Protective effect of cerium oxide nanoparticles on cisplatin and oxaliplatin primary toxicities in male albino rats.

Cisplatin and oxaliplatin are widely used anticancer drugs. Their use is restricted by their dose-limiting side effects: nephrotoxicity and neurotoxicity, respectively. Cerium oxide nanoparticles (CONPs) are promising antioxidant and anti-inflammatory agent. To test the possible ameliorative impact of CONPs on the toxic effect of cisplatin and oxaliplatin in male albino rats. Forty eight rats were divided into 6 groups: control group, CONPs group, cisplatin group, cisplatin and CONPs group, oxaliplatin group, and oxaliplatin and CONPs group. After 4 weeks, serum urea and creatinine, renal tissue level of interleukin 10 (IL10), and total antioxidant (TAO) were measured in control, CONPs, and cisplatin groups. The other kidney was used for histopathological and immunohistochemical studies. The right sciatic nerves and the lumbar spinal cord of rats from control, CONPs, and oxaliplatin groups were used for immunohistochemical evaluations of nitrotyrosine, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP). Cisplatin significantly increased serum urea and creatinine levels, significantly decreased the kidney level of IL10 and TAO with marked tubular necrosis, hemorrhage and renal damage. Also, it decreased IL10 immunohistochemical expression. CONPs significantly decreased the serum urea and creatinine level and increased IL10 and TAO with lower renal damage and strong IL10 expression compared with cisplatin group. Oxaliplatin significantly decreased MBP immunoreactivity and increased nitrotyrosine immunoreactivity. In the lumbar spinal cord, GFAP immunoreactivity was significantly increased. CONPs significantly increased MBP and decreased nitrotyrosine immunoreactivity. GFAP immunoreactivity was significantly decreased. CONPs ameliorated cisplatin and oxaliplatin primary toxicities through anti-inflammatory and antioxidant characteristics.

A Pilot Study of Extended Adjuvant Therapy with Metronomic Docetaxel for Patients with Operable Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast(TNBC) cancer is a molecular subtype of breast cancer with poor prognosis and did not get approved targeted therapy till now. In the last years, metronomic chemotherapy (mCTH) was investigated to improve treatment outcomes in TNBC patients both in early and metastatic setting due to its anti-angiogenic and immune-stimulatory mechanisms. The aim of this study is to evaluate the efficacy and safety of extended adjuvant chemotherapy with metronomic docetaxel for patients with operable TNBC. METHODS: 31 women with clinically and pathologically proved operable TNBC, either node-negative or node-positive with tumor size ≥ 0,5 cm were enrolled after finishing the primary standard of care treatment.  The patients were subjected to extended adjuvant therapy for 6 months with metronomic low dose docetaxel with starting dose of 15mg/m2 in weekly bases for 4 weeks then the dose was escalated to 20 mg/m2 once per week if there were no side effects. RESULTS: After a median follow up of 36 months (range 6-52), 24 patients (77.4%) were still alive. During the period of follow-up, 12 patients (38.7%) showed disease relapse and 19(61.3%) cases remain free of the disease. The estimated mean of DFS in our study was 38.26 months (95%CI; 31.87 - 44.65) with 2 and 3 years DFS rate of 70.5 % and 56.4% respectively while  the estimated mean of OS was 43.75 months (95% CI; 38.35 - 49.16) with 2 and 3 years OS rates 83.3% and 78.1% respectively, Generally the treatment was tolerated with mild to moderate hematological and non hematological adverse events, all are grade 1,2 and treatment-related deaths were not observed. CONCLUSION: Extended adjuvant treatment for 6 months with metronomic docetaxel after the primary standard of care therapy was tolerated and has an encouraging survival benefit in patients with operable TNBC and these results need further evaluation in randomized control studies.
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Circulating methylated RUNX3 and SFRP1 genes as a noninvasive panel for early detection of colorectal cancer.

