The Mutational Profile of Unicystic Ameloblastoma.

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The aim of this study was to characterize the mutation profile of UAM ( n = 39) and to compare it to conventional AM ( n = 39). The associations between mutation status and recurrence probability were also analyzed. In the mandible, 94% of UAMs (29/31, including 8/8 luminal, 6/8 intraluminal, and 15/15 mural subtypes) and 74% of AMs (28/38) revealed BRAF V600E mutations. Among the BRAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS (p.Q61R), and 2 FGFR2 (p.C383R) activating mutations were identified in AM. Of the 3 maxillary UAMs, only 1 revealed a BRAF V600E mutation. Taken together, our findings demonstrate high frequency of activating BRAF V600E mutations in both UAM and AM of the mandible. In maxillary UAMs, the BRAF V600E mutation prevalence appears to be lower as was shown for AM previously. It could therefore be argued that UAM and AM are part of the spectrum of the same disease. AMs without BRAF V600E mutations were associated with an increased rate of local recurrence ( P = 0.0003), which might indicate that routine mutation testing also has an impact on prognosis.

Performing routine follow-up biopsy 1 year after diagnosis does not affect long-term outcomes in coeliac disease.

BACKGROUND: A repeat biopsy is recommended, but often omitted in coeliac disease patients on a gluten-free diet. The effect of performing or not performing repeat biopsies is currently unknown. AIM: To identify factors associated with and the significance of lacking biopsy for long-term outcome. Predictors and the importance of incomplete histological recovery after 1 year was investigated in re-biopsied patients. METHODS: A total of 760 patients participated in a nationwide follow-up study. Medical data were gathered via interviews and patient records, and blood samples were drawn for serology. Current symptoms and well-being were assessed by validated PGWB, SF-36 and GSRS questionnaires. RESULTS: Malabsorption was more common among those with a repeat biopsy (46%) than those without repeat biopsy (33%), P < 0.001, as were severe symptoms at diagnosis (24% vs. 16%, P = 0.05) and concomitant gastrointestinal (40% vs. 32%, P = 0.049) or musculoskeletal (35% vs. 27%, P = 0.023) diseases such as arthritis, osteoporosis and back pain. Repeat biopsy was more rare in subjects diagnosed in private care (11% vs. 23%, P < 0.001) or by screening (10% vs. 16%, P = 0.010). The groups were comparable as to current symptoms and dietary adherence, but those without re-biopsy were less confident of their diet (89% vs. 94%, P = 0.002) and more often seropositive on diet (14% vs. 9%, P = 0.012). They reported better SF-36 physical functioning (P = 0.043) and less pain and indigestion (P = 0.013 and P = 0.046 respectively) and total GSRS (P = 0.052) score. Incomplete mucosal recovery was predicted by more advanced histological (P < 0.001) and serological (P = 0.001) disease at diagnosis, whereas the groups did not differ in long-term adherence, symptoms, seropositivity, questionnaire scores, frequency of fractures or malignancies. CONCLUSIONS: Severe disease at diagnosis predicted the record of a repeat biopsy and incomplete mucosal recovery. Neither lacking biopsy nor incomplete recovery in a relative short time span of 1 year was associated with poorer long-term outcome, although survival bias cannot be excluded.

Activating ERBB4 mutations in non-small cell lung cancer.

Recent efforts to comprehensively characterize the mutational landscape of non-small cell lung cancer have identified frequent mutations in the receptor tyrosine kinase ERBB4. However, the significance of mutated ERBB4 in non-small cell lung cancer remains elusive. Here, we have functionally characterized nine ERBB4 mutations previously identified in lung adenocarcinoma. Four out of the nine mutations, Y285C, D595V, D931Y and K935I, were found to be activating, increasing both basal and ligand-induced ErbB4 phosphorylation. According to structural analysis, the four activating mutations were located at critical positions at the dimerization interfaces of the ErbB4 extracellular (Y285C and D595V) and kinase (D931Y and K935I) domains. Consistently, the mutations enhanced ErbB4 dimerization and increased the trans activation in ErbB4 homodimers and ErbB4-ErbB2 heterodimers. The expression of the activating ERBB4 mutants promoted survival of NIH 3T3 cells in the absence of serum. Interestingly, serum starvation of NIH 3T3 cells expressing the ERBB4 mutants only moderately increased the phosphorylation of canonical ErbB signaling pathway effectors Erk1/2 and Akt as compared with wild-type ERBB4. In contrast, the mutations clearly enhanced the proteolytic release of signaling-competent ErbB4 intracellular domain. These results suggest the presence of activating driver mutations of ERBB4 in non-small cell lung cancer.

