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.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

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. We hypothesized that the race would affect AHR the most thereby highlighting the importance of maximal effort in swim AHR. METHODS: 10 female and 15 male swimmers completed three conditions (sanctioned race of different distances, 8 min field swim challenge and swim practice). Forced vital capacity (FVC), forced expired volume in 1 second (FEV1) and forced expiratory flow (FEF25-75) were measured at rest and after each exercise condition (at 6 and 10 min) in accordance with standard protocols. AHR was defined as a decrease in FEV1 of ≥10% post exercise. RESULTS: A significant increase in FEV1 and FEF25-75 was observed for both post swim field test and post-race. The practice condition reduced FEV1 in 44% of swimmers although the magnitude of change was small. There was a wide variability in the individual responses to the 3 conditions and AHR was diagnosed in one swimmer (race condition). CONCLUSION: All conditions have poor sensitivity to diagnose EIB and total accumulated ventilation (distance swum) did not influence AHR. These results also indicate that elite swimmers, despite many risk factors, are not limited by respiratory function in race conditions. It is proposed that the swim field test not be used for AHR assessment in swimmers due to too high relative humidity.

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. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the α carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.

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. These studies demonstrated that the cyano-substituent plays a special role in favouring the formation of the 6,6,5-ring fused adduct 27 under thermodynamically controlled conditions. The utility of the cyclo-adduct 57 (see Scheme 12) as a precursor for the naturally occurring histrionicotoxins is illustrated by the synthesis of three "unsymmetrical" (i.e. with each side chain bearing different functional groups) members of the histrionicotoxin family HTX-259A, HTX-285C and HTX-285E (2, 3 and 4 respectively).

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. Video of work tasks was recorded on 22 subjects (video was recorded on 7 of the subjects for whom HR was monitored through a full working day) and analyzed for working pace and proportion of time spent on each task. RESULTS: HR during a full day (9.0 ± 1.2 hours) of tree planting work was 115.2 ± 8.8 beats.min-1, and working HR was 128.2 ± 15.6 beats.min-1 for 82.5 ± 6.8% of the work day. Mean work pace was 452 ± 174 trees.h-1, and the proportion of time spent planting each tree was 53 ± 8% of the working time. Significant (P < 0.05) positive correlations were found between work pace and experience level, and between work pace and working HR, and a significant (P < 0.05) negative correlation was found between experience level and HR for a given work pace. No significant relationships were found between experience level or work pace and the proportion of time spent planting each tree. CONCLUSIONS: Tree planters work at approximately 65% of age-predicted HRmax, and maintain HR at approximately 59% of HRmax throughout the entire working day. Productivity in these workers appears to be related to effort rather than to experience or task efficiency per se.

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. RIU sensitivity in the order of 55% is attainable for porous alumina providing excellent signal-to-noise ratio, which exceeds the sensitivity of current interferometric transducers. Finally, as a proof-of-principle, we demonstrate biosensing with two distinct immunoglobulin antibodies.

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. Due to their cell permeability, they can interact with extra- and intracellular targets, thus opening opportunities for interfering with novel biochemical pathways. We herein describe the preclinical stages of typical small-molecule research programmes and outline hurdles that may have to be overcome. A few examples of small molecules that are currently under clinical evaluation and arose from diverse discovery pathways will be discussed.

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. The past decade has, therefore, seen diverse proof-of-principle studies involving pSi-based optical and electrochemical transducers, which are highlighted here. We also provide comparative analysis of transducer sensitivity, robustness and susceptibility to interferences and cover strategies for sensitivity enhancement by means of signal amplification.

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. Upon acclimatization to altitude, CBF returns towards normal sea-level values in subsequent days and weeks, mediated by a progressive increase in PO2, first through hyperventilation followed by erythropoiesis. With long-term altitude exposure, a number of mechanisms play a role in regulating CBF, including acid-base balance, hematological modifications, and angiogenesis. Finally, several cerebrovascular disorders are associated with altitude exposure. Existing gaps in our knowledge of CBF and altitude, and areas of future investigation include effects of longer exposures, intermittent hypoxia, and gender differences in the CBF responses to altitude.

