Repurposing metformin for cancer treatment: current clinical studies.

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment

Notifications of hospital events to outpatient clinicians using health information exchange: a post-implementation survey

Background The trend towards hospitalist medicine can lead to disjointed patient care. Outpatient clinicians may be unaware of patients’ encounters with a disparate healthcare system. Electronic notifications to outpatient clinicians of patients’ emergency department (ED) visits and inpatient admissions and discharges using health information exchange can inform outpatient clinicians of patients’ hospital-based events.Objective Assess outpatient clinicians’ impressions of a new, secure messaging-based, patient event notification system.Methods Twenty outpatient clinicians receiving notifications of hospital-based events were recruited and 14 agreed to participate. Using a semi-structured interview, clinicians were asked about their use of notifications and the impact on their practices.Results Nine of 14 interviewed clinicians (64%) thought that without notifications, they would have heard about fewer than 10% of ED visits before the patient’s next visit. Nine clinicians (64%) thought that without notifications, they would have heard about fewer than 25% of inpatient admissions and discharges before the patient’s next visit. Six clinicians (43%) reported that they call the inpatient team more often because of notifications. Eight users (57%) thought that notifications improved patient safety by increasing their awareness of the patients’ clinical events and their medication changes. Key themes identified were the importance of workflow integration and a desire for more clinical information in notifications.Conclusions The notification system is perceived by clinicians to be of value. These findings should instigate further message-oriented use of health information exchange and point to refinements that can lead to even greater benefits

The application of differential ratings of perceived exertion to Australian Football League matches

Objectives: To investigate the application of differential ratings of perceived exertion for the examination of internal load during Australian Football League (AFL) matches. Design: Single cohort, observational study. Methods: Using the centiMax rating of perceived exertion (RPE) scale, 26 professional AFL players provided ratings for match exertion (RPE-M), along with differential ratings for breathlessness (RPE-B), leg exertion (RPE-L), and technical demand (RPE-T) following 129 matches (5.0 ± 1.6 matches per player). Global positioning satellite (GPS) and accelerometer measures were also collected. Data were analysed using magnitude-based inferences. Results: RPE scores were 93.0 ± 8.2 AU (RPE-M), 89.0 ± 11.0 AU (RPE-B), 91.5 ± 9.8 AU (RPE-L), and 87.0 ± 10.0 AU (RPE-T). There was a most likely small difference between RPE-L and RPE-T (5.5%; ±90% confidence limits 1.9%), a likely small difference between RPE-L and RPE-B (3.5%; ±1.5%) and a possibly small difference between RPE-B and RPE-T (1.9%; ±1.9%). Within-player correlations between RPE and GPS measures were small for RPE-M (r = 0.14–0.28), unclear to small for RPE-B (r = 0.06–0.24) and unclear to moderate for RPE-L (r = 0.06–0.37). Differential RPE's combined to explain 76% of the variance in RPE-M. For all RPE scores, within-player variability was moderate to high (typical error: 7.9–12.4%), and the thresholds for a likely between-match change were 8.8–13.7%. Conclusions: As differential RPE's represent distinct sensory inputs, the collection of these scores facilitate the interpretation of internal match loads and therefore represent a valuable addition to match data collection procedures. Moderate to high within-player variability should be considered when interpreting between-match changes in all RPE scores

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Achieving high-sensitivity for clinical applications using augmented exome sequencing

daSNVs in ACMG genes where inadequate coverage was observed among at least one platform, using WES/ACE data normalized to both 12 Gb and 100× mean coverage. (XLSX 312 kb