No abstract

Amino acids are among the earliest identified inducers of yeast-to-hyphal transitions in Candida albicans , an opportunistic fungal pathogen of humans. Here, we show that the morphogenic amino acids arginine, ornithine and proline are internalized and metabolized in mitochondria via a PUT1 - and PUT2 -dependent pathway that results in enhanced ATP production. Elevated ATP levels correlate with Ras1/cAMP/PKA pathway activation and Efg1-induced gene expression. The magnitude of amino acid-induced filamentation is linked to glucose availability; high levels of glucose repress mitochondrial function thereby dampening filamentation. Furthermore, arginine-induced morphogenesis occurs more rapidly and independently of Dur1,2-catalyzed urea degradation, indicating that mitochondrial-generated ATP, not CO 2 , is the primary morphogenic signal derived from arginine metabolism. The important role of the SPS-sensor of extracellular amino acids in morphogenesis is the consequence of induced amino acid permease gene expression, i.e., SPS-sensor activation enhances the capacity of cells to take up morphogenic amino acids, a requisite for their catabolism. C . albicans cells engulfed by murine macrophages filament, resulting in macrophage lysis. Phagocytosed put1-/- and put2 -/- cells do not filament and exhibit reduced viability, consistent with a critical role of mitochondrial proline metabolism in virulence.

Purpose: Bone marrow-derived progenitor cells, including VEGFR2þ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. Experimental Design: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.Results: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P ¼ 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P ¼ 0.04), LOX activity (P ¼ 0.03), and collagen crosslinking (P ¼ 0.012).Conclusions: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted.

Oxygen intake, ventilation and heart rate were measured in six subjects performing ergometer exercise at various altitudes from sea level to 7,440 m (24,400 ft) (Bar. 300 mm Hg) during a Himalayan expedition lasting 8 months. Oxygen intake for a given work rate was constant and independent of altitude, up to the maximum work rate that could be maintained for 5 min. Maximum oxygen intake declined with increase of altitude, reaching 1.46 liters/min at 7,440 m (24,400 ft) in the best subject. Ventilation (STPD) for a given work rate was independent of altitude in light and moderate exercise but increased at each altitude as maximum oxygen intake was approached. Ventilation values of 140–200 liters (BTPS)/min were observed at altitudes above 4,650 m (15,300 ft). Heart rates at altitude were higher at low and moderate work intensities, but the same as or lower than the corresponding sea-level value for the same work load, as maximum oxygen intake was approached. Breathing oxygen at sea-level pressure at 5,800 m (19,000 ft) reduced ventilation and heart rate for a given work rate, restored work capacity almost to sea-level values and increased maximum heart rate. With the aid of data on blood, lung diffusion, and cardiac output from companion studies, the oxygen transport system was analyzed in three subjects, including a high-altitude Sherpa; and evidence is put forward that lung diffusion, cardiac output, and the high oxygen cost of extreme ventilation all contributed to the limitation of exercise at 5,800 m (19,000 ft). respiration, work and altitude; ventilation, work and altitude; heart rate, work and altitude; O2 transport system at high altitudes; altitude acclimatization Submitted on July 29, 1963

A. Sánchez, L.L. Couëtil, M.P. Ward, and S.P. Clark Inflammatory Airway Disease (IAD), exercise-induced pulmonary hemorrhage (EIPH), and upper airway obstruction (UAO) are common respiratory tract diseases that can decrease performance. The purpose of this retrospective study was to compare bronchoalveolar lavage fluid cytology and arterial blood gas analysis during a treadmill test by poorly performing racehorses presented to Purdue University. One hundred thirty-two horses with a history of poor performance were included in this study. Ten horses with no history or diagnosis of EIPH, IAD, or UAO served as controls. Horses were evaluated by rhinolaryngoscopy for upper airway abnormalities and underwent a standardized treadmill test, and samples were collected for blood gas analysis. Horses with IAD or EIPH had a more severe exercise-induced hypoxemia, (mean Ϯ SD; 84.8 Ϯ 1.5 and 86.0 Ϯ 1.7 mm Hg average PaO 2 , respectively), than horses in the control group (92.8 Ϯ 2.1 mm Hg). The average PaO 2 of horses with only UAO (88.3 Ϯ 3.3 mm Hg) was not significantly different from control horses. Gas exchanges were the most severely impaired in horses affected with both EIPH and UAO because they exhibited the lowest PaO 2 and highest PaCO 2 values (66.5 Ϯ 15.2 and 52.2 Ϯ 6.3 mm Hg, respectively).