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KRAS and BRAF are key proto-oncogenes of MAPK/ERK pathway and are essential for cell growth and proliferation. Mutations of these oncogenes are known to have role in pathogenesis of epithelial ovarian carcinoma (EOC). However, limited studies have evaluated the role of KRAS and BRAF protein expression. Hence, this study aimed to explore their role in EOC patients, specifically to correlate KRAS and BRAF protein expression with the histological subtypes and other histopathological prognostic factors. Immunohistochemistry was performed using paraffin-embedded tumor tissue blocks of 55 untreated and histologically confirmed EOC patients and 20 benign ovarian tumors to study KRAS and BRAF protein expression. Data were analyzed using SPSS software. Cytoplasmic expression of both KRAS and BRAF was observed in EOC and benign tumors. KRAS protein expression was significantly higher in serous EOC patients than the mucinous EOC patients (P = 0.016). KRAS expression was also significantly positively correlated with the presence of lymphatic permeation (P = 0.030), while a trend toward significance was found with vascular permeation (P = 0.052). Furthermore, BRAF protein expression was significantly higher in EOC patients than in benign ovarian tumors (P = 0.027). Its expression was significantly higher in patients with moderately/poorly differentiated tumors than well-differentiated tumors (P = 0.008), and in patients having serous EOC than in mucinous EOC (P = 0.001). A trend of higher BRAF expression was also observed in patients with lymphnode metastasis (P = 0.079). KRAS and BRAF proteins have a potential role in EOCs. However, further studies in larger group of patients and follow-up for a longer period are required to identify their role in prognosis.

Purpose: Uncontrolled cytokine signal transduction largely associated with oncogene activation, can have disastrous biological consequences. The suppressor of cytokine signaling (SOCS) proteins represent one of the mechanisms by which this rampant signaling can be dissipated. Thus, we aimed to study the expression of SOCS-1, SOCS-2, and SOCS-3 in patients having benign thyroid disease and papillary thyroid cancer. Materials and Methods: SOCS protein expression was studied in 45 patients with benign thyroid disease and in 83 papillary thyroid cancer patients by immunohistochemistry and their association with clinicopathological characteristics and overall survival in cancer patients were analyzed using SPSS software. Results: Expressions of SOCS proteins were significantly higher in papillary thyroid cancer than in patients having benign disease. SOCS-1 expression was predominantly higher in males (P = 0.004), unilateral tumors (P = 0.030), and noninflammatory conditions (P = 0.028). SOCS-1 expression was also able to predict poor overall survival in subgroup of papillary thyroid cancer patients having larger tumor size (P = 0.013) and advanced stage disease (P = 0.033). Expression of SOCS-2 significantly correlated with tumor size (P = 0.017), extrathyroidal extension (P = 0.000), residual disease (P = 0.043), and treatment (P = 0.007), while preponderance of SOCS-3 expression was observed in males (P = 0.030) and in patients having extrathyroidal extension (P = 0.011) and absence of metastasis (P = 0.032). Conclusion: Expression of the studied SOCS proteins may be a consequence of activation of Janus kinase-signal transducers and activators of transcription and other pathways supporting growth and survival of cancer cells that are sustained by several cytokines. Thus, SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in development and pathogenesis of papillary thyroid cancer.

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM., BRCA1 loss can result in collapse of replication forks into DNA double strand breaks that can contribute to malignant transformation. Here, the authors find that BRCA1 promotes the expression of RRM2 protecting glioblastoma cells from replication stress, DNA damage and apoptosis.

Circulating levels of TNF-αand the adhesion molecules L-Selectin and VCAM-1 as well as their expression in the primary tumors of patients with benign thyroid diseases and papillary thyroid carcinoma (PTC) have been determined in this study. The serum levels of TNF-α, L-Selectin, and VCAM-1 were significantly higher in patients with both benign thyroid diseases and PTC as compared to the healthy individuals. However, the levels of only TNF-αand L-Selectin, and not VCAM-1, were significantly higher in patients with PTC in comparison to those observed in patients with benign thyroid diseases. Further the expression of TNF-αand L-Selectin was also significantly higher in the primary tumors of PTC patients, relative to the benign thyroid diseases. The expression of L-Selectin and VCAM-1 significantly correlated with aggressive tumor behavior. In PTC patients, the circulating TNF-αlevels significantly positively correlated with the levels of L-Selectin, while TNF-αimmunoreactivity was significantly associated with VCAM-1 expression. Serum TNF-αwas found to be a significant prognosticator for OS in PTC patients. Overall the results signify that the interaction between TNF-αand the adhesion molecules may have a role in thyroid carcinogenesis and understanding this complexity may offer potential therapeutic targets for better management of thyroid cancer.

Introduction: 5-flourouracil (5-FU) is one of the standard chemotherapeutic drugs used today in the treatment of colorectal cancer patients. Disruption of 5-FU metabolic pathway may contribute to altered effectiveness towards 5-FU-based therapy. Hence, the study of 5-FU metabolizing enzymes might have the potential efficacy to predict survival and response to treatment in colorectal cancer patients. Materials and methods: Immunohistochemical localization of 5-FU metabolic enzymes (TS, MTHFR, DPYD, and TP) was evaluated in 143 untreated patients with colorectal cancer; their prognostic and predictive values were also evaluated. Results: Immuno-positivity for TS, MTHFR, DPYD, and TP was observed in 77%, 75%, 88%, and 96% of colorectal cancer patients, respectively. Univariate survival analysis in total patients showed that low DPYD expression significantly predicted adverse overall survival ( P=0.042). Moreover, subgroup of colon cancer patients with low TS expression was associated with unfavorable prognosis. TP expression also emerged as a prognosticator in the subgroup of early and advanced stage patients. Additionally, when effect of co-expression of 5-FU metabolic enzymes was evaluated in total patients, low coexpression of all four proteins was predictive of poor overall survival than for individuals expressing high coexpression of these proteins ( P=0.045). In contrast, none of the 5-FU metabolic enzymes—either singly or on coexpression—emerged as a useful biomarker of potential therapeutic value when evaluated in the subgroup of patients treated with 5-FU alone or 5-FU plus oxaliplatin. Conclusion: The above findings suggest that coexpression of 5-FU metabolic enzymes possess significant prognostic value and could be useful biomarkers in colorectal cancer patients.

Glioblastoma (GBM, WHO grade IV astrocytoma) is among the deadliest of solid tumors with median survival rates of only approximately 15 months. In spite of concerted efforts, molecular mechanisms/genes causing high recurrence and treatment resistance are poorly understood. The tumor suppressor BRCA1 plays a critical role in maintaining genomic stability, in general, and replication stress (RS), in particular. Numerous reports have demonstrated that wild type BRCA1 loss impairs the growth of several cancers (breast, ovarian, lung, prostate and colon). Our data show considerably higher level of RS in malignant gliomas compared to other solid tumors (breast, prostate ovarian) and identify a novel role for BRCA1, where high BRCA1 expression negatively associates with glioma patient survival. BRCA1 plays an unexpected tumor-promoting role in GBM, safeguarding a protective response to supraphysiological RS levels via transcriptional regulation of RRM2 expression. shRNA-mediated knockdown of BRCA1 or chemical inhibition of RRM2 both induce GBM cell death due to accumulation of RS-induced DNA damage in vitro and extend survival of tumor bearing mice in vivo, highlighting the clinical relevance of our findings. Acknowledgements: This work was supported by Danish Cancer Society Foundation.

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.

Introduction: Wnt signaling pathway is often dysregulated in the pathogenesis of various malignancies, including breast cancer. This might be related to methylation of the genes encoding antagonists of this signaling pathway. Aim: The aim of the study was to analyze the methylation status of the promoter regions of Wnt antagonists-secreted frizzled-related protein 1 (sFRP1) and Dickkopf 3 (DKK3) and to determine their correlation with clinicopathological parameters and survival outcome in patients with primary invasive ductal breast cancer. Materials and Methods: The methylation status of sFRP1 and DKK3 was analyzed in 160 breast tumor samples using methylation-specific polymerase chain reaction. Statistical analysis was performed using SPSS software. P ≤ 0.05 was considered as statistically significant. Results: The promoter region of sFRP1 and DKK3 genes was found to be methylated in 76% and 64% of total invasive ductal breast cancer patients, respectively. The promoter methylation in sFRP1 and DKK3 genes was significantly associated with larger tumor size, positive lymph nodes, advanced stage, and perinodal extension of breast tumors. Further, sFRP1 methylation was associated with human epidermal growth factor receptor 2-positive tumors while DKK3 methylation was associated with Grade 3 tumors. Survival analysis demonstrated that sFRP1 methylation was correlated with reduced overall survival in breast cancer patients. Conclusion: Promoter methylation of Wnt pathway antagonists is frequent in breast cancer ultimately leading to probable upregulation of the pathway in these tumors. Hence, sFRP1 and DKK3 methylation may be used as a valuable biomarker in clinical breast cancer management.

Background: Gentamicin is a commonly used antibiotic for the treatment of Gram-negative infections, but nephrotoxicity limits its use. Cyperus scariosus Linn. (CS) has been found to have antioxidant properties in vitro. Objectives: The aim of this study was to evaluate the nephroprotective effects of CS in gentamicin-induced acute kidney injury (AKI). Methods: The animals were divided into nine groups. AKI was produced with a 100 mg/kg intraperitoneal (i.p.) injection of gentamicin for 7 days. Next, α-lipoic acid 100 mg/kg i.p. served as the active control, while the test drug (CS) was given in two doses (150 mg/kg and 250 mg/kg orally) for 10 days. Distilled water, 1 ml/day orally for 7 days, served as the vehicle control. The protective and curative effects, respectively, were assessed by the administration of CS before and after the induction of AKI. The effects of CS on AKI were assessed by serological and histopathological parameters. Results: Serum creatinine was significantly increased (P < 0.05) while 24 hours urine output, urine creatinine, and serum protein were significantly decreased (P < 0.05) in rats treated with gentamicin as compared to the control group. As the active control, α-lipoic acid showed nephroprotective effects on the urinary, serological, and histopathological parameters. C. scariosus Linn., as a preventive and curative therapy, restored urine output and altered the serological parameters non-significantly compared to the disease-control group. It also preserved the normal kidney architecture, as evidenced by histopathological parameters. Conclusions: In our study, hydroalcoholic extract of Cyperus scariosus Linn. offered nephroprotection in the form of AKI prevention and for the treatment of established AKI.

We report a case of 25 years old male patient with antitubercular drugs induced exanthematous reaction and hepatotoxicity that was complicated by levofloxacin induced toxic epidermal necrolysis. The patient was allergic to ciprofloxacin and ofloxacin. Cross reactivity between ciprofloxacin and levofloxacin might be responsible for causing this reaction. Issues of cross sensitivity should be kept in mind and the same class of drugs should strictly be avoided to prevent such complications.

Background Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results We found that the resistant cell lines showed 7–100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2071-1) contains supplementary material, which is available to authorized users.

Introduction: Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. Aims: To study occurrence, age, sex and site distribution of various salivary gland lesions and compare with findings of other workers. Methods and Material: The material required for the study was collected from January 2010 to December 2012 from the department of pathology, N.H.L.Municipal medical college, Ahmedabad for 3 years. Results: Of the total 60 cases, 21 were diagnosed as non neoplastic lesions and 39 as neoplastic lesions of which 24 were benign and 15 were malignant. Among the all salivary gland lesions, pleomorphic adenoma is commonest, and comprises of 30% of all lesions. Of the non neoplastic lesions, sialadenitis is commonest and of malignant neoplastic lesions mucoepidermoid carcinoma is more frequent. Conclusions: Histopathological examination of salivary gland lesions is the most important method in differential diagnosis of nonneoplastic and neoplastic lesions and in establishing the final diagnosis. Histopathological Study of Salivary Gland Lesions

Background: Thymidylate synthase (TS) plays a critical role in nucleotide metabolism and is an important target for 5-fluorouracil (5-FU), the standard chemotherapeutic drug for treatment of colorectal cancer (CRC). Aims and Methods: The present study aimed to evaluate TS variable number tandem repeat sequences (VNTR) polymorphism by polymerase chain reaction and TS protein expression by immunohistochemistry and its association with clinicopathological parameters in untreated CRC patients (n = 100). Further, the prognostic and predictive role of TS has been evaluated. Results: For TS VNTR polymorphism, the observed frequencies of 2R/2R, 2R/3R, and 3R/3R genotypes were 22%, 51%, and 27%, respectively. When immunohistochemical localization was studied, cytoplasmic staining for TS was observed in 70% of patients. A significant inverse correlation was noted between TS protein expression and tumor, node, metastasis staging (P = 0.027), Dukes' staging (P = 0.039), and lymph node status (P = 0.012) of CRC patients. However, there was no significant correlation between TS VNTR polymorphism and TS protein expression. On survival analysis, a significantly shorter overall survival (OS) was seen in CRC patients with negative protein expression (P = 0.031). Moreover, the subgroup of CRC patients treated only with surgery also showed a trend of poor OS in patients with negative TS protein expression (P = 0.058). However, neither TS polymorphism nor its protein expression was able to predict relapse-free survival. Conclusion: Negative TS protein expression may be related to unfavorable clinical outcome in CRC patients. However, further studies in a larger set of patients are necessary to better assess TS as a prognostic and predictive marker for 5-FU response in CRC patients.

Morbidly obese women are at increased risk of obstetric complications and poor neonatal outcomes. Gastric bypass surgery is being performed with increased frequency in reproductive-aged women to treat morbid obesity. Both maternal and fetal complications have been reported in women who underwent gastric bypass surgery. Current recommendations advise delaying pregnancy for at least 1 year following bariatric surgery. This guideline is meant to discourage women from becoming pregnant during the rapid weight loss phase of the first post-surgical year. Pregnancy during this time could lead to a malnourished fetus, due to some protein malnutrition, possibly resulting in complications such as low birth weight or malformation. However, data validating this concern are lacking. We report a case of 37-year-old woman who had laparoscopic bypass surgery, as treatment for morbid obesity, 6 months prior to her pregnancy with good outcome despite the short duration between gastric bypass surgery and pregnancy.

In recent times, focus on plant research has increased all over the world. Centella asiatica is an important medicinal herb that is widely used in the orient and is becoming popular in the West. Triterpenoid, saponins, the primary constituents of Centella asiatica are manly believed to be responsible for its wide therapeutic actions. Apart from wound healing, the herb is recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, diseases of the female genitourinary tract and also for relieving anxiety and improving cognition. The present review attempts to provide comprehensive information on pharmacology, mechanisms of action, various preclinical and clinical studies, safety precautions and current research prospects of the herb. At the same time, studies to evaluate the likelihood of interactions with drugs and herbs on simultaneous use, which is imperative for optimal and safe utilization of the herb, are discussed.