Risk of posterior capsular rupture during phacoemulsification cataract surgery in eyes with previous intravitreal antivascular endothelial growth factor injections

Purpose: To investigate if previous intravitreal anti vascular endothelial growth factor (VEGF) injections are a predictor for posterior capsule rupture (PCR) during phacoemulsification cataract surgery. Setting: National Health Service: Whipps Cross University Hospital Eye Treatment Centre. District General, London, United Kingdom Design: Single centre, retrospective, electronic medical record (EMR) database study with univariate analysis. Methods: EMR (Medisoft) was used to extract data for eyes undergoing phacoemulsification surgery between 01.08.16 to 01.01.18. Patient demographics, indication for intravitreal therapy, treatment type, number of previous intravitreal injections (IVI), diabetic status, surgeon grade and operative complications were included as variables for analysis. Results: Data was available for 4047 cataract operations. Of these, 108 had undergone previous anti-VEGF IVI treatment. Three eyes were noted to have pre-operative PC trauma and were excluded from the final analysis. The logistic regression analysis after exclusion of the eyes with pre-existing damage to the PC confirmed that prior anti-VEGF IVI treatment was associated with an increased risk of PCR when compared to the non IVI group (9.26% vs 1.88%, p<0.0001). There is a dose dependent relationship between the number of anti-VEGF injections and the likelihood of PCR. Conclusions: Previous intravitreal anti-VEGF injections are significantly correlated with an increased risk of surgical PCR despite the absence of visible structural damage to the PC pre-operatively

The ALMA Frontier Fields Survey

CONTEXT: Dusty star-forming galaxies are among the most prodigious systems at high redshift (z > 1), characterized by high star-formation rates and huge dust reservoirs. The bright end of this population has been well characterized in recent years, but considerable uncertainties remain for fainter dusty star-forming galaxies, which are responsible for the bulk of star formation at high redshift and thus play a key role in galaxy growth and evolution. AIMS: In this first paper of our series, we describe our methods for finding high redshift faint dusty galaxies using millimeter observations with ALMA. METHODS: We obtained ALMA 1.1 mm mosaic images for three strong-lensing galaxy clusters from the Frontier Fields Survey, which constitute some of the best studied gravitational lenses to date. The ≈2′ × 2′ mosaics overlap with the deep HST WFC3/IR footprints and encompass the high magnification regions of each cluster for maximum intrinsic source sensitivity. The combination of extremely high ALMA sensitivity and the magnification power of these clusters allows us to systematically probe the sub-mJy population of dusty star-forming galaxies over a large surveyed area. RESULTS: We present a description of the reduction and analysis of the ALMA continuum observations for the galaxy clusters Abell 2744 (z = 0.308), MACS J0416.1-2403 (z = 0.396) and MACS J1149.5+2223 (z = 0.543), for which we reach observed rms sensitivities of 55, 59 and 71 μJy beam-1 respectively. We detect 12 dusty star-forming galaxies at S/N ≥ 5.0 across the three clusters, all of them presenting coincidence with near-infrared detected counterparts in the HST images. None of the sources fall close to the lensing caustics, thus they are not strongly lensed. The observed 1.1 mm flux densities for the total sample of galaxies range from 0.41 to 2.82 mJy, with observed effective radii spanning ≲0.̋05 to 0.̋37 ± 0.̋21 . The lensing-corrected sizes of the detected sources appear to be in the same range as those measured in brighter samples, albeit with possibly larger dispersion

An In Silico Modeling Approach to Understanding the Dynamics of Sarcoidosis

BACKGROUND: Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis. METHODOLOGY/RESULTS: Based upon the literature, we developed a computational model of known interactions between essential immune cells (antigen-presenting macrophages, effector and regulatory T cells) and cytokine mediators (IL-2, TNFα, IFNγ) of granulomatous inflammation during sarcoidosis. The dynamics of these interactions are described by a set of ordinary differential equations. The model predicts bistable switching behavior which is consistent with normal (self-limited) and "sarcoidosis-like" (sustained) activation of the inflammatory components of the system following a single antigen challenge. By perturbing the influence of model components using inhibitors of the cytokine mediators, distinct clinically relevant disease phenotypes were represented. Finally, the model was shown to be useful for pre-clinical testing of therapies based upon molecular targets and dose-effect relationships. CONCLUSIONS/SIGNIFICANCE: Our work illustrates a dynamic computer simulation of granulomatous inflammation scenarios that is useful for the investigation of disease mechanisms and for pre-clinical therapeutic testing. In lieu of relevant in vitro or animal surrogates, our model may provide for the screening of potential therapies for specific sarcoidosis disease phenotypes in advance of expensive clinical trials

Characteristic Evolution and Matching

I review the development of numerical evolution codes for general relativity based upon the characteristic initial value problem. Progress in characteristic evolution is traced from the early stage of 1D feasibility studies to 2D axisymmetric codes that accurately simulate the oscillations and gravitational collapse of relativistic stars and to current 3D codes that provide pieces of a binary black hole spacetime. Cauchy codes have now been successful at simulating all aspects of the binary black hole problem inside an artificially constructed outer boundary. A prime application of characteristic evolution is to extend such simulations to null infinity where the waveform from the binary inspiral and merger can be unambiguously computed. This has now been accomplished by Cauchy-characteristic extraction, where data for the characteristic evolution is supplied by Cauchy data on an extraction worldtube inside the artificial outer boundary. The ultimate application of characteristic evolution is to eliminate the role of this outer boundary by constructing a global solution via Cauchy-characteristic matching. Progress in this direction is discussed.Comment: New version to appear in Living Reviews 2012. arXiv admin note: updated version of arXiv:gr-qc/050809

The ALMA Frontier Fields Survey. II. Multiwavelength Photometric analysis of 1.1 mm continuum sources in Abell 2744, MACSJ0416.1-2403 and MACSJ1149.5+2223

CONTEXT: The Hubble and Spitzer Space Telescope surveys of the Frontier Fields provide extremely deep images around six massive, strong-lensing clusters of galaxies. The ALMA Frontier Fields survey aims to cover the same fields at 1.1 mm, with maps reaching (unlensed) sensitivities of <70 μJy, in order to explore the properties of background dusty star-forming galaxies. AIMS: We report on the multi-wavelength photometric analysis of all 12 significantly detected (>5σ) sources in the first three Frontier Fields clusters observed by ALMA, based on data from Hubble and Spitzer, the Very Large Telescope and the Herschel Space Observatory. METHODS: We measure the total photometry in all available bands and determine the photometric redshifts and the physical properties of the counterparts via SED-fitting. In particular, we carefully estimate the far-infrared (FIR) photometry using 1.1 mm priors to limit the misidentification of blended FIR counterparts, which strongly affect some flux estimates in previous FIR catalogs. Due to the extremely red nature of these objects, we used a large range of parameters (e.g. 0.0 <Av< 20.0) and templates (including AGNs and ULIRGs models). RESULTS: We identify robust near-infrared (NIR) counterparts for all 11 sources with Ks detection, the majority of which are quite red, with eight having F814W − Ks ≳ 4 and five having F160W − [ 4.5 ] ≳ 3. From the FIR point of view, all our objects have zphot ~ 1–3, whereas based on the optical SED one object prefers a high-z solution (z ≥ 7). Five objects among our sample have spectroscopic redshifts from the GLASS survey for which we can reproduce their SEDs with existing templates. This verification confirms the validity of our photometric redshift methodology. The mean redshift of our sample is zphot = 1.99 ± 0.27. All 1.1 mm selected objects are massive (10.0 < log  [ M⋆(M⊙) ] < 11.5), with high star formation rates (⟨ log [ SFR(M⊙/ yr) ] ⟩ ≈ 1.6) and high dust contents (8.1 < log  [ Mdust(M⊙) ] < 8.8), consistent with previous ALMA surveys

Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy

c-Abl phosphorylation of ΔNp63α is critical for cell viability

The p53 family member p63 has been shown to be critical for growth, proliferation and chemosensitivity. Here we demonstrate that the c-Abl tyrosine kinase phosphorylates the widely expressed ΔNp63α isoform and identify multiple sites by mass spectrometry in vitro and in vivo. Phopshorylation by c-Abl results in greater protein stability of both ectopically expressed and endogenous ΔNp63α. c-Abl phosphorylation of ΔNp63α induces its binding to Yes-associated protein (YAP) and silencing of YAP by siRNA reduces the c-Abl-induced increase of ΔNp63α levels. We further show that cisplatin induces c-Abl phosphorylation of ΔNp63α and its binding to YAP. Overexpression of ΔNp63α, but not the c-Abl phosphosites mutant, protects cells from cisplatin treatment. Finally, we demonstrate the rescue of p63 siRNA-mediated loss of viability with p63siRNA insensitive construct of ΔNp63α but not the phosphosites mutant. These results demonstrate that c-Abl phosphorylation of ΔNp63α regulates its protein stability, by inducing binding of YAP, and is critical for cell viability

Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations

Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin’s chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68–0.86; rs1105879 OR = 0.77 95% CI = 0.69–0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk