Long-Term (10-Year) Gastrointestinal and Genitourinary Toxicity after Treatment with External Beam Radiotherapy, Radical Prostatectomy, or Brachytherapy for Prostate Cancer

Objective.To examine gastrointestinal (GI) and genitourinary (GU) toxicity profiles of patients treated in 1999 with external beam radiotherapy (RT), prostate interstitial brachytherapy (PI) or radical prostatectomy (RP). Methods. TThe records of 525 patients treated in 1999 were reviewed to evaluate toxicity. Late GI and GU morbidities were graded according to the RTOG late morbidity criteria. Other factors examined were patient age, BMI, smoking history, and medical co-morbidities. Due to the low event rate for late GU and GI toxicities, a competing risk regression (CRR) analysis was done with death as the competing event. Results. Median follow-up time was 8.5 years. On CRR univariate analysis, only the presence of DM was significantly associated with GU toxicity grade >2 (P = 0.43, HR 2.35, 95% Cl = 1.03–5.39). On univariate analysis, RT and DM were significantly associated with late GI toxicity. On multivariable analysis, both variables remained significant (RT: P = 0.038, HR = 4.71, CI = 1.09–20.3; DM: P = 0.008, HR = 3.81, 95% Cl = 1.42–10.2). Conclusions. Late effects occur with all treatment modalities. The presence of DM at the time of treatment was significantly associated with worse late GI and GU toxicity. RT was significantly associated with worse late GI toxicity compared to PI and RP

UV-dropout Galaxies in the GOODS-South Field from WFC3 Early Release Science Observations

We combine new high sensitivity ultraviolet (UV) imaging from the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope (HST) with existing deep HST/Advanced Camera for Surveys (ACS) optical images from the Great Observatories Origins Deep Survey (GOODS) program to identify UV-dropouts, which are Lyman break galaxy (LBG) candidates at z~1-3. These new HST/WFC3 observations were taken over 50 sq.arcmin in the GOODS-South field as a part of the Early Release Science program. The uniqueness of these new UV data is that they are observed in 3 UV/optical (WFC3 UVIS) channel filters (F225W, F275W and F336W), which allows us to identify three different sets of UV-dropout samples. We apply Lyman break dropout selection criteria to identify F225W-, F275W- and F336W-dropouts, which are z~1.7, 2.1 and 2.7 LBG candidates, respectively. Our results are as follows: (1) these WFC3 UVIS filters are very reliable in selecting LBGs with z~2.0, which helps to reduce the gap between the well studied z~>3 and z~0 regimes, (2) the combined number counts agrees very well with the observed change in the surface densities as a function of redshift when compared with the higher redshift LBG samples; and (3) the best-fit Schechter function parameters from the rest-frame UV luminosity functions at three different redshifts fit very well with the evolutionary trend of the characteristic absolute magnitude, and the faint-end slope, as a function of redshift. This is the first study to illustrate the usefulness of the WFC3 UVIS channel observations to select z<3 LBGs. The addition of the new WFC3 on the HST has made it possible to uniformly select LBGs from z~1 to z~9, and significantly enhance our understanding of these galaxies using HST sensitivity and resolution.Comment: Accepted for publication in ApJ (24 pages, 7 figures

Stellar Populations of Lyman Break Galaxies at z=1-3 in the HST/WFC3 Early Release Science Observations

We analyze the spectral energy distributions (SEDs) of Lyman break galaxies (LBGs) at z=1-3 selected using the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) UVIS channel filters. These HST/WFC3 observations cover about 50 sq. arcmin in the GOODS-South field as a part of the WFC3 Early Release Science program. These LBGs at z=1-3 are selected using dropout selection criteria similar to high redshift LBGs. The deep multi-band photometry in this field is used to identify best-fit SED models, from which we infer the following results: (1) the photometric redshift estimate of these dropout selected LBGs is accurate to within few percent; (2) the UV spectral slope (beta) is redder than at high redshift (z>3), where LBGs are less dusty; (3) on average, LBGs at z=1-3 are massive, dustier and more highly star-forming, compared to LBGs at higher redshifts with similar luminosities (0.1L*<~L<~2.5L*), though their median values are similar within 1-sigma uncertainties. This could imply that identical dropout selection technique, at all redshifts, find physically similar galaxies; and (4) stellar masses of these LBGs are directly proportional to their UV luminosities with a logarithmic slope of ~0.46, and star-formation rates are proportional to their stellar masses with a logarithmic slope of ~0.90. These relations hold true --- within luminosities probed in this study --- for LBGs from z~1.5 to 5. The star-forming galaxies selected using other color-based techniques show similar correlations at z~2, but to avoid any selection biases, and for direct comparison with LBGs at z>3, a true Lyman break selection at z~2 is essential. The future HST UV surveys, both wider and deeper, covering a large luminosity range are important to better understand LBG properties, and their evolution.Comment: Accepted for publication in ApJ (29 pages, 9 figures

Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome

This work was funded by grants number 18237 and 20089 from Arthritis Research UK (http://www.arthritisresearchuk.org) to MB and the William Harvey Research Foundation. EC was recipient of short-term travel fellowships from EMBO (ASTF 318-2010) and EFIS-IL

Hepatic histological findings in suspected drug‐induced liver injury: Systematic evaluation and clinical associations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102713/1/hep26709.pd

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women

Background Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. Objective We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. Study Design Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days’ and 22 weeks 6 days’ gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. Results Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. Conclusion In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies

Synthesizing habitat connectivity analyses of a globally important human-dominated tiger-conservation landscape

As ecological data and associated analyses become more widely available, synthesizing results for effective communication with stakeholders is essential. In the case of wildlife corridors, managers in human-dominated landscapes need to identify both the locations of corridors and multiple stakeholders for effective oversight. We synthesized five independent studies of tiger (Panthera tigris) connectivity in central India, a global priority landscape for tiger conservation, to quantify agreement on landscape permeability for tiger movement and potential movement pathways. We used the latter analysis to identify connectivity areas on which studies agreed and stakeholders associated with these areas to determine relevant participants in corridor management. Three or more of the five studies’ resistance layers agreed in 63% of the study area. Areas in which all studies agree on resistance were of primarily low (66%, e.g., forest) and high (24%, e.g., urban) resistance. Agreement was lower in intermediate resistance areas (e.g., agriculture). Despite these differences, the studies largely agreed on areas with high levels of potential movement: >40% of high average (top 20%) current-flow pixels were also in the top 20% of current-flow agreement pixels (measured by low variation), indicating consensus connectivity areas (CCAs) as conservation priorities. Roughly 70% of the CCAs fell within village administrative boundaries, and 100% overlapped forest department management boundaries, suggesting that people live and use forests within these priority areas. Over 16% of total CCAs’ area was within 1 km of linear infrastructure (437 road, 170 railway, 179 transmission line, and 339 canal crossings; 105 mines within 1 km of CCAs). In 2019, 78% of forest land diversions for infrastructure and mining in Madhya Pradesh (which comprises most of the study region) took place in districts with CCAs. Acute competition for land in this landscape with globally important wildlife corridors calls for an effective comanagement strategy involving local communities, forest departments, and infrastructure planners

VEGF and Angiopoietin-1 Exert Opposing Effects on Cell Junctions by Regulating the Rho GEF Syx

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser806, which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx−/− mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function

Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib

<p>Abstract</p> <p>Background:</p> <p>Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; <it>TNFRSF6</it>), a cell surface receptor that regulates apoptosis and its signaling apparatus.</p> <p>Methods:</p> <p>Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas-mediated programmed cell death.</p> <p>Results:</p> <p>We found an ALPS patient that harbored a heterozygous A530G mutation in the FasL gene that replaced Arg with Gly at position 156 in the protein's extracellular Fas-binding region. This produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis.</p> <p>Conclusion:</p> <p>Our data explain how a naturally occurring heterozygous human FasL mutation can dominantly interfere with normal FasL apoptotic function and lead to an ALPS phenotype, designated Type Ib.</p

The potential of urinary metabolites for diagnosing multiple sclerosis

A definitive diagnostic test for multiple sclerosis (MS) does not exist; instead physicians use a combination of medical history, magnetic resonance imaging, and cerebrospinal fluid analysis (CSF). Significant effort has been employed to identify biomarkers from CSF to facilitate MS diagnosis; however none of the proposed biomarkers have been successful to date. Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, non-invasive, inexpensive, and efficient diagnostic tool for various human diseases. Nevertheless, urinary metabolites have not been extensively explored as a source of biomarkers for MS. Instead, we demonstrate that urinary metabolites have significant promise for monitoring disease-progression, and response to treatment in MS patients. NMR analysis of urine permitted the identification of metabolites that differentiate experimental autoimmune encephalomyelitis (EAE)-mice (prototypic disease model for MS) from healthy and MS drug-treated EAE mice