Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies.

Oligomannose-type glycans on HIV-1 gp120 form a patch that is targeted by several broadly neutralizing antibodies (bnAbs) and that therefore is of interest to vaccine design. However, attempts to elicit similar oligomannose-specific bnAbs by immunizing with oligomannosidic glycoconjugates have only been modestly successful so far. A common assumption is that eliciting oligomannose-specific bnAbs is hindered by B cell tolerance, resulting from the presented oligomannosides being sensed as self molecules. Here, we present data, along with existing scientific evidence, supporting an additional, or perhaps alternate, explanation: serum mannosidase trimming of the presented oligomannosides in vivo. Mannosidase trimming lessens the likelihood of eliciting antibodies with capacity to bind full-sized oligomannose, which typifies the binding mode of existing bnAbs to the oligomannose patch. The rapidity of the observed trimming suggests the need for immunization strategies and/or synthetic glycosides that readily avoid or resist mannosidase trimming upon immunization and can overcome possible tolerance restrictions.

Improved limb salvage for patients with vascular disease and tissue loss associated with new model of provision targeted at the diabetic foot.

AIMS: The establishment of a vascular surgeon-led emergency diabetic foot service in 2006 has evolved to provide lower limb wound care for patients with and without diabetes. We aimed to determine whether the service was associated with sustained, improved limb salvage rates for the whole population, analyse key aspects of service provision and compare outcomes against published studies. METHODS: The vascular unit serves a largely rural population of approximately 240,000. Data was collected prospectively on lower limb amputations, arterial and minor surgical interventions from 2006 to 2015, and retrospectively retrieved for 2004-2005, prior to service commencement. Data was also collected on referral patterns, volume of patient admissions and attendances, and delays. Lower limb amputation rates were compared against published data and analysis of admission trends and delays employed non-parametric tests. RESULTS: Age/gender adjusted major lower limb amputations for the populations with and without diabetes were 412/100,000 in 2004 and 15/100,000 in 2005 respectively. Following service introduction, major amputations reduced and since 2012 have been sustained at between 15-44/100,000 and 1-3/100,000 for patients with and without diabetes respectively, comparing favourably with published data. Vascular interventions have remained static, but referrals of patients directly to the service and numbers of minor procedures have increased. CONCLUSIONS: The sustained decreases in all major lower limb amputations that have coincided with the development of a core team approach to providing rapid access and comprehensive care for patients with emergency diabetic foot problems may indicate that this service design benefits patients with and without diabetes.