Miracle-dz/UniFAR-FTUs huggingface dataset:
Selective estrogen receptor modulators and betulinic acid act synergistically to target ERα and SP1 transcription factor dependent Pygopus expression in breast cancer

Aims Estrogen and progesterone hormone receptor (ER and PR) expression in invasive breast cancer predicts response to hormone disruptive therapy. Pygopus2 (hPYGO2) encodes a chromatin remodelling protein important for breast cancer growth and cell cycle progression. The aims of this study were to determine the mechanism of expression of hPYGO2 in breast cancer and to examine how this expression is affected therapeutically. Methods hPYGO2 and ER protein expression was examined in a breast tumour microarray by immunohistochemistry. hPYGO2 RNA and protein expression was examined in ER+ and ER− breast cancer cell lines in the presence of selective estrogen hormone receptor modulator drugs and the specificity protein-1 (SP1) inhibitor, betulinic acid (BA). The effects of these drugs on the ability for ER and SP1 to bind the hPYGO2 promoter and affect cell cycle progression were studied using chromatin immunoprecipitation assays. Results hPYGO2 was expressed in seven of eight lines and in nuclei of 98% of 65 breast tumours, including 3 Ductal carcinoma in situ and 62 invasive specimens representing ER-negative (22%) and ER-positive (78%) cases. Treatment with either 4-Hydroxytamoxifen (OHT) or fulvestrant reduced hPYGO2 mRNA 10-fold and protein 5–10-fold within 4 h. Promoter analysis indicated an ER/SP1 binding site at nt −225 to −531 of hPYGO2. SP1 RNA interference and BA reduced hPYGO2 protein and RNA expression by fivefold in both ER- and ER+ cells. Further attenuation was achieved by combining BA and 4-OHT resulting in eightfold reduction in cell growth. Conclusions Our findings reveal a mechanistic link between hormone signalling and the growth transcriptional programme. The activation of its expression by ERα and/or SP1 suggests hPYGO2 as a theranostic target for hormone therapy responsive and refractory breast cancer.
UMEÅ UNIVERSITY MEDICAL DISSERTATIONS

9 INTRODUCTION . 10 1 Regulation of transcription in eukaryotes . 10 1.1 Recruitment of co-activators and co-repressors . 10 1.2 Regulation of the activity of transcription factors . 11 2 Regulation of transcription factors by phosphorylation and dephosphorylation . 12 3 Granulocyte-macrophage colony-stimulating factor (GM-CSF) . 12 4 Transforming growth factor-β (TGF-β)/Smad signaling . 14 4.1 Activation of TGF-β receptors . 14 4.2 Smad proteins . 15 4.3 Regulation of activation of Smads.16 4.4 Nuclear translocation of Smads.17 4.5 Smad transcription complexes.18 4.6 Interaction with other signal pathways.18 5 Calcium signaling.19 6 Ca/calmodulin-dependent protein kinase II.22 6.1 Autoinhibition and activation of CaMK II . 23 6.2 Autophosphorylation of CaMK II . 23 6.3 CaMK II signaling by phosphorylation . 24 7 Calcineurin . 24 7.1 Domain structure of calcineurin . 24 7.2 Activation of calcineurin . 25 7.3 Calcineurin signaling.26 8 The transcription factor Ets1 . 26 8.1 Structure and function of the Ets1 domains.27 8.2 Regulation of Ets1 . 29 9 RUNX family transcription factors . 30 9.1 Functional domains of RUNX proteins . 31 9.2 RUNX isoforms.32
Syncope: A videometric analysis of 56 episodes of transient cerebral hypoxia

