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Background Chronic inflammation plays an important role in head and neck squamous cell carcinomas (HNSCC). This study addresses the impact of two single nucleotide polymorphisms (SNP) Asp299Gly and Thr399Ile of the toll-like receptor (TLR) 4 gene on the clinical outcome while accounting for the influence of adjuvant systemic therapy in a large cohort of HNSCC patients. Methods Genotype analysis was done using DNA from tissue samples from 188 patients with HNSCC; TLR4 protein expression was assessed immunohistochemically in tissue microarrays. Classical survival models were used for statistical analyses. Results Ten percent of patients with HNSCC presented with the TLR4 299Gly and 17% with the TLR4 399Ile allele. Patients with the heterozygous genotype TLR4 Asp299Gly had a significantly reduced disease-free and overall survival. Also, patients with the heterozygous genotype TLR4 Thr399Ile had a reduced disease-free survival. Notably, these associations seem to be attributable to relatively poor therapy response as e.g. reflected in a significantly shorter DFS among HNSCC patients carrying the Asp299Gly variant and receiving adjuvant systemic therapy. Conclusion According to this study, TLR4 299Gly und 399Ile alleles may serve as markers for prognosis of head and neck cancer in patients with adjuvant systemic therapy, particularly chemotherapy, and might indicate therapy resistance.

Drawing fromextensive archival work and long-term ethnographic research, this book focuseson the so-called Bhotiyas, former trans-Himalayan traders and a Scheduled Tribeof India who reside in several high valleys of the Kumaon Himalaya. The area islocated in the border triangle between India, the Tibet Autonomous Region (TAR,People's Republic of China), and Nepal, where contestations over politicalboundaries have created multiple challenges as well as opportunities for localmountain communities. Basedon an analytical framework that is grounded in and contributes to recentadvances in the field of border studies, the author explores how theBhotiyas have used their agency to developa flourishing trans-Himalayan trade under British colonial influence; to assertan identity and win legal recognition as a tribal community in the politicalsetup of independent India; and to innovate their pastoral mobility in thecontext of ongoing state and market reforms. By examining theBhotiyas' trade, identity and mobility thisbook shows how and why the Himalayan border region has evolved as an agentive siteof political action for a variety of different actors.

Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease of the skin, with both vascular and metabolic effects. Aggravating factors have been identified that initiate and maintain inflammation, including expression of Th1-, Th17-, and Th22-cell derived cytokines. Recently, we showed that the evolutionarily ancient and highly conserved damage-associated molecular pattern molecule \"high mobility group box 1 (HMGB1)\" is significantly increased in the serum of PV patients with disease progression and is decreased under standard therapies. To better understand the role of HMGB1 in the pathogenesis of PV, we recruited 22 untreated psoriatic patients with either mild or severe disease, defined by the Psoriasis Area Severity Index. We assessed HMGB1 and receptor for advanced glycation end products (RAGE) expression in the skin by immunohistochemistry and analyzed the immune-phenotype of Treg and Th17 cells by flow cytometry. We found increased staining for HMGB1 in the dermis of psoriatic plaques in comparison to uninvolved skin of patients with PV. In addition, the major histocompatibility complex class III-encoded DNA and HMGB1 RAGE, induced by HMGB1, were highly expressed on psoriatic CD8+ T cells and CD4+ Treg. High expression of HMGB1 in the lesional skin was associated with even higher expression of its receptor, RAGE, on the cell surface of keratino-cytes in patients with severe PV. The presence of HMGB1 and RAGE signaling may impact orchestration of chronic inflammation in PV which might have implications for Treg and Th17 cells.

Asteroseismology probes the internal structures of stars by using their natural pulsation frequencies 1 . It relies on identifying sequences of pulsation modes that can be compared with theoretical models, which has been done successfully for many classes of pulsators, including low-mass solar-type stars 2 , red giants 3 , high-mass stars 4 and white dwarfs 5 . However, a large group of pulsating stars of intermediate mass—the so-called δ Scuti stars—have rich pulsation spectra for which systematic mode identification has not hitherto been possible 6 , 7 . This arises because only a seemingly random subset of possible modes are excited and because rapid rotation tends to spoil regular patterns 8 – 10 . Here we report the detection of remarkably regular sequences of high-frequency pulsation modes in 60 intermediate-mass main-sequence stars, which enables definitive mode identification. The space motions of some of these stars indicate that they are members of known associations of young stars, as confirmed by modelling of their pulsation spectra. The pulsation spectra of intermediate-mass stars (so-called δ Scuti stars) have been challenging to analyse, but new observations of 60 such stars reveal remarkably regular sequences of high-frequency pulsation modes.