Early dental epithelial transcription factors distinguish ameloblastoma from keratocystic odontogenic tumor.

The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes.

Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease.

BACKGROUND: Refractory coeliac disease (RCD) is thought to be a rare disorder, but the accurate prevalence is unknown. AIM: We aimed to identify the prevalence of and the risk factors for developing RCD in a Finnish population where the clinical detection rate of coeliac disease is high. METHODS: The study involved 11 hospital districts in Finland where the number of treated RCD patients (n = 44), clinically diagnosed coeliac disease patients (n = 12 243) and adult inhabitants (n = 1.7 million) was known. Clinical characteristics at diagnosis of coeliac disease between the RCD patients and patients with uncomplicated disease were compared. RESULTS: The prevalence of RCD was 0.31% among diagnosed coeliac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated coeliac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years, P < 0.001), more often males (41% vs. 24%, P = 0.012) and seronegative (30% vs. 5%, P < 0.001) at the diagnosis of coeliac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of coeliac disease, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhoea in 54% (vs. 38%, P = 0.050). CONCLUSIONS: Refractory coeliac disease is very rare in the general population. Patients of male gender, older age, severe symptoms or seronegativity at the diagnosis of coeliac disease are at risk of future refractory coeliac disease and should be followed up carefully.

Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the Finnish population.

Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.

Genome-wide analysis of extended pedigrees confirms IL2-IL21 linkage and shows additional regions of interest potentially influencing coeliac disease risk.

Coeliac disease is a chronic inflammatory condition of the small intestine, triggered by dietary exposure to gluten in genetically susceptible individuals. Risk alleles at HLA-DQA1 and HLA-DQB1 are necessary for disease development, but are alone not sufficient for disease onset. We aimed to identify novel loci underlying susceptibility to coeliac disease through the use of extended Finnish and Hungarian families with multiple affected individuals. An initial whole-genome linkage approach yielded several loci that were followed up further using the Immunochip custom array. Loci with a parametric logarithm of odds (LOD) score of >1.3 were identified at 4q, 6p [human leukocyte antigen (HLA) region], 6q, 7p, 17p, 17q and at 22p. The 4q and 6q loci have been identified previously in coeliac disease risk, whereas follow-up analyses indicate that the 17p and 22p loci may be novel risk loci for coeliac disease. These loci harbour previously described risk variants for other autoimmune diseases, but their segregation patterns do not explain the linkage to coeliac disease. We followed up the linkage to the 4q region, containing the previously described interleukin (IL)2 and IL21 genes. The risk variants at 4q in the studied pedigrees are most likely distinct from previously described risk variants, indicating that the observed linkage may be due to rare high-risk variants of still unknown nature. The importance of this locus to coeliac disease risk was further shown by the finding that serum levels of IL21 were elevated in both untreated and treated coeliac patients compared to controls.

Fine mapping of the CELIAC2 locus on chromosome 5q31-q33 in the Finnish and Hungarian populations.

Celiac disease is a chronic inflammation of the small intestine, arising in genetically predisposed individuals as a result of ingestion of dietary gluten. The only confirmed and functionally characterised genetic risk factors for celiac disease are the DQ2 or DQ8 heterodimers at the major histocompatibility complex (MHC) class II locus (CELIAC1). These genes are necessary but alone not sufficient for disease onset. Genome-wide linkage scans have suggested chromosome 5q31-q33 (CELIAC2) as an important risk locus for celiac disease. This region has also been associated to other inflammatory disorders, although as yet, no clear gene associations have been found. In the current study, 11 celiac disease candidate loci were screened for genetic linkage in the Hungarian population. As the CELIAC2 locus showed the strongest evidence for linkage, this locus was selected for follow-up. Seventeen candidate genes were selected from the CELIAC2 locus, and genotyped using 48 haplotype tagging single nucleotide polymorphisms (SNPs) in large Finnish and Hungarian family materials. A subset of these, 40 tagging SNPs in 15 genes, were genotyped in an independent set of Finnish and Hungarian cases and controls. We confirmed linkage of this region with celiac disease and report strong linkage in both the Finnish and Hungarian populations. The association analysis showed modest associations throughout the whole region. These association findings were not replicated in the case-control datasets. Our study strongly supports the role of the CELIAC2 locus in celiac disease, but it also highlights the need for a more powerful study design in the region, to locate the true disease risk variants.

