Pretreatment oral hygiene habits and survival of head and neck squamous cell carcinoma (HNSCC) patients.

BACKGROUND: The survival time of patients with head and neck squamous cell carcinoma (HNSCC) is related to health behavior, such as tobacco smoking and alcohol consumption. Poor oral health (OH), dental care (DC) and the frequent use of mouthwash have been shown to represent independent risk factors for head and neck cancerogenesis, but their impact on the survival of HNSCC patients has not been systematically investigated. METHODS: Two hundred seventy-six incident HNSCC cases recruited for the ARCAGE study were followed through a period of 6-10 years. Interview-based information on wearing of dentures, gum bleeding, teeth brushing, use of floss and dentist visits were grouped into weighted composite scores, i.e. oral health (OH) and dental care (DH). Use of mouthwash was assessed as frequency per day. Also obtained were other types of health behavior, such as smoking, alcohol drinking and diet, appreciated as both confounding and study variables. Endpoints were progression-free survival, overall survival and tumor-specific survival. Prognostic values were estimated using Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: A good dental care score, summarizing annual dental visits, daily teeth cleaning and use of floss was associated with longer overall survival time (p = .001). The results of the Cox regression models similarly suggested a higher risk of tumor progression and shortened overall survival in patients with poor dental care, but the results lost their statistical significance after other types of health behavior had been controlled for. Frequent use of mouthwash (≥ 2 times/day) significantly increased the risk of tumor-specific death (HR = 2.26; CI = 1.19-4.32). Alcohol consumption and tobacco smoking were dose-dependently associated with tumor progression and shorter overall survival. CONCLUSION: Frequent mouthwash use of ≥ 2 times/day seems to elevate the risk of tumor-specific death in HNSCC patients. Good dental care scores are associated with longer overall survival.

Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children.

BACKGROUND: Islet autoimmunity commonly develops early in infancy. We assessed whether specific parameters of early growth (including weight gain) were associated with the development of islet autoimmunity in children of type 1 diabetes patients, taking individual developmental patterns into account. METHODS: Growth parameters were estimated in n = 1011 children followed from birth in the prospective BABYDIAB and BABYDIET studies using longitudinal models. Cox proportional hazard models, adjusted for study, sex, gestational age, birth weight percentile, and maternal type 1 diabetes status, were calculated to assess hazard ratios (HR) for islet autoimmunity with corresponding 95% confidence intervals (95% CI) by 2 SD increases in growth parameters. In a subset of n = 170 infants, we investigated whether the growth hormones insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) were in the causal pathway. RESULTS: We found an early age at infant body mass index (BMI) peak to be associated with the development of islet autoimmunity [HR 0.60 (95% CI 0.41-0.87), per 2 SD increase in age]. Islet autoimmunity was also associated with BMI difference between infant BMI peak and childhood BMI rebound [HR 1.52 (95% CI 1.04-2.22)], but not after adjustment for age at infant BMI peak, and not with other parameters such as peak height and weight velocity during infancy. Serum concentrations of IGF-1 and IGFBP-3 at birth, 9 months, and 2 yr, respectively, were not significantly different between children with and without later islet autoimmunity. CONCLUSIONS: Variations in early growth rate have subtle effects on the risk of islet autoimmunity with growth hormones unlikely to be in the causal pathway.

α-Catulin downregulates E-cadherin and promotes melanoma progression and invasion.

Metastasis is associated with poor prognosis for melanoma responsible for about 90% of skin cancer-related mortality. To metastasize, melanoma cells must escape keratinocyte control, invade across the basement membrane and survive in the dermis by resisting apoptosis before they can intravasate into the circulation. α-Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor-kappa B and Rho signaling pathways, binds to ß-catenin and increases the level of both α-catenin and ß-catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that α-catulin is highly expressed in melanoma cells. Expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. Knockdown of α-catulin promoted adhesion to and inhibited migration away from keratinocytes in an E-cadherin-dependent manner and decreased the transmigration through a keratinocyte monolayer, as well as in Transwell assays using collagens, laminin and fibronectin coating. Moreover, knockdown promoted homotypic spheroid formation and concomitantly increased E-cadherin expression along with downregulation of transcription factors implicated in its repression (Snail/Slug, Twist and ZEB). Consistent with the molecular changes, α-catulin provoked invasion of melanoma cells in a three-dimensional culture assay by the upregulation of matrix metalloproteinases 2 and 9 and the activation of ROCK/Rho. As such, α-catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference.

Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children.

