Hypoxia Potentiates Glioma-Mediated Immunosuppression

Glioblastoma multiforme (GBM) is a lethal cancer that exerts potent immune suppression. Hypoxia is a predominant feature of GBM, but it is unclear to the degree in which tumor hypoxia contributes to this tumor-mediated immunosuppression. Utilizing GBM associated cancer stem cells (gCSCs) as a treatment resistant population that has been shown to inhibit both innate and adaptive immune responses, we compared immunosuppressive properties under both normoxic and hypoxic conditions. Functional immunosuppression was characterized based on production of immunosuppressive cytokines and chemokines, the inhibition of T cell proliferation and effector responses, induction of FoxP3+ regulatory T cells, effect on macrophage phagocytosis, and skewing to the immunosuppressive M2 phenotype. We found that hypoxia potentiated the gCSC-mediated inhibition of T cell proliferation and activation and especially the induction of FoxP3+T cells, and further inhibited macrophage phagocytosis compared to normoxia condition. These immunosuppressive hypoxic effects were mediated by signal transducer and activator of transcription 3 (STAT3) and its transcriptionally regulated products such as hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Inhibitors of STAT3 and HIF-1α down modulated the gCSCs' hypoxia-induced immunosuppressive effects. Thus, hypoxia further enhances GBM-mediated immunosuppression, which can be reversed with therapeutic inhibition of STAT3 and HIF-1α and also helps to reconcile the disparate findings that immune therapeutic approaches can be used successfully in model systems but have yet to achieve generalized successful responses in the vast majority of GBM patients by demonstrating the importance of the tumor hypoxic environment

Global burden of disease due to smokeless tobacco consumption in adults : analysis of data from 113 countries

BACKGROUND: Smokeless tobacco is consumed in most countries in the world. In view of its widespread use and increasing awareness of the associated risks, there is a need for a detailed assessment of its impact on health. We present the first global estimates of the burden of disease due to consumption of smokeless tobacco by adults. METHODS: The burden attributable to smokeless tobacco use in adults was estimated as a proportion of the disability-adjusted life-years (DALYs) lost and deaths reported in the 2010 Global Burden of Disease study. We used the comparative risk assessment method, which evaluates changes in population health that result from modifying a population's exposure to a risk factor. Population exposure was extrapolated from country-specific prevalence of smokeless tobacco consumption, and changes in population health were estimated using disease-specific risk estimates (relative risks/odds ratios) associated with it. Country-specific prevalence estimates were obtained through systematically searching for all relevant studies. Disease-specific risks were estimated by conducting systematic reviews and meta-analyses based on epidemiological studies. RESULTS: We found adult smokeless tobacco consumption figures for 115 countries and estimated burden of disease figures for 113 of these countries. Our estimates indicate that in 2010, smokeless tobacco use led to 1.7 million DALYs lost and 62,283 deaths due to cancers of mouth, pharynx and oesophagus and, based on data from the benchmark 52 country INTERHEART study, 4.7 million DALYs lost and 204,309 deaths from ischaemic heart disease. Over 85 % of this burden was in South-East Asia. CONCLUSIONS: Smokeless tobacco results in considerable, potentially preventable, global morbidity and mortality from cancer; estimates in relation to ischaemic heart disease need to be interpreted with more caution, but nonetheless suggest that the likely burden of disease is also substantial. The World Health Organization needs to consider incorporating regulation of smokeless tobacco into its Framework Convention for Tobacco Control

CT-based classification of long spinal allograft fusion

Anterior column reconstruction of the thoracolumbar spine by structural allograft has an increased potential for biological fusion when compared to synthetic reconstructive options. Estimation of cortical union and trabecular in-growth is, however, traditionally based on plain radiography, a technique lacking in sensitivity. A new assessment method of bony union using high-speed spiral CT imaging is proposed which reflects the gradually increasing biological stability of the construct. Grade I (complete fusion) implies cortical union of the allograft and central trabecular continuity. Grade II (partial fusion) implies cortical union of the structural allograft with partial trabecular incorporation. Grade III (unipolar pseudarthrosis) denotes superior or inferior cortical non-union of the central allograft with partial trabecular discontinuity centrally and Grade IV (bipolar pseudarthrosis) suggests both superior and inferior cortical non-union with a complete lack of central trabecular continuity. Twenty-five patients underwent anterior spinal reconstruction for a single level burst fracture between T4 and L5. At a minimum of two years follow up the subjects underwent high-speed spiral CT scanning through the reconstructed region of the thoracolumbar spine. The classification showed satisfactory interobserver (kappa score = 0.91) and intraobserver (kappa score = 0.95) reliability. The use of high-speed CT imaging in the assessment of structural allograft union may allow a more accurate assessment of union. The classification system presented allows a reproducible categorization of allograft incorporation with implications for treatment

Selective Hydrogenation of Levulinic Acid Using Ru/C Catalysts Prepared by Sol-Immobilisation