Linkage and association study of FcgammaR polymorphisms in celiac disease.

The Fcgamma receptor cluster on chromosome 1q23 contains a number of genes that may affect susceptibility to celiac disease, but previous studies have yielded contradictory results. We studied the FcgammaRIIa*A519G (rs1801274) and FcgammaRIIIa*A559C (rs396991) single nucleotide polymorphisms in celiac disease families from Hungary and Finland and in celiac disease case-control materials from Hungary and Italy. Neither the Hungarian nor the Italian case-control material or a meta-analysis of the combined case-control material showed significant single-marker or haplotype association. In addition, neither linkage nor family-based association tests showed evidence for association in the Finnish or Hungarian family material. This study thus does not support a previous publication showing FcgammaR association with celiac disease.

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative dermatitis herpetiformis association.

BACKGROUND: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. METHODS: In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. RESULTS AND CONCLUSION: The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.

Prevalence of work-aggravated symptoms in clinically established asthma.

This population-based cross-sectional survey assessed the prevalence of work-aggravated asthma symptoms and the effect of the work environment on the aggravation of symptoms of established asthma. A questionnaire was sent to 2,613 persons (aged 20-65 yrs) with asthma. The analyses were restricted to the 969 respondents who were currently employed. The effect of occupational exposure on the aggravation of asthma symptoms at work was assessed according to both self-reported and expert-evaluated exposure. Approximately 21% of the respondents reported work-aggravated asthma symptoms at least weekly during the past month. The prevalence of those with work-aggravated symptoms increased by age, self-reported occupational exposure to dusts, abnormal temperatures or poor indoor air quality, physically strenuous work, and chemicals, and expert-evaluated probability of daily occupational exposure to airborne dusts, gases or fumes. Aggravation of asthma symptoms at work is common among employed adults with asthma. Both self-reported and expert-evaluated exposure to dusts, abnormal temperatures or poor indoor air quality, physically strenuous work, and chemicals explained the significant worsening of symptoms. The findings suggest a marked role of the work environment in the aggravation of symptoms of established asthma.

Excess incidence of asthma among Finnish cleaners employed in different industries.

The incidence and risk of asthma among female cleaners employed in different industries was explored. An increased risk of asthma has been associated with the cleaning profession, in some but not all studies. All Finnish females employed as cleaners and all those employed in administrative work were followed for asthma incidence through a record linkage in 1986-1998. An individual was defined as an "incident case of asthma" if they received rights for special reimbursement of asthma medication from the national health insurance or were recognized as having occupational asthma. Age-adjusted relative risks (RR) were estimated for cleaners in comparison with those employed in administrative work. There were 2,414 and 5,235 cases of asthma among the cleaners and administrative workers, respectively. The RR was 1.50 (95% confidence interval (CI) 1.43-1.57) in cleaners. The risk was increased in cleaners working in nearly all major sectors of economic activity, but cleaners employed by companies concerned with the manufacture of basic metals (RR 2.47; 95% CI 1.68-3.64) and food products (RR 2.19; 95% CI 1.69-2.85) had the highest risk. Only 25 of the "cases of asthma" among cleaners had been recognized as being occupational asthma. It could be concluded that cleaners have an increased risk of persistent adult-onset asthma. Factors inherent to the environment where cleaning is performed or differences in the cleaning agents used may explain the observed differences between industries.

Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population.

