Validity of the Public Health Accreditation Board’s Governance Measures

Background. The dynamics through which governance operates and impacts performance has been the focus of scholars in recent years. This is also true in public health systems, where there is a growing tendency to understand governance mechanisms and dimensions, as illustrated in the Public Health Accreditation Board’s (PHAB’s) Domain 12, which tends to measure governance engagement in health departments. The development of Domain 12 standards and measures has undergone systematic revisions by subject matters and experts. However, there is still a need for a scientific approach to assess the validity of such measures, or examine whether they measure what they were set to measure. Objectives. To provide an understanding of how governance, and public health governance in particular, has been operationalized and measured in the literature; what measures offer high degrees of validity; and evidence of the conformity and validity, or the lack thereof, of Domain 12 standards and measures. The project findings will enable accreditation experts in PHAB to improve their understanding and use of the standards and measures. Methods. This study was divided into three separate papers. First, a systematic review of the literature of public health governance measures and validity studies was conducted. Second, we employed empirical data, using Chi-Square test and t-test, of health departments’ characteristics and performance in relation to Domain 12 to assess the conformance of Domain 12 measures against the existing governance structure and the type of governing entities. Third, health departments’ performance scores in Domain 12 were tested against their performance scores in the other domains (convergent validity). Results. Surveys and questionnaires were the most commonly used instruments in the literature to evaluate governance. A large number of governance dimensions emerged but few validity studies were performed to assess these dimensions. In terms of governance conformance of PHAB’s Domain 12, the resulted associations were statistically insignificant, which indicate that there is no evidence to support the conformity of PHAB’s Domain 12 measures. As for the convergent validity study, results showed a lack of meaningful associations (few statistically significant associations) between Domain 12 measures and measures under other PHAB’s domains. Conclusion. Although there seems to be no one particular and valid measure of governance with the various governance measures and few validity studies that the literature yielded, the literature review may assist in identifying appropriate theoretical frameworks for measuring public health governance. Also, despite the fact that the analysis of conformity and the validity study show no evidence of “valid” measures of Domain 12, other attributes must be considered such as data limitations and inadequacies in the data collection process, in addition to conducting more validity studies using different validation approaches

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-target-ed therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desa-turase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desatura-tion in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lip-otoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological ma-nipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) pri-marily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the sat-uration state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mech-anisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies