44 research outputs found
Multifunctionality of Prostatic Acid Phosphatase in Prostate Cancer Pathogenesis
The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wildtype PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies
Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease
For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27- year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient
Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals
Cell fractionation indicates that the compounds access the nucleus. The most potent compounds were exposed to HEK cells at a concentration of 1Â ÎźM for 24Â h, after which the nucleus was separated from the cytoplasm. The concentration of these two blue compounds could be observed by the relative higher intensity in the nucleus compared to that in the cytoplasm. (PDF 3721 kb
GBT440 Inhibits Sickling of Sickle Cell Trait Blood under In Vitro Conditions Mimicking Strenuous Exercise
In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death. We report that GBT440, an agent being developed for the treatment of SCD, increases the affinity of oxygen for Hb and inhibits in vitro polymerization of a mixture of HbS and HbA that simulates SCT blood. Moreover, GBT440 prevents sickling of SCT blood under in vitro conditions mimicking strenuous exercise with hypoxia, dehydration and acidosis. Together, our results indicate that GBT440 may have the potential to protect SCT individuals from sickling-related complications during conditions that favor HbS polymerization
Spatial and temporal regulation of coronary vessel formation by calcineurin-NFAT signaling
Formation of the coronary vasculature requires reciprocal signaling between
endothelial, epicardially derived smooth muscle and underlying myocardial
cells. Our studies show that calcineurin-NFAT signaling functions in
endothelial cells within specific time windows to regulate coronary vessel
development. Mouse embryos exposed to cyclosporin A (CsA), which inhibits
calcineurin phosphatase activity, failed to develop normal coronary
vasculature. To determine the cellular site at which calcineurin functions for
coronary angiogenesis, we deleted calcineurin in endothelial, epicardial and
myocardial cells. Disruption of calcineurin-NFAT signaling in endothelial
cells resulted in the failure of coronary angiogenesis, recapitulating the
coronary phenotype observed in CsA-treated embryos. By contrast, deletion of
calcineurin in either epicardial or myocardial cells had no effect on coronary
vasculature during early embryogenesis. To define the temporal requirement for
NFAT signaling, we treated developing embryos with CsA at overlapping windows
from E9.5 to E12.5 and examined coronary development at E12.5. These
experiments demonstrated that calcineurin-NFAT signaling functions between
E10.5 and E11.5 to regulate coronary angiogenesis. Consistent with these in
vivo observations, endothelial cells exposed to CsA within specific time
windows in tissue culture were unable to form tubular structures and their
cellular responses to VEGF-A were blunted. Thus, our studies demonstrate
specific temporal and spatial requirements of NFAT signaling for coronary
vessel angiogenesis. These requirements are distinct from the roles of NFAT
signaling in the angiogenesis of peripheral somatic vessels, providing an
example of the environmental influence of different vascular beds on the in
vivo endothelial responses to angiogenic stimuli