A person-centered, transdiagnostic schema and mode profile approach to predict outcome in time-limited schema group therapy.

OBJECTIVE: This study employs a person-centered transdiagnostic approach to examine how schema and mode profiles predict symptom severity reduction in schema group therapy for patients with personality disorders and enduring clinical syndromes. METHOD: We analyzed symptom reduction in 248 patients across three formats of manualized, time-limited schema group therapy. Latent profile analysis and mixed multilevel modeling were used to determine the extent to which schema/mode classes predict symptom reduction, and whether the inclusion of individual schemas and modes enhances these predictions. RESULTS: No significant differences in treatment outcomes were found across the group modalities. A three latent profile solution for schemas and modes showed external validity with clinical variables and demonstrated that declines in symptom severity varied by schema and mode class, even after adjusting for baseline symptom severity. Adding the Vulnerability to Harm schema and Vulnerable Child mode to the model increased the explained variance. CONCLUSION: Patients with more severe personality problems show more substantial symptom reduction. Both schema and mode profiles significantly contribute to predicting post-treatment symptom levels. Understanding these profiles may help therapists tailor interventions more effectively, consistent with Young's theoretical model.Trial registration: ISRCTN.org identifier: ISRCTN17262253.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Effective operators in t-channel single top production and decay.

The production of a single top quark in the t-channel and its subsequent decay is studied at NLO accuracy in QCD, augmented with the relevant dimension-6 effective operators from the Standard Model Effective Theory. We examine various kinematic and angular distributions for proton-proton collisions at the LHC at 13 TeV, in order to assess the sensitivity to these operators, both with and without the top quark narrow width approximation. Our results will be helpful when devising strategies to establish bounds on their coefficients, including the amount of CP violation of the weak dipole operator.

Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report.

BACKGROUND: Uterine serous carcinoma (USC) shows greater morphological, clinical and molecular similarities to high-grade ovarian tubal serous carcinoma than to other types of endometrial cancer. As high-grade ovarian tubal serous carcinoma is known to be associated with BRCA1/2 pathogenic germline mutations (PMs), we aimed to explore whether USC is also a constituent of hereditary breast and ovarian cancer syndrome. METHODS: Pubmed, EMBASE and Web of Science were searched in July 2016 for articles assessing the association between USC and germline BRCA1/2-PMs. Pooled analysis and comparisons were performed using a random effects logistic model, stratifying for ethnicity (Ashkenazi versus non-Ashkenazi). In addition, tumour tissue from an USC case with a hereditary BRCA1-PM was analysed for loss of heterozygosity at the BRCA1 locus and was functionally analysed for homologous recombination proficiency. RESULTS: The search yielded 1893 citations, 10 studies were included describing 345 USC patients. For Ashkenazi Jews, the pooled odds ratio of having a germline BRCA1/2-PM was increased in USC patients compared with the general Ashkenazi population: odds ratio 5.4 (95%confidence interval: 2.2-13.1). In the patient with USC, we identified the known germline BRCA1-PM in the tumour DNA. Furthermore, we showed both loss of heterozygosity of the wild-type allele and a deficiency of homologous recombination. CONCLUSION: This study suggests that USC may be an overlooked component of BRCA1/2-associated hereditary breast and ovarian cancer syndrome. Screening for germline BRCA1/2-PMs should be considered in patients diagnosed with USC, especially in cases with a positive first-degree family history for breast and/or ovarian cancer.

Changes in symptom severity, schemas and modes in heterogeneous psychiatric patient groups following short-term schema cognitive-behavioural group therapy: a naturalistic pre-treatment and post-treatment design in an outpatient clinic.

UNLABELLED: Schema therapy has proven to be an effective treatment for patients with borderline personality disorder. However, little is known of its merits in other psychiatric (personality) disorders. OBJECTIVE: This study investigated whether schema therapy in a group setting (group schema cognitive-behavioural therapy [SCBT-g]) was associated with changes in symptom and schema and mode severity. Furthermore, the aim was to search for baseline predictors and possible mediators of treatment outcome. DESIGN AND METHOD: Sixty-three heterogeneous psychiatric outpatients who attended the SCBT-g were included as participants. In this naturalistic pre-treatment and post-treatment design, data were available on the Symptom Checklist 90, the Schema Questionnaire and the Young-Atkinson Mode Inventory. RESULTS: All outcome measurements showed changes with moderate to high effect sizes, with 53.2% of the patients showing a significant reduction in severity of psychiatric symptoms and schemas and modes. Higher pre-treatment levels of the schema domain Other Directedness predicted greater symptom reduction. Pre-treatment to mid-treatment changes in schema severity predicted subsequent symptom improvement, but change in symptoms and schemas proved to be strongly correlated. CONCLUSIONS: In this naturalistic study, SCBT-g was associated with reduced symptom and schema and mode severity in more than half of the psychiatric outpatients. Furthermore, the results suggest that changes in schemas and symptomatology mutually reinforce each other. KEY PRACTITIONER MESSAGE: Over 50% of ambulatory patients show clinical improvement after treatment in a short-term schema therapy group. Other Directedness seems to be a predictor of schema group therapy success. More randomized controlled trial studies and prediction and mediation studies on (short-term) schema group therapy are sorely needed.

The impact of next generation sequencing on the analysis of breast cancer susceptibility: a role for extremely rare genetic variation?

Women with a family history of breast cancer have an approximately twofold elevated risk of the disease. Even though an array of genes has been associated with breast cancer risk the past two decades, variants within these genes jointly explain at most 40% of this familial risk. Many explanations for this 'missing heritability' have been proposed, including the existence of many very rare variants, interactions between genetic and environmental factors and structural genetic variation. In this review, we discuss how next generation sequencing will teach us more about the genetic architecture of breast cancer, with a specific focus on very rare genetic variants. While such variants potentially explain a substantial proportion of familial breast cancer, assessing the breast cancer risks conferred by them remains challenging, even if this risk is relatively high. To assess more moderate risks, epidemiological approaches will require very large patient cohorts to be genotyped for the variant, only achievable through international collaboration. How well we will be able to eventually resolve the missing heritability for breast cancer in a clinically meaningful way crucially depends on the underlying complexity of the genetic architecture.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Restoration of nucleotide excision repair in a helicase-deficient XPD mutant from intragenic suppression by a trichothiodystrophy mutation.

The UV-sensitive V-H1 cell line has a T46I substitution mutation in the Walker A box in both alleles of XPD and lacks DNA helicase activity. We characterized three partial revertants that curiously display intermediate UV cytotoxicity (2- to 2.5-fold) but normal levels of UV-induced hprt mutations. In revertant RH1-26, the efficient removal of pyrimidine (6-4) pyrimidone photoproducts from both strands of hprt suggests that global-genomic nucleotide excision repair is normal, but the pattern of cyclobutane pyrimidine dimer removal suggests that transcription-coupled repair (TCR) is impaired. To explain the intermediate UV survival and lack of RNA synthesis recovery in RH1-26 after 10 J of UV/m(2), we propose a defect in repair-transcription coupling, i.e., the inability of the cells to resume or reinitiate transcription after the first TCR event within a transcript. All three revertants carry an R658H suppressor mutation, in one allele of revertants RH1-26 and RH1-53 and in both alleles of revertant RH1-3. Remarkably, the R658H mutation produces the clinical phenotype of trichothiodystrophy (TTD) in several patients who display intermediate UV sensitivity. The XPD(R658H) TTD protein, like XPD(T46I/R658H), is codominant when overexpressed in V-H1 cells and partially complements their UV sensitivity. Thus, the suppressing R658H substitution must restore helicase activity to the inactive XPD(T46I) protein. Based on current knowledge of helicase structure, the intragenic reversion mutation may partially compensate for the T46I mutation by perturbing the XPD structure in a way that counteracts the effect of this mutation. These findings have implications for understanding the differences between xeroderma pigmentosum and TTD and illustrate the value of suppressor genetics for studying helicase structure-function relationships.

Enhanced UV-induced mutagenesis in the UV61 cell line, the Chinese hamster homologue of Cockayne's syndrome B, is associated with defective transcription coupled repair of cyclobutane pyrimidine dimers.

Cells from Cockayne's syndrome (CS) patients are hypersensitive to the cytotoxic effects of UV-irradiation and are defective in transcription coupled repair (TCR). We have examined the mutagenic consequences of impaired TCR in the Chinese hamster cell line UV61, the rodent homologue of CS complementation group B. Analysis of the two major UV-induced photolesions, cyclobutane pyrimidine dimers (CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4 PP), revealed that repair of CPD from the transcribed strand was strongly reduced in UV61 cells, but repair of 6-4 PP was indistinguishable from that in wild-type hamster cells. UV-induced mutation induction was enhanced in UV61 compared to that observed in repair proficient cells. The spectrum of UV-induced base substitutions in UV61 was clearly different from that observed in wild-type hamster cells and resembled the spectrum previously observed in nucleotide excision repair deficient hamster cells. In UV61 cells a strong strand bias for mutation induction was found; assuming that premutagenic lesions occur at dipyrimidine sequences, 76% of the mutations could be attributed to lesions in the transcribed strand. These data strongly favour the hypothesis that defective TCR of CPD is responsible for the enhanced UV-induced mutagenesis in UV61 cells.

Impairment of nucleotide excision repair by apoptosis in UV-irradiated mouse cells.

We investigated the relationship between nucleotide excision repair (NER) activity and apoptosis in UV-irradiated cells. Mouse erythroleukemia (MEL) and lymphoma (GRSL) cells exhibited enhanced sensitivity to the cytotoxic effects of UV radiation compared to hamster cell lines, although normal UV-induced hprt mutation frequencies were found. Determination of UV-induced repair replication revealed a limited capacity of MEL and GRSL cells to perform NER consistent with poor removal of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts from transcriptionally active genes during the first 8 h after UV exposure. However, both cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts appeared to be processed to almost normal level 24 h after UV treatment. In parallel, we observed that the UV-irradiated MEL and GRSL cells suffered from severe DNA fragmentation particularly 24 h after UV exposure. Taken together, these data indicate a reduced repair of UV-induced photolesions in apoptotic cells, already established at the early onset of apoptosis. To test whether inhibition of repair in cells was due to inactivation of NER or to apoptosis-induced chromatin degradation, we performed in vitro excision assays using extracts from UV-irradiated MEL cells. These experiments showed that the NER capacity during early apoptosis was intact, indicating that slow removal of UV-induced photolesions in apoptotic cells is due to substrate modification (presumably degradation of chromatin) rather than direct inhibition of factors involved in NER.

Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells.

Irradiation of cells with short wave ultraviolet light (UV-C) induces both cyclobutane pyrimidine dimers (CPD) as well as pyrimidine 6-4 pyrimidone photoproducts (6-4 PP). We have focused on the removal of both types of DNA photolesions from the transcriptionally active adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT) genes and the inactive c-mos gene. Induction levels of both CPD and 6-4 PP were similar for all three genes analyzed, with the induction of 6-4 PP being about 3-fold lower than of CPD. Repair of CPD was analyzed using the CPD-specific enzyme T4 endonuclease V; repair of 6-4 PP was examined employing Escherichia coli UvrABC excinuclease. Unlike the HPRT gene, in which CPD were removed selectively from the transcribed strand, both strands of the 16-kilobase fragment encompassing the 2.6-kilobase APRT gene were repaired efficiently. This suggests the existence of multiple transcription units in the APRT region including transcription units running in the opposite direction of the APRT gene. Only a marginal part of the CPD was removed from the inactive c-mos gene after 24 h. In all three genes investigated, 6-4 PP were repaired more rapidly than CPD and, as demonstrated for the HPRT and APRT genes, without strand specificity. The difference in the repair phenotype of CPD between the HPRT gene and the APRT gene coincides with differences between both genes with regard to the DNA strand distribution of previously published UV-induced mutations.