Purpose To evaluate the accuracy of integrated 18 F-FDG PET/MR imaging for locoregional tumour evaluation compared to 18 F-FDG PET/CT and MR imaging in initial tumour and recurrence diagnosis in histopathologically confirmed head and neck squamous cell carcinoma (HNSCC). Methods 18 F-FDG PET/CT and integrated 18 F-FDG PET/MR imaging were performed for initial tumour staging or recurrence diagnosis in 25 patients with HNSCC. MR, fused 18 F-FDG PET/CT and fused 18 F-FDG PET/MR images were analysed by two independent readers in separate sessions in random order. In initial tumour staging, T and N staging was performed while individual lesions were analysed in patients with suspected cancer recurrence. In T and N staging, histopathological results after tumour resection served as the reference standard while histopathological sampling as well as cross-sectional and clinical follow-up were accepted in cancer recurrence diagnosis. The diagnostic accuracy of each modality was calculated separately for T and N staging as well as for tumour recurrence, and compared using McNemar’s test. Values of p <0.017 were considered statistically significant after Bonferroni correction. Results In 12 patients undergoing 18 F-FDG PET/CT and 18 F-FDG PET/MR for initial tumour staging, T staging was accurate in 50 % with MRI, in 59 % with PET/CT and in 75 % with PET/MR while N staging was accurate in 75 % with MRI, in 77 % with PET/CT and in 71 % with PET/MR in relation to the reference standard. No significant differences were observed in T and N staging among the three modalities ( p  > 0.017). In 13 patients undergoing hybrid imaging for cancer recurrence diagnosis, diagnostic accuracy was 57 % with MRI and in 72 % with 18 F-FDG PET/CT and 18 F-FDG PET/MR, respectively. Again, no significant differences were found among the three modalities ( p  > 0.017). Conclusion In this initial study, no significant differences were found among 18 F-FDG PET/MR, 18 F-FDG PET/CT and MRI in local tumour staging and cancer recurrence diagnosis.

Universal access to sustainable and modern energy is considered key to a wide range of aspired development outcomes. Related initiatives are particularly contested when it comes to a tree-based form of bioenergy that is used in large quantities all around the world and that ranks among the most commercialised but least regulated commodities in sub-Saharan Africa, namely charcoal. Throughout the region charcoal is used for residential cooking and heating by millions of households. While consumers are mainly located in urban and peri-urban settings, the growing demand for charcoal is largely met by rural dryland populations whose production-end practices have long been considered a major cause of deforestation and land degradation. Recent charcoal policies aim to create and support sustainable production pathways, especially through the provisioning of appropriate technologies (for instance, more efficient kilns) and improved managerial mechanisms (such as standardised environmental assessments). In order to make local forms of knowledge and practice more relevant to ongoing scholarly and political discussions on the charcoal sector, this paper proposes the notion of fuelscape as a conceptual space where the environmental and livelihood impacts of charcoal production can be revealed, compared and debated. This proposition is developed in three parts. In the first part, we introduce fuelscapes as a critical tool through which to approach (dryland) energy landscapes. In the second part, we explore how local stakeholders in Central Pokot, Kenya, account for the shifting significance and contested meaning of commercialised charcoal production in temporal, material and social terms. The discussion then captures contested fuelscapes more broadly and with reference to three interrelated themes; namely historicity, complexity and diversity. We conclude by suggesting key areas of strategic lesson-drawing for future charcoal research and policy in sub-Saharan drylands.

This article introduces one of South Asia＇s most important border regions into academic discourse, namely, the Central Himalayan mountain rim separating India and the Tibetan Autonomous Region （People＇s Republic of China）. What makes this border region so interesting is a tangled interplay of changing environmental, cultural, and political forms to which the local populations constantly have to adapt in order to make a living there. We focused on the so-called ＇Bhotiyas＇ of Uttarakhand, former trans- Himalayan traders whose ethnicity and livelihood was traditionally associated with the Indo-Chinese border that was sealed as a result of the India-China war in 1962. Drawing on the work of borderland scholarship, we identified the key processes and developments that changed the perspective of this area. Competing political aspirations as well as the ＇Bhotiyas＇ countervailing strategies were considered equally important for understanding local livelihoods and identities within the dynamics of a ＇high mountain border region＇. Through an exemplary analysis of historical differences of power in one ＇Bhotiya＇ valley, we further explored the ways in which shifting socio-spatial constellations are creatively re-interpreted by the borderlanders.

Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory T cells (T(reg)). To study the role of T(reg) in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the induction and expansion of IL-10(+) T(reg )type 1 (Tr1) was established. An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic cells (iDC), CD4(+)CD25(- )T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) +/- 1 nM rapamycin. Autologous iDC and CD4(+)CD25(-) T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays +/- neutralizing anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-beta and IFN-gamma in ELISA. In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3(+)CD4(+)CD25(-)IL2Rbeta(+)IL2Rgamma(+)FoxP3(+)CTLA-4(+)IL-10(+) cells with suppressor activity (mean suppression +/- SD = 58 +/- 12%). These suppressor cells produced IL-10 (mean +/- SD = 535 +/- 12 pg/ml) and TGF-beta (mean +/- SD = 512 +/- 38 pg/ml), but no IL-4 or IFN-gamma. Suppressor function of co-cultures correlated with the percent of expanding IL-10(+) Tr1 cells (r (2 )=( )0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive activity. Suppression was cell-contact independent. The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4(+)CD25(high)FoxP3(+) nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical role in cancer progression.

Human CD4 + CD25 high FOXP3 + T regulatory cells (Treg) can suppress responder T cell (RC) functions by various mechanisms. In co-cultures of Treg and autologous activated RC, both cell subsets up-regulate the expression of granzymes and perforin, which might contribute to Treg-mediated suppression. Here, we investigate the sensitivity and resistance of Treg and RC to granzyme/perforin-mediated death. CD4 + CD25 neg RC were single cell-sorted from the peripheral blood of 25 cancer patients and 15 normal controls. These RC were carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled and co-cultured with autologous CD4 + CD25 high FOXP3 + Treg ± 150 or ±1,000 IU/mL of interleukin-2 (IL-2) to evaluate suppression of RC proliferation. In addition, survival of the cells co-cultured for 24 h and 5 days was measured using a flow-based cytotoxicity assay. Freshly isolated Treg and RC expressed granzyme A (GrA), granzyme B (GrB), and perforin. Percentages of positive cells were higher in cancer patients than controls ( p  < 0.01) and increased upon OKT3 and IL-2 stimulation. Treg, co-cultured with RC at 150 IU/mL of IL-2, no longer expressed cytotoxins and became susceptible to RC-mediated, granzyme/perforin-dependent death. However, in co-cultures with 1,000 IU/mL of IL-2, Treg became resistant to apoptosis and induced GrB-dependent, perforin-independent death of RC. When the GrB inhibitor I or GrB-specific and GrA-specific small inhibitory ribonucleic acids were used to block the granzyme pathway in Treg, RC death, and Treg-mediated suppression of RC, proliferation were significantly inhibited. Human CD4 + CD25 high Treg and CD4 + CD25 neg RC reciprocally regulate death/growth arrest by differentially utilizing the granzyme–perforin pathway depending on IL-2 concentrations.

The ‘holy grail’ in planet hunting is the detection of an Earth-analogue: a planet with similar mass as the Earth and an orbit inside the habitable zone. If we can find such an Earth-analogue around one of the stars in the immediate solar neighbourhood, we could potentially even study it in such great detail to address the question of its potential habitability. Several groups have focused their planet detection efforts on the nearest stars. Our team is currently performing an intensive observing campaign on the α Centauri system using the High Efficiency and Resolution Canterbury University Large Échelle Spectrograph (Hercules) at the 1 m McLellan telescope at Mt John University Observatory in New Zealand. The goal of our project is to obtain such a large number of radial velocity (RV) measurements with sufficiently high temporal sampling to become sensitive to signals of Earth-mass planets in the habitable zones of the two stars in this binary system. Over the past few years, we have collected more than 45 000 spectra for both stars combined. These data are currently processed by an advanced version of our RV reduction pipeline, which eliminates the effect of spectral cross-contamination. Here we present simulations of the expected detection sensitivity to low-mass planets in the habitable zone by the Hercules programme for various noise levels. We also discuss our expected sensitivity to the purported Earth-mass planet in a 3.24-day orbit announced by Dumusque et al. (2012).