6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer

In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC50 of 2.3 +/- 0.6 mu mol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance-associated protein 1 (MRP1; LC50 of 4.5 +/- 0.9 mu mol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH2-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38(MAPK) is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells

Self-Trapped Exciton Defects in a Charge Density Wave: Electronic Excitations of BaBiO3

In the previous paper, it was shown that holes doped into BaBiO3 self-trap as small polarons and bipolarons. These point defects are energetically favorable partly because they undo locally the strain in the charge-density-wave (Peierls insulator) ground state. In this paper the neutral excitations of the same model are discussed. The lowest electronic excitation is predicted to be a self-trapped exciton, consisting of an electron and a hole located on adjacent Bi atoms. This excitation has been seen experimentally (but not identified as such) via the Urbach tail in optical absorption, and the multi-phonon spectrum of the ``breathing mode'' seen in Raman scattering. These two phenomena occur because of the Franck-Condon effect associated with oxygen displacement in the excited state.Comment: 5 pages with 7 embedded figures. See also cond-mat/0108089 on polarons and bipolarons in BaBiO3 contains background informatio

Helium bubble formation in ultrafine and nanocrystalline tungsten under different extreme conditions

We have investigated the effects of helium ion irradiation energy and sample temperature on the performance of grain boundaries as helium sinks in ultrafine grained and nanocrystalline tungsten. Irradiations were performed at displacement and non-displacement energies and at temperatures above and below that required for vacancy migration. Microstructural investigations were performed using Transmission Electron Microscopy (TEM) combined with either in-situ or ex-situ ion irradiation. Under helium irradiation at an energy which does not cause atomic displacements in tungsten (70 eV), regardless of temperature and thus vacancy migration conditions, bubbles were uniformly distributed with no preferential bubble formation on grain boundaries. At energies that can cause displacements, bubbles were observed to be preferentially formed on the grain boundaries only at high temperatures where vacancy migration occurs. Under these conditions, the decoration of grain boundaries with large facetted bubbles occurred on nanocrystalline grains with dimensions less than 60 nm. We discuss the importance of vacancy supply and the formation and migration of radiation-induced defects on the performance of grain boundaries as helium sinks and the resulting irradiation tolerance of ultrafine grained and nanocrystalline tungsten to bubble formatio

A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosis

Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable

Probability amplitude in quantum like games

Examples of games between two partners with mixed strategies, calculated by the use of the probability amplitude are given. The first game is described by the quantum formalism of spin one half system for which two noncommuting observables are measured. The second game corresponds to the spin one case. Quantum logical orthocomplemented nondistributive lattices for these two games are presented. Interference terms for the probability amplitudes are analyzed by using so called contextual approach to probability (in the von Mises frequency approach). We underline that our games are not based on using of some microscopic systems. The whole scenario is macroscopic.Comment: Quantum-like model

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Design and Baseline Characteristics

Introduction: The TROPHIES observational study enrolled patients with type 2 diabetes mellitus (T2DM) initiating their first injectable treatment with the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) dulaglutide or liraglutide. This manuscript focuses on the study design, baseline characteristics of the enrolled population, and factors associated with GLP-1 RA choice. Methods: TROPHIES is a prospective, observational, 24-month study conducted in France, Germany, and Italy. Inclusion criteria include adult patients with T2DM, naïve to injectable antihyperglycemic treatments, initiating dulaglutide or liraglutide per routine clinical practice. The primary outcome is the duration of treatment on dulaglutide or liraglutide without a significant treatment change. Results: The analysis included 2181 patients (dulaglutide, 1130; liraglutide, 1051) (cutoff date May 15, 2019). The population was 56% male with mean [standard deviation (SD)] patient characteristics at baseline as follows: age, 59.2 (11.0) years; body mass index (BMI), 33.9 (6.6) kg/m2; T2DM duration, 8.5 (6.9) years; and glycated hemoglobin (HbA1c), 8.2 (1.3)%. Between-cohort demographic and clinical characteristics were balanced. The mean (SD) HbA1c and BMI values for French, German, and Italian patients were, respectively, 8.6 (1.4)%, 8.2 (1.4)%, 8.0 (0.8)%; 33.3 (6.1) kg/m2, 36.0 (7.2) kg/m2, and 32.6 (5.9) kg/m2. Conclusion: This study analysis at baseline provides an opportunity to evaluate between-country differences in baseline HbA1c, weight, macrovascular complications, and factors driving GLP-1 RA selection for patients with T2DM in daily practice

Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors

Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV

Cytoreductive Surgery (CRS) and HIPEC for Advanced Ovarian Cancer with Peritoneal Metastases: Italian PSM Oncoteam Evidence and Study Purposes

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be designed from a patient’s perspective and focus on meaningful measures of benefit. Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery with regional chemotherapy, has been proposed to treat advanced ovarian cancer. Preliminary results to date have shown promising results, with improved survival outcomes and tumor regression. As knowledge about the disease process increases, practice guidelines will continue to evolve. In this review, we have reported a broad overview of advanced ovarian cancer management, and an update of the current evidence. The future perspectives of the Italian Society of Surgical Oncology (SICO) are discussed conclusively

A Serum Resistin and Multicytokine Inflammatory Pathway Is Linked With and Helps Predict All-cause Death in Diabetes

Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1 beta, IL-6, IL-8, and TNF-alpha, that is associated with cardiovascular disease.Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D.Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification.Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase=1.34, P<.001). In CEA patients, REMAP was associated with mortality (HR=1.64, P=.04) and a modest change was observed when plaque stability was taken into account (HR=1.58; P=.07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P<.05-<.001).Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1 beta monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested