A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.

Lessons learnedThe combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.BackgroundAndrogen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.MethodsThis phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.ResultsSix patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.ConclusionThe combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43

Plasma proteins in a standardised skin mini-erosion (II): effects of extraction pressure

BACKGROUND: A standardised suction technique has been used to sample plasma proteins in dermal interstitial fluid (IF) serially for 5 to 6 days from a suction-induced skin mini-erosion. Increased protein concentrations ascribed to inflammation have been shown from day 1 onward. In this study, we assessed the effect of two different extraction pressures on IF sample composition. METHODS: Total protein concentration and the concentrations of insulin, prealbumin, albumin, transferrin, IgG and alpha-2-macroglobulin were assessed daily in healthy volunteers. Samples were extracted at 50 mmHg and 200 mmHg below the atmospheric. RESULTS: At 0 h after forming the erosion, mean total IF protein content (relative to plasma) was lower in the samples extracted at -200 mmHg than at -50 mmHg (26 +/-13% (SD) vs 48 +/-9.8%; p < 0.05). There were no significant differences at 24, 48, 72 or 96 h. Of the individual proteins, expressed as area units (AU) for area under the curve (AUC) from 0–96 h, albumin was lower in IF sampled at -200 mmHg (2.49 +/- 0.68 vs 3.08 +/- 0.36 AU; p < 0.05), as was transferrin (1.91 +/- 0.52 vs 2.40 +/- 0.42 AU; p < 0.05). Extraction volumes were significantly higher at -200 mmHg (AUC diff: 60%; p < 0.05). CONCLUSIONS: Samples of IF extracted at 0 h at -200 mmHg contained lower protein concentrations, indicating an increased water fraction and an intact sieve function of the vascular wall. The difference in protein concentration extracted at higher and lower pressure from 24 h onward was less pronounced. Lower pressure should be used to sample substances of greater molecular size

Plasma proteins in a standardised skin mini-erosion (I): permeability changes as a function of time

BACKGROUND: A standardised technique using a suction-induced mini-erosion that allows serial sampling of dermal interstitial fluid (IF) for 5 to 6 days has been described. In the present study, we studied permeability changes as a function of time. METHODS: We examined IF concentrations of total protein concentration and the concentration of insulin (6.6 kDa), prealbumin (55 kDa), albumin (66 kDa), transferrin (80 kDa), IgG (150 kDa) and alpha-2-macroglobulin (720 kDa) as a function of time, using an extraction pressure of 200 mmHg below atmospheric. RESULTS: At 0 h after forming the erosion, mean total IF protein content (relative to plasma) was 26 ± 13% (SD). For the individual proteins, the relative mean concentrations were 65 ± 36% for insulin, 48 ± 12% for albumin, 30 ± 19% for transferrin, 31 ± 15%for IgG and 19.5 ± 10% for alpha-2-macroglobulin. At 24 h, the total IF protein content was higher than at 0 h (56 ± 26% vs 26 ± 13%; p < 0.05, diff: 115%), as were some of the individual protein concentrations: prealbumin (50 ± 24 vs 25 ± 13%; p < 0.05), albumin (68 ± 21 vs 48 ± 12%; p < 0.05) and IgG (55 ± 30 vs 31 ± 15%; p = 0.05). ln the interval 24 h to 96 h the concentrations were relatively unchanged. CONCLUSIONS: The results indicate that fluid sampled at 0 h after forming the erosion represents dermal IF before the full onset of inflammation. From 24 h onward, the sampled fluid reflects a steady state of increased permeability induced by inflammation. This technique is promising as a tool for clinically sampling substances that are freely distributed in the body and as a model for studying inflammation and vascular permeability

Near-infrared spectroscopy detects age-related differences in skeletal muscle oxidative function: promising implications for geroscience

