Evaluation of genotoxicity induced by exposure to antineoplastic drugs in lymphocytes of oncology nurses and pharmacists

ABSTRACT: The hazards of handling antineoplastic drugs have been raised and discussed in several studies. Introduction of new antineoplastics together with abuse of safety standards have contributed to the exposure risk for personnel who handle these substances. Interactions of antineoplastic drugs with biological structures vary according to the drug(s) and the individual's genetic susceptibility. This study was carried out to evaluate the genome damage induced by exposure to antineoplastic drugs in nurses (n = 20) and pharmacists (n = 18) working in the Oncology Department of Tanta Cancer Center. Thirty subjects matched in age, gender and smoking habit were selected as controls. Both chromosomal aberration analysis and micronucleus assay were used to evaluate genome damage in peripheral blood lymphocytes of the study subjects. The numbers of aberrant lymphocytes, as well as chromosomal aberration and micronuclei frequencies, were significantly increased in exposed personnel in comparison to matched controls. Compared with pharmacists, nurses showed notably higher level of chromosome damage. On the other hand, no significant difference in micronuclei frequency was observed between nurses and pharmacists. Correlation analyses pointed to the influence of age and duration of occupational exposure on the level of chromosome damage among exposed subjects. The results of this study confirmed that handling antineoplastic drugs without appropriate precautions imposed a genotoxic risk for exposed healthcare workers. These results address the need for regular biomonitoring of exposed personnel. In addition, they call attention to the need for proper implementation of intervention measures aiming to eliminate or significantly reduce worker exposure and prevent untoward biological effects

Upregulation of Toll-like receptor 2 and nuclear factor-kappa B expression in experimental colonic schistosomiasis

Role of different mediators was described in the development of the granulomatous response and fibrosis observed in intestinal schistosomiasis. However, both Toll-like receptor 2 (TLR2) and nuclear factor kappa B (NF-κB) have not yet been investigated in intestinal schistosomiasis. This study aimed to characterize the role of TLR2 and NF-κB in the pathogenesis of intestinal schistosomiasis. Experimental animals were divided into two groups; group I: non-infected control group and group II: mice infected subcutaneously with S. mansoni cercariae. Colon samples were taken from infected mice, every two weeks, starting from the 6th week postinfection (PI) till 18th week PI. Samples were subjected to histopathological and immunohistochemical studies. Colon of S. mansoni infected mice showed histopathological changes in the form of mucosal degeneration, transmural mononuclear cellular infiltration and granulomas formation. Immunostained sections revealed significant increase in TLR2 and NF-κB positive cells in all layers of the colon, cells of the granuloma and those of the lymphoid follicles 10 weeks PI. All these changes decreased gradually starting from 12 weeks PI onward to be localized focally at 18 weeks PI. In conclusion, recruitment and activation of inflammatory cells to the colonic mucosa in intestinal schistosomiasis are multifactorial events involving TLR2 that can trigger the NF-κB pathways. Hence, down-regulation of both TLR2 and NF-κB could be exploited in the treatment of colonic schistosomiasis

Histopathology and electron microscopy evaluation of the sildenafil effect on diabetic rats' retinae

Purpose: Although there is increasing evidence that phosphodiesterase-5 (PDE-5) inhibitors modify the effect of diabetes on different tissues, its effect on diabetic retinopathy is not well studied. Methods: Forty male Sprague–Dawley (SD) rats were divided into four groups: group I = control group that received no treatment; group II (diabetic group), in which diabetes was induced by a single streptozotocin injection; group III (sildenafil small dose, SSD), in which diabetes was similarly introduced (however, rats received daily oral 1 mg/kg sildenafil citrate (SC) for 3 months); and group IV (sildenafil large dose, SLD), which was as in group 3, but SC was 2.5 mg/kg. After 3 months, globes were removed and retinae were dissected; one globe from each rat was examined by light microscopy (LM), and the other by electron microscopy (EM). Results: In contrast to the control group, diabetic rats in group II demonstrated well-established diabetic changes in the form of capillary congestion, decreased cell population, hyaline changes of capillary walls, and degenerated nerve fiber layer by LM. Similarly, EM demonstrated photoreceptor degeneration, mitochondrial cristolysis, and vacuolated depleted cells among other features in group II. These diabetic features were less prominent in group III and nearly absent in group IV. Conclusion: SC use in the early stages of DR may prevent/delay diabetic retinopathy development or progression in diabetic rat models, an effect that seems to be dose-related

GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort.

This study evaluates changes in metabolite levels in hepatocellular carcinoma (HCC) cases vs. patients with liver cirrhosis by analysis of human blood plasma using gas chromatography coupled with mass spectrometry (GC-MS). Untargeted metabolomic analysis of plasma samples from participants recruited in Egypt was performed using two GC-MS platforms: a GC coupled to single quadruple mass spectrometer (GC-qMS) and a GC coupled to a time-of-flight mass spectrometer (GC-TOFMS). Analytes that showed statistically significant changes in ion intensities were selected using ANOVA models. These analytes and other candidates selected from related studies were further evaluated by targeted analysis in plasma samples from the same participants as in the untargeted metabolomic analysis. The targeted analysis was performed using the GC-qMS in selected ion monitoring (SIM) mode. The method confirmed significant changes in the levels of glutamic acid, citric acid, lactic acid, valine, isoleucine, leucine, alpha tocopherol, cholesterol, and sorbose in HCC cases vs. patients with liver cirrhosis. Specifically, our findings indicate up-regulation of metabolites involved in branched-chain amino acid (BCAA) metabolism. Although BCAAs are increasingly used as a treatment for cancer cachexia, others have shown that BCAA supplementation caused significant enhancement of tumor growth via activation of mTOR/AKT pathway, which is consistent with our results that BCAAs are up-regulated in HCC

Workflow of our GC-MS based untargeted metabolomic and targeted analyses for biomarker discovery.

<p>The number of candidate metabolites analyzed at specific steps is shown in parenthesis.</p

List of nine analytes confirmed by targeted analysis with their expected retention time and molecular weights for quantifier (M1) and qualifier fragments (M2-M3).

<p>* Number of TMS in Fiehn library</p><p>Fragment with a molecular weight of 73 was also monitored by default for all the analytes.</p

Characteristics of the study cohort.

<p>Characteristics of the study cohort.</p

Metabolites with significant changes in their levels in HCC vs. cirrhosis based on targeted analysis of plasma by GC-SIM-MS.

<p>The metabolites in the top two panels show increasing trend with the progression of HCC. The metabolites in the bottom panel are down-regulated in HCC vs. cirrhosis. While lactic acid and citric acid show decreasing trend with the progression of HCC, sorbose is down-regulated overall in HCC vs. cirrhosis.</p

Pathway and network analysis of 24 metabolites recognized by IPA from the candidates discovered by GC-MS and LC-MS based analyses.

<p>A: top 10 canonical pathways based on 24 metabolites. B: network involving 13 out of the 24 metabolites (up-regulated in HCC vs. cirrhosis marked in red, down-regulated in HCC vs. cirrhosis marked in green).</p

Example of a retrieved EIC for valine.

<p>The inset in the top left shows the expected ratios for the fragments based on the library to guide the visual inspection. The doted vertical lines show the expected and estimated elution time of the analyte. Although, the background signal of 73 from other compounds is reflected in the apex score, its impact on the AUC is diminished by baseline correction.</p