Miracle-dz/UniFAR-FTUs huggingface dataset:
Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients

Obesity and metabolic syndrome are recognized risk factors for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC). Dysregulation of adipokines, particularly the decreased secretion of adiponectin, appears to play a key role. To investigate the association between adiponectin and hepatocarcinogenesis, we conducted a large‐scale retrospective cohort study. We enrolled 325 patients with CHC (146 men, 179 women; mean age 58.0 ± 10.3 years) whose serum samples were collected between January 1994 and December 2002. Subjects were divided into two groups according to their serum adiponectin levels. We evaluated the association between adiponectin level and the risk of subsequent HCC development using univariate and multivariate Cox proportional hazard regression. Because average serum adiponectin level was higher in females than males, each gender was analyzed separately. Patients with CHC had significantly higher adiponectin levels than healthy controls. During the follow‐up period (mean: 9.0 years), HCC developed in 122 subjects. Unexpectedly, subjects with higher serum adiponectin levels had a higher incidence of HCC (males: p = 0.032; females: p = 0.01; log‐rank test). Multivariate analysis revealed that a high serum adiponectin level was independently associated with HCC development (hazard ratio [HR] = 2.07; p = 0.031 in females and HR = 1.82; p = 0.05 in males). Isoform analysis revealed that middle‐ and low‐molecular‐weight isoforms contributed to the risk of HCC. In conclusion, Patients who had CHC with high serum adiponectin levels had a higher risk of liver cancer development. Adiponectin may thus be tumorigenic or indicate a liver disease state independently of other clinical parameters.
Single Particle Characterization of Iron-induced Pore-forming α-Synuclein Oligomers*

Aggregation of α-synuclein is a key event in several neurodegenerative diseases, including Parkinson disease. Recent findings suggest that oligomers represent the principal toxic aggregate species. Using confocal single-molecule fluorescence techniques, such as scanning for intensely fluorescent targets (SIFT) and atomic force microscopy, we monitored α-synuclein oligomer formation at the single particle level. Organic solvents were used to trigger aggregation, which resulted in small oligomers (“intermediate I”). Under these conditions, Fe3+ at low micromolar concentrations dramatically increased aggregation and induced formation of larger oligomers (“intermediate II”). Both oligomer species were on-pathway to amyloid fibrils and could seed amyloid formation. Notably, only Fe3+-induced oligomers were SDS-resistant and could form ion-permeable pores in a planar lipid bilayer, which were inhibited by the oligomer-specific A11 antibody. Moreover, baicalein and N′-benzylidene-benzohydrazide derivatives inhibited oligomer formation. Baicalein also inhibited α-synuclein-dependent toxicity in neuronal cells. Our results may provide a potential disease mechanism regarding the role of ferric iron and of toxic oligomer species in Parkinson diseases. Moreover, scanning for intensely fluorescent targets allows high throughput screening for aggregation inhibitors and may provide new approaches for drug development and therapy.
Quantifying cerebral hypoxia by near-infrared spectroscopy tissue oximetry: the role of arterial-to-venous blood volume ratio

Abstract. Tissue oxygenation estimated by near-infrared spectroscopy (NIRS) is a volume-weighted mean of the arterial and venous hemoglobin oxygenation. In vivo validation assumes a fixed arterial-to-venous volume-ratio (AV-ratio). Regulatory cerebro-vascular mechanisms may change the AV-ratio. We used hypotension to investigate the influence of blood volume distribution on cerebral NIRS in a newborn piglet model. Hypotension was induced gradually by inflating a balloon-catheter in the inferior vena cava and the regional tissue oxygenation from NIRS (rStO2,NIRS) was then compared to a reference (rStO2,COX) calculated from superior sagittal sinus and aortic blood sample co-oximetry with a fixed AV-ratio. Apparent changes in the AV-ratio and cerebral blood volume (CBV) were also calculated. The mean arterial blood pressure (MABP) range was 14 to 82 mmHg. PaCO2 and SaO2 were stable during measurements. rStO2,NIRS mirrored only 25% (95% Cl: 21% to 28%, p<0.001) of changes in rStO2,COX. Calculated AV-ratio increased with decreasing MABP (slope: −0.007·mmHg−1, p<0.001). NIRS estimates that CBV decreased with decreasing MABP (slope: 0.008 ml/100 g/mmHg, p<0.001). Thus, cerebral NIRS oximetry responded poorly to changes in tissue oxygenation during hypotension induced by decreased preload. An increase in the AV-ratio during hypotension due to arterial vasodilation and, possibly, cerebral venous collapse may be a part of the explanation.
BRAF mutation and RASSF1A expression in thyroid carcinoma of southern Italy

Aim of this work is to provide a detailed comparison of clinical‐pathologic features between well‐differentiated and poorly differentiated tumors according to their BRAF and RASSF1A status. We analyzed RASSF1A methylation by MSP and BRAF mutation by LCRT‐PCR with LightMix® kit BRAF V600E in neoplastic thyroid tissues. Immunohistochemical evaluation of RASSF1A expression was also performed by standard automated LSAB‐HRP technique. An overall higher degree of RASSF1A over‐expression than normal thyroid parenchyma surrounding tumors (P < 0.05) has been found in all malignant well‐differentiated lesions. Moreover, statistically significant higher levels of RASSF1A expression were observed in differentiated cancers associated to an inflammatory autoimmune background (P = 0.01). Amplifiable DNA for LC PCR with LightMix® kit BRAF V600E was obtained in nine PTCs, four FVPTCs, five ATCs, and one control. The V600E mutation was found in 13 of 18 (72%) tumors. BRAF was mutated in 6 of 9 (66%) classical PTC, in 2 of 4 (50%) follicular variant PTC and in all ACs (100%). The overall frequency of RASSF1A promoter methylation observed was 20.5% (9 cases out 44). Hypermethylation of RASSF1A in primary tumors was variable according to histotypes ranging from100% (5/5) in ACs to only 12.5% (4/32) in PTCs. We show a correlation between RASSF1A methylation status and RASSF1A protein expression. Finally, we conclude that BRAF V600E mutation and RASSF1A methylation were pathogenetic event restricted to a subgroup of PTC/FVPTCs in early stage and to clinically aggressive ATCs. J. Cell. Biochem. 114: 1174–1182, 2013. © 2012 Wiley Periodicals, Inc.
A Novel Integrated Magnetic Structure Based DC/DC Converter for Hybrid Battery/Ultracapacitor Energy Storage Systems

This manuscript focuses on a novel actively controlled hybrid magnetic battery/ultracapacitor based energy storage system (ESS) for vehicular propulsion systems. A stand-alone battery system might not be sufficient to satisfy peak power demand and transient load variations in hybrid and plug-in hybrid electric vehicles (HEV, PHEV). Active battery/ultracapacitor hybrid ESS provides a better solution in terms of efficient power management and control flexibility. Moreover, the voltage of the battery pack can be selected to be different than that of the ultracapacitor, which will result in flexibility of design as well as cost and size reduction of the battery pack. In addition, the ultracapacitor bank can supply or recapture a large burst of power and it can be used with high C-rates. Hence, the battery is not subjected to supply peak and sharp power variations, and the stress on the battery will be reduced and the battery lifetime would be increased. Utilizing ultracapacitor results in effective capturing of the braking energy, especially in sudden braking conditions.
Identification of a Crucial Histidine Involved in Metal Transport Activity in the Arabidopsis Cation/H+ Exchanger CAX1*

