Search for Gamma-Ray Spectral Lines from Dark Matter Annihilation up to 100 TeV toward the Galactic Center with MAGIC.

Linelike features in TeV γ rays constitute a "smoking gun" for TeV-scale particle dark matter and new physics. Probing the Galactic Center region with ground-based Cherenkov telescopes enables the search for TeV spectral features in immediate association with a dense dark matter reservoir at a sensitivity out of reach for satellite γ-ray detectors, and direct detection and collider experiments. We report on 223 hours of observations of the Galactic Center region with the MAGIC stereoscopic telescope system reaching γ-ray energies up to 100 TeV. We improved the sensitivity to spectral lines at high energies using large-zenith-angle observations and a novel background modeling method within a maximum-likelihood analysis in the energy domain. No linelike spectral feature is found in our analysis. Therefore, we constrain the cross section for dark matter annihilation into two photons to ⟨σv⟩≲5×10^{-28} cm^{3} s^{-1} at 1 TeV and ⟨σv⟩≲1×10^{-25} cm^{3} s^{-1} at 100 TeV, achieving the best limits to date for a dark matter mass above 20 TeV and a cuspy dark matter profile at the Galactic Center. Finally, we use the derived limits for both cuspy and cored dark matter profiles to constrain supersymmetric wino models.

Transarterial chemoembolisation for palliative treatment of renal cell carcinoma in two dogs with pulmonary metastasis.

Two dogs with anorexia and rapid weight loss were referred to our hospital due to a right renal mass and several pulmonary nodules. Both dogs underwent needle core biopsy of the mass, followed by transarterial chemoembolisation of the renal mass. A catheter was inserted from the femoral artery and advanced into the right renal artery. A suspension of carboplatin (100 mg/m2 ) and equivalent lipiodol was administered via the inserted multipurpose catheter. Immediately after, under fluoroscopic guidance, pulse injections of small amounts of gelatin particles (diameter 1 mm) dissolved in iohexol were administered until complete embolisation of the renal artery. Histopathologic diagnosis was renal cell carcinoma in both dogs. Clinical signs improved for 134 and 358 days after transarterial chemoembolisation. In addition, postoperative radiographs demonstrated a decrease in the tumour size. The dogs died 215 and 525 days after the initial evaluation, respectively. As a palliative treatment, transarterial chemoembolisation might help reduce the tumour volume and improve the quality of life in dogs with renal cell carcinoma and distant metastases.

Direct Measurement of the Nickel Spectrum in Cosmic Rays in the Energy Range from 8.8 GeV/n to 240 GeV/n with CALET on the International Space Station.

The relative abundance of cosmic ray nickel nuclei with respect to iron is by far larger than for all other transiron elements; therefore it provides a favorable opportunity for a low background measurement of its spectrum. Since nickel, as well as iron, is one of the most stable nuclei, the nickel energy spectrum and its relative abundance with respect to iron provide important information to estimate the abundances at the cosmic ray source and to model the Galactic propagation of heavy nuclei. However, only a few direct measurements of cosmic-ray nickel at energy larger than ∼3 GeV/n are available at present in the literature, and they are affected by strong limitations in both energy reach and statistics. In this Letter, we present a measurement of the differential energy spectrum of nickel in the energy range from 8.8 to 240 GeV/n, carried out with unprecedented precision by the Calorimetric Electron Telescope (CALET) in operation on the International Space Station since 2015. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The particle's energy is measured by a homogeneous calorimeter (1.2 proton interaction lengths, 27 radiation lengths) preceded by a thin imaging section (3 radiation lengths) providing tracking and energy sampling. This Letter follows our previous measurement of the iron spectrum [1O. Adriani et al. (CALET Collaboration), Phys. Rev. Lett. 126, 241101 (2021).PRLTAO0031-900710.1103/PhysRevLett.126.241101], and it extends our investigation on the energy dependence of the spectral index of heavy elements. It reports the analysis of nickel data collected from November 2015 to May 2021 and a detailed assessment of the systematic uncertainties. In the region from 20 to 240 GeV/n our present data are compatible within the errors with a single power law with spectral index -2.51±0.07.

Measurement of the Iron Spectrum in Cosmic Rays from 10 GeV/n to 2.0 TeV/n with the Calorimetric Electron Telescope on the International Space Station.

