Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.

Field versus race pace conditions to provoke exercise-induced bronchoconstriction in elite swimmers: Influence of training background.

Background: Diagnosing Airway hyper-responsiveness (AHR) requires bronchial provocation tests that are performed at rest and after exercise or hyperventilation in either a lab or field setting. Presently, it is unclear whether the proposed AHR field test for swimming induces sufficient provocation due to lack of intensity. Thus we aimed to examine how the 8 minute field swim test compared to all out racing and a lower intensity practice exposure affected AHR.

Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System.

Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging.

Intramolecular nitrone dipolar cycloadditions: control of regioselectivity and synthesis of naturally-occurring spirocyclic alkaloids.

The intramolecular nitrone dipolar cycloaddition of in situ-generated nitrones such as compound 26 has been used for the synthesis of cyclic isoxazolidines 27 and 29. The regioselectivity of the intramolecular cycloaddition depends on the nature of the terminal substituent on the dipolarophile. The influence of the substituent on the regioselectivity of the cycloaddition has been examined using several model systems and two methods of nitrone formation.

Physical exertion and working efficiency of reforestation workers.

Background: The purpose of this study was to quantify the physical exertion during tree planting work and to examine the relationships between exertion, task efficiency, and productivity.

Methods: Heart rate (HR) was monitored on 34 tree planters while they worked. HR data was collected for a complete working day on 19 subjects and for shorter periods of time on 15 subjects.

Nanoporous alumina-based interferometric transducers ennobled.

A high fidelity interferometric transducer is designed based on platinum-coated nanoporous alumina films. The ultrathin metal coating significantly improves fidelity of the interferometric fringe patterns in aqueous solution and increases the signal-to-noise ratio. The performance of this transducer is tested with respect to refractive index unit (RIU) sensitivity measured as a change in effective optical thickness (EOT) in response to a solvent change and compared to porous silicon based transducers.

Development of small-molecule therapies for autoimmune diseases.

Until the recent advent of genetically engineered drugs, small molecules constituted the predominant method of treatment for autoimmune diseases. Both modalities have advantages and disadvantages; while protein-based therapeutics interfere very selectively with the function of their biological targets, they have to be administered subcutaneously or intravenously. Small molecules have the potential for oral administration.

Porous silicon biosensors on the advance.

Biosensor research is a rapidly expanding field with an immense market potential spanning a broad spectrum of applications including biomedical diagnostics, environmental monitoring, veterinary and food quality control. Porous silicon (pSi) is a nanostructured material poised to take centre stage in the biosensor development effort. This can be ascribed to the ease and speed of fabrication, remarkable optical and morphological properties of the material (including tuneable pore size and porosity), large internal surface area and the versatile surface chemistry.

Cerebrovascular responses to altitude.

The regulation of cerebral blood flow (CBF) is a complex process that is altered significantly with altitude exposure. Acute exposure produces a marked increase in CBF, in proportion to the severity of the hypoxia and mitigated by hyperventilation-induced hypocapnia when CO(2) is uncontrolled. A number of mediators contribute to the hypoxia-induced cerebral vasodilation, including adenosine, potassium channels, substance P, prostaglandins, and NO.

Human lung density is not altered following normoxic and hypoxic moderate-intensity exercise: implications for transient edema.

The purpose of this study was to examine the effects of exercise on extravascular lung water as it may relate to pulmonary gas exchange. Ten male humans underwent measures of maximal oxygen uptake (Vo2 max) in two conditions: normoxia (N) and normobaric hypoxia of 15% O2 (H). Lung density was measured by quantified MRI before and 48.

Pulmonary oedema following exercise in humans.

Pulmonary physiologists have documented many transient changes in the lung and the respiratory system during and following exercise, including the incomplete oxygen saturation of arterial blood in some subjects, possibly due to transient pulmonary oedema. The large increase in pulmonary arterial pressure during exercise, leading to either increased pulmonary capillary leakage and/or pulmonary capillary stress failure, is likely to be responsible for any increase in extravascular lung water during exercise. The purpose of this article is to summarise the studies to date that have specifically examined lung water following exercise.

The effects of 10 weeks of reforestation work on body composition.

Objective: To document changes in body composition and body mass in male and female tree planters.

Methods: Height, mass, skin-fold thickness, and limb girths were measured in 17 male and 5 female tree planters before and after 10 weeks of work.

Results: Significant decreases were found in body mass (80.

Effects of upper extremity exercise training on peak aerobic and anaerobic fitness in patients after transplantation.

We found that patients with transplants, regardless of transplant type, and sedentary control subjects experience significant increases in aerobic fitness after 10 weeks of Dragon boat training. However, the magnitude of improvement in aerobic fitness depends on the transplant type, with patients having cardiac transplant experiencing greater relative changes in response to training than patients with noncardiac transplant. It also appears that patients with cardiac and noncardiac transplants have an increased reliance on anaerobic energy systems during exercise conditions compared with healthy control subjects.

Effects of pseudoephedrine on maximal cycling power and submaximal cycling efficiency.

Purpose: To study the effects of a therapeutic dose of pseudoephedrine on anaerobic cycling power and aerobic cycling efficiency.

Methods: Eleven healthy moderately trained males (VO (2peak) 4.4 +/- 0.

Cardiovascular and splenic responses to exercise in humans.

To investigate splenic erythrocyte volume after exercise and the effect on hematocrit- and hemoglobin-based plasma volume equations, nine men cycled at an intensity of 60% maximal O(2) uptake for 5-, 10-, or 15-min duration, followed by an incremental ride to exhaustion. The reduction in spleen volume, calculated using (99m)Tc-labeled erythrocytes, was not significantly different among the three submaximal rides (5 min = 28%, 10 min = 30%, 15 min = 36%; P = 0.26).