MEK inhibition in pancreas cancer

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is resistant to chemotherapy. Gemcitabine, a nucleoside analogue, is an important component of treatment for locally advanced and metastatic PDAC, but provides only modest survival benefit. The enzyme Ribonucleotide Reductase (RR) catalyses the conversion of ribonucleotides into deoxyribonucleotides, required for DNA synthesis and repair. Several studies have demonstrated that RR large subunit-1 (RRM1) is associated with gemcitabine resistance in PDAC. The RAS/RAF/MEK/ERK signalling pathways regulates cellular proliferation, differentiation and survival. Targeting downstream effectors of the RAS gene by direct inhibition of MEK (MAPKK) proteins is a rational therapeutic strategy, since aberrant activation of this pathway occurs frequently in PDAC. In this study, the ability of pimasertib (AS703026), a highly selective and allosteric MEK1/2 inhibitor, to enhance gemcitabine efficacy was tested and the molecular mechanism of their interaction was investigated. Synergistic antiproliferative effects and increased apoptosis were observed when pimasertib was combined sequentially with gemcitabine in human pancreatic cancer cells. Importantly, pimasertib reduced the expression of RRM1 protein and this was associated with sensitivity to gemcitabine. Pre-treatment with the proteasome inhibitor MG132 impaired RRM1 downregulation induced by pimasertib, suggesting RRM1 is degraded through the ubiquitin-proteasome system. Immunoprecipitation experiments indicated enhanced MDM2-mediated polyubiquitination of RRM1 through lys48-mediated linkage following pimasertib treatment, an effect in part mediated by AKT. Finally, the combination treatment of pimasertib with gemcitabine caused significant tumor growth delay in an orthotopic pancreatic cancer model, with RRM1 downregulation in pimasertib-treated mice. These results indicate MEK as a potential target to sensitize gemcitabine therapy through modulation of RRM1 protein stability and underline the importance of drug scheduling in achieving efficacious antitumor activity. This study has provided mechanistic insights to the synergistic interaction between gemcitabine and pimasertib that could be further investigated in design of future clinical trials

once weekly administration of high dosage etanercept in patients with plaque psoriasis results of a pilot experience power study

Abstract Etanercept is a soluble tumour necrosis factor receptor fusion protein which is approved for the treatment of plaque psoriasis at the dose of either 25mg twice weekly (BIW) or, for the initial 12 weeks, 50mg BIW. Alternative dosing regimens have not been evaluated in psoriasis. In this study, we compare the efficacy and tolerability of two etanercept dosing regimens--50mg BIW and 100mg once weekly (OW)--for 12 weeks in 108 patients with moderate-to-severe recalcitrant psoriasis. Efficacy measures included Psoriasis Area and Severity Index (PASI), severity of pruritus recorded on a visual analogue scale (VAS) and the influence on quality of life assessed by means of Dermatology Life Quality Index (DLQI). Both etanercept regimens caused a significant change in all the efficacy parameters after 4 weeks and 12 weeks, at a comparable rate. At week 12, a PASI improvement of at least 50% from baseline (PASI 50) was achieved by 74% of patients treated with 50mg BIW and 78% of patients treated with 100mg OW. A PASI 75 response was obtained in 54% and 50% of patients treated with 50mg BIW and 100mg OW, respectively. Treatment was well tolerated with similar type and frequency of adverse events between the two groups

RF and THz Identification Using a New Generation of Chipless RFID Tags

This article presents two chipless RFID approaches where data are reading using electromagnetic waves and where the medium encoding the data is completely passive. The former approach rests on the use of RF waves (more precisely the ultra-wide band UWB). The tags developed for this application are comparable with very specific, planar, conductive, radar targets where the relation between the tag geometry and its electromagnetic signature is perfectly known and is used to encode the data. The principle of operation as well as the realization process of the RF tags presented in this paper is similar to those already reported in the literature. However, contrary to the majority of chipless RFID tags, these labels do not present an antenna function dissociated from the circuit part where the data are stored. Here, functions such as the receiver, the treatment and the emitter of the signal are closely dependent. The data storage capacity of the RF chipless tags is proportional to of the used frequency bandwidth. As radio spectrum is regulated, the number of possible encoding bits is thus strongly limited with this technology. This is the reason why we introduce a new family of tags radically different from the preceding one, where data is encoded in volume thanks to a multilayer structure operating in the THz domain. These two approaches although different are complementary and allow to increase significantly the data storage capacity of the chipless tags. Simulation and experimental results are reported in this paper for both configurations. We demonstrate a coding capacity of 3.3 bit/cm2 for RFID chipless tags and a potential 10 bits coding capacity in the THz domain

