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#28934061   2017/09/21 Save this To Up

Current Safety Issues with Quadrivalent Meningococcal Conjugate Vaccines.

Invasive meningococcal disease, although rare, can present as sudden, life-threatening disease with high risk of mortality or severe long-term sequelae. The main prevention strategy for invasive meningococcal disease in the United States is the routine vaccination of adolescents and other persons at increased risk of meningococcal disease with quadrivalent meningococcal conjugate vaccines. Two such vaccines are currently licensed and available in the United States, Menactra® (Sanofi Pasteur) and Menveo® (Glaxo Smith Kline), and usage in the adolescent population have steadily increased since their introduction. Although early reports raised concerns about a possible association of Menactra with Guillain-Barré syndrome, a comprehensive safety review determined that if such risk existed it was no more than 0.66 cases per 1 million vaccinations. More recently, a study found an elevated risk of Bell's palsy when Menveo was administered concomitantly with other vaccines but no association was found when the vaccine was administered alone. In this commentary, we describe the current state of knowledge with respect to the safety of quadrivalent meningococcal conjugate vaccines, and we identify potential areas for safety research for these vaccines.

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#28933832   2017/09/21 Save this To Up

Detoxification of atrazine by low molecular weight thiols in alfalfa (Medicago sativa).

Low molecular weight (LMW) thiols in higher plants are a group of sulfur-rich non-protein compounds and play primary and multiple roles in cellular redox homeostasis, enzyme activities, and xenobiotics detoxification. This study focused on identifying thiols-related protein genes from the legume alfalfa exposed to the herbicide atrazine (ATZ) residues in environment. Using high-throughput RNA-sequencing, a set of ATZ-responsive thiols-related protein genes highly up-regulated and differentially expressed in alfalfa were identified. Most of the differentially expressed genes (DEGs) were involved in regulation of biotic and abiotic stress responses. By analyzing the genes involved in thiols-mediated redox homeostasis, we found that many of them were thiols-synthetic enzymes such as γ-glutamylcysteine synthase (γECS), homoglutathione synthetase (hGSHS) and glutathione synthetase (GSHS). Using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we further characterized a group of ATZ-thiols conjugates, which are the detoxified forms of ATZ in plants. Cysteine S-conjugate ATZ-HCl+Cys was the most important metabolite detected by the mass spectrometry. Several other ATZ-conjugates were also examined as ATZ-detoxified metabolites. Such results were validated by characterizing their analogs in rice. Our data showed that some conjugates under ATZ stress were detected in both plants, indicating that some detoxified mechanisms and pathways can be shared by the two plant species. Overall, these results indicate that LMW thiols play critical roles in detoxification of ATZ in the plants.

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#28933740   2017/09/21 Save this To Up

Synthesis, Characterization and In Vitro Evaluation of a Novel Glycol Chitosan-EDTA Conjugate to Inhibit Aminopeptidase-Mediated Degradation of Thymopoietin Oligopeptides.

In this study, a novel conjugate consisting of glycol chitosan (GCS) and ethylene diamine tetraacetic acid (EDTA) was synthesized and characterized in terms of conjugation and heavy metal ion chelating capacity. Moreover, its potential application as a metalloenzyme inhibitor was evaluated with three thymopoietin oligopeptides in the presence of leucine aminopeptidase. The results from FTIR and NMR spectra revealed that the covalent attachment of EDTA to GCS was achieved by the formation of amide bonds between the carboxylic acid group of EDTA and amino groups of GCS. The conjugated EDTA lost part of its chelating capacity to cobalt ions compared with free EDTA as evidenced by the results of cobalt ion chelation-mediated fluorescence recovery of calcein. However, further investigation confirmed that GCS-EDTA at low concentrations significantly inhibited leucine aminopeptidase-mediated degradation of all thymopoietin oligopeptides.

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#28932211   2017/09/21 Save this To Up

Strain Level Streptococcus Colonization Patterns during the First Year of Life.

