Yield of Surveillance Colonoscopy in Older Adults with a History of Polyps: A Systematic Review and Meta-Analysis.

BACKGROUND: The benefit of surveillance colonoscopy in older adults is not well described. AIMS: To quantify the detection of colorectal cancer (CRC) and advanced polyps during surveillance colonoscopy in older adults with a history of colon polyps. METHODS: We conducted a systematic review (MEDLINE, Cochrane Library, Web of Science, and Embase) for all published studies through May 2020 in adults age > 70 undergoing surveillance colonoscopy. The main outcome was CRC and advanced polyps detection. We performed meta-analysis to pool results by age (>70 vs. 50-70). RESULTS: The search identified 6239 studies, of which 569 underwent full-text review and 64 data abstraction, of which 19 were included. The risk of detecting CRC (N = 11) was higher in those >70 compared to 50-70 (risk ratio 1.5 (95% CI 1.1-2.2); risk difference 0.8% (95% CI -0.2%-1.8%)). Similarly, the risk of detecting advanced polyps (N = 8) was higher in those >70 compared to 50-70 (risk ratio 1.3 (95% CI 1.2-1.3), risk difference 2.7% (95% CI 1.3%-4.0%)). Most studies did not stratify results by baseline polyp risk. CONCLUSIONS: The detection of CRC and advanced polyps during surveillance colonoscopy in older individuals was higher than in younger controls; however, the absolute risk increase for both was small. These differences must be weighed against competing medical problems and limited life expectancy in older adults when making decisions about surveillance colonoscopy. More primary data on the risks of CRC and advanced polyps accounting for number of past colonoscopies, prior polyp risk, and duration of time since last polyp are needed.

Benefits of implementing student-led review and mock examinations in the medical undergraduate gross anatomy curriculum.

Anatomy consists of material that continually defines a student's undergraduate medical curriculum, and thus attaining a solid understanding of it is critical for academic success. Student exposure to anatomy prior to matriculation to the United States (US) medical school is highly variable, with some first introduced to the material in medical school. As a result, students without foundation in anatomy can struggle with adapting to the self-directed learning style that is required to excel with a prosection-based (i.e. hands-off analysis of a cadaver previously dissected by a professional) approach. In this study, second-year US medical students who have previously excelled in the first-year courses at the University of South Florida Morsani College of Medicine (in collaboration with faculty advisors) designed and offered a mock practical examination that mirrors the official practical exam specific to each course: a timed practical examination using dissected human cadavers and radiological imaging to assess anatomical knowledge, followed by a review session. Since the mock practical and review session was designed from a student's perspective, the material could be tailored to specifically address topics that students historically have struggled with. Students who participated in the mock practical and associated review sessions reported feeling more confident than their peers who did not participate. In addition, they significantly outperformed their peers on the official practical examination, independent of any demographic factors or educational background. This study demonstrates the benefits of incorporating peer-assisted learning (PAL) into the anatomical component of the medical school curriculum.

Saccharomyces genome database informs human biology.

The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is an expertly curated database of literature-derived functional information for the model organism budding yeast, Saccharomyces cerevisiae. SGD constantly strives to synergize new types of experimental data and bioinformatics predictions with existing data, and to organize them into a comprehensive and up-to-date information resource. The primary mission of SGD is to facilitate research into the biology of yeast and to provide this wealth of information to advance, in many ways, research on other organisms, even those as evolutionarily distant as humans. To build such a bridge between biological kingdoms, SGD is curating data regarding yeast-human complementation, in which a human gene can successfully replace the function of a yeast gene, and/or vice versa. These data are manually curated from published literature, made available for download, and incorporated into a variety of analysis tools provided by SGD.

The Saccharomyces Genome Database Variant Viewer.

The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer.

Childhood neglect predicts disorganization in schizophrenia through grey matter decrease in dorsolateral prefrontal cortex.

OBJECTIVE: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. METHOD: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. RESULTS: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. CONCLUSION: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC.

Future innovations in anti-platelet therapies.

Platelets have long been recognized to be of central importance in haemostasis, but their participation in pathological conditions such as thrombosis, atherosclerosis and inflammation is now also well established. The platelet has therefore become a key target in therapies to combat cardiovascular disease. Anti-platelet therapies are used widely, but current approaches lack efficacy in a proportion of patients, and are associated with side effects including problem bleeding. In the last decade, substantial progress has been made in understanding the regulation of platelet function, including the characterization of new ligands, platelet-specific receptors and cell signalling pathways. It is anticipated this progress will impact positively on the future innovations towards more effective and safer anti-platelet agents. In this review, the mechanisms of platelet regulation and current anti-platelet therapies are introduced, and strong, and some more speculative, potential candidate target molecules for future anti-platelet drug development are discussed.

An Introduction to the Saccharomyces Genome Database (SGD).

The Saccharomyces Genome Database (SGD) is a well-established, key resource for researchers studying Saccharomyces cerevisiae. In addition to updating and maintaining the official genomic sequence of this highly studied organism, SGD provides integrated data regarding gene functions and phenotypes, which are extracted from the published literature. The vast amount and variety of data housed in the database can prove challenging to navigate for the first-time user. Therefore, this chapter serves as an introduction describing how to search the database in order to discover new information. We introduce the different types of pages on the website, and describe how to manipulate the tables and diagrams therein to display, download, or analyze the data using various SGD tools.

Biomarkers' Responses to Reductive Dechlorination Rates and Oxygen Stress in Bioaugmentation Culture KB-1TM.

Using mRNA transcript levels for key functional enzymes as proxies for the organohalide respiration (OHR) rate, is a promising approach for monitoring bioremediation populations in situ at chlorinated solvent-contaminated field sites. However, to date, no correlations have been empirically derived for chlorinated solvent respiring, Dehalococcoides mccartyi (DMC) containing, bioaugmentation cultures. In the current study, genome-wide transcriptome and proteome data were first used to confirm the most highly expressed OHR-related enzymes in the bioaugmentation culture, KB-1TM, including several reductive dehalogenases (RDases) and a Ni-Fe hydrogenase, Hup. Different KB-1™ DMC strains could be resolved at the RNA and protein level through differences in the sequence of a common RDase (DET1545-like homologs) and differences in expression of their vinyl chloride-respiring RDases. The dominant strain expresses VcrA, whereas the minor strain utilizes BvcA. We then used quantitative reverse-transcriptase PCR (qRT-PCR) as a targeted approach for quantifying transcript copies in the KB-1TM consortium operated under a range of TCE respiration rates in continuously-fed, pseudo-steady-state reactors. These candidate biomarkers from KB-1TM demonstrated a variety of trends in terms of transcript abundance as a function of respiration rate over the range: 7.7 × 10-12 to 5.9 × 10-10 microelectron equivalents per cell per hour (µeeq/cell∙h). Power law trends were observed between the respiration rate and transcript abundance for the main DMC RDase (VcrA) and the hydrogenase HupL (R² = 0.83 and 0.88, respectively), but not transcripts for 16S rRNA or three other RDases examined: TceA, BvcA or the RDase DET1545 homologs in KB1TM. Overall, HupL transcripts appear to be the most robust activity biomarker across multiple DMC strains and in mixed communities including DMC co-cultures such as KB1TM. The addition of oxygen induced cell stress that caused respiration rates to decline immediately (>95% decline within one hour). Although transcript levels did decline, they did so more slowly than the respiration rate observed (transcript decay rates between 0.02 and 0.03 per hour). Data from strain-specific probes on the pangenome array strains suggest that a minor DMC strain in KB-1™ that harbors a bvcA homolog preferentially recovered following oxygen stress relative to the dominant, vcrA-containing strain.

The chaperone protein HSP47: a platelet collagen binding protein that contributes to thrombosis and hemostasis.

Essentials Heat shock protein 47 (HSP47), a collagen specific chaperone is present on the platelet surface. Collagen mediated platelet function was reduced following blockade or deletion of HSP47. GPVI receptor regulated signalling was reduced in HSP47 deficient platelets. Platelet HSP47 tethers to exposed collagen thus modulating thrombosis and hemostasis. SUMMARY: Objective Heat shock protein 47 (HSP47) is an intracellular chaperone protein that is vital for collagen biosynthesis in collagen secreting cells. This protein has also been shown to be present on the surface of platelets. Given the importance of collagen and its interactions with platelets in triggering hemostasis and thrombosis, in this study we sought to characterize the role of HSP47 in these cells. Methods and Results The deletion of HSP47 in mouse platelets or its inhibition in human platelets reduced their function in response to collagen and the GPVI agonist (CRP-XL), but responses to thrombin were unaltered. In the absence of functional HSP47, the interaction of collagen with platelets was reduced, and this was associated with reduced GPVI-collagen binding, signalling and platelet activation. Thrombus formation on collagen, under arterial flow conditions, was also decreased following the inhibition or deletion of HSP47, in the presence or absence of eptifibatide, consistent with a role for HSP47 in enhancing platelet adhesion to collagen. Platelet adhesion under flow to von Willebrand factor was unaltered following HSP47 inhibition. Laser-induced thrombosis in cremaster muscle arterioles was reduced and bleeding time was prolonged in HSP47-deficient mice or following inhibition of HSP47. Conclusions Our study demonstrates the presence of HSP47 on the platelet surface, where it interacts with collagen, stabilizes platelet adhesion and increases collagen-mediated signalling and therefore thrombus formation and hemostasis.

