Relationship between polymorphism rs2794521 in CRP gene and survival of depressive patients with chronic heart failure.

OBJECTIVE: Currently, there is a lack of studies combining the relationship between depression, chronic heart failure (CHF) and CRP polymorphisms (SNPs). The objective of the study was the investigation of the potential influence of rs2794521 in CRP on the survival and clinical profile of patients suffering from both depression and CHF. PATIENTS AND METHODS: 103 CHF individuals were studied to evaluate depression occurrence and to compare values of cardiac, laboratory and nutritional parameters depending on CRP genotypes. RESULTS: The higher frequency of CC genotype was found in depressive patients (p=0.021). Serum CRP concentration was significantly higher in depressed patients than in non-depressed ones (p=0.032). CC depressive individuals demonstrated greater frequency of NYHA grade III-IV (p<0.001) and higher level of circulating CRP (p=0.001) and TNF-α (p=0.042) compared with CT or TT carriers. CC individuals were more frequently classified as moderately or severely malnourished according to SGA (p=0.014). CC genotype was associated with a higher risk of early death during the 72 months of the follow-up (HR=4.01; p=0.006 for CC vs. CT vs. TT and HR=4.46; p<0.001 for CC vs. CT+TT). CONCLUSIONS: CC genotype of CRP more frequently occurs in depressive CHF patients, and it is associated with worse clinical outcomes and disease prognosis.

Effect of polymorphism rs1799964 in TNF-α gene on survival in depressive patients with chronic heart failure.

OBJECTIVE: To date, there are no literature reports combining the relationship between depression and chronic heart failure (CHF) in relations to selective nutritional, cardiac and laboratory parameters. The aim of this study was to correlate the rs1799964 genotypes in TNF-α with clinical outcomes of depressive CHF patients. PATIENTS AND METHODS: 94 CHF patients were enrolled to assess depression prevalence and to compare values of cardiac, laboratory and nutritional parameters between depressed and non-depressed patients with different rs1799964 genotypes. RESULTS: Depression was diagnosed in 66 individuals (70.2%). We noted significant reduction of EF% in CC genotype carriers compared to other patients (mean EF%: 36±11 CC vs. 44±14 CT and 46±7 TT; p=0.023) and worse outcomes in NYHA examination (p=0.033). We noticed a significant increase in serum CRP and TNF-α in CC patients (p=0.003 and p<0.001). Compared with T allele carriers, the CHF patients bearing CC genotype were more frequently diagnosed as cachectic (cachexia incidence for CC - 80% vs. 28% for CT and 38.7% for TT; p=0.017). CC genotype of rs1799964 was found as unfavorable factor affecting survival of depressive CHF patients (HR=8.87; p<0.001). CONCLUSIONS: The presence of the CC genotype in patients with depression and CHF can be considered an unfavorable prognostic factor related to the risk of shortening the life expectancy and deteriorating its quality, which is reflected in the severity of inflammation.

MiRNA and lung cancer radiosensitivity: a mini-review.

Radiotherapy (RTH) is still one of the leading treatment options for lung cancer patients. This treatment option is especially significant for patients with diagnosis of locally advanced or advanced tumor. To date, it is difficult to predict RTH outcomes basing only on patients' clinical features. Moreover, there are no established molecular markers, which could improve the prediction of RTH efficacy. Among the most promising markers which could serve as valuable biomarkers of RTH, miRNAs seem to be the most appropriate. According to literature reports, these molecules may be used for the prediction of RTH response, selection of patients who could benefit from RTH, as well as to estimate the risk of toxicity after irradiation. Moreover, thanks to the possibility of its testing in blood samples whenever it is required, miRNAs seem to be a much more attractive predictive marker of response to RTH than other molecular factors. In the present mini-review, we discuss recent findings of experimental studies (cell cultures analysis) and clinical studies concerning the relationship between miRNAs and sensitivity of lung tumors to RTH.

Methylation of the DCLK1 promoter region in circulating free DNA and its prognostic value in lung cancer patients.