A 1% Ru/C catalyst prepared by the sol immobilization method showed a high yield of γ-valerolactone from levulinic acid. We performed an optimization of the catalyst by varying the preparation variables involved in the sol immobilization method and detremined that the ratio of PVA, NaBH4 to Ru and heat treatment conditions play a crucial role in the synthesis of active and selective catalysts. By varying these parameters we have identified the optimum conditions for catalyst preparation by providing well dispersed nanoparticles of RuOx on the carbon support that are reducible under low reaction temperature and in turn gave an enhanced catalytic activity. In contrast to a catalyst prepared without using a PVA stabiliser, the use of a small amount PVA (PVA/Ru = 0.1) provided active nanoparticles, by controlling the steric size of the Ru nanoparticles. An optimum amount of NaBH4 was required in order to provide the reducible Ru species on the surface of catalyst and further increase in NaBH4 was found to cause a decline in activity that was related to the kinetics of nanoparticle formation during catalyst preparation. A variation of heat treatment temperature showed a corresponding decrease in catalytic activity linked with the sintering and an increase in particle size

Mechanically controlled quantum interference in graphene break junctions

The ability to detect and distinguish quantum interference signatures is important for both fundamental research and for the realization of devices such as electron resonators1, interferometers2 and interference-based spin filters3. Consistent with the principles of subwavelength optics, the wave nature of electrons can give rise to various types of interference effects4, such as Fabry–Pérot resonances5, Fano resonances6 and the Aharonov–Bohm effect7. Quantum interference conductance oscillations8 have, indeed, been predicted for multiwall carbon nanotube shuttles and telescopes, and arise from atomic-scale displacements between the inner and outer tubes9,10. Previous theoretical work on graphene bilayers indicates that these systems may display similar interference features as a function of the relative position of the two sheets11,12. Experimental verification is, however, still lacking. Graphene nanoconstrictions represent an ideal model system to study quantum transport phenomena13–15 due to the electronic coherence16 and the transverse confinement of the carriers17. Here, we demonstrate the fabrication of bowtie-shaped nanoconstrictions with mechanically controlled break junctions made from a single layer of graphene. Their electrical conductance displays pronounced oscillations at room temperature, with amplitudes that modulate over an order of magnitude as a function of subnanometre displacements. Surprisingly, the oscillations exhibit a period larger than the graphene lattice constant. Charge-transport calculations show that the periodicity originates from a combination of the quantum interference and lattice commensuration effects of two graphene layers that slide across each other. Our results provide direct experimental observation of a Fabry–Pérot-like interference of electron waves that are partially reflected and/or transmitted at the edges of the graphene bilayer overlap region.Accepted Author ManuscriptQN/van der Zant LabBN/Cees Dekker La

A prospective randomised controlled trial of femoral ring allograft versus a titanium cage in circumferential lumbar spinal fusion with minimum 2-year clinical results

The original publication can be found at www.springerlink.comThe literature reports on the safety and efficacy of titanium cages (TCs) with additional posterior fixation for anterior lumbar interbody fusion. However, these papers are limited to prospective cohort studies. The introduction of TCs for spinal fusion has resulted in increased costs, without evidence of superiority over the established practice. There are currently no prospective controlled trials comparing TCs to femoral ring allografts (FRAs) for circumferential fusion in the literature. In this prospective, randomised controlled trial, our objective was to compare the clinical outcome following the use of FRA (current practice) to the use of TC in circumferential lumbar spinal fusion. Full ethical committee approval and institutional research and development departmental approval were obtained. Power calculations estimated a total of 80 patients (40 in each arm) would be required to detect clinically relevant differences in functional outcome. Eighty-three patients were recruited for the study fulfilling strict entry requirements (>6 months chronic discogenic low back pain, failure of conservative treatment, one- or two-level discographically proven discogenic low back pain). The patients completed the Oswestry Disability Index (ODI), Visual Analogue Score (VAS) for back and leg pain and the Short-Form 36 (SF-36) preoperatively and also postoperatively at 6, 12 and 24 months, respectively. The results were available for all the 83 patients with a mean follow-up of 28 months (range 24–75 months). Five patients were excluded on the basis of technical infringements (unable to insert TC in four patients and FRA in one patient due to the narrowing of the disc space). From the remaining 78 patients randomised, 37 received the FRA and 41 received the TC. Posterior stabilisation was achieved with translaminar or pedicle screws. Baseline demographic data (age, sex, smoking history, number of operated levels and preoperative outcome measures) showed no statistical difference between groups (p11 points in all domains (p<0.03) except that of general health and emotional role. For patients who received the TC, mean VAS improved by 1.1 points (p=0.004), mean ODI improved by 6 points (p=0.01) and SF-36 improved significantly in only two of the eight domains (bodily pain and physical function). Revision procedures and complications were similar in both groups. In conclusion, this prospective, randomised controlled clinical trial shows the use of FRA in circumferential lumbar fusion to be associated with superior clinical outcomes when compared to those observed following the use of TCs. The use of TCs for circumferential lumbar spinal fusion is not justified on the basis of inferior clinical outcome and the tenfold increase in cost.Patrick J. McKenna, Brian J. C. Freeman, Robert C. Mulholland, Michael P. Grevitt, John K. Webb and S. H. Mehdia