Expression of claudin‐11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ

The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, and the prognosis of patients with metastatic disease is poor. There is an emerging need to identify molecular markers for predicting aggressive behaviour of cSCC. Here, we have examined the role of tight junction (TJ) components in the progression of cSCC. The expression pattern of mRNAs for TJ components was determined with RNA sequencing and oligonucleotide array‐based expression analysis from cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK, n=5). The expression of CLDN11 was specifically elevated in primary cSCC cell lines (n=5), but low or absent in metastatic cSCC cell lines (n=3) and NHEKs. Claudin‐11 was detected in cell‐cell contacts of primary cSCC cells in culture by indirect immunofluorescence analysis. Analysis of a large panel of tissue samples from sporadic UV‐induced cSCC (n=65), cSCC in situ (n=56), actinic keratoses (n=31), seborrhoeic keratoses (n=7) and normal skin (n=16) by immunohistochemistry showed specific staining for claudin‐11 in intercellular junctions of keratinizing tumor cells in well and moderately differentiated cSCCs, whereas no staining for claudin‐11 was detected in poorly differentiated tumors. The expression of claudin‐11 in cSCC cells was dependent on the activity of p38δ MAPK and knock‐down of claudin‐11 enhanced cSCC cell invasion. These findings provide evidence for the role of claudin‐11 in regulation of cSCC invasion and suggest loss of claudin‐11 expression in tumor cells as a biomarker for advanced stage of cSCC.     

Gastrointestinal stromal tumors in patients with neurofibromatosis: imaging features with clinicopathologic correlation

OBJECTIVE: The purpose of this study was to evaluate the clinical, pathologic, and imaging features of gastrointestinal stromal tumors that occur in patients with neurofibromatosis. CONCLUSION: Gastrointestinal stromal tumors that occur in patients with neurofibromatosis commonly originate from the proximal small intestine and are often multiple. The cross-sectional imaging appearance of gastrointestinal stromal tumors that occur in patients with neurofibromatosis is similar to that of gastrointestinal stromal tumors that occur in the general population.     

Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.     

Neuropeptide Y and Y2‐receptor are involved in development of diabetic retinopathy and retinal neovascularization

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium‐derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro‐NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2‐receptor as a putative mediator of angiogenic NPY signaling in the retina.

METHODS: Frequencies of proline7 (Pro7) carriers in the prepro‐NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2‐receptor in hyperoxemia‐induced retinal neovascularization was investigated in Y2‐receptor knockout mice (Y2 ^?/? ) and in rats administered Y2‐receptor mRNA antisense oligonucleotide.

RESULTS: The carriers having Pro7 in the preproNPY are markedly over‐represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2 ^?/? ‐mice, and significantly inhibited in rats treated with the Y2‐receptor antisense oligonucleotide.

CONCLUSIONS: NPY and Y2‐receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.     

IGF‐I concentrations are positively associated with carotid artery atherosclerosis in women

BACKGROUND. Alterations in the growth hormone (GH)/insulin‐like growth factor I (IGF‐I) axis are associated with increased cardiovascular morbidity and mortality, but previous studies have yielded conflicting results. In addition, the T1169A polymorphism in the GH1 gene has been associated with IGF‐I levels.

AIMS. To investigate whether IGF‐I concentrations and the T1169A polymorphism of the GH1 gene are associated with cardiovascular risk factors and the intima media thickness (IMT) of the carotid artery.

METHODS. Fasting plasma IGF‐I concentrations (n = 1008) were measured in a large population‐based OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort. Genotype variants were determined by the restriction fragment length polymorphism method.

RESULTS. Low IGF‐I concentrations associated with several cardiovascular risk factors including age, adiposity, and high triglyceride, fasting insulin and C‐reactive protein concentrations in the analysis of all subjects. In the multivariate models, however, IGF‐I concentrations were positively associated with the mean IMT of women (ß = 0.127, P = 0.009) whereas the association in men was weaker and negative (ß = ?0.088, P = 0.034). The 1169A allele was associated with low low‐density lipoprotein cholesterol in both sexes and with low systolic blood pressure levels in women.

CONCLUSIONS. IGF‐I concentrations were associated with several traditional cardiovascular risk factors. The observed gender difference in the association between IGF‐I concentrations and carotid artery atherosclerosis warrants further study. The GH1 1169A allele may be associated with a favourable metabolic profile.     

Familial resemblance and diversity in bone mass and strength in the population are established during the first year of postnatal life

Familial resemblance and diversity in bone structure and strength in adulthood are determined in part during growth. Whether these characteristics are established during gestation or shortly after birth is not known. Total‐body, lumbar spine, and femoral neck size and mass and indices of tibial bending strength and distal radial compressive strength were measured using bone densitometry and quantitative computed tomography in 236 girls at 18.5 years of age. Among them, 219, 141, and 105 girls had crown‐heel length (CHL) and weight recorded at birth and at 6 and 12 months of age, and then height and weight were recorded at 3, 5, 10, 13, and 15 years of age in 181, 176, 127, 111, and 228 girls, respectively. Of these girls, 101 and 93 girls also had bone structure assessed at 11 and 13 years of age, respectively. Similar bone measurements were made once in 78 mother‐father pairs. CHL and weight at birth did not correlate or did so weakly with bone traits in girls at 18 years of age. By contrast, CHL at 6 months correlated with the height, bone traits, and strength at puberty and at 18 years of age (r = 0.24–0.56, p < .001) in girls and with their parents' height and bone traits (r = 0.15–0.37, p < .05). When the girls' CHL at 6 months was stratified into quartiles, the absolute and relative differences in bone traits observed at puberty (～11.5 years) were maintained as these traits tracked during the ensuing 7 years. Similarly, weight at 6 months correlated with the girls' bone traits at puberty and 18 years of age (r = 0.22–0.55, p < .05). During puberty and at 18 years of age, the girls' bone traits correlated with the corresponding traits in their parents (r = 0.32–0.43, p < .01). It is concluded that familial resemblance in bone structural strength and the position of an individual's bone traits relative to others in adulthood are likely to be established during the first year of life. Thus susceptibility to bone fragility late in life has its antecedents established early in life. © 2010 American Society for Bone and Mineral Research     

Force production capacity and acute neuromuscular responses to fatiguing loading in women with fibromyalgia are not different from those of healthy women

OBJECTIVE: To compare the maximal and explosive strength characteristics of the leg muscles in premenopausal women with fibromyalgia (FM) with those of healthy female controls (HC) and to examine acute neuromuscular fatigue during heavy resistance loading and short term recovery from fatigue in these 2 groups. METHODS: Subjects were 11 women with FM, 38.6 (5.8) years old, and 12 healthy female controls, 37.3 (6.1) years old. The following were recorded before, during, and after a fatiguing loading session: maximal bilateral concentric and isometric force, isometric force-time curves and relaxation-time curves with agonist-antagonist neural activation (by EMG) of the leg muscles, muscle pain, and blood lactate concentrations. RESULTS: At baseline all the measured muscle strength characteristics were comparable between the study groups. The heavy fatiguing loading led to considerable and comparable acute fatigue found in both muscle strength characteristics and agonist-antagonist electromyography in both groups. The respective changes in blood lactate concentration and subjectively perceived muscular pain in the loaded muscles during strenuous resistance loading and recovery from fatigue were similar in both groups. CONCLUSION: Premenopausal women with FM do not demonstrate lower dynamic or isometric muscle strength characteristics compared to matched healthy controls. Second, the similar neuromuscular responses recorded during and after the fatiguing loading strongly support the hypothesis of normal muscle structure and neuromuscular function in patients with FM.