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 48.0 +/- 7.4 and 100.7 +/- 15.1 min following 60 min of cycling exercise in N (intensity = 61.6 +/- 9.5% Vo2 max) and 55.5 +/- 9.8 and 104.3 +/- 9.1 min following 60 min cycling exercise in H (intensity = 65.4 +/- 7.1% hypoxic Vo2 max), where Vo2 max = 65.0 +/- 7.5 ml x kg(-1) x min(-1) (N) and 54.1 +/- 7.0 ml x kg(-1) x min(-1) (H). Two subjects demonstrated mild exercise-induced arterial hypoxemia (EIAH) [minimum arterial oxygen saturation (SaO2 min) = 94.5% and 93.8%], and seven subjects demonstrated moderate EIAH (SaO2 min = 91.4 +/- 1.1%) as measured noninvasively during the Vo2 max test in N. Mean lung densities, measured once preexercise and twice postexercise, were 0.177 +/- 0.019, 0.181 +/- 0.019, and 0.173 +/- 0.019 g/ml (N) and 0.178 +/- 0.021, 0.174 +/- 0.022, and 0.176 +/- 0.019 g/ml (H), respectively. No significant differences (P > 0.05) were found in lung density following exercise in either condition or between conditions. Transient interstitial pulmonary edema did not occur following sustained steady-state cycling exercise in N or H, indicating that transient edema does not result from pulmonary capillary leakage during sustained submaximal exercise.

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. A limited number of studies have been completed with the specific purpose of identifying pulmonary oedema following exercise or a similar intervention. Of these, approximately 50% have observed a positive change and the remaining have provided results that are either inconclusive or show no change in extravascular lung water. While it is difficult to draw a firm conclusion from these studies, we believe that pulmonary oedema does occur in some humans following exercise. As such, this is a phenomenon of significance to pulmonary and exercise physiologists. This possibility warrants further study in the area with more precise measurement tools than has previously been undertaken.

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 (80.6 +/- 10.7 kg vs 76.8 +/- 8.5 kg) and body fat (13.3% +/- 5.5% vs. 10.4% +/- 5.0%) in the men (P < .05). No changes in skin-fold-corrected limb girths were found in the men or women. Initial body mass was significantly (P < .05) correlated with mass loss in men (r2 = .46) and women (r2 = .67). Estimated daily energy consumption was 20680.1 +/- 2204.5 kJ for men and 14516.6 +/- 2077.3 kJ for women, and estimated daily fat consumption was 194.2 +/- 30.1 g for men and 132.3 +/- 35.6 g for women. CONCLUSIONS: Ten weeks of tree planting leads to significant decreases in body mass and body fat in men while maintaining skin-fold-corrected limb girths.

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 +/- 0.8 L x min(-1) participated in a double-blinded crossover design. Subjects underwent baseline (B) tests for anaerobic (Wingate test) and aerobic (VO (2peak) test) cycling power. Subjects ingested either 60 mg of pseudoephedrine hydrochloride (D) or a placebo (P) and, after 90 min of rest, a Wingate and a cycling efficiency test were performed. During the cycling efficiency test, heart rate (HR) and VO(2) were averaged for the last 5 min of a 10-min cycle at 40% and 60% of the peak power achieved during the VO (2peak) test. RESULTS: There were no significant differences in peak power (B = 860 +/- 154, D = 926 +/- 124, P = 908 +/- 118 W), total work (B = 20 +/- 3, D = 21 +/- 3, P = 21 +/- 3 kJ), or fatigue index (B = 39 +/- 8, D = 45 +/- 5, P = 43 +/- 5%). There were no significant differences in HR at 40% power (D = 138 +/- 10, P = 137 +/- 10 beats.min-1) or 60% power (D = 161 +/- 11, P = 160 +/- 11 beats x min(-1). There were no significant differences in cycling efficiency at 40% power (D = 18.8 +/- 1.8, P = 18.5 +/- 1.8%) or 60% power (D = 20.3 +/- 2.0, P = 20.1 +/- 2.1%). CONCLUSION: A therapeutic dose of pseudoephedrine hydrochloride does not affect anaerobic cycling performance or aerobic cycling efficiency.

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). The incremental ride to exhaustion resulted in a 56% reduction in spleen volume, which recovered to baseline levels within 20 min. Plasma catecholamines were inversely related to spleen volume after exercise (r = 0.70-0.84; P < 0.0001). There were no differences in red cell or total blood volume pre- to postexercise; however, a significant reduction in plasma volume was observed (18.9%; P < 0.01). There was no difference between the iodinated albumin and the hematocrit and hemoglobin methods of assessing plasma volume changes. These results suggest that the spleen regulates its volume in response to an intensity-dependent signal, and plasma catecholamines appear partially responsible. Splenic release of erythrocytes has no effect on indirect measures of plasma volume.