Physiological integration of coral colonies is correlated with bleaching resistance

Inter-module physiological integration of colonial organisms can facilitate colony-wide coordinated responses to stimuli that strengthen colony fitness and stress resistance. In scleractinian corals, whose colonial integration ranges from isolated polyps to a seamless continuum of polyp structures and functions, this coordination improves responses to injury, predation, disease, and stress and may be one of the indications of an evolutionary origin of Symbiodinium symbiosis. However, observations of species-specific coral bleaching patterns suggest that highly integrated coral colonies may be more susceptible to thermal stress, and support the hypothesis that communication pathways between highly integrated polyps facilitate the dissemination of toxic byproducts created during the bleaching response. Here we reassess this hypothesis by parameterizing an integration index using 7 skeletal features that have been historically employed to infer physiological integration. We examine the relationship between this index and bleaching response across a phylogeny of 88 diverse coral species. Correcting for phylogenetic relationships among species in the analyses reveals significant patterns among species characters that could otherwise be obscured in simple cross-species comparisons using standard statistics, whose assumptions of independence are violated by the shared evolutionary history among species. Similar to the observed benefits of in creased coloniality for other types of stressors, the results indicate a significantly reduced bleaching response among coral species with highly integrated colonies

Reading handwritten digits: a ZIP code recognition system

A neural network algorithm-based system that reads handwritten ZIP codes appearing on real US mail is described. The system uses a recognition-based segmenter, that is a hybrid of connected-components analysis (CCA), vertical cuts, and a neural network recognizer. Connected components that are single digits are handled by CCA. CCs that are combined or dissected digits are handled by the vertical-cut segmenter. The four main stages of processing are preprocessing, in which noise is removed and the digits are deslanted, CCA segmentation and recognition, vertical-cut-point estimation and segmentation, and directly lookup. The system was trained and tested on approximately 10000 images, five- and nine-digit ZIP code fields taken from real mail

Oncological outcomes of visibly complete transurethral resection prior to neoadjuvant chemotherapy for bladder cancer

ABSTRACT Purpose: To evaluate the potential oncologic benefit of a visibly complete transurethral resection of a bladder tumor (TURBT) prior to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Materials and Methods: We identified patients who received NAC and RC between 2011-2021. Records were reviewed to assess TURBT completeness. The primary outcome was pathologic downstaging (<ypT2N0), with complete pathologic response (ypT0N0) and survival as secondary endpoints. Logistic regression and Cox proportional hazards models were utilized. Results: We identified 153 patients, including 116 (76%) with a complete TURBT. Sixty-four (42%) achieved <ypT2N0 and 43 (28%) achieved ypT0N0. When comparing those with and without a complete TURBT, there was no significant difference in the proportion with <ypT2N0 (43% vs 38%, P=0.57) or ypT0N0 (28% vs 27%, P=0.87). After median follow-up of 3.6 years (IQR 1.5-5.1), 86 patients died, 37 died from bladder cancer, and 61 had recurrence. We did not observe a statistically significant association of complete TURBT with cancer-specific or recurrence-free survival (p≥0.20), although the hazard of death from any cause was significantly higher among those with incomplete TURBT even after adjusting for ECOG and pathologic T stage, HR 1.77 (95% CI 1.04-3.00, P=.034). Conclusions: A visibly complete TURBT was not associated with pathologic downstaging, cancer-specific or recurrence-free survival following NAC and RC. These data do not support the need for repeat TURBT to achieve a visibly complete resection if NAC and RC are planned

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK (grant number: C347/A18077). Support was also provided by an Experimental Cancer Medicine Centre grant (no grant number) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) (grant numbers: A46/CCR - CCR4057 & CCR4058).This is the accepted manuscript of a paper published in Clinical Cancer Research, February 15, 2015 21; 739, doi: 10.1158/1078-0432.CCR-14-190

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers.

PURPOSE: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. EXPERIMENTAL DESIGN: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. RESULTS: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. CONCLUSIONS: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).This study was supported by Merck & Co., Inc. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research U.K. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research), the National Institute for Health Research (NIHR) Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research), the NIHR Clinical Research Facility (to the Royal Marsden NHS Foundation Trust) and the Cancer Research UK and EPSRC Cancer Imaging Centre. T.A. Yap is the recipient of the 2011 Rebecca and Nathan Milikowsky – PCF Young Investigator Award and is supported by the NIHR. M.O. Leach is an NIHR Senior Investigator.This is the accepted manuscript. The final version is available from AACR at http://clincancerres.aacrjournals.org/content/early/2014/09/19/1078-0432.CCR-14-0868

Prevalence of Propionibacterium acnes in Intervertebral Discs of Patients Undergoing Lumbar Microdiscectomy: A Prospective Cross-Sectional Study

