Earth current monitoring circuit for inductive loads

The search for higher magnetic fields in particle accelerators increasingly demands the use of superconducting magnets. This magnet technology has a large amount of magnetic energy storage during operation at relatively high currents. As such, many monitoring and protection systems are required to safely operate the magnet, including the monitoring of any leakage of current to earth in the superconducting magnet that indicates a failure of the insulation to earth. At low amplitude, the earth leakage current affects the magnetic field precision. At a higher level, the earth leakage current can additionally generate local losses which may definitively damage the magnet or its instrumentation. This paper presents an active earth fault current monitoring circuit, widely deployed in the converters for the CERN Large Hadron Collider (LHC) superconducting magnets. The circuit allows the detection of earth faults before energising the circuit as well as limiting any eventual earth fault current. The electrical stress on each circuit component is analyzed and advice is given for a totally safe component selection in relation to a given load

Fishes of southern South America: a story driven by temperature

The latitudinal extension of southern South America imposes a thermal gradient that affects the structure of marine and freshwater fish assemblages and the biology of the species through direct exposure to the temperature gradients or by means of a web of historical and ecological relationships. We have reviewed biological and ecological data of marine and freshwater fishes from the southern Neotropics, including Patagonia, and report several examples of dependence on temperature, from glacial times to today’s climate change. We were able to identify historic and present effects on the diversity of fish assemblages, isolation, southern limits for the distribution of species, and morphological variation among populations. There is a wide range of characteristics that exemplify an adaptation to low temperatures, including biochemical peculiarities, physiological adjustments, and alternative life history patterns, and these appear in both freshwater and marine, and native and exotic fishes. The consequences of stable temperature regimes in both the ocean and thermal streams deserve special mention as these shape specialists under conditions of low selective pressure. At present, habitat use and interactions among species are being subject to changes as consequences of water temperature, and some of these are already evident in the northern and southern hemispheres.Facultad de Ciencias Naturales y Muse

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P <. 001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P =. 01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P <. 001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P =. 02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P =. 01). Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research

Polymorphic Cis- and Trans-Regulation of Human Gene Expression

Using genetic and molecular analyses, we identified over 1,000 polymorphic regulators that regulate expression levels of human genes

Novel therapies in breast cancer: what is new from ASCO 2008

<p>Abstract</p> <p>Introduction</p> <p>Breast cancer is the most common female cancer and the second most common cause of female cancer-related deaths in the United States. World-wide, more than one million women will be diagnosed with breast cancer annually. In 2007, more than 175,000 women were diagnosed with breast cancer in the United States. However, deaths due to breast cancer have decreased in the recent years in part because of improved screening techniques, surgical interventions, understanding of the pathogenesis of the disease, and utilization of traditional chemotherapies in a more efficacious manner. One of the more exciting areas of improvement in the treatment of breast cancer is the entrance of novel therapies now available to oncologists. In the field of cancer therapeutics, the area of targeted and biologic therapies has been progressing at a rapid rate, particularly in the treatment of breast cancer.</p> <p>Since the advent of imatinib for the successful treatment of chronic myelogenous leukemia in the 2001, clinicians have been searching for comparable therapies that could be as efficacious and as tolerable. In order for targeted therapies to be effective, the agent must be able to inhibit critical regulatory pathways which promote tumor cell growth and proliferation. The targets must be identifiable, quantifiable and capable of being interrupted.</p> <p>In the field of breast cancer, two advances in targeted therapy have led to great strides in the understanding and treatment of breast cancer, namely hormonal therapy for estrogen positive receptor breast cancer and antibodies directed towards the inhibition of human epidermal growth factor receptor (HER)2. These advances have revolutionized the understanding and the treatment strategies for breast cancer. Building upon these successes, a host of novel agents are currently being investigated and used in clinical trials that will hopefully prove to be as fruitful. This review will focus on novel therapies in the field of breast cancer with a focus on metastatic breast cancer (MBC) and updates from the recent annual ASCO meeting and contains a summary of the results.</p

Reduced costs with bisoprolol treatment for heart failure - An economic analysis of the second Cardiac Insufficiency Bisoprolol Study (CIBIS-II)

Background Beta-blockers, used as an adjunctive to diuretics, digoxin and angiotensin converting enzyme inhibitors, improve survival in chronic heart failure. We report a prospectively planned economic analysis of the cost of adjunctive beta-blocker therapy in the second Cardiac Insufficiency BIsoprolol Study (CIBIS II). Methods Resource utilization data (drug therapy, number of hospital admissions, length of hospital stay, ward type) were collected prospectively in all patients in CIBIS . These data were used to determine the additional direct costs incurred, and savings made, with bisoprolol therapy. As well as the cost of the drug, additional costs related to bisoprolol therapy were added to cover the supervision of treatment initiation and titration (four outpatient clinic/office visits). Per them (hospital bed day) costings were carried out for France, Germany and the U.K. Diagnosis related group costings were performed for France and the U.K. Our analyses took the perspective of a third party payer in France and Germany and the National Health Service in the U.K. Results Overall, fewer patients were hospitalized in the bisoprolol group, there were fewer hospital admissions perpatient hospitalized, fewer hospital admissions overall, fewer days spent in hospital and fewer days spent in the most expensive type of ward. As a consequence the cost of care in the bisoprolol group was 5-10% less in all three countries, in the per them analysis, even taking into account the cost of bisoprolol and the extra initiation/up-titration visits. The cost per patient treated in the placebo and bisoprolol groups was FF35 009 vs FF31 762 in France, DM11 563 vs DM10 784 in Germany and pound 4987 vs pound 4722 in the U.K. The diagnosis related group analysis gave similar results. Interpretation Not only did bisoprolol increase survival and reduce hospital admissions in CIBIS II, it also cut the cost of care in so doing. This `win-win' situation of positive health benefits associated with cost savings is Favourable from the point of view of both the patient and health care systems. These findings add further support for the use of beta-blockers in chronic heart failure

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design