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

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 1 ΟM for 24 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

Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals.

Viral capsid assembly involves the oligomerization of the capsid nucleoprotein (NP), which is an essential step in viral replication and may represent a potential antiviral target. An in vitro transcription-translation reaction using a wheat germ (WG) ext

A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease

New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg/day) in patients with sickle cell anemia (HbSS). The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof-of-concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg/day, or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg/day, or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg/day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased hemoglobin and reduction in hemolysis and percent of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. ClinicalTrials.gov identification: #NCT02285088 and #NCT03041909