Background The relationship between intervertebral disc degeneration and chronic infection by Propionibacterium acnes is controversial with contradictory evidence available in the literature. Previous studies investigating these relationships were under-powered and fraught with methodical differences;moreover, they have not taken into consideration P. acnes' ability to form biofilms or attempted to quantitate the bioburden with regard to determining bacterial counts/genome equivalents as criteria to differentiate true infection from contamination. The aim of this prospective cross-sectional study was to determine the prevalence of P. acnes in patients undergoing lumbar disc microdiscectomy. Methods and Findings The sample consisted of 290 adult patients undergoing lumbar microdiscectomy for symptomatic lumbar disc herniation. An intraoperative biopsy and pre-operative clinical data were taken in all cases. One biopsy fragment was homogenized and used for quantitative anaerobic culture and a second was frozen and used for real-time PCR-based quantification of P. acnes genomes. P. acnes was identified in 115 cases (40%), coagulase-negative staphylococci in 31 cases (11%) and alpha-hemolytic streptococci in 8 cases (3%). P. acnes counts ranged from 100 to 9000 CFU/ml with a median of 400 CFU/ml. The prevalence of intervertebral discs with abundant P. acnes (>= 1x10(3) CFU/ml) was 11% (39 cases). There was significant correlation between the bacterial counts obtained by culture and the number of P. acnes genomes detected by real-time PCR (r = 0.4363, p<0.0001). Conclusions In a large series of patients, the prevalence of discs with abundant P. acnes was 11%. We believe, disc tissue homogenization releases P. acnes from the biofilm so that they can then potentially be cultured, reducing the rate of false-negative cultures. Further, quantification study revealing significant bioburden based on both culture and real-time PCR minimize the likelihood that observed findings are due to contamination and supports the hypothesis P. acnes acts as a pathogen in these cases of degenerative disc disease

Comparison of three methods for detection of gametocytes in Melanesian children treated for uncomplicated malaria

Background: Gametocytes are the transmission stages of Plasmodium parasites, the causative agents of malaria. As their density in the human host is typically low, they are often undetected by conventional light microscopy. Furthermore, application of RNA-based molecular detection methods for gametocyte detection remains challenging in remote field settings. In the present study, a detailed comparison of three methods, namely light microscopy, magnetic fractionation and reverse transcriptase polymerase chain reaction for detection of Plasmodium falciparum and Plasmodium vivax gametocytes was conducted.Methods. Peripheral blood samples from 70 children aged 0.5 to five years with uncomplicated malaria who were treated with either artemether-lumefantrine or artemisinin-naphthoquine were collected from two health facilities on the north coast of Papua New Guinea. The samples were taken prior to treatment (day 0) and at pre-specified intervals during follow-up. Gametocytes were measured in each sample by three methods: i) light microscopy (LM), ii) quantitative magnetic fractionation (MF) and, iii) reverse transcriptase PCR (RTPCR). Data were analysed using censored linear regression and Bland and Altman techniques.Results: MF and RTPCR were similarly sensitive and specific, and both were superior to LM. Overall, there were approximately 20% gametocyte-positive samples by LM, whereas gametocyte positivity by MF and RTPCR were both more than two-fold this level. In the subset of samples collected prior to treatment, 29% of children were positive by LM, and 85% were gametocyte positive by MF and RTPCR, respectively.Conclusions: The present study represents the first direct comparison of standard LM, MF and RTPCR for gametocyte detection in field isolates. It provides strong evidence that MF is superior to LM and can be used to detect gametocytaemic patients under field conditions with similar sensitivity and specificity as RTPCR

Genetic Diversity of Polymorphic Vaccine Candidate Antigens (Apical Membrane Antigen-1, Merozoite Surface Protein-3, and Erythrocyte Binding Antigen-175) in Plasmodium falciparum Isolates from Western and Central Africa

The malaria vaccine candidate antigens erythrocyte binding antigen 175 (EBA-175), merozoite surface protein 3 (MSP-3), and apical membrane antigen (AMA-1) from Plasmodium falciparum isolates from countries in central and west Africa were assessed for allelic diversity. Samples were collected on filter paper from 600 P. falciparum-infected symptomatic patients in Cameroon, Republic of Congo, Burkina Faso, Ghana, and Senegal and screened for class-specific amplification fragments. Genetic diversity, assessed by mean heterozygosity, was comparable among countries. We detected a clinical increase in eba 175 F-allele frequency from west to east across the study region. No statistical difference in msp-3 allele distribution between countries was observed. The ama-1 3D7 alleles were present at a lower frequency in central Africa than in West Africa. We also detected little to no genetic differentiation among sampling locations. This finding indicates that, at least at the level of resolution offered by restriction fragment length polymorphism analysis, these antigens showed remarkable genetic homogeneity throughout the region sampled, perhaps caused by balancing selection to maintain a diverse array of antigen haplotyes