Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Ca2+‐Dependent Metalloprotease‐2 in Stimulating Ca2+ATPase Activity Under Peroxynitrite Treatment in Bovine Pulmonary Artery Smooth Muscle Membrane

We have determined effect of the oxidant peroxynitrite (ONOO ‐) on Ca 2+ ‐dependent matrix metalloprotease‐2 (MMP‐2) activity and the role of the protease on Ca 2+ ATPase activity in bovine pulmonary vascular smooth muscle plasma membrane under ONOO ‐‐triggered conditions. The smooth muscle plasma membrane possesses a 72‐kDa protease activity in a gelatin‐containing zymogram. The 72‐kDa protease activity has been found to be inhibited by tissue inhibitor of metalloprotease‐2 (TIMP‐2), indicating that the protease is the matrix metalloprotease‐2 (MMP‐2). Treatment of the membrane suspension with ONOO ‐ caused stimulation of the MMP‐2 activity (as evidenced by 14 C‐gelatin degradation) and also increased Ca 2+ ATPase activity. The ONOO ‐‐triggered protease activity and the Ca 2+ ATPase activity were found to be inhibited by the antioxidants: vitamin E, thiourea, and mannitol. Pretreatment with catalase and superoxide dismutase did not significantly alter ONOO ‐‐stimulated MMP‐2 activity and Ca 2+ ATPase activity, indicating that peroxide and superoxide are not present in appreciable amount in ONOO ‐. Under both basal and ONOO ‐ triggered conditions, the MMP‐2 activity and the Ca 2+ ATPase activity were also inhibited by EGTA, 1:10‐phenanthroline, and TIMP‐2. However, the ONOO ‐‐stimulated MMP‐2 activity and the Ca 2+ ATPase activity were found to be insensitive to phenylmethylsulfonylfluoride, Bowman‐Birk inhibitor, chymostatin, leupeptin, antipain, N ‐ethylmaleimide, and pepstatin. These results suggest that ONOO ‐ caused stimulation of MMP‐2 activity and that the increased MMP‐2 activity subsequently played a pivotal role in stimulating Ca 2+ ATPase activity in bovine pulmonary vascular smooth muscle plasma membrane.
Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27

Background Activation of the renin–angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin–) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. Objective Tissue renin–angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. Method Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 mg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. Results Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. Conclusions Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal ‘vasculotoxic’ agent in malignant hypertension. J Hypertens 16:635–643 © 1998 Lippincott-Raven Publishers.
Medication use among children with asthma in East Harlem.

PURPOSE To examine daily use of antiinflammatory medication among children with asthma in East Harlem, where hospitalization rates for asthma are among the highest in the United States. METHODS We analyzed parent/guardian reports of medications used by children with current asthma (defined as physician diagnosis and wheezing during the previous 12 months) identified from a cross-sectional survey conducted in 2 elementary schools. RESULTS From an overall sample of 1319 children, 298 with current asthma were included in this analysis. Most of those with asthma were Puerto Rican (136 [46%]) or black (98 [33%]), 168 (57%) were boys, and the median age was 8 years old. Overall, 65 (22%) were using antiinflammatory medication on a daily basis. A subgroup of 107 children with asthma had been hospitalized during the previous 12 months or had used beta(2)-agonist on a daily basis, suggesting persistent or severe asthma. Of these 107 children, 42 (39%) were taking antiinflammatory medication on a daily basis. Multivariate analysis of these 107 children revealed that daily use of antiinflammatory medication was associated with using a spacer tube (adjusted odds ratio [AOR]: 3. 08; 95% confidence interval [CI]: 1.27,7.47) and having seen a physician in the past 6 months (AOR: 3.46; CI: 1.01,11.9). Compared with Puerto Ricans, blacks (AOR:.32; CI:.12,.89) or children of other races/ethnicities (AOR:.27; CI:.09,.85) were less likely to use antiinflammatory medication on a daily basis. CONCLUSION Daily use of antiinflammatory medication for children with persistent or severe asthma in East Harlem was underused. Differences in access to care may explain some findings; however, reasons for ethnic differences in use remain unclear. Both community interventions and additional provider education are needed.
Treatment of chronic myeloid leukemia in the blastic phase with fludarabine, cytosine arabinoside and G‐CSF (FLAG)

Abstract: The present study was undertaken to evaluate the efficacy of the association of fludarabine plus Ara‐C and G‐CSF (FLAG) in the treatment of 15 patients with chronic myeloid leukemia in the blastic phase (CML‐BP). Patients achieving a partial remission (PR) after the first course received a second FLAG. Complete remission (CR) was consolidated with another FLAG regimen. Patients were then submitted to an individualized program of treatment depending on age and suitable donors. Overall seven patients achieved CR (46.7%), three (20%) showed a primary resistant disease, while three (20%) died during remission induction therapy. Five of them received a consolidation therapy; in two cases further treatment was not performed because of severe toxicity. Median overall survival and disease‐free survival were of 7.5 and 4.5 months, respectively. FLAG proved to be effective in achieving a high CR rate in patients with CML‐BP. Median overall survival and disease‐free survival were not significantly improved compared to previous studies. Nevertheless, the treatment was well tolerated even in a group of heavily pretreated patients, allowing further transplantation opportunities in younger patients.
Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination

Blood–brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal‐appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ‐associated protein zonula occludens‐1 (ZO‐1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil‐red O (ORO)+ active plaques, affecting 42% of vessel segments, but less frequent in ORO− inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre‐lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease‐modifying therapy. Copyright © 2003 John Wiley & Sons, Ltd.
Racial differences in the use of drug therapy for HIV disease in an urban community.

BACKGROUND Guidelines for drug therapy in human immunodeficiency virus (HIV) disease are based primarily on the stage of the disease. To determine whether sociodemographic characteristics of patients influence drug therapy in practice, we analyzed the use of antiretroviral therapy and prophylactic therapy for Pneumocystis carinii pneumonia (PCP) in an urban population infected with HIV. METHODS All patients presenting for the first time to our HIV clinic from March 1990 through December 1992 were enrolled. Data on sociodemographic and clinical variables and on drug use were collected at the time of presentation and after six months. We asked whether patients with CD4+ cell counts of 500 or less per cubic millimeter were receiving antiretroviral therapy at the time of presentation, and whether patients with CD4+ cell counts of 200 or less per cubic millimeter were receiving PCP prophylaxis. RESULTS Among the 838 patients enrolled, 656 (79 percent) were blacks, 167 (20 percent) were non-Hispanic whites, and 15 (2 percent) were Asian or Hispanic descent or were not racially classified. There were no racial differences in the stage of HIV disease at the time of presentation. However, there were racial disparities in the receipt of antiretroviral therapy: 63 percent of eligible whites but only 48 percent of eligible blacks received such therapy (P = 0.003). PCP prophylaxis was received by 82 percent of eligible whites but only 58 percent of eligible blacks (P < 0.001). There were no significant differences in the receipt of drug therapy with respect to age, sex, mode of HIV transmission, type of insurance, income, education, or place of residence. In a logistic-regression analysis, race was the feature most strongly associated with the receipt of drug therapy. When blacks were compared with whites, the adjusted relative odds were 0.59 (95 percent confidence interval, 0.38 to 0.93) for the receipt of an antiretroviral agent and 0.27 (95 percent confidence interval, 0.13 to 0.56) for the receipt of PCP prophylaxis. CONCLUSIONS Among patients infected with HIV, blacks were significantly less likely than whites to have received antiretroviral therapy or PCP prophylaxis when they were first referred to an HIV clinic. This disparity suggests a need for culturally specific interventions to ensure uniform access to care, including drug therapy, and uniform standards of care.
A Weak Lck Tail Bite Is Necessary for Lck Function in T Cell Antigen Receptor Signaling*

Src family kinases are suppressed by a “tail bite” mechanism, in which the binding of a phosphorylated tyrosine in the C terminus of the protein to the Src homology (SH) 2 domain in the N-terminal half of the protein forces the catalytic domain into an inactive conformation stabilized by an additional SH3 interaction. In addition to this intramolecular suppressive function, the SH2 domain also mediates intermolecular interactions, which are crucial for T cell antigen receptor (TCR) signaling. To better understand the relative importance of these two opposite functions of the SH2 domain of the Src family kinase Lck in TCR signaling, we created three mutants of Lck in which the intramolecular binding of the C terminus to the SH2 domain was strengthened. The mutants differed from wild-type Lck only in one to three amino acid residues following the negative regulatory tyrosine 505, which was normally phosphorylated by Csk and dephosphorylated by CD45 in the mutants. In the Lck-negative JCaM1 cell line, the Lck mutants had a much reduced ability to transduce signals from the TCR in a manner that directly correlated with SH2-Tyr(P)505 affinity. The mutant with the strongest tail bite was completely unable to support any ZAP-70 phosphorylation, mitogen-activated protein kinase activation, or downstream gene activation in response to TCR ligation, whereas other mutants had intermediate abilities. Lipid raft targeting was not affected. We conclude that Lck is regulated by a weak tail bite to allow for its activation and service in TCR signaling, perhaps through a competitive SH2 engagement mechanism.
Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtype-selective ligands BQ123 and BQ3020: evidence for expression of ETB receptors in human vascular smooth muscle.

