Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.

Purpose Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin.Patients and methods This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies.Results Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate.Conclusion To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed

Why Human Health and Health Ethics Must Be Central to Climate Change Deliberations

Jerome Singh argues that health ethics principles must be afforded equal status to economics principles in climate change deliberations, and that the health community must play more of a leadership role

Interpersonal and affective dimensions of psychopathic traits in adolescents : development and validation of a self-report instrument

We report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = .73, Self-Centredness α = .70, Callous-Unemotional α = .69, and Manipulativeness α = .83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behaviour, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a first-order model represented by four correlated factors that was invariant across gender and age was confirmed. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents

Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

BACKGROUND: Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of extracellular superoxide dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway. METHODS: Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury. RESULTS: Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p < 0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p < 0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT. CONCLUSION: This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway

Assessing stability and change of four performance measures: a longitudinal study evaluating outcome following total hip and knee arthroplasty

BACKGROUND: Physical performance measures play an important role in the measurement of outcome in patients undergoing hip and knee arthroplasty. However, many of the commonly used measures lack information on their psychometric properties in this population. The purposes of this study were to examine the reliability and sensitivity to change of the six minute walk test (6MWT), timed up and go test (TUG), stair measure (ST), and a fast self-paced walk test (SPWT) in patients with hip or knee osteoarthritis (OA) who subsequently underwent total joint arthroplasty. METHODS: A sample of convenience of 150 eligible patients, part of an ongoing, larger observational study, was selected. This included 69 subjects who had a diagnosis of hip OA and 81 diagnosed with knee OA with an overall mean age of 63.7 ± 10.7 years. Test-retest reliability, using Shrout and Fleiss Type 2,1 intraclass correlations (ICCs), was assessed preoperatively in a sub-sample of 21 patients at 3 time points during the waiting period prior to surgery. Error associated with the measures' scores and the minimal detectable change at the 90% confidence level was determined. A construct validation process was applied to evaluate the measures' abilities to detect deterioration and improvement at two different time points post-operatively. The standardized response mean (SRM) was used to quantify change for all measures for the two change intervals. Bootstrapping was used to estimate the 95% confidence intervals (CI) for the SRMs. RESULTS: The ICCs (95% CI) were as follows: 6MWT 0.94 (0.88,0.98), TUG 0.75 (0.51, 0.89), ST 0.90 (0.79, 0.96), and the SPWT 0.91 (0.81, 0.97). Standardized response means varied from .79 to 1.98, being greatest for the ST and 6MWT over the studied time intervals. CONCLUSIONS: The test-retest estimates of the 6MWT, ST, and the SPWT met the requisite standards for making decisions at the individual patient level. All measures were responsive to detecting deterioration and improvement in the early postoperative period

Does true Gleason pattern 3 merit its cancer descriptor?

Nearly five decades following its conception, the Gleason grading system remains a cornerstone in the prognostication and management of patients with prostate cancer. In the past few years, a debate has been growing whether Gleason score 3 + 3 = 6 prostate cancer is a clinically significant disease. Clinical, molecular and genetic research is addressing the question whether well characterized Gleason score 3 + 3 = 6 disease has the ability to affect the morbidity and quality of life of an individual in whom it is diagnosed. The consequences of treatment of Gleason score 3 + 3 = 6 disease are considerable; few men get through their treatments without sustaining some harm. Further modification of the classification of prostate cancer and dropping the label cancer for Gleason score 3 + 3 = 6 disease might be warranted

Integrated knowledge translation in population health intervention research: a case study of implementation and outcomes from a school-based project.

BACKGROUND: Integrated knowledge translation (IKT) is encouraged in population health intervention research (PHIR) to ensure the co-production of policy-relevant research, yet there is little published literature that reports its implementation and outcomes. The purpose of this study was to describe and evaluate the IKT approach used in a school-based PHIR project to understand how the research informed policy and practice and identify what influenced the IKT process. METHODS: A case study approach was used to provide an in-depth description of the IKT process and understand the co-production and application of research evidence. Data were collected through document review, a survey with all elementary school principals in the school board (n = 18) following dissemination of School Reports and interviews with the IKT research team (including two researchers and three knowledge users). RESULTS: Approximately half of the principals reported reading their School Report (52%) and almost all of these principals attributed the partial or full adoption, or implementation, of a new practice as a result of using the information (89%). Key themes related to the IKT process emerged across the interviews, including supportive relationships, role clarity, competing priorities and the complexities of population health interventions. CONCLUSIONS: The findings suggest that, while IKT can support policy and practice, it can be challenging to maintain engagement due to differing priorities and role ambiguity. Additional recognition, investment and research would enable better implementation of the approach, thereby bridging the gap between research, policy and practice

Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology