Application of genomicsassisted breeding for generation of climate resilient crops: progress and prospects

CCAFS Climat

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins

Improving Health Behaviors Through Community Engagement: Challenge for a Healthier Louisiana

There is increasing recognition that community-based approaches may have merit in improving physical activity and healthy eating behaviors. The “Challenge for a Healthier Louisiana” program supported twelve projects that addressed the root causes of obesity through integrated community-level changes. Partnerships provided community-based obesity prevention by promoting healthier eating and/or physical activity through enhanced infrastructure, policy changes, and programming. To evaluate whether the program resulted in changes in healthy eating and/or physical activity among adults, surveys were conducted pre- and postintervention among participants. Participants who were exposed to physical activity programs were more likely to adopt the consumption of fruits (odds ratio = 2.0; 95% confidence interval [1.1, 3.6]), were more likely to eat vegetables once per day (p =.028), and were more likely to participate in physical activity (p =.053). Participants who were exposed to healthy eating programs were more likely to eat fruit once per day (p =.035), were more likely to eat vegetables at least once per day (p =.008), and were more likely to participate in physical activity (p =.018). In conclusion, there is some indication that the Challenge for a Healthier Louisiana program produced changes in health behaviors among program participants; however, the sustainability of these changes will require further evaluation

Massively parallelizable list-mode reconstruction using a Monte Carlo-based elliptical Gaussian model

Purpose: A fully three-dimensional (3D) massively parallelizable list-mode ordered-subsets expectation-maximization (LM-OSEM) reconstruction algorithm has been developed for high-resolution PET cameras. System response probabilities are calculated online from a set of parameters derived from Monte Carlo simulations. The shape of a system response for a given line of response (LOR) has been shown to be asymmetrical around the LOR. This work has been focused on the development of efficient region-search techniques to sample the system response probabilities, which are suitable for asymmetric kernel models, including elliptical Gaussian models that allow for high accuracy and high parallelization efficiency. The novel region-search scheme using variable kernel models is applied in the proposed PET reconstruction algorithm...This work was partially supported by Spain’s Ministry of Science and Innovation through CDTI’s CENIT program (AMIT project) and INNPACTO (PRECISION project), Instituto de Salud Carlos III (PI09/91058 and PI09/91065), and Project Nos. TEC2010-21619-C04-03 and TEC2011-28972- C02-02, Comunidad de Madrid (ARTEMIS S2009/DPI- 1802), and the European Regional Development Funds (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and finance by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Publicad

Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.  Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).  Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.  Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker

Preliminary Real-World Evaluation of an Intervention for Parents of Adolescents: The Open Door Approach to Parenting Teenagers (APT)

Most parenting interventions report high dropout rates for parents who exhibit clinically high levels of stress and/or are parents of adolescents with severe emotional and/or behavioral difficulties. The objective of this preliminary study was to evaluate the feasibility and real-world effectiveness of the Open Door Approach to Parenting Teenagers (APT), a six-session individually delivered face-to-face intervention for typically hard to engage parents of 11 to 21-year-olds. A one-group, pre-post evaluation design was adopted due to the naturalistic clinic-based setting of the study. Participants were 279 parents reporting clinical levels of stress relating to parenting an adolescent. Parents receiving the APT intervention demonstrated lower dropout rates than other parenting programs and reported high scores across several items relating to service satisfaction. The APT intervention was associated with significant reductions in parental stress and improvements in parent-adolescent relationships immediately post-intervention. Findings suggest that parents found the APT intervention acceptable and beneficial, and further suggest that the intervention is feasible and effective in retaining hard to engage parents. Moreover, preliminary findings suggest that the APT intervention is a promising intervention that may support parents who fail to engage in group programs. However, further research is required to establish the efficacy of the intervention