Search results for " Mutation"

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch r…

2022

Abstract Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This com…

Project introduction. Atelier 1 - Land trouvé. Methodologies and strategies

2016

The Po river has an inflection near the centre of Piacenza. In the riverbed (Maggi islets) and on the two shores, there are peculiar places with historical-naturalistic values (wetland areas near to Trebbia river; farmhouses; Genio Pontieri barrack; old industrial traces; canals; rural fields). You can imagine the curve of the river like an expanded strip that extends and compresses itself into a sinusoidal mud. Railway and roads cross the river defining, together with the adjacent railway bridge, the gateway to the city but also the connection with a large scale of the territory. Between local and global levels, pre-existing elements are reference of distances and heights in a changing sys…

A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report

2012

Abstract Background Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan. Case presentation We des…

Quantitative Prediction of the Landscape of T Cell Epitope Immunogenicity in Sequence Space

2019

Immunodominant T cell epitopes preferentially targeted in multiple individuals are the critical element of successful vaccines and targeted immunotherapies. However, the underlying principles of this "convergence" of adaptive immunity among different individuals remain poorly understood. To quantitatively describe epitope immunogenicity, here we propose a supervised machine learning framework generating probabilistic estimates of immunogenicity, termed "immunogenicity scores," based on the numerical features computed through sequence-based simulation approximating the molecular scanning process of peptides presented onto major histocompatibility complex (MHC) by the human T cell receptor (T…

Molecular epidemiology of HIV-1 subtype B in the Basque Country (Spain)

2012

The goal of this work was to study the HIV-1 subtype B epidemic in the Basque Country (Spain). For this, we used HIV samples submitted for genotypic testing of anti-retroviral resistance mutations from 2005 until 2008. Consequently, 2115 HIV-1 sequences comprising protease and retrotranscriptase (PR/RT) coding regions were analyzed. HIV transmission groups were identified by phylogenetic analysis. The 10 largest such groups were subsequently subjected to Bayesian phylogenetic and coalescent reconstructions, using a relaxed molecular clock model. The results obtained show that these groups have been long-standing: most of them were originated in the late 70s or early 80s, and none after the …

Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets

2020

Autosomal recessive mutations in genes required for cytotoxicity are causative of a life-threatening, early-onset hyperinflammatory syndrome termed familial hemophagocytic lymphohistiocytosis (FHL). Mutations in UNC13D cause FHL type 3. UNC13D encodes Munc13-4, a member of the Unc13 protein family which control SNARE complex formation and vesicle fusion. We have previously identified FHL3-associated mutations in the first intron of UNC13D which control transcription from an alternative transcriptional start site. Using isoform specific antibodies, we demonstrate that this alternative Munc13-4 isoform with a unique N-terminus is preferentially expressed in human lymphocytes and platelets, as…

Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy

2017

Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape…

Diagnosis of exon 12‐positive polycythemia vera rescued by NGS

2020

Abstract A JAK2V617F‐negative polycythemia associated with low serum epo needs to be tested for an exon 12 JAK2 mutation. When negative, due to potential serious complications in PV, a next generation sequencing is necessary to rule out false negative results.

Mutant HRAS as novel target for MEK and mTOR inhibitors.

2015

HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an imp…

2020

X-chromosomal retinitis pigmentosa (RP) frequently is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. We evaluated the potential of PTC124 (Ataluren, TranslamaTM) treatment to promote ribosomal read-through of premature termination codons (PTC) in RPGR. Expression constructs in HEK293T cells showed that the efficacy of read-through reagents is higher for UGA than UAA PTCs. We identified the novel hemizygous nonsense mutation c.1154T > A, p.Leu385* (NM_000328.3) causing a UAA PTC in RPGR and generated patient-derived fibroblasts. Immunocytochemistry of serum-starved control fibroblasts showed the RPGR protein in a dot-like expression pattern along the primary…