Motivation: We have previously developed a rule-based approach for extracting information on the regulation of gene expression in yeast. The biomedical literature, however, contains information on ...several other equally important regulatory mechanisms, in particular phosphorylation, which we now expanded for our rule-based system also to extract. Results: This paper presents new results for extraction of relational information from biomedical text. We have improved our system, STRING-IE, to capture both new types of linguistic constructs as well as new types of biological information i.e. (de-)phosphorylation. The precision remains stable with a slight increase in recall. From almost one million PubMed abstracts related to four model organisms, we manage to extract regulatory networks and binary phosphorylations comprising 3319 relation chunks. The accuracy is 83–90% and 86–95% for gene expression and (de-)phosphorylation relations, respectively. To achieve this, we made use of an organism-specific resource of gene/protein names considerably larger than those used in most other biology related information extraction approaches. These names were included in the lexicon when retraining the part-of-speech (POS) tagger on the GENIA corpus. For the domain in question, an accuracy of 96.4% was attained on POS tags. It should be noted that the rules were developed for yeast and successfully applied to both abstracts and full-text articles related to other organisms with comparable accuracy. Availability: The revised GENIA corpus, the POS tagger, the extraction rules and the full sets of extracted relations are available from Contact:saric@eml-r.org
The incidence of hepatocellular carcinoma (HCC) in cirrhotic and noncirrhotic liver is increasing in the world, probably because of the high prevalence of infections by hepatitis B and C viruses. ...Despite numerous publications on hepatic resection, prognostic factors for intrahepatic recurrence and survival are not well known for patients with HCC without cirrhosis.
One hundred eight consecutive patients with HCC in noncirrhotic liver have been treated by hepatic resection in the past 18 years in our center. Clinical, biologic, and histopathologic parameters of these patients were collected. Risk factors for intrahepatic recurrence and prognostic factors for survival were evaluated by univariate and multivariate analyses.
Postoperative morbidity and mortality rates were 23% and 6.5%, respectively. The 3- and 5-year disease-free and overall survival rates were 55% and 43%, and 43% and 29%, respectively. Blood transfusion, absence of tumor capsule, and daughter nodules were independently associated with overall survival. But the only risk factors for recurrence were blood transfusion, absence of tumor capsule, daughter nodules, and margin resection < 10 mm.
In the treatment of HCC without cirrhosis, hepatectomy remains a safe and legitimate treatment, but longterm results are impaired by a high rate of early recurrence likely related to metastatic dissemination. Only histopathologic factors related to the tumor are predictive of recurrence and overall survival.
Abstract Macroprolactin is an antigen–antibody complex of higher molecular mass than prolactin (>150 kDa), consisting of monomeric prolactin and immunoglobulin G. The term ‘macroprolactinemia’ is ...used when the concentration of macroprolactin exceeds 60% of the total serum prolactin concentration determined by polyethylene glycol precipitation. The gold standard technique for the diagnosis of macroprolactinemia is gel filtration chromatography. The prevalence of macroprolactinemia in hyperprolactinemic populations varies between 15% and 35%. Although the pathogenesis of these antibodies is not clear, it is possible that changes in the pituitary prolactin molecule represent increased antigenicity to the immune system, leading to the production of anti-prolactin antibodies. Mild hyperprolactinemia usually occurs because macroprolactin is not cleared readily from the circulation due to its higher molecular weight. Moreover, the hypothalamic negative feedback mechanism for autoantibody-bound prolactin is inactive because macroprolactin cannot access the hypothalamus, resulting in hyperprolactinemia. Reduced in-vivo bioactivity of macroprolactin may be the reason for the lack of hyperprolactinemic symptoms. It also seems that anti-prolactin autoantibodies may compete with prolactin molecules for receptor binding, resulting in low bioactivity. Additionally, the large molecular size of macroprolactin confined in the intravascular compartment prevents its passage through the capillary endothelium to the target cells, which may be the reason for the lack of symptoms. Macroprolactinemia is considered to be a benign clinical condition in patients with normal concentrations of bioactive monomeric prolactin, with a lack, or low incidence, of hyperprolactinemic symptoms and negative pituitary imaging. In such cases with resistance to anti-prolactinaemic drugs, no pharmacological treatment, diagnostic investigations or prolonged follow-up are required. However, macroprolactinemia may also occur in patients with conventional symptoms of hyperprolactinemia who cannot be differentiated from patients with true hyperprolactinemia. These symptoms are mainly attributed to excess levels of monomeric prolactin, and this is of concern. The diagnosis of macroprolactinemia is misleading and inappropriate. A multitude of physiological, pharmacological and pathological causes, including stress, prolactinomas, hypothyroidism, renal and hepatic failure, intercostal nerve stimulation and polycystic ovary disease, can contribute to increased levels of monomeric prolactin. It is important for patients with elevated monomeric prolactin levels to undergo routine evaluation to identify the exact pathological state and introduce adequate treatment, regardless of the presence of macroprolactin. In addition, macroprolactinemia occasionally occurs due to macroprolactin associated with pituitary adenomas, with biological activity of macroprolactin comparable with that of monomeric prolactin. In cases when excess macroprolactin occurs with clinical manifestations of hyperprolactinemia, macroprolactinemia should be regarded as a pathological biochemical variant of hyperprolactinemia. An individualized approach to the management of such patients with macroprolactinemia may be necessary, and pituitary imaging, dopamine treatment and prolonged follow-up should be applied.
A general reaction network for filamentous self-assembly unifies mechanistic descriptions and links the overall scaling behaviour to the underlying rate-determining steps.
