Gamma-ray emission from massive young stellar objects

Context.Massive stars form in dense and massive molecular cores. The exact formation mechanism is unclear, but it is possible that some massive stars are formed by processes similar to those that produce the low-mass stars, with accretion/ejection phenomena occurring at some point of the evolution of the protostar. This picture seems to be supported by the detection of a collimated stellar wind emanating from the massive protostar IRAS 16547-4247. A triple radio source is associated with the protostar: a compact core and two radio lobes. The emission of the southern lobe is clearly non-thermal. Such emission is interpreted as synchrotron radiation produced by relativistic electrons locally accelerated at the termination point of a thermal jet. Since the ambient medium is determined by the properties of the molecular cloud in which the whole system is embedded, we can expect high densities of particles and infrared photons. Because of the confirmed presence of relativistic electrons, inverse Compton and relativistic Bremsstrahlung interactions are unavoidable. Aims.We aim to make quantitative predictions of the spectral energy distribution of the non-thermal spots generated by massive young stellar objects, with emphasis on the particular case of IRAS 16547-4247. Methods.We study the high-energy emission generated by the relativistic electrons which produce the non-thermal radio source in IRAS 16547-4247. We also study the result of proton acceleration at the terminal shock of the thermal jet and make estimates of the secondary gamma rays and electron-positron pairs produced by pion decay. Results.We present spectral energy distributions for the southern lobe of IRAS 16547-4247, for a variety of conditions. We show that high-energy emission might be detectable from this object in the gamma-ray domain. The source may also be detectable in X-rays through long exposures with current X-ray instruments. Conclusions.Gamma-ray telescopes such as GLAST, and even ground-based Cherenkov arrays of new generation can be used to study non-thermal processes occurring during the formation of massive stars.

A microquasar model applied to unidentified gamma-ray sources

Among unidentified gamma-ray sources in the galactic plane, there are some that present significant variability and have been proposed to be high-mass microquasars. To deepen the study of the possible association between variable low galactic latitude gamma-ray sources and microquasars, we have applied a leptonic jet model based on the microquasar scenario that reproduces the gamma-ray spectrum of three unidentified gamma-ray sources, 3EG J1735-1500, 3EG J1828+0142 and GRO J1411-64, and is consistent with the observational constraints at lower energies. We conclude that if these sources were generated by microquasars, the particle acceleration processes could not be as efficient as in other objects of this type that present harder gamma-ray spectra. Moreover, the dominant mechanism of high-energy emission should be synchrotron self-Compton (SSC) scattering, and the radio jets may only be observed at low frequencies. For each particular case, further predictions of jet physical conditions and variability generation mechanisms have been made in the context of the model. Although there might be other candidates able to explain the emission coming from these sources, microquasars cannot be excluded as counterparts. Observations performed by the next generation of gamma-ray instruments, like GLAST, are required to test the proposed model.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BACKGROUND: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

Interleukin-1- and type I interferon-dependent enhanced immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef vaccine vector with dual deletions of type I and type II interferon-binding proteins.

UNLABELLED: NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C-ΔB19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4(+) T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector. IMPORTANCE: NYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.

High mass microquasars and low latitude gamma-ray sources

Population studies of unidentified EGRET sources suggest that there exist at least three different populations of galactic gamma-ray sources. One of these populations is formed by young objects distributed along the galactic plane with a strong concentration toward the inner spiral arms of the Galaxy. Variability, spectral and correlation analysis indicate that this population is not homogeneous. In particular, there is a subgroup of sources that display clear variability in their gamma-ray fluxes on timescales from days to months. Following the proposal by Kaufman Bernad\'o et al. (2002), we suggest that this group of sources might be high-mass microquasars, i.e. accreting black holes or neutron stars with relativistic jets and early-type stellar companions. We present detailed inhomogeneous models for the gamma-ray emission of these systems that include both external and synchrotron self-Compton interactions. We have included effects of interactions between the jet and all external photon fields to which it is exposed: companion star, accretion disk, and hot corona. We make broadband calculations to predict the spectral energy distribution of these objects from radio up to GeV energies. The results and predictions can be tested by present and future gamma-ray instruments like INTEGRAL, AGILE, and GLAST.

AGNs and microquasars as high-energy gamma-ray sources

The possible associations between the microquasars LS 5039 and LS I +61 303 and the EGRET sources 3EG J1824-1514 and 3EG J0241+6103 suggest that microquasars could also be sources of high-energy gamma-rays. In this work, we present a detailed numerical inverse Compton (IC) model, based on a microquasar scenario, that reproduces the high-energy gamma-ray spectra and variability observed by EGRET for the mentioned sources. Our model considers a population of relativistic electrons entrained in a cylindrical inhomogeneous jet that interact through IC scattering with both the radiation and the magnetic fields.

Should Koos I Vestibular Schwannomas Be Treated Early with Gamma Knife Surgery? A Prospective Series of 42 Consecutive Cases

Background: Gamma Knife surgery (GKS) for vestibular schwannomas (VS) has a long-term clinical and scientific track record. After a period of de-escalation of dose prescription, results show a high rate of tumor control with improvement of clinical outcome (less than 1% facial palsy, 50-70% hearing preservation). Currently, there is controversial data about the active early treatment of intracanalicular (Koos I) VS. Methods: We prospectively analyzed 208 VS, focusing on 42 Koos I patients treated with GKS as first intention in Lausanne University Hospital, between July 2010 and February 2015. We concentrated on patient, tumor, and dosimetric characteristics. Special attention was given on the dose to the cochlea and its impact in maintaining serviceable hearing. Results: The mean follow-up period was 1.7 years (range 0.6-4.2). Twenty-six (61.9%) were females and 16 (38.1%) males. Preoperative serviceable hearing was present in 33 (78.57%) patients. The mean maximal diameter was 7.7 (5-10). The median target volume at the moment of GKS was 90 mm3 (range 17-317). The median prescription isodose volume was 118 mm3 (range 37-603). The median marginal dose administrated was 12 Gy (range 11-12). The median number of shots was 2 (range 1-9). The median isodose prescription was 50% (range 45-80%). The median maximal dose received by the cochlea in patients in GR class 1 and 2 was 4.2 Gy (mean 4.4 Gy, range 1.8-7.6). Our preliminary results showed 98% tumor control, with 30% shrinkage on MRI. The actuarial probability of keeping the same audition class for those with functional hearing at GKS was 80% at 3 years; the probability of keeping a functional hearing was more than 90%. A paraclinical evolution (on MRI and/or audiometry) at the time diagnosis, before GKS, was associated with a less good prognosis (p < 0.05). Conclusions: Our preliminary data suggest that Koos I patients should be treated early with GKS, before tumor growth, and/or hearing deterioration, as they have the highest probability of hearing preservation. The results in terms of functional outcome seemed comparable to, or even better than, the other Koos classes (i.e., larger lesions).

Gamma Knife Surgery versus Linac for Brain Metastasis: Which Technique for Which Patient? Analysis of an Historical Cohort of 63 Consecutive Patients Harboring 130 Lesions