Age is the greatest risk factor for chronic disease and is associated with a marked decline in functional capacity and quality of life. A key factor contributing to loss of function in older adults is the decline in skeletal muscle function. While the exact mechanism(s) remains incompletely understood, age-related mitochondrial dysfunction is thought to play a major role. To explore this question further, we studied 15 independently living seniors (age: 72 ± 5 years; m/f: 4/11; BMI: 27.6 ± 5.9) and 17 young volunteers (age: 25 ± 4 years; m/f: 8/9; BMI: 24.0 ± 3.3). Skeletal muscle oxidative function was measured in forearm muscle from the recovery kinetics of muscle oxygen consumption using near-infrared spectroscopy (NIRS). Muscle oxygen consumption was calculated as the slope of change in hemoglobin saturation during a series of rapid, supra-systolic arterial cuff occlusions following a brief bout of exercise. Aging was associated with a significant prolongation of the time constant of oxidative recovery following exercise (51.8 ± 5.4 sec vs. 37.1 ± 2.1 sec, P = 0.04, old vs. young, respectively). This finding suggests an overall reduction in mitochondrial function with age in nonlocomotor skeletal muscle. That these data were obtained using NIRS holds great promise in gerontology for quantitative assessment of skeletal muscle oxidative function at the bed side or clinic

The TIGRE gamma-ray telescope

TIGRE is an advanced telescope for gamma-ray astronomy with a few arcmin resolution. From 0.3 to 10 MeV it is a Compton telescope. Above 1 MeV, its multi-layers of double sided silicon strip detectors allow for Compton recoil electron tracking and the unique determination for incident photon direction. From 10 to 100 MeV the tracking feature is utilized for gamma-ray pair event reconstruction. Here we present TIGRE energy resolutions, background simulations and the development of the electronics readout system

Minute-of-Arc Resolution Gamma ray Imaging Experiment—MARGIE

MARGIE (Minute-of-Arc Resolution Gamma-ray Imaging Experiment) is a large area(∼104 cm2), wide field-of-view (∼1 sr), hard X-ray/gamma-ray (∼20–600 keV) coded-mask imaging telescope capable of performing a sensitive survey of both steady and transient cosmic sources. MARGIE has been selected for a NASA mission-concept study for an Ultra Long Duration (100 day) Balloon flight. We describe our program to develop the instrument based on new detector technology of either cadmium zinc telluride (CZT) semiconductors or pixellated cesium iodide (CsI) scintillators viewed by fast-timing bi-directional charge-coupled devices (CCDs). The primary scientific objectives are to image faint Gamma-Ray Bursts (GRBs) in near-real-time at the low intensity (high-redshift) end of the logN-logS distribution, thereby extending the sensitivity of present observations, and to perform a wide field survey of the Galactic plane

MARGIE: A gamma-ray burst ultra-long duration balloon mission

We are designing MARGIE as a 100 day ULDB mission to: a) detect and localize gamma-ray bursts; and b) survey the hard X-ray sky. MARGIE will consist of one small field-of-view (FOV) and four large FOV coded mask modules mounted on a balloon gondola. The burst position will be calculated onboard and disseminated in near-real time, while information about every count will be telemetered to the ground for further analysis. In a 100-day mission we will localize ∼40 bursts with peak photon fluxes from 0.14 to ∼5 ph cm−2 s−1 using 1 s integrations; the typical localization resolution will be better than ∼2 arcminutes

Tracking and imaging gamma ray experiment (TIGRE) for 1 to 100 MEV gamma ray astronomy

A large international collaboration from the high energy astrophysics community has proposed the Tracking and Imaging Gamma Ray Experiment (TIGRE) for future space observations. TIGRE will image and perform energy spectroscopy measurements on celestial sources of gamma rays in the energy range from 1 to 100 MeV. This has been a difficult energy range experimentally for gamma ray astronomy but is vital for the future considering the recent exciting measurements below 1 and above 100 MeV. TIGRE is both a double scatter Compton and gamma ray pair telescope with direct imaging of individual gamma ray events. Multi‐layers of Si strip detectors are used as Compton and pair converters CsI(Tl) scintillation detectors are used as a position sensitive calorimeter. Alternatively, thick GE strip detectors may be used for the calorimeter. The Si detectors are able to track electrons and positrons through successive Si layers and measure their directions and energy losses. Compton and pair events are completely reconstructed allowing each event to be imaged on the sky. TIGRE will provide an order‐of‐magnitude improvement in discrete source sensitivity in the 1 to 100 MeV energy range and determine spectra with excellent energy and excellent angular resolutions. It’s wide field‐of‐view of π sr permits observations of the entire sky for extended periods of time over the life of the mission