High level of miR-21, miR-10b, and miR-31 expression in bilateral vs. unilateral breast carcinomas

We analyzed the expression of several microRNAs (miRs) implicated in breast cancer (BC) pathogenesis (miR-21, miR-10b, miR17-5p, mir-31, miR-155, miR-200c, miR-18a, miR-205, and miR-27a) in 80 breast carcinomas obtained from patients with bilateral BC (biBC) and 40 cases of unilateral BC (uBC). Unexpectedly, three miRs (miR-21, miR-10b and miR-31) demonstrated significantly higher level of expression in biBC vs. uBC (P = 0.0001, 0.00004 and 0.0002, respectively). Increased contents of miR-21, miR-10b and miR-31 were observed in all categories of biBC tumors, i.e., in synchronous biBC as well as in first and second tumors from metachronous biBC cases. Synchronous biBC showed more similarity of miR expression profiles within pairs that the metachronous doublets (P = 0.004). This study suggests that bilateral breast tumors have somewhat distinct pattern of molecular events as compared to the unilateral disease.     

Glycine- and GABA-activated Currents in Identified Glial Cells of the Developing Rat Spinal Cord Slice

In the neonatal rat spinal cord, four types of glial cells, namely astrocytes, oligodendrocytes and two types of precursor cells, can be distinguished based on their membrane current patterns and distinct morphological features. In the present study, we demonstrate that these cells respond to the inhibitory neurotransmitters glycine and GABA, as revealed with the whole-cell recording configuration of the patch-clamp technique. All astrocytes and glial precursor cells and a subpopulation of oligodendrocytes responded to glycine. The involvement of glycine receptors was inferred from the observation that the response was blocked by strychnine and that the induced current reversed close to the Cl^- equilibrium potential. GABA induced large membrane currents in astrocytes and precursor cells while oligodendrocytes showed only small responses. The GABA-activated current was due to the activation of GABA_A receptors since muscimol mimicked and bicuculline blocked the response; moreover, the reversal potential was close to the Cl^- equilibrium potential. Besides the increase in a Cl^- conductance, GABA^A receptor activation also induced a block of the resting K⁺ conductance, as observed previously in Bergmann glial cells. Our experiments show that while glial GABA_A receptors are found in many brain regions and the spinal cord, glial glycine receptors have so far been detected only in the spinal cord. The restricted coexpression of glial and neuronal glycine receptors in a defined central nervous system grey matter area implies that such glial receptors may be involved in synaptic transmission.     

Retinal and retinol are potential regulators of gene expression in the keratinocyte cell line HaCaT

Please cite this paper as: Retinal and retinol are potential regulators of gene expression in the keratinocyte cell line HaCaT. Experimental Dermatology 2010. Abstract: Vitamin A is a pivotal regulator of differentiation and growth of developing and adult skin. Retinoic acid is the major physiologically active form of vitamin A regulating the expression of different genes through retinoic acid nuclear receptors. Here, we present evidence that other vitamin A derivates – retinol and retinal – are also capable of functioning as regulators of gene expression in the keratinocyte cell line HaCaT. We have shown that all‐trans retinol (ATRol) and all‐trans retinal (ATRal) are capable of modulating gene expression in keratinocytes, which is not because of vitamin A metabolism in the cells, and retinol and retinal modulate gene expression through nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Based on the data, we propose that ATRol and all‐trans retinal, in addition to all‐trans retinoic acid, can function as important regulators of gene expression manifesting their effect through the nuclear receptors RARs and RXRs.     

Is nutrient intake a gender-specific cause for enhanced susceptibility to alcohol-induced liver disease in women?

AIM: Women have a higher susceptibility to alcohol-induced liver disease (ALD) than men. Gender-related differences in food preference were described in previous studies for several populations, but not in alcohol abusers. As certain micronutrients are reported to take influence on the development of ALD in animal experiments, the hypothesis of the present retrospective cross-sectional study was that gender-dependent (micro-) nutrient intake in patients with ALD may cause the higher susceptibility of women to this disease. METHODS: In 210 patients (male: 158, female: 52) with different stages of ALD (ALD1: mild stage of liver damage; ALD2: moderately severe changes of the liver with signs of hepatic inflammation; ALD3: severely impaired liver function) and in 336 controls (male: 208, female: 128), nutrient intake was determined by a computer-guided diet history, and related to the severity of ALD in dependence on the sex of the patients. RESULTS: No significant differences between males and females with ALD were calculated for the intake (per kg body weight/day) of protein, carbohydrates, fat, and the intake (per kg body weight/day) of most micronutrients. In females with ALD, higher intake was found for vitamin C (ALD3), calcium (ALD2), iron (ALD1 and ALD2), and zinc (ALD1), but the consumption of none of these micronutrients seems to contribute to a higher susceptibility to ALD in females. CONCLUSION: Though the present study confirms the higher susceptibility to ALD in women, the data of calculated daily macro- and micronutrient intake do not suggest any explicit influence of gender-specific nutrition in the development of ALD.     

Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrectomy

Background

MicroRNAs are endogenously expressed regulatory noncoding RNAs. Previous studies have shown altered expression levels of several microRNAs in renal cell carcinoma.

Methods

We examined the expression levels of selected microRNAs in 38 samples of conventional renal cell carcinoma (RCC) and 10 samples of non-tumoral renal parenchyma using TaqMan real-time PCR method.

Results

The expression levels of miRNA-155 (p < 0.0001), miRNA-210 (p < 0.0001), miRNA-106a (p < 0.0001) and miRNA-106b (p < 0.0001) were significantly over-expressed in tumor tissue, whereas the expression of miRNA-141 (p < 0.0001) and miRNA-200c (p < 0.0001) were significantly decreased in RCC samples. There were no significant differences between expression levels of miRNA-182 and miRNA-200b in tumor samples and renal parenchyma. Our data suggest that expression levels of miRNA-106b are significantly lower in tumors of patients who developed metastasis (p = 0.030) and miR-106b is a potential predictive marker of early metastasis after nephrectomy in RCC patients (long-rank p = 0.032).

Conclusions

We have confirmed previous observations obtained by miRNA microarray analysis using standardized real-time PCR method. For the first time, we have identified a prognostic significance of miRNA-106b, which, after validation on a larger group of patients, maybe useful as a promising biomarker in patients with RCC.     

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

The surface comparison of different serine-threonine and tyrosine kinases reveals a set of 30 residues whose spatial positions are highly conserved. The comparison between active and inactive conformations identified the residues whose positions are the most sensitive to activation. Based on these results, we propose a model of protein kinase activation. This model explains how the presence of a phosphate group in the activation loop determines the position of the catalytically important aspartate in the Asp-Phe-Gly motif. According to the model, the most important feature of the activation is a "spine" formation that is dynamically assembled in all active kinases. The spine is comprised of four hydrophobic residues that we detected in a set of 23 eukaryotic and prokaryotic kinases. It spans the molecule and plays a coordinating role in activated kinases. The spine is disordered in the inactive kinases and can explain how stabilization of the whole molecule is achieved upon phosphorylation.     

Nosocomial bacteremia due to an as yet unclassified acinetobacter genomic species 17-like strain

We describe a case of bacteremia due to an as yet unclassified Acinetobacter genomic species 17-like strain. The recognition of this microorganism as non-Acinetobacter baumannii may have important epidemiological implications, as it relieves the hospital of the implementation of barrier precautions for patients infected or colonized as may be necessary with a multiresistant A. baumannii epidemic.     

Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects

Purpose: Polycyclic aromatic hydrocarbons are activated by cytochrome P450 1A1 (CYP1A1) and inactivated by glutathione S-transferase mu (GSTM1). Therefore, it is expected that a combination of proficient CYP1A1 genotype with deficient GSTM1 variant would result in particularly elevated lung cancer (LC) risk, especially for squamous cell carcinoma (SCC). This study was aimed to validate whether the CYP1A1-C ³⁸⁰¹ (CYP1A1*2) allele has an unfavorable significance alone and/or in combination with the GSTM1 deficiency. Methods: We compared the distribution of CYP1A1 and GSTM1 genotypes in LC patients (n=141), healthy donors (HD, n=204), and elderly tumor-free smokers and non-smokers (ED, n=246). Results: CYP1A1*2 allele carriers demonstrated a clear-cut association with SCC: the adjusted odds ratios (OR) were 2.22 (95% CI=1.06–4.63) and 2.27 (95% CI=1.14–4.52) when HD and ED were used as referents, respectively. CYP1A1*2(+)/GSTM1(-) combined genotypes were overrepresented in the SCC patients (14/70, 20.0%) and underrepresented in the ED (19/246, 7.7%) as compared to the intermediate prevalence in the HD (26/204, 12.7%); the adjusted OR for SCC versus ED reached 3.85 (95% CI=1.43–10.33). Conclusions: In agreement with some literature data, our results support the concerted role of CYP1A1 and GSTM1 at-risk genotypes in SCC predisposition.     

A novel approach for assessment of cancer predisposing roles of GSTM1 and GSTT1 genes: use of putatively cancer resistant elderly tumor-free smokers as the referents

We applied an alternative approach to assess the controversial evidence for the role of GSTM1 and GSTT1 deficiencies (null genotypes) in cancer susceptibility. In this study setting, the prevalence of GSTM1 and GSTT1 null genotypes in the lung cancer patients (LCs, n = 167) were compared with those in the group of putatively cancer resistant individuals, i.e. elderly tumor-free donors (EDs, n = 324). Healthy middle-aged donors (HDs, n = 339) were used as another comparison group. Our results support the previous conclusions of a modest protective effect associated with presence of at least one functional copy of GSTM1 gene; the prevalence of GSTM1 deficiency in LCs (54%) did not differ from that observed in HDs (54%), but showed a significant increase when compared with EDs (45%) (OR = 1.46, 95% CI = 1.00-2.12). Furthermore, in agreement with mechanistic considerations, the GSTM1 null genotypes were more prevalent in squamous cell carcinoma patients (58%) and in lung cancer patients with seemingly low cumulative carcinogen exposure dose (non-smokers: 63%; patients aged below 50 years: 76%). Contrary to GSTM1, no significant effect in the lung cancer proneness was observed for the GSTT1 genotypes. The results of this study are thus in good agreement with the body of literature data, including several published meta-analyses. Consequently, the suggested study design involving additional "cancer resistant" group of non-affected subjects appears to provide highly demonstrative data and to be well suited for pilot investigations and for resolving controversial issues.