Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Primary HPV testing: U.S. women's awareness and acceptance of an emerging screening modality.

BACKGROUND: Primary HPV testing (without the Pap test) has recently been recommended as a cervical cancer screening option in the United States. U.S. women's awareness and acceptance of primary HPV testing were evaluated. METHODS: Data from a 2015 web-based survey of U.S. adults was examined. Analyses were limited to women who were ≥18years old, had not undergone a hysterectomy, had not been diagnosed with cervical cancer, and would accept cervical cancer screening (N=1309). Logistic regression was used to identify predictors of acceptance of primary HPV testing every 3years. RESULTS: Primary HPV testing every 3years was the least accepted cervical cancer screening option (13.5%), and annual Pap testing was the most accepted (41.2%). Most women (65.2%) reported that they were unsure how the HPV test is administered. HPV-vaccinated women were more likely to accept primary HPV testing every 3years than unvaccinated women (Adj OR=1.80, 95% CI=1.22-2.63, p=0.003). And, women who had participated in HPV testing at any interval were more likely to accept primary HPV testing every 3years than those who did not have regular HPV tests or were unsure how often they had HPV tests (Adj OR=1.74, 95% CI=1.20-2.52, p=0.003). CONCLUSIONS: Acceptance of primary HPV testing among U.S. women was low and associated with variables which may be indicative of general HPV awareness. Widespread adoption of primary HPV testing may require increasing women's familiarity with the HPV test and screening guidelines.

Critical considerations for the practical utility of health equity tools: a concept mapping study.

BACKGROUND: Promoting health equity within health systems is a priority and challenge worldwide. Health equity tools have been identified as one strategy for integrating health equity considerations into health systems. Although there has been a proliferation of health equity tools, there has been limited attention to evaluating these tools for their practicality and thus their likelihood for uptake. METHODS: Within the context of a large program of research, the Equity Lens in Public Health (ELPH), we conducted a concept mapping study to identify key elements and themes related to public health leaders and practitioners' views about what makes a health equity tool practical and useful. Concept mapping is a participatory mixed-method approach to generating ideas and concepts to address a common concern. Participants brainstormed responses to the prompt "To be useful, a health equity tool should…" After participants sorted responses into groups based on similarity and rated them for importance and feasibility, the statements were analyzed using multidimensional scaling, then grouped using cluster analysis. Pattern matching graphs were constructed to illustrate the relationship between the importance and feasibility of statements, and go-zone maps were created to guide subsequent action. RESULTS: The process resulted in 67 unique statements that were grouped into six clusters: 1) Evaluation for Improvement; 2) User Friendliness; 3) Explicit Theoretical Background; 4) Templates and Tools 5) Equity Competencies; and 6) Nothing about Me without Me- Client Engaged. The result was a set of concepts and themes describing participants' views of the practicality and usefulness of health equity tools. CONCLUSIONS: These thematic clusters highlight the importance of user friendliness and having user guides, templates and resources to enhance use of equity tools. Furthermore, participants' indicated that practicality was not enough for a tool to be useful. In addition to practical characteristics of the tool, a useful tool is one that encourages and supports the development of practitioner competencies to engage in equity work including critical reflections on power and institutional culture as well as strategies for the involvement of community members impacted by health inequities in program planning and delivery. The results of this study will be used to inform the development of practical criteria to assess health equity tools for application in public health.

Experimental Study and Modelling of Fresh Behaviours of Basalt Fibre-Reinforced Mortar Based on Average Water Film Thickness and Fibre Factor.

Though previous studies have indicated that the fresh behaviours of plain mortar/concrete are mainly governed by the average water film thickness (AWFT), whether the concept of AWFT is also applicable to fibrous mortar/concrete still needs to be explored. Furthermore, for fibrous mortar/concrete, it is obvious that the fibres added also have certain effects on the fresh behaviours. In two previous studies on basalt fibre-reinforced mortar (BFRM), the integral effects of the AWFT and fibre dosage as well as the integral effects of the AWFT and fibre length were individually investigated. In this study, a fibre factor (FF) defined as the fibre volume multiplied by the fibre aspect ratio was employed and 24 extra mortar groups were tested. A total of 68 mortar groups were applied in numerical analysis. The results of the regression analysis yielded good correlations of the workability, fluidity, cohesiveness, and adhesiveness of BFRM with the AWFT and FF, suggesting that the AWFT and FF are together the governing parameters controlling the fresh behaviours of BFRM. Hence, the AWFT and FF may be used to develop a model for the fresh properties of BFRM.

Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.

The path to the clinic: a comprehensive review on direct KRASG12C inhibitors.

The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRASG12C mutation. Adagrasib (MRTX849) and other direct KRASG12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12C inhibitors and summarize the ongoing clinical trials of all direct KRASG12C inhibitors.

A 'health broker' role as a catalyst of change to promote health: an experiment in deprived Dutch neighbourhoods.

Urban social entrepreneurs have been suggested to play an essential part in the success of local health promotion initiatives. Up to now, roles like these have only been identified in retrospect. This prospective collaborative study explored the possibilities of institutionalizing a comparable role for a 'health broker' in four Dutch municipalities as an additional investment to promote health in deprived neighbourhoods. The theoretical notions of public and policy entrepreneurs as well as of boundary spanners were adopted as a reference framework. Documents produced by the collaborative project served as input for a qualitative analysis of the developments. We succeeded in implementing a 'health broker' role comparable to that of a bureaucratic public entrepreneur holding a formal non-leadership position. The role was empowered by sharing it among multiple professionals. Although positioned within one sector, the occupants of the new role felt more entitled to cross sectoral borders and to connect to local residents, compared to other within-sector functions. The 'health broker' role had the potential to operate as an 'anchoring point' for the municipal health sector (policy), public health services (practice) and/or the local residents (public). It was also possible to specify potential 'broking points', i.e. opportunities for health promotion agenda setting and opportunities to improve cross-sectoral collaboration, citizen participation and political and administrative support for health promotion efforts. The 'health broker' role we developed and implemented reflects the notion of systematic rather than individual entrepreneurship. Such a collective entrepreneurship may create additional opportunities to gradually strengthen local health promotion efforts.