Pneumococcal pneumonia has decreased significantly since the implementation of the pneumococcal conjugate vaccine (PCV), nevertheless, in many developing countries pneumonia mortality in infants remains high. We have undertaken a study of the nasopharyngeal (NP) microbiome during the first year of life in infants from The Philippines and South Africa. The study entailed the determination of the Streptococcus sp. carriage using a lytA qPCR assay, whole metagenomic sequencing, and in silico serotyping of Streptococcus pneumoniae, as well as 16S rRNA amplicon based community profiling. The lytA carriage in both populations increased with infant age and lytA+ samples ranged from 24 to 85% of the samples at each sampling time point. We next developed informatic tools for determining Streptococcus community composition and pneumococcal serotype from metagenomic sequences derived from a subset of longitudinal lytA-positive Streptococcus enrichment cultures from The Philippines (n = 26 infants, 50% vaccinated) and South African (n = 7 infants, 100% vaccinated). NP samples from infants were passaged in enrichment media, and metagenomic DNA was purified and sequenced. In silico capsular serotyping of these 51 metagenomic assemblies assigned known serotypes in 28 samples, and the co-occurrence of serotypes in 5 samples. Eighteen samples were not typeable using known serotypes but did encode for capsule biosynthetic cluster genes similar to non-encapsulated reference sequences. In addition, we performed metagenomic assembly and 16S rRNA amplicon profiling to understand co-colonization dynamics of Streptococcus sp. and other NP genera, revealing the presence of multiple Streptococcus species as well as potential respiratory pathogens in healthy infants. A range of virulence and drug resistant elements were identified as circulating in the NP microbiomes of these infants. This study revealed the frequent co-occurrence of multiple S. pneumoniae strains along with Streptococcus sp. and other potential pathogens such as S. aureus in the NP microbiome of these infants. In addition, the in silico serotype analysis proved powerful in determining the serotypes in S. pneumoniae carriage, and may lead to developing better targeted vaccines to prevent invasive pneumococcal disease (IPD) in these countries. These findings suggest that NP colonization by S. pneumoniae during the first years of life is a dynamic process involving multiple serotypes and species.

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#28931515   2017/09/21 Save this To Up

Gemtuzumab Ozogamicin Makes a Comeback.

After being pulled from the market 7 years ago, gemtuzumab ozogamicin has been reapproved by the FDA, this time for adults newly diagnosed with acute myeloid leukemia, as well as patients 2 years of age and older with relapsed/refractory disease. The CD33-targeting antibody-drug conjugate can be given as a single agent or in combination with chemotherapy.

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#28929266   2017/09/20 Save this To Up

Brazilian meningococcal C conjugate vaccine: physicochemical, immunological, and thermal stability characteristics.

High temperature is known to cause some instability in polysaccharide-protein conjugated vaccines and studies under stress conditions may be useful in determining whether short-term accidental exposure to undesired conditions can compromise product quality. In this study, we examined the structural stability of three industrial batches of Brazilian Meningococcal C conjugate bulk (MPCT) incubated at 4, 37, and 55 °C for 5 weeks. The effect of exposure to the storage temperatures was monitored by HPLC-SEC, CZE, CD and NMR techniques. The immunological significance of any physicochemical changes observed in MPCT was determined by SBA and ELISA assays of serum from immunized mice. Fluorescence emission spectra at 4 and 37 °C were similar among all samples and compatible with the native fold of the carrier protein. Fluorescence spectra of MPCT stored at 55 °C decreased in intensity and had a significant red-shift, indicating conformational changes. Far-UV CD spectra revealed a trend toward loss of structural conformation as storage temperature was increased to 55 °C. The NMR data showed modified signal intensity of the aromatic and aliphatic residues, mainly for samples incubated at 55 °C, suggesting a partial loss of tertiary structure. About 50% free saccharide content was found in bulks stored at 55 °C, but no difference was observed in the IgG or SBA titers. The present study showed physicochemical methods alone are insufficient to predict the biological activity of a MPCT conjugate vaccine without extensive validation against immunological data. However, they provide a sensitive means of detecting changes induced in a vaccine exposed to adverse environmental condition.

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#28928078   2017/09/20 Save this To Up

A nationwide study on the impact of pneumococcal conjugate vaccination on antibiotic use and ventilation tube insertion in Denmark 2000-2014.

Introduction of Pneumococcal Conjugated Vaccines (PCV) in national immunization programs have been successful in reducing the number of invasive and lower respiratory pneumococcal infections. The impact of the vaccines on upper respiratory infections caused by pneumococci is less clear although these account for most pneumococcal infections. In this study, we used likely proxies for respiratory infections in children, such as antibiotic use and ventilation tube insertions (VTI), to estimate the impact of the vaccine on a national level. The study was designed as a population-based retrospective observational study, comparing trends in the incidence rate of antibiotic prescriptions and VTIs in the period 2000-2014, where PCV7 was introduced in 2007 and PCV13 in 2010. The introduction of PCV7 and PCV13 correlated with changes in the incidence rate from an almost steady increase in prescription of antibiotics in the pre-PCV period to a decreasing incidence for all children age 0-15years. The 2.4 DDD per person year in 2014 was at almost the same level of antibiotic use as in 2000 at 2.3 DDD per person year. Similar patterns were observed in the mostly vaccinated age groups below 5years of age. For VTI we observed a decreasing incidence rate in the years following introduction of PCV13 ending with a slightly higher incidence at 35 per 1000 person years in 2014 compared to 31 in year 2000. We conclude that the steady increase in antibiotic use and VTI in the pre-PCV period have been partially reversed to near year 2000 levels after the introduction of PCV. This indicates that implementation of pneumococcal vaccines in the Childhood Vaccination Programme has likely reduced the incidence of upper respiratory diseases due to pneumococci in Denmark.

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#28928039   2017/09/20 Save this To Up

Vaccination Coverage of Adolescents With Chronic Medical Conditions.

Adolescents with chronic medical conditions (CMCs) are at increased risk of vaccine-preventable infections. Little is known about their vaccine uptake.

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#28927194   2017/09/20 Save this To Up

Finding a facile way for the bacterial DNA transformation by biosynthesized gold nanoparticles.

The major problem encountered during genetic manipulation of bacteria is the inability to get transformed because of their natural non-competency. In this study, to overcome this problem, a cost-effective method was developed by combining the properties of gold nanoparticles (GNPs) and the Yoshida effect. Various parameters, including GNP:plasmid ratio, pH and time, were optimized for stability of the GNP-plasmid conjugate. With non-competent Gram-negative cells, the efficiency ranged between 0.1 and 0.45 × 104 transformants μg-1, while the range was (0.02-0.2) × 104 transformants μg-1 with Gram-positive bacteria. GNPs can serve efficiently as a vehicle for better transformation in bacteria.

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#28926265   2017/09/19 Save this To Up

Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells.

Platinum resistance in ovarian cancer is the major determinant of disease prognosis. Resistance can first appear at the onset of disease or develop in response to platinum-based chemotherapy. Due to poor response to alternate chemotherapies and lack of targeted therapies, there is an urgent clinical need for a new avenue toward treatment of platinum-resistant (PR) ovarian cancer. Nanoscale delivery systems hold potential to overcome resistance mechanisms. In this work, we present tobacco mosaic virus (TMV) as a nanocarrier for cisplatin for treatment of PR ovarian cancer cells. The TMV-cisplatin conjugate (TMV-cisPt) was synthesized using a charge-driven reaction that, like a classic click reaction, is simple and reliable for large-scale production. Up to ∼1900 cisPt were loaded per TMV-cisPt with biphasic release profiles characterized by a fast half-life (t1) of ∼1 h and slow half-life (t2) of ∼12 h independent of pH. Efficient cell uptake of TMV was observed when incubated with ovarian cancer cells, and TMV-cisPt demonstrated superior cytotoxicity and DNA double strand breakage (DSB) in platinum-sensitive (PS) and PR cancer cells when compared to free cisplatin. The cytotoxicity in PR ovarian cancer cells and overall lower effective dosage requirement makes TMV-cisPt a powerful candidate for improved ovarian cancer treatment strategies.

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