Clinical Research and Development of Tuberculosis Diagnostics: Moving From Silos to Synergy

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations

Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth

Copyright: © 2015 Kung et al. Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2á and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole

Nanoscale Metallic Iron for Environmental Remediation: Prospects and Limitations

The amendment of the subsurface with nanoscale metallic iron particles (nano-Fe0) has been discussed in the literature as an efficient in situ technology for groundwater remediation. However, the introduction of this technology was controversial and its efficiency has never been univocally established. This unsatisfying situation has motivated this communication whose objective was a comprehensive discussion of the intrinsic reactivity of nano-Fe0 based on the contemporary knowledge on the mechanism of contaminant removal by Fe0 and a mathematical model. It is showed that due to limitations of the mass transfer of nano-Fe0 to contaminants, available concepts cannot explain the success of nano-Fe0 injection for in situ groundwater remediation. It is recommended to test the possibility of introducing nano-Fe0 to initiate the formation of roll-fronts which propagation would induce the reductive transformation of both dissolved and adsorbed contaminants. Within a roll-front, FeII from nano-Fe0 is the reducing agent for contaminants. FeII is recycled by biotic or abiotic FeIII reduction. While the roll-front concept could explain the success of already implemented reaction zones, more research is needed for a science-based recommendation of nano- Fe0 for subsurface treatment by roll-front

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

PURPOSE: This randomized, open -label trial compared the efficacy and safety of adjuvant nabpaclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment -naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m(2)) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28 -day cycles. The primary end point was independently assessed disease -free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nabpaclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P =.18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P=.02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P =.045). At a 16 -month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P =.0232). At the 5 -year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P =.0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade >= 3 treatment -emergent adverse events. Two patients per study arm died of treatment -emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine

104 Administration of a DNA immunostimulant does not mitigate bovine herpesvirus-1 recrudescence in dexamethasone challenged beef cattle

Abstract The study objective was to determine the effect of a DNA immunostimulant on recrudescence of bovine herpesvirus-1 (BHV-1) after dexamethasone challenge in beef cattle. It was hypothesized that the DNA immunostimulant would mitigate stress-induced immunosuppression; thereby, reducing the incidence of BHV-1 recrudescence. Steers (n=10) and heifers (n=10; initial BW = 489 kg ± 57 kg) were stratified by pre-existing BHV-1 antibody titer, sex and initial BW and randomly assigned to treatment (n=4 pens/treatment; 2 or 3 animals/pen). All calves were administered 40 mg of dexamethasone i.v. at 0600 h from d 0 to 2, 166-d subsequent to BHV-1 challenge with 1.0 × 108 plaque-forming units per nostril. On d 1, calves were administered treatments consisting of 2 mL i.m. of DNA immunostimulant (Zelnate; ZEL) or sterile saline (CON). Once daily (0600) from d 0 to 12, a whole blood was obtained via jugular venipuncture for complete blood count (CBC) analysis and nasal swabs were collected to determine BHV-1 prevalence via virus isolation testing. A repeated measures mixed model was used to test the effect of treatment, day and their interaction for CBC variables. There was a treatment × day interaction for eosinophils (P = 0.02) and percent eosinophils (P = 0.03). Eosinophils were greater (P &lt; 0.01) for ZEL on d 3 and 6 post-dexamethasone challenge. On d 11 and 12, eosinophils for CON rebounded such that their concentration was greater than ZEL (P &lt; 0.01). Lymphocytes, neutrophil and monocyte concentration did not differ (P ≥ 0.44); however, a day effect (P ≤ 0.01) existed such that each variable increased transiently after dexamethasone challenge. All cattle had BHV-1 present in a nasal swab sample on at least one sample day, with prevalence of BHV-1 in nasal swab samples being greatest on d 5 (80% positive; P = 0.01). However, no treatment differences were detected for BHV-1 prevalence in this study. The DNA immunostimulant altered eosinophil concentrations but did not mitigate BHV-1 recrudesce after dexamethasone challenge</jats:p

3 Administration of a DNA immunostimulant does not mitigate bovine herpesvirus-1 recrudescence in dexamethasone challenged beef cattle

Abstract The study objective was to determine the effect of a DNA immunostimulant on recrudescence of bovine herpesvirus-1 (BHV-1) after dexamethasone challenge in beef cattle. It was hypothesized that the DNA immunostimulant would mitigate stress-induced immunosuppression; thereby, reducing the incidence of BHV-1 recrudescence. Steers (n = 10) and heifers (n = 10; initial BW = 489 kg ± 57 kg) were stratified by pre-existing BHV-1 antibody titer, sex and initial BW and randomly assigned to treatment (n = 4 pens/treatment; 2 or 3 animals/pen). All calves were administered 40 mg of dexamethasone i.v. at 0600 h from d 0 to 2, 166-d subsequent to BHV-1 challenge with 1.0 × 108 plaque-forming units per nostril. On d 1, calves were administered treatments consisting of 2 mL i.m. of DNA immunostimulant (Zelnate; ZEL) or sterile saline (CON). Once daily (0600) from d 0 to 12, a whole blood was obtained via jugular venipuncture for complete blood count (CBC) analysis and nasal swabs were collected to determine BHV-1 prevalence via virus isolation testing. A repeated measures mixed model was used to test the effect of treatment, day and their interaction for CBC variables. There was a treatment × day interaction for eosinophils (P = 0.02) and percent eosinophils (P = 0.03). Eosinophils were greater (P &lt; 0.01) for ZEL on d 3 and 6 post-dexamethasone challenge. On d 11 and 12, eosinophils for CON rebounded such that their concentration was greater than ZEL (P &lt; 0.01). Lymphocytes, neutrophil and monocyte concentration did not differ (P ≥ 0.44); however, a day effect (P ≤ 0.01) existed such that each variable increased transiently after dexamethasone challenge. All cattle had BHV-1 present in a nasal swab sample on at least one sample day, with prevalence of BHV-1 in nasal swab samples being greatest on d 5 (80% positive; P = 0.01). However, no treatment differences were detected for BHV-1 prevalence in this study. The DNA immunostimulant altered eosinophil concentrations but did not mitigate BHV-1 recrudesce after dexamethasone challenge</jats:p