratio contributes to differentiate IGM from malignant breast lesions, thus has potential to influence clinical decision making for further biopsies.

Serum sonic hedgehog (SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer.

Serum from one hundred and ten breast cancer patients and thirty healthy female volunteers, were prospectively collected and evaluated for serum levels of Shh and IL-6 using human Shh and IL-6 specific enzyme-linked immunoassays. All patients were regularly monitored for event free survival (EFS) and overall survival (OS). Overall outcome analysis was based on serum Shh and IL-6 levels. In patients with progressive metastatic BC, both serum Shh and IL-6 concentrations were elevated in 44% (29 of 65) and 63% (41 of 65) of patients, respectively, at a statistically significant level [Shh (p = 0.0001) and IL-6 (p = 0.0001)] compared to the low levels in healthy volunteers. Serum levels tended to increase with metastatic progression and lymph node positivity. High serum Shh and IL-6 levels were associated with poor EFS and OS opposite to the negative or lower levels in serum Shh and IL-6. The elevated levels of both serum Shh and IL-6 were mainly observed in BC patients who had a significantly higher risk of early recurrence and bone metastasis, and associated with a worse survival for patients with progressive metastatic BC. Further studies are warranted for validating these biomarkers as prognostic tools in a larger patient cohort and in a longer follow-up study.

The protective effect of the proteasome inhibitor bortezomib on the uterus of ovariectomized rats.

Bortezomib (BORT) is an anti-tumour agent that inhibits proteasome, which is responsible for the degradation of many intracellular proteins. Although some side-effects and chemotherapeutic effects of BORT are known, there has not been enough research regarding its effects on different tissues of proteasome inhibition in the senile period (post-menopausal). The aim of this study was to investigate the safety of using BORT during the post-menopausal period. The post-menopausal effects of BORT were investigated on ovariectomized (OVX) Spraque-Dawley rats. The female rats were separated into three groups: control, ovariectomized (OVX), and OVX + BORT. OVX and OVX + BORT groups consisted of six rats in each. BORT was administered intraperitoneally in a dosage of 0.2 mg/kg two days a week for four weeks after OVX. The uteri of the rats were investigated using morphometrical, histopathological, and immunohistopathological methods. A striking atrophy in the endometrium and myometrium was observed due to an estrogen deficiency in the OVX group. The partial protective effect of BORT administration was observed morphometrically and histopathologically. In immunohistochemical research, cytoplasmic NF-KB activity was observed in the presence of proteasome inhibition in the endometrium. In light of these findings, the limited protective effects of post-menopausal BORT administration are worth mentioning.

Is the lateralization distance important in terms in patients undergoing the modified Limberg flap procedure for treatment of pilonidal sinus?

BACKGROUND: The aim of this study was to determine whether the lateralization distance causes differences in the flattening ratio of the natal cleft, early complications, or recurrence rates in patients with sacrococcygeal pilonidal sinus disease undergoing the modified Limberg flap. METHODS: This clinical study was conducted from March 2012 to April 2013. Forty patients with sacrococcygeal pilonidal sinus disease were divided into two groups of 20 patients, each according to the lateralization distance of the lower part of the Limberg flap incision (Group I, 1 cm lateralized; Group II, 2 cm lateralized). Early wound complications, recurrence rates, and the flattening ratio of the natal cleft were evaluated. RESULTS: No statistically significant differences in operating time (mean 42.2 ± 5.7 and 42.3 ± 6.4 min, respectively; p = 0.855), drain removal time [median 3 (range 2-10) and 4 (range 2-14) days, respectively; p = 0.1], or length of hospitalization [median 1 (range 1-3) and 1 (range 1-4) days, respectively; p = 0.775] were found between the groups. The mean follow-up period was 12.8 ± 3.7 months. Recurrence was observed in only one patient of Group II. There were no statistically significant differences in the flattening ratio of the natal cleft, overall wound complications, or recurrence between the two groups. CONCLUSIONS: No statistically significant differences in early complications or recurrence rates were found between the two different lateralization distances in the modified Limberg flap procedure. Therefore, we conclude that 1-cm lateralization of the lower part of the incision is sufficient.

Reliability of MDCT, with MPR and hydro-CT technique, in resectability and lymphnode staging of gastric cancer.

AIM: The aim of this study was to evaluate the reliability of thin-slice hydro-multidetector row computed tomography (MDCT) in assessing resectability and lymph node staging of gastric cancer. METHODS: Sixty-one patients (37 males, 24 females; mean age 61 years) with gastric cancer, and whose surgery was planned, underwent preoperative abdominopelvic hydro-MDCT at slice thickness of 5 mm. We evaluated the tumor stage, depth of tumor invasion into the gastric wall, metastasis of lymph node, and presence/absence of distant metastases on the CT images produced with multiplanar reconstruction (MPR) and hydro-CT technique. The results were compared with pathological and surgical findings. Diagnostic accuracy was also analyzed. RESULTS: Of 61 patients with gastric cancer, 6 (14%) were inoperable, 45 (68%) were advanced stage, and 10 (16%) were early stage gastric cancer patients. The detection rate of the primary tumor was 97% for MDCT; the overall accuracy of MDCT in the determination of the depth of invasion and serosal involvement when compared with pathological staging were 84% and 95%, respectively; the overall accuracy rate in lymph node staging was 73.5%. CONCLUSION: MDCT can improve the accuracy of preoperative T and N staging of gastric cancer and will contribute to treatment strategies for patients with advanced stage gastric cancer.

The effects of Trolox treatment on experimental strangulation ileus.

BACKGROUND: Intestinal ischemia-reperfusion injury is a serious and widespread clinical problem. Trolox effectively prevents lipid peroxidation in oxidative stress and protects cell injury. The aim of this study is to investigate the effect of Trolox alone on the intestinal ischemia-reperfusion injury in strangulation ileus model, which has not been investigated previously. METHODS: Twenty-eight Sprague-Dawley rats randomly divided into four groups were used. Group Laparotomy + Physiological Saline underwent laparotomy and was administered physiological saline; Group Laparotomy + Trolox was administered Trolox. Group Strangulation + Physiological Saline was administered physiological saline before reperfusion following strangulation ileus; Group Strangulation + Trolox was administered Trolox. RESULTS: Histopathological study was evaluated and catalase, malondialdehyde, superoxide dismutase measurements were performed in intestinal samples. Serum biochemistry parameters were evaluated. The higher grade (grade > or = 2) was significantly observed to decrease in Group Strangulation + Trolox when compared with Group Strangulation + Physiological Saline (p = 0.04). In Group Laparotomy + Trolox, when compared with Group Laparotomy + Physiological Saline, the higher grade was found to be significantly lower (p = 0.03). The catalase values were found to be significantly lower in Group Strangulation + Trolox, when compared with Group Strangulation + Physiological Saline, and in Group Laparotomy + Trolox, when compared with Group Laparotomy + Physiological Saline (p < 0.01). CONCLUSIONS: Trolox is a powerful antioxidant as well as effectively prevents ischemia-reperfusion injury of the strangulated intestine segment.

Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells.

Transforming growth factor-beta type 1 (TGF-beta) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-beta in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-beta is mediated through the proinflammatory cytokine, interleukin-1alpha (IL-1alpha). Using gene expression array analysis, we identified IL-1alpha as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-beta stimulation. Cell proliferation assays verified that recombinant IL-1alpha was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1alpha prevented the growth proliferative effects of TGF-beta. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-beta induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1alpha gene expression. These studies demonstrate a novel role for IL-1alpha in mediating a proliferative response to TGF-beta signaling, and suggest that therapies directed against IL-1alpha could abate the growth proliferative effects of TGF-beta without compromising its tumor suppressive function.

Mutation of the PIK3CA oncogene in human cancers.

It is now well established that cancer is a genetic disease and that somatic mutations of oncogenes and tumour suppressor genes are the initiators of the carcinogenic process. The phosphatidylinositol 3-kinase signalling pathway has previously been implicated in tumorigenesis, and evidence over the past year suggests a pivotal role for the phosphatidylinositol 3-kinase catalytic subunit, PIK3CA, in human cancers. In this review, we analyse recent reports describing PIK3CA mutations in a variety of human malignancies, and discuss their possible implications for diagnosis and therapy.