Miracle-dz/UniFAR-FTUs huggingface dataset:
Estrogen receptor-alpha-interacting cytokeratins potentiate the antiestrogenic activity of fulvestrant

Fulvestrant (ICI 182, 780) is a selective estrogen receptor downregulator (SERD) and potent antiestrogen. In estrogen receptor alpha positive ERα(+) breast cancer, the drug immobilizes ERα in the nuclear matrix, inducing receptor polyubiquitination and subsequent degradation via the 26S proteasome. We previously reported that fulvestrant-induced ERa degradation depends on the interaction of ERα with cytokeratins 8 and 18 (CK8/CK18). Here we further investigate the role of these two cytokeratins in the antagonistic activity of the SERD. Using ER-responsive reporter assays, we demonstrate greater antiestrogenic activity of fulvestrant in CK8/CK18(+) vs. CK8/CK18(-) cancer cells and loss of CK8/CK18 expression was observed in a breast cancer cell model for acquired fulvestrant resistance. In contrast, the presence of CK8/CK18 had no effect on the antiestrogenic activity of 4-hydroxytamoxifen, which was unable to induce an interaction between these CKs and ERα. By utilizing the ligand activity inversion ERα mutant L540Q to further examine the mechanism of fulvestrant action, we demonstrate that the ERα mutant does not interact with CK8/CK18 in the presence of fulvestrant and L540Q is not immobilized to the nuclear matrix after antiestrogen treatment. In transcription assays, fulvestrant displayed agonist activity, stimulating L540Q-mediated gene expression. In addition, fulvestrant did not induce an ERβ interaction with CK8/CK18 and subsequent ERb degradation. Collectively, these results suggest that CK8/18 play an important role in the antiestrogenic action of fulvestrant in breast cancer cells and that these two cytokeratins could serve as prognostic markers for SERD therapy response in breast cancer patients.
Cell Signaling Modifiers in Prostate Cancer

Despite advances in the treatment of hormone-refractory prostate cancer (HRPC) with docetaxel chemotherapy as evidenced by the TAX 327 and SWOG 99-16 trials, therapeutic options remain limited in patients with cancer that progresses while they are receiving hormone manipulation and chemotherapy. Targeted therapies against receptor tyrosine kinases of the ErbB family have shown some promise in the treatment of HRPC; however, patient characteristics defining susceptibility to ErbB-targeted therapies remain unknown in HRPC and limits their efficacy in the clinic. Targeted inhibition of downstream pathways, namely mammalian target of rapamycin (mTOR) may prove to be important in the treatment of HRPC because of the prevalence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss, and it has been shown preclinically that mTOR inhibition reverses the phenotype of PTEN loss. Further investigation is necessary for the targeted inhibition of receptor tyrosine kinases and mTOR in HRPC. However, these classes of drugs may prove efficacious as tumoricidal agents or as chemo- and radiosensitizers.
Disruption of CFTR-dependent lipid rafts reduces bacterial levels and corneal disease in a murine model of Pseudomonas aeruginosa keratitis.

PURPOSE Pseudomonas aeruginosa enters corneal epithelial cells in vitro via membrane microdomains or lipid rafts. Bacterial entry, mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), promotes infection and disease. This study was conducted to determine whether P. aeruginosa and CFTR are colocalized to rafts in isogenic corneal cells expressing wild-type (WT) or mutant DeltaF508-CFTR and whether disruption of the rafts both in vitro and in vivo affects the bacterial levels and the course of the disease. METHODS Transformed human corneal epithelial cells from a patient homozygous for DeltaF508-CFTR, and the same cells corrected with WT-CFTR, were exposed to six isolates of P. aeruginosa-three invasive and three cytotoxic strains-in the presence of beta-cyclodextrin (CD), which disrupts rafts. Association and cellular uptake of the invasive strains were measured, as was lactate dehydrogenase release induced by the cytotoxic strains. Scratch-injured mouse eyes were infected with the six P. aeruginosa strains, and the effect of prophylactic or therapeutic administration of CD on bacterial levels and disease was evaluated. RESULTS P. aeruginosa and CFTR were colocalized with lipid rafts in cells with WT-CFTR, and CD treatment of these cells disrupted bacterial association, internalization, and cytotoxic effects. Cells expressing DeltaF508-CFTR were marginally affected by CD. Prophylactic and therapeutic topical application of CD ameliorated corneal disease and reduced the bacterial count in the eye. CONCLUSIONS P. aeruginosa enters human corneal epithelial cells via lipid rafts containing CFTR, and disruption of raft-mediated uptake of this organism by CD protects against disease and reduces bacterial levels in the mouse model of keratitis.
Adhesion of Streptococcus mutans to different types of brackets.

OBJECTIVE To examine the difference in the adhesion of Streptococcus mutans to three different types of orthodontic brackets and the effect of the presence of an early salivary pellicle and Streptococcus sanguis on adhesion. MATERIALS AND METHODS Three adhesion experiments were performed using stainless steel, ceramic, and plastic orthodontic brackets. In the first experiment a clinical strain of S mutans adhered to the three different types of brackets (n = 6 for each). For the second, the brackets were treated with saliva before adhesion of S mutans (n = 6 per type of bracket). Finally, the third experiment concerned saliva coated brackets (n = 6 per type of bracket), but before S mutans, S sanguis bacteria were allowed to adhere. The bacteria were always allowed to adhere for 90 minutes in all the experiments. Adhesion was quantitated by a microbial culture technique by treating the brackets with adhering bacteria with trypsin and enumerating the total viable counts of bacteria recovered after cultivation. RESULTS There were consistently no differences in the adherence to stainless steel, ceramic, or plastic brackets. The presence of an early salivary pellicle and S sanguis reduced the number of adhering S mutans to all three types of brackets. CONCLUSIONS Adhesion of bacteria to orthodontic brackets depends on several factors. The presence of a salivary pellicle and other bacterial species seem to have a significant effect on the adhesion of S mutans, reducing their numbers and further limiting any differences between types of brackets.
Introducing chemists to food allergy

Adverse reactions to food may be toxic or non toxic, depending on the susceptibility to a certain food; non toxic reactions that involve immune mechanisms are termed allergy if they are IgE‐mediated. If no immunological mechanism is responsible, it is termed intolerance. The following disorders are considered a consequence of food allergy: gastrointestinal reactions (oral allergy syndrome, vomiting, diarrhea, protein‐induced enterocolitic syndrome, eosinophilic gastroenteritis); respiratory reactions (rhinitis, asthma, laryngeal edema); cutaneous reactions (urticaria‐angioedema, atopic dermatitis); anaphylaxis. There is much recent evidence to consider celiac disease an immunological disorder. Food allergy diagnosis is based on history, SPT, specific IgE, food challenges. DBPCFC is fundamental for diagnosing true food allergy; patients who have had anaphylaxis to food must not undergo DBPCFC. Rapidly progressive respiratory reactions and anaphylactic shock are life‐threatening reactions that can be caused by food allergy. The doses of food inducing anaphylaxis can be very low, therefore commercial cross‐contamination with an unsuspected food during food processing can be risky for the food allergic patient. The prevention of severe anaphylactic food reactions may lie in interdisciplinary collaboration among allergologists, chemists, food technologists, and experts in food industry research.
An analysis of the Icelandic Supreme Court judgement on the Health Sector Database Act

Six years after the Icelandic Health Sector Database Act came into force, the Supreme Court of Iceland as court of appeal was asked to give a judgement on the constitutionality of the Act. The appellant had unsuccessfully applied to the Director General of Public Health to prevent the transfer of her deceased father’s medical records to the Health Sector Database. The court of first instance, the Reykjavik District Court, dismissed the case for lack of legal standing. The Icelandic Supreme Court decided that the appellant had legal standing due to the fact that from the data related to hereditary characteristics of her father information about the plaintiff herself could be inferred. The Icelandic Supreme Court further discussed privacy and data protection issues with regard to the Health Sector Database, coming to the conclusion that the one-way encryption system was a sufficiently safe mechanism for data protection, but that due to the richness of data to be entered into the Health Sector Database, individuals could be identifiable. DOI: 10.2966/scrip.010204. 241 © Renate Gertz 2004. This work is licensed through SCRIPT-ed Open Licence (SOL). * Research Fellow, AHRB Centre, School of Law, University of Edinburgh. Acknowledgement: The author would like to thank Dr G T Laurie for his advice. Any mistakes, of course, are the author’s own. (2004) 1:2 SCRIPT-ed 242
NF-κB Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells

ABSTRACT Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-κB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-α), which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-α and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-κB activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-κB binding sites (designated κB-1 and κB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-κB component p65/RelA. Mutation of the κB-1 site, but not the κB-2 site, impaired responsiveness to TNF-α and LMP1 in reporter assays. A mutant XMRV with a mutation at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-α and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the κB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-κB activation may promote XMRV spread in humans.
Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

ALK‐1 is a transforming growth factor β(TGF‐β) superfamily receptor that is predominantly expressed in endothelial cells and is essential for angiogenesis, as demonstrated by the embryonic lethal phentoype when targeted for deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia. Although ALK‐1 and the endothelial‐ specific TGF‐P superfamily coreceptor, endoglin, form a heteromeric complex and bind similar TGF‐β super‐ family ligands, their signaling mechanisms remain poorly characterized. Here we report the identification of CK2β, the regulatory subunit of protein kinase CK2, as a novel enhancer of ALK‐1 signaling. The cytoplas‐ mic domain of ALK‐1 specifically binds to CK2β in vitro and in vivo. NAAIRS mutagenesis studies define amino acid sequences 181‐199 of CK2β and 207‐212 of ALK‐1 as the interaction domains, respectively. The ALK‐1/ CK2β interaction specifically enhanced Smad1/5/8 phosphorylation and ALK‐1‐mediated reporter activa‐ tion in response to TGF‐β 1 and BMP‐9 treatment. In a reciprocal manner, siRNA‐mediated silencing of endog‐ enous CK2β inhibited TGF‐β 1 and BMP‐9‐stimulated Smad1/5/8 phosphorylation and ALK‐1‐mediated re‐ porter activation. Functionally, CK2β enhanced the ability of activated or ligand‐stimulated ALK‐1 to inhibit endothelial cell migration. Similarly, ALK‐1 and CK2βantagonized endothelial tubule formation in Matrigel. These studies support CK2β as an important regulator of ALK‐1 signaling and ALK‐1‐mediated functions in endothelial cells. —Lee, N. Y. , Haney, J. C. , Sogani, J., Blobe, G. C. Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling. FASEB J. 23, 3712‐3721 (2009). www.fasebj. org
An Immersive Virtual Reality Platform to Enhance Walking Ability of Children with Acquired Brain Injuries

