Control of amino-acid transport coordinates metabolic reprogramming in T cell malignancy

This study explores the regulation and importance of System L amino acid transport in a murine model of T cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). There has been a strong focus on glucose transport in leukemias but the present data show that primary T-ALL cells have increased transport of multiple nutrients. Specifically, increased leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1α (HIF1α) and c-Myc; drivers of glucose metabolism in T cells. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1α or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the predominant amino acid transporter in primary PTEN(-/-) T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data reveal the importance of regulated amino acid transport for T cell malignancies, highlighting how a single amino acid transporter can play a key role.Leukemia accepted article preview online, 26 May 2017. doi:10.1038/leu.2017.160.</p

The Great American Biotic Interchange: Dispersals, Tectonics, Climate, Sea Level and Holding Pens

The biotic and geologic dynamics of the Great American Biotic Interchange are reviewed and revised. Information on the Marine Isotope Stage chronology, sea level changes as well as Pliocene and Pleistocene vegetation changes in Central and northern South America add to a discussion of the role of climate in facilitating trans-isthmian exchanges. Trans-isthmian land mammal exchanges during the Pleistocene glacial intervals appear to have been promoted by the development of diverse non-tropical ecologies

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

The protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines [HT-29, Cl.19A, Caco-2, SW480, HCT-8 and T84]. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1–100 nM) or AP2 (10–100 μM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1–1 nM) or AP2 (1–300 μM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours. © 2001 Cancer Research Campaign http://www.bjcancer.co

THE IMPACT OF AN ACUTE EXERCISE AND NUTRITION INTERVENTION ON ADVERSE POSTPRANDIAL METABOLIC OUTCOMES

Lexi J. Ater, Ellie K. Plantz, Turner D. Manning, Elizabeth S. Edwards, FACSM, Jeremy D. Akers, Stephanie P. Kurti. James Madison University, Harrisonburg, VA. Background: Postprandial metabolic responses have been shown to be a better predictor of myocardial infarction and cardiovascular disease risk compared to fasting levels alone. Even a single high-fat, high-carbohydrate meal (HFHCM) results in adverse triglyceride (TRG), glucose (GLU), and metabolic load index (MLI; summation of TRG and GLU) in older adults (OA). Existing research suggests that either acute postprandial exercise (EX) or a high-polyphenol nutritional intervention may attenuate the adverse postprandial responses, however there is no study assessing the combined effect of a minimally processed, high-polyphenol and EX intervention in OA. Therefore, the purpose of this study was to determine whether a nutrition intervention in combination with acute exercise alters postprandial TRG, GLU and MLI more than either intervention alone. Methods: In a randomized crossover design, OA (n=10, 4 M/6 F, 57 ± 6.9 years) completed the following 4 conditions: (1) traditional HFHCM (T-HFHCM) alone, (2) T-HFHCM + EX, (3) a HFHCM with polyphenols (P-HFHCM) alone, (4) a P-HFHCM + EX. Participants consumed 12 kcals/kg BW in all HFHCM conditions. The P-HFHCM was created by a dietitian to be matched in fat and CHO content to the T-HFHCM (~58% saturated fat, ~38% CHO, ~33g added sugar). EX was performed 30 mins after the pie was consumed and consisted of walking at a self-selected speed and grade to expend 25% of the kcals consumed from the HFHCM (~30 mins EX/participant). Blood GLU and TRG were measured at baseline, 30, 60, 90 mins, and every hour for 6 hours post-prandially. Results: There was a significant increase in TRG, GLU and MLI post-HFHCM (p’s \u3e 0.05), which was attenuated by EX similarly in the T-HFHCM + EX and P-HFHCM + EX conditions (p \u3c 0.001) without any impact of the meal intervention alone (p = 0.180). Interestingly, there was a time*condition interaction for TRG and MLI, where the P-HFHCM, P-HFHCM+ EX and T-HFHCM + EX all had a significant and similar attenuation of TRG compared to the T-HFHCM alone (p \u3c 0.001). Conclusions: A HFHCM intervention combined with EX lowers postprandial GLU and TRG more than a T-HFHCM, however increasing polyphenol content elicits similar TRG reductions as completing postprandial EX alone. Still, because GLU reductions were not seen in the P-HFHC alone, there is justification to encourage OA to consume high polyphenol meals and engage in postprandial EX