Associations between the age at surgical repair in patients with abdominal aortic aneurysms and aortoiliac occlusive disease and smoking and dyslipidemia with reference to PON1–108C>T genotype

Wstęp. Patogeneza tętniaków aorty brzusznej (AAA) i miażdżycy aortalno-biodrowej (AIOD) jest uwarunkowana wieloma czynnikami. Czynniki genetyczne i środowiskowe wpływają zarówno na inicjację, jak i progresję zmian w aorcie. W niniejszym badaniu oceniono asocjacje między wiekiem operacyjnym chorych z AAA i AIOD a występowaniem i nasileniem uznanych czynników ryzyka chorób naczyń oraz genotypem PON1–108C>T. Materiał i metody. Badanie przeprowadzono w grupach 330 chorych z AAA oraz 250 chorych z AIOD. Polimorfizm PON1–108C>T oznaczono za pomocą metody PCR-RFLP. Wyniki. Częstość występowania allela PON1–108T w grupach AAA (0,462) i AIOD (0,479) okazała się zbliżona. W obu grupach chorych młodszy wiek operowanych wiązał się istotnie z paleniem tytoniu, wysokimi stężeniami cholesterolu całkowitego (TC), frakcji LDL i triglicerydów oraz wartościami stosunku cholesterolu całkowitego i frakcji HDL. W przypadku AAA występował również ujemny związek z wartościami wskaźnika masy ciała. Wysoki odsetek cholesterolu frakcji HDL wykazywał ochronny efekt w odniesieniu do progresji AAA/AIOD. W AIOD występował również dodatni związek z wartościami stosunku stężenia cholesterolu frakcji HDL i LDL i występowaniem cukrzycy. Asocjacje między cholesterolem frakcji HDL a wiekiem chorych na AIOD okazały się silniejsze u nosicieli allela –108T. Wykazano niezależne powiązanie pomiędzy wiekiem operacyjnym w przypadku AAA a obecnością nałogu palenia tytoniu oraz wartością triglicerydów u operowanego. Stwierdzono też istnienie zależności pomiędzy wiekiem operacyjnym w przypadku AIOD a wartościami TC, obecnością nałogu palenia tytoniu oraz występowaniem cukrzycy u chorego. Powyższe oddziaływania występowały w większym nasileniu u osób będących homozygotami –108CC. Wnioski. Palenie tytoniu i zaburzenia gospodarki lipidowej są czynnikami o przeważającym wpływie na szybszą progresję AAA i AIOD. U osób, u których te czynniki nie występują, w szczególności w przypadku AIOD, genetycznie uwarunkowane obniżone stężenie paraoksonazy 1 może wpływać na przyspieszoną progresję zmian w aorcie.Background. The pathogenesis of abdominal aortic aneurysms (AAA) and aorto-iliac occlusive disease (AIOD) is multifactorial, and both genetic and environmental factors are involved in the initiation and progression of pathological changes in the aorta. This study is concerned with associations between the age of AAA and AIOD surgical repair and the classical vascular risk factors as well as the paraoxonase 1 (PON1)–108C>T genotypes. Material and methods. The study was conducted on 2 groups: the first group comprised 330 subjects with AAA, and the second group 250 subjects with AIOD. PON1–108C>T polymorphism was ascertained by the PCR-RFLP method. Results. The frequencies of –108T allele, which determine lower paraoxonase level, were similar in the groups of AAA (0.462) and AIOD (0.479) patients. The lower surgical repair age in patients in both groups was significantly associated with smoking and the higher levels of total cholesterol (TC), low density lipoprotein cholesterol (LDLC), and triglicerides (TG) and values of TC/HDLC. In the AAA group the same negative relation was noted with BMI index. The higher values of %HDLC display the protective effect on AAA/AIOD progression. In the AIOD group positive relations were also seen with HDLC/LDLC index and diabetes. Associations between high density lipoprotein cholesterol (HDLC) fraction and age of AIOD repair were stronger in –108T allele carriers. Age of AAA surgical repair was independently related to smoking and TG level, and age of AIOD surgical repair was independently related to smoking, diabetes and TC level. These effects were stronger in PON1–108CC homozygotes. Conclusions. Smoking and impaired lipid profile are prevailing factors determining the rate of AAA and AIOD progression. In the absence of these risk factors, the genetically determined low paraoxonase level may induce the progression of alterations in the aorta, particularly in the case of AIOD

Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele

Abstract. Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading -if untreated -to rupture. It is a common disease of the elderly, with a complex etiology. Several genetic, biochemical and environmental factors are recognized as relevant for the pathogenesis of AAA. We determined the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (C677T) in 63 patients with AAA and compared it to that in 75 subjects of the population sample. The frequencies of the C/C, C/T and T/T genotypes were 65%, 27%, and 8% in the population sample and 33%, 60%, and 6% in the patients. This corresponds to a 4.4-fold greater risk of AAA in subjects who have the 677C/T variant of MTHFR, as compared with those who are 677C/C (p<0.0001; 95% CI=2.11-9.34). The frequency of allele MTHFR 677T in patients (0.37) was higher than in the population sample (0.21; p < 0.007). This association between the common allele of the MTHFR gene -MTHFR 677T -and the development of AAA suggests that elevated homocysteine (Hcy) may disturb the function of the aortic wall. The disturbance may involve enhancement of elastin degradation, the process enhanced by mild hyperhomocysteinemia in minipigs. The magnitude of this effect, which refers to the AAA patients unselected for familial occurrence, indicates that the disturbance of aortic wall physiology caused by the presence of the MTHFR 677T allele is greater than the effect of the earlier described allele disequilibrium at the polymorphic alleles of the PAI1 (plasminogen activator inhibitor 1) gene seen only in familial cases of AAA

Nel positively regulates the genesis of retinal ganglion cells by promoting their differentiation and survival during development

Peer reviewedPublisher PD

BRCA1: A Novel Prognostic Factor in Resected Non-Small-Cell Lung Cancer

BACKGROUND: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). METHODOLOGY AND PRINCIPAL FINDINGS: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). CONCLUSIONS: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements