Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility

Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.Red Tematica de Investigacion Cooperative en Cancer RD06/0020/1054 Danish Cancer Society "Europe Against Cancer": European Prospective Investigation into Cancer and Nutrition (EPIC) deCODE Genetics/AMGE

New basal cell carcinoma susceptibility loci.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.NCI\SAIC-Frederick, Inc. (SAIC-F) 10XS170 Roswell Park Cancer Institute 10XS171 Science Care Inc. X10S172 Laboratory, Data Analysis and Coordinating Center (LDACC) HHSN268201000029C SAIC-F 10ST1035 HHSN261200800001E Brain Bank DA006227 DA033684 N01MH000028 University of Geneva MH090941 MH101814 University of Chicago MH090951 MH090937 MH101820 MH101825 University of North Carolina-Chapel Hill MH090936 MH101819 Harvard University MH090948 Stanford University MH101782 Washington University St Louis MH101810 University of Pennsylvania MH10182

Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPURPOSE: To test an aqueous eye drop solution containing a high concentration of dexamethasone in a cyclodextrin-based drug delivery system. This system increases both drug solubility in aqueous eye drops and drug permeability into the eye, through drug cyclodextrin-polymer co-complexes. METHODS: 2-hydroxypropyl-beta-cyclodextrin is a water-soluble oligosaccharide that can be used to dissolve lipophilic drugs, such as dexamethasone, in aqueous solutions. Co-complexation with a polymer further increases the solubility and increases drug permeability through biologic membranes. Eye drops containing dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-beta-cyclodextrin, and polymer were given to patients before cataract surgery, and the resultant dexamethasone concentration was measured from aqueous humor samples. RESULTS: The dexamethasone-cyclodextrin drops give a significantly higher concentration of dexamethasone in aqueous humor than dexamethasone alcohol 0.1% (Maxidex). Heating of the dexamethasone-cyclodextrin-polymer co-complexes appears to enhance the permeability of the drug into the eye. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of dexamethasone in aqueous eye drops and the permeability of the drug into the human eye. Dexamethasone concentration levels in the human aqueous humor exceed those reported with currently available steroid eye drops

Epidemiology of liver cirrhosis morbidity and mortality in Iceland

BACKGROUND: The mortality from liver cirrhosis in Iceland is the lowest in the Western world. OBJECTIVE: To study the epidemiology of liver cirrhosis mortality and morbidity in Iceland and to obtain a reliable separation between alcoholic cirrhosis (AC) and non-alcoholic cirrhosis (NAC) by using multiple data sources. METHODS: The study included the whole population of Iceland. Mortality was studied through death certificate data for the period 1951-90 and morbidity (clinical incidence) through hospital, autopsy and biopsy records for the period 1971-90. RESULTS: The average mortality for AC in age group 20 years and older was 8.6 and for NAC 19.2 per 10(6)/year and the average clinical incidence was 22.1 per 10(6)/year for AC and 25.9 per 10(6)/year for NAC. In the morbidity study 44% of cases were due to AC. In the mortality study 24% of cases were due to AC but the data suggested an underreporting of AC for males at a rate of 30%. There was a significant decrease in AC mortality with time but no change in NAC. Average alcohol consumption of inhabitants aged over 15 years increased from 2.1 to 4.9 litres per year (130%) during the period 1951-90. CONCLUSION: The incidence of cirrhosis in Iceland is very low for both AC and NAC, accounting for only 0.2% of total deaths. The reasons are unknown. The low incidence of AC in Iceland is probably partly due to low alcohol consumption. The decreasing incidence of AC despite 130% increase in alcohol consumption is thought to be due to intensive treatment of alcoholism. A low prevalence of hepatitis B and C probably contributes to the low incidence of NAC

Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPURPOSE: To test an aqueous eye drop solution containing a high concentration of dexamethasone in a cyclodextrin-based drug delivery system. This system increases both drug solubility in aqueous eye drops and drug permeability into the eye, through drug cyclodextrin-polymer co-complexes. METHODS: 2-hydroxypropyl-beta-cyclodextrin is a water-soluble oligosaccharide that can be used to dissolve lipophilic drugs, such as dexamethasone, in aqueous solutions. Co-complexation with a polymer further increases the solubility and increases drug permeability through biologic membranes. Eye drops containing dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-beta-cyclodextrin, and polymer were given to patients before cataract surgery, and the resultant dexamethasone concentration was measured from aqueous humor samples. RESULTS: The dexamethasone-cyclodextrin drops give a significantly higher concentration of dexamethasone in aqueous humor than dexamethasone alcohol 0.1% (Maxidex). Heating of the dexamethasone-cyclodextrin-polymer co-complexes appears to enhance the permeability of the drug into the eye. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of dexamethasone in aqueous eye drops and the permeability of the drug into the human eye. Dexamethasone concentration levels in the human aqueous humor exceed those reported with currently available steroid eye drops

Caffeine exposure from beverages and its association with self-reported sleep duration and quality in a large sample of Icelandic adolescents.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPrevious risk assessments have concluded that adolescent's caffeine exposure from energy drinks (ED) are of limited concern. Recent surveys have, however, shown substantial increase in consumption. This cross-sectional survey conducted in 2020 estimated caffeine exposure from beverages among ∼80% of all 13-15-year-old adolescents (n = 10358) relative to the European Food Safety Authority's level of no safety concern of (3.0 mg/kg bw) and level for effects on sleep (1.4 mg/kg bw). Associations with self-reported sleep duration and quality were also explored. ED consumers were more likely to exceed the limit of no safety concern (prevelance: 12-14%) compared to non-ED-consumers (1-2%). Exceeding the limit for effects on sleep was also higher among ED consumers (31-38%) than non-ED-consumers (5-8%). Across categories of low (3.0 mg/kg bw) caffeine intake, the prevalence of participants sleeping <6 h increased from 3% to 24%, respectively. The corresponding adjusted Prevalence Ratio was 4.5 (95% CI: 3.6, 5.7) and mean decrease in duration of sleep was 0.74 h (95% CI: 0.65, 0.84). In conclusion, caffeine intake from beverages above the limit of no safety concern was largely confined to ED consumers. Consistent with effects from intervention studies in adults, caffeine intake was strongly associated with self-reported sleep duration in this representative population. Keywords: Adolescents; Beverages; Caffeine; Energy drinks; Risk assessment; Sleep duration.Icelandic Ministry of Industries and Innovatio