First-line therapy in HER2 positive metastatic breast cancer. Is the mosaic fully completed or are we missing additional pieces?

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC). HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC. This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles. There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective

Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer. Clinical results and biological observations in taxane-pretreated patients

Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2). Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy

The ATLAS Barrel Level-1 Muon Trigger Calibration

The ATLAS experiment uses a system of three concentric Resistive Plate Chambers detectors layers for the level-1 muon trigger in the air-core barrel toroid region. The trigger classifies muons within different programmable transverse momentum ranges, and tags the identified tracks with the corresponding bunch crossing number. The algorithm looks for hit coincidences within different detector layers inside the programmed geometrical road which defines the transverse momentum cut. The on-detector electronics providing the trigger and detector readout functionalities collects input signals coming from the RPC front-end. Because of the different time-of-flights and cables and optical fibres lengths, signals have to be adjusted in time in order to be correctly aligned before being processed. Programmable delay logics are provided in the trigger and readout system to allow for time adjustment, for hit signals as well as for LHC Timing, Trigger and Control signals. The trigger calibration provides the set of numbers used during electronics initialization for correctly aligning signals inside the trigger and readout system. The functionality scheme and the algorithm of the calibration are presented

The ATLAS barrel level-1 Muon Trigger Sector-Logic/RX off-detector trigger and acquisition board

The ATLAS experiment uses a system of three concentric layers of Resistive Plate Chambers (RPC) detector for the Level-1 Muon Trigger in the air-core barrel toroid region. The trigger algorithm looks for hit coincidences within different detector layers inside the programmable geometrical road which defines the transverse momentum cut. The on-detector electronics that provides the trigger and detector readout functionalities collects input signals coming from the RPC front-end. Trigger and readout data are then sent via optical fibres to the off-detector electronics. Six or seven optical fibres from one of the 64 trigger sectors go to one Sector-Logic/RX module, that later elaborates the collected trigger and readout data, and sends data respectively to the Read-Out Driver modules and to the Central Level-1 Trigger. We present the functionality and the implementation of the VME Sector-Logic/RX module, and the configuration of the system for the first cosmic ray data collected using this module

New psychoactive substances: evolution in the exchange of information and innovative legal responses in the european union

At the end of 2019, the European Monitoring Centre for Drugs and Drug Addiction was monitoring around 790 new psychoactive substances, more than twice the total number of controlled substances under the United Nations Conventions. These substances, which are not subject to international drug controls, include a wide range of molecules, including the assortment of drugs such as synthetic cannabinoids, stimulants, opiates, and benzodiazepines. Most of them are sold as “legal” substitutes for illicit drugs, while others are intended for small groups willing to experiment with them in order to know their possible new effects. At the national level, various measures have been taken to control new substances and many European countries have responded with specific legislation in favor of consumer safety and by extending or adapting existing drug laws to incorporate the new psychoactive substances. Moreover, since 1997, an early warning system has been created in Europe for identifying and responding quickly to the risks of new psychoactive substances. In order to establish a quicker and more effective system to address the criminal activities associated with new dangerous psychoactive substances, the European legal framework has considerably changed over the years

Ageing test of the ATLAS RPCs at X5-GIF

An ageing test of three ATLAS production RPC stations is in course at X5-GIF, the CERN irradiation facility. The chamber efficiencies are monitored using cosmic rays triggered by a scintillator hodoscope. Higher statistics measurements are made when the X5 muon beam is available. We report here the measurements of the efficiency versus operating voltage at different source intensities, up to a maximum counting rate of about 700Hz/cm^2. We describe the performance of the chambers during the test up to an overall ageing of 4 ATLAS equivalent years corresponding to an integrated charge of 0.12C/cm^2, including a safety factor of 5.Comment: 4 pages. Presented at the VII Workshop on Resistive Plate Chambers and Related Detectors; Clermont-Ferrand October 20th-22nd, 200

Sex differences in oxidative stress level and antioxidative enzymes expression and activity in obese pre-diabetic elderly rats treated with metformin or liraglutide