There are no population-based follow-up studies to estimate the fraction of asthma incidence that is attributable to work. In Finland, individuals with clinically well-established persistent asthma are registered for reimbursement of medication from the national health insurance scheme. We combined, at an individual level, these data with the population census data of 1985, 1990, and 1995 to estimate the attributable fraction of work in adult-onset persistent asthma. Our follow-up study covered the entire 25- to 59-yr-old employed population of Finland in 1986-1998. Relative risks (RR) for occupational categories were estimated in comparison to those employed in administrative work. There were 49,575 incident cases of asthma. The attributable fraction of occupation was 29% (95% CI 25-33%) for men and 17% (95% CI 15-19%) for women. The risk was increased especially in agricultural work, manufacturing work, and service work. In addition to already established risk occupations of occupational asthma, such as food and beverage work, the analysis identified a large number of occupations with significant excess of asthma incidence. The results indicate that the impact of occupational factors in the inception of adult-onset persistent asthma, and consequently the potential for prevention, is much larger and more widely spread than generally assumed.

Incidence of occupational asthma by occupation and industry in Finland.

BACKGROUND: Systematic research on occupation or industry-specific incidence of occupational asthma (OA) is sparse. We calculated the incidence of notified OA by occupation, industry and causative agent in Finland for the years 1989-95. METHODS: The numbers of cases of reported OA were retrieved from the Finnish Registry of Occupational Diseases for the population between 20 and 64 years of age. The numbers of employed workers were retrieved from Statistics Finland. Incidence rates were calculated for each occupation, industry and the total workforce. RESULTS: Altogether 2602 cases of OA were notified and the mean annual incidence rate was 17.4 cases/100,000 employed workers. The incidence rate was the highest in bakers, other painters and lacquerers, veterinary surgeons, chemical workers, farmers, animal husbandry workers, other food manufacturing workers, welders, plastic product workers, butchers and sausage makers, and floor layers. Cases caused by animal epithelia, hairs and secretions or flours, grains, and fodders accounted for 60% of the total. CONCLUSIONS: Estimation of occupation and industry-specific incidence rates forms the basis for successful prevention of OA, but necessitates collection of data over several years from well-established surveillance systems.

Collaboration between developing and developed countries and between developing countries in occupational health research and surveillance.

Collaborative occupational health and safety studies between counterparts in developing and developed countries and between developing countries have demonstrated their potential for improving occupational health and safety. Such collaboration in occupational health and safety is encouraged in the development of infrastructure in research empowerment and capacity building. This action includes the setting of priorities, the identification and documentation of problems, sponsorship, data bases and surveillance systems, technical support, methodology, publishing, research and training programs, controlled intervention, information exchange, and networking. Examples of priorities in occupational health and safety in the developing world include the informal sector (informally hired and independent workers), temporary work, pesticides, accidents, dusts, carcinogens, solvents, ergonomics, women and child labor, human immunodeficiency virus/acquired immunodeficiencey syndrome (HIV/AIDS), and transfer of hazardous materials and technologies. The sustainability of occupational health and safety structures and functions in the developing countries is a primary concern. Socioethical principles emphasize local, national, mutual and global gains. Examples of collaboration are given. Pervasive problems and strategies toward their solution are highlighted.

Agricultural work during pregnancy and selected structural malformations in Finland.

We studied the relation between birth defects and maternal agricultural work in a nationwide time- and area-matched case-referent series of 1,306 pairs of infants (581 orofacial clefts, 365 central nervous system defects, 360 skeletal defects) obtained through the Finnish Register of Congenital Malformations. We supplemented the Register data, including the mothers' latest and previous pregnancies, diseases, consumption of drugs and alcohol, smoking habits, and the like, with detailed interviews on the mothers' work conditions. When all of the birth defects were pooled and agricultural work was compared with nonagricultural work in the first trimester of pregnancy, the adjusted odds ratio was 1.4 [95% confidence interval (CI) = 0.9-2.0]. For orofacial clefts, the corresponding odds ratio was 1.9 (95% CI = 1.1-3.5). An industrial hygienist's blinded assessment indicated that seven mothers of infants with orofacial clefts and three reference mothers had been exposed to pesticides in agricultural work; the adjusted odds ratio for work with pesticide exposure, when compared with unexposed agricultural work, was 1.9 (95% CI = 0.4-8.3). Exposure to solvents did not explain the observed association.