The formation of filaments ...from naturally occurring protein molecules is a process at the core of a range of functional and aberrant biological phenomena, such as the assembly of the cytoskeleton or the appearance of aggregates in Alzheimer's disease. The macroscopic behaviour associated with such processes is remarkably diverse, ranging from simple nucleated growth to highly cooperative processes with a well-defined lagtime. Thus, conventionally, different molecular mechanisms have been used to explain the self-assembly of different proteins. Here we show that this range of behaviour can be quantitatively captured by a single unifying Petri net that describes filamentous growth in terms of aggregate number and aggregate mass concentrations. By considering general features associated with a particular network connectivity, we are able to establish directly the rate-determining steps of the overall aggregation reaction from the system's scaling behaviour. We illustrate the power of this framework on a range of different experimental and simulated aggregating systems. The approach is general and will be applicable to any future extensions of the reaction network of filamentous self-assembly.
High-spin terminating bands in heavy nuclei were first identified in nuclei around Er-158(90). While examples of terminating states have been identified in a number of erbium isotopes, almost nothing ...is known about the states lying beyond band termination. In the present work, the high-spin structure of Er-156,Er-157,Er-158 has been studied using the Gammasphere spectrometer. The subject of triaxial superdeformation and 'wobbling' modes in Lu nuclei has rightly attracted a great deal of attention. Very recently four strongly or superdeformed (SD) sequences have been observed in Hf-174, and cranking calculations using the Ultimate Cranker code predict that such structures may have significant triaxial deformation. We have performed two experiments in an attempt to verify the possible triaxial nature of these bands. A lifetime measurement was performed to confirm the large (and similar) deformation of the bands. In addition, a high-statistics, thin-target experiment took place to search for linking transitions between the SD bands, possible wobbling modes, and new SD band structures.
Abstract Objectives Dietary fibre (DF) is one of the components of diet that strongly contributes to health improvements, particularly on the gastrointestinal system. Hence, this work intended to ...evaluate the relations between some sociodemographic variables such as age, gender, level of education, living environment or country on the levels of knowledge about dietary fibre (KADF), its sources and its effects on human health, using a validated scale. Study design The present study was a cross-sectional study. Methods A methodological study was conducted with 6010 participants, residing in 10 countries from different continents (Europe, America, Africa). The instrument was a questionnaire of self-response, aimed at collecting information on knowledge about food fibres. The instrument was used to validate a scale (KADF) which model was used in the present work to identify the best predictors of knowledge. The statistical tools used were as follows: basic descriptive statistics, decision trees, inferential analysis ( t -test for independent samples with Levene test and one-way ANOVA with multiple comparisons post hoc tests). Results The results showed that the best predictor for the three types of knowledge evaluated (about DF, about its sources and about its effects on human health) was always the country, meaning that the social, cultural and/or political conditions greatly determine the level of knowledge. On the other hand, the tests also showed that statistically significant differences were encountered regarding the three types of knowledge for all sociodemographic variables evaluated: age, gender, level of education, living environment and country. Conclusions The results showed that to improve the level of knowledge the actions planned should not be delineated in general as to reach all sectors of the populations, and that in addressing different people, different methodologies must be designed so as to provide an effective health education.
During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) ...(NR1I3) controls phase I (cytochrome P450 CYP 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid‐responsive gene, via proinflammatory cytokine interleukin 1β (IL‐1β) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL‐1β decreases CAR expression and decreases phenobarbital‐ or bilirubin‐mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor κB (NF‐κB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL‐1β, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)‐mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF‐κB activation, or by overexpression of SRIkBα, a NF‐κB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL‐1β inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF‐κB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long‐standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004.)
In an attempt to improve upon the end results obtained in treating colorectal cancer it was apparent that the earlier the diagnosis that could be obtained, the better the chance for obtaining desired ...results. In the case of more advanced tumors typified by later stage colorectal cancer, surgical debulking is an important part of the treatment strategy. Here the use of additional therapeutic modalities including chemotherapy and present day immunotherapy has failed to accomplish the desired improvements that have been sought after. Adjuvant therapy, has offered little to the overall survival. The concept of early detection is now recognized as the initial step in reaching proper end results and can readily be demonstrated from colorectal cancer studies. Here survival has been found to be a reflection of the stage at which the tumor is first identified and treated. When specific monoclonals targeting colorectal cancer are employed diagnostically, we have been able to demonstrate detection of colorectal cancer at its inception as a premalignant lesion, such that genotypic features can be identified before the phenotypic appearance of cancer can be noted.
The development of new cardioprotective approaches using in vivo models of ischemic heart disease remains challenging as differences in cardiac physiology, phenotype, and disease progression between ...humans and animals influence model validity and prognostic value. Furthermore, economical and ethical considerations have to be taken into account, especially when using large animal models with relevance for conducting preclinical studies. The development of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has opened new opportunities for in vitro studies on cardioprotective compounds. However, the immature cellular phenotype of iPSC-CMs remains a roadblock for disease modeling. Here, we show that metabolic maturation renders the susceptibility of iPSC-CMs to hypoxia further toward a clinically representative phenotype. iPSC-CMs cultured in a conventional medium did not show significant cell death after exposure to hypoxia. In contrast, metabolically matured (MM) iPSC-CMs showed inhibited mitochondrial respiration after exposure to hypoxia and increased cell death upon increased durations of hypoxia. Furthermore, we confirmed the applicability of MM iPSC-CMs for in vitro studies of hypoxic damage by validating the known cardioprotective effect of necroptosis inhibitor necrostatin-1. Our results provide important steps to improving and developing valid and predictive human in vitro models of ischemic heart disease.
PDF
