Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental ...factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10–20%) than among Asians (50–60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.
Basal cell carcinoma Wong, C S M; Strange, R C; Lear, J T
BMJ,
10/2003, Letnik:
327, Številka:
7418
Journal Article
Recenzirano
Odprti dostop
The authors of this review aim to provide a comprehensive overview of basal cell carcinoma, concentrating in particular on incidence, risk factors, molecular genetics, clinical features, and treatment
The loci encoding the glutathione-S-transferase (GST) enzymes comprise a large supergene family located on at least seven chromosomes. The function of the GST enzymes has traditionally been ...considered to be the detoxication of electrophiles by glutathione conjugation. A wide variety of endogenous (e.g. by-products of reactive oxygen species activity) and exogenous (e.g. polycyclic aromatic hydrocarbons) electrophilic substrates have been identified. Interestingly, recent data has suggested a role, at least for the pi class gene product, in jun kinase inhibition. Since many GST genes are polymorphic, there has been considerable interest in determining whether particular allelic variants are associated with altered risk (or outcome) of a variety of diseases. We describe recent studies in patients with asthma and cutaneous basal cell carcinoma that demonstrate associations between GSTP1 and GSTT1 genotypes and disease phenotypes. Thus, GSTP1val(105)/val(105) was protective against asthma symptoms and GSTT1 null was associated with a subgroup of basal cell carcinoma patients who develop large numbers of primary tumours in clusters. Importantly, these associations were characterised by relatively large odds ratios (0.11 and 7.4, respectively) implying that the allelic variants exert a substantial biological effect. These and other data indicate the importance of GST polymorphism in determining disease phenotype.
Prion infection is characterized by the conversion of host cellular prion protein (PrPC) into disease-related conformers (PrPSc) and can be arrested in vivo by passive immunization with anti-PrP ...monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrPC rather than PrPSc. We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrPC and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrPC conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular β-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.
Summary
Background
Low testosterone levels occur in over 40% of men with type 2 diabetes mellitus (T2DM) and have been associated with increased mortality. Testosterone replacement together with ...statins and phosphodiesterase 5 inhibitors (PDE5I) are widely used in men with T2DM.
Purpose
To determine the impact of testosterone and testosterone replacement therapy (TRT) on mortality and assess the independence of this effect by adjusting statistical models for statin and PDE5I use.
Methods
We studied 857 men with T2DM screened from five primary care practices during April 2007–April 2009. Of the 857 men, 175/637 men with serum total testosterone ≤ 12 nmol/l or free testosterone (FT) ≤ 0.25 nmol/l received TU for a mean of 3.8 ± 1.2 (SD) years. PDE5I and statins were prescribed to 175/857 and 662/857 men respectively. All‐cause mortality was the primary end‐point. Cox regression models were used to compare survival in the three testosterone level/treatment groups, the analysis adjusted for age, statin and PDE5I use, BMI, blood pressure and lipids.
Results
Compared with the Low T/untreated group, mortality in the Normal T/untreated (HR: 0.62, CI: 0.41–0.94) or Low T/treated (HR: 0.38, CI: 0.16–0.90) groups was significantly reduced. PDE5I use was significantly associated with reduced mortality (HR: 0.21, CI: 0.066–0.68). After repeating the Cox regression in the 682 men not given a PDE5I, mortality in the Normal T/untreated and Low T/treated groups was significantly lower than that in the reference Low T/untreated group. Mortality in the PDE5I/treated was significantly reduced compared with the PDE5I/untreated group (OR: 0.06, CI: 0.009–0.47).
Conclusions
Testosterone replacement therapy is independently associated with reduced mortality in men with T2DM. PDE5I use, included as a confounding factor, was associated with decreased mortality in all patients and, those not on TRT, suggesting independence of effect. The impact of PDE5I treatment on mortality (both HR and OR < 0.25) needs confirmation by independent studies.
Abstract
Europa is a premier target for advancing both planetary science and astrobiology, as well as for opening a new window into the burgeoning field of comparative oceanography. The potentially ...habitable subsurface ocean of Europa may harbor life, and the globally young and comparatively thin ice shell of Europa may contain biosignatures that are readily accessible to a surface lander. Europa’s icy shell also offers the opportunity to study tectonics and geologic cycles across a range of mechanisms and compositions. Here we detail the goals and mission architecture of the Europa Lander mission concept, as developed from 2015 through 2020. The science was developed by the 2016 Europa Lander Science Definition Team (SDT), and the mission architecture was developed by the preproject engineering team, in close collaboration with the SDT. In 2017 and 2018, the mission concept passed its mission concept review and delta-mission concept review, respectively. Since that time, the preproject has been advancing the technologies, and developing the hardware and software, needed to retire risks associated with technology, science, cost, and schedule.
Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at ...least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility.
Background
The nature and extent of inflammation seen in multiple sclerosis (MS) varies throughout the course of the disease. Changes seen in CD4+ T-helper cells in relapsing–remitting (RR) MS and ...secondary progressive (SP) MS might differ qualitatively and/or quantitatively.
Objective
The objective of this paper is to study the frequencies of all major CD4+ T-helper subtypes – Th17, Th22 and Th1 lineage cells – in relapse, remission and secondary progression alongside CCR6 status, a chemokine receptor involved in migration of these cells into the central nervous system.
Methods
We compared 100 patients (50 RRMS and 50 SPMS) and 50 healthy volunteers and performed flow cytometric analysis of lymphocytes in blood samples.
Results
We demonstrated raised frequencies of various cell types along the Th17 axis; Th17, Th17.1 (IL-17+ interferon gamma+) and dual IL-17+ IL-22+ cells in RRMS. Th22 and CCR6+ Th1 cells (nonclassical Th1) were also increased in RRMS. All these cells were CCR6+. Only Th17 frequencies were elevated in SPMS.
Conclusions
Increased frequencies of Th17 cells are implicated both in RRMS and SPMS. The CCR6 pathway includes Th17, Th22 and Th1 nonclassical cells, of which Th22 and Th1 cells represent the greatest subsets in MS.
Background: The relationship between asthma severity and atopy is complex. Many studies have failed to show significant relationships between clinical severity or lung function and markers of atopic ...sensitisation. Aim: To determine whether increasing asthma severity is related to atopic sensitisation in a population of children with asthma. Methods: A total of 400 children (7–18 years) with asthma were recruited as part of a multicentre study of the genetics of asthma. Detailed phenotypic data were collected on all participants. Associations between measures of asthma severity and atopic sensitisation were sought using multilevel models allowing variation at the individual and family level. Results: Children recruited to the study had a range of asthma severities, with just over a third having mild persistent asthma. The logarithm of total serum IgE was associated with increased asthma severity score, decreased FEV1, increased airways obstruction, risk of hospital admission, and inhaled steroid use. Increasing skin prick test reactivity to a panel of seven aeroallergens was associated with increased risk of hospital admission, use of an inhaled steroid, and airways obstruction. The results remained highly significant after corrections for age, gender, and birth order. Conclusions: In children with asthma, increasing atopy is associated with increasing asthma severity. However, the relationships between asthma severity and skin prick tests, and asthma severity and total serum IgE values, appear subtly different.
Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more ...years, we studied the association of VDR single nucleotide polymorphisms (A/G1229, C/G3444, G/A3944, CC20965, CC30056, F/f30875, C/T48200, T/t65013) with outcome or disability. ff30875 frequency was lower in cases with EDSS ≥ 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% CI = 0.20–0.70). The association of ff30875 with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% CI = 0.14–1.34) and high exposure (odds ratio = 0.34, 95% CI = 0.16–0.73).
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