The HI - Star Formation Connection: Open Questions

We show data from the Survey of Ionization in Neutral Gas Galaxies (SINGG) and Survey of Ultraviolet emission in Neutral Gas Galaxies (SUNGG) which survey the star formation properties of HI selected galaxies as traced by H-alpha and ultraviolet emission, respectively. The correlations found demonstrate a strong relationship between the neutral ISM, young massive stars, and the evolved stellar populations. For example the correlation between R band surface brightness and the HI cycling time is tighter than the Kennicutt-Schmidt Star Formation Law. Other scaling relations from SINGG give strong direct confirmation of the downsizing scenario: low mass galaxies are more gaseous and less evolved into stars than high mass galaxies. There are strong variations in the H-alpha to UV flux ratios within and between galaxies. The only plausible explanations for this result are that either the escape fraction of ionizing photons or the upper end of the IMF varies with galaxy mass. We argue for the latter interpretation, although either result has major implications for astrophysics. A detailed dissection of the massive star content in the extended HI disk of NGC2915 provides a consistent picture of continuing star formation with a truncated or steep IMF, while other GALEX results indicate that star formation edges seen in Halpha are not always apparent in the UV. These and other recent results settle some old questions but open many new questions about star formation and its relation to the ISM.Comment: To appear in AIP Conference Proceedings, "The Evolution of Galaxies through the Neutral Hydrogen Window", Feb 1-3 2008, Arecibo, Puerto Rico, eds. R. Minchin & E. Momjian. 7 page

GPGPU computation and visualization of three-dimensional cellular automata

This paper presents a general-purpose simulation approach integrating a set of technological developments and algorithmic methods in cellular automata (CA) domain. The approach provides a general-purpose computing on graphics processor units (GPGPU) implementation for computing and multiple rendering of any direct-neighbor three-dimensional (3D) CA. The major contributions of this paper are: the CA processing and the visualization of large 3D matrices computed in real time; the proposal of an original method to encode and transmit large CA functions to the graphics processor units in real time; and clarification of the notion of top-down and bottom-up approaches to CA that non-CA experts often confuse. Additionally a practical technique to simplify the finding of CA functions is implemented using a 3D symmetric configuration on an interactive user interface with simultaneous inside and surface visualizations. The interactive user interface allows for testing the system with different project ideas and serves as a test bed for performance evaluation. To illustrate the flexibility of the proposed method, visual outputs from diverse areas are demonstrated. Computational performance data are also provided to demonstrate the method’s efficiency. Results indicate that when large matrices are processed, computations using GPU are two to three hundred times faster than the identical algorithms using CPU

Nucleotide polymorphism and copy number variant detection using exome capture and next-generation sequencing in the polyploid grass \u3ci\u3ePanicum virgatum\u3c/i\u3e

Switchgrass (Panicum virgatum) is a polyploid, outcrossing grass species native to North America and has recently been recognized as a potential biofuel feedstock crop. Significant phenotypic variation including ploidy is present across the two primary ecotypes of switchgrass, referred to as upland and lowland switchgrass. The tetraploid switchgrass genome is approximately 1400 Mbp, split between two subgenomes, with significant repetitive sequence content limiting the efficiency of re-sequencing approaches for determining genome diversity. To characterize genetic diversity in upland and lowland switchgrass as a first step in linking genotype to phenotype, we designed an exome capture probe set based on transcript assemblies that represent approximately 50 Mb of annotated switchgrass exome sequences. We then evaluated and optimized the probe set using solid phase comparative genome hybridization and liquid phase exome capture followed by next-generation sequencing. Using the optimized probe set, we assessed variation in the exomes of eight switchgrass genotypes representing tetraploid lowland and octoploid upland cultivars to benchmark our exome capture probe set design. We identified ample variation in the switchgrass genome including 1 395 501 single nucleotide polymorphisms (SNPs), 8173 putative copy number variants and 3336 presence/absence variants. While the majority of the SNPs (84%) detected was bi-allelic, a substantial number was tri-allelic with limited occurrence of tetra-allelic polymorphisms consistent with the heterozygous and polyploid nature of the switchgrass genome. Collectively, these data demonstrate the efficacy of exome capture for discovery of genome variation in a polyploid species with a large, repetitive and heterozygous genome

Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme

Background: LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals. Notably, cancer cells can support unusual L1 retrotransposition and L1-associated sequence rearrangement mechanisms following DNA damage. Recent reports suggest that L1 is mobile in epithelial tumours and neural cells but, paradoxically, not in brain cancers. Results: Here, using retrotransposon capture sequencing (RC-seq), we surveyed L1 mutations in 14 tumours classified as glioblastoma multiforme (GBM) or as a lower grade glioma. In four GBM tumours, we characterised one probable endonuclease-independent L1 insertion, two L1-associated rearrangements and one likely Alu-Alu recombination event adjacent to an L1. These mutations included PCR validated intronic events in MeCP2 and EGFR. Despite sequencing L1 integration sites at up to 250× depth by RC-seq, we found no tumour-specific, endonuclease-dependent L1 insertions. Whole genome sequencing analysis of the tumours carrying the MeCP2 and EGFR L1 mutations also revealed no endonuclease-dependent L1 insertions. In a complementary in vitro assay, wild-type and endonuclease mutant L1 reporter constructs each mobilised very inefficiently in four cultured GBM cell lines. Conclusions: These experiments altogether highlight the consistent absence of canonical L1 retrotransposition in GBM tumours and cultured cell lines, as well as atypical L1-associated sequence rearrangements following DNA damage in vivo

In vivo measurement of skin surface strain and sub-surface layer deformation induced by natural tissue stretching.

Stratum corneum and epidermal layers change in terms of thickness and roughness with gender, age and anatomical site. Knowledge of the mechanical and tribological properties of skin associated with these structural changes are needed to aid in the design of exoskeletons, prostheses, orthotics, body mounted sensors used for kinematics measurements and in optimum use of wearable on-body devices. In this case study, optical coherence tomography (OCT) and digital image correlation (DIC) were combined to determine skin surface strain and sub-surface deformation behaviour of the volar forearm due to natural tissue stretching. The thickness of the epidermis together with geometry changes of the dermal-epidermal junction boundary were calculated during change in the arm angle, from flexion (90°) to full extension (180°). This posture change caused an increase in skin surface Lagrange strain, typically by 25% which induced considerable morphological changes in the upper skin layers evidenced by reduction of epidermal layer thickness (20%), flattening of the dermal-epidermal junction undulation (45-50% reduction of flatness being expressed as Ra and Rz roughness profile height change) and reduction of skin surface roughness Ra and Rz (40-50%). The newly developed method, DIC combined with OCT imaging, is a powerful, fast and non-invasive methodology to study structural skin changes in real time and the tissue response provoked by mechanical loading or stretching

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure. © 2014 European Association of Urology

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide

There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers

Accumulation of copy number alterations and clinical progression across advanced prostate cancer

Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10−6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes