Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis

The Lutonium: A Sub-Nanojoule Asynchronous 8051 Microcontroller

We describe the Lutonium, an asynchronous 8051 microcontroller designed for low Et/sup 2/. In 0.18 /spl mu/m CMOS, at nominal 1.8 V, we expect a performance of 0.5 nJ per instruction at 200 MIPS. At 0.5 V, we expect 4 MIPS and 40 pJ/instruction, corresponding to 25,000 MIPS/Watt. We describe the structure of a fine-grain pipeline optimized for Et/sup 2/ efficiency, some of the peripherals implementation, and the advantages of an asynchronous implementation of a deep-sleep mechanism

Nursing care for patient with Crohn's disease in the surgical department

U radu se prikazuje vanjskotrgovinska razmjena Republike Hrvatske od 2012. do 2016. godine. Glavne komponente vanjskotrgovinske razmjene su, izvoz i uvoz, a njihov odnos iskazuje se na vanjskotrgovinskoj bilanci, u pozitivnom iznosu kao suficit, u negativnom kao deficit. Rad prikazuje kretanje izvoza i uvoza u apsolutnim iznosima i strukturu vanjskotrgovinske bilance te daje pregled vanjskotrgovinske razmjene s najvažnijim zemljama partnerima Republike Hrvatske. Činjenica je da sve zemlje teže ostvarivanju suficita, stoga se u radu naglašava važnost i mogućnosti stimuliranja izvoza u Republici Hrvatskoj. Metodom intervjua, na primjeru iz prakse jednog izvoznika, prikazani su problemi s kojima se susreće u poslovanju.This thesis discusses foreign trade in the Republic of Croatia since 2012 until 2016. Relations in the foreign trade are determined by Croatia's foreign trade policy. Key foreign trade components have been defined, as well as import and export. Their relations are shown in the foreign trade balance, in the positive amount as surplus and in the negative as deficit. This thesis shows the movement of exports and imports in absolute terms and structure of foreign trade balance and it gives an overview of foreign trade with the most important Croatia's partner countries. It is a fact that all countries seek to achieve a surplus, therefore, the importance and the possibility of export stimulation has been emphasized. This paper shows, in an interview, all the problems that a Croatian exporter has had during his business experience

Fat, fibre and cancer risk in African Americans and rural Africans

Rates of colon cancer are much higher in African Americans (65: 100,000) than in rural South Africans (Peer reviewe

Fat, fibre and cancer risk in African Americans and rural Africans

Rates of colon cancer are much higher in African Americans (65: 100,000) than in rural South Africans (Peer reviewe

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants:Application to BRCA1 and BRCA2

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.</p

Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article