Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.

Background: Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.

'Difficult to diagnose' desmoid tumours: a potential role for CTNNB1 mutational analysis.

Aims: The utility of CTNNB1 (encoding β-catenin) genotyping for diagnosing sporadic desmoid tumours (DT) when traditional clinicopathological parameters were inconclusive was evaluated.

Methods And Results: Cases included were: (i) new primary lesions where initial DT diagnosis was inconclusive; and (ii) possible recurrent DT versus scar. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained via needle biopsy or a surgical excision (57 specimens) as part of initial assessment.

Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target.

Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased β-catenin signalling.

Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma.

Purpose: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition.

Experimental Design: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR).

High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma.

Well-differentiated liposarcoma (WDLS) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma (DDLS) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component. Cytogenetically, WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes, including MDM2, TSPAN31, CDK4, and others mainly derived from chromosome bands 12q13-15. However, the 12q13-15 amplicon is large and discontinuous.

Expression of 'drugable' tyrosine kinase receptors in malignant peripheral nerve sheath tumour: potential molecular therapeutic targets for a chemoresistant cancer.

Aims: Novel therapeutic approaches for the treatment of malignant peripheral nerve sheath tumors (MPNSTs) are critically needed. Tyrosine kinase receptors are commonly deregulated in cancer and constitute attractive targets. We assessed the protein expression level of a panel of ‘drugable’ TKRs in a relatively large cohort of human plexiform and MPNST surgical specimens.

Autistic regression in a child with Silver-Russell syndrome and maternal UPD 7.

Silver-Russell syndrome (SRS) is a heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features. In 5-10% of SRS patients, a maternal uniparental disomy of chromosome 7 (UPD7) can be detected. We describe a 4.

LQT5 masquerading as LQT2: a dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current.

Aims: KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of-function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of I(Ks) current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype.

Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.

The relative frequency of the different forms of SCID may vary in different countries. The most frequent form in Israel is the autosomal-recessive T-B- SCID or Omenn syndrome while X-linked SCID is rare. We report our immunological and genetic analyses in multicentre study of patients presenting with either T-B- SCID or Omenn syndrome.

Diagnosis, management, and outcome of patients with dedifferentiated liposarcoma systemic metastasis.

Background: Dedifferentiated liposarcomas (DDLPSs) result in worse patient outcomes than well-differentiated tumors despite shared molecular derangements. Prevalence and pattern of DDLPS systemic metastases have not been extensively reported; information regarding diagnosis, treatment, and outcomes of metastatic DDLPS patients is limited. Our study seeks to address this knowledge gap.

Pleomorphic liposarcoma: clinical observations and molecular variables.

Background: Pleomorphic liposarcoma (PLS) is a rare high-grade sarcoma that has lipoblastic differentiation. In this study, the authors evaluated PLS natural history, patient outcomes, and commonly deregulated protein biomarkers.

Methods: Medical records from patients (n = 155) who had PLS from 1993 to 2010 were reviewed.

Fetal optic nerve sheath measurement as a non-invasive tool for assessment of increased intracranial pressure.

Objectives: To describe the sonographic technique for assessment of the fetal optic nerve sheath and to report on three fetuses with intracranial lesions and enlarged optic nerve sheath diameter (ONSD) compared with normal controls matched for gestational age (GA).

Methods: In this cross-sectional study ONSD was measured sonographically in three fetuses (aged 23, 24 and 35 gestational weeks) with intracranial findings associated with increased intracranial pressure (ICP; dural thrombosis and intracranial tumors) as well as 42 healthy controls matched for GA ± 1 week (aged 22-25 and 34-36 weeks). For fetal eye assessment, transabdominal and transvaginal routes and high-resolution transducers were used for optimal visualization depending on fetal position.

Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors.

Purpose: MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed.

Experimental Design: Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses.

Dermatofibrosarcoma protuberans with unusual sarcomatous transformation: a series of 4 cases with molecular confirmation.

Dermatofibrosarcoma protuberans (DFSP) is a superficial sarcoma of intermediate malignancy usually composed of monotonous short spindle cells with storiform architecture. The tumor cells are diffusely reactive for CD34 and characterized by a translocation involving chromosomes 17 and 22 or a supernumerary ring chromosome that results in the fusion of exon 2 of platelet-derived growth factor beta (PDGFβ; 22q13) to various exons of collagen type 1 alpha 1 (COL1A1; 17q22). In some tumors, fibrosarcomatous transformation can occur and is characterized by a monotonous spindle cell proliferation arranged in fascicles or a herringbone-type pattern.

