RECRUDESCENCE OF ONCHOCERCIASIS IN THE COMOÉ VALLEY IN SOUTHWEST BURKINA FASO.

: Onchocerciasis control by vector control was instigated in southwest Burkina Faso in January 1969 by ORSTOM/OCCGE, and continued until operations were taken over by the WHO Onchocerciasis Control Programme (OCP) in February 1975, which itself ceased operations in the area in 1989 when onchocerciasis was judged to have been reduced to insignificant levels. Initially (1969-1975) vector immigration maintained unacceptably high levels of transmission, but OCP was much larger than the preceding campaign and in 1975 the Annual Transmission Potential (ATP) dropped below 100 at all sites in the Comoé river valley except Folonzo, which continued to be subject to reinvasion, along with the whole of the Léraba river valley. However, after the southern extension of the OCP in 1979, ATPs dropped below 100 everywhere in the Comoé basin (including the Léraba valley), and further dropped to insignificant levels after the western extension of the OCP in 1985. Thus transmission dropped more quickly in the Comoé river valley than the Léraba river valley (which had been subject to vector reinvasion), and this was also reflected in prevalence of microfilaraemia in the human population. After 1986 prevalence was less than 5% in all villages in the Comoé river valley (except for two, which subsequently dropped to 0% and 3.7% by 1999). However, in 2001 (12 years after the cessation of vector control) the prevalence in one village in the Comoé river valley had increased to 39.6%, and two more had increased above 5% by 2007. New epidemiological surveys in 2011 and 2012 showed that in 13 out of 30 villages in the Comoé river valley prevalence of microfilaraemia was above 5%, although this was not observed in the Léraba river valley where prevalence remained low. This is the first documented case of recrudescence of onchocerciasis in the old OCP area, and the reasons are not clear. It is possible that there has been immigration of parasites with humans or vectors from areas where there has been a shorter period of control, or that control has been less effective. It is possible that in spite of very low levels of transmission the local parasite population was never reduced to a level below the transmission breakpoint, or that there has been a local recrudescence due to stochastic population effects. In any case it is clear that the distribution of ivermectin against lymphatic filariasis in the area since 2004 has failed to prevent the recrudescence of onchocerciasis, and the Burkina Faso Programme National de Lutte contre l'Onchocercose (PNLO - Ministere de la Santé) has instigated a programme of Community Directed Treatment with Ivermectin specifically aimed at onchocerciasis in accordance with the strategy developed by APOC and recommended to governments by OCP when it was dissolved in 2002.<br/

Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)+/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial.

Background In HR+/HER2- early BC, high tumour infiltrating lymphocytes (TIL) levels predict higher pathological complete response to neoadjuvant chemotherapy, but are associated with shorter overall survival (Denkert, Lancet Oncol 2018). HR+/HER2- BC is a biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes, with different clinical behaviour (Cejalvo, CTR 2018). Little is known concerning the distribution of TIL levels and immune infiltrate composition across intrinsic subtypes in HR+/HER2- BC. Methods Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 postmenopausal patients with HR+/HER2- early BC from the LETLOB trial (neoadjuvant letrozole+/-lapatinib) (Guarneri, JCO 2014). Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. Relative leukocyte fractions were calculated using CIBERSORT (Newman, Nature Methods 2015), a deconvolution method based on RNA gene-expression signatures. Pre-treatment stromal TILs were assessed on centralized HES slides according to recommendations (Salgado, Ann Oncol 2015). Results Intrinsic subtype distribution was as follows: basal 18% (N = 12), HER2-enriched 8% (N = 5), Luminal A 39% (N = 25), Luminal B 36% (N = 24). Non-luminal subtypes (HER2-enriched and Basal) had significantly higher baseline TIL levels than luminal subtypes (median (range): 7 (0-100) and 2 (0-35), respectively; p = 0.038). Non-luminal subtypes also presented higher fractions of CD4 memory activated T-cells (p = 0.018), γδ T-cells (p = 0.010) and M1 macrophages (p = 0.001) and lower fractions of T-regulatory cells (p = 0.002) than luminal subtypes. Conclusions In HR+/HER2- early BC, non-luminal subtypes show higher TIL levels and a more pro-inflammatory anti-tumour immune infiltrate composition. This immune heterogeneity across intrinsic subtypes should be considered when analysing the complex prognostic role of TILs in HR+/HER2- early BC