The Calorimetric Electron Telescope (CALET), in operation on the International Space Station since 2015, collected a large sample of cosmic-ray iron over a wide energy interval. In this Letter a measurement of the iron spectrum is presented in the range of kinetic energy per nucleon from 10 GeV/n to 2.0 TeV/n allowing the inclusion of iron in the list of elements studied with unprecedented precision by space-borne instruments. The measurement is based on observations carried out from January 2016 to May 2020. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The energy is measured by a homogeneous calorimeter with a total equivalent thickness of 1.2 proton interaction lengths preceded by a thin (3 radiation lengths) imaging section providing tracking and energy sampling. The analysis of the data and the detailed assessment of systematic uncertainties are described and results are compared with the findings of previous experiments. The observed differential spectrum is consistent within the errors with previous experiments. In the region from 50 GeV/n to 2 TeV/n our present data are compatible with a single power law with spectral index -2.60±0.03.

Liposome induction of CD8+ T cell responses depends on CD169+ macrophages and Batf3-dependent dendritic cells and is enhanced by GM3 inclusion.

Cancer vaccines aim to efficiently prime cytotoxic CD8+ T cell responses which can be achieved by vaccine targeting to dendritic cells. CD169+ macrophages have been shown to transfer antigen to dendritic cells and could act as an alternative target for cancer vaccines. Here, we evaluated liposomes containing the CD169/Siglec-1 binding ligand, ganglioside GM3, and the non-binding ligand, ganglioside GM1, for their capacity to target antigens to CD169+ macrophages and to induce immune responses. CD169+ macrophages demonstrated specific uptake of GM3 liposomes in vitro and in vivo that was dependent on a functional CD169 receptor. Robust antigen-specific CD8+ and CD4+ T and B cell responses were observed upon intravenous administration of GM3 liposomes containing the model antigen ovalbumin in the presence of adjuvant. Immunization of B16-OVA tumor bearing mice with all liposomes resulted in delayed tumor growth and improved survival. The absence of CD169+ macrophages, functional CD169 molecules, and cross-presenting Batf3-dependent dendritic cells (cDC1s) significantly impaired CD8+ T cell responses, while B cell responses were less affected. In conclusion, we demonstrate that inclusion of GM3 in liposomes enhance immune responses and that splenic CD169+ macrophages and cDC1s are required for induction of CD8+ T cell immunity after liposomal vaccination.

CT cholangiography in dogs with gallbladder mucocoele.

OBJECTIVES: To summarise CT cholangiography findings in dogs with gallbladder mucocoele. MATERIALS AND METHODS: Each of 10 dogs with gallbladder mucocoele underwent CT cholangiography using meglumine iotroxate before cholecystectomy. The following structures of the biliary system were evaluated: the right and left hepatic ducts, common hepatic duct, cystic duct, common bile duct and gallbladder. RESULTS: The hepatic duct, cystic duct, common bile duct and gallbladder were imaged by contrast-enhanced CT cholangiography. The passage of the contrast medium through the bile duct into the duodenum was visible in nine dogs. The curved planar reformation images of two dogs showed they had filling defects in the bile duct system. In one dog with hyperbilirubinaemia due to chronic hepatitis, the bile duct system was not completely contrast-enhanced. Surgical exploration revealed no evidence of common bile duct obstruction in any dog. CLINICAL SIGNIFICANCE: CT cholangiography delineates the structural characteristics of the biliary system and partially estimates its patency in dogs with gallbladder mucocoele. Therefore this procedure may be useful as a preoperative screen of the bile duct system in dogs with gallbladder mucocoele.

Gallbladder Agenesis in 17 Dogs: 2006-2016.

BACKGROUND: Gallbladder agenesis (GBA) is extremely rare in dogs. HYPOTHESIS/OBJECTIVES: To describe the history, clinical signs, diagnosis, treatment, and outcomes of dogs with GBA. ANIMALS: Seventeen client-owned dogs with GBA. METHODS: Medical records from 2006 through 2016 were retrospectively reviewed. Dogs were included when GBA was suspected on abdominal ultrasonography and confirmed by gross evaluation. Signalment, clinical signs, clinicopathological data, diagnostic imaging, histopathology, treatment, and outcome were recorded. RESULTS: Dogs were of 6 different breeds, and Chihuahuas (10 of 17) were most common. Median age at presentation was 1.9 (range, 0.7-7.4) years. Clinical signs included vomiting (5 of 17), anorexia (2 of 17), ascites (2 of 17), diarrhea (1 of 17), lethargy (1 of 17), and seizures (1 of 17). All dogs had increased serum activity of at least 1 liver enzyme, most commonly alanine aminotransferase (15 of 17). Fifteen dogs underwent computed tomography (CT) cholangiography; common bile duct (CBD) dilatation was confirmed in 12, without evidence of bile duct obstruction. Gross evaluation confirmed malformation of the liver lobes in 14 of 17 dogs and acquired portosystemic collaterals in 5 of 17. Ductal plate malformation was confirmed histologically in 16 of 17 dogs. During follow-up (range, 4-3,379 days), 16 of 17 dogs remained alive. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with GBA exhibit clinicopathological signs of hepatobiliary injury and hepatic histopathological changes consistent with a ductal plate abnormality. Computed tomography cholangiography was superior to ultrasound examination in identifying accompanying nonobstructive CBD distention. Computed tomography cholangiography combined with laparoscopic liver biopsy is the preferable approach to characterize the full disease spectrum accompanying GBA in dogs.