In plants, yeast, and bacteria, cation/H+ exchangers (CAXs) have been shown to translocate Ca2+ and other metal ions utilizing the H+ gradient. The best characterized of these related transporters is the plant vacuolar localized CAX1. We have used site-directed mutagenesis to assess the impact of altering the seven histidine residues to alanine within Arabidopsis CAX1. The mutants were expressed in a Saccharomyces cerevisiae strain that is sensitive to Ca2+ and other metals. By utilizing a yeast growth assay, the H338A mutant was the only mutation that appeared to alter Ca2+ transport activity. The CAX1 His338 residue is conserved among various CAX transporters and may be located within a filter for cation selection. We proceeded to mutate His338 to every other amino acid residue and utilized yeast growth assays to estimate the transport properties of the 19 CAX mutants. Expression of 16 of these His338 mutants could not rescue any of the metal sensitivities. However, expression of H338N, H338Q, and H338K allowed for some growth on media containing Ca2+. Most interestingly, H338N exhibited increased tolerance to Cd2+ and Zn2+. Endomembrane fractions from yeast cells were used to measure directly the transport of H338N. Although the H338N mutant demonstrated 25% of the wild type Ca2+/H+ transport, it showed an increase in transport for both Cd2+ and Zn2+ reflected in a decrease in the Km for these substrates. This study provides insights into the CAX cation filter and novel mechanisms by which metals may be partitioned across membranes.
Development and external validation of a prognostic model in newly diagnosed Parkinson disease

Objective: To develop a prognostic model to predict disease outcomes in individual patients with Parkinson disease (PD) and perform an external validation study in an independent cohort. Methods: Model development was done in the Comorbidity and Aging in Rehabilitation Patients: The Influence on Activities (CARPA) cohort (Netherlands). External validation was performed using the Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort (UK). Both are longitudinal incident cohort studies that prospectively followed up patients with PD from the time of diagnosis. A composite outcome measure was made in which patients were classified as having an unfavorable prognosis when they had postural instability or dementia at the 5-year assessment (or at the last assessment before loss to follow-up), or had died before this time. The final model was derived with a backward selection strategy from candidate predictor variables that were measured at baseline. Results: In the resulting model, higher patient age, higher Unified Parkinson's Disease Rating Scale motor examination axial score, and a lower animal fluency score were all associated with a higher probability of an unfavorable outcome. External validation confirmed good discriminative ability between favorable and unfavorable outcomes with an area under the receiver operating characteristic curve of 0.85 (95% confidence interval 0.77–0.93) and a well-calibrated model with a calibration slope of 1.13 and no significant lack of fit (Hosmer-Lemeshow test: p = 0.39). Conclusion: We constructed a model that allows individual patient prognostication at 5 years from diagnosis, using a small set of predictor variables that can easily be obtained by clinicians or research nurses.
Impact of imperfect channel state information on the performance of wireless sensor networks

The performance of wireless sensor networks (WSN) is often assessed without paying close attention to the effects of channel state information recovery, which is assumed to be exactly known. This work focuses on the effects of imperfect knowledge of the channel state information on a WSN whose sensors measure a target parameter and send it to a common fusion center by an amplify-and-forward technique. A baseline estimation rule, consisting in disregarding the presence of noise in the estimated channel gain, is considered. Two other estimation rules are also studied, based on the joint processing of the received samples during the sensing and training intervals: i) a maximum a posteriori rule consisting in maximizing the a posteriori probability of the target parameter; ii) a least-squares rule based on the minimization of the mean-square error of the estimated target parameter. In both cases, conditionally on the target parameter, the received samples are assumed to be jointly Gaussian distributed as far as concerns the derivation of the estimation rule. Numerical results illustrate the merits of the proposed estimation rules by showing the MSE performance with different network parameters.
Modulations of VEGF and iNOS in the rat heart by low level laser therapy are associated with cardioprotection and enhanced angiogenesis

It has been shown previously that low‐level laser therapy (LLLT) significantly reduces infarct size following induction of myocardial infarction in rats and dogs. The aim of the present study was to investigate the effect of LLLT on the expression of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS).
Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas.

