Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypoxia‐driven proliferation of human pulmonary artery fibroblasts: cross‐talk between HIF‐1α and an autocrine angiotensin system

Pulmonary artery adventitial fibroblasts (FBPA) may play a central role in lung vascular remodeling under conditions of hypoxia and inflammation, the result being pulmonary hypertension and cor pulmonale. In cultured human FBPA, both angiotensin II (Ang II) and hypoxia promoted cell cycle progression and cell proliferation and suppressed apoptosis. These effects were further enhanced when both stimuli were applied simultaneously. Hypoxia elevated the expression of hypoxia‐inducible factor 1α (HIF‐1α) and increased the expression of genes regulated by the hypoxia‐responsive element (HRE). Up‐regulation of both angiotensin‐converting enzyme (ACE) and Ang II receptor type 1 (AT1) was also observed. Exogenous Ang II further increased HIF/HRE‐dependent signaling in FBPA, whereas suppression of the autocrine ACE‐Ang II‐AT1 loop with inhibitors of ACE, AT1, and phosphatidylinositol 3‐kinase (PI3K) reduced the proliferative response to both hypoxia and exogenous Ang II. Overexpression of HIF‐1α by transient transfection caused the same proliferative effect and up‐regulation of AT1 expression that were observed under hypoxic conditions. In contrast, small interfering RNA targeting HIF‐1α inhibited hypoxia‐induced ACE and AT1 expression. Our studies indicate that the ACE‐Ang II‐AT1 system serves as a positive feedback loop and fosters FBPA proliferation under hypoxic conditions, with the PI3K‐HIF‐HRE axis as the central effector pathway. This pathway may thus facilitate vascular remodeling under hypoxic conditions.
Using Directed Information to Build Biologically Relevant Influence Networks

The systematic inference of biologically relevant influence networks remains a challenging problem in computational biology. Even though the availability of high-throughput data has enabled the use of probabilistic models to infer the plausible structure of such networks, their true interpretation of the biology of the process is questionable. In this work, we propose a network inference methodology, based on the directed information (DTI) criterion, that incorporates the biology of transcription within the framework so as to enable experimentally verifiable inference. We use publicly available embryonic kidney and T-cell microarray datasets to demonstrate our results. We present two variants of network inference via DTI--supervised and unsupervised--and the inferred networks relevant to mammalian nephrogenesis and T-cell activation. Conformity of the obtained interactions with the literature as well as comparison with the coefficient of determination (CoD) method are demonstrated. Apart from network inference, the proposed framework enables the exploration of specific interactions, not just those revealed by data. To illustrate the latter point, a DTI-based framework to resolve interactions between transcription factor modules and target coregulated genes is proposed. Additionally, we show that DTI can be used in conjunction with mutual information to infer higher-order influence networks involving cooperative gene interactions.
Gamma-secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cells.

OBJECTIVE To investigate the effect of the gamma-secretase inhibitors (GSIs) on the growth of human tongue carcinoma cells and to provide the molecular mechanism for potential application of GSIs in the treatment of tongue carcinoma. MATERIALS AND METHODS Human tongue carcinoma Tca8113 cells were cultured with the GSI L-685 458. Cell growth was determined by the methylthiazole tetrazolium method. Cell cycle and apoptosis were analyzed by flow cytometry and/or confocal microscopy. RT-PCR and Western blot were employed to determine the intracellular expression levels. Nuclear factor kappa B (NF-kappaB) activation was examined by electrophoretic mobility shift assay. RESULTS L-685,458 dose-dependently inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0-G1 cell cycle arrest and apoptosis. The mRNA and protein levels of Hairy/Enhancer of Split-1, a target of Notch activation, were decreased dose-dependently by L-685,458. Furthermore, L-685,458 down-regulated cyclin D1, B-cell lymphocytic-leukemia proto-oncogene 2 and c-Myc expressions, which are regulated by the transcription factor NF-kappaB. Coincident with this observation, L-685,458 induced a dose-dependent reduction of constitutive NF-kappaB activation in Tca8113 cells. CONCLUSIONS The GSI L-685,458 may have a therapeutic value for the treatment of human tongue carcinoma. Moreover, the effects of L-685,458 in tumor inhibition may act partially via the modulation of Notch and NF-kappaB.
Host Factors and Biomarkers Associated with Poor Outcomes in Adults with Invasive Pneumococcal Disease

