International Differences in Treatment and Clinical Outcomes for High Grade Glioma

Background

High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan.

Method

Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities.

Results

294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities.

Conclusion

Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment.     

Decoding Diffusivity in Multiple Sclerosis: Analysis of Optic Radiation Lesional and Non-Lesional White Matter

Objectives

Diffusion tensor imaging (DTI) has been suggested as a new promising tool in MS that may provide greater pathological specificity than conventional MRI, helping, therefore, to elucidate disease pathogenesis and monitor therapeutic efficacy. However, the pathological substrates that underpin alterations in brain tissue diffusivity are not yet fully delineated. Tract-specific DTI analysis has previously been proposed in an attempt to alleviate this problem. Here, we extended this approach by segmenting a single tract into areas bound by seemingly similar pathological processes, which may better delineate the potential association between DTI metrics and underlying tissue damage.

Method

Several compartments were segmented in optic radiation (OR) of 50 relapsing-remitting MS patients including T2 lesions, proximal and distal parts of fibers transected by lesion and fibers with no discernable pathology throughout the entire length of the OR.

Results

Asymmetry analysis between lesional and non-lesional fibers demonstrated a marked increase in Radial Diffusivity (RD), which was topographically limited to focal T2 lesions and potentially relates to the lesional myelin loss. A relative elevation of Axial Diffusivity (AD) in the distal part of the lesional fibers was observed in a distribution consistent with Wallerian degeneration, while diffusivity in the proximal portion of transected axons remained normal. A moderate, but significant elevation of RD in OR non-lesional fibers was strongly associated with the global (but not local) T2 lesion burden and is probably related to microscopic demyelination undetected by conventional MRI.

Conclusion

This study highlights the utility of the compartmentalization approach in elucidating the pathological substrates of diffusivity and demonstrates the presence of tissue-specific patterns of altered diffusivity in MS, providing further evidence that DTI is a sensitive marker of tissue damage in both lesions and NAWM. Our results suggest that, at least within the OR, parallel and perpendicular diffusivities are affected by tissue restructuring related to distinct pathological processes.     

Immunogens Modeling a Fusion-Intermediate Conformation of gp41 Elicit Antibodies to the Membrane Proximal External Region of the HIV Envelope Glycoprotein

The membrane proximal external region (MPER) of the gp41 subunit of the HIV-1 envelope glycoprotein (Env) contains determinants for broadly neutralizing antibodies and has remained an important focus of vaccine design. However, creating an immunogen that elicits broadly neutralizing antibodies to this region has proven difficult in part due to the relative inaccessibility of the MPER in the native conformation of Env. Here, we describe the antigenicity and immunogenicity of a panel of oligomeric gp41 immunogens designed to model a fusion-intermediate conformation of Env in order to enhance MPER exposure in a relevant conformation. The immunogens contain segments of the gp41 N- and C-heptad repeats to mimic a trapped intermediate, followed by the MPER, with variations that include different N-heptad lengths, insertion of extra epitopes, and varying C-termini. These well-characterized immunogens were evaluated in two different immunization protocols involving gp41 and gp140 proteins, gp41 and gp160 DNA primes, and different immunization schedules and adjuvants. We found that the immunogens designed to reduce extension of helical structure into the MPER elicited the highest MPER antibody binding titers, but these antibodies lacked neutralizing activity. The gp41 protein immunogens also elicited higher MPER titers than the gp140 protein immunogen. In prime-boost studies, the best MPER responses were seen in the groups that received DNA priming with gp41 vectors followed by gp41 protein boosts. Finally, although titers to the entire protein immunogen were similar in the two immunization protocols, MPER-specific titers differed, suggesting that the immunization route, schedule, dose, or adjuvant may differentially influence MPER immunogenicity. These findings inform the design of future MPER immunogens and immunization protocols.     

Whole-body to tissue concentration ratios for use in biota dose assessments for animals

Environmental monitoring programs often measure contaminant concentrations in animal tissues consumed by humans (e.g., muscle). By comparison, demonstration of the protection of biota from the potential effects of radionuclides involves a comparison of whole-body doses to radiological dose benchmarks. Consequently, methods for deriving whole-body concentration ratios based on tissue-specific data are required to make best use of the available information. This paper provides a series of look-up tables with whole-body:tissue-specific concentration ratios for non-human biota. Focus was placed on relatively broad animal categories (including molluscs, crustaceans, freshwater fishes, marine fishes, amphibians, reptiles, birds and mammals) and commonly measured tissues (specifically, bone, muscle, liver and kidney). Depending upon organism, whole-body to tissue concentration ratios were derived for between 12 and 47 elements. The whole-body to tissue concentration ratios can be used to estimate whole-body concentrations from tissue-specific measurements. However, we recommend that any given whole-body to tissue concentration ratio should not be used if the value falls between 0.75 and 1.5. Instead, a value of one should be assumed.     

Reduced oxygen tension results in reduced human T cell proliferation and increased intracellular oxidative damage and susceptibility to apoptosis upon activation

Cell culture and in vitro models are the basis for much biological research, especially in human immunology. Ex vivo studies of T cell physiology employ conditions attempting to mimic the in vivo situation as closely as possible. Despite improvements in controlling the cellular milieu in vitro, most of what is known about T cell behavior in vitro is derived from experiments on T cells exposed to much higher oxygen levels than are normal in vivo. In this study, we report a reduced proliferative response and increased apoptosis susceptibility after T cell activation at 2% oxygen compared to in air. To explain this observation, we tested the hypothesis of an impaired efficacy of intracellular protective mechanisms including antioxidant levels, oxidized protein repair (methionine sulfoxide reductases), and degradation (proteasome) activities. Indeed, after activation, there was a significant accumulation of intracellular oxidized proteins at more physiological oxygen levels concomitant with a reduced GSH:GSSG ratio. Proteasome and methionine sulfoxide reductase activities were also reduced. These data may explain the increased apoptotic rate observed at more physiological oxygen levels. Altogether, this study highlights the importance of controlling oxygen levels in culture when investigating oxygen-dependent phenomena such as oxidative stress.     

Low-salinity transitions drive abrupt microbial response to sea-level change

The salinisation of many coastal ecosystems is underway and is expected to continue into the future because of sea-level rise and storm intensification brought about by the changing climate. However, the response of soil microbes to increasing salinity conditions within coastal environments is poorly understood, despite their importance for nutrient cascading, carbon sequestration and wider ecosystem functioning. Here, we demonstrate deterioration in the productivity of a top-tier microbial group (testate amoebae) with increasing coastal salinity, which we show to be consistent across phylogenetic groups, salinity gradients, environment types and latitude. Our results show that microbial changes occur in the very early stages of marine inundation, presaging more radical changes in soil and ecosystem function and providing an early warning of coastal salinisation that could be used to improve coastal planning and adaptation.     

Rapid Isolation of Extracellular Vesicles from Cell Culture and Biological Fluids Using a Synthetic Peptide with Specific Affinity for Heat Shock Proteins

Recent studies indicate that extracellular vesicles are an important source material for many clinical applications, including minimally-invasive disease diagnosis. However, challenges for rapid and simple extracellular vesicle collection have hindered their application. We have developed and validated a novel class of peptides (which we named venceremin, or Vn) that exhibit nucleotide-independent specific affinity for canonical heat shock proteins. The Vn peptides were validated to specifically and efficiently capture HSP-containing extracellular vesicles from cell culture growth media, plasma, and urine by electron microscopy, atomic force microscopy, sequencing of nucleic acid cargo, proteomic profiling, immunoblotting, and nanoparticle tracking analysis. All of these analyses confirmed the material captured by the Vn peptides was comparable to those purified by the standard ultracentrifugation method. We show that the Vn peptides are a useful tool for the rapid isolation of extracellular vesicles using standard laboratory equipment. Moreover, the Vn peptides are adaptable to diverse platforms and therefore represent an excellent solution to the challenge of extracellular vesicle isolation for research and clinical applications.     

Structure and mechanism of a coreceptor for infection by a pathogenic feline retrovirus

Infection of T lymphocytes by the cytopathic retrovirus feline leukemia virus subgroup T (FeLV-T) requires FeLIX, a cellular coreceptor that is encoded by an endogenous provirus and closely resembles the receptor-binding domain (RBD) of feline leukemia virus subgroup B (FeLV-B). We determined the structure of FeLV-B RBD, which has FeLIX activity, to a 2.5-A resolution by X-ray crystallography. The structure of the receptor-specific subdomain of this glycoprotein differs dramatically from that of Friend murine leukemia virus (Fr-MLV), which binds a different cell surface receptor. Remarkably, we find that Fr-MLV RBD also activates FeLV-T infection of cells expressing the Fr-MLV receptor and that FeLV-B RBD is a competitive inhibitor of infection under these conditions. These studies suggest that FeLV-T infection relies on the following property of mammalian leukemia virus RBDs: the ability to couple interaction with one of a variety of receptors to the activation of a conserved membrane fusion mechanism. A comparison of the FeLV-B and Fr-MLV RBD structures illustrates how receptor-specific regions are linked to conserved elements critical for postbinding events in virus entry.