Summary Background: Acquired brain injury (ABI) may result in lifelong impairment of physical, cognitive, and psychosocial functions. Several rehabilitative treatments are often needed to support walking recovery, thus participants’ engagement becomes a crucial aspect, especially when patients are children. In the last few years, traditional physiotherapy (PT) has been flanked by innovative technologies for rehabilitation in the fields of robotics and Virtual Reality (VR). Preliminary results have shown interesting perspectives in the use of a VR system, the GRAIL (Gait Real-time Analysis Interactive Lab), in improving walking abilities in a small group of children with ABI, although further insights are needed about its use as rehabilitative tool in the pediatric population. Objectives: To evaluate the efficacy of a rehabilitation treatment on a GRAIL system for the improvement of walking abilities, in a group of children suffering from ABI. Methods: 12 children with ABI (study group – SG; mean age = 12.1 ± 3.8 years old) underwent a 10-session treatment with the GRAIL, an instrumented multi-sensor platform based on immersive VR for gait training and rehabilitation in engaging VR environments. Before (T0) and at the end of the treatment (T1), the participants were assessed by means of functional scales (Gross Motor Function Measure (GMFM), Functional Assessment Questionnaire (FAQ), 6-Minute Walk Test (6minWT) and the 3D-Gait Analysis, over ground (OGA) and on GRAIL (GGA). Results: All the participants completed the rehabilitative treatment. The functional evaluations showed an improvement in Gross Motor abilities (GMFM-88, p = 0.008), especially in standing (GMFM-D, p = 0.007) and walking (GMFM-E, p = 0.005), an increase of the endurance (6minWT, p = 0.002), and enhanced autonomy in daily life activities (FAQ, p = 0.025). OGA identified a significant decrease of the Gillette Gait Index for the impaired side and a general increase of symmetry. GGA showed improvements in spatiotemporal parameters and joints range of motion that moved towards normality and symmetry recovery. Conclusions: A 10-session treatment with GRAIL on children with ABI led to improvements in their walking abilities and enhanced their engagement during the training. This is desirable when long life impairments are faced and children’s motor functions have to be regained and it supports the leading role that VR might have in the rehabilitation field.
Hippocampal place cells can develop distinct representations of two visually identical environments

The pattern separation ability of hippocampal place cells was tested in an environment in which two visually identical rectangular compartments (Box A and Box B) were connected by a hidden door. Small ensembles of neurons were recorded with tetrodes while the rat searched for randomly distributed loci for reinforcing brain stimulation. The first recording session in Box A was conducted after the rat had explored the environment for the first time for 30 min. Immediately thereafter, a hidden door between Box A and Box B was opened to let the rat into the unexplored compartment, and a 5‐min recording session was run with the door concealed. A rearrangement of place fields in Box B was observed in 18/20 neurons and in 5/6 ensembles. Most place fields did not change between two successive sessions in Box B. When the rat returned to Box A, the ensembles of neurons were as likely to adopt the original Box A firing field pattern as the more recent Box B pattern. In order to control for the influence of extra‐arena cues, the rat was gradually lifted in a closed bucket from Box A into Box B while the whole arena was rotated by 90°. All but one neuron and all the ensembles followed the intra‐arena cues. Both rotated Box B and Box A firing field patterns were represented but Box B pattern was stronger among the neuronal ensembles. These findings indicate that hippocampal place cells not only can develop distinct representations of two visually identical environments but also can selectively reactivate either one of these representations depending on the rat's recent experience. Hippocampus 1999;9:235–246. © 1999 Wiley‐Liss, Inc.
Die backside stress modification by coating of Si3N4 or AlN layers

The ability to improve the mechanical properties of a microelectronic package, including reducing the thermal-mechanical stress and increasing the die breaking strength is a long-sought goal in electrical assembly and packaging technology. Failure modes related with die backside stress caused by warpage or cosmetic defects may occur without a well control of die-backside stress. In this study, the modifications of die backside stress by coating of a thin layer of AlN or Si3N4 have been investigated. The simulation through the Finite Element Method (FEM) indicated that the stress distribution can be modified after coating and it is strongly related to the thickness of the coated layer, as the stress of die backside surface reduces. Die breaking strength has been measured by 3 point bending test and the measurement results are compared between samples with and without coatings. It is demonstrated that the die breaking strength is related with the thickness and the surface roughness of the coating layer of AlN or Si3N4. Improvement in the die breaking strength can be realized when the thickness and surface roughness are both optimized. The results suggested the additional coating of the die backside may be a feasible way to improve the mechanical properties of the electronic packages.
Driver Fatigue Detection Based Intelligent Vehicle Control

Driver fatigue problem is one of the important factors that cause traffic accidents. Therefore the vision-based driver fatigue detection is the most prospective commercial applications of HCI. However, it is a challenging issue due to a variety of factors such as head and eyes moving fast, external illuminations interference and realistic lighting conditions, etc. This tends to significantly limit its scope of application. In this paper, we present an intelligent vehicle control based on driver fatigue detection. Firstly, the face is located using Haar algorithm and eye location is found with projection technique. After finding eye templates, we propose a new real time eye tracking method based on unscented Kalman filter. Thirdly, driver fatigue can be detected whether the eyes are closed over 5 consecutive frames using vertical projection matching. Finally, if driver fatigue is confirmed, the vehicle cruise control is start-up with slow speed, and maintains set slow speed such as 5 km/h. The experimental results show that intelligent vehicle control based on driver fatigue detection will be availability in traffic
Warfarin Exposure and the Risk of Thromboembolic and Major Bleeding Events Among Medicaid Patients with Atrial Fibrillation

Background: Outcomes of anticoagulation have been assessed in commercially insured populations, but similar data do not exist for Medicaid populations. Objective: To assess the association between warfarin exposure and rates of thromboembolic and bleeding events among patients with nonvalvular atrial fibrillation (NVAF) enrolled in California Medicaid. Methods: Using a retrospective cohort design based on administrative claims data, we selected Medicaid enrollees aged 50 years and older based on their first claim with a diagnosis of AF between January 1, 1998, and March 31, 2002. Patients were excluded if they had selected contraindications to warfarin, claims for valve replacement procedures, or evidence that AF resulted from transient or reversible causes. Pharmacy claims and prothrombin time tests were used to define subsequent periods of warfarin use (exposure) and nonuse (nonexposure) by all patients. The relative rates of hospitalization for thromboembolic and bleeding events associated with periods of warfarin exposure versus nonexposure were estimated. Results: The 4355 study patients had a mean age of 74 years, and 65% were female. Fifty-nine percent filled any prescriptions for warfarin following AF diagnosis. Across all patients, warfarin exposure occurred during 37% of days after diagnosis. Thromboembolic events were 27% less frequent during periods of warfarin exposure relative to periods of non-exposure (p < 0.01). Major bleeding events were not significantly more common during periods of warfarin exposure (p = 0.55). Conclusions: In this Medicaid population with NVAF, warfarin use was low and was associated with a relatively modest reduction in thromboembolic events, with no increase in major bleeding risk.
The role of parenteral lipids in the development of advanced intestinal failure-associated liver disease in infants: a multiple-variable analysis.

BACKGROUND Given the recent interest in the role of ω-6 lipids in the development of intestinal failure-associated liver disease (IFALD), the authors sought to examine the role of parenteral lipids in the development of a serum conjugated bilirubin >100 µmol/L (5.9 mg/dL; CB100) in infants. METHOD Between 2003 and 2004, data were collected prospectively on infants undergoing an abdominal surgical procedure. Univariate logistic regression models for the prediction of CB100 by 1 year postoperatively were developed. Predictors significant at the 0.2 level on univariate analysis were entered into a backward stepwise multiple variable logistic regression. RESULTS Of 152 infants who received parenteral nutrition (PN) postoperatively, 22 developed CB100. Predictors that met criteria for consideration in the multiple-variable model were age, weight, small bowel length, presence of a stoma, proportion of enteral feeds postoperatively, septic episodes, days of maximal PN amino acid (>2.5 g/kg/d), days of maximal lipid (>2.5 g/kg/d), and PN duration. The final model included septic episodes (odds ratio, 3.23; 95% confidence interval, 1.8-5.9) and days of lipid >2.5 g/kg/d (1.04; 1.003-1.06). At 60 days of maximal lipid, the odds of advanced IFALD were increased 10-fold. CONCLUSIONS This model suggests a key role of parenteral lipids and septic events in the development of CB100 from IFALD. These data may provide targets, such as careful line care, reduction in maximal lipid dose, or alternate lipids such as ω-3 fatty acids, to prevent CB100, an identified marker of subsequent liver failure from IFALD.