The incidence of type 1 diabetes is rising worldwide, particularly in young children. Since type 1 diabetes is preceded by autoimmunity to islet antigens, there must be a consequent increase in the incidence of islet autoimmunity in young children or a more rapid rate of progression to diabetes once islet autoimmunity initiates. This study was to determine whether the incidence of islet autoimmunity or the rate of progression from autoimmunity to diabetes onset has changed over a 20-year period in children genetically predisposed to type 1 diabetes. Between 1989 and 2010, children who were first-degree relatives of patients with type 1 diabetes and who were born in Germany were prospectively followed from birth without intervention. A total of 324 children (BABYDIAB study) born between 1989 and 2000 and 216 children (TEDDY study) born between 2004 and 2010 with matched HLA genotypes were recruited before age 3 months and included for analysis. Children were followed for the development of autoantibodies to insulin, GAD, and IA-2, and for progression to diabetes. The cumulative frequency of diabetes by age 4 years was 2.5% (95% CI 0.8-4.2%) in BABYDIAB children and 6.2% (95% CI 2.3-10.1%) in TEDDY children (p = 0.03). The cumulative frequency of islet autoantibodies by age 4 years was similar in the children from both studies (11.3% vs 13.9%). Progression to diabetes from the development of islet autoantibodies was markedly increased in autoantibody-positive children from the more recently recruited TEDDY cohort (50% progression within 85.2 months for BABYDIAB children vs 9.6 months for TEDDY children; p = 0.009), also if children were further selected on the basis of high-risk HLA genotypes or the development of autoantibodies to multiple islet antigens (p = 0.01). The findings suggest that recent increasing incidence of type 1 diabetes in young children could be due to weakening of mechanisms that normally regulate autoimmune destruction of islet beta cells.

Compromised gut microbiota networks in children with anti-islet cell autoimmunity.

The gut microbiome is suggested to play a role in the pathogenesis of autoimmune disorders such as type 1 diabetes. Evidence of anti-islet cell autoimmunity in type 1 diabetes appears in the first years of life; however, little is known regarding the establishment of the gut microbiome in early infancy. Here, we sought to determine whether differences were present in early composition of the gut microbiome in children in whom anti-islet cell autoimmunity developed. We investigated the microbiome of 298 stool samples prospectively taken up to age 3 years from 22 case children in whom anti-islet cell autoantibodies developed, and 22 matched control children who remained islet cell autoantibody-negative in follow-up. The microbiome changed markedly during the first year of life, and was further affected by breast-feeding, food introduction, and birth delivery mode. No differences between anti-islet cell autoantibody-positive and -negative children were found in bacterial diversity, microbial composition, or single-genus abundances. However, substantial alterations in microbial interaction networks were observed at age 0.5 and 2 years in the children in whom anti-islet cell autoantibodies developed. The findings underscore a role of the microbiome in the pathogenesis of anti-islet cell autoimmunity and type 1 diabetes.

Respiratory infections in early life and the development of islet autoimmunity in children at increased type 1 diabetes risk: evidence from the BABYDIET study.

IMPORTANCE: There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context. OBJECTIVE: To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk. DESIGN: Prospective cohort study with daily infection records and regular assessment of islet autoimmunity. SETTING: Diabetes Research Institute, Munich, Germany. PARTICIPANTS: A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90,750 person-days during their first 3 years of life. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use. RESULTS: An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08-1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80). CONCLUSIONS AND RELEVANCE: Respiratory infections in early childhood are a potential risk factor for the development of T1D.

Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.

Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and ß-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and ß-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action.

Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes.

OBJECTIVE: Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development. RESEARCH DESIGN AND METHODS: The study analyzed 29 metabolites of amino acid metabolism and 511 lipids assigned to 12 lipid clusters in children, with a type 1 diabetic parent, who first developed autoantibodies at age 2 years or younger (n = 13), at age 8 years or older (n = 22), or remained autoantibody-negative, and were matched for age, date of birth, and HLA genotypes (n = 35). Ultraperformance liquid chromatography and mass spectroscopy were used to measure metabolites and lipids quantitatively in the first autoantibody-positive and matched autoantibody-negative serum samples and in a second sample after 1 year of follow-up. RESULTS: Differences in the metabolite profiles were observed relative to age and islet autoantibody status. Independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids than autoantibody-negative children and independent of age at first autoantibody appearance (P < 0.0001). Consistent with our hypothesis, children who developed autoantibodies by age 2 years had twofold lower concentration of methionine compared with those who developed autoantibodies in late childhood or remained autoantibody-negative (P < 0.0001). CONCLUSIONS: Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy.

Endothelial cell-based methods for the detection of cyanobacterial anti-inflammatory and wound-healing promoting metabolites.

Acute lung injury is accompanied by an increased endothelial chemokine production and adhesion molecule expression, which may result in an extensive neutrophil infiltration. Moreover, a destruction of the alveolar epithelium and capillary endothelium may result in permeability edema. As such, the search for novel anti-inflammatory substances, able to downregulate these parameters as well as the tissue damage holds therapeutic promise. We therefore describe here the use of human endothelial cell-based in vitro assays for the detection of anti-inflammatory and wound-healing metabolites from cyanobacteria.