Background Invasive pneumococcal disease (IPD) causes considerable morbidity and mortality. We aimed to identify host factors and biomarkers associated with poor outcomes in adult patients with IPD in Japan, which has a rapidly-aging population. Methods In a large-scale surveillance study of 506 Japanese adults with IPD, we investigated the role of host factors, disease severity, biomarkers based on clinical laboratory data, treatment regimens, and bacterial factors on 28-day mortality. Results Overall mortality was 24.1%, and the mortality rate increased from 10.0% in patients aged ˂50 years to 33.1% in patients aged ≥80 years. Disease severity also increased 28-day mortality, from 12.5% among patients with bacteraemia without sepsis to 35.0% in patients with severe sepsis and 56.9% with septic shock. The death rate within 48 hours after admission was high at 54.9%. Risk factors for mortality identified by multivariate analysis were as follows: white blood cell (WBC) count <4000 cells/μL (odds ratio [OR], 6.9; 95% confidence interval [CI], 3.7–12.8, p < .001); age ≥80 years (OR, 6.5; 95% CI, 2.0–21.6, p = .002); serum creatinine ≥2.0 mg/dL (OR, 4.5; 95% CI, 2.5–8.1, p < .001); underlying liver disease (OR, 3.5; 95% CI, 1.6–7.8, p = .002); mechanical ventilation (OR, 3.0; 95% CI, 1.7–5.6, p < .001); and lactate dehydrogenase ≥300 IU/L (OR, 2.4; 95% CI, 1.4–4.0, p = .001). Pneumococcal serotype and drug resistance were not associated with poor outcomes. Conclusions Host factors, disease severity, and biomarkers, especially WBC counts and serum creatinine, were more important determinants of mortality than bacterial factors.
Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia.

PURPOSE Rai's and Binet's staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet's classification in 145 patients. PATIENTS AND METHODS Our series consisted of 83 VH mutated (MT) and 62 VH unmutated (UM) patients. MT cases predominated within Binet's stage A (70%), whereas UM cases predominated among stages B and C (62%). RESULTS Median overall survival (OS) was 84 months for UM patients and was not achieved for the MT group (70% 12-year survival, P <.0001). Concerning Binet's stage A, both median OS and progression-free survival were significantly shorter for UM patients when compared with those of MT patients (97 months v not achieved, P =.0017; and 42 v 156 months, P <.0001), which compared favorably with the classical A' and A" substaging. The VH mutational profile could also segregate stage B and C patients into two groups with different survival patterns (median OS, 78 v 120 months for UM and MT patients, respectively; P =.002). CONCLUSION The significant survival differences observed between the VH mutational groups, among stage A and stage B and C patients, indicate that Binet's classification and VH genes are independent prognostic variables and are most likely complementary.
[The effect of lead exposure on pathohistological changes in the liver and kidney in relation to age in rats].

Histopathological alterations in the liver and kidneys were examined in adult female rats and in their offspring form two matings after oral exposure to 7500 ppm lead (acetate) in drinking water. The length of exposure was up to 20 weeks. To estimate the reversibility of the effects in a number of exposed females lead administration was discontinued five weeks before their second breeding with unexposed males (the recovered group). In the group of exposed adult females histopathological changes in parenchymal organs were analogous to those seen in their pups from the first (shorter exposure), and second offspring (longer exposure to lead). Fatty and/or hydropic degenerative changes in the liver and kidneys and haemosiderosis of the liver were observed in both adult females and their young. In the liver of exposed pups the presence of numerous large foci of extramedullary erythropoiesis was also detected. In the kidneys of exposed adult females non-specific chronic inflammatory changes were seen. In the group of recovered females, after discontinuation of oral exposure to lead, histopathological findings indicated the reversibility of morphological changes. In their "recovered" pups the findings were also almost normal. It may be concluded that young rats are more susceptible to adverse action of lead than their mothers. (ABSTRACT TRUNCATED AT 250 WORDS)
sei-Deep brain stimulation for the treatment of drug-refractory epilepsy in a patient with a hypothalamic hamartoma

D. , Hypothalamic hamartomas (HHs) are developmental malformations associated with a range of neurological problems, including intractable seizures. There is increasing evidence of the epileptogenicity of the hamartoma and of the inhomogeneous distribution of the epileptic abnormalities within the malformation. The management strategy for treatment and results differ according to the insertion plane and the extension of the malformation into the hypothalamus. Cases characterized by extensive involvement of the hypothalamus are particularly challenging. The authors describe the case of a patient with drug-resistant epilepsy and a large hypothalamic hamartoma with an extensive area of attachment. The patient underwent implantation of 2 deep brain electrodes. The intraoperative recording showed a synchronous interictal epileptic discharge in the left temporal lobe and on the left side of the lesion. The patient was treated with chronic high-frequency stimulation. No side effects due to the stimulation were reported. At 18 months’ follow-up, a reduction in complex partial seizure frequency was reported, but no significant reduction in overall seizure frequency was noticed (p = 0.14, t-test). The authors report on neurophysiological studies of the relationship between HH and epilepsy, and also discuss the literature on chronic high-frequency stimulation, including its rationale and the results of chronic stimulation of various targets for the treatment of drug-resistant epilepsy due to HH. (DOI: 10.3171/2010.11.FOCUS10241)
Recombinant Human Annexin A5 Inhibits Proinflammatory Response and Improves Cardiac Function and Survival in Mice With Endotoxemia*

