Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course

Background The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production. Case presentation We describe two siblings with severe familial forms of juvenile arthritis in which whole-exome-sequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delC¸. p.(T276fs*2) in FAMIN. Conclusions The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. Materials and methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Results: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. Conclusion: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.Key Objective: High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1). Knowledge Generated: We found that ALK amplification or clonal mutation was associated with inferior prognosis in patients with HR-NB and both are independent prognostic variables on multivariate analysis. To our knowledge, this is the first study to report the highly prognostic significance of ALK amplification in HR-NB. Relevance: As ALK can be targeted therapeutically, this study convincingly argues for the introduction of ALK inhibitors for upfront management of patients with HR-NB with ALK aberrations. Importantly, the prognostic significance of ALK alterations included a subgroup of trial patients treated with the current standard of care for HR-NB including anti-GD2 immunotherapy.info:eu-repo/semantics/publishedVersio

Software Engineering Methods for Designing Parallel and Distributed Applications from Sequential Programs in Scientific Computing

Although quite a few large scale applications have been ported to multiprocessors in recent years, no framework has yet been set up for the process of designing parallel and distributed applications from sequential programs that takes into account the specific needs of large scale scientific applications where programs have complex, irregular control flow and data structures. This paper proposes such a framework and reports on its application in the portable parallelization of the industrial Computational Fluid Dynamics (CFD) software package TfC (TASCflow for CAD) within the scope of an interdisciplinary research project. 1

Parallel and Distributed Implementation of Large Scale Industrial Applications

In many branches of industry, computer simulation has become an indispensable design tool that replaces a great deal of experiments in product design and thus reduces costs and time to market. However, simulation requires large amounts of computational resources. Parallel and distributed computing is a way to provide the required compute power especially to small and medium size companies or research facilities who cannot afford access to supercomputers. Interdisciplinary collaboration is required to port large scale industrial applications to parallel and distributed platforms efficiently. We report on results achieved in such a joint project of two medium size companies and two academic research groups. In a well-defined software engineering process, we have parallelized a state of the art CFD simulation package for execution on a wide range of hardware platforms based on PVM and MPI. Test runs show very good performance and scalability. We have worked out an object oriented redesign..