Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.

BackgroundPatients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.MethodsTumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.ResultsThree of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted.ConclusionNGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors

Spin-phonon interaction in doped high-TC_C superconductors from density functional calculations

Effects of coupling between phonon distortions and stripe-like spin waves in the CuO plane of HgBa$_2$CuO$_4$ are studied by band calculations. Local exchange enhancements depend sensitively on the local structure around Cu sites. Interactions where spin waves have twice as long wave length as phonon waves can lead to a 'dip' in the density of states (DOS) below the Fermi energy, $E_F$. This type of interaction is compatible with several seemingly contradictory observations among high-$T_C$ cuprates, like the isotope effect, anti-ferromagnetic fluctuations, stripes and pseudogaps. It can also account for a large $T_C$.Comment: (5 pages, 2 figures

Stem Cells in Aggregate Form to Enhance Chondrogenesis in Hydrogels

There are a variety of exciting hydrogel technologies being explored for cartilage regenerative medicine. Our overall goal is to explore whether using stem cells in an aggregate form may be advantageous in these applications. 3D stem cell aggregates hold great promise as they may recapitulate the in vivo skeletal tissue condensation, a property that is not typically observed in 2D culture. We considered two different stem cell sources, human umbilical cord Wharton’s jelly cells (hWJCs, currently being used in clinical trials) and rat bone marrow-derived mesenchymal stem cells (rBMSCs). The objective of the current study was to compare the influence of cell phenotype, aggregate size, and aggregate number on chondrogenic differentiation in a generic hydrogel (agarose) platform. Despite being differing cell sources, both rBMSC and hWJC aggregates were consistent in outperforming cell suspension control groups in biosynthesis and chondrogenesis. Higher cell density impacted biosynthesis favorably, and the number of aggregates positively influenced chondrogenesis. Therefore, we recommend that investigators employing hydrogels consider using cells in an aggregate form for enhanced chondrogenic performance

GPU Concurrency: Weak Behaviours and Programming Assumptions

Concurrency is pervasive and perplexing, particularly on graphics processing units (GPUs). Current specifications of languages and hardware are inconclusive; thus programmers often rely on folklore assumptions when writing software. To remedy this state of affairs, we conducted a large empirical study of the concurrent behaviour of deployed GPUs. Armed with litmus tests (i.e. short concurrent programs), we questioned the assumptions in programming guides and vendor documentation about the guarantees provided by hardware. We developed a tool to generate thousands of litmus tests and run them under stressful workloads. We observed a litany of previously elusive weak behaviours, and exposed folklore beliefs about GPU programming---often supported by official tutorials---as false. As a way forward, we propose a model of Nvidia GPU hardware, which correctly models every behaviour witnessed in our experiments. The model is a variant of SPARC Relaxed Memory Order (RMO), structured following the GPU concurrency hierarchy

S and D Wave Mixing in High TcT_c Superconductors

For a tight binding model with nearest neighbour attraction and a small orthorhombic distortion, we find a phase diagram for the gap at zero temperature which includes three distinct regions as a function of filling. In the first, the gap is a mixture of mainly $d$-wave with a smaller extended $s$-wave part. This is followed by a region in which there is a rapid increase in the $s$-wave part accompanied by a rapid increase in relative phase between $s$ and $d$ from 0 to $\pi$. Finally, there is a region of dominant $s$ with a mixture of $d$ and zero phase. In the mixed region with a finite phase, the $s$-wave part of the gap can show a sudden increase with decreasing temperature accompanied with a rapid increase in phase which shows many of the characteristics measured in the angular resolved photoemission experiments of Ma {\em et al.} in $\rm Bi_2Sr_2CaCu_2O_8$Comment: 12 pages, RevTeX 3.0, 3 PostScript figures uuencoded and compresse

Synchrotron radiography and x-ray topography studies of hexagonal habitus SiC bulk crystals

Phase-sensitive synchrotron radiation (SR) radiography was combined with x-ray diffraction topography to study structural defects of SiC crystals. The particular bulk SiC crystals examined had a low micropipe density and a hexagonal habitus composed of prismatic, pyramidal, and basal faces well developed. X-ray diffraction topography images of the sliced (0001) wafers, which were formed due to the complex lattice distortions associated with defective boundaries, demonstrated the existence of two-dimensional defective boundaries in the radial direction, normal to the (0001) planes. In particular, those parallel to the 〈1120〉 directions extended rather far from the seed. On the other hand, by phase-sensitive SR radiography the effect of micropipe collection was detected. Micropipes grouped mostly in the vicinities of the defective boundaries but rarely appeared between groups. Some general remarks about possible reasons for the development of such peculiar defect structures were mad

Exposing errors related to weak memory in GPU applications

© 2016 ACM.We present the systematic design of a testing environment that uses stressing and fuzzing to reveal errors in GPU applications that arise due to weak memory effects. We evaluate our approach on seven GPUS spanning three NVIDIA architectures, across ten CUDA applications that use fine-grained concurrency. Our results show that applications that rarely or never exhibit errors related to weak memory when executed natively can readily exhibit these errors when executed in our testing environment. Our testing environment also provides a means to help identify the root causes of such errors, and automatically suggests how to insert fences that harden an application against weak memory bugs. To understand the cost of GPU fences, we benchmark applications with fences provided by the hardening strategy as well as a more conservative, sound fencing strategy

Critical Properties in Photoemmision Spectra for One Dimensional Orbitally Degenerate Mott Insulator

Critical properties in photoemission spectra for the one-dimensional Mott insulator with orbital degeneracy are studied by exploiting the integrable {\it t-J} model, which is a supersymmetric generalization of the SU($n$) degenerate spin model. We discuss the critical properties for the holon dispersion as well as the spinon dispersions, by applying the conformal field theory analysis to the exact finite-size energy spectrum. We study the effect of orbital-splitting on the spectra by evaluating the momentum-dependent critical exponents.Comment: 8 pages, REVTeX, 2 figures(available upon request), accepted for publication in JPSJ 68 (1999) No.