Objectives:Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-&agr; expression, cardiac function, and animal survival in endotoxemia. Design:Prospective experimental study. Setting:University laboratory. Subjects:Adult male C57BL/6 mice. Interventions:Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 &mgr;g/kg, IV). Cytokine expression and cardiac function were assessed, and animal survival was monitored. Measurements and Main Results:Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-&kgr;B activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-&agr; and interleukin-1&bgr; while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein. Conclusions:Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.
Correlates and consequences of harsh discipline for young children.

OBJECTIVE To examine the incidence, predictors, and consequences of harsh discipline in a sample of low-birth-weight children at 1 and 3 years of age. DESIGN Analysis of data from the Infant Health and Development Program, an 8-site randomized clinical trial of low-birth-weight infants. The sample for analysis consisted of 715 children who were 3 years of age. The independent measurements of primary interest were the mother's hitting and scolding of her child as disciplinary practice. Analyses were run separately for boys and girls. Bivariate and logistic analyses were used to examine the predictors of the mother's hitting and scolding behavior. Multivariate analysis of variance was used to examine the consequences of the mother's harsh discipline on a child's IQ measured at age 3 years. MAIN OUTCOME MEASURES The mother's self-report of whether she used more than 1 physical punishment in the past week, as well as an observer's report from 2 home visits of whether the mother hit or scolded the child during the 2-hour home visit. In addition, the Stanford-Binet Intelligence Scale was used to examine the consequences of persistent harsh discipline on child well-being. RESULTS Findings demonstrate child, maternal, and environmental factors that might aggravate a parent's use of corporal punishment. Boys received higher amounts of harsh discipline on all outcome measures. For boys, growing up in an impoverished home was predictive of the greater likelihood of receiving harsh punishment. Using IQ at age 3 years as the outcome measure, girls were found to be vulnerable to persistent harsh discipline and lack of maternal warmth. Maternal harsh discipline in a context of low maternal warmth was associated with IQ scores for girls that are 12 points lower than the IQ scores of girls who received low punishment and high warmth.
Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity.

BACKGROUND We tested the hypothesis that celiprolol and bisoprolol have differential effects on blood pressure (BP), flow-mediated dilation (FMD), and vascular stiffness. METHODS We analyzed 102 hypertensives (mean age: 59±14 years) who were being treated other than beta-blockers. They were randomized to receive add-on treatment with either celiprolol 100-200mg (C group) or bisoprolol 2.5-5mg (B group), and followed up for 3 months. In addition to clinic, home, and ambulatory BP monitoring, the FMD, radial augmentation index (AI), brachial-ankle pulse wave velocity (baPWV), urine albumin-to-creatinine ratio, and baroreflex sensitivity (BRS) were measured at baseline and at the end of the study. RESULTS Compared to the baseline values, home and 24-hour BP were significantly lowered in the third month in both groups (all Ps < 0.05). Pulse rate (PR) and baPWV were reduced (P < 0.001), and BRS was increased significantly only in the B group (P = 0.02). Radial AI was unchanged in the C group but was significantly increased in the B group (P < 0.001). Central BP was significantly reduced in the C group (P = 0.003) but was unchanged in the B group. FMD was significantly increased in both groups (both P < 0.01). CONCLUSION Bisoprolol achieved the greater reduction of PR and improved BRS and vascular stiffness, whereas, celiprolol reduced the central BP level. In treated hypertensive patients, add-on use of celiprolol may be favorable in uncomplicated stage of hypertension. On the other hand, bisoprolol may be useful in hypertensives with cardiac or vascular diseases who have advanced atherosclerotic changes and sympathetic nervous system activation.
Risk factors among IDUs who give injections to or receive injections from other drug users.

AIMS To assess risk factors associated with injection drug users (IDUs) who give injections to or receive injections from other IDUs. DESIGN AND SETTING IDUs were recruited into a cross-sectional study using targeted sampling methods in Oakland, Richmond, and San Francisco, California from August 1996 to January 1997. "Street docs" are IDUs who reported having given injections to other IDUs in the past month. "Injection recipients" are IDUs who reported having received injections from other people in the past month. PARTICIPANTS Of 1166 IDUs interviewed, 283 (24%) reported being injection recipients and 427 (37%) reported being street docs. MEASUREMENTS Socio-demographic characteristics and injection-related risk behaviors. FINDINGS Injection recipients and street docs were significantly more likely (p < 0.001) than other IDUs to report sharing syringes (33% of injection recipients, 21% of street docs and 7% of others), cookers (71% of injection recipients, 55% of street docs and 24% of others), rinse water (44% of injection recipients, 35% of street docs and 13% of others), and filters (60% of injection recipients, 47% of street docs and 20% of others). In a logistic regression model, injection recipients (adjusted odds ratio (AOR) = 4.29) and street docs (AOR = 1.91) were more likely than other IDUs to report having shared syringes. CONCLUSIONS Giving and receiving injections is common among IDUs in the San Francisco Bay area. Qualitative and epidemiological studies are needed to understand better the infectious disease risks associated with giving and receiving injections. Interventions need to address these issues and provide practical solutions.
Transcript Profiling of Wheat Genes Expressed During Feeding by Two Different Biotypes of Diuraphis noxia

ABSTRACT Diuraphis noxia (Kurdjumov) (Russian wheat aphid) has severe economic impacts on wheat and barley production in the United States. The interaction between the Russian wheat aphid and its cereal hosts is poorly understood. However, the recent appearance of new biotypes in the United States showed that specific interactions exist between wheat resistance loci and Russian wheat aphid biotypes. At present, Dn7 is the only known gene in hexaploid wheat that confers resistance against all U.S. Russian wheat aphid biotypes. This study was conducted to investigate the molecular mechanism of Dn7-mediated resistance against two U.S. Russian wheat aphid biotypes (Russian wheat aphid 1 and Russian wheat aphid 2). Using GeneChip Wheat Genome Arrays, we compared transcript profiles of resistant and susceptible lines infested with either Russian wheat aphid 1 or Russian wheat aphid 2 using two time intervals (5 and 48 h after infestation). Russian wheat aphid feeding on hexaploid wheat led to the induction of groups of genes functioning in oxidative and general stress, photosynthesis, cell respiration and energy production, signal transduction, calcium-dependent signaling, pathogenesis related (PR) responses, and defense compound synthesis. The number of differentially expressed genes was higher in plants infested with Russian wheat aphid 1 compared with those infested with Russian wheat aphid 2. Although most genes involved in basic cellular functions were shared, unique genes were also obtained. This finding may indicate subtle differences in genes induced in response to different virulence proteins.
Long term outcome of patients with localized aggressive non-Hodgkin lymphoma treated with PROMECE-CYTABOM plus involved-field radiation therapy: a study by the Gruppo Italiano Studio Linfomi

We conducted a retrospective analysis on 168 adult patients with newly diagnosed, limited-stage (I and II) diffuse large B-cell lymphoma (DLBCL) treated from 1988 to 2004 with PROMECE-CYTABOM (P-C) plus involved-field radiation therapy (IF-RT). At the end of P-C, the overall response rate was 92%. Radiotherapy (RT) was delivered to 84% of cases. With a median follow-up of 95 months, overall survival (OS), relapse free survival (RFS), and failure free survival at 5 and 10 years was 84% and 77%, 81% and 75%, 71% and 67%, respectively. Age (>60 years, p = 0.002), serum albumin (<3.5 g/dL; p = 0.015), and RT (p < 0.001) were independent predictors of OS. For patients in complete remission the administration of RT didn't improve both RFS and OS. This study confirms that patients with localized aggressive lymphoma have a high chance of cure with anthracycline containing regimens. Though the regimen used to treat these patients does not contain rituximab, results are considered excellent both in terms of efficacy and safety.
hZimp10 is an androgen receptor co‐activator and forms a complex with SUMO‐1 at replication foci

The androgen receptor (AR) plays a central role in male sexual development and in normal and malignant prostate cell growth and survival. It has been shown that transcriptional activation of AR is regulated through interaction with various co‐factors. Here we identify a novel PIAS‐like protein, hZimp10, as an AR‐interacting protein. The transactivation domain (TAD) of AR and the central region of hZimp10 were found to be responsible for the interaction. A strong intrinsic transactivation domain was identified in the C‐terminal, proline‐rich region of hZimp10. Endogenous AR and hZimp10 proteins were co‐stained in the nuclei of prostate epithelial cells from human tissue samples. In human prostate cancer cells, hZimp10 augmented the transcriptional activity of AR. Moreover, hZimp10 co‐localized with AR and SUMO‐1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo. Studies using sumoylation deficient AR mutants suggested that the augmentation of AR activity by hZimp10 is dependent on the sumoylation of the receptor. Taken together, these data demonstrate that hZimp10 is a novel AR co‐regulator.