Discovery of compounds that reactivate p53 mutants in vitro and in vivo

The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53null or p53WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations

Evaluating Palliative Care Needs in Middle Eastern Countries

WOS: 000347152600006PubMed ID: 25302525Background: Cancer incidence in Middle Eastern countries, most categorized as low- and middle-income, is predicted to double in the next 10 years, greater than in any other part of the world. While progress has been made in cancer diagnosis/treatment, much remains to be done to improve palliative care for the majority of patients with cancer who present with advanced disease. Objective: To determine knowledge, beliefs, barriers, and resources regarding palliative care services in Middle Eastern countries and use findings to inform future educational and training activities. Design: Descriptive survey. Setting/Subjects: Fifteen Middle Eastern countries; convenience sample of 776 nurses (44.3%), physicians (38.3%) and psychosocial, academic, and other health care professionals (17.4%) employed in varied settings. Measurements: Palliative care needs assessment. Results: Improved pain management services are key facilitators. Top barriers include lack of designated palliative care beds/services, community awareness, staff training, access to hospice services, and personnel/time. The nonexistence of functioning home-based and hospice services leaves families/providers unable to honor patient wishes. Respondents were least satisfied with discussions around advance directives and wish to learn more about palliative care focusing on communication techniques. Populations requiring special consideration comprise: patients with ethnic diversity, language barriers, and low literacy; pediatric and young adults; and the elderly. Conclusions: The majority of Middle Eastern patients with cancer are treated in outlying regions; the community is pivotal and must be incorporated into future plans for developing palliative care services. Promoting palliative care education and certification for physicians and nurses is crucial; home-based and hospice services must be sustained.MECCFunding was provided by MECC. Ronit Esther, MECC coordinator, is acknowledged for assistance with data collection and manuscript formatting. ONS leaders Barbara Lubejko, RN, MS, Project Manager/Education Team and Nurse Peer Review Leader/Approver Unit and Kate Shaughnessy Hankle, MBA, CVA, Management of International and Leadership Development are acknowledged for their assistance with survey revision and qualitative data analysis