A prospective multicenter evaluation of initial treatment choice in metastatic renal cell carcinoma prior to the immunotherapy era: The MaRCC Registry experience

INTRODUCTION: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS AND MATERIALS: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. RESULTS: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. CONCLUSION: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints

The Virasoro vertex algebra and factorization algebras on Riemann surfaces

This paper focuses on the connection of holomorphic two-dimensional factorization algebras and vertex algebras which has been made precise in the forthcoming book of Costello-Gwilliam. We provide a construction of the Virasoro vertex algebra starting from a local Lie algebra on the complex plane. Moreover, we discuss an extension of this factorization algebra to a factorization algebra on the category of Riemann surfaces. The factorization homology of this factorization algebra is computed as are the correlation functions. We provide an example of how the Virasoro factorization algebra implements conformal symmetry of the beta-gamma system using the method of effective BV quantization

Extubation Failure after Neonatal Cardiac Surgery: A Multicenter Analysis

Objectives To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. Study design We conducted a prospective observational study of neonates ≤30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. Results We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). Conclusions In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication

The Grizzly, November 19, 2015

On the Way to the Final Four • Watson Finalists Prepare for Next Steps • U-Imagine Center Offers First Course • Committee Searches for Violence Prevention Educator • International Perspective: Dealing With Graduation Concerns Abroad • Warming Up to the Challenge • Podcast Roars to Life • Preparing for Professional Life • Opinions: It\u27s On Us is Insufficient; Wellness Critics are Ill-Informed • New Era Begins for Women\u27s Basketball • Two Wrestlers Named Preseason All-Americans • Final Four Boundhttps://digitalcommons.ursinus.edu/grizzlynews/1678/thumbnail.jp

Metabolic flexibility as a major predictor of spatial distribution in microbial communities

A better understand the ecology of microbes and their role in the global ecosystem could be achieved if traditional ecological theories can be applied to microbes. In ecology organisms are defined as specialists or generalists according to the breadth of their niche. Spatial distribution is often used as a proxy measure of niche breadth; generalists have broad niches and a wide spatial distribution and specialists a narrow niche and spatial distribution. Previous studies suggest that microbial distribution patterns are contrary to this idea; a microbial generalist genus (Desulfobulbus) has a limited spatial distribution while a specialist genus (Methanosaeta) has a cosmopolitan distribution. Therefore, we hypothesise that this counter-intuitive distribution within generalist and specialist microbial genera is a common microbial characteristic. Using molecular fingerprinting the distribution of four microbial genera, two generalists, Desulfobulbus and the methanogenic archaea Methanosarcina, and two specialists, Methanosaeta and the sulfate-reducing bacteria Desulfobacter were analysed in sediment samples from along a UK estuary. Detected genotypes of both generalist genera showed a distinct spatial distribution, significantly correlated with geographic distance between sites. Genotypes of both specialist genera showed no significant differential spatial distribution. These data support the hypothesis that the spatial distribution of specialist and generalist microbes does not match that seen with specialist and generalist large organisms. It may be that generalist microbes, while having a wider potential niche, are constrained, possibly by intrageneric competition, to exploit only a small part of that potential niche while specialists, with far fewer constraints to their niche, are more capable of filling their potential niche more effectively, perhaps by avoiding intrageneric competition. We suggest that these counter-intuitive distribution patterns may be a common feature of microbes in general and represent a distinct microbial principle in ecology, which is a real challenge if we are to develop a truly inclusive ecology

Twisted characters and holomorphic symmetries

We consider holomorphic twists of arbitrary supersymmetric theories in four dimensions. Working in the BV formalism, we rederive classical results characterizing the holomorphic twist of chiral and vector supermultiplets, computing the twist explicitly as a family over the space of nilpotent supercharges in minimal supersymmetry. The BV formalism allows one to work with or without auxiliary fields, according to preference; for chiral superfields, we show that the result of the twist is an identical BV theory, the holomorphic $\beta\gamma$ system with superpotential, independent of whether or not auxiliary fields are included. We compute the character of local operators in this holomorphic theory, demonstrating agreement of the free local operators with the usual index of free fields. The local operators with superpotential are computed via a spectral sequence, and are shown to agree with functions on a formal mapping space into the derived critical locus of the superpotential. We consider the holomorphic theory on various geometries, including Hopf manifolds and products of arbitrary pairs of Riemann surfaces, and offer some general remarks on dimensional reductions of holomorphic theories along the $(n-1)$-sphere to topological quantum mechanics. We also study an infinite-dimensional enhancement of the flavor symmetry in this example, to a recently-studied central extension of the derived holomorphic functions with values in the original Lie algebra that generalizes the familiar Kac--Moody enhancement in two-dimensional chiral theories

The Lantern, 2014-2015

• The Retreat • Part of Eve\u27s Discussion • Buchanan • Hypotheticals • The Baby Hippo • Sertraline and Cheerios • Margins • Anatomy of Me • Orange • Ode to Mathematics • Garden Path • Periphery • 10n Power=Our Maybe Domains • Hillside • Baltimore//Analogues • Work is a Religion • At the Bridal Shower • November • Revisionist History • Cold Front • Lung (for D. Avitabile) • Tether • Hold Still • Reverb • An Almost English Major and His Daughter • Clocks • In the Kitchen on a Sunday Afternoon • Amy • Nine • Customary Thoughts • Showers • Te Encuentro • I Find You • Literary Analysis • The Diamond on My Face • Catherine • Hunsberger Woods, 11:42 on a School Night • Cabbage • After Class • For Chell • To Whom It May Concern • Contra • Shards • Smoke and Roses • Polaroid • Spring\u27s Debut • The Deadline • A Previous Life • Wet Canvas • Obsessions and Compulsions • For Xandra • The Seagulls of 17th Street • No Man\u27s Land • Summer Flowers • Float • Dana Reads • A Barcelona Moment • Business Meeting • Posted • Champagnehttps://digitalcommons.ursinus.edu/lantern/1181/thumbnail.jp

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer

Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia

Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl− secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl− secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl− currents which were inhibited by NPPB (calcium-activated Cl− channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl− secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl− currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl− secretion and enhanced ASL height in non-CF and CF bronchial epithelia