D469del-COMP retention in chondrocytes stimulates caspase-independent necroptosis.

Mutations in the cartilage oligomeric matrix protein gene (COMP) cause pseudoachondroplasia (PSACH). This dysplasia results from the intracellular retention of mutant COMP protein and premature death of growth-plate chondrocytes. Toward better understanding of these underlying mechanisms, we examined D469del-COMP activation of the unfolded protein response and cell death pathways in rat chondrosarcoma cells.

Chop (Ddit3) is essential for D469del-COMP retention and cell death in chondrocytes in an inducible transgenic mouse model of pseudoachondroplasia.

Cartilage oligomeric matrix protein (COMP), a secreted glycoprotein synthesized by chondrocytes, regulates proliferation and type II collagen assembly. Mutations in the COMP gene cause pseudoachondroplasia and multiple epiphyseal dysplasia. Previously, we have shown that expression of D469del-COMP in transgenic mice causes intracellular retention of D469del-COMP, thereby recapitulating pseudoachondroplasia chondrocyte pathology.

The allele distribution in next-generation sequencing data sets is accurately described as the result of a stochastic branching process.

With the availability of next-generation sequencing (NGS) technology, it is expected that sequence variants may be called on a genomic scale. Here, we demonstrate that a deeper understanding of the distribution of the variant call frequencies at heterozygous loci in NGS data sets is a prerequisite for sensitive variant detection. We model the crucial steps in an NGS protocol as a stochastic branching process and derive a mathematical framework for the expected distribution of alleles at heterozygous loci before measurement that is sequencing.

Deep sequencing of MYC DNA-binding sites in Burkitt lymphoma.

Background: MYC is a key transcription factor involved in central cellular processes such as regulation of the cell cycle, histone acetylation and ribosomal biogenesis. It is overexpressed in the majority of human tumors including aggressive B-cell lymphoma. Especially Burkitt lymphoma (BL) is a highlight example for MYC overexpression due to a chromosomal translocation involving the c-MYC gene.

Anti-Yo antibody associated with occult fallopian tube carcinoma.

This is the case report of a 61-year-old woman who presented with progressive diplopia and ataxia. Her cerebrospinal fluid revealed high titers of anti-Yo (PCA-1) antibody and a magnetic resonance imaging with contrast showed cerebellar degeneration. Extensive imaging workup was negative for malignancy and she was otherwise asymptomatic.

Treatment failure in pneumonia: impact of antibiotic treatment and cost analysis.

The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy.

JC virus granule cell neuronopathy is associated with VP1 C terminus mutants.

The polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML). We described a novel JCV-variant with a 10 bp deletion in the C terminus of the VP1 capsid protein, JCV(GCN1). This mutant was associated with lytic infection of cerebellar granule cell neurons and cerebellar atrophy in an human immunodeficiency virus/PML patient.

Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly.

Primary autosomal recessive microcephaly (MCPH) is a congenital disorder characterized by a pronounced reduction of brain size and mental retardation. We present here a consanguineous Turkish family clinically diagnosed with MCPH and without linkage to any of the known loci (MCPH1-MCPH7). Autozygosity mapping identified a homozygous region of 15.

Comparative analysis with collagen type II distinguishes cartilage oligomeric matrix protein as a primary TGFβ-responsive gene.

Objective: This study aims to investigate the regulation of expression of Cartilage oligomeric matrix protein (COMP), which is predominately expressed by chondrocytes and functions to organize the extracellular matrix. Mutations in COMP cause two skeletal dysplasias: pseudoachondroplasia and multiple epiphyseal dysplasia. The mechanism controlling COMP expression during chondrocyte differentiation is still poorly understood.

Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot.

Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot.

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction.

Background: There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ.

S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs).

Placenta microbiology and histology and the risk for severe retinopathy of prematurity.

Purpose: To test the hypothesis that the presence of bacteria and/or histologic inflammation in the placenta of infants born preterm is associated with an increased risk for severe retinopathy of prematurity (ROP).

Methods: This was a prospective cohort study. Exploratory and multivariable data analyses were used, including logistic regression models with interaction terms.

Persistence after birth of systemic inflammation associated with umbilical cord inflammation.

Intrauterine inflammation is followed by elevated concentrations of inflammation-related proteins in the newborn's blood. Many of these proteins have short half-lives. The persistence of this postnatal inflammation has not previously been investigated.

Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas.

Background: Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation.

Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer.

Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome.

Generation of neural stem cells from discarded human fetal cortical tissue.

Neural stem cells (NSCs) reside along the ventricular zone neuroepithelium during the development of the cortical plate. These early progenitors ultimately give rise to intermediate progenitors and later, the various neuronal and glial cell subtypes that form the cerebral cortex. The capacity to generate and expand human NSCs (so called neurospheres) from discarded normal fetal tissue provides a means with which to directly study the functional aspects of normal human NSC development.

Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries less than 28 weeks of gestation.

Problem: Inflammation within the preterm placenta is common and leads to adverse outcomes for premature infants. The risks of complications are different between iatrogenic (e.g.

International Internet-based assessment of observer variability for diagnostically challenging endometrial biopsies.

Context: Endometrial carcinoma of endometrioid histology is frequently preceded by endometrial hyperplasia, from which localized, premalignant lesions called endometrial intraepithelial neoplasia (EIN) emerge. Diagnostic criteria for EIN have been developed by histopathologic correlation with clinical outcome, molecular changes, and objective computerized histomorphometry. However, several benign mimics of EIN continue to cause diagnostic confusion.

Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma.

Purpose: PTK787/ZK 222584 (PTK/ZK; vatalanib), an orally active, multitargeted angiogenesis inhibitor, has shown tolerability and promising activity in early-phase studies, which led to a phase III trial in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4).

Patients And Methods: Patients (N = 1,168) with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to receive FOLFOX4 plus PTK/ZK or placebo (ClinicalTrials.gov identifier: NCT00056459).

Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma.

Purpose: Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors.

Methods: Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4).

Extreme RNA editing in coding islands and abundant microsatellites in repeat sequences of Selaginella moellendorffii mitochondria: the root of frequent plant mtDNA recombination in early tracheophytes.

Using an independent fosmid cloning approach and comprehensive transcriptome analysis to complement data from the Selaginella moellendorffii genome project, we determined the complete mitochondrial genome structure of this spikemoss. Numerous recombination events mediated mainly via long sequence repeats extending up to 7 kbp result in a complex mtDNA network structure. Peculiar features associated with the repeat sequences are more than 80 different microsatellite sites (predominantly trinucleotide motifs).

Composite transcriptome assembly of RNA-seq data in a sheep model for delayed bone healing.

Background: The sheep is an important model organism for many types of medically relevant research, but molecular genetic experiments in the sheep have been limited by the lack of knowledge about ovine gene sequences.

Results: Prior to our study, mRNA sequences for only 1,556 partial or complete ovine genes were publicly available. Therefore, we developed a composite de novo transcriptome assembly method for next-generation sequence data to combine known ovine mRNA and EST sequences, mRNA sequences from mouse and cow, and sequences assembled de novo from short read RNA-Seq data into a composite reference transcriptome, and identified transcripts from over 12 thousand previously undescribed ovine genes.

Genetic causes of nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip with or without an associated cleft palate (NSCLP) is one of the most common birth defects affecting 135,000 babies worldwide each year. It causes severe facial dysmorphism and treatment requires a multifaceted team approach. While treatment modalities have improved, the costs to families and the health care resources are still enormous.