Iron Metabolism in the Tumor Microenvironment-Implications for Anti-Cancer Immune Response

New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: i) the "hot" tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and ii) the "cold" tumors, which are often very poor in immune cells, mainly due to immune exclusion

Studying essential DNA metabolism proteins in Xenopus egg extract

The correct duplication of genetic information is essential to maintain genome stability, which is lost in cancer cells. Replication fork integrity is ensured by a number of DNA metabolism proteins that assist replication of chromatin regions difficult to replicate due to their intrinsic DNA sequence composition, coordinate repair of DNA molecules resulting from aberrant replication events or protect replication forks in the presence of lesions impairing their progression. Some DNA metabolism genes involved in DNA repair are essential in higher eukaryotes even in unchallenged conditions, suggesting the existence of biological processes requiring these specialized functions in organisms with complex genomes. The impact on cell survival of null mutants of many DNA metabolism genes has precluded complete in depth analysis of their function. Cell free extracts represent a fundamental tool to overcome survival issues. The Xenopus laevis egg cell free extract is an ideal system to study replication-associated functions of essential genes. We are taking advantage of this system together with innovative imaging and proteomic based experimental approaches to characterize the molecular function of essential DNA metabolism proteins. Using this approach we have uncovered the role of some essential homologous recombination and fork protection proteins in chromosomal DNA replication and we have characterized some of the factors required for faithful replication of specific vertebrate genomic regions. This approach will be instrumental to study the molecular mechanisms underlying the function of a number of essential DNA metabolism proteins involved in the maintenance of genome stability in complex genomes

safety of nintedanib plus docetaxel in advanced non squamous nsclc nsnsclc patients the preliminary results of the seneca second line nintedanib in non small cell lung cancer trial

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End-stage renal disease costs for patients new to hemodialysis in Italy: The FARO-2 Study

Background: Increasing incidence and prevalence of end-stage renal disease (ESRD) together with the presence of several comorbidities in chronic kidney disease patients (CKD) could be associated with a relevant economic burden. Aim: The aim of this analysis was to estimate the direct healthcare costs of ESRD and its major comorbidities in Italian patients who were na\uefve to hemodialysis (HD) recruited for the FARO-2 study. Methods: The FARO-2 study was a retrospective observational study conducted in Italy that evaluated the patterns of treatment of secondary hyperparathyroidism (SHPT) and related costs in patients na\uefve to HD. The observational period was 2006\u20132008. Costs were measured in Euros (reference year: 2008). Resource use for the first 2 periods of 6 months of HD was monetized, with reimbursement calculated for SHPT drugs, phosphate binders, and erythropoietin-stimulating agents (ESAs); HD sessions; and hospitalizations due to ESRD and its major comorbidities. The analysis was performed by the Italian National Health Service (INHS) perspective. Results: 567 patients were observed for at least 2 periods of 6 months. During the first 12 months after the initiation of HD, average direct healthcare costs were assessed using the percentage of patients treated and the average daily dosages (for drugs), the percentage of patients hospitalized and the types of hospitalizations (for inpatients), and the average weekly frequency of HD sessions. Total per-patient yearly costs totaled 34,789.9 \u20ac: HD accounted for 66.1% of expenditures, with hospitalizations and drugs accounting for 12.9% and 21.0% of expenditures, respectively (including 17.1% for ESAs). Conclusions: Patients na\uefve to HD have a significant impact on Italian National Health Service expenditures, although only the costs related to treatment of ESRD and its comorbidities were calculated in the present study. The major cost drivers were HD and ESAs, while SHPT drugs and phosphate binders together accounted for only 3.9% of direct healthcare expenditures

Evaluating targets and costs of treatment for secondary hyperparathyroidism in incident dialysis patients: the FARO-2 study

Results: Two prominent treatment groups were identified, ie, one on oral calcitriol (n=105) and the other on intravenous paricalcitol (n=33); the intravenous calcitriol and intravenous paricalcitol + cinacalcet combination groups were not analyzed due to low patient numbers. At baseline, serum PTH levels were significantly higher in the intravenous paricalcitol group (P<0.0001). At the second survey, the intravenous paricalcitol group showed a higher percentage of patients at target for PTH than in the oral calcitriol group without changing the percentage of patients at target for phosphate. Moreover, between baseline and the second survey, intravenous paricalcitol significantly increased both the percentage of patients at target for PTH (P=0.033) and the percentage of patients at target for the combined endpoint PTH, calcium, and phosphate (P=0.001). The per-patient weekly pharmaceutical costs related to SHPT treatment, erythropoietin-stimulating agents and phosphate binders accounted for 186.32\u20ac and 219.94\u20ac at baseline for oral calcitriol and intravenous paricalcitol, respectively, while after 6 months, the costs were 180.51\u20ac and 198.79\u20ac, respectively. Either at the beginning of dialysis or 6 months later, the total cost of SHPT treatment was not significantly lower in the oral calcitriol group compared with the intravenous paricalcitol group, with a difference among groups that decreased by 46% between the two observations. The cost of erythropoietin stimulating agents at the second survey was lower ( 1222%) in the intravenous paricalcitol group than in the oral calcitriol group (132.13\u20ac versus 168.36\u20ac, respectively)

Prognosis and determinants of serum PTH changes over time in 1-5 CKD stage patients followed in tertiary care

International Guidelines for mineral bone disorders recommend that in Non Dialytic-Chronic Kidney Disease (ND-CKD) clinical decisions should be based on the trend of serum PTH changes over time rather than on a single value. However, the prognostic impact of these changes in ND-CKD patients remains unknown. We performed a multicenter cohort study in ND-CKD patients (stage 1-5) followed for 36 months in 24 Italian Nephrology Units. PTH changes (\u394PTH) were defined as the absolute differences between all available PTH measurements following the first control and basal value. Primary endpoint in this subanalysis was renal death (End-Stage Renal Disease (ESRD) or all-causes death before ESRD). Association between renal death and \u394PTH was assessed by time-dependent Cox model for repeated measurements. Out of the original cohort (N = 884), we selected 543 patients (66.3\ub115.4 ys, 58.4% males) with at least two serum PTH measurements. At baseline, eGFR was 36 (IQR: 22.4-56.8) mL/min/1.73m2 and serum PTH 46 (IQR: 28-81) pg/mL. \u394PTH was in median 0 (IQR:-18/18) pg/mL. Basal predictors of longitudinal PTH increments were higher serum phosphate, more advanced CKD stages and lower serum PTH. Fully adjusted Cox model with \u394PTH quartiles as discrete time-dependent covariate showed a significant risk of renal death in the highest quartile (HR: 1.91; 95%CI:1.08-3.38; P = 0.026). Considering \u394PTH, as continuous time-dependent variable, (HR:1.02; 95%C.I.: 1.01-1.04; P = 0.004), risk of renal death progressively rose as \u394PTH increased. An increment in serum PTH over time is associated with a worse prognosis in ND-CKD patients, independently from baseline or any absolute concentration of serum PTH and phosphate

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results