PURPOSE To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated. PATIENTS AND METHODS Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks. RESULTS The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane. CONCLUSION The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.
Double-Label Confocal Laser-Scanning Microscopy, Image Restoration, and Real-Time Three-Dimensional Reconstruction to Study Axons in the Central Nervous System and Their Contacts With Target Neurons

The current double tracing–double confocal laser-scanning method was developed to reconstruct identified nerve fibers and their contacts with identified target neurons in the rat brain in three dimensions. It intends to fill the gap between conventional light microscopic and electron microscopic neuroanatomic tracing. The steps involved are as follows: (1) injection of two neuroanatomic tracers—Phaseolus vulgaris leucoagglutinin (PHA-L) to label fibers innervating a particular brain area and Neurobiotin to label prospective target neurons in that area; (2) immunofluorescence detection of the labeled fibers (fluorophore Cy5, infrared emission), together with fluorochromated avidin detection of the taken-up Neurobiotin (Cy2 or Alexa 488; green emission); (3) acquisition of Z-series of confocal images at high magnification with a laser-scanning microscope using the laser lines 488 nm and 647 nm; and (4) computer-processing and three-dimensional reconstruction of the labeled fibers and the presumed target dendrites. Rotation on the computer of the three-dimensional reconstructed fibers and dendrites along all three spatial axes enabled the authors to determine whether “true” or “false” contacts occur. In a true contact no space was present between the apposing structures, whereas a false contact consisted of two differently stained structures close to each other but separated by a narrow, optically empty space. One important phenomenon in the three-dimensional reconstruction of double-stained structures that needed correction was “twin image mismatch”—i.e., the observation that a three-dimensional reconstruction of a small test object (double-stained on purpose) produced two slightly shifted objects, each associated with its particular fluorochrome. To measure the actual twin image mismatch of the confocal instrument and to obtain accurate correction factors the authors took in each session in which they obtained image series of the real experiments, with both laser wavelengths Z-series of images of multifluorescent microspheres (500-nm diameter) and of thin, double-stained fibers. Given the small dimensions of the structures of interest, i.e., synaptic contacts, it is necessary in this type of research that the optical characteristics of the imaging system—e.g., the alignment errors and chromatic aberration that produce twin image mismatch—be precisely known.
Molecular markers for drug resistance in malaria: use in treatment, diagnosis and epidemiology

Purpose of review Malaria and the increasing role of drug resistance as an obstacle to its control are global problems. The identification and implications of molecular markers for antimalarial drug resistance - the subject of this review - are key issues in elucidating and eventually controlling resistance. Recent findings Recent achievements include the successful expression of the Plasmodium falciparum chloroquine resistance transporter gene, pfcrt, in yeast, the identification of polymorphisms on the γ-glutamylcysteine synthetase gene, ggcs, as potential determinants of chloroquine and mefloquine resistance, and the usefulness of a combined Plasmodium falciparum dihydrofolate reductase gene, pfdhfr, 59ARG and Plasmodium falciparum dihydropteroate synthase gene, pfdhps, 540GLU marker in reliably representing resistance to antifolates. Moreover, treatment with sulfadoxine-pyrimethamine in the presence of pfdhfr 108ASP alone delayed parasite clearance and increased gametocytogony without an overt loss of the overall therapeutic efficacy of the drug. Summary The use of pfdhfr and pfdhps markers in determining antifolate resistance of Plasmodium falciparum has been consolidated. Similar progress has been made with pfcrt markers for chloroquine resistance, auguring well the operational deployment of molecular techniques. Regarding the molecular basis of resistance to arylaminoalcohols, related drugs, and artemisinin and its derivatives, answers remain elusive, but there are promising new leads.
Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Resveratrol (3, 5, 4′‐trihydroxy‐trans‐stilbene), a natural polyphenol present in grapes and peanuts, has been reported to exert a variety of potentially therapeutic effects. The aim of this study was to determine the contribution of the gastrointestinal (GI) tract to the glucuronidation of this compound and its cis‐isomer, which also occurs naturally. For this purpose, glucuronidation of the two resveratrol isomers was investigated in human microsomes prepared from: stomach, duodenum, four segments of the remaining small intestine (S‐1 to S‐4) and colon, and from the human intestinal cell lines Caco‐2 and PD‐7. cis‐ and trans‐Resveratrol were efficiently glucuronidated in the GI tract with the formation of both 3‐O‐ and 4′‐O‐glucuronides, however, the two stereoisomers were glucuronidated at different rates depending on the donor and the segment considered. Microsomes prepared from Caco‐2 and PD‐7 cells also efficiently glucuronidated cis‐resveratrol and, to a lesser extent, the trans‐isomer, however, only the 3‐O‐glucuronide was formed. Among the UDP‐glucuronosyltransferases (UGT) that are known to be expressed in the GI tract, the isoforms UGT1A1, 1A6, 1A8, 1A9 and 1A10 were active in glucuronidating trans‐ and/or cis‐resveratrol. The results demonstrate that the GI tract may contribute significantly to the first pass metabolism of these naturally occurring polyphenols. Copyright © 2006 John Wiley & Sons, Ltd.
A Novel Functional T Cell Hybridoma Recognizes Macrophage Cell Death Induced by Bacteria: A Possible Role for Innate Lymphocytes in Bacterial Infection