Endoscopic photodynamic therapy using talaporfin sodium for recurrent intranasal carcinomas after radiotherapy in three dogs.

Radiation is the treatment of choice for canine nasal tumours but, in almost all cases, there is local recurrence associated with poor prognosis. This report describes the effect of endoscopic photodynamic therapy using talaporfin sodium for canine intranasal carcinoma recurring after radiation therapy. Rhinoscopic photodynamic therapy was administered after radiation therapy in three dogs with recurrent intranasal carcinoma. Two to 24 illuminations of a 665-nm diode laser were performed two hours after intravenous bolus injection of 5·0 mg/kg of talaporfin sodium. Photodynamic therapy induced almost complete remission and prolonged survival time in all cases suggesting that it might be a useful treatment for intranasal carcinomas that recur after radiation.

Adenosquamous carcinoma of the oesophagus in a dog.

A six-year-old mixed-breed male dog weighing 7.0 kg was presented with chronic vomiting and regurgitation. Endoscopic examination revealed prominent oesophageal dilation in the thoracic region, multiple small greyish-white nodules over the oesophageal lumen and cauliflower-like masses in the caudal oesophagus. Histopathological studies revealed a characteristic pattern of coexisting elements of infiltrating adenocarcinoma and squamous cell carcinoma. Immunohistochemical staining with anti-cytokeratin AE1 + AE3 was positive in both types of neoplastic cells. Neoplastic glandular cells stained positively for cytokeratin 8 while neoplastic squamous cells stained positively for cytokeratin 5/6. On the basis of these findings, the dog was diagnosed with oesophageal adenosquamous carcinoma. The case history and findings suggest that the malignancy might have developed from Barrett's oesophagus following irritation of the oesophageal mucosa due to chronic vomiting and regurgitation.

Insulin stimulates the expression of the SHARP-1 gene via multiple signaling pathways.

The rat enhancer of split- and hairy-related protein-1 (SHARP-1) is a basic helix-loop-helix transcription factor. An issue of whether SHARP-1 is an insulin-inducible transcription factor was examined. Insulin rapidly increased the level of SHARP-1 mRNA both in vivo and in vitro. Then, signaling pathways involved with the increase of SHARP-1 mRNA by insulin were determined in H4IIE rat hepatoma cells. Pretreatments with LY294002, wortmannin, and staurosporine completely blocked the induction effect, suggesting the involvement of both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) pathways. In fact, overexpression of a dominant negative form of atypical protein kinase C lambda (aPKCλ) significantly decreased the induction of the SHARP-1 mRNA. In addition, inhibitors for the small GTPase Rac or Jun N-terminal kinase (JNK) also blocked the induction of SHARP-1 mRNA by insulin. Overexpression of a dominant negative form of Rac1 prevented the activation by insulin. Furthermore, actinomycin D and cycloheximide completely blocked the induction of SHARP-1 mRNA by insulin. Finally, when a SHARP-1 expression plasmid was transiently transfected with various reporter plasmids into H4IIE cells, the promoter activity of PEPCK reporter plasmid was specifically decreased. Thus, we conclude that insulin induces the SHARP-1 gene expression at the transcription level via a both PI 3-K/aPKCλ/JNK- and a PI 3-K/Rac/JNK-signaling pathway; protein synthesis is required for this induction; and that SHARP-1 is a potential repressor of the PEPCK gene expression.

Intraoperative identification of canine hepatocellular carcinoma with indocyanine green fluorescent imaging.

OBJECTIVES: To evaluate the feasibility of high-sensitivity near-infrared fluorescence imaging with indocyanine green for intraoperative identification of hepatocellular carcinoma in dogs. METHODS: Twelve hepatic nodules were surgically resected from six dogs. In each dog, 0 · 5 mg/kg indocyanine green was intravenously injected for 12 to 18 hours preoperatively. The hepatic nodules were investigated under laparotomy using a near-infrared fluorescence imaging light camera system prior to resection. Resected nodules were histopathologically diagnosed and their fluorescence images were evaluated. RESULTS: Of the 12 hepatic nodules, 6 were diagnosed as hepatocellular carcinoma and 6 as nodular hyperplasia. Indocyanine green-fluorescence was observed in four large hepatocellular carcinoma nodules and one case of nodular hyperplasia, whereas it was absent in the remaining nodules. The sensitivity and positive predictive values of indocyanine green fluorescent imaging for hepatocellular carcinoma was 71 · 4 and 80 · 0%, respectively. Complete resection of the hepatic masses was achieved in all dogs. CLINICAL SIGNIFICANCE: Near-infrared fluorescence imaging may be feasible for intraoperative mapping of hepatocellular carcinomas in hepatic lobes and may help increase the chance of complete resection of hepatocellular carcinoma in dogs.

Interstitial lung disease induced by gefitinib and toll-like receptor ligands is mediated by Fra-1.

The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment.

Endoscopic treatment for deep-seated or multiple intraparenchymal tumors: technical note.

Although endoscopic biopsy is a well-established technique in the treatment of intraventricular or cystic tumors, solid intraparenchymal tumors have not been considered candidates for this procedure. The purpose of this study is to describe strategies of neuroendoscopic treatment in patients with solid intraparenchymal tumors. Six patients with deep-seated or multiple intraparenchymal tumors underwent neuroendoscopic biopsy combined with frame-based or frameless stereotaxy during the one year period between October 2006 and September 2007. After histological diagnosis, all patients were treated with radiotherapy and chemotherapy or chemotherapy alone. Three patients were diagnosed histopathologically as having malignant glioma, and three with malignant lymphoma. A tumor was removed completely in one patient using an endoscopic procedure. Tumors disappeared in three patients with radiotherapy and chemotherapy after an endoscopic procedure. The growth of the tumor was controlled with therapy in one patient. Only in one patient was there a malignant transformation and growth of tumor was recognized in spite of therapy. Neuroendoscopic treatment may be a useful option in the management of deep-seated or multiple intraparenchymal tumors.

Inhibition of angiogenic factor production from murine mast cells by an antiallergic agent (epinastine hydrochloride) in vitro.

Angiogenesis is an important event both in the development of allergic inflammatory responses and in the pathophysiology of tissue remodeling in allergic diseases. In the present study, therefore, we examined the influence of antihistamines on angiogenesis through the choice of epinastine hydrochloride (EP) and murine mast cells in vitro. Mast cells (5 x 10(5) cells/mL) presensitized with murine IgE specific for ovalbumin (OVA) were stimulated with 10 ng/mL OVA in the presence of various concentrations of EP for 4 hours. The levels of angiogenesis factors, keratinocyte-derived chemokine (KC), tumor necrosis factor-alpha (TNF), and vascular endothelial growth factor (VEGF) in culture supernatants, were examined by ELISA. We also examined mRNA expression for the angiogenesis factors by RT-PCR. EP significantly inhibited the production of KC, TNF, and VEGF induced by IgE-dependent mechanism at more than 25 ng/mL. Semiquantitative analysis using RT-PCR showed that EP also significantly reduced mRNA expressions for KC, TNF, and VEGF. These results strongly suggest that EP suppresses angiogenesis factor production through the inhibition of mRNA expression in mast cells and results in favorable modification of clinical conditions of allergic diseases.

S100B protein expression in the amnion and amniotic fluid in pregnancies complicated by pre-eclampsia.

Our aim was to investigate the expression of S100B protein in the amnion and to assess the amniotic fluid concentration in pregnancies complicated by pre-eclampsia. Samples were obtained from women who developed pre-eclampsia (n = 7), pre-eclampsia with intrauterine growth retardation (IUGR) (n = 4), normotensive IUGR (n = 7) and gestational hypertension (n = 4) during pregnancy and healthy controls who delivered at term (n = 35). To determine the difference in the expression of S100B in the amnion, we performed immunohistochemistry, western blot analysis and RT-PCR. Using enzyme-linked immunosorbent assay (ELISA), we assessed the S100B concentration in amniotic fluid. The S100B mRNA expression in the amnion of pre-eclamptic patients and patients with pre-eclampsia with IUGR was significantly higher than that in the control. The amniotic fluid S100B protein concentration of the pre-eclampsia and normotensive IUGR cases was significantly higher than that of the control. This study shows that amnion could be a source responsible for the increased concentration of S100B in amniotic fluid. In pre-eclampsia, reactive oxygen species (ROS) are generated by oxidative stress. Some pathological conditions that develop during pregnancy and are related to hypoxic stress can affect the elevation of S100B concentration in the amnion.