INTRODUCTION: The possibility of detection of suppressor genes methylation in circulating free DNA (cf-DNA) of cancer patients and the lack of methylation in healthy individuals makes this epigenetic alternation an ideal diagnostic marker of neoplastic processes. Moreover, hypermethylation in several genes promoter was described as a biomarker of lung cancer. Methylation in the gene encoding doublecortin-like kinase 1 (DCLK1) is observed in patients with colorectal cancer and cholangiocarcinoma. However, there are no studies concerning DCLK1 methylation in lung cancer patients. The aims of the study was to evaluate the frequency of DCLK1 promoter methylation in cf-DNA of lung cancer patients and of healthy persons as well as the usefulness of this test for predicting the lung cancer course. MATERIALS AND METHODS: DCLK1 methylation status was evaluated in DNA isolated from peripheral blood plasma from 65 lung cancer patients and 95 healthy individuals. After DNA bisulfitation, DCLK1 methylation was determined using the qMSP-PCR technique. Moreover, the presence of DCLK1 methylation was correlated with the overall survival (OS) probability of lung cancer patients. RESULTS: DCLK1 promoter methylation was detected in 32 lung cancer patients (49.2 %) and 8 healthy individuals (8.4 %). The methylation of the region before transcription start site (TSS) and the region after TSS of DCLK1 gene was detected in 28 and 11 patients, respectively. In seven cases (10.8 %), the DCLK1 promoter methylation in both regions was reported simultaneously. The methylation was observed slightly frequently in patients with small cell lung cancer (75 % of SCLC patients). The median overall survival of patients with DCLK1 promoter methylation was lower than that of patients without DCLK1 gene modification (p = <0.001, HR = 4.235). CONCLUSIONS: The evaluation of DCLK1 promoter region methylation may be useful in both early diagnosis and prediction of the course of lung cancer.

The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient.

PURPOSE: Chemotherapy with platinum compounds and gemcitabine is frequently used in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients in which tyrosine kinase inhibitors (EGFR or ALK) cannot be administered. Unfortunately, less than half of the patients achieve the benefit from chemotherapy. Gemcitabine is an analog of deoxycytidine (pyrimidine antimetabolite) with antitumor activity. The excess of deoxycytidine synthesized by RRM1 enzyme activity may be a cause of competitive displacement of gemcitabine, which reduces the efficacy of this cytostatic. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of the RRM1 promoter (-37C>A, -524C>T) and the effectiveness of first-line chemotherapy based on platinum compounds and gemcitabine in NSCLC patients. PATIENTS AND METHODS: SNPs were determined by SNaPshot PCR(®) in DNA isolated from peripheral blood of 91 NSCLC patients. RESULTS: The median progression-free survival (PFS) was significantly longer in carriers of AA (-37C>A) as well as CC (-524C>T) genotype of RRM1 compared to patients with other genotypes (10.5 vs 3.5 months, p = 0.0437; HR = 2.17, 95 % CI 1.02-4.62 and 10.5 vs 3.5 months, p = 0.0343; HR = 2.12, 95 % CI 1.06-4.27). In addition, the CC genotype carriers (-37C>A) showed a significant increase in the risk of shortening overall survival (OS) in comparison to patients with AA or AC genotypes (9.5 vs 18 months, p = 0.0193; HR = 2.13, 95 % CI 1.13-4.03). CONCLUSIONS: Presence of rare AA (-37C>A) and CC (-524C>T) genotypes of the RRM1 may be favorable predictive factors for chemotherapy with platinum compounds and gemcitabine in NSCLC patients.

Retrospective analysis of second-line chemotherapy outcomes with paclitaxel or docetaxel in correlation with STMN1 polymorphism in advanced non-small cell lung cancer patients.

PURPOSE: Second-line chemotherapy of advanced non-small cell lung cancer (NSCLC) with docetaxel or pemetrexed allows to achieve objective response rate only in 5-10 % of patients. Recent studies have shown that single nucleotide polymorphisms (SNPs) in genes encoding proteins which regulate dynamics of microtubules may be considered as predictive factors of response to taxane-based chemotherapy. STMN1 gene encodes stathmin 1, which plays role in cell division by regulation of microtubules depolarisation, and this process may be associated with taxanes' effectiveness. MATERIALS AND METHODS: Using HRM-PCR technique, we evaluated the -2166C>T SNP of STMN1 gene in DNA from peripheral blood leucocytes of 54 advanced NSCLC patients treated in second-line monotherapy with docetaxel or paclitaxel. RESULTS: Patients with TT genotype of STMN1 gene demonstrated significantly longer progression-free survival (PFS) and the lower risk of early disease progression after second-line treatment compared to patients with other STMN1 genotypes (median PFS: 7 and 2 months; p = 0.0154; HR = 0.371; 95 % CI 0.184-0.743). Early disease progression during second-line chemotherapy was significantly more frequently observed in patients with CC genotype of STMN1 in contrast to patients with presence of T allele (median PFS: 2 and 4 months; p = 0.0385; HR = 1.776; 95 % CI 0.905-3.445). CONCLUSION: Only selected NSCLC patients could benefit from second-line chemotherapy. Therefore, investigations of novel predictive molecular factors for proper qualification of patients to second-line taxane-based chemotherapy are justified. Studied SNP of STMN1 gene may have potential predictive role in such therapy.

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients.

INTRODUCTION: Platinum-based chemotherapy and 3rd generation drugs is still the main treatment option for advanced non-small cell lung cancer (NSCLC) patients without activating EGFR mutations or ALK rearrangements. However, the side effects associated with cytostatics are well known. Changes in the genes (e.g. single nucleotide polymorphisms, SNPs) encoding proteins regulating DNA repair or cell division could potentially influence on both the susceptibility of cancer cells to chemotherapy, and the occurrence of toxicities. MATERIALS AND METHODS: In presented study, the relationship between the fourteen SNPs in nine DNA repair and cell division regulating genes: ERCC1, XPD, XPA, XPC, XRCC1, XPG, RRM1, BRCA1, STMN1 and the toxicity of first-line chemotherapy in NSCLC patients were investigated. SNPs were determined by SNaPshot PCR® in DNA isolated from peripheral blood of 55 NSCLC patients treated with platinum compound and vinorelbine. The toxicity of therapy was evaluated according to the Common Toxicity Criteria (CTC) Version 4.03. RESULTS: The odds ratio (OR) of severe haematological toxicity was significantly lower in carriers of the T allele of XRCC1 gene (1196A > G, OR = 0.22, 95 % CI: 0.06-0.82, p = 0.018) and higher in the carriers of the T allele (2704C > A) of XPC gene (OR: 7.50, 95 % CI: 0.89-63.17, p = 0.036) compared to the remaining patients. Risk of severe hepatotoxicity was significantly lower in carriers of the C allele of STMN1 (-2166T > C, OR = 0.09, 95 % CI: 0.01-1.12, p = 0.025) than in patients with T allele of this gene. In carriers of G allele (2251A > C, OR: 0.24, 95 % CI: 0.07-0.81, p = 0.017) and T (934G > A, OR: 0.26, 95 % CI: 0.07-0.90, p = 0.029) of XPD gene, risk of severe nephrotoxicity was significantly lower than in other patients. CONCLUSIONS: Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.

Neurotransmitters and substances of abuse: effects on adult neurogenesis.

Neurogenesis in the adult brain is now a well-recognized phenomenon. The compelling subject of interest now is that besides the intrinsic, what are the environmental factors which affect neural stem cells ability to maintain themselves and enter the pool of the adult brain. While the molecular and cellular mechanisms that regulate this process remain to be elucidated, substantial data implicate common pathways involving action of neurotransmitters through neurotrophic factors to regulate the neural stem cells. This transmitter-mediated neurotrophic factor pathway could be altered by extrinsic environmental factors including enriched environment, exercise, stress, and drug abuse (i.e. alcohol, opioid, methamphetamine). Our special attention focuses on the role of neurotransmitters; among them are serotonin (5-HT), glutamate and gamma-amino-butyric acid (GABA). Substances of abuse including alcohol, which may interact through these neurotransmitters and neurotrophic factors to affect neurogenesis, are also reviewed.

Fetal alcohol effects: mechanisms and treatment.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Edward P. Riley. The presentations were (1) Does alcohol withdrawal contribute to fetal alcohol effects? by Jennifer D. Thomas and Edward P. Riley; (2) Brain damage and neuroplasticity in an animal model of binge alcohol exposure during the "third trimester equivalent," by Charles R. Goodlett, Anna Y. Klintsova, and William T. Greenough; (3) Ganglioside GM1 reduces fetal alcohol effects, by Basalingappa L. Hungund; and (4) Fetal alcohol exposure alters the wiring of serotonin system at mid-gestation, by F. Zhou, Y. Sari, Charles Goodlett, T. Powrozek, and Ting-Kai Li.

Effect of neuropeptide Y (NPY) on oral ethanol intake in Wistar, alcohol-preferring (P), and -nonpreferring (NP) rats.

BACKGROUND: Neuropeptide Y (NPY) deficient mice consume more ethanol than controls, whereas NPY over-expressing mice consume less ethanol than controls. Thus, ethanol drinking may be inversely associated with NPY activity. To determine whether exogenously administered NPY would alter ethanol intake, two experiments were conducted. METHODS: A within-subject design was used with intracerebroventricular (ICV) administration of NPY or artificial cerebral spinal fluid (aCSF) into the lateral ventricles. Infusions were separated by 2 to 7 days. In experiment 1, male Wistar rats (n = 10) were tested for the effects of NPY on an intake of 5% sucrose or 8% (w/v) ethanol during daily 2-hr testing periods with food and water available at all other times. In experiment 2, male alcohol-preferring (P) and alcohol-nonpreferring (NP) rats (n = 8/line) were tested for the effects of NPY on 8% (w/v) ethanol intake. RESULTS: In experiment 1, NPY (5, 10, 20 microg) significantly increased sucrose intake relative to aCSF baseline in Wistar rats, a finding consistent with previous observations of the orexigenic effects of the peptide. However, NPY (10 microg) did not alter ethanol intake in Wistar rats. In experiment 2, NPY (5 and 10 microg) significantly decreased ethanol intake in P rats, but not in NP rats. CONCLUSION: The reduction in ethanol intake seen with the P rats is consistent with the postulated negative relationship between NPY activity and ethanol intake. The lack of effect of NPY on ethanol intake in Wistar and NP rats may be related to the lower baseline levels of ethanol intake in these rats or to differential central nervous system basal NPY activity or sensitivity to the peptide.

Alcohol deters the outgrowth of serotonergic neurons at midgestation.

We have previously demonstrated that treatment of pregnant C57BL mice from gestation days 8 to 14 with alcohol with 20% ethanol-derived calories (EDC) reduced the number of serotonin (5-HT) neurons and retarded their migration in the fetal brains. In the present study, we obtained similar results with the use of 25% EDC and extended our previous findings by demonstrating that besides the alteration of the number of 5-HT neurons, prenatal alcohol exposure also affects their projecting fibers in their early development. Pregnant C57BL mice were divided into an alcohol-exposed (ALC) group given 25% EDC (4.49%, v/v), a pair-fed group to the ethanol-fed group (PF) and a chow-fed group (Chow). The PF and Chow groups served as controls. Our results showed that in the ALC group, when compared with the control groups, prenatal alcohol exposure with 25% EDC reduced the number of 5-HT-immunoreactive neurons in both the median and dorsal raphe, and the amount of 5-HT-immunoreactive fibers in the medial forebrain bundle (MFB). The diameter of the 5-HT-immunoreactive MFB was also reduced as a result of treatment. No significant differences of the above parameters were found between the PF and Chow groups. The previous and present work confirmed that alcohol reduces the normal formation and growth of 5-HT neurons in the midbrain. Furthermore, the projection of 5-HT fibers, in density as well as in distribution, is reduced in the major trajectory bundle. This may affect the amount of 5-HT fibers available to the forebrain. In light of the importance of the 5-HT system in brain development, alcohol may affect the growth of the forebrain through its effect on 5-HT signaling.

Nitric oxide synthase-containing neurons in the myenteric plexus of the rat gastrointestinal tract: distribution and regional density.

Nitrergic (NO) neurons play crucial inhibitory roles in the control of gut motility. Variations in the density of these neurons within the gastrointestinal tract (GI) may provide useful functional information, but, most surveys available have employed limited and/or highly localized samples. It remains unclear to what extent (a) NO neurons are concentrated disproportionately in particular GI regions, or (b) variations in NO cell number merely reflect changes in overall myenteric neuron density. This experiment surveyed the distributions of neuronal nitric oxide synthase-positive (NOS+) and other myenteric neurons in the GI tract, using immunohistochemical and Cuprolinic blue counterstaining techniques. Adjustable sampling grids superimposed on wholemounts were used to investigate the topographic patterns in the stomach (90 sampling sites; 45 per side) and proximal duodenum (63 loci). We present four major findings: First, variations were detected in the number of NOS+ neurons in specific regions of the stomach (e.g., corpus > antrum approximately equal to forestomach) and along both longitudinal (oral > anal) and circumferential (mesenteric > antimesenteric) axes in the duodenum. Second, the variations in NOS+ neuronal counts within each organ covaried with the total number of myenteric neurons at different locations (stomach, r=0.77; duodenum, r=0.59), suggesting that local myenteric plexus density is a factor determining NOS+ cell concentrations. Third, in contrast to such a principle of covariation within each organ, NOS+ neurons constituted a consistently smaller proportion of gastric (20%) than of duodenal (28%) myenteric plexus neurons, suggesting that a second principle controls the characteristic percentages of the myenteric plexus that express NOS in different organs. Fourth, the regional samples were used to extrapolate the overall number of NOS+ and total myenteric cells in the rat stomach (43,000; 217,000) and first 3.5 cm of the small intestine (29,000; 103,000). These results, taken together, also suggest that the surveying protocol used is capable of detecting subtle differences in cellular distributions, thus providing a practical strategy for investigating patterns of chemical phenotypes within the GI tract.