Our aim was to characterize and determine the function of endothelin (ET) receptor subtypes in human vascular tissue. Reverse transcriptase-polymerase chain reaction with nested oligonucleotide primers detected the presence of mRNA encoding both ETA and ETB receptors in the media from aorta and pulmonary and coronary arteries. In situ hybridization confirmed the presence of mRNA for both subtypes in the media of coronary arteries. Saturation binding assays using 125I-ET-1 found a single population of high-affinity ET receptors (n = three patients, +/- SEM) in aorta (Kd = 0.507 +/- 0.020 nM; Bmax = 9 +/- 4 fmol/mg protein) and pulmonary (Kd = 0.845 +/- 0.245 nM; Bmax = 15 +/- 10 fmol/mg protein) and coronary arteries (Kd = 0.141 +/- 0.020 nM; Bmax = 71 +/- 21 fmol/mg protein). Using media from coronary arteries, the ETA-selective ligand BQ123 (cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]) and the ETB-selective ligand BQ3020 (Ala11,15-Ac-ET-1[6-21]) both produced biphasic competition binding curves against 125I-ET-1, confirming the presence of high- and low-affinity sites corresponding to the two subtypes: BQ123 (KdETA = 0.85 +/- 0.03 nM; KdETB = 7.58 +/- 2.27 microM; ETA/ETB, 87%:13%) and BQ3020 (KdETA = 0.22 +/- 0.04 microM; KdETB = 0.77 +/- 0.34 nM; ETA/ETB, 62%:38%). BQ123 (0.1 microM) caused a significant parallel rightward shift of ET-1-induced vasoconstriction of coronary arteries in vitro, but BQ3020 and Ala1,3,11,15-ET-1 failed to show any agonist activity when tested at concentrations of < or = 3 microM in three vessels. (ABSTRACT TRUNCATED AT 250 WORDS)
PRL phosphatases as potential molecular targets in cancer

The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL-1, PRL-2, and PRL-3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Individual PRLs are overexpressed in a variety of cancer cell lines and tissues when compared with their normal counterparts. More importantly, several recent studies have shown that PRL-3 is expressed at higher levels and at a greater frequency in colorectal cancer metastases compared with primary colorectal tumors and normal colon tissue. Ectopic expression of PRLs in nontumorigenic cells can influence proliferation and the migratory and invasive properties of cells, while knockdown of endogenous PRL-3 or PRL-1 in cancerous cells using small interfering RNA can abrogate cell motility and ability to metastasize in a mouse model. However, the exact biological function and cellular substrates of the PRLs remain unclear. This review will discuss what is known about the PRLs, what makes the PRLs possible attractive targets for therapeutic intervention, and the possible future directions in PRL biology and inhibitor identification.
LRP2/megalin is required for patterning of the ventral telencephalon

Megalin is a low-density lipoprotein receptor-related protein (LRP2) expressed in the neuroepithelium and the yolk sac of the early embryo. Absence of megalin expression in knockout mice results in holoprosencephaly, indicating an essential yet unidentified function in forebrain development. We used mice with complete or conditional megalin gene inactivation in the embryo to demonstrate that expression of megalin in the neuroepithelium but not in the yolk sac is crucial for brain development. During early forebrain development, megalin deficiency leads to an increase in bone morphogenic protein (Bmp) 4 expression and signaling in the rostral dorsal neuroepithelium, and a subsequent loss of sonic hedgehog (Shh) expression in the ventral forebrain. As a consequence of absent SHH activity, ventrally derived oligodendroglial and interneuronal cell populations are lost in the forebrain of megalin–/– embryos. Similar defects are seen in models with enhanced signaling through BMPs, central regulators of neural tube patterning. Because megalin mediates endocytic uptake and degradation of BMP4, these findings indicate a role for megalin in neural tube specification, possibly by acting as BMP4 clearance receptor in the neuroepithelium.
Est-il possible d’améliorer le rendement et la teneur en protéines du blé en Agriculture Biologique au moyen de cultures intermédiaires ou de cultures associées ?