NSD3S stabilizes MYC through hindering its interaction with FBXW7.

The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.

A web services choreography scenario for interoperating bioinformatics applications.

BACKGROUND: Very often genome-wide data analysis requires the interoperation of multiple databases and analytic tools. A large number of genome databases and bioinformatics applications are available through the web, but it is difficult to automate interoperation because: 1) the platforms on which the applications run are heterogeneous, 2) their web interface is not machine-friendly, 3) they use a non-standard format for data input and output, 4) they do not exploit standards to define application interface and message exchange, and 5) existing protocols for remote messaging are often not firewall-friendly. To overcome these issues, web services have emerged as a standard XML-based model for message exchange between heterogeneous applications. Web services engines have been developed to manage the configuration and execution of a web services workflow. RESULTS: To demonstrate the benefit of using web services over traditional web interfaces, we compare the two implementations of HAPI, a gene expression analysis utility developed by the University of California San Diego (UCSD) that allows visual characterization of groups or clusters of genes based on the biomedical literature. This utility takes a set of microarray spot IDs as input and outputs a hierarchy of MeSH Keywords that correlates to the input and is grouped by Medical Subject Heading (MeSH) category. While the HTML output is easy for humans to visualize, it is difficult for computer applications to interpret semantically. To facilitate the capability of machine processing, we have created a workflow of three web services that replicates the HAPI functionality. These web services use document-style messages, which means that messages are encoded in an XML-based format. We compared three approaches to the implementation of an XML-based workflow: a hard coded Java application, Collaxa BPEL Server and Taverna Workbench. The Java program functions as a web services engine and interoperates with these web services using a web services choreography language (BPEL4WS). CONCLUSION: While it is relatively straightforward to implement and publish web services, the use of web services choreography engines is still in its infancy. However, industry-wide support and push for web services standards is quickly increasing the chance of success in using web services to unify heterogeneous bioinformatics applications. Due to the immaturity of currently available web services engines, it is still most practical to implement a simple, ad-hoc XML-based workflow by hard coding the workflow as a Java application. For advanced web service users the Collaxa BPEL engine facilitates a configuration and management environment that can fully handle XML-based workflow.

Biosphere: the interoperation of web services in microarray cluster analysis.

UNLABELLED: The growing use of DNA microarrays in biomedical research has led to the proliferation of analysis tools. These software programs address different aspects of analysis (e.g. normalisation and clustering within and across individual arrays) as well as extended analysis methods (e.g. clustering, annotation and mining of multiple datasets). Therefore, microarray data analysis typically requires the interoperability of multiple software programs involving different analysis types and methods. Such interoperation is often hampered by the heterogeneity inherent in the software tools (which may function by implementing different interfaces and using different programming languages). To address this problem, we employed the simple object access protocol (SOAP)-based web service approach that provides a uniform programmatic interface to these heterogeneous software components. To demonstrate this approach in the microarray context, we created a web server application, Biosphere, which interoperates a number of web services that are geographically widely distributed. These web services include a clustering web service, which is a suite of different clustering algorithms for analysing microarray data; XEMBL, developed at the European Bioinformatics Institute (EBI) for retrieving EMBL Nucleotide Sequence Database sequence data; and three gene annotation web services: GetGO, GetHAPI and GetUMLS. GetGO allows retrieval of Gene Ontology (GO) annotation, and the other two web services retrieve annotation from the biomedical literature that is indexed based on the Medical Subject Headings (MeSH) terms. With these web services, Biosphere allows the users to do the following: (i) cluster gene expression data using seven different algorithms; (ii) visualise the clustering results that are grouped statistically in colour; and (iii) retrieve sequence, annotation and citation data for the genes of interest. AVAILABILITY: Biosphere and its web services described in Web Service Description Language (WSDL) can be accessed at http://rook.cecid.hku.hk:8280/BiosphereServer.

Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations.

OBJECTIVE: A single-nucleotide polymorphism in the PTPN22 gene encoding the lymphoid protein tyrosine phosphatase (Lyp) has recently been identified as a functional variant associated with susceptibility to rheumatoid arthritis (RA), type 1 diabetes, and systemic lupus erythematosus. To determine whether association of this variant (PTPN22 1858T) with RA is reproducible and is also observed in another autoimmune condition, Crohn's disease, we investigated the association between the PTPN22 1858T allele and RA and Crohn's disease in a Canadian population. METHODS: Two RA case-control cohorts representing a total of 1,234 patients and 791 healthy controls as well as a cohort of 455 patients with Crohn's disease and 190 controls were genotyped for the PTPN22 C1858T polymorphism, and genotype frequencies were compared between patients and controls. RESULTS: Significant association of the PTPN22 1858T allele with RA was detected in both the Toronto-based RA cohort (P = 1.6 x 10(-6), odds ratio [OR] 1.8) and the Halifax-based RA cohort (P = 9.4 x 10(-4), OR 1.94). Association of the risk allele with RA was not affected by sex, age at disease onset, or the presence of either rheumatoid factor or rheumatoid nodules. No association between the PTPN22 risk allele and Crohn's disease was detected. CONCLUSION: These observations confirm the association of RA susceptibility with the PTPN22 1858T allele. However, the data also reveal a lack of association between this variant and Crohn's disease, suggesting that the PTPN22 1858T allele is a risk allele for multiple, but not all, autoimmune diseases.