Aim To determine the effects of metformin or liraglutide on oxidative stress level and antioxidative enzymes gene ex - pression and activity in the blood and vessels of pre-diabet - ic obese elderly Sprague-Dawley (SD) rats of both sexes. Methods Male and female SD rats were assigned to the following groups: a) control group (fed with standard ro - dent chow); b) high-fat and high-carbohydrate diet (HSHFD) group fed with HSHFD from 20-65 weeks of age; c) HSHFD+metformin treatment (50 mg/kg/d s.c.); and d) HSHFD+liraglutide treatment (0.3 mg/kg/d s.c). Oxidative stress parameters (ferric reducing ability of plasma and thiobarbituric acid reactive substances) and superoxide dis - mutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and gene expression were determined from serum, aortas, and surface brain blood vessels (BBV). Results HSHFD increased body weight in both sexes com - pared with the control group, while liraglutide prevented this increase. Blood glucose level did not change. The lira - glutide group had a significantly increased antioxidative ca - pacity compared with the HSHFD group in both sexes. The changes in antioxidative enzymes’ activities in plasma were more pronounced in male groups. The changes in gene ex - pression of antioxidative enzymes were more prominent in microvessels and may be attributed to weight gain preven - tion. Conclusions Obesity and antidiabetic drugs caused sexrelated differences in the level of antioxidative parameters. Liraglutide exhibited stronger antioxidative effects than metformin. These results indicate that weight gain due to HSHFD is crucial for developing oxidative stress and for in - hibiting antioxidative protective mechanism

Physician associates working in secondary care teams in England: Interprofessional implications from a national survey

Physician associates (PAs) are a new type of healthcare professional to the United Kingdom; however, they are well established in the United States (where they are known as physician assistants). PAs are viewed as one potential solution to the current medical workforce doctor shortage. This study investigated the deployment of PAs within secondary care teams in England, through the use of a cross-sectional electronic, self-report survey. The findings from 14 questions are presented. Sixty-three PAs working in a range of specialties responded. A variety of work settings were reported, most frequently inpatient wards, with work generally taking place during weekdays. Both direct and non-direct patient care activities were reported, with the type of work undertaken varying at times, depending on the presence or absence of other healthcare professionals. PAs reported working within a variety of secondary care team staffing permutations, with the majority of these being interprofessional. Line management was largely provided by consultants; however day-to-day supervision varied, often relating to different work settings. A wide variation in ongoing supervision was also reported. Further research is required to understand the nature of PAs' contribution to collaborative care within secondary care teams in England

The Muon Spectrometer Barrel Level-1 Trigger of the ATLAS Experiment at LHC

The proton-proton beam crossing at the LHC accelerator at CERN will have a rate of 40 MHz at the project luminosity. The ATLAS Trigger System has been designed in three levels in order to select only interesting physics events reducing from that rate of 40 MHz to the foreseen storage rate of about 200 Hz. The First Level reduces the output rate to about 100 kHz. The ATLAS Muon Spectrometer has been designed to perform stand-alone triggering and measurement of muon transverse momentum up to 1 TeV/c with good resolution (from 3% at 10 GeV/c up to 10% at 1 TeV/c). In the Barrel region of the Muon Spectrometer the Level-1 trigger is given by means of three layers of Resistive Plate Chamber detectors (RPC): a gaseous detector working in avalanche mode composed by two plates of high-resistivity bakelite and two orthogonal planes of read-out strips. The logic of the Level-1 barrel muon trigger is based on the search of patterns of RPC hits in the three layers consistent with a high transverse momentum muon track originated from the interaction vertex. The associated trigger electronics is based on dedicated processors, the Coincidence Matrix boards, performing space coincidences and time gates and providing the RPC readout as well. A detailed simulation of the ATLAS Experiment and of both the hardware components and the logic of the Level-1 Muon Trigger in the barrel of the Muon Spectrometer has been performed. This simulation has been used not only to evaluate the performances of the system but also to define the hardware set-up such as the cabling of both the trigger detectors and the trigger electronics modules. A description of both the Level-1 Muon Trigger system in the barrel and the RPC detectors, with their cosmic rays quality tests, will be presented together with the trigger performances and rates calculations evaluated for muons over a wide range of pT and preliminary studies on the impact of accidental triggers due to low energy background particles in the experimental area