A Variant in a MicroRNA complementary site in the 3' UTR of the KIT oncogene increases risk of acral melanoma.

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3' untranslated region (3' UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3' UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma

Visual Field Endpoints Based on Subgroups of Points May Be Useful in Glaucoma Clinical Trials: A Study With the Humphrey Field Analyzer and Compass Perimeter

PRECIS: Visual field endpoints based on average deviation of specific subsets of points rather than all points may offer a more homogenous dataset without necessarily worsening test-retest variability and so may be useful in clinical trials. PURPOSE: To characterize outcome measures encompassing particular subsets of visual field points and compare them as obtained with Humphrey (HVF) and Compass perimeters. METHODS: 30 patients with imaging-based glaucomatous neuropathy performed a pair of 24-2 tests with each of 2 perimeters. Non-weighted mean deviation (MD) was calculated for the whole field and separate vertical hemifields, and again after censoring of points with low sensitivity (MDc) and subsequently including only "abnormal" points with total deviation probability of <5% (MDc5%) or <2% (MDc2%). Test-retest variability was assessed using Bland-Altman 95% limits of agreement (95%LoA). RESULTS: For the whole field, using HVF, MD was -7.5±6.9▒dB, MDc -3.6±2.8▒dB, MDc5% -6.4±1.7▒dB and MDc2% -7.3±1.5▒dB. With Compass MD was -7.5±6.6, MDc -2.9±1.7▒dB, MDc5% -6.3±1.5, and MDC2% -7.9±1.6. The respective 95% LoA were 5.5, 5.3, 4.6 and 5.6 with HVF, and 4.8, 3.7, 7.1 and 7.1 with Compass. The respective number of eligible points were 52, 42±12, 20±11 and 15±9 with HVF, and 52, 41.2±12.6, 10±7 and 7±5 with Compass. With both machines, standard deviation (SD) and 95%LoA increased in hemifields compared to the total field, but this increase was mitigated after censoring. CONCLUSIONS: Restricting analysis to particular subsets of points of interest in the visual field after censoring points with low sensitivity, as compared with using the familiar total field mean deviation, can provide outcome measures with a broader range of mean deviation, a markedly reduced SD and therefore more homogenous dataset, without necessarily worsening test-retest variability

Sunscreens - Which and what for?

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Tyrosine kinase signalling in breast cancer

Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors to signalling molecules on neighbouring cells. Receptors of the tyrosine kinase family play an important role in the integration and interpretation of these external stimuli, allowing a cell to respond appropriately to its environment. The activation of receptor tyrosine kinases (RTKs) is tightly controlled, allowing a normal cell to correctly integrate its external environment with internal signal transduction pathways. In contrast, due to numerous molecular alterations arising during the course of malignancy, a tumour is characterized by an abnormal response to its environment, which allows cancer cells to evade the normal mechanisms controlling cellular proliferation. Alterations in the expression of various RTKs, in their activation, and in the signalling molecules lying downstream of the receptors play important roles in the development of cancer. This topic is the major focus of the thematic review section of this issue of Breast Cancer Research

Gold colloidal nanoparticle electrodeposition on a silicon surface in a uniform electric field

The electrodeposition of gold colloidal nanoparticles on a silicon wafer in a uniform electric field is investigated using scanning electron microscopy and homemade electrochemical cells. Dense and uniform distributions of particles are obtained with no aggregation. The evolution of surface particle density is analyzed in relation to several parameters: applied voltage, electric field, exchanged charge. Electrical, chemical, and electrohydrodynamical parameters are taken into account in describing the electromigration process

Higher education delays and shortens cognitive impairment. A multistate life table analysis of the US Health and Retirement Study

Improved health may extend or shorten the duration of cognitive impairment by postponing incidence or death. We assess the duration of cognitive impairment in the US Health and Retirement Study (1992–2004) by self reported BMI, smoking and levels of education in men and women and three ethnic groups. We define multistate life tables by the transition rates to cognitive impairment, recovery and death and estimate Cox proportional hazard ratios for the studied determinants. 95% confidence intervals are obtained by bootstrapping. 55 year old white men and women expect to live 25.4 and 30.0 years, of which 1.7 [95% confidence intervals 1.5; 1.9] years and 2.7 [2.4; 2.9] years with cognitive impairment. Both black men and women live 3.7 [2.9; 4.5] years longer with cognitive impairment than whites, Hispanic men and women 3.2 [1.9; 4.6] and 5.8 [4.2; 7.5] years. BMI makes no difference. Smoking decreases the duration of cognitive impairment with 0.8 [0.4; 1.3] years by high mortality. Highly educated men and women live longer, but 1.6 years [1.1; 2.2] and 1.9 years [1.6; 2.6] shorter with cognitive impairment than lowly educated men and women. The effect of education is more pronounced among ethnic minorities. Higher life expectancy goes together with a longer period of cognitive impairment, but not for higher levels of education: that extends life in good cognitive health but shortens the period of cognitive impairment. The increased duration of cognitive impairment in minority ethnic groups needs further study, also in Europe

Expression of hepcidin mRNA is uniformly suppressed in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The present study evaluated the expression of hepcidin mRNA in hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>Samples of cancerous and non-cancerous liver tissue were taken from 40 patients with HCC who underwent hepatectomy. Expression of hepcidin mRNA was evaluated by real-time PCR, and compared in tumors differing in their degree of differentiation, number of tumors, and vessel invasion. Correlations between hepcidin expression and the interval until HCC recurrence, and the serum concentration of hepcidin were evaluated, together with the expression of mRNAs for other iron metabolism molecules, ferroportin and transferrin receptor 2 (Trf2).</p> <p>Results</p> <p>Hepcidin mRNA expression in non-cancerous and cancerous tissues was 1891.8 (32.3–23187.4) and 53.4 (1.9–3185.8), respectively (<it>P </it>< 0.0001). There were no significant differences in hepcidin expression among tumors differing in their degree of differentiation, number of tumors, or vessel invasion. There was no significant correlation between hepcidin expression and the interval until HCC recurrence. The serum concentration of hepcidin-25 was not correlated with hepcidin-mRNA expression. Finally, there were no significant differences in the expression of mRNA for ferroportin and Trf2 between cancerous and non-cancerous tissues.</p> <p>Conclusion</p> <p>Expression of hepcidin mRNA is strikingly suppressed in cancerous, but not in non-cancerous tissues, in patients with HCC, irrespective of ferroportin or Trf2 expression. Uniform suppression of hepcidin may be linked to the development of HCC.</p

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis