Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805

Purpose—Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Experimental Design—We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables. Results—High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021) and for patients treated with placebo (p = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). MVD was not associated with DFS (p = 1.00). On multivariable analysis, MVD remained independently associated with improved OS (p = 0.013). High MVD correlated with Fuhrman grade 1–2 (p \u3c 0.001), clear cell histology (p \u3c 0.001), and absence of necrosis (p \u3c 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions—High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials

Testing gravitational-wave searches with numerical relativity waveforms: Results from the first Numerical INJection Analysis (NINJA) project

The Numerical INJection Analysis (NINJA) project is a collaborative effort between members of the numerical relativity and gravitational-wave data analysis communities. The purpose of NINJA is to study the sensitivity of existing gravitational-wave search algorithms using numerically generated waveforms and to foster closer collaboration between the numerical relativity and data analysis communities. We describe the results of the first NINJA analysis which focused on gravitational waveforms from binary black hole coalescence. Ten numerical relativity groups contributed numerical data which were used to generate a set of gravitational-wave signals. These signals were injected into a simulated data set, designed to mimic the response of the Initial LIGO and Virgo gravitational-wave detectors. Nine groups analysed this data using search and parameter-estimation pipelines. Matched filter algorithms, un-modelled-burst searches and Bayesian parameter-estimation and model-selection algorithms were applied to the data. We report the efficiency of these search methods in detecting the numerical waveforms and measuring their parameters. We describe preliminary comparisons between the different search methods and suggest improvements for future NINJA analyses.Comment: 56 pages, 25 figures; various clarifications; accepted to CQ

Journal of Microelectronic Research - May 2003

https://scholarworks.rit.edu/meec_archive/1012/thumbnail.jp

Digits Lost or Gained? Evidence for Pedal Evolution in the Dwarf Salamander Complex (Eurycea, Plethodontidae)

Change in digit number, particularly digit loss, has occurred repeatedly over the evolutionary history of tetrapods. Although digit loss has been documented among distantly related species of salamanders, it is relatively uncommon in this amphibian order. For example, reduction from five to four toes appears to have evolved just three times in the morphologically and ecologically diverse family Plethodontidae. Here we report a molecular phylogenetic analysis for one of these four-toed lineages – the Eurycea quadridigitata complex (dwarf salamanders) – emphasizing relationships to other species in the genus. A multilocus phylogeny reveals that dwarf salamanders are paraphyletic with respect to a complex of five-toed, paedomorphic Eurycea from the Edwards Plateau in Texas. We use this phylogeny to examine evolution of digit number within the dwarf−Edwards Plateau clade, testing contrasting hypotheses of digit loss (parallelism among dwarf salamanders) versus digit gain (re-evolution in the Edwards Plateau complex). Bayes factors analysis provides statistical support for a five-toed common ancestor at the dwarf-Edwards node, favoring, slightly, the parallelism hypothesis for digit loss. More importantly, our phylogenetic results pinpoint a rare event in the pedal evolution of plethodontid salamanders

Erratum: “Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data” (2019, ApJ, 879, 10)

Due to an error at the publisher, in the published article the number of pulsars presented in the paper is incorrect in multiple places throughout the text. Specifically, "222" pulsars should be "221." Additionally, the number of pulsars for which we have EM observations that fully overlap with O1 and O2 changes from "168" to "167." Elsewhere, in the machine-readable table of Table 1 and in Table 2, the row corresponding to pulsar J0952-0607 should be excised as well. Finally, in the caption for Table 2 the number of pulsars changes from "188" to "187.

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

AlgT (sigma^22) controls alginate production and tolerance to environmental stress in Pseudomonas syringae

Pseudomonas aeruginosa and the phytopathogen P. syringae produce the exopolysaccharide alginate, which is a copolymer of D-mannuronic and L-guluronic acids. One of the key regulatory genes controlling alginate biosynthesis in P. aeruginosa is algT, which encodes the alternate sigma factor, s22. In the present study, the algT gene product from P. syringae pv. syringae showed 90% amino acid identity with its P. aeruginosa counterpart, and sequence analysis of the region flanking algT in P. syringae revealed the presence of nadB, mucA, and mucB in an arrangement virtually identical to that of P. aeruginosa. An algT mutant of P. syringae was defective in alginate production but could be complemented with wild-type algT from P. syringae or P. aeruginosa when expressed in trans. The algT mutant also displayed increased sensitivity to heat, paraquat, and hydrogen peroxide (H2O2); the latter two compounds are known to generate reactive oxygen intermediates. Signals for activation of algT gene expression in P. syringae were investigated with an algTPeer reviewedEntomology and Plant Patholog