Tissue microarray-chip featuring computerized immunophenotypical characterization more accurately subtypes ampullary adenocarcinoma than routine histology

BACKGROUND Ampullary adenocarcinomas (AACs) are heterogeneous tumors currently classified into three important sub-classes (SC): Intestinal (INT), Pancreato-Biliary (PB) and Mixed-Type (MT). The different subgroups have similar clinical presentation and are treated by pancreatoduodenectomy with curative intent. However, they respond differently to chemotherapy and have different prognostic outcomes. The SC are often difficult to identify with conventional histology alone. The clinical outcome of all three remains unclear, particularly for MT. AIM To identify two main subtypes of AACs, using an immunohistochemical (IHC) score based on CDX2, CK7 and CK20. METHODS Tissue samples from 21 patients who had undergone resection of AAC were classified by HE histology and IHC expression of CDX2, CK7 and CK 20. An IHC score was obtained for each marker by counting the number of positive cells (0 = no stained cells; 1 < 25%; 2 < 50% and 3 > 50%) and their intensity (1 = weak; 2 = moderate and 3 = strong). A global score (GS) was then obtained by summation of the IHC scores of each marker. The MT tumors were grouped either with the INT or PB group based on the predominant immuno-molecular phenotype, obtaining only two AACs subtypes. The overall survival in INT and PB patients was obtained by Kaplan-Meier methods. RESULTS Histological parameters defined the AACs subtypes as follows: 15% INT, 45% PB and 40% MT. Using IHC expression and the GS, 75% and 25% of MT samples were assigned to either the INT or the PB group. The mean value of the GS was 9.5 (range 4-16). All INT samples had a GS above the average, distinct from the PB samples which had a GS score significantly below the average (P = 0.0011). The INT samples were identified by high expression of CDX2 and CK20, whereas PB samples exhibited high expression of CK7 and no expression of CK20 (P = 0.0008). The INT group had a statistically significant higher overall survival than in the PB group (85.7 mo vs 20.3 mo, HR: 8.39; 95%CI: 1.38 to 18.90; P = 0.0152). CONCLUSION The combination of histopathological and molecular criteria enables the classification of AACs into two clinically relevant histo-molecular phenotypes, which appear to represent distinct disorders with potentially significant changes to the current therapeutic strategies

High-energy emission from a magnetar giant flare in the Sculptor galaxy

Magnetars are the most highly magnetized neutron stars in the cosmos (with magnetic field 1013–1015 G). Giant flares from magnetars are rare, short-duration (about 0.1 s) bursts of hard X-rays and soft γ rays1,2. Owing to the limited sensitivity and energy coverage of previous telescopes, no magnetar giant flare has been detected at gigaelectronvolt (GeV) energies. Here, we report the discovery of GeV emission from a magnetar giant flare on 15 April 2020 (refs. 3,4 and A. J. Castro-Tirado et al., manuscript in preparation). The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope detected GeV γ rays from 19 s until 284 s after the initial detection of a signal in the megaelectronvolt (MeV) band. Our analysis shows that these γ rays are spatially associated with the nearby (3.5 megaparsecs) Sculptor galaxy and are unlikely to originate from a cosmological γ-ray burst. Thus, we infer that the γ rays originated with the magnetar giant flare in Sculptor. We suggest that the GeV signal is generated by an ultra-relativistic outflow that first radiates the prompt MeV-band photons, and then deposits its energy far from the stellar magnetosphere. After a propagation delay, the outflow interacts with environmental gas and produces shock waves that accelerate electrons to very high energies; these electrons then emit GeV γ rays as optically thin synchrotron radiation. This observation implies that a relativistic outflow is associated with the magnetar giant flare, and suggests the possibility that magnetars can power some short γ-ray bursts

Search for extended gamma-ray emission from the Virgo galaxy cluster with Fermi-LAT

Galaxy clusters are one of the prime sites to search for dark matter (DM) annihilation signals. Depending on the substructure of the DM halo of a galaxy cluster and the cross sections for DM annihilation channels, these signals might be detectable by the latest generation of $\gamma$-ray telescopes. Here we use three years of Fermi Large Area Telescope (LAT) data, which are the most suitable for searching for very extended emission in the vicinity of nearby Virgo galaxy cluster. Our analysis reveals statistically significant extended emission which can be well characterized by a uniformly emitting disk profile with a radius of 3\deg that moreover is offset from the cluster center. We demonstrate that the significance of this extended emission strongly depends on the adopted interstellar emission model (IEM) and is most likely an artifact of our incomplete description of the IEM in this region. We also search for and find new point source candidates in the region. We then derive conservative upper limits on the velocity-averaged DM pair annihilation cross section from Virgo. We take into account the potential $\gamma$-ray flux enhancement due to DM sub-halos and its complex morphology as a merging cluster. For DM annihilating into $b\overline{b}$, assuming a conservative sub-halo model setup, we find limits that are between 1 and 1.5 orders of magnitude above the expectation from the thermal cross section for $m_{\mathrm{DM}}\lesssim100\,\mathrm{GeV}$. In a more optimistic scenario, we exclude $\langle \sigma v \rangle\sim3\times10^{-26}\,\mathrm{cm^{3}\,s^{-1}}$ for $m_{\mathrm{DM}}\lesssim40\,\mathrm{GeV}$ for the same channel. Finally, we derive upper limits on the $\gamma$-ray-flux produced by hadronic cosmic-ray interactions in the inter cluster medium. We find that the volume-averaged cosmic-ray-to-thermal pressure ratio is less than $\sim6\%$.Comment: 15 pages, 11 figures, 4 tables, accepted for publication in ApJ; corresponding authors: T. Jogler, S. Zimmer & A. Pinzk

Unresolved Gamma-Ray Sky through its Angular Power Spectrum

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15

Search for Early Gamma-ray Production in Supernovae Located in a Dense Circumstellar Medium with the Fermi LAT

Supernovae (SNe) exploding in a dense circumstellar medium (CSM) are hypothesized to accelerate cosmic rays in collisionless shocks and emit GeV gamma rays and TeV neutrinos on a time scale of several months. We perform the first systematic search for gamma-ray emission in Fermi LAT data in the energy range from 100 MeV to 300 GeV from the ensemble of 147 SNe Type IIn exploding in dense CSM. We search for a gamma-ray excess at each SNe location in a one year time window. In order to enhance a possible weak signal, we simultaneously study the closest and optically brightest sources of our sample in a joint-likelihood analysis in three different time windows (1 year, 6 months and 3 months). For the most promising source of the sample, SN 2010jl (PTF10aaxf), we repeat the analysis with an extended time window lasting 4.5 years. We do not find a significant excess in gamma rays for any individual source nor for the combined sources and provide model-independent flux upper limits for both cases. In addition, we derive limits on the gamma-ray luminosity and the ratio of gamma-ray-to-optical luminosity ratio as a function of the index of the proton injection spectrum assuming a generic gamma-ray production model. Furthermore, we present detailed flux predictions based on multi-wavelength observations and the corresponding flux upper limit at 95% confidence level (CL) for the source SN 2010jl (PTF10aaxf).Comment: Accepted for publication in ApJ. Corresponding author: A. Franckowiak ([email protected]), updated author list and acknowledgement

Multiwavelength Evidence for Quasi-periodic Modulation in the Gamma-ray Blazar PG 1553+113

We report for the first time a gamma-ray and multi-wavelength nearly-periodic oscillation in an active galactic nucleus. Using the Fermi Large Area Telescope (LAT) we have discovered an apparent quasi-periodicity in the gamma-ray flux (E >100 MeV) from the GeV/TeV BL Lac object PG 1553+113. The marginal significance of the 2.18 +/-0.08 year-period gamma-ray cycle is strengthened by correlated oscillations observed in radio and optical fluxes, through data collected in the OVRO, Tuorla, KAIT, and CSS monitoring programs and Swift UVOT. The optical cycle appearing in ~10 years of data has a similar period, while the 15 GHz oscillation is less regular than seen in the other bands. Further long-term multi-wavelength monitoring of this blazar may discriminate among the possible explanations for this quasi-periodicity.Comment: 8 pages, 5 figures. Accepted to The Astrophysical Journal Letters. Corresponding authors: S. Ciprini (ASDC/INFN), S. Cutini (ASDC/INFN), S. Larsson (Stockholm Univ/KTH), A. Stamerra (INAF/SNS), D. J. Thompson (NASA GSFC

The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats.</p> <p>Results</p> <p>The effect of <it>N</it>-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively.</p> <p>Conclusion</p> <p>These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.</p