Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P=0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P=0.07), time to PD (4.5 vs 2.2 months, P=0.13) and clinical benefit (CR+PR+SD) (58 vs 37%, P=0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC

Thermodynamic analysis of the Quantum Critical behavior of Ce-lattice compounds

A systematic analysis of low temperature magnetic phase diagrams of Ce compounds is performed in order to recognize the thermodynamic conditions to be fulfilled by those systems to reach a quantum critical regime and, alternatively, to identify other kinds of low temperature behaviors. Based on specific heat ($C_m$) and entropy ($S_m$) results, three different types of phase diagrams are recognized: i) with the entropy involved into the ordered phase ($S_{MO}$) decreasing proportionally to the ordering temperature ($T_{MO}$), ii) those showing a transference of degrees of freedom from the ordered phase to a non-magnetic component, with their $C_m(T_{MO})$ jump ($\Delta C_m$) vanishing at finite temperature, and iii) those ending in a critical point at finite temperature because their $\Delta C_m$ do not decrease with $T_{MO}$ producing an entropy accumulation at low temperature. Only those systems belonging to the first case, i.e. with $S_{MO}\to 0$ as $T_{MO}\to 0$, can be regarded as candidates for quantum critical behavior. Their magnetic phase boundaries deviate from the classical negative curvature below $T\approx 2.5$\,K, denouncing frequent misleading extrapolations down to T=0. Different characteristic concentrations are recognized and analyzed for Ce-ligand alloyed systems. Particularly, a pre-critical region is identified, where the nature of the magnetic transition undergoes significant modifications, with its $\partial C_m/\partial T$ discontinuity strongly affected by magnetic field and showing an increasing remnant entropy at $T\to 0$. Physical constraints arising from the third law at $T\to 0$ are discussed and recognized from experimental results

The prototype colliding-wind pinwheel WR 104

Results from the most extensive study of the time-evolving dust structure around the prototype "Pinwheel" nebula WR 104 are presented. Encompassing 11 epochs in three near-infrared filter bandpasses, a homogeneous imaging data set spanning more than 6 years (or 10 orbits) is presented. Data were obtained from the highly successful Keck Aperture Masking Experiment, which can recover high fidelity images at extremely high angular resolutions, revealing the geometry of the plume with unprecedented precision. Inferred properties for the (unresolved) underlying binary and wind system are orbital period 241.5 +/- 0.5 days and angular outflow velocity of 0.28 +/- 0.02 mas/day. An optically thin cavity of angular size 13.3 +/- 1.4 mas was found to lie between the central binary and the onset of the spiral dust plume. Rotational motion of the wind system induced by the binary orbit is found to have important ramifications: entanglement of the winds results in strong shock activity far downstream from the nose of the bowshock. The far greater fraction of the winds participating in the collision may play a key role in gas compression and the nucleation of dust at large radii from the central binary and shock stagnation point. Investigation of the effects of radiative braking pointed towards significant modifications of the simple hydrostatic colliding wind geometry, extending the relevance of this phenomena to wider binary systems than previously considered. Limits placed on the maximum allowed orbital eccentricity of e < 0.06 argue strongly for a prehistory of tidal circularization in this system. Finally we discuss the implications of Earth's polar (i < 16 deg) vantage point onto a system likely to host supernova explosions at future epochs.Comment: 35 pages, 8 figures, Accepted for publication in Astrophysical Journa

Habitat determinants of golden‐headed lion tamarin (Leontopithecus chrysomelas) occupancy of cacao agroforests: Gloomy conservation prospects for management intensification

Organismal distributions in human‐modified landscapes largely depend on the capacity of any given species to adapt to changes in habitat structure and quality. The golden‐headed lion tamarin (GHLT; Leontopithecus chrysomelas) is an Endangered primate from the Brazilian Atlantic Forest whose remaining populations occupy heterogeneous landscapes consisting primarily of shade cacao (Theobroma cacao) agroforestry, locally known as cabrucas. This cash crop can coexist with high densities of native tree species and holds a significant proportion of the native fauna, but its widely extolled wildlife‐friendly status is increasingly threatened by management intensification. Although this potentially threatens to reduce the distribution of GHLTs, the main determinants of tamarin's occupancy of cabrucas remain unknown, thereby limiting our ability to design and implement appropriate conservation practices. We surveyed 16 cabruca patches in southern Bahia, Brazil, and used occupancy modeling to identify the best predictors of GHLT patch occupancy. Key explanatory variables included vegetation structure, critical resources, landscape context, human disturbance, and predation pressure. We found a negative relationship between GHLT occupancy and the prevalence of jackfruit trees (Artocarpus heterophylus), which is likely associated with the low representation of other key food species for GHLTs. Conversely, cabrucas retaining large‐diameter canopy trees have a higher probability of GHLT occupancy, likely because these trees provide preferred sleeping sites. Thus, key large tree resources (food and shelter) are currently the main drivers of GHLT occupancy within cabruca agroecosystems. Since both factors can be directly affected by crop management practices, intensification of cabrucas may induce significant habitat impacts on GHLT populations over much of their remaining range‐wide distribution

Perspectives of Portuguese People with Physical Disabilities Regarding Their Sexual Health: A Focus Group Study

The World Health Organization has considered sexual health as a major dimension of global health and a sexual right. However, the sexual health of people with physical disabilities is still poorly addressed by health and social care professionals, and it is very stigmatized by society. This study aimed to assess the perspectives of Portuguese people living with physical disabilities regarding issues affecting their sexual health. Nine women and 17 men with different physical disabilities participated in the study. Participants were recruited from a professional rehabilitation facility located in the North of Portugal and were assigned to four groups in one-hour sessions. Three main categories emerged from the content analysis: (1) meanings and beliefs regarding sexuality; (2) experiences of sexuality; (3) necessary changes. Despite the positive social changes towards sexuality, participants expressed that their sexual rights are still unfulfilled, as they live in a context that perpetuates their dependency. They pointed out low self-esteem, prejudice and social isolation, poor architectural accessibility and scarcity of financial support as some of the barriers to their lives and their sexual health. Finally, participants identified the main needs regarding their sexual health, such as: access to specialized information; training for health professionals. This study gives voice to people with physical disabilities and sheds light into both individual and contextual factors affecting their sexual health. Of utmost importance, this study draws attention to the need for reinforcing sexuality of people with disabilities in the social agenda and brings implications for future research and practice.This study was supported by a Grant attributed to the first author by the Portuguese Foundation for Science and Technology (SFRH/BD/112168/2015)info:eu-repo/semantics/publishedVersio

SPARC, FOXP3, CD8 and CD45 Correlation with Disease Recurrence and Long-Term Disease-Free Survival in Colorectal Cancer

BACKGROUND: SPARC is a matricellular protein involved in tissue remodelling, cell migration and angiogenesis, while forkhead box P3 (FOXP3) protein functions as a transcription factor involved in immune cell regulation. Both SPARC and FOXP3 can play an anti-tumorigenic role in cancer progression. The aim was to determine if SPARC, FOXP3, CD8 and CD45RO expression levels are associated with colorectal cancer (CRC) stage, disease outcome and long-term cancer-specific survival (CSS) in stage II and III CRC. METHODS AND FINDINGS: SPARC expression was initially assessed in 120 paired normal and stage I-IV CRCs. Subsequently, approximately 1000 paired patient samples of stage II or III CRCs in tissue microarrays were stained for SPARC, FOXP3, CD8 or CD45RO. Proportional hazards modelling assessed correlations between these markers and clinicopathological data, including disease outcome and cancer specific survival (CSS). Both SPARC and FOXP3 expression were significantly greater in CRC than normal colon (p<0.0001). High SPARC expression correlated with good disease outcome (≥60 mths without disease recurrence, p = 0.0039) and better long-term CSS in stage II CRC (<0.0001). In stage III CRC, high SPARC expression correlated with better long-term CSS (p<0.0001) and less adjuvant chemotherapy use (p = 0.01). High FOXP3 correlated with a good disease outcome, better long-term CSS and less adjuvant chemotherapy use in stage II (p<0.0037, <0.0001 and p = 0.04 respectively), but not in stage III CRC. High CD8 and CD45RO expression correlated with better disease outcome in stage II CRC, and better CSS, but the differences were not as marked as for SPARC and FOXP3. CONCLUSIONS: These data suggest that high SPARC and FOXP3 are associated with better disease outcome in stage II CRC and may be prognostic indicators of CSS. Further assessment of whether these markers predict patients at high risk of recurrence with stage II CRC and functional studies of these effects are underway