OBJECTIVE: This study was conducted to assess the methylation status of runt-related transcription factor 3 (RUNX3) and secreted frizzled-related protein 1 (SFRP1) genes in paired tissue and serum samples of colorectal cancer (CRC), adenomatous, and control subjects and elucidate the association between methylation status on RUNX3 and SFRP1 mRNA expression. METHODS: Methylation status of RUNX3 and SFRP1 in paired tissue and serum samples and RUNX3 and SFRP1 mRNA expression in tissue from 85 patients with CRC, 40 with adenoma, and 40 healthy controls were determined using methylation-specific PCR and reverse transcription PCR. RESULTS: The frequency RUNX3 and SFRP1 genes methylation was significantly higher in both tissues and serum of CRC patients and was significantly associated with absence of its corresponding mRNA expression. The concordance between tissue and serum methylation status was 94.4% for RUNX3 and 94.3% for SFRP1. Tissue RUNX3 methylation status detected CRC with 63.53% sensitivity and 80.00% specificity, while serum RUNX3 methylation status detected CRC with 60.00% sensitivity and 82.50% specificity. Tissue SFRP1 methylation status showed a sensitivity of 82.35% and specificity of 65.00%, while serum SFRP1 methylation status showed a sensitivity of 77.65% and specificity of 70.00% in detection of CRC. RUNX3/SFRP1/carcinoembryonic antigen (CEA) panel identified CRC with sensitivity of 89.41% in tissue and 84.71% in serum. CONCLUSION: Our results verified the reliability of using serum RUNX3 and SFRP1 methylation status as a noninvasive biomarker for diagnosis of CRC and that combined detection of RUNX3/SFRP1/CEA panel might be a promising strategy for early detection of CRC.

Genetic and epigenetic modifications of adiponectin gene: Potential association with breast cancer risk.

BACKGROUND: Adipokines produced by adipose tissue are directly linked to obesity and may contribute to the pathogenesis of cancer. We hypothesized that genetic and epigenetic modifications in the adiponectin (ADIPOQ) gene and their impact on serum ADIPOQ levels may participate in increasing breast cancer (BC) risk. The present study aimed to investigate ADIPOQ +45 T/G gene polymorphism, methylation status at CpG sites -74 nucleotides (nt) and -283 nt of the ADIPOQ gene, and ADIPOQ serum levels in BC obese women. METHODS: Serum ADIPOQ was measured by an enzyme-linked immunosorbent assay. ADIPOQ +45 T/G gene polymorphism and ADIPOQ promoter methylation status were determined using a polymerase chain reaction (PCR) and a methylation-specific PCR, respectively, in 120 obese women with BC and 120 age-matched controls. RESULTS: ADIPOQ +45 GG genotype carriers had a significant increased risk of developing BC (odds ratio = 6.2, 95% confidence interval = 1.3-29.6, p = 0.02). ADIPOQ gene methylation at site -74 nt resulted in a 1.7-fold increased BC risk. Methylation at site -283 nt resulted in a 1.9-fold increased BC risk. Moreover serum levels of ADIPOQ were significantly decreased in BC patients and down-regulated in the presence of methylation in both examined sites. By contrast, no association between ADIPOQ gene polymorphism and serum ADIPOQ level was detected. Using both methylated sites in one panel detected cancer breast with 76.67% sensitivity and 62.18% accuracy. CONCLUSIONS: ADIPOQ +45 T/G polymorphism and ADIPOQ promoter methylation were found to be associated with BC risk in obese Egyptian women.

C-MYC and BCL2: Correlation between Protein Over-Expression and Gene Translocation and Impact on Outcome in Diffuse Large B Cell Lymphoma

Background: Due to lack of availability of gene expression profiling (GEP) for most developing countries and clinicians; the immunohistochemistry (IHC) is mostly used in the clinical application. The aim of our study is to check the possibility of using IHC to detect MYC and BCL2 in our patients with diffuse large B-cell lymphoma (DLBCL) instead of GEP to stratify them into high and low-risk groups. This will help in a proper treatment choice of subsequent improvement in the survival outcome. Method: During the study period, 90 DLBCL patients were eligible. MYC and BCL2 evaluated by IHC and gene rearrangement by real-time PCR (RT-PCR) and correlated with clinical-pathological features and survival. Results: Through IHC, the expression of MYC, BCL2, and double expression was detected in 35.6%, 46.7% and 30% of patients, respectively. While by RT-PCR, it was 4.53±0.74 for MYC compared with 2.18±0.78 for BCL-2. Most patients with BCL2+/MYC+; double-expressor and double-hit lymphomas (DEL and DHL) had high stage (III, IV), more extra-nodal involvement, (P value <0.001) and intermediate to high International Prognostic Index (IPI) risk profile (P-value <0.001). The median overall survival was 14 months and 6 months for DEL and DHL, respectively. While all patients with DHL died during the follow-up period, the median PFS were only 2 months for DEL. There was a statistically significant correlation between mRNA of MYC and BCL2 with their protein expression (p<0.001). Conclusion: Our results confirmed the unique characters and poor outcome associated with DEL and DHL mandated the need for more intense therapy and not the standard protocol. Moreover, the significant correlation between protein overexpression and gene rearrangement may open the door for the possibility to use IHC instead of RT-PCR in developing countries.

miR-146a and miR-196a-2 genes polymorphisms and its circulating levels in lung cancer patients.

Recently, MicroRNAs polymorphisms and their serum expression have been linked to increase risk of various cancers. The aim of this study was to elucidate the association between single nucleotide polymorphisms of miR-146a and miR-196a-2 and their serum expression and lung cancer risk. One hundred and twenty lung cancer patients and 120 health controls were included in this study. Genotyping and expression for miR-146a and miR-196a-2 were performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and quantitative real-time PCR. Individuals carrying miR-146a CG and CC genotypes had significantly increased risk for lung cancer than those carrying miR-146a GG genotype. MiR-146a expression significantly decreased in miR-146a CG and CC genotypes carriers as compared with GG genotype carriers. MiR-196a-2 CT and TT genotypes were significantly associated with increased lung cancer while the highest expression of MiR-196a-2 was detected in miR-196a-2 CC genotype carriers. Serum miR-146a was significantly decreased in lung cancer patients while serum miR-196a-2 expression was significantly increased in lung cancer patients. In conclusion, miR-146a and miR-196a-2 genes polymorphisms and their circulating levels were associated with lung cancer risk in Egyptians and may be helpful in early detection of lung cancer.

Thioredoxin-Interact ing-Pro t e in [TXNIP] and Transglutaminase 2 [TGM2] Expression in Meningiomas of Different Grades and the Role of Their Expression in Meningioma Recurrence and Prognosis

Background: Meningiomas are common central nervous system (CNS) tumors that account for thirty percent of primary intracranial tumors.. The accuracy of predicting meningioma recurrence and progression is not enough. So, there is a real need for discovering recent factors for identification of the relapse risk, progression rates, which patients will need aggressive treatment and predicting and improving patients' survival. Thioredoxin-interacting-protein [TXNIP] is an alpha-arrestin-protein family member that is mapped on chromosome 1-q21­22 and is found to participate in cellular redox reactions regulations and control. Transglutaminase 2 (TGM2) is a transglutaminase enzyme family member that is found in many human cells, it may act as an enzyme, a structural protein and also has multiple roles in many cellular activities. Aim of our study: It was to explore the expression of TXNIP, TGM2 and Ki-67 using immunohistochemistry in different pathological grades of meningiomas, and to investigate the relevance between their expressions, clinicopathological criteria, disease recurrence and prognosis of meningioma patients. Methods: we included 50 cases of meningioma of different pathological grades; all patients were managed according to their grade by surgery alone, with radiotherapy or combined modalities. Sections from paraffin blocks prepared from samples of all patients stained by TXNIP, TGM2 and Ki-67 using immunohistochemistry. Results: high expression of TXNIP in 28 out of 50 (56%) cases of meningioma of different pathological grades and was positively correlated with meningioma lower grade, low KI labeling index (p=0.000), adequacy of resection, negatively correlated with high incidence of recurrence after surgery and it was negatively correlated with meningioma higher pathological grades (p=0.000). We detected high expression of TGM2 in 21 out of 50 (42%) cases of meningioma and it was positively correlated with meningioma higher grade (p= 0.002), high KI labeling index (p=0.000), high incidence of recurrence after surgery, progression to higher pathological grades and was negatively correlated with adequacy of resection of meningioma (p=0.000). Conclusion: There is inverse relation between both [TXNIP and TGM2 expression in meningiomas and the combination of decreased expression of TXNIP and increased expression of TGM2 could predict risk of meningioma recurrence and progression in to higher pathological grades.

CYP1A1 gene polymorphisms and smoking status as modifier factors for lung cancer risk.

OBJECTIVE: Lung cancer remains the most prevalent malignancy worldwide. Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes. Several metabolic enzymes are currently under investigation for their possible role in lung cancer susceptibility, including members of the cytochrome P450 (CYP) superfamily. The aim of this work was to identify the correlation between CYP1A1 m1 and m2 polymorphisms and lung cancer risk and figure its interactions with smoking as genetic modifiers in the etiology of lung cancer in the Egyptian population. MATERIALS AND METHODS: One hundred and ten patients with lung cancer and one hundred and ten controls were enrolled in the study. CYP1A1 m1 and m2 polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism. RESULTS: Subjects carrying TC and CC genotypes of CYP1A1 m1 and AG and GG genotypes of CYP1A1 m2 were significantly more likely to develop lung cancer especially squamous cell carcinoma. The proportion of lung cancer attributable to the interaction of smoking and CYP1A1 m1 and CYP1A1 m2 polymorphisms was 32% and 52% respectively. CONCLUSION: Our results revealed that CYP1A1 m1 and m2 polymorphisms contribute to smoking related lung cancer risk in the Egyptian population.