Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity

Prevalence of Cam Morphology in Females with Femoroacetabular Impingement

Cam and pincer are two common morphologies responsible for femoroacetabular impingement. Previous literature has reported that cam deformity is predominantly a male morphology, while being significantly less common in females. The purpose of this study was to determine the prevalence of cam morphology in female subjects diagnosed with symptomatic FAI. All females presenting to the senior author’s clinic diagnosed with symptomatic FAI between December 2006 and Cam and pincer are two common morphologies responsible for femoroacetabular impingement. Previous literature has reported that cam deformity is predominantly a male morphology, while being significantly less common in females. Cam morphology is commonly assessed with the alpha angle, measured on radiographs. The purpose of this study was to determine the prevalence of cam morphology utilizing the alpha angle in female subjects diagnosed with symptomatic FAI. All females presenting to the senior author’s clinic diagnosed with symptomatic FAI between December 2006 and January 2013 were retrospectively reviewed. Alpha (α) angles were measured on AP (anteroposterior) and lateral (Dunn 90°, cross-table lateral, and/or frog-leg lateral) plain radiographs by two blinded physicians, and the largest measured angle was used. Using Gosvig et al.’s classification, alpha angle was characterized as (pathologic > 57°), borderline (51-56°), subtle (46-50°), very subtle (43-45°), or normal (≤42°). Three hundred and ninety-one patients (438 hips) were analyzed (age 36.2 ± 12.3 years). Among the hips included, 35.6% were normal, 14.6% pathologic, 15.1% borderline, 14.6% subtle, and 20.1% very subtle. There was no correlation between alpha angle and patient age (R = 0.17) or body mass index (BMI) (R = 0.05). The intraclass correlation coefficient (ICC) for α-angle measurements was 0.84. Sixty-four percent of females in this cohort had an alpha angle > 42°. Subtle cam deformity plays a significant role in the pathoanatomy of female patients with symptomatic FAI. As the majority of revision hip arthroscopies are performed due to incomplete cam correction, hip arthroscopists need to be cognizant of and potentially surgically address these subtle lesions

Impact of operative indication and surgical complexity on outcomes after thoracic endovascular aortic repair at National Surgical Quality Improvement Program Centers

IntroductionThoracic endovascular aortic repair (TEVAR) devices are increasingly being utilized to treat aortic pathologies outside of the original Food & Drug Administration (FDA) approval for nonruptured descending thoracic aorta aneurysms (DTAs). The objective of this study was to evaluate the outcomes of patients undergoing TEVAR, elucidating the role of surgical and pathologic variables on morbidity and mortality.MethodsNational Surgical Quality Improvement Program (NSQIP) data were reviewed for all patients undergoing endovascular thoracic aorta repair from 2005 to 2007. The patients' operative indication and surgical complexity were used to divide them into study and control populations. Comorbid profiles were assessed utilizing a modified Charlson Comorbidity Index (CCI). Thirty-day occurrences of mortality and serious adverse events (SAEs) were used as study endpoints. Univariate and multivariate models were created using demographic and clinical variables to assess for significant differences in endpoints (P ≤ .05).ResultsA total of 440 patients undergoing TEVAR were identified. When evaluating patients based on operative indication, the ruptured population had increased mortality and SAE rates compared to the nonruptured DTA population (22.6% vs 6.2%;P < .01 and 35.5% vs 9.1%;P < .01, respectively). Further analysis by surgical complexity revealed increased mortality and SAE rates when comparing the brachiocephalic aortic debranching population to the noncovered left subclavian artery population (23.1% vs 6.5%; P = .02 and 30.8% vs 9.1%; P < .01, respectively). Multivariate analysis demonstrated that operative indication was not a correlate of mortality or SAEs (odds ratio [OR], 0.95; P = .92 and OR, 1.42; P = .39, respectively); however, brachiocephalic aortic debranching exhibited a deleterious effect on mortality (OR, 8.75; P < .01) and SAE rate (OR, 6.67; P = .01).ConclusionThe operative indication for a TEVAR procedure was not found to be a predictor of poor patient outcome. Surgical complexity, specifically the need for brachiocephalic aortic debranching and aortoiliac conduit, was shown to influence the occurrence of SAEs in a multivariate model. Comparative data, such as these, illustrate real-world outcomes of patients undergoing TEVAR outside of the original FDA-approved indications. This information is of paramount importance to various stakeholders, including third-party payers, the device industry, regulatory agencies, surgeons, and their patients

Elective affinities of the Protestant ethic : Weber and the chemistry of capitalism

Peer reviewedPostprin

Chandra Observation of the Globular Cluster NGC 6440 and the Nature of Cluster X-ray Luminosity Functions

As part of our campaign to determine the nature of the various source populations of the low-luminosity globular cluster X-ray sources, we have obtained a Chandra X-ray Observatory ACIS-S3 image of the globular cluster NGC 6440. We detect 24 sources to a limiting luminosity of ~2 times 10^31 erg/s (0.5-2.5keV) inside the cluster's half-mass radius, all of which lie within ~2 core radii of the cluster center. We also find excess emission in and around the core which could be due to unresolved point sources. Based upon X-ray luminosities and colors, we conclude that there are 4-5 likely quiescent low-mass X-ray binaries and that most of the other sources are cataclysmic variables. We compare these results to Chandra results from other globular clusters and find the X-ray luminosity functions differ among the clusters.Comment: 9 pages, 4 figures, accepted by ApJ, minor changes, added table of clusters' physical parameter

The MeerKAT Fornax Survey

We present the science case and observations plan of the MeerKAT Fornax Survey, an HI and radio continuum survey of the Fornax galaxy cluster to be carried out with the SKA precursor MeerKAT. Fornax is the second most massive cluster within 20 Mpc and the largest nearby cluster in the southern hemisphere. Its low X-ray luminosity makes it representative of the environment where most galaxies live and where substantial galaxy evolution takes place. Fornax's ongoing growth makes it an excellent laboratory for studying the assembly of clusters, the physics of gas accretion and stripping in galaxies falling in the cluster, and the connection between these processes and the neutral medium in the cosmic web. We will observe a region of 12 deg$^2$ reaching a projected distance of 1.5 Mpc from the cluster centre. This will cover a wide range of environment density out to the outskirts of the cluster, where gas-rich in-falling groups are found. We will: study the HI morphology of resolved galaxies down to a column density of a few times 1e+19 cm$^{-2}$ at a resolution of 1 kpc; measure the slope of the HI mass function down to M(HI) 5e+5 M(sun); and attempt to detect HI in the cosmic web reaching a column density of 1e+18 cm$^{-2}$ at a resolution of 10 kpc.Comment: Proceedings of Science, "MeerKAT Science: On the Pathway to the SKA", Stellenbosch, 25-27 May 201

Characterization of time-resolved laser differential phase using 3D complementary cumulative distribution functions

An experimental method for characterizing the time-resolved phase noise of a fast switching tunable laser is discussed. The method experimentally determines a complementary cumulative distribution function of the laser's differential phase as a function of time after a switching event. A time resolved bit error rate of differential quadrature phase shift keying formatted data, calculated using the phase noise measurements, was fitted to an experimental time-resolved bit error rate measurement using a field programmable gate array, finding a good agreement between the time-resolved bit error rates

Roundtable on Epistemic Democracy and its Critics

On September 3, 2015, the Political Epistemology/Ideas, Knowledge, and Politics section of the American Political Science Association sponsored a roundtable on epistemic democracy as part of the APSA’s annual meetings. Chairing the roundtable was Daniel Viehoff, Department of Philosophy, University of Sheffield. The other participants were Jack Knight, Department of Political Science and the Law School, Duke University; Hélène Landemore, Department of Political Science, Yale University; and Nadia Urbinati, Department of Political Science, Columbia University. We thank the participants for permission to republish their remarks, which they edited for clarity after the fact

Quality of Dementia Care in the Community: Identifying Key Quality Assurance Components

Background: Primary care-based memory clinics (PCMCs) have been established in several jurisdictions to improve the care for persons with Alzheimer’s disease and related dementias. We sought to identify key quality indicators (QIs), quality improvement mechanisms, and potential barriers and facilitators to the establishment of a quality assurance framework for PCMCs. Methods: We employed a Delphi approach to obtain consensus from PCMC clinicians and specialist physicians on QIs and quality improvement mechanisms. Thirty-eight candidate QIs and 19 potential quality improvement mechanisms were presented to participants in two rounds of electronic Delphi surveys. Written comments were collected and descriptively analyzed. Results:The response rate for the first and second rounds were 21.3% (n = 179) and 12.8% (n = 88), respectively. The majority of respondents were physicians. Fourteen QIs remained after the consensus process. Ten quality improvement mechanisms were selected with those characterized by specialist integration, such as case discussions and mentorships, being ranked highly. Written comments revealed three major themes related to potential barriers and facilitators to quality assurance: 1) perceived importance, 2) collaboration and role clarity, and 3) implementation process.Conclusion:We successfully utilized a consultative process among primary and specialty providers to identify core QIs and quality improvement mechanisms for PCMCs. Identified quality improvement mechanisms highlight desire for multi-modal education. System integration and closer integration between PCMCs and specialists were emphasized as essential for the provision of high-quality dementia care in community settings.Alzheimer Society of Canada, Canadian Institutes of Health Research (CIHR), Schlegel-University of Waterloo-Research Institute for Agin