123 research outputs found
Matrix metalloproteinase inhibitors: current developments and future perspectives
Malignant tumors are characterized by invasive growth and metastasis. To
facilitate this invasive behavior, the enzymatic breakdown of the
extracellular matrix (ECM) is a prerequisite. Many human tumors are
characterized by locally increased concentrations of matrix
metalloproteinases (MMPs), enzymes that are able to degrade this ECM. A
vast number of matrix metalloproteinase inhibitors (MMPIs) have been
developed in recent years and after extensive preclinical testing, the
results of the first clinical studies with several of these compounds have
recently been presented. In this review we will describe some of the basic
concepts of the degradation of the ECM, with special emphasis on the role
of MMPs in the progression of cancer. Furthermore we will review the
results of preclinical and clinical studies with MMPIs and discuss their
future perspective
A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer
PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and
pharmacokinetics of a fixed dose of paclitaxel followed by increasing
doses of carboplatin, given weekly to patients with advanced esophageal or
gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered
on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a
1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5
mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS:
Forty patients [36 males; median (range) age, 57 (40-74) years] were
enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg
x min/ml and consisted of treatment delay attributable to
myelosuppression. No grade 3/4 treatment-related nonhematological toxicity
was observed. The highest dose intensity (>95% of the planned dose over
time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean
(+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and
7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6
liter/h/m(2), which is not significantly different from historical data (P
= 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to
previous findings. Of 37 patients evaluable for response, 1 had complete
response, 19 had partial response, and 10 had stable disease, accounting
for an overall response rate of 54%. CONCLUSIONS: This regimen is very
tolerable and effective, and the recommended doses for additional studies
are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x
min/ml
Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus
BACKGROUND: We have previously reported a favourable response rate in
patients with advanced esophageal cancer after treatment with a biweekly
regimen of paclitaxel and cisplatin. In this study we investigate the
feasibility and efficacy of this regimen in a neo-adjuvant setting.
PATIENTS AND METHODS: Patients with resectable squamous cell carcinoma of
the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2)
every 2 weeks. Patients received three courses and responding patients
received three additional courses; thereafter, patients were referred for
surgery. Patient characteristics of 50 eligible patients were as follows:
male, 60%; median age, 62 years (range 45-78); median World Health
Organization performance status of 1 (range 0-2). RESULTS: Ninety-four per
cent of patients received at least three courses of chemotherapy.
Haematological toxicity consisted of National Cancer Institute-Common
Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with
neutropenic fever occurring in only two patients (4%). The overall
response rate was 59%. Pathological examination showed tumour-free margins
in 38 patients. In seven patients no residual tumour was found. The median
overall survival was 20 months and the 1- and 3-year survival rates were
68% and 30%, respectively. CONCLUSIONS: This dose-dense schedule of
paclitaxel and cisplatin administered biweekly is well tolerated and the
observed overall and complete response rates are promising
The Buffer Gas Beam: An Intense, Cold, and Slow Source for Atoms and Molecules
Beams of atoms and molecules are stalwart tools for spectroscopy and studies
of collisional processes. The supersonic expansion technique can create cold
beams of many species of atoms and molecules. However, the resulting beam is
typically moving at a speed of 300-600 m/s in the lab frame, and for a large
class of species has insufficient flux (i.e. brightness) for important
applications. In contrast, buffer gas beams can be a superior method in many
cases, producing cold and relatively slow molecules in the lab frame with high
brightness and great versatility. There are basic differences between
supersonic and buffer gas cooled beams regarding particular technological
advantages and constraints. At present, it is clear that not all of the
possible variations on the buffer gas method have been studied. In this review,
we will present a survey of the current state of the art in buffer gas beams,
and explore some of the possible future directions that these new methods might
take
The emerging structure of the Extended Evolutionary Synthesis: where does Evo-Devo fit in?
The Extended Evolutionary Synthesis (EES) debate is gaining ground in contemporary evolutionary biology. In parallel, a number of philosophical standpoints have emerged in an attempt to clarify what exactly is represented by the EES. For Massimo Pigliucci, we are in the wake of the newest instantiation of a persisting Kuhnian paradigm; in contrast, Telmo Pievani has contended that the transition to an EES could be best represented as a progressive reformation of a prior Lakatosian scientific research program, with the extension of its Neo-Darwinian core and the addition of a brand-new protective belt of assumptions and auxiliary hypotheses. Here, we argue that those philosophical vantage points are not the only ways to interpret what current proposals to ‘extend’ the Modern Synthesis-derived ‘standard evolutionary theory’ (SET) entail in terms of theoretical change in evolutionary biology. We specifically propose the image of the emergent EES as a vast network of models and interweaved representations that, instantiated in diverse practices, are connected and related in multiple ways. Under that assumption, the EES could be articulated around a paraconsistent network of evolutionary theories (including some elements of the SET), as well as models, practices and representation systems of contemporary evolutionary biology, with edges and nodes that change their position and centrality as a consequence of the co-construction and stabilization of facts and historical discussions revolving around the epistemic goals of this area of the life sciences. We then critically examine the purported structure of the EES—published by Laland and collaborators in 2015—in light of our own network-based proposal. Finally, we consider which epistemic units of Evo-Devo are present or still missing from the EES, in preparation for further analyses of the topic of explanatory integration in this conceptual framework
Factor Structure, Reliability and Criterion Validity of the Autism-Spectrum Quotient (AQ): A Study in Dutch Population and Patient Groups
The factor structure of the Dutch translation of the Autism-Spectrum Quotient (AQ; a continuous, quantitative measure of autistic traits) was evaluated with confirmatory factor analyses in a large general population and student sample. The criterion validity of the AQ was examined in three matched patient groups (autism spectrum conditions (ASC), social anxiety disorder, and obsessive–compulsive disorder). A two factor model, consisting of a “Social interaction” factor and “Attention to detail” factor could be identified. The internal consistency and test–retest reliability of the AQ were satisfactory. High total AQ and factor scores were specific to ASC patients. Men scored higher than women and science students higher than non-science students. The Dutch translation of the AQ is a reliable instrument to assess autism spectrum conditions
Burden-shifting of water quantity and quality stress from mega-city Shanghai
Much attention has been paid to burden-shifting of CO2 emissions from developed regions to developing regions through trade. However, less discussed is that trade also acts as a mechanism enabling wealthy consumers to shift water quantity and quality stress to their trading partners. In this study we investigate how Shanghai, the largest mega-city in China, draws water resources from all over China and outsources its pollution through virtual quantity and quality water flows associated with trade. The results show that Shanghai’s consumption of goods and services in 2007 led to 11.6 billion m3 of freshwater consumption, 796 thousand tons of COD, and 16.2 thousand tons of NH3-N in discharged wastewater. Of this, 79% of freshwater consumption, 82.9% of COD and 82.5% of NH3-N occurred in other Chinese Provinces which provide goods and services to Shanghai. Thirteen Provinces with severe and extreme water quantity stress accounted for 60% of net virtual water import to Shanghai, while 19 Provinces experiencing water quality stress endured 79% of net COD outsourcing and 75.5% of net NH3-N outsourcing from Shanghai. In accordance with the three ‘redlines’ recently put forward by the Chinese central government to control water pollution and cap total water use in all provinces, we suggest that Shanghai should share its responsibility for reducing water quantity and quality stress in its trading partners through taking measures at provincial, industrial and consumer levels. In the meantime, Shanghai needs to enhance demand side management by promoting low water intensity consumption
Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism.
International audienceno abstrac
Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder:The ENIGMA adventure
International audienc
Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure
Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses
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