The effects of anodal stimulation on electrocardiogram, left ventricular dyssynchrony, and acute haemodynamics in patients with biventricular pacemakers.

Aims: Anodal stimulation (ANS) is a recognized phenomenon among patients with cardiac resynchronization therapy (CRT); this is noted during left ventricular (LV) pacing by the LV tip to right ventricular (RV) ring configuration. Its incidence varies according to the implanted hardware. We aim at evaluating the incidence of ANS and its acute haemodynamic effects among CRT patients.

Israeli children with autism spectrum disorder are not macrocephalic.

The prevalence of macrocephaly in autism spectrum disorder is reported to be much higher than in the general population, 12% to 37%. Progressive macrocephaly is even considered a warning sign for the development of autism. We evaluated the prevalence of an abnormal head circumference in children with autism in Israel and compared it with the head circumferences of children with developmental language disorder and children with normal development.

A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum.

The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity.

Does normal fetal brain ultrasound predict normal neurodevelopmental outcome in congenital cytomegalovirus infection?

Objective: We evaluated the neuropsychological outcome of children with proven congenital cytomegalovirus (CMV) infection and normal consecutive fetal neurosonographic examinations.

Methods: We retrospectively reviewed laboratory and imaging findings of children with congenital CMV infection. The study group consisted of children with a positive polymerase chain reaction (PCR) in amniotic fluid and virus isolation in urine in the first week of life, and normal fetal ultrasonographic (US) examination findings, including a normal multiplanar neurosonographic evaluation.

Revealing retroperitoneal liposarcoma morphology using optical coherence tomography.

A new approach to distinguish normal fat, well-differentiated (WD), and dedifferentiated liposarcoma (LS) tumors is demonstrated, based on the use of optical coherence tomography (OCT). OCT images show the same structures seen with conventional histological methods. Our visual grading analysis is supported by numerical analysis of observed structures for normal fat and WDLS samples.

Epithelioid sarcoma and unclassified sarcoma with epithelioid features: clinicopathological variables, molecular markers, and a new experimental model.

Background: Epithelioid sarcoma (ES) and unclassified sarcoma with epithelioid features (USEF) are clinically and therapeutically unresolved. We compared ES and USEF patients' clinical behavior, treatment, outcome, and molecular marker expression. Furthermore, preclinical ES study models were developed to enable comprehensive benchside investigations.

Prenatal brain disruption in molybdenum cofactor deficiency.

Molybdenum cofactor deficiency is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures and be mistaken for ischemic encephalopathy. We describe a patient whose prenatal sonography at 35 weeks' gestation revealed diffuse brain damage with multiple subcortical cavities, ventriculomegaly, dysgenesis of the corpus callosum, and a hypoplastic cerebellum with an enlarged cisterna magna. Magnetic resonance imaging (MRI) later revealed brain atrophy, and multicystic encephalomalacia with hypoplastic vermis and cerebellum.

TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.

Background: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.

Autophagy blockade enhances HDAC inhibitors' pro-apoptotic effects: potential implications for the treatment of a therapeutic-resistant malignancy.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, highly metastatic, poor prognosis tumors for which effective therapeutic strategies are currently lacking. We summarize recent work focusing on preclinical evaluation of histone deacetylase inhibitors (HDACis) for the treatment of MPNST. HDACis are a novel drug class with anti-cancer therapeutic promise.

Juvenile Leigh syndrome, optic atrophy, ataxia, dystonia, and epilepsy due to T14487C mutation in the mtDNA-ND6 gene: a mitochondrial syndrome presenting from birth to adolescence.

An increasing number of reports describe mutations in mitochondrial DNA coding regions, especially in mitochondrial DNA- encoded nicotinamide adenine dinucleotide dehydrogenase subunit genes of the respiratory chain complex I, as causing early-onset Leigh syndrome. The authors report the molecular findings in a 24-year-old patient with juvenile-onset Leigh syndrome presenting with optic atrophy, ataxia dystonia, and epilepsy. A brain magnetic resonance imaging revealed bilateral basal ganglia and thalamic hypointensities, and a magnetic resonance spectroscopy revealed an increased lactate peak.