Background Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D-β-hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. Methods and Results Type 2 diabetic (db/db) and their corresponding wild-type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl-CoA:3-oxoacid-CoA transferase and restored decreased expression of mitochondrial β-hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP-mediated oxygen consumption in cardiac mitochondria from both wild-type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule-associated protein 1 light chain 3-mediated autophagosome formation. Conclusions Moderate elevation in circulating D-β-hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.

Background

Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic.

Patients and methods

Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic.

Results

In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively.

Conclusions

Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making.

Clinical trial registration

NCT00976911.

Using an impact-parameter tag to select an enriched sample of Z0bb» events, we have measured the difference between the average charged multiplicity of bb» and all hadronic Z0 decays to be 2.11.8(stat) 0.6(syst) tracks per event. The resulting total (nonleading) charged multiplicity for Z0 bb» events is 23.1(12.0)1.8 0.6 tracks. A comparison of this nonleading multiplicity to hadronic multiplicity data in the range of 10 to 60 GeV supports the hypothesis of flavor-independent hadronic fragmentation, and yields a measurement of the average energy fraction of bottom hadrons in Z0 decays of xEb=0.620.100.04. © 1992 The American Physical Society.

A search for pair production of stable charged particles from Z decay has been performed with the Mark II detector at the SLAC Linear Collider. Particle masses are determined from momentum, ionization energy loss, and time-of-flight measurements. A limit excluding pair production of stable fourth-generation charged leptons and stable mirror fermions with masses between the muon mass and 36.3 GeV/c2 is set at the 95% confidence level. Pair production of stable supersymmetric scalar leptons with masses between the muon mass and 32.6 GeV/c2 is also excluded. © 1990 The American Physical Society.

We have measured the fraction of bb» events in hadronic Z0 decays, Rbb», using the vertex detector system of the Mark II detector at the SLAC Linear Collider. We tag bb» events by requiring the coincidence of three or more tracks with significant impact parameters. This tag is 50% efficient and results in a sample of 85% purity. We find Rbb»=0.251+0.049+0.030, in good agreement with other measurements and the standard model prediction. © 1991 The American Physical Society.