Management of Bladder Cancer following Solid Organ Transplantation

Objective. Present our experience managing bladder cancer following liver and renal transplantation. Methods. Single institution retrospective review of patients diagnosed with bladder urothelial carcinoma (BUC) following solid organ transplantation between January 1992 and December 2007. Results. Of the 2,925 renal and 2,761 liver transplant recipients reviewed, we identified eleven patients (0.2%) following transplant diagnosed with BUC. Two patients with low grade T1 TCC were managed by TURBT. Three patients with CIS and one patient with T1 low grade BUC were treated by TURBT and adjuvant BCG. All four are alive and free of recurrence at a mean follow-up of 51 ± 22 months. One patient with T1 high grade BUC underwent radical cystectomy and remains disease free with a follow-up of 98 months. Muscle invasive TCC was diagnosed in four patients at a median of 3.6 years following transplantation. Two patients are recurrence free at 24 and 36 months following radical cystectomy. Urinary diversion and palliative XRT were performed in one patient with un-resectable disease. Conclusions. Bladder cancer is uncommon following renal and liver transplantation, but it can be managed successfully with local and/or extirpative therapy. The use of intravesical BCG is possible in select immunosuppressed patients

Observational Constraints on the Ages of Molecular Clouds and the Star-Formation Timescale: Ambipolar-Diffusion--Controlled or Turbulence-Induced Star Formation?

We revisit the problem of the star formation timescale and the ages of molecular clouds. The apparent overabundance of star-forming molecular clouds over clouds without active star formation has been thought to indicate that molecular clouds are "short-lived" and that star formation is "rapid". We show that this statistical argument lacks self-consistency and, even within the rapid star-formation scenario, implies cloud lifetimes of approximately 10 Myr. We discuss additional observational evidence from external galaxies that indicate lifetimes of molecular clouds and a timescale of star formation of approximately 10 Myr . These long cloud lifetimes in conjunction with the rapid (approximately 1 Myr) decay of supersonic turbulence present severe difficulties for the scenario of turbulence-controlled star formation. By contrast, we show that all 31 existing observations of objects for which the linewidth, the size, and the magnetic field strength have been reliably measured are in excellent quantitative agreement with the predictions of the ambipolar-diffusion theory. Within the ambipolar-diffusion-controlled star formation theory the linewidths may be attributed to large-scale non-radial cloud oscillations (essentially standing large-amplitude, long-wavelength Alfven waves), and the predicted relation between the linewidth, the size, and the magnetic field is a natural consequence of magnetic support of self-gravitating clouds.Comment: 7 pages, 2 figures, uses emulateapj; accepted for publication in Ap

The effect of magnetic fields on star cluster formation

We examine the effect of magnetic fields on star cluster formation by performing simulations following the self-gravitating collapse of a turbulent molecular cloud to form stars in ideal MHD. The collapse of the cloud is computed for global mass-to-flux ratios of infinity, 20, 10, 5 and 3, that is using both weak and strong magnetic fields. Whilst even at very low strengths the magnetic field is able to significantly influence the star formation process, for magnetic fields with plasma beta < 1 the results are substantially different to the hydrodynamic case. In these cases we find large-scale magnetically-supported voids imprinted in the cloud structure; anisotropic turbulent motions and column density structure aligned with the magnetic field lines, both of which have recently been observed in the Taurus molecular cloud. We also find strongly suppressed accretion in the magnetised runs, leading to up to a 75% reduction in the amount of mass converted into stars over the course of the calculations and a more quiescent mode of star formation. There is also some indication that the relative formation efficiency of brown dwarfs is lower in the strongly magnetised runs due to the reduction in the importance of protostellar ejections.Comment: 16 pages, 9 figures, 8 very pretty movies, MNRAS, accepted. Version with high-res figures + movies available from http://www.astro.ex.ac.uk/people/dprice/pubs/mcluster/index.htm

Statistical competencies for medical research learners: What is fundamental?

IntroductionIt is increasingly essential for medical researchers to be literate in statistics, but the requisite degree of literacy is not the same for every statistical competency in translational research. Statistical competency can range from 'fundamental' (necessary for all) to 'specialized' (necessary for only some). In this study, we determine the degree to which each competency is fundamental or specialized.MethodsWe surveyed members of 4 professional organizations, targeting doctorally trained biostatisticians and epidemiologists who taught statistics to medical research learners in the past 5 years. Respondents rated 24 educational competencies on a 5-point Likert scale anchored by 'fundamental' and 'specialized.'ResultsThere were 112 responses. Nineteen of 24 competencies were fundamental. The competencies considered most fundamental were assessing sources of bias and variation (95%), recognizing one's own limits with regard to statistics (93%), identifying the strengths, and limitations of study designs (93%). The least endorsed items were meta-analysis (34%) and stopping rules (18%).ConclusionWe have identified the statistical competencies needed by all medical researchers. These competencies should be considered when designing statistical curricula for medical researchers and should inform which topics are taught in graduate programs and evidence-based medicine courses where learners need to read and understand the medical research literature

A mutation-specific, single-arm, phase 2 study of dovitinib in patients with advanced malignancies.