Computational models for the simulation of the elastic and fracture properties of highly porous 3D-printed hydroxyapatite scaffolds

Bone scaffolding is a promising approach for the treatment of critical-size bone defects. Hydroxyapatite can be used to produce highly porous scaffolds as it mimics the mineralized part of bone tissue, but its intrinsic brittleness limits its usage. Among 3D printing techniques, vat photopolymerization allows for the best printing resolution for ceramic materials. In this study, we implemented a Computed micro-Tomography based Finite Element Model of a hydroxyapatite porous scaffold fabricated by vat photopolymerization. We used the model in order to predict the elastic and fracture properties of the scaffold. From the stress–strain diagram of a simulated compression test, we computed the stiffness and the strength of the scaffolds. We found that three morphometric features substantially affect the crack pattern. In particular, the crack propagation is not only dependent on the trabecular thickness but also depends on the slenderness and orientation of the trabeculae with respect to the load. The results found in this study can be used for the design of ceramic scaffolds with heterogeneous pore distribution in order to tailor and predict the compressive strength

Mechanical Properties of Robocast Glass Scaffolds Assessed through Micro-CT-Based Finite Element Models

In this study, the mechanical properties of two classes of robocast glass scaffolds are obtained through Computed micro-Tomography (micro-CT) based Finite Element Modeling (FEM) with the specific purpose to explicitly account for the geometrical defects introduced during manufacturing. Both classes demonstrate a fiber distribution along two perpendicular directions on parallel layers with a (Formula presented.) tilting between two adjacent layers. The crack pattern identified upon compression loading is consistent with that found in experimental studies available in literature. The finite element models have demonstrated that the effect of imperfections on elastic and strength properties may be substantial, depending on the specific type of defect identified in the scaffolds. In particular, micro-porosity, fiber length interruption and fiber detaching were found as key factors. The micro-pores act as stress concentrators promoting fracture initiation and propagation, while fiber detachment reduces the scaffold properties substantially along the direction perpendicular to the fiber plane

Ultrasonographic diagnosis of placenta accreta spectrum (PAS) disorder: Ideation of an ultrasonographic score and correlation with surgical and neonatal outcomes

The objective of this study was to evaluate a novel ultrasonographic scoring system for the diagnosis of PAS and the prediction of maternal and neonatal outcomes. In this retrospective study, 138 patients with at least one previous caesarean section (CS) and placenta previa were included. They were divided into four groups ranging from Group 0 (Non PAS) to Group 3 (Placenta Percreta) according to the histological or surgical confirmation. Their ultrasound examinations during pregnancy were reviewed according to the nine different ultrasound signs reported by the European Working Group on Abnormally Invasive Placenta. For each parameter, 0 to 2 points were assigned. The sum of the points reflects the severity of PAS with a maximum score of 20. The scoring system revealed good performances in evaluation metrics, with an overall accuracy of 94%. In addition to this, patients’ characteristics and surgical and neonatal outcomes were analyzed with an evidence of higher incidence of complications in severe forms. Our study suggests that antenatal ultrasonographic diagnosis of PAS is feasible with sufficient level of accuracy. This will be important in identifying high-risk patients and implementing preventive strategy

Therapeutic Drug Monitoring of Antifungal Drugs: Another Tool to Improve Patient Outcome?