L’objectif du travail est de trouver des systemes de culture durables pour produire des rendements de ble reguliers et de bon niveau avec une teneur en proteines satisfaisante en AB. Notre demarche repose sur une valorisation optimale des ressources naturelles en azote provenant de la mineralisation du sol et de la fixation symbiotique. D’une part, des cultures intermediaires ont ete semees en ete et enfouies avant le semis du ble afin de limiter les pertes hivernales d’azote nitrique. D’autre part, le ble a ete cultive en association avec une legumineuse a graines. Les cultures intermediaires sont efficaces dans leur role de piege a nitrate et permettent d‘augmenter le rendement et la teneur en proteines du ble lors des annees pluvieuses. En culture associee, le rendement du ble est reduit mais la teneur en proteines est significativement augmentee. Ainsi, en AB, les cultures associees sont plus efficaces pour utiliser les ressources naturelles en azote. Il reste cependant i) a optimiser les itineraires techniques de ces deux systemes de culture, et, ii) determiner la place des associations au sein des rotations et analyser leur effet a moyen terme pour la gestion des bio-agresseurs.
[Expression of plasma miR-106a in colorectal cancer and its clinical significance].

OBJECTIVE To detect plasma miR-106a level in patients with colorectal cancer (CRC) and analyze its correlation to the clinicopathological features and disease diagnosis. METHODS miRNA expression profiling was performed using miRNA microarray chip for 3 colorectal adenocarcinoma samples and matched normal tissues. Plasma samples was collected from 50 colorectal cancer patients for quantitative analysis of miR-106a using real-time RT-PCR using 47 plasma samples from healthy volunteer as the control. Forty plasma samples were collected from these patients 7 days after operation to examine the changes in miR-106a expression. RESULTS miR-106a was differentially expressed in colorectal adenocarcinoma compared to normal tissues. The plasma levels of miR-106a expression were significantly higher in the cancer patients than in the healthy control group (P=0.012). miR-106a expression significantly decreased after the operation compared with its preoperative level (P<0.01), and no correlation was found between preoperative plasma miR-106a and the clinicopathological features including lymph node metastasis and TNM stage (P>0.05). miR-106a showed a receiver operating characteristic (ROC) curve area of 66.1%, a sensitivity of 62.3%, and a specificity of 68.2% in discriminating colorectal cancer patients from the control subjects. CONCLUSION plasma miR-106a is up-regulated in CRC patients, suggesting its potential value for the diagnosis of CRC.
Characterizing anterior cingulate activation in chronic schizophrenia: a group and single‐subject fMRI study

Objective: Functional abnormalities of the dorsal anterior cingulate (dAC) region have been emphasized in schizophrenia, particularly in relation to cognitive deficits. In this study, we sought to further evaluate the notion of dAC hypofunction in chronic schizophrenia patients using a cognitive task specifically designed to activate this region, enabling both group and single‐subject level analyses.
Occupational exposure to eight organic dusts and respiratory cancer among Finns

Background: There is inconclusive evidence concerning cancer risks of organic dusts. Aim: The carcinogenic exposures are mainly inhalatory and the authors therefore studied associations between occupational exposure to eight different organic dusts and respiratory cancers in Finland. Methods: The authors followed up a cohort of all economically active Finns born between 1906 and 1945 for 30 million person-years during 1971–95. Incident cases of nasal, laryngeal, and lung cancer and mesotheliomas were identified through a record linkage with the Finnish Cancer Registry. Occupations from the population census in 1970 were converted to exposures to eight organic dusts with a job-exposure matrix (FINJEM). Cumulative exposure (CE) was calculated as a product of prevalence, level, and estimated duration of exposure. Standardised incidence ratios (SIR) and 95% confidence intervals (CI) adjusted for age, period, and social class were calculated for each organic dust using the economically active population as the reference. Results: A total of 20 426 incident cases of respiratory cancer were observed. Slightly increased risk was observed among men exposed to wood dust for nasal cancer (SIR 1.42, 95% CI 0.79 to 2.44). For laryngeal cancer, men exposed to plant dust (mainly grain millers) had a raised SIR in the high exposure class (SIR 3.55, 95% CI 1.30 to 7.72). Men exposed to wood dust had a raised SIR for lung cancer, but only in the low exposure class (SIR 1.11, 95% CI 1.04 to 1.18). Women exposed to wood dust showed an increased SIR for mesotheliomas in the low exposure class (SIR 4.57, 95% CI 1.25 to 11.7) and some excess in the medium exposure category. Conclusions: Exposure to organic dusts is unlikely to be a major risk factor of respiratory cancer. Even exposure to wood dust which is a major exposure in Finland seems to have minor effect for nasal cancer. The authors found suggestive evidence that exposure to grain dust may increase the risk of laryngeal cancer, and some support to the hypothesis that exposure to textile dust, and to plant and animal dust (agricultural dusts) may decrease the risk of lung cancer.