Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.     

Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.     

Genetic background of HSH in three Polish families and a patient with an X;9 translocation

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation. The translocation patient has long been considered as an example of the X-linked form of HSH. We identified six TRPM6 gene mutations, of which five were novel, in the Polish patients. All the alterations were either nonsense/splicing or missense mutations. The clinical picture of the patients was similar to the HSH patients reported earlier. No genotype-phenotype correlation could be detected. Sequencing did not reveal any TRPM6 or TRPM7 gene mutations in the female HSH patient with an X;9 translocation. Isolation of the translocation breakpoint showed that the chromosome 9 specific breakpoint mapped within satellite III repeat sequence. The X-chromosomal breakpoint was localised to the first intron of the vascular endothelial growth factor gene, VEGFD. No other sequence alterations were observed within the VEGFD gene. Even though the VEGFD gene was interrupted by the X;9 translocation, it seems unlikely that VEGFD is causing the translocation patient's HSH-like phenotype. Furthermore, re-evaluation of patient's clinical symptoms suggests that she did not have a typical HSH.     

Self-reinforced composites of bioabsorbable polymer and bioactive glass with different bioactive glass contents. Part II: In vitro degradation

The in vitro degradation behavior of self-reinforced bioactive glass-containing composites was investigated comparatively with plain self-reinforced matrix polymer. The materials used were spherical bioactive glass 13-93 particles, with a particle size distribution of 50-125 microm, as a filler material and bioabsorbable poly-L,DL-lactide 70/30 as a matrix material. The composites containing 0, 20, 30, 40 and 50 wt.% of bioactive glass were manufactured using twin-screw extruder followed by self-reinforcing. The samples studied were characterized determining the changes in mechanical properties, thermal properties, molecular weight, mass loss and water absorption in phosphate-buffered saline at 37 degrees C for up to 104 weeks. The results showed that the bioactive glass addition modified the degradation kinetics and material morphology of the matrix material. It was concluded that the optimal bioactive glass content depends on the applications of the composites. The results of this study could be used as a guideline when estimating the best filler content of other self-reinforced osteoconductive filler containing composites which are manufactured in a similar way.     

Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions

Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized by the accumulation of multiple mitochondrial DNA (mtDNA) deletions in post-mitotic tissues. Mutations in six different genes have been described to cause the autosomal dominant form of the disease, but only mutations in the DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the genetic background of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound heterozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2 (TK2) in arPEO patients. TK2 is an enzyme of the mitochondrial nucleotide salvage pathway and its loss-of-function mutations have previously been shown to underlie the early-infantile myopathic form of mtDNA depletion syndrome (MDS). Our TK2 activity measurements of patient fibroblasts and mutant recombinant proteins show that the combination of the identified arPEO variants, R225W and T230A, leads to a significant reduction in TK2 activity, consistent with the late-onset phenotype, whereas homozygosity for R225W, previously associated with MDS, leads to near-total loss of activity. Our finding identifies a new genetic cause of arPEO with multiple mtDNA deletions. Furthermore, MDS and multiple mtDNA deletion disorders are manifestations of the same pathogenic pathways affecting mtDNA replication and repair, indicating that MDS-associated genes should be studied when searching for genetic background of PEO disorders.     

Comparison between the disease-specific Airways Questionnaire 20 and the generic 15D instruments in COPD

Background  

Given that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population.     

Effects of the Preschool-Based Family-Involving DAGIS Intervention on Family Environment: A Cluster Randomised Trial

Interventions promoting young children’s healthy energy balance-related behaviours (EBRBs) should also examine changes in the family environment as this is an important determinant that may affect the effectiveness of the intervention. This study examines family environmental effects of the Increased Health and Wellbeing in Preschools (DAGIS) intervention study, and whether these effects differed when considering three parental educational level (PEL) groups. The DAGIS intervention was conducted in preschools and involving parents in Southern Finland from September 2017 to May 2018. It was designed as a randomised trial, clustered at preschool-level. Parents of 3–6-year-olds answered questionnaires recording PEL, parental role modelling for EBRBs, and the family environment measured as EBRBs availability and accessibility. Linear Mixed Models with Repeated Measures were used in order to detect intervention effects. Models included group by time interactions. When examining intervention effects separated by PEL groups, models with three-level interactions (group × time-points × PEL) were evaluated. There was an interaction effect for the availability of sugary everyday foods and drinks (p = 0.002). The analyses showed that the control group increased availability (p = 0.003), whereas in the intervention group no changes were detected (p = 0.150). In the analysis separated by PEL groups, changes were found only for the accessibility of sugary treats at home; the high PEL control group increased the accessibility of sugary treats (p = 0.022) (interaction effect: p = 0.027). Hence, results suggest that the DAGIS multicomponent intervention had a limited impact on determinants for children’s healthy EBRBs, and no impact was found in the low PEL group.