Right versus left-sided colon cancer: Is it time to consider these as different diseases?

Primary tumour location has emerged as an important characteristic in understanding the outcomes for patients with colorectal cancer. Recent international re-appraisal of randomised controlled data as well as case series and epidemiological databases clearly demonstrate that primary tumour location is both an independent prognostic marker and has predictive value in relation to anti-EGFR therapy. Consequently, location should be taken into consideration in the clinical management of patients affected by colon cancer as well as informing research and the design of future clinical trials

High-throughput time-resolved FRET reveals Akt/PKB activation as a poor prognostic marker in breast cancer

Abstract Dysregulation of the Akt/PKB pathway has been associated with poor prognosis in several human carcinomas. Current approaches to assess Akt activation rely on intensity-based methods, which are limited by the subjectivity of manual scoring and poor specificity. Here, we report the development of a novel assay using amplified, time-resolved Förster resonance energy transfer (FRET), which is highly specific and sensitive and can be adapted to any protein. Using this approach to analyze primary breast tissue microarrays, we quantified levels of activated pAkt at a spatial resolution that revealed molecular heterogeneity within tumors. High pAkt status assessed by amplified FRET correlated with worse disease-free survival. Our findings support the use of amplified FRET to determine pAkt status in cancer tissues as candidate biomarker for the identification of high-risk patients. Cancer Res; 74(18); 4983–95. ©2014 AACR.</jats:p

Functional implications of assigned, assumed and assembled PKC structures

The empirical derivation of PKC (protein kinase C) domain structures and those modelled by homology or imputed from protein behaviour have been extraordinarily valuable both in the elucidation of PKC pathway mechanisms and in the general lessons that extrapolate to other signalling pathways. For PKC family members, there are many domain/subdomain structures and models, covering all of the known domains, variably present in this family of protein serine/threonine kinases (C1, C2, PB1, HR1, kinase domains). In addition to these structures, there are a limited number of complexes defined, including the structure of the PKC epsilon V3-14-3-3 complex. In the context of structure-driven insights into PKC pathways, there are several broadly applicable principles and mechanisms relevant to the operation of and intervention in signalling pathways. These principles have an impact in unexpected ways, from the regulation of membrane targeting, through strategies for pharmacological intervention, to biomarkers.</p

A NECTAr-based upgrade for the Cherenkov cameras of the H.E.S.S. 12-meter telescopes

International audienceThe High Energy Stereoscopic System (H.E.S.S.) is one of the three arrays of imaging atmospheric Cherenkov telescopes (IACTs) currently in operation. It is composed of four 12-meter telescopes and a 28-meter one, and is sensitive to gamma rays in the energy range  ~ 30 GeV – 100 TeV. The cameras of the 12-m telescopes recently underwent a substantial upgrade, with the goal of improving their performance and robustness. The upgrade involved replacing all camera components except for the photomultiplier tubes (PMTs). This meant developing new hardware for the trigger, readout, power, cooling and mechanical systems, and new software for camera control and data acquisition. Several novel technologies were employed in the cameras: the readout is built around the new NECTAr digitizer chip, developed for the next generation of IACTs; the camera electronics is fully controlled and read out via Ethernet using a combination of FPGA and embedded ARM computers; the software uses modern libraries such as Apache Thrift, ØMQ and Protocol buffers. This work describes in detail the design and the performance of the upgraded cameras

Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care

Ammando 61, 62 , F. de Palma 45

See paper for full list of authors - 13 pages, 9 figures, accepted for publication in A&AInternational audienceThe addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV. Such an extension of the instrument's energy range is particularly beneficial for studies of Active Galactic Nuclei with soft spectra, as expected for those at a redshift > 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553+113 (0.43 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Multiple observational campaigns of PKS 2155-304 and PG 1553+113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument. A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters. The energy spectra of PKS 2155-304 and PG 1553+113 were reconstructed down to energies of 80 GeV for PKS 2155-304, which transits near zenith, and 110 GeV for the more northern PG 1553+113. The measured spectra, well fitted in both cases by a log-parabola spectral model (with a 5.0 sigma statistical preference for non-zero curvature for PKS 2155-304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E ~ 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155-304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties

Sensitivity of the Cherenkov Telescope Array to the gamma-ray emission from neutrino sources detected by IceCube

Gamma-ray observations of the astrophysical neutrino sources are fundamentally important for understanding the underlying neutrino production mechanism. We investigate the Cherenkov Telescope Array (CTA) ability to detect the very-high-energy (VHE) gamma-ray counterparts to the neutrino-emitting Active Galaxies. The CTA performance under different configurations and array layouts is computed based on the neutrino and gamma-ray simulations of steady and transient types of sources, assuming that the neutrino events are detected with the IceCube neutrino telescope. The CTA detection probability is calculated for both CTA sites taking into account the visibility constraints. We find that, under optimal observing conditions, CTA could observe the VHE gamma-ray emission from at least 3 neutrino events per year