Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study

Background

Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.

Methods

Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.

Results

Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982 – SLC45A2, rs12203592 – IRF4, rs258322 – CDK10, rs1805007 – MC1R, rs1805008 - MC1R, rs910873 - PIGU, rs17305573- PIGU, and rs1885120 - MTAP) and higher for one SNP (rs6001027 – PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22–2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34–0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03–9.43; P = 2×10⁻⁵). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).

Conclusion

Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.     

Concordance of effects of medical interventions on hospital admission and readmission rates with effects on mortality

Background:

Many clinical trials examine a composite outcome of admission to hospital and death, or infer a relationship between hospital admission and survival benefit. This assumes concordance of the outcomes “hospital admission” and “death.” However, whether the effects of a treatment on hospital admissions and readmissions correlate to its effect on serious outcomes such as death is unknown. We aimed to assess the correlation and concordance of effects of medical interventions on admission rates and mortality.

Methods:

We searched the Cochrane Database of Systematic Reviews from its inception to January 2012 (issue 1, 2012) for systematic reviews of treatment comparisons that included meta-analyses for both admission and mortality outcomes. For each meta-analysis, we synthesized treatment effects on admissions and death, from respective randomized trials reporting those outcomes, using random-effects models. We then measured the concordance of directions of effect sizes and the correlation of summary estimates for the 2 outcomes.

Results:

We identified 61 meta-analyses including 398 trials reporting mortality and 182 trials reporting admission rates; 125 trials reported both outcomes. In 27.9% of comparisons, the point estimates of treatment effects for the 2 outcomes were in opposite directions; in 8.2% of trials, the 95% confidence intervals did not overlap. We found no significant correlation between effect sizes for admission and death (Pearson r = 0.07, p = 0.6). Our results were similar when we limited our analysis to trials reporting both outcomes.

Interpretation:

In this metaepidemiological study, admission and mortality outcomes did not correlate, and discordances occurred in about one-third of the treatment comparisons included in our analyses. Both outcomes convey useful information and should be reported separately, but extrapolating the benefits of admission to survival is unreliable and should be avoided.Health care decisions often rely on effects of interventions described using rates of admission or readmission to hospital.^1,2 These outcomes are typically regarded as indicators of insufficient quality of care and inefficient spending of health care resources;^1,2 however, whether they can predict other serious clinical outcomes, such as death, is unknown.Although effects on admission or readmission rates are often analyzed using large sets of routinely collected data, such as from administrative databases and electronic health records, many randomized controlled trials (RCTs) also collect data on admission rates, and some RCTs collect mortality data. Moreover, some trials combine death and admission to hospital as the primary composite outcome³ to increase the study’s power to detect significant differences and reduce the required study size.⁴ However, the interpretation of such a combination is difficult when the treatment effects on the 2 components are not concordant,⁵ for example, when more patients survive but rates of admission increase. In such cases, composite outcomes may dilute or obscure clinically significant treatment effects on important individual components,^4,6 and incomplete disclosure of individual effects may mislead the interpretation of the results.⁴We investigated systematic reviews of treatment comparisons that included meta-analyses of RCTs assessing effects on both rates of admission and mortality. We used the reported trial data to assess whether effects on admission rates were concordant with effects on mortality or whether it was possible to identify interventions and diseases in which these 2 outcomes would provide differing pictures of the merits of the tested interventions.     

Birth Weight and Polycystic Ovary Syndrome in Adult Life: Is There a Causal Link?

Objectives

Several studies have demonstrated associations of birth weight with metabolic and reproductive abnormalities in adults. The aim of this study was to investigate the birth weight in women with PCOS and its correlation with clinical and biochemical characteristics of the syndrome.

Materials and Methods

We studied 288 women with PCOS according to the NIH criteria and 166 women with normal cycle and without clinical hyperandrogenism. Birth weight and anthropometric characteristics were recorded, and levels of serum androgens, SHBG, insulin and fasting glucose were measured.