Gene expressions of canine angiopoietin-1 and -2 in normal tissues and spontaneous tumours.

The angiopoietin (Ang) family of proteins are central to the regulation of angiogenesis. The purposes of this study were to determine cDNA sequences of canine Ang-1 and Ang-2 and investigate their expressions in normal tissues and spontaneous tumours. The cDNA sequences of canine Ang-1 and Ang-2 were 1,494 and 1,488 bp, and the deduced amino acid sequences were 497 and 495 residues, respectively. The cDNA sequences of canine Ang-1 and Ang-2 showed high homology with those of the other mammalian species. Canine Ang-1 and Ang-2 mRNA were detectable in all 22 normal tissues and spontaneous tumours. Higher mRNA expression level of canine Ang-2 was demonstrated in mammary simple carcinomas, haemangiosarcoma and hepatocellular carcinoma in comparison with normal tissues.

The expression of fractalkine in the endometrium during the menstrual cycle.

OBJECTIVE: The objective of the study was to evaluate the presence of fractalkine in the endometrium of the uterus and the change of fractalkine protein levels during menstrual cycle. METHODS: Twelve samples of endometrium of the uterus were obtained from gynecological patients who underwent total hysterectomy. Western blotting, RT-PCR and immunohistochemistry were performed. RESULTS: Fractalkine protein was detected in the endometrium of the uterus. Positive staining was confirmed in the epithelial cells and grandular cells in the endometrium. Expression levels of fractalkine protein and mRNA in the endometrium during secretory phase were significantly higher than those during proliferative phase. Immunohistochemical analysis using an anti-CX3CR1 antibody demonstrated positive staining in the glandular cells of the endometrium of the uterus. CONCLUSION: Fractalkine was expressed in the endometrium and its production was up-regulated during secretory phase.

Pulmonary adenosquamous carcinoma in a dog.

A mass that developed in the lung of a 10-year-old mixed-breed dog was pathologically examined. Histopathological examination showed papillary and tubular growth of glandular epithelium-like cells in some areas and growth of squamous cells arranged in nests in other areas, showing coexistence of adenocarcinoma and squamous cell carcinoma in a lung tumour. Immunohistochemical staining with anti-keratin-cytokeratin antibody was strongly positive for cytoplasms in both components. Electron microscopically, the neoplastic cells of the adenocarcinoma component had features of glandular cells, with microvilli, numerous free ribosomes, large round secretory granules and intercellular desmosomes. Non-keratinized squamous cells had tonofilaments and intercellular desmosomes. These findings led to the diagnosis of primary adenosquamous carcinoma, which demonstrates phenotypic profiles characteristic of both epidermal keratinocytes and glandular epithelium.

[Surgical resection for T4 lung cancer invading thoracic aorta].

The prognosis of the lung cancer patients with aortic invasion is thought to be very poor in general. Thoracic aorta resection and reconstruction was performed in 6 patients, aortic arch in 2, descending aorta in 4. An intraoperative and a postoperative major complication occurred in each 1 patient. Five patients survived more than 1 year after operation, and 1 of them has been living without relapse for more than 5 years. Pulmonary resection with the involved aorta can be done safely using cardiopulmonary bypass, with encouraging long-term survivals in patients without N2 or N3 nodal metastasis.

Fractalkine in the peritoneal fluid of women with endometriosis.

OBJECTIVE: The objective of this study was to evaluate the presence of fractalkine in the ascites and the association between fractalkine levels in the ascites and endometriosis. METHODS: Peritoneal fluids and peripheral blood samples were obtained from patients undergoing laparoscopy for infertility work-up or laparoscopic cystectomy. Three samples of peritoneum were obtained from patients undergoing hysterectomy. Western blotting, RT-PCR and immunohistochemistry were performed. RESULTS: Fractalkine protein was detected in the ascites. Positive staining was confirmed in peritoneal surface cells and perivascular cells of the peritoneum. CX3CR1 positive cells were present in the cells in the peritoneal fluid. The fractalkine concentrations in the ascites of patients with endometriosis were lower than those without endometriosis. There was no significant difference between serum fractalkine levels in patients with and without endometriosis. CONCLUSION: The decreased level of fractalkine found in the peritoneal fluid of patients with endometriosis may contribute to the pathogenesis of endometriosis.