Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer.

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients' aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells

High discharge rate characteristics of nickel-cadmium batteries for pulse load filtering

Several tests of specially fabricated nickel-cadmium batteries having circular disk type electrodes were considered. These batteries were evaluated as filter elements between a constant current power supply and a five hertz pulsed load demanding approximately twice the power supply current during the load on portion of the cycle. Short tests lasting 10,000 cycles were conducted at up to a 21 C rate and an equivalent energy density of over 40 Joules per pound. In addition, two batteries were subjected to 10 to the 7 charge/discharge cycles, one at a 6.5 C rate and the other at a 13 C rate. Assuming an electrode to battery weight ratio of 0.5, these tests represent an energy density of about 7 and 14 Joules per pound respectively. Energy density, efficiency, capacitance, average voltage, and available capacity were tracked during these tests. After 10 to the 7 cycles, capacity degradation was negligible for one battery and about 20% for the other. Cadmium electrode failure may be the factor limiting lifetime at extremely low depth of discharge cycling. The output was examined and a simple equivalent circuit was proposed

GNAM and OHP: Monitoring Tools for ATLAS experiment at LHC.

ATLAS is one of the four experiments under construction along the Large Hadron Collider (LHC) ring at CERN. The LHC will produce interactions at a center-of-mass energy equal to âs = 14 TeV at 40 MHz rate. The detector consists of more than 140 million electronic channels. The challenging experimental environment and the extreme detector complexity impose the necessity of a common scalable distributed monitoring framework, which can be tuned for the optimal use by different ATLAS sub-detectors at the various levels of the ATLAS data flow. This note presents two monitoring tools that have been developed for this aim within the architecture ATLAS Monitoring Framework and the Data Acquisition System: GNAM and OHP. The first one is a framework for online histogram production; the second one is graphical application for histogram presentation. This tools are now widely used during the ATLAS commissioning and their performances are reported in this not

A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide

The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 μM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a β-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs

Diabetes Mellitus and Cardiovascular Prevention: The Role and the Limitations of Currently Available Antiplatelet Drugs

Diabetes mellitus (DM) is associated with macrovascular and microvascular complications. Platelets have a “key role” in atherogenesis and its thrombotic complications in subjects with DM. Moreover, the concomitant presence of multiple “classical” cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk. Antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis (cardiovascular events, ischaemic stroke, and peripheral arterial occlusive disease). The role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention, and, also in diabetic patients, the decision to give primary prophylaxis should be taken on an individual-patient basis, after a careful evaluation of the balance between the expected benefits and the risk of major bleedings. Although, currently, treatment has proven useful in reducing vascular events, diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients. This paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs, and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development

Misalignment of hemodynamic forces in the left ventricle is associated with adverse remodeling following STEMI

Abstract Funding Acknowledgements Type of funding sources: None. Background Infarct size (IS), area at risk (AAR) and microvascular obstruction (MVO) are well known predictors of adverse remodeling (aLVr) following acute myocardial infarction, while the pathogenic role of left ventricular (LV) hemodynamic forces (HDFs) is still unknown. Recent evidence suggests the role of HDFs in negative remodeling after pathogenic events. Purpose To identify LV HDFs patterns associated with aLVr in reperfused ST-segment elevation MI (STEMI) patients. Methods Forty-nine acute STEMI patients underwent CMR at 1 week (baseline) and 4 months (follow-up) after MI. The following parameters were measured: left ventricular end-diastolic and end-systolic volume index for body surface area (LVEDVi and LVESVi), left ventricular ejection fraction (LVEF) and LV mass index, AAR and IS. LV HDFs were computed at baseline from cine CMR long axis datasets using a novel method based on LV endocardial boundary tracking. LV HDFs were calculated both in apex-base (A-B) and latero-septal (L-S) directions. The distribution of LV HDFs were evaluated by L-S over A-B HDFs ratio (L-S/A-B HDFs ratio %). All HDFs parameters are computed over the entire heartbeat, in systole and diastole. aLVr was defined as an absolute increase in LVESV of at least 15% (ΔLV-ESV ≥15%). Results Patients with aLVr (n = 18; 37%) had significant greater value of AAR (32 ± 23 vs 22 ± 18; p = 0.03) and slightly larger IS (23 ± 16 vs 15 ± 11; p= 0.07) at baseline. In patients with aLVr at FU, baseline systolic L-S HDF were lower (2.7 ± 0.9 vs 3.6 ± 1; p = 0.027) while diastolic L-S/A-B HDF ratio was significantly higher (28 ± 14 vs 19 ± 6; p = 0.03), reflecting higher grade of diastolic HDFs misalignment. At univariate logistic regression analysis, higher IS [Odd ratio (OR) 1.05; 95% confidence interval (95% CI) 1.01-1.1; p= 0.04] L-S HDFs (OR 0.41; 95% CI 0.2-0.9; p= 0.04] and higher diastolic L-S/A-B HDFs ratio (OR 1.1; 95% CI 1.01-1.2; p= 0.05) were associated with aLVr at FU (Table). At multivariate logistic regression analysis, L-S/A-B HDF ratio remained the only independent predictor of adverse LV remodeling after correction for other baseline determinants. Conclusion Misalignment of diastolic HDFs following STEMI is associated with aLVr observed after 4 months. Predictors of adverse remodeling Univariate Multivariate Parameter OR (95% CI) P OR (95% CI) P IS (%) 1.05 (1.01-1.1) 0.042 - - Systolic L-S HDF 0.41 (0.2-0.9) 0.04 - - Diastolic L-S/A-B HDF Ratio 1.1 (1.01-1.2) 0.05 1.1 (1.01-1.2) 0.04 A-B:apex-base; L-S: latero-septal; HDFs: hemodynamic forces Abstract Figure. Diastolic HDFs distribution and aLV

Electronic and Magnetic Structures of Sr2FeMoO6

We have investigated the electronic and magnetic structures of Sr2FeMoO6 employing site-specific direct probes, namely x-ray absorption spectroscopy with linearly and circularly polarized photons. In contrast to some previous suggestions, the results clearly establish that Fe is in the formal trivalent state in this compound. With the help of circularly polarized light, it is unambiguously shown that the moment at the Mo sites is below the limit of detection (< 0.25mu_B), resolving a previous controversy. We also show that the decrease of the observed moment in magnetization measurements from the theoretically expected value is driven by the presence of mis-site disorder between Fe and Mo sites.Comment: To appear in Physical Review Letter

Status of COLDDIAG: A Cold Vacuum Chamber for Diagnostics

One of the still open issues for the development of superconducting insertion devices is the understanding of the beam heat load. With the aim of measuring the beam heat load to a cold bore and the hope to gain a deeper understanding in the beam heat load mechanisms, a cold vacuum chamber for diagnostics is under construction. The following diagnostics will be implemented: i) retarding field analyzers to measure the electron energy and flux, ii) temperature sensors to measure the total heat load, iii) pressure gauges, iv) and mass spectrometers to measure the gas content. The inner vacuum chamber will be removable in order to test different geometries and materials. This will allow the installation of the cryostat in different synchrotron light sources. COLDDIAG will be built to fit in a short straight section at ANKA. A first installation at the synchrotron light source Diamond is foreseen in June 2011. Here we describe the technical design report of this device and the planned measurements with beam.Comment: Presented at First International Particle Accelerator Conference, IPAC'10, Kyoto, Japan, from 23 to 28 May 201