We have established a novel TCRαβ (TCRVβ6)+CD4−CD8− T cell hybridoma designated B6HO3. When the B6HO3 cells were cocultured with bacterial-infected J774 macrophage-like cells, IFN-γ production by B6HO3 cells was triggered through direct cell-cell contact with dying J774 cells infected with Listeria monocytogenes (LM), Shigella flexneri, or Salmonella typhimurium that expressed the type III secretion system, but not with intact J774 cells infected with heat-killed LM, nonhemolytic lysteriolysin O-deficient (Hly−) LM, plasmid-cured Shigella, or stationary-phase Salmonella. However, the triggering of B6HO3 cells for IFN-γ production involved neither dying hepatoma cells infected with LM nor dying J774 cells caused by gliotoxin treatment or freeze thawing. Cycloheximide and Abs to H-2Kd, H-2Dd, Iad, CD1d, TCRVβ6, and IL-12 did not inhibit the contact-dependent IFN-γ response, indicating that this IFN-γ response did not require de novo protein synthesis in bacterial-infected J774 cells and was TCR and IL-12 independent. Thus, in an as yet undefined way, B6HO3 hybridoma recognizes a specialized form of macrophage cell death resulting from bacterial infection and consequently produces IFN-γ. Moreover, contact-dependent interaction of minor subsets of splenic αβ T cells, including NKT cells with dying LM-infected J774 and bone marrow-derived macrophage (BMM) cells, proved to provide an IFN-γ-productive stimulus for these minor T cell populations, to which the parental T cell of the B6HO3 hybridoma appeared to belong. Unexpectedly, subsets of γδ T and NK cells similarly responded to dying LM-infected macrophage cells. These results propose that innate lymphocytes may possess a recognition system sensing macrophage cell “danger” resulting from bacterial infection.
Characterization and functional investigation of single nucleotide polymorphisms (SNPs) in the human TLR5 gene

Toll‐like receptors recognize pathogen‐associated molecular patterns (PAMPs) and TLR5 is the pathogen recognition receptor (PRR) for bacterial flagellin. Patients carrying a R392 stop polymorphism display an inflammatory phenotype and increased susceptibility to pneumonia caused by the flagellated bacteria Legionella pneumophila. While this suggests that TLR5 mutations may be clinically relevant, functional data are not available for the majority of the other TLR5 polymorphisms. We have characterized all known single nucleotide polymorphisms (SNPs) of TLR5 for their functional relevance upon stimulation in transiently transfected CHO‐K1 cells. Among the 13 missense SNPs of TLR5 reported in the human genetic databases, three SNPs (c.1174C>T, p.R392X; c.2081A>G, p.D694G; and c.2464C>T, p.L822F) were found to be functionally relevant in transiently transfected CHO‐K1 cells. The prevalences of these functionally relevant SNPs in our investigation were 11.9 %, 0 %, and 0 %, in healthy donors. The p.D694G and p.L822F SNPs are of low frequency in the Caucasian population though further investigations of the common p.R392X variant alone or of functional relevant TLR5 SNPs in combination with other TLR SNPs will elucidate their possible role on disease susceptibility in humans and may facilitate clinical diagnosis. © 2006 Wiley‐Liss, Inc.