Objectives: We present the retrospective analysis of a single-institution experience for radiosurgery (RS) in brain metastasis (BM) with Gamma Knife (GK) and Linac. Methods: From July 2010 to July 2012, 28 patients (with 83 lesions) had RS with GK and 35 patients (with 47 lesions) with Linac. The primary outcome was the local progression-free survival (LPFS). The secondary outcome was the overall survival (OS). Apart a standard statistical analysis, we included a Cox regression model with shared frailty, to modulate the within-patient correlation (preliminary evaluation showed a significant frailty effect, meaning that the correlation within patient could be ignored). Results: The mean follow-up period was 11.7 months (median 7.9, 1.7-22.7) for GK and 18.1 (median 17, 7.5-28.7) for Linac. The median number of lesions per patient was 2.5 (1-9) in GK compared with 1 (1-3) in Linac. There were more radioresistant lesions (melanoma) and more lesions located in functional areas for the GK group. The median dose was 24 Gy (GK) compared with 20 Gy (Linac). The LPFS actuarial rate was as follows: for GK at 3, 6, 9, 12, and 17 months: 96.96, 96.96, 96.96, 88.1, and 81.5%, and remained stable till 32 months; for Linac at 3, 6, 12, 17, 24, and 33 months, it was 91.5, 91.5, 91.5, 79.9, 55.5, and 17.1%, respectively (p = 0.03, chi-square test). After the Cox regression analysis with shared frailty, the p-value was not statistically significant between groups. The median overall survival was 9.7 months for GK and 23.6 months for Linac group. Uni- and multivariate analysis showed a lower GPA score and noncontrolled systemic status were associated with lower OS. Cox regression analysis adjusting for these two parameters showed comparable OS rate. Conclusions: In this comparative report between GK and Linac, preliminary analysis showed that more difficult cases are treated by GK, with patients harboring more lesions, radioresistant tumors, and highly functional located. The groups look, in this sense, very heterogeneous at baseline. After a Cox frailty model, the LPFS rates seemed very similar (p < 0.05). The OS was similar, after adjusting for systemic status and GPA score (p < 0.05). The technical reasons for choosing GK instead of Linac were the anatomical location related to highly functional areas, histology, technical limitations of Linac movements, especially lower posterior fossa locations, or closeness of multiple lesions to highly functional areas optimal dosimetry with Linac

Identifying variable gamma-ray sources through radio observations

We present preliminary results of a campaign undertaken with different radio interferometers to observe a sample of the most variable unidentified EGRET sources. We expect to detect which of the possible counterparts of the gamma-ray sources (any of the radio emitters in the field) varies in time with similar timescales as the gamma-ray variation. If the gamma-rays are produced in a jet-like source, as we have modelled theoretically, synchrotron emission is also expected at radio wavelengths. Such radio emission should appear variable in time and correlated with the gamma-ray variability.

Involvement of a transforming-growth-factor-beta-like molecule in tumor-cell-derived inhibition of nitric-oxide synthesis in cerebral endothelial cells.

Nitric oxide (NO) has been shown to exert cytotoxic effects on tumor cells. We have reported that EC219 cells, a rat-brain-microvessel-derived endothelial cell line, produced NO through cytokine-inducible NO synthase (iNOS), the induction of which was significantly decreased by (a) soluble factor(s) secreted by DHD/PROb, an invasive sub-clone of a rat colon-carcinoma cell line. In this study, the DHD/PROb cell-derived NO-inhibitory factor was characterized. Northern-blot analysis demonstrated that the induction of iNOS mRNA in cytokine-activated EC219 cells was decreased by PROb-cell-conditioned medium. When DHD/PROb cell supernatant was fractionated by affinity chromatography using Con A-Sepharose or heparin-Sepharose, the NO-inhibitory activity was found only in Con A-unbound or heparin-unbound fractions, respectively, indicating that the PROb-derived inhibitory factor was likely to be a non-glycosylated and non-heparin-binding molecule. Pre-incubation of DHD/PROb-cell supernatant with anti-TGF-beta neutralizing antibody completely blocked the DHD/PROb-derived inhibition of NO production by EC219 cells. Addition of exogenous TGF-beta 1 dose-dependently inhibited NO release by EC219 cells. The presence of active TGF-beta in the DHD/PROb cell supernatant was demonstrated using a growth-inhibition assay. Moreover, heat treatment of medium conditioned by the less invasive DHD/REGb cells, which constitutively secreted very low levels of active TGF-beta, increased both TGF-beta activity and the ability to inhibit NO production in EC219 cells. Thus, DHD/PROb colon-carcinoma cells inhibited NO production in EC219 cells by secreting a factor identical or very similar to TGF-beta.