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Net Reclassification Index and Integrated Discrimination Index Are Not Appropriate for Testing Whether a Biomarker Improves Predictive Performance.

Toxicol Sci. 2017 Mar 01;156(1):11-13

Authors: Burch PM, Glaab WE, Holder DJ, Phillips JA, Sauer JM, Walker EG

Abstract
One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing.

PMID: 27815493 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-DE-19-001 from the NIH Guide for Grants and Contracts. The National Institute of Dental and Craniofacial Research (NIDCR) intends to continue support for research conducted within a national Dental Practice-Based Research Network (DPBRN). The NIDCR will fund one national DPBRN Administrative and Resource Center led by a National Network Director and one national DPBRN Coordinating Center, funded with companion awards, to support the infrastructure for and implementation of multiple prospective observational studies and clinical trials. This funding opportunity announcement (FOA) is soliciting applications for the national DPBRN Administrative and Resource Center; a separate companion FOA is soliciting applications for the national DPBRN Coordinating Center (RFA-DE-19-002). The main goals of the cooperative agreement funded under this FOA are to maximize efficiencies to conduct national oral health research studies in dental practices on topics of importance to practitioners and their patients, to provide evidence useful in daily patient care, and to facilitate the translation of research findings into clinical practice. It is expected that the DPBRN will build on the significant investment to date by the NIDCR and will demonstrate continued growth and productivity.

Funding Opportunity RFA-DE-19-002 from the NIH Guide for Grants and Contracts. The National Institute of Dental and Craniofacial Research (NIDCR) intends to continue support for research conducted within a national Dental Practice-Based Research Network (DPBRN). The NIDCR will fund one national DPBRN Administrative and Resource Center led by a National Network Director and one national DPBRN Coordinating Center, funded as companion awards, to support the infrastructure for and implementation of multiple prospective observational studies and clinical trials. This funding opportunity announcement (FOA) is soliciting applications for the national DPBRN Coordinating Center; a separate FOA is soliciting applications for the national DPBRN Administrative and Resource Center (RFA-DE-19-002 ). This clinical research network will develop and conduct multiple prospective, observational clinical studies and clinical trials, on topics of interest to practitioners and their patients. Studies will be conducted in participating dental offices with consenting patients. The role of the national Coordinating Center will be to centralize and harmonize study operations, data management, and biostatistical support, to facilitate rapid development and implementation of oral health studies conducted in the national DPBRN.

Notice NOT-OD-18-135 from the NIH Guide for Grants and Contracts

Notice NOT-AT-18-009 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-704 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research projects focused on adducts to cellular macromolecules as indicators of exposures to cancer risk factors relevant to human populations. The priority is on projects that will focus on adductomic approaches, i.e., address some aspects of the totality of adducts. These projects should explore the basic aspects of adducts/adductomics that may have a potential utility in cancer detection, cancer prevention, and/or assessing cancer risks. The projects should be relevant to adducts in humans and human populations but may be conducted using various model systems (e.g., cultured cells, animals, etc.). The use of human biospecimens is encouraged and expected if appropriate but not required. In well-justified cases, innovative studies using the adductomic approaches in the context of cancer etiology and/or gene-environment interaction research may also be appropriate. For projects intended for NIEHS support, the focus may be on innovative technology and method development.

Funding Opportunity PAR-18-703 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research projects focused on adducts to cellular macromolecules as indicators of exposures to cancer risk factors relevant to human populations. The priority is on projects that will focus on adductomic approaches, i.e., address some aspects of the totality of adducts. These projects should explore the basic aspects of adducts/adductomics that may have a potential utility in cancer detection, cancer prevention, and/or assessing cancer risks. The projects should be relevant to adducts in humans and human populations but may be conducted using various model systems (e.g., cultured cells, animals, etc.). The use of human biospecimens is encouraged and expected if appropriate but not required. In well-justified cases, innovative studies using the adductomic approaches in the context of cancer etiology and/or gene-environment interaction research may also be appropriate. For projects intended for NIEHS support, the focus may be on innovative technology and method development.

Funding Opportunity PA-18-705 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) for projects to transfer technology out of the NIH intramural research labs into the private sector. If selected for SBIR funding, the SBC will be granted a royalty-free, non-exclusive patent license agreement for internal research use for the term of and within the field of use of the SBIR award to technologies held by NIH with the intent that the SBC will develop the invention into a commercial product to benefit the public.

Notice NOT-OD-18-138 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-18-702 from the NIH Guide for Grants and Contracts. The purpose of the administrative supplement is to provide support for NIH-funded investigators to participate in an entrepreneurship training course, the Concept to Clinic: Commercializing Innovation (C3i) Program. The C3i Program is designed to provide medical device innovators with the specialized business frameworks and essential tools for successful translation of biomedical technologies from the lab (concept) to the market (clinic). Through this program, the NIH fosters the development and commercialization of early-stage biomedical technologies by engaging investigators who are interested in better understanding the value of their innovation in addressing an unmet market need. The curriculum and customized mentoring provided by the C3i Program are intended to guide investigators as they assess the commercial viability and potential business opportunity for their innovation. Prospective applicants are strongly encouraged to contact NIH Scientific/Research staff for more information about the program before applying.

Funding Opportunity PA-18-700 from the NIH Guide for Grants and Contracts. The purpose of the NIDCD Research Dissertation Fellowship for Au.D. Audiologists (F32) program is to support a comprehensive, rigorous biomedical research training, and dissertation research leading to a research doctorate (i.e., Ph.D.) in the biomedical, behavioral, or clinical sciences.

Notice NOT-AR-18-018 from the NIH Guide for Grants and Contracts

Notice NOT-NS-18-049 from the NIH Guide for Grants and Contracts

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/03/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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35 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/03/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Statins in conditions other than hypocholesterolemic effects for chronic subdural hematoma therapy, old drug, new tricks?

Oncotarget. 2017 Apr 18;8(16):27541-27546

Authors: Zou H, Zhu XX, Ding YH, Zhang GB, Geng Y, Huang DS

Abstract
Chronic subdural hematoma (CSDH) is one of the most common intracranial hematomas worldwide with a high incidence in the general population. However, the optimum treatment for CSDH is Burr-hole drainage with or without rinse Considering the poor outcomes of CSDH in aged patients, and ambiguous prediction of recurrence in many sides of recurrent CSDHs who have been analyzed, new effective therapies are needed for those CSDHs who are predicated to have poor prognosis for surgery and/or have a higher risk of recurrence. Statins, which is the first-line treatment for patients with high cholesterol and coronary heart disease. However, statins are still not solely limited in the treatment of these diseases. It has been demonstrated that statins could improve CSDH due to its effect of regulation of angiogenesis and inflammation. In this review, in order to provide potential new treatment for CSDH we summarize the recent findings of statins in CSDH in order to try to clarify the mechanisms of this effect.

PMID: 28177914 [PubMed - indexed for MEDLINE]

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New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate.

Oncotarget. 2017 Jan 03;8(1):1007-1022

Authors: Cui J, Hollmén M, Li L, Chen Y, Proulx ST, Reker D, Schneider G, Detmar M

Abstract
Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

PMID: 27894093 [PubMed - indexed for MEDLINE]