Development of a Novel Combination Therapy targeting MET and LGR5 to overcome Colorectal Cancer Resistance

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Salinity Variations and Chemical Compositions of Waters in the Frio Formation, Texas Gulf Coast

Waters produced from sandstone reservoirs of the deep Frio Formation exhibit spatial variations in chemical composition that roughly coincide with the major tectonic elements (Houston and Rio Grande Embayments, San Marcos Arch) and corresponding depositional systems (Houston and Norias deltas, Greta-Carancahua barrier/strandplain system) that were respectively active along the upper, lower, and middle Texas Coast during Frio deposition. Waters of the upper coast typically have relatively high salinities (maximum total dissolved solids >80,000 mg/L), high calcium (200 to 9,000 mg/L), high sodium (>15,000 µg/L), relatively high potassium (>150 mg/L), low to moderate Cl/Na ratios (1.4 to 1.9), and high Cl/Br ratios (>400). When compared with adjacent areas of Frio production, waters of the middle coast have lower salinities (maximum total dissolved solids 80,000 mg/L, extremely high calcium (1,800 to 34,000 mg/L), high sodium (>15,000 mg/L), high potassium (>150), extremely high Cl/Na ratios (>2), and low Cl/Br ratios (<250). Calcium concentrations actually exceed sodium concentrations in some South Texas waters.Bureau of Economic Geolog

Quality of Data Downloads: Bibliographic Databases Frequently Used for Systematic Reviews

Objectives: To assess the quality of data downloaded from a variety of bibliographic databases commonly searched in systematic reviews, in order to provide guidance on the order in which database records should be uploaded into a citation manager and which record should be used as the “primary record” during the duplicate removal process. Methods: We downloaded the bibliographic records of a random sampling of two hundred journal articles from the following databases: MEDLINE (via PubMed and Ovid), Embase, Web of Science, Scopus, Cochrane, CINAHL (via Ebsco), International Pharmaceutical Abstracts (via Ebsco), Sociological Abstracts (via Proquest), and Google Scholar. We required that each article be available in at least three databases and that each database contain at least fifty of these articles. We then assessed the completeness and correctness of the downloads using the full-text article as our gold standard. Records were scored on presence, completeness, and correctness of the following fields: title, authors, digital object identifier (DOI), volume, issue, pages, publication year, accession number, abstract, and URL. Using these data, we calculated an overall score for each database and a head-to-head score for each database combination using the article overlap for each database pair

Knowing When to Stop: Final Results vs. Work Involved in Systematic Review Database Searching

Objectives: To examine the relationship between the amount of work involved for the systematic review (SR) team for each additional database searched in an SR versus the number of unique articles included in the final review that were retrieved from each additional database searched. Methods: We reviewed SRs and meta-analyses published in JAMA, Lancet, and Annals of Internal Medicine from January 2012 to December 2015, selecting those journals as high impact factor journals that have published over more than 50 SRs per year since 2012. We required that all papers in our analysis report a complete search strategy, with the total number of citations retrieved from each database and a complete list of articles included in the final analysis. We then used lists of included journals from each database to determine in which database(s) each of the included articles were indexed, and we calculated the percentage of articles included in each SR that could be located by searching each database. We then compared the number of results added by searching each additional database to the total number of papers added to the review phase to estimate the amount of work required for each additional paper identified. Results: Ninety-seven SRs met our inclusion criteria. These SRs included an average of 48.13 journal articles and searched an average of 4.43 databases each. Of these, the journal articles included in 16 SRs could all be found in one database; the articles included in 58 SRs could all be found in two databases. For 20 SRs, all included articles could be found in three databases, and the remaining three SRs included articles that could be found in four databases. For 96 SRs, over 90% of articles could be found in two databases. Conclusions: In total, 99% of articles included in each SR were found in two databases, with the majority being found in PubMed/MEDLINE, Embase, or Cochrane. SRs that found articles in three or more databases screened an additional 923 records in order to find one additional included article, plus an additional 2410 records from databases that did not return any additional included articles, adding an average of 756 hours of work to each SR. SRs for which articles were found in four databases screened an average of 1440 records in order to find one additional included article, plus an additional 8963 records from databases that did not return any additional included articles

GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins.

Many intrinsically disordered proteins (IDPs) participate in coupled folding and binding reactions and form alpha helical structures in their bound complexes. Alanine, glycine, or proline scanning mutagenesis approaches are often used to dissect the contributions of intrinsic helicities to coupled folding and binding. These experiments can yield confounding results because the mutagenesis strategy changes the amino acid compositions of IDPs. Therefore, an important next step in mutagenesis-based approaches to mechanistic studies of coupled folding and binding is the design of sequences that satisfy three major constraints. These are (i) achieving a target intrinsic alpha helicity profile; (ii) fixing the positions of residues corresponding to the binding interface; and (iii) maintaining the native amino acid composition. Here, we report the development of a G: enetic A: lgorithm for D: esign of I: ntrinsic secondary S: tructure (GADIS) for designing sequences that satisfy the specified constraints. We describe the algorithm and present results to demonstrate the applicability of GADIS by designing sequence variants of the intrinsically disordered PUMA system that undergoes coupled folding and binding to Mcl-1. Our sequence designs span a range of intrinsic helicity profiles. The predicted variations in sequence-encoded mean helicities are tested against experimental measurements.The US-National Science Foundation and US-National Institutes of Health supported this work through grants MCB-1121867 and 5RO1 NS056114, respectively to R.V.P. J.C. and S.L.S. were supported by the Wellcome Trust (WT 095195MA). M.D.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) studentship.This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/protein/gzw03

Victim, perpetrator, family, and incident characteristics of infant and child homicide in the United States Air Force

Objective: The present study describes factors related to fatal abuse in three age groups in the United States Air Force (USAF). Method: Records from 32 substantiated cases of fatal child abuse in the USAF were independently reviewed for 60 predefined factors. Results: Males were over-represented in young child victims (between 1 year and 4 years of age) and child victims (between 4 years and 15 years of age) but not in infant victims (between 24 hours and 1 year of age). African-American infant victims and perpetrators were over-represented. Younger victims were more likely to have been previously physically abused by the perpetrator. Perpetrators were predominantly male and the biological fathers of the victims. Infant and young child perpetrators reported childhood abuse histories, while child perpetrators reported the highest frequency of mental health contact. Victims’ families reported significant life stressors. Families of young child victims were more likely divorced, separated, or single. Incidents with infants and young children tended to occur without witnesses; incidents with child victims tended to have the victim’s sibling(s) and/or mother present. Fatal incidents were more frequent on the weekend, in the home, and initiated by some family disturbance. Conclusions: Differences among groups in factors related to infant and child homicide across age groups may assist in the development of more tailored abuse prevention efforts and may also guide future investigations

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design