A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance

Background: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). Objective: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. Methods: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. Results: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD. Conclusion: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity

Особенности конфликтогенных зон у больных невротическими расстройствами женщин

Представлены данные о различии конфликтогенных зон у женщин и мужчин, страдающих невротическими расстройствами. Показано, что выявленные особенности необходимо учитывать в диагностике и психотерапии невротических расстройств.The authors report the data about the differences in conflectogenic zones among women and men with neurotic disorders. It was shown that the revealed peculiarities should be taken into consideration in diagnosis and psychotherapy of neurotic disorders

Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA)

INTRODUCTION: Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. METHODS: We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. RESULTS: A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. CONCLUSIONS: This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought

Multifactorial Analysis of Differences Between Sporadic Breast Cancers and Cancers Involving BRCA1 and BRCA2 Mutations

Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-µm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138-45

The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer

The etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia. The sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data. As of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals. This resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/

Tissue microarrays: a practical guide

Tissue microarrays are a recent innovation in the field of pathology. They were originally designed as a high-throughput approach for researchers to assess the expression of interesting candidate disease-related genes or gene products simultaneously on hundreds of tissue samples. However, their use is becoming more widespread in routine pathology, for example for quality assurance and for the optimisation of diagnostic reagents such as monoclonal antibodies and gene probes. Several molecular and conventional pathological techniques can be performed on a single tissue array, thereby enabling morphology, DNA, RNA and protein targets to be analysed on sequential sections through multiple tissue samples. Moreover, compared with full-face tissue sections, tissue microarrays are a cost- and time-efficient, effective approach to analysing biomarker expression on a large number of samples. Whilst tissue microarrays are available from commercial sources, many pathology laboratories prefer to make in-house arrays from their often extensive pathology archive to facilitate the correlation of their findings with clinical parameters. The technical skills necessary to produce tissue arrays are well within the capacity of most laboratories. However, several pitfalls to successful array production exist. The present article describes the applications of this technique and details practical points for optimal tissue array production

Differential diagnosis of serous papillary carcinoma of the gynaecological tract and basal breast carcinoma: An immunohistochemical approach

Aims: There is a high frequency of serous gynaecological and basal breast cancers in patients with germline BRCA1 mutations. These patients often undergo prophylactic salpingo-oophorectomies, where small tumours may be identified in which morphological distinction between primary serous and metastatic basal breast cancer may be problematic. These two cancer types share similar molecular genetics and have immunophenotypic overlap. We aimed to develop an immunohistochemical panel which could differentiate between these two tumour types

Estimates of carnivore densities in a human-dominated agricultural matrix in South Africa

Populations of carnivore species outside protected areas may be of considerable importance for conservation, as many protected areas do not provide sufficient space for viable populations. Data on carnivore population sizes and trends are often biased towards protected areas, and few studies have examined the role of unprotected areas for carnivore conservation. We used camera-trapping data and spatial capture–recapture models to estimate population densities for four sympatric carnivores: the African leopard Panthera pardus, spotted hyaena Crocuta crocuta, brown hyaena Parahyaena brunnea and African civet Civettictis civetta in Platjan, a predominantly agricultural, mixed land-use system, South Africa. Mean densities per 100 km2 for the leopard were 2.20 (95% CI 1.32–3.68) and 2.18 (95% CI 1.32–3.61) for left and right flank data, respectively; spotted hyaena, 0.22 (95% CI 0.06–0.81); brown hyaena, 0.74 (95% CI 0.30–1.88); and African civet 3.60 (95% CI 2.34–5.57; left flanks) and 3.71 (95% CI 2.41–5.72; right flanks). Our results indicate that although densities are lower than those reported for protected areas, humans and predators coexist in this unprotected agricultural matrix. We suggest that increased conservation effort should be focused in such areas, to mitigate human–carnivore conflicts. Our study improves the knowledge available for carnivore populations on privately owned, unprotected land, and may benefit conservation planning

High resolution spatial mapping of brominated pyrrole-2-aminoimidazole alkaloids distributions in the marine sponge Stylissa flabellata via MALDI-mass spectrometry imaging

A number of pharmacologically active brominated pyrrole-2-aminoimidazole (B-P-2-AI) alkaloids have been isolated from several families of marine sponges, including those belonging to the genus Stylissa. In the present study, MALDI mass spectrometry imaging (MALDI-imaging) was applied to determine the spatial distribution of B-P-2-AIs within 20 μm cross sections of S. flabellata. A number of previously characterised B-P-2-AIs were readily identified by MALDI-imaging and confirmed by MS-MS and NMR profiling. Unknown B-P-2-AIs were also observed. Discrete microchemical environments were revealed for several B-P-2-AIs including dibromophakellin which was localised within the external pinacoderm and internal network of choanoderm chambers. Additionally, dibromopalau'amine and konbu'acidin B were also found to be confined to the choanoderm, while sceptrin was found to be highly abundant within the mesohyl. Further brominated compounds of unknown structure were also observed to have distinct localisation in both choanoderm chambers and the pinacoderm. These findings provide insights into the chemical ecology of S. flabellata, as most B-P-2-AIs were found on highly exposed surfaces, where they may act to prevent pathogens, predation and/or biofouling. Moreover this study demonstrates the power of MALDI-imaging to visualise the location of a range of metabolites in situ and to characterise compounds by MS-MS directly from intact specimens without the need for extraction. These methodologies facilitate selective targeting of micro-regions of sponge to screen for symbiotic microbial candidates or genes that may be involved in the production of the correlated compounds, and may represent a change in paradigm for natural product drug development