Introduction: This study aimed to examine the relationship among adequate dose, serum concentration and clinical outcome in a non-selected group of hospitalized patients receiving antifungals. Methods: Prospective cross-sectional study performed between March 2015 and June 2015. Dosage of antifungals was considered adequate according to the IDSA guidelines, whereas trough serum concentrations (determined with HPLC) were considered adequate as follows: fluconazole > 11\ua0\ub5g/ml, echinocandins > 1\ua0\ub5g/ml, voriconazole 1\u20135.5\ua0\ub5g/ml and posaconazole > 0.7\ua0\ub5g/ml. Results: During the study period, 84 patients (65.4% male, 59.6\ua0years) received antifungals for prophylaxis (40.4%), targeted (31.0%) and empirical therapy (28.6%). The most frequent drug was micafungin (28/84; 33.3%) followed by fluconazole (23/84; 27.4%), voriconazole (15/84; 17.9%), anidulafungin (8/84; 9.5%), posaconazole (7/84; 8.3%) and caspofungin (3/84; 3.6%). Considerable interindividual variability was observed for all antifungals with a large proportion of the patients (64.3%) not attaining adequate trough serum concentrations, despite receiving an adequate antifungal dose. Attaining the on-target serum antifungal level was significantly associated with a favorable clinical outcome (OR = 0.02; 95% CI 0.01\u20130.64; p = 0.03), whereas the administration of an adequate antifungal dosage was not. Conclusions: With the standard antifungal dosage, a considerable proportion of patients have low drug concentrations, which are associated with poor clinical outcome

Mechanisms of Alcohol Addiction: Bridging Human and Animal Studies

Aim: The purpose of this brief narrative review is to address the complexities and benefits of extending animal alcohol addiction research to the human domain, emphasizing Allostasis and Incentive Sensitization, two models that inform many pre-clinical and clinical studies. Methods: The work reviewed includes a range of approaches, including: a) animal and human studies that target the biology of craving and compulsive consumption; b) human investigations that utilize alcohol self-administration and alcohol challenge paradigms, in some cases across 10 years; c) questionnaires that document changes in the positive and negative reinforcing effects of alcohol with increasing severity of addiction; and d) genomic structural equation modeling based on data from animal and human studies. Results: Several general themes emerge from specific study findings. First, positive reinforcement is characteristic of early stage addiction and sometimes diminishes with increasing severity, consistent with both Allostasis and Incentive Sensitization. Second, evidence is less consistent for the predominance of negative reinforcement in later stages of addiction, a key tenant of Allostasis. Finally, there are important individual differences in motivation to drink at a given point in time as well as person-specific change patterns across time. Conclusions: Key constructs of addiction, like stage and reinforcement, are by necessity operationalized differently in animal and human studies. Similarly, testing the validity of addiction models requires different strategies by the two research domains. Although such differences are challenging, they are not insurmountable, and there is much to be gained in understanding and treating addiction by combining pre-clinical and clinical approaches.Fil: Kramer, John. University of Iowa; Estados UnidosFil: Dick, Danielle M.. University of Virginia; Estados UnidosFil: King, Andrea. University of Chicago; Estados UnidosFil: Ray, Lara A.. University of California at Los Angeles; Estados UnidosFil: Sher, Kenneth J.. University of Missouri; Estados UnidosFil: Vena, Ashley. University of Chicago; Estados UnidosFil: Vendruscolo, Leandro F.. National Institutes of Health; Estados UnidosFil: Acion, Laura. University of Iowa; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; Argentin

An observational study to assess Italian obstetrics providers' knowledge about preventive practices and diagnosis of congenital cytomegalovirus

Congenital cytomegalovirus (cCMV) infection can be easily prevented by hygienic measures. Up to date the majority of the studies in literature highlighted a reduction in cCMV antenatal counseling and its prevention. Our purpose was to evaluate obstetrics providers' knowledge about cCMV infection, management and the behavioral practices to avoid it. This is a cross-sectional survey carried out in Umberto I Hospital, "Sapienza"University of Rome between November 2019 and January 2020. We recruited 148 specialists and residents in Obstetrics and Gynecology through online anonymous multiple-choice 13-questions, 10 min-survey comparing responses between the two groups. A total of 94.6% of all participants said they always prescribe cytomegalovirus (CMV) serum screening: 73.6% of them regularly counsel about preventive practices, with specialists recording higher percentages (85.4 vs. 65.1%, p<0.005). We identified a good knowledge about the diagnostic pathway, but only 58.1% of our population knows the correct time of late amniocentesis. 12.2% of providers do not consider magnetic resonance (MRI) as a complementary exam. Prevention of maternal seroconversion is crucial: even if our data show an acceptable knowledge about antenatal counseling, we encourage clinicians to firmly inform and educate women about behavioral measures