Results

Birth weight data were available for 243/288 women with PCOS and age- and BMI-matched 101/166 controls. No differences were found (p> 0.05) in birth weight among women with PCOS and normal controls. Birth weight of PCOS women was negatively correlated with DHEAS levels (p = 0.031, r = -0.143) and positively correlated with waist circumference (p <0.001, r = 0.297) and body mass index (BMI) (p = 0.040, r = 0.132). Birth weight of controls was negatively correlated with SHBG levels (p = 0.021, r = -0.234). Women from both groups were further divided in 6 categories according to birth weight (A. <2.500 gr, B. 2.501-3.000 gr, C. 3.001-3.500 gr, D. 3.501-4.000 gr, E. 4.001-4.500 gr, F. > 4.500 gr). No statistically significant differences were observed in the distribution percentages between PCOS women and controls. (A. 7% vs 7.9%, B. 26.8% vs 20.8%, C. 39.1% vs 48.5%, D. 21.4% vs 20.8%, E. 4.9% vs 2%, F. 0.8% vs 0%), (in all comparisons, p> 0.05).

Conclusions

Women with PCOS do not differ from controls in birth weight distribution. However, birth weight may contribute to subtypes of the syndrome that are characterized by adrenal hyperandrogenism and central obesity.     

Synthesis of Some 2′,3′-Dideoxy-2′-C-Methyl-Substituted Nucleosides

Abstract

Nucleoside analogues analogues1-(2′,3′-dideoxy-2′-C-hydroxymethyl-β-D-erythro-pentofuranos-yl)thymine (1), 2′,3′-dideoxy-2′-C-hydroxymethylcytidine (2), 2′,3′-dideoxy-2′-C-hydroxymethyladenosine (3), 1-(2′-C-azidomethyl-2′,3′-dideoxy-β-D-erythro-pento-furanosyl)thymine (4), 2′-C-azidomethyl-2′,3′-dideoxycytidine (5), and 2′3′-dideoxy-2′-C-methylcytidine (6) have been synthesized from (S)-4-hydroxymethyl-y-butyro-lactone (7)     

The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration

Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users.Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions.The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.     

Trapping of metalloradical intermediates of the S-states at liquid helium temperatures. Overview of the phenomenology and mechanistic implications

The oxygen-evolving complex (OEC) of photosystem II (PSII) consists of a Mn cluster (believed to be tetranuclear) and a tyrosine (Tyr Z or Y(Z)). During the sequential absorption of four photons by PSII, the OEC undergoes four oxidative transitions, S(0) to S(1), ..., S(3) to (S(4))S(0). Oxygen evolves during the S(3) to S(0) transition (S(4) being a transient state). Trapping of intermediates of the S-state transitions, particularly those involving the tyrosyl radical, has been a goal of ultimate importance, as that can test critically models employing a role of Tyr Z in proton (in addition to electron) transfer, and also provide important clues about the mechanism of water oxidation. Until very recently, however, critical experimental information was lacking. We review and evaluate recent observations on the trapping of metalloradical intermediates of the S-state transitions, at liquid helium temperatures. These transients are assigned to Tyr Z(*) magnetically interacting with the Mn cluster. Besides the importance of trapping intermediates of this unique catalytic mechanism, liquid helium temperatures offer the additional advantage that proton motions (unlike electron transfer) are blocked except perhaps across strong hydrogen bonds. This paper summarizes the recent observations and discusses the constraints that the phenomenology imposes.     

Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1) vaccines

Background

Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation.

Methods

We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis.

Results

Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 µg (even with as little as 1.875 µg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines.

Conclusions

Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed.     

Guidelines on chemotherapy in advanced stage gynecological malignancies: an evaluation of 224 professional societies and organizations

Background

Clinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence.

Methods

We examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed.

Results

Among 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p = 0.033), response rates (p = 0.024), symptoms relief (p = 0.005), quality of life (p = 0.001) and toxicity (p = 0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy.

Conclusions

Clinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence.     

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV

We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56 μM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.