Genome-Wide Maps of Circulating miRNA Biomarkers for Ulcerative Colitis

Inflammatory Bowel Disease – comprised of Crohn's Disease and Ulcerative Colitis (UC) - is a complex, multi-factorial inflammatory disorder of the gastrointestinal tract. In this study we have explored the utility of naturally occurring circulating miRNAs as potential blood-based biomarkers for non-invasive prediction of UC incidences. Whole genome maps of circulating miRNAs in micro-vesicles, Peripheral Blood Mononuclear Cells and platelets have been constructed from a cohort of 20 UC patients and 20 normal individuals. Through Significance Analysis of Microarrays, a signature of 31 differentially expressed platelet-derived miRNAs has been identified and biomarker performance estimated through a non-probabilistic binary linear classification using Support Vector Machines. Through this approach, classifier measurements reveal a predictive score of 92.8% accuracy, 96.2% specificity and 89.5% sensitivity in distinguishing UC patients from normal individuals. Additionally, the platelet-derived biomarker signature can be validated at 88% accuracy through qPCR assays, and a majority of the miRNAs in this panel can be demonstrated to sub-stratify into 4 highly correlated intensity based clusters. Analysis of predicted targets of these biomarkers reveal an enrichment of pathways associated with cytoskeleton assembly, transport, membrane permeability and regulation of transcription factors engaged in a variety of regulatory cascades that are consistent with a cell-mediated immune response model of intestinal inflammation. Interestingly, comparison of the miRNA biomarker panel and genetic loci implicated in IBD through genome-wide association studies identifies a physical linkage between hsa-miR-941 and a UC susceptibility loci located on Chr 20. Taken together, analysis of these expression maps outlines a promising catalog of novel platelet-derived miRNA biomarkers of clinical utility and provides insight into the potential biological function of these candidates in disease pathogenesis

Sexual (Dis)satisfaction and Its Contributors Among People Living with HIV Infection in Sweden

Earlier research reports lower sexual satisfaction among people living with HIV (PLHIV) compared to HIV-negative persons. A number of psychosocial factors directly associated with sexual dissatisfaction have been identified. Little is known about sexual satisfaction and their contributors among PLHIV in Sweden. The aim of this study was to examine direct and indirect effects of variables within sociodemographic, clinical HIV-related, psychological, and sexual domains on sexual(dis)satisfaction among PLHIV in Sweden. Data for this study was derived from a national representative, anonymous survey among PLHIV conducted in 2014 (n=1096). Statistical analysis included four steps: descriptive analyses, identification of variables associated with sexual (dis)satisfaction, identification of variables associated with those contributors of sexual (dis)satisfaction, and a path model integrating all these analyses. A total of 49% of participants reported being sexually dissatisfied and no significant differences were observed when non-heterosexual men, heterosexual men and women were compared. Among women, a negative change in sex life after HIV diagnosis and distress with orgasmic difficulties were directly associated with sexual dissatisfaction. For men, hopelessness, high HIV stigma, sexual inactivity in the last 6 months, and a negative change in sex life after HIV diagnosis were directly associated with sexual dissatisfaction. Path analyses showed in both men and women significant indirect association between not being involved in an intimate relationship, lower self-reported CD4 cell counts, and perceiving obligation to disclose HIV status to sexual partners as a barrier to look for a long-term partner and sexual dissatisfaction. Our results show that despite good treatment outcomes, the HIV diagnosis has a negative bearing on sexual satisfaction. The need for gender-tailored interventions and clinical implications of these findings are discussed

Host Genes Related to Paneth Cells and Xenobiotic Metabolism Are Associated with Shifts in Human Ileum-Associated Microbial Composition

The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn’s disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R) and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3–V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA) support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions