3,541 research outputs found
A Kriging and stochastic collocation ensemble for uncertainty quantification in engineering applications
FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome
<p>Abstract</p> <p>Background</p> <p>Ichthyosis Prematurity Syndrome (IPS) is an autosomal recessive disorder characterized by premature birth, non-scaly ichthyosis and atopic manifestations. The disease was recently shown to be caused by mutations in the gene encoding the fatty acid transport protein 4 (FATP4) and a specific reduction in the incorporation of very long chain fatty acids (VLCFA) into cellular lipids.</p> <p>Findings</p> <p>We screened probands from five families segregating IPS for mutations in the <it>FATP4 </it>gene. Four probands were compound heterozygous for four different mutations of which three are novel. Four patients were heterozygous and one patient homozygous for the previously reported non-sense mutation p.C168X (c.504c > a). All patients had clinical characteristics of IPS and a similar clinical course.</p> <p>Conclusions</p> <p>Missense mutations and non-sense mutations in <it>FATP4 </it>are associated with similar clinical features suggesting that missense mutations have a severe impact on FATP4 function. The results broaden the mutational spectrum in <it>FATP4 </it>associated with IPS for molecular diagnosis of and further functional analysis of FATP4.</p
Human DNA polymerase Ξ² polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity
DNA polymerase Ξ² (Pol Ξ²) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol Ξ² variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol Ξ² and proliferating cell nuclear antigen (PCNA). These defects impair the DNA repair capacity of Pol Ξ² in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol Ξ² in pol Ξ²β/β mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol Ξ²β/β MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers
Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase Ξ²
Background: Altered expression of DNA polymerase Ξ² (Pol Ξ²) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol Ξ² over-expression has not yet been evaluated in a mouse model. Methodology/Principal Findings: We have recently developed a novel transgenic mouse model that over-expresses Pol Ξ². These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner's gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol Ξ² over-expression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol Ξ² expression. We observed elevated expression of Pol Ξ² in stomach adenomas and thyroid follicular carcinomas, but reduced Pol Ξ² expression in esophageal adenocarcinomas and squamous carcinomas. Conclusions/Significance: These data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation
Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable Ξ²-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the β€3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue
The feasibility of gene therapy in the treatment of head and neck cancer
Standard approach to the treatment of head and neck cancer include surgery, chemotherapy, and radiation. More recently, dramatic increases in our knowledge of the molecular and genetic basis of cancer combined with advances in technology have resulted in novel molecular therapies for this disease. In particular, gene therapy, which involves the transfer of genetic material to cells to produce a therapeutic effect, has become a promising approach. Clinical trials concerning gene therapy strategies in head and neck cancer as well as combination of these strategies with chemotherapy and radiation therapy will be discussed
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