Mrk 421, Mrk 501, and 1ES 1426+428 at 100 GeV with the CELESTE Cherenkov Telescope

We have measured the gamma-ray fluxes of the blazars Mrk 421 and Mrk 501 in the energy range between 50 and 350 GeV (1.2 to 8.3 x 10^25 Hz). The detector, called CELESTE, used first 40, then 53 heliostats of the former solar facility "Themis" in the French Pyrenees to collect Cherenkov light generated in atmospheric particle cascades. The signal from Mrk 421 is often strong. We compare its flux with previously published multi-wavelength studies and infer that we are straddling the high energy peak of the spectral energy distribution. The signal from Mrk 501 in 2000 was weak (3.4 sigma). We obtain an upper limit on the flux from 1ES 1426+428 of less than half that of the Crab flux near 100 GeV. The data analysis and understanding of systematic biases have improved compared to previous work, increasing the detector's sensitivity.Comment: 15 pages, 14 figures, accepted to A&A (July 2006) August 19 -- corrected error in author lis

Very-high energy gamma-ray astronomy: A 23-year success story in high-energy astroparticle physics

Very-high energy (VHE) gamma quanta contribute only a minuscule fraction - below one per million - to the flux of cosmic rays. Nevertheless, being neutral particles they are currently the best "messengers" of processes from the relativistic/ultra-relativistic Universe because they can be extrapolated back to their origin. The window of VHE gamma rays was opened only in 1989 by the Whipple collaboration, reporting the observation of TeV gamma rays from the Crab nebula. After a slow start, this new field of research is now rapidly expanding with the discovery of more than 150 VHE gamma-ray emitting sources. Progress is intimately related with the steady improvement of detectors and rapidly increasing computing power. We give an overview of the early attempts before and around 1989 and the progress after the pioneering work of the Whipple collaboration. The main focus of this article is on the development of experimental techniques for Earth-bound gamma-ray detectors; consequently, more emphasis is given to those experiments that made an initial breakthrough rather than to the successors which often had and have a similar (sometimes even higher) scientific output as the pioneering experiments. The considered energy threshold is about 30 GeV. At lower energies, observations can presently only be performed with balloon or satellite-borne detectors. Irrespective of the stormy experimental progress, the success story could not have been called a success story without a broad scientific output. Therefore we conclude this article with a summary of the scientific rationales and main results achieved over the last two decades.Comment: 45 pages, 38 figures, review prepared for EPJ-H special issue "Cosmic rays, gamma rays and neutrinos: A survey of 100 years of research

Very High Energy Gamma-ray spectral properties of Mrk 501 from CAT Cerenkov telescope observations in 1997

The BL Lac object Mrk 501 went into a very high state of activity during 1997, both in VHE gamma-rays and X-rays. We present here results from observations at energies above 250 GeV carried out between March and October 1997 with the CAT Cerenkov imaging Telescope. The average differential spectrum between 30 GeV and 13 TeV shows significant curvature and is well represented by phi_0 * E_TeV^{-(alpha + beta*log10(E_TeV))}, with: phi_0 = 5.19 +/- 0.13 {stat} +/- 0.12 {sys-MC} +1.66/-1.04 {sys-atm} * 10^-11 /cm^2/s/TeV alpha = 2.24 +/- 0.04 {stat} +/- 0.05 {sys} beta = 0.50 +/- 0.07 {stat} (negligible systematics). The TeV spectral energy distribution of Mrk 501 clearly peaks in the range 500 GeV-1 TeV. Investigation of spectral variations shows a significant hardness-intensity correlation with no measurable effect on the curvature. This can be described as an increase of the peak TeV emission energy with intensity. Simultaneous and quasi-simultaneous CAT VHE gamma-ray and BeppoSAX hard X-ray detections for the highest recorded flare on 16th April and for lower-activity states of the same period show correlated variability with a higher luminosity in X-rays than in gamma-rays. The observed spectral energy distribution and the correlated variability between X-rays and gamma-rays, both in amplitude and in hardening of spectra, favour a two-component emission scheme where the low and high energy components are attributed to synchrotron and inverse Compton (IC) radiation, respectively.Comment: Submitted to Astronomy and Astrophysics, 8 pages including 6 figures. Published with minor change

Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies

PURPOSE: The prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials. METHODS: A retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease. RESULTS: Overall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P &lt; .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P &lt; .0001), LumB (HR, 0.52; P &lt; .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77). CONCLUSION: In this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like