BACKGROUND: Receptor tyrosine kinases (RTKs) play key roles in tumorigenesis. The multi-RTK inhibitor dovitinib has demonstrated promising antitumor activity in multiple cancers. PATIENTS AND METHODS: In this phase 2, open-label, single-arm study, patients with advanced malignancies with RTK-pathway genetic aberrations whose disease progressed on/following standard treatment received dovitinib (500 mg/day; 5-days-on/2-days-off). The primary endpoint was clinical benefit rate (CBR; complete response, partial response [PR], or stable disease [SD] for ≥ 16 weeks). RESULTS: Of 80 patients enrolled, common tumors included gastrointestinal stromal tumors (GIST; 20.0%), colorectal cancer (CRC; 18.8%), and ovarian cancer (10.0%). Patients were heavily pretreated (median prior lines = 4; 67.5% had ≥ 3 prior lines). Genetic aberrations included CONCLUSIONS: In this heterogeneous patient population, the safety profile was acceptable for dovitinib therapy. A subset of patients with RTK pathway-activated tumors experienced clinical benefit. However, the primary endpoint was not met, suggesting further refinement of predictive biomarkers is required

Design, assessment, and in vivo evaluation of a computational model illustrating the role of CAV1 in CD4+ T-lymphocytes

Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4+ T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4+ immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4+ T-cell model was constructed and simulated under CAV1+/+, CAV1+/−, and CAV1−/− conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4+ T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4+ T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia

Development and Testing of Cool-Season Grass Species, Varieties and Hybrids for Biomass Feedstock Production in Western North America

Breeding of native cool-season grasses has the potential to improve forage production and expand the range of bioenergy feedstocks throughout western North America. Basin wildrye (Leymus cinereus) and creeping wildrye (Leymus triticoides) rank among the tallest and most rhizomatous grasses of this region, respectively. The objectives of this study were to develop interspecific creeping wildrye (CWR) × basin wildrye (BWR) hybrids and evaluate their biomass yield relative to tetraploid ‘Trailhead’, octoploid ‘Magnar’ and interploidy-hybrid ‘Continental’ BWR cultivars in comparison with other perennial grasses across diverse single-harvest dryland range sites and a two-harvest irrigated production system. Two half-sib hybrid populations were produced by harvesting seed from the tetraploid self-incompatible Acc:641.T CWR genet, which was clonally propagated by rhizomes into isolated hybridization blocks with two tetraploid BWR pollen parents: Acc:636 and ‘Trailhead’. Full-sib hybrid seed was also produced from a controlled cross of tetraploid ‘Rio’ CWR and ‘Trailhead’ BWR plants. In space-planted range plots, the ‘Rio’ CWR × ‘Trailhead’ BWR and Acc:641.T CWR × Acc:636 BWR hybrids displayed high-parent heterosis with 75% and 36% yield advantages, respectively, but the Acc:641.T CWR × ‘Trailhead’ BWR hybrid yielded significantly less than its BWR high-parent in this evaluation. Half-sib CWR × BWR hybrids of Acc:636 and ‘Trailhead’ both yielded as good as or better than available BWR cultivars, with yields similar to switchgrass (Panicum virgatum), in the irrigated sward plots. These results elucidate opportunity to harness genetic variation among native grass species for the development of forage and bioenergy feedstocks in western North America

Committing to ecological restoration: Efforts around the globe need legal and policy clarification

At the September 2014 United Nations Climate Summit, governments rallied around an international agreement—the New York Declaration on Forests—that underscored restoration of degraded ecosystems as an auspicious solution to climate change. Ethiopia committed to restore more than one-sixth of its land. Uganda, the Democratic Republic of Congo, Guatemala, and Colombia pledged to restore huge areas within their borders. In total, parties committed to restore a staggering 350 million hectares by 2030.Fil: Suding, Kathering. State University Of Colorado-boulder; Estados UnidosFil: Higgs, Eric. University Of Victoria; CanadáFil: Palmer, Margaret. University of Maryland; Estados UnidosFil: Callicott, J. Baird. University Of North Texas; Estados UnidosFil: Anderson, Christopher Brian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Baker, Matthew. University Of Maryland; Estados UnidosFil: Gutrich, John J.. Southern Oregon University; Estados UnidosFil: Hondula, Kelly L.. University of Maryland; Estados UnidosFil: Lafevor, Matthew C.. University of Maryland; Estados UnidosFil: Larson, Brendon M. H.. University Of Waterloo; CanadáFil: Randall, Alan. Ohio State University; Estados Unidos. University Of Sidney; AustraliaFil: Ruhl, J. B.. Vanderbilt University; Estados UnidosFil: Schwartz, Katrina Z. S.. Woodrow Wilson International Center for Scholars; Estados Unido

CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation