Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.

Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA damage signaling is known to affect the fitness of HSCs, the data argue that caPOT1 mutations do not cause significant telomere damage. Furthermore, hESC lines with caPOT1 mutations showed no detectable telomere damage response while showing consistent telomere elongation. Thus, caPOT1 mutations are likely selected for during cancer progression because of their ability to elongate telomeres and extend the proliferative capacity of the incipient cancer cells.

Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita.

Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo.

Translating research evidence into practice to reduce health disparities: a social determinants approach.

Translating research evidence to reduce health disparities has emerged as a global priority. The 2008 World Health Organization Commission on Social Determinants of Health recently urged that gaps in health attributable to political, social, and economic factors should be closed in a generation. Achieving this goal requires a social determinants approach to create public health systems that translate efficacy documented by research into effectiveness in the community. We review the scope, definitions, and framing of health disparities and explore local, national, and global programs that address specific health disparities. Such efforts translate research evidence into real-world settings and harness collaborative social action for broad-scale, sustainable change.

Public health emergency preparedness exercises: lessons learned.

The Harvard School of Public Health Center for Public Health Preparedness exercise program has two aims: (1) educating the public health workforce on key public health system emergency preparedness issues, and (2) identifying specific systems-level challenges in the public health response to large-scale events. Rigorous evaluation of 38 public health emergency preparedness (PHEP) exercises employing realistic scenarios and reliable and accurate outcome measures has demonstrated the usefulness of PHEP exercises in clarifying public health workers' roles and responsibilities, facilitating knowledge transfer among these individuals and organizations, and identifying specific public health systems-level challenges.

Public health systems research in emergency preparedness: a review of the literature.

BACKGROUND: Despite the acknowledged promise of developing a public health systems research (PHSR) agenda for emergency preparedness, there has been no systematic review of the literature in this area. The purpose of this study was to conduct a systematic literature review in order to identify and characterize the PHSR literature produced in the U.S. in the past 11 years in the field of public health emergency preparedness. EVIDENCE ACQUISITION: Articles were searched in MEDLINE and EMBASE, as well as in the gray literature. Two independent reviewers classified the articles according to study design and IOM public health emergency preparedness (PHEP) research goal areas. EVIDENCE SYNTHESIS: From January 1, 1997, through December 31, 2008, there were 547 articles that met the inclusion criteria that were published. It was possible to classify 314 (57%) articles into at least one of the four IOM PHEP research goal areas. Of these, 61 (11%) addressed Research Area 1 (usefulness of training); 39 (7%) addressed Research Area 2 (communications in preparedness and response); 193 (35%) addressed Research Area 3 (sustainable preparedness and response systems); and 39 (7%) addressed Research Area 4 (criteria and metrics to measure effectiveness and efficiency). Twenty-one studies (4%) could be classified into more than one category. The majority of the articles (81%), including commentaries/reviews and case studies, were based on qualitative analysis. Commentaries/review articles were the most common study types (62%). CONCLUSIONS: Since 2001, the PHSR literature on PHEP issues has grown at about 33% per year. However, most studies lack a rigorous design, raising questions about the validity of the results.