Resistance to targeted EGFR inhibitors is likely to develop in EGFR mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR TKIs including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002 or AZD9291. Compared to parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumours in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumours. Further, these findings suggest that NRAS modifications in tumour samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.

Background: This study assesses the net benefit and the cost-effectiveness of the Coordinated Approach to Child Health (CATCH) intervention program, using parameter estimates from the El Paso trial. There were two standard economic measures used. First, from a societal perspective on costs, cost-effectiveness ratios (CER) were estimated, revealing the intervention costs per qualityadjusted life years (QALYs) saved. QALY weights were estimated using National Health Interview Survey (NHIS) data. Second, the net benefit (NB) of CATCH was estimated, which compared the present value of averted future costs with the cost of the CATCH intervention. Using National Health and Nutrition Examination Survey I (NHANES) and NHANES follow-up data, we predicted the number of adult obesity cases avoided for ages 40-64 with a lifetime obesity progression model.

IntroductionThe objective of our study was to estimate the long-term cost-effectiveness of a lifestyle modification program led by community health workers (CHWs) for low-income Hispanic adults with type 2 diabetes.MethodsWe forecasted disease outcomes, quality-adjusted life years (QALYs) gained, and lifetime costs associated with attaining different hemoglobin A1c (A1c) levels. Outcomes were projected 20 years into the future and discounted at a 3.0% rate. Sensitivity analyses were conducted to assess the extent to which our results were dependent on assumptions related to program effectiveness, projected years, discount rates, and costs.ResultsThe incremental cost-effectiveness ratio of the intervention ranged from $10,995 to $33,319 per QALY gained when compared with usual care. The intervention was particularly cost-effective for adults with high glycemic levels (A1c > 9%). The results are robust to changes in multiple parameters.ConclusionThe CHW program was cost-effective. This study adds to the evidence that culturally sensitive lifestyle modification programs to control diabetes can be a cost-effective way to improve health among Hispanics with diabetes, particularly among those with high A1c levels.

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084-94. Ó2016 AACR.

The association between tuberculosis and underlying risk factors was evaluated in Texas patients hospitalized in the 15 counties along the Mexico border within the remaining non-border counties. A case control analysis of the hospital discharge dataset from the Texas Health Care Information Council was performed for the years 1999-2001. A discharge diagnosis of tuberculosis identified cases (N = 4,915). Deep venous thrombosis, pulmonary embolism, and acute appendicitis conditions identified controls (N = 70,808). Risk factors associated with tuberculosis were identified by logistic regression. Diabetes patients were almost twice as likely to have tuberculosis after adjusting by sex, age, and race/ethnicity. The association was strong for the population in the Texas border region, where there are higher incidence rates of tuberculosis (odds ratio [OR](adj) = 1.82; 95% CI = 1.57-2.12) compared with non-border counties (OR(adj) = 1.51; 95% CI = 1.36-1.67).