Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model

BACKGROUND AND AIMS: DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. METHODS: A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. RESULTS: We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. CONCLUSION: Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention

FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

False-positive I-131 accumulation in hepatic hydatid cyst in a patient with thyroid carcinoma

20th Annual Congress of the European-Association-of-Nuclear-Medicine -- 2007 -- Copenhagen, DENMARKWOS: 000253283900906European Assoc Nucl Me

Preparation of nano-scale magnetite Fe3O4 and its effects on the bulk bi-2223 superconductors

Nano-scale magnetite (Fe3O4) powders were prepared from metallic iron and distilled water by wet milling technique. Magnetite powders so obtained were added to Bi1.6Pb0.4Sr2Ca2Oy superconductor by 0.00 0.05, 0.10 and 0.30 wt (x), with solid state reaction method. The structural and superconducting properties were studied by x-ray diffraction, transmission electron microscopy, magnetization and magnetic susceptibility measurements. Single-phase magnetite samples with average particle size about 25 nm were obtained with the wet milling technique. Nanoscale magnetite additions up to 0.10 wt % enhance the critical current density (J(c)) of the superconductor preserving the fraction of the high T, phase Bi-2223. Magnetite additions above 0.10 wt % decrease the critical parameters (T-c, J(c)) and the fraction of the high T-c phase

Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome?

OBJECTIVES: The goal was to investigate the neuroimmune axis in irritable bowel syndrome (IBS) by analyzing the neuroendocrine and cellular immune responses to nutrient load. METHODS: In the fasting state and 20, 40, 70, and 100 min following nutrient load, blood samples were collected and cardiovascular recordings were accomplished in 15 female IBS patients and 15 healthy women. Plasma norepinephrine, prolactin, cortisol, and growth hormone were analyzed, and blood pressure and heart rate responses were measured. The distribution of peripheral leukocytes and lymphocyte subpopulations and the in vitro production of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) after whole blood stimulation with in lipopolysaccharide (LPS) were analyzed. RESULTS: IBS patients demonstrated significantly greater postprandial increases in plasma norepinephrine and systolic blood pressure (p < 0.05), but no cortisol response. A postprandial redistribution of circulating leukocytes and lymphocyte subpopulations was observed in both groups, including significant increases in the numbers of leukocytes and granulocytes and significant decreases in the numbers of monocytes, T-cells, and natural killer (NK) cells (all p < 0.05). However, IBS patients demonstrated significantly greater postprandial increases in leukocytes and granulocytes, while changes in the numbers of monocytes and NK cells were significantly diminished (all p < 0.05). Patients also failed to show the postprandial decrease in the in vitro TNF-alpha production observed in controls. Postprandial norepinephrine concentrations were negatively correlated with NK cell numbers in IBS patients (r= 0.58, p < 0.05) but not controls. CONCLUSIONS: IBS may involve an autonomic hyper-responsiveness to visceral stimuli, which occurs throughout the entire gut, is independent of acutely perceived GI symptoms, and does not necessarily involve HPA axis activation. Women with IBS show altered cellular immune responses to food intake, which may at least in part be mediated by adrenergic mechanisms. Thus, autonomic disturbances may have implications for cellular immune function along the neuroendocrine-immune axis in patients with IBS.Sigrid Elsenbruch, Gerald Holtmann, Deniz Oezcan, Andreas Lysson, Onno Janssen, Marion U Goebel and Manfred Schedlowsk