Association between serum heat shock proteins and gamma-delta t cells—an outdated clue or a new direction in searching for an anticancer strategy? A short report

HSPs demonstrate a strong association with gamma-delta (γδ) T cells. Most of the studies regarding interactions between the parameters were conducted in the 1990s. Despite promising results, the concept of targeting γδ T cells by HSPs seems to be a forgotten direction due to potent non-peptidic phosphoantigens rather than HSPs have been found to be the essential stimulatory components for human γδ cells. Currently, with greater knowledge of lymphocyte diversity, and more accurate diagnostic methods, we decided to study the correlation once again in the neoplas-tic condition. Twenty-one children with newly diagnosed acute lymphoblastic leukaemia (ALL) were enrolled on the study. Serum HSP90 concentrations were evaluated by an enzyme-linked immunosorbent assay (ELISA), subsets of γδ T cells (CD3+ γδ, CD3+ γδ HLA/DR+, CD4+ γδ and CD8+ γδ) by flow cytometry. We have shown statistically relevant correlations between serum HSP90 and CD3+ HLA/DR+ γδ T cells in paediatric ALL at diagnosis (R = 0.53, p < 0.05), but not after induction chemotherapy. We also have demonstrated decreased levels of both serum HSP90 and CD3+ HLA/DR+ γδ T cells before treatment, which may indirectly indicate dose-dependent unknown interaction between the parameters. The results of our study may be a good introduction to research on the association between HSPs and CD3+ HLA/DR+ γδ T cells, which could be an interesting direction for the development of anti-cancer strategies, not just for childhood ALL

Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303)

Context: Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. Objectives: We evaluated HRQOL with the EuroQol (EQ-5D™) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. Methods: A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. Results: Mean index scores remained stable (0.78 at baseline [n = 267], 0.79 at eight weeks [n = 186], P = 0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P = 0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P = 0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. Conclusion: Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration

Observations of Seyferts by OSSE and parameters of their X-ray/gamma-ray sources

We present a summary of spectra of Seyfert galaxies observed by the OSSE detector aboard Compton Gamma Ray Observatory. We obtain average spectra of Seyferts of type 1 and 2, and find they are well fitted by thermal Comptonization. We present detailed parameter ranges for the plasma temperature and the Compton parameter in the case of spherical and slab geometries. We find both the average and individual OSSE spectra of Seyfert 2s are significantly harder than those of Seyfert 1s, which difference can be due to anisotropy of Compton reflection and/or Thomson-thick absorption.Comment: ApJ, 10 Nov. 2000, in press, 13 page

Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer

Background: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). Patients and methods: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). Results: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). Conclusions: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns

Emission of Positron Annihilation Line Radiation by Clusters of Galaxies

Clusters of galaxies are enriched with positrons from jets of active galactic nuclei (AGNs) or from the interaction of cosmic rays with the intracluster gas. We follow the cooling of these positrons and show that their eventual annihilation with cluster electrons yields a narrow annihilation line. Unlike annihilation in the interstellar medium of galaxies, the line produced in clusters is not smeared by three-photon decay of positronium, because positronium formation is suppressed at the high (>~ 1 keV) temperature of the cluster electrons. We show that if AGN jets are composed of e^+e^- pairs, then the annihilation line from rich clusters within a distance of 100 Mpc might be detectable with future space missions, such as INTEGRAL or EXIST.Comment: 39 pages, 11 figures, submitted to Ap

The major upgrade of the MAGIC telescopes, Part II: A performance study using observations of the Crab Nebula

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes located in the Canary island of La Palma, Spain. During summer 2011 and 2012 it underwent a series of upgrades, involving the exchange of the MAGIC-I camera and its trigger system, as well as the upgrade of the readout system of both telescopes. We use observations of the Crab Nebula taken at low and medium zenith angles to assess the key performance parameters of the MAGIC stereo system. For low zenith angle observations, the standard trigger threshold of the MAGIC telescopes is ~50GeV. The integral sensitivity for point-like sources with Crab Nebula-like spectrum above 220GeV is (0.66+/-0.03)% of Crab Nebula flux in 50 h of observations. The angular resolution, defined as the sigma of a 2-dimensional Gaussian distribution, at those energies is < 0.07 degree, while the energy resolution is 16%. We also re-evaluate the effect of the systematic uncertainty on the data taken with the MAGIC telescopes after the upgrade. We estimate that the systematic uncertainties can be divided in the following components: < 15% in energy scale, 11-18% in flux normalization and +/-0.15 for the energy spectrum power-law slope.Comment: 21 pages, 25 figures, accepted for publication in Astroparticle Physic

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab

MAGIC observations of MWC 656, the only known Be/BH system

Context: MWC 656 has recently been established as the first observationally detected high-mass X-ray binary system containing a Be star and a black hole (BH). The system has been associated with a gamma-ray flaring event detected by the AGILE satellite in July 2010. Aims: Our aim is to evaluate if the MWC 656 gamma-ray emission extends to very high energy (VHE > 100 GeV) gamma rays. Methods. We have observed MWC 656 with the MAGIC telescopes for $\sim$23 hours during two observation periods: between May and June 2012 and June 2013. During the last period, observations were performed contemporaneously with X-ray (XMM-Newton) and optical (STELLA) instruments. Results: We have not detected the MWC 656 binary system at TeV energies with the MAGIC Telescopes in either of the two campaigns carried out. Upper limits (ULs) to the integral flux above 300 GeV have been set, as well as differential ULs at a level of $\sim$5% of the Crab Nebula flux. The results obtained from the MAGIC observations do not support persistent emission of very high energy gamma rays from this system at a level of 2.4% the Crab flux.Comment: Accepted for publication in A&A. 5 pages, 2 figures, 2 table