Updated regulation curation model at the Saccharomyces Genome Database.

Database URL: http://www.yeastgenome.org.

PPARγ agonists negatively regulate αIIbß3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity.

Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbß3. PPARγ agonists disrupt the interaction of Gα13 with integrin ß3. This is attributed to an upregulation of protein kinase A activity. SUMMARY: Background Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. Objectives Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbß3 mediated signaling. Both GPVI and GPCR signaling pathways lead to αIIbß3 activation, and signaling through αIIbß3 plays a critical role in platelet function and normal hemostasis. Methods The effects of PPARγ agonists on the regulation of αIIbß3 outside-in signaling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signaling components downstream of αIIbß3 activation were also determined following adhesion to fibrinogen by Western blotting. Results Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbß3 signaling, including the integrin ß3 subunit, Syk, PLCγ2, focal adhesion kinase (FAK) and Akt, was also observed as a result of reduced interaction of the integrin ß3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was because of an increase in PKA activity following treatment with PPARγ receptor agonists. Conclusions This study provides further evidence for antiplatelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbß3 outside-in signaling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation.

Curated protein information in the Saccharomyces genome database.

Due to recent advancements in the production of experimental proteomic data, the Saccharomyces genome database (SGD; www.yeastgenome.org ) has been expanding our protein curation activities to make new data types available to our users. Because of broad interest in post-translational modifications (PTM) and their importance to protein function and regulation, we have recently started incorporating expertly curated PTM information on individual protein pages. Here we also present the inclusion of new abundance and protein half-life data obtained from high-throughput proteome studies. These new data types have been included with the aim to facilitate cellular biology research. Database URL: : www.yeastgenome.org.

Outreach and online training services at the Saccharomyces Genome Database.

The Saccharomyces Genome Database (SGD; www.yeastgenome.org ), the primary genetics and genomics resource for the budding yeast S. cerevisiae , provides free public access to expertly curated information about the yeast genome and its gene products. As the central hub for the yeast research community, SGD engages in a variety of social outreach efforts to inform our users about new developments, promote collaboration, increase public awareness of the importance of yeast to biomedical research, and facilitate scientific discovery. Here we describe these various outreach methods, from networking at scientific conferences to the use of online media such as blog posts and webinars, and include our perspectives on the benefits provided by outreach activities for model organism databases. Database URL: http://www.yeastgenome.org.

Integration of new alternative reference strain genome sequences into the Saccharomyces genome database.

The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org/) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. To provide a wider scope of genetic and phenotypic variation in yeast, the genome sequences and their corresponding annotations from 11 alternative S. cerevisiae reference strains have been integrated into SGD. Genomic and protein sequence information for genes from these strains are now available on the Sequence and Protein tab of the corresponding Locus Summary pages. We illustrate how these genome sequences can be utilized to aid our understanding of strain-specific functional and phenotypic differences.Database URL: www.yeastgenome.org.

The regulation of integrin-linked kinase in human platelets: evidence for involvement in the regulation of integrin alpha 2 beta 1.

BACKGROUND: Activation of the platelet integrin alpha 2 beta 1 is closely regulated due to the high thrombogenicity of its ligand. As a beta 1 interacting kinase, ILK represents a candidate intracellular regulator of alpha 2 beta 1 in human platelets. OBJECTIVES: We investigated the regulation of ILK in human platelets and the role of ILK in regulating alpha 2 beta 1 activation in HEL cells, a megakaryocytic cell line. METHODS: An in-vitro kinase assay was used to determine the effect of platelet agonists on ILK kinase activity together with the contribution of PI3K and PKC on ILK activation. Interaction of ILK with beta 1-integrin subunits was investigated by coimmunoprecipitation and the role of ILK in regulating alpha 2 beta 1 function assessed by overexpression studies in HEL cells. RESULTS: We report that collagen and thrombin modulate ILK kinase activity in human platelets in an aggregation-independent manner. Furthermore, ILK activity is dually regulated by PI3K and PKC in thrombin-stimulated platelets and regulated by PI3K in collagen-stimulated cells. ILK associates with the beta 1-integrin subunits immunoprecipitated from platelet cell lysates, an association which increased upon collagen stimulation. Overexpression of ILK in HEL cells enhanced alpha 2 beta 1-mediated adhesion whereas overexpression of kinase-dead ILK reduced adhesion, indicating a role for this kinase in the positive regulation of alpha 2 beta 1. CONCLUSIONS: Our findings that ILK regulates alpha 2 beta 1 in HEL cells, is activated in platelets and associates with beta 1-integrins, raise the possibility that it may play a key role in adhesion events upon agonist stimulation of platelets.

Quercetin inhibits collagen-stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway.

BACKGROUND: The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven a successful approach to the prevention of thrombosis. A variety of molecules present in the diet have been shown to inhibit platelet activation, including the antioxidant quercetin. OBJECTIVES: In this report we investigate the molecular mechanisms through which quercetin inhibits collagen-stimulated platelet aggregation. METHODS: The effect of quercetin on platelet aggregation, intracellular calcium release, whole cell tyrosine phosphorylation and intracellular signaling events including tyrosine phosphorylation and kinase activity of proteins involved in the collagen-stimulated glycoprotein (GP) signaling pathway were investigated. RESULTS: We report that quercetin inhibits collagen-stimulated whole cell protein tyrosine phosphorylation and intracellular mobilization of calcium, in a concentration-dependent manner. Quercetin was also found to inhibit various events in signaling generated by the collagen receptor GPVI. This includes collagen-stimulated tyrosine phosphorylation of the Fc receptor gamma-chain, Syk, LAT and phospholipase Cgamma2. Inhibition of phosphorylation of the Fc receptor gamma-chain suggests that quercetin inhibits early signaling events following stimulation of platelets with collagen. The activity of the kinases that phosphorylate the Fc receptor gamma-chain, Fyn and Lyn, as well as the tyrosine kinase Syk and phosphoinositide 3-kinase was also inhibited by quercetin in a concentration-dependent manner, both in whole cells and in isolation. CONCLUSIONS: The present results provide a molecular basis for the inhibition by quercetin of collagen-stimulated platelet activation, through inhibition of multiple components of the GPVI signaling pathway, and may begin to explain the proposed health benefits of high quercetin intake.

Tropisetron compared with a metoclopramide-based regimen in the prevention of chemotherapy-induced nausea and vomiting.

This randomised, open, parallel group study compared the antiemetic efficacy and tolerability of tropisetron with metoclopramide plus lorazepam in 102 patients receiving a first course of non-cisplatin-containing chemotherapy. Control of acute vomiting by tropisetron was significantly superior to that of the metoclopramide regimen, with total control (no vomiting) in 45% of 51 patients in the tropisetron group compared with 22% of 51 patients in the metoclopramide group (P = 0.013); total and partial control (< 5 vomits) occurred in 67 and 47% of patients, respectively (P = 0.044). The incidences of acute nausea and of delayed nausea and emesis were similar in the two treatment groups. Both tropisetron and metoclopramide were well tolerated; no adverse effects were attributed to tropisetron administration with the exception of headache. One patient in the metoclopramide group reported confusion and tremor thought to be related to the antiemetic therapy. Tropisetron is an effective and well-tolerated agent in the prevention of chemotherapy-induced vomiting. The control of acute nausea was similar in the two treatment groups, but tropisetron was superior to a metoclopramide-based regimen in the control of acute vomiting.

Integrin-linked kinase regulates the rate of platelet activation and is essential for the formation of stable thrombi.

BACKGROUND: Integrin-linked kinase (ILK) and its associated complex of proteins are involved in many cellular activation processes, including cell adhesion and integrin signaling. We have previously demonstrated that mice with induced platelet ILK deficiency show reduced platelet activation and aggregation, but only a minor bleeding defect. Here, we explore this apparent disparity between the cellular and hemostatic phenotypes. METHODS: The impact of ILK inhibition on integrin αII b ß3 activation and degranulation was assessed with the ILK-specific inhibitor QLT0267, and a conditional ILK-deficient mouse model was used to assess the impact of ILK deficiency on in vivo platelet aggregation and thrombus formation. RESULTS: Inhibition of ILK reduced the rate of both fibrinogen binding and α-granule secretion, but was accompanied by only a moderate reduction in the maximum extent of platelet activation or aggregation in vitro. The reduction in the rate of fibrinogen binding occurred prior to degranulation or translocation of αII b ß3 to the platelet surface. The change in the rate of platelet activation in the absence of functional ILK led to a reduction in platelet aggregation in vivo, but did not change the size of thrombi formed following laser injury of the cremaster arteriole wall in ILK-deficient mice. It did, however, result in a marked decrease in the stability of thrombi formed in ILK-deficient mice. CONCLUSION: Taken together, the findings of this study indicate that, although ILK is not essential for platelet activation, it plays a critical role in facilitating rapid platelet activation, which is essential for stable thrombus formation.