To investigate the clinical features of transient cerebral hypoxia, syncope was induced in 56 of 59 healthy volunteers through a sequence of hyperventilation, orthostasis, and Valsalva maneuver. All events were monitored on video by two cameras. Complete syncope with falling and loss of consciousness was observed in 42 subjects, lasting 12.1 ± 4.4 seconds. Myoclonic activity occurred in 38 of these 42 episodes (90%). The predominant movement pattern consisted of multifocal arrhythmic jerks both in proximal and distal muscles. Superposition of generalized myoclonus was common. Additional movements such as head turns, oral automatisms, and righting movements occurred in 79%. Eyes remained open throughout syncope in most subjects and initial upward deviation was common. Sixty percent reported visual and auditory hallucinations. Thirteen subjects had incomplete syncope with falls but partially preserved consciousness. These episodes were shorter and usually not accompanied by myoclonus and hallucinations. Transient amnesia and unresponsiveness without falling occurred in 1 subject.
Cudrania tricupidata Bureau (CTB) Glycoprotein Inhibits Proliferation by Di(2-ethylhexyl) phthalate in Primary Splenocytes: Responses in Cell Proliferation Signaling

The aim of the present study was to evaluate inhibitory effect of CTB glycoprotein isolated from Cudrania tricuspidata Bureau on DEHP-induced cell proliferation in lymphocytes. Our results revealed that DEHP increased lymphocyte proliferation as confirmed by increasing [3H]thymidine incorporation, and proliferating cell nuclear antigen (PCNA), cyclin D1, and cyclin-dependent kinase (CDK)-4 expression. This was accompanied by induced intracellular Ca2+ level, protein kinase C (PKC) translocation from cytosol to membrane, ERK1/2 phosphorylation, and nuclear factor (NF)-κB transcriptional activation in DEHP-treated cells. However, CTB glycoprotein (100 μg/ml) reduced labeled thymidine incorporation and PCNA expression in DEHP-treated cells. Additionally CTB glycoprotein reduced Ca2+ level, PKC translocation, ERK1/2 phosphorylation, NF-κB transcriptional activation, cell cycle proteins (cyclin D1 and CDK4) expression in cells. The activation of NF-κB was collectively blocked by pretreatment with PKC inhibitor (staurosporine) and ERK1/2 inhibitor (PD98059), respectively. The results from these experiments indicate that CTB glycoprotein inhibits cell proliferation via down regulations of Ca2+/PKC, ERK1/2, and cell cycle proteins induced by DEHP. Therefore, we suggest that the CTB glycoprotein might be one component for prevention of cell proliferation-related immune diseases.
FSTL 3 and its role in mediating fibrosis and hypertrophy in diet-induced obesity

Metabolic syndrome (MetS) is a conglomeration of several risk factors for cardiovascular disease, with obesity currently being one of the common causes of disability and death in the United States. Underlying the obesity, however, there is metabolic imbalance that could be exacerbating the issue of metabolic syndrome. Approximately 34% of adults over 20 years old matched the criteria for metabolic syndrome. The risk factors for cardiovascular disease (CVD) associated with metabolic syndrome can, over time, lead to severe CVDs, such as heart failure (HF). Metabolic syndrome can also lead to developing metabolic heart disease over time. Understanding the development of cardiac hypertrophy and fibrosis in diet-induced metabolic heart disease allow development of an early treatment of metabolic heart disease (MHD) and HF. This study looked at one potential mediator and its role in cardiac hypertrophy and fibrosis, follistatin-like 3 (FSTL3). FSTL3 is an extracellular antagonist of members of the TGF-β superfamily. The goal of our study was to determine the effect, if any, a knockout of FSTL3 would have on the development of cardiac hypertrophy and fibrosis after a high-fat, high-sucrose diet for five months. FSTL3 knockout mice were given a high-fat, high-sucrose (HFHS) diet for five months. These mice were then sacrificed and their hearts were analyzed
Nicolau syndrome secondary to subcutaneous Bortezomib injection

the characteristic clinical triad and positive medical history for recurrent pulmonary infections. The differential diagnosis of XHED includes skin fragility syndrome, focal dermal hypoplasia syndrome, aplasia cutis, dyskeratosis and congenital pachyonychia, which are all characterized by impaired ectodermal development. Vitiligo on the other hand is an acquired autoimmune disorder, affecting up to 2% of the worldwide population. Recent studies point to a decreased risk of both non-melanoma skin cancer and sun damage in vitiligo, even in patients treated with phototherapy. The decreased prevalence of skin cancer on vitiligo-affected skin may be related to the increased p53 gene-mediated tumour suppression or to the autoimmune cytotoxic-T-cell responses. Current clinical guidelines for vitiligo recommend preliminary assessment of patient’s characteristics for balancing the benefit–risk ratios of different treatment regimens, but these do not include less-common disease associations. Up to now, there has only been one report of multiple actinic keratoses and concomitant squamous cell carcinomas, in a vitiligo patient with a carrier status for X-HED, which had developed after a 3-year long PUVA treatment. Ectodermal dysplasias syndromes are associated with defective skin barrier functions as well as with perturbations of NFkB signalling and related chemokine expression, resulting in chronic inflammation and hyperplasia of the skin. Christ–Siemens–Touraine syndrome has rarely been associated with depigmentation or autoimmune disorders and a susceptibility to photodamage and skin cancer has not previously been recognised. This risk may be significant given that X-HED patients have natural behavioural preferences to avoid sunlight due to comorbid symptoms such as heat intolerance and eccrine sweat gland dysfunction. Our patient developed multiple lichenoid keratoses (or Lichen planus-like keratosis) at a young age following a brief course of mild intensity phototherapy. This case underlines the importance of careful patient selection and thorough consideration of risk factors for photodamage prior to initiation of treatment for vitiligo.
A Framework for Variational Grid Generation: Conditioning the Jacobian Matrix with Matrix Norms

Functionals for variational grid generation, in which the Jacobian matrix and matrix norms play a central role, are presented. All first-order geometric qualities of a structured grid (length, area, volume, angle between sides, aspect ratio, grid alignment) are determined by the Jacobian matrix of the induced mapping between the logical and physical regions. Grids with desirable quality can be generated by requiring the Jacobian matrix or the corresponding metric tensor to have certain properties. Functionals can be obtained by integrating over the logical or physical domain a power of the norm of a matrix derived from the Jacobian matrix. A judicious choice of this derived matrix results in a functional whose minima are mappings with desired features. Many well-known grid generators fit in this framework; for example, the harmonic generator arises when one drives the metric tensor toward the identity. The framework provides insight into what grid qualities these functionals describe. Three new directional control functionals are proposed and tested.
VEGF-A and its inhibitors in age-related macular degeneration - pharmacokinetic differences and their retinal and systemic implications

Age-related macular degeneration (AMD) is the main cause for legal blindness in the industrialized countries. In its exudative form, vessels grow from the choroid into the subretinal and retinal space, resulting in a rapid loss of vision. A major factor in the development of neovascularization is Vascular Endothelial Growth Factor (VEGF) A, which is therapeutically inhibited to treat exudative (wet) AMD. In addition to its pathological effects, VEGF-A has important physiological functions both systemically and in the retina. Current VEGF-antagonists are the Fab-Fragment ranibizumab, the fusion protein aflibercept and the off-label used antibody bevacizumab. In addition, the aptamer pegaptanib is approved for the treatment of AMD. These molecules differ on a molecular level, which impacts on their pharmacological behavior such as their effects on retinal cells, ocular and systemic clearance, or systemic VEGF-A inhibition. These differences may result in different systemic and retinal effects of the respective therapeutic molecule, which may cause different long term effects after prolonged usage.
Machine Learning Techniques Applied to Data Analysis and Anomaly Detection in ECG Signals

ABSTRACT In this article Tomasz Andrysiak presents the use of sparse representation of a signal based on overcomplete dictionaries of base functions and a QRS detection method using artificial neural network to detect anomalies in the analyzed ECG signals. Performance of the proposed method was tested by means of a widely available database of ECG signals, i.e., the MIT-BIH Arrhythmia Database, and the obtained experimental results confirmed its effectiveness for anomaly detection in the analyzed ECG signals. The current dynamic and intensive development of information technologies and more excellent methods of processing, analysis, and recognition of signals have enriched medicine with new quality techniques in diagnosis and therapy. At present, a special interest is put to noninvasive diagnostic methods for rapid and objective determination of vital signs and, in particular, automatic electrocardiogram performed outside medical facilities. The sparse representation of a signal was performed in an adaptive manner by means of the matching pursuit algorithm. In each step of the algorithm, there was implemented a linear signal decomposition of features belonging to the dictionary with redundancy. Two kinds of dictionaries were tested. The first type included elements that form the analytical base functions, and the second represented the essential components of the ECG signal searched with the use of the K-Singular Value Decomposition (K-SVD) algorithm. Recognition of the QRS was realized by means of a unidirectional, multidimensional neural network with backpropagation of an error. For this solution, tests were performed on a selection of appropriate neural network architectures and the impact of a particular activation function on the recognition results. Anomaly detection was realized with estimation of sparse representation parameters of the tested ECG signal within the field of the recognized QRS complex, and it was compared with the reference values. Performance of the proposed method was tested using a widely available database of ECG signals—MIT-BIH Arrhythmia Database. The obtained experimental results confirmed the effectiveness of the proposed method of anomaly detection in the analyzed ECG signals.
Candida endophthalmitis associated with intraocular lens implantation: efficacy of fluconazole therapy

Summary. Four patients with Candida parapsilosis endophthalmitis following intraocular lens implantation were treated with oral fluconazole. All had failed prior therapy with intravitreal amphotericin B. The only patient who had the lens implant removed was cured after treatment with fluconazole for one year. Three patients who did not have the lens implant removed had resolution of symptoms and return of visual acuity towards normal during the year they were on fluconazole. However, five months after therapy had been stopped, all three had decreasing visual acuity, and in two, culture of vitreous fluid yielded C. parapsilosis. Fluconazole may be effective for treatment of endophthalmitis associated with an intraocular lens implant, but only when the implant is removed also.
Vasoconstrictor endothelin receptors characterized in human renal artery and vein in vitro

1 We have identified the endothelin receptors present in the media of human main stem renal artery and vein and characterized the subtypes mediating vasoconstriction in these blood vessels in vitro. 2 Messenger RNA encoding both ETA and ETB receptors was identified in the smooth muscle layer of human renal artery and vein by reverse transcriptase‐polymerase chain reaction assay. In cryostat‐cut cross‐sections of both vessels autoradiographical visualisation suggested a majority of ETA receptors. Intense binding was obtained to the non‐selective ligand [125I]‐ET‐1 and the ETA‐selective [125I]‐PD151242 but only weak labelling of sites by the ETB‐selective [125I]‐BQ3020. 3 ET‐1 potently constricted renal artery and vein preparations with EC50 values of 4.06 nm and 1.00 nm, respectively. Sarafotoxin 6b was approximately ten times less potent than ET‐1 with EC50 values of 36.3 nm and 13.8 nm respectively. In the renal artery, ET‐3 and sarafotoxin 6c showed little or no activity up to 300 nm. Responses to these peptides were more variable in the renal vein. Preparations from three individuals did not respond to ET‐3 but in three further cases, although ET‐3 was much less potent than ET‐1, full dose‐response curves were obtained. S6c elicited dose‐related contractions in vein preparations from 5/6 individuals and although more potent than ET‐1, the maximum response was 30–60% of that obtained to ET‐1. 4 ET‐1‐induced vasoconstriction of renal artery and vein was antagonized by the ETA‐selective, BQ123 (3–10μm). The dose‐response curves to ET‐1 were displaced in a parallel rightward fashion with no attenuation of the maximum responses. pA2 values were estimated to be 6.8 ± 0.1 and 6.8 ± 0.4 for artery and vein respectively. 5 These data suggest that mRNA encoding both ETA and ETB receptors is present in the media of human main stem renal artery and vein. However, autoradiographical studies indicate that the majority of ET receptors expressed are of the ETA subtype. The relative potencies of ET‐1 and ET‐3 as vasoconstrictors of renal blood vessels in vitro is consistent with this being an ETA‐mediated response, and therefore whilst responses to S6c indicate that constrictor ETB receptors may be present in renal veins from some individuals these are likely to be of less importance in these blood vessels.
Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world

Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1948. The frequencies of the common alleles of the apoE gene were (with 95% confidence intervals) ϵ2 = 0.085 (0.068–0.105), ϵ3 = 0.741 (0.712–0.769), and ϵ4 = 0.174 (0.150–0.200). These frequencies were compared to findings in 45 other study populations around the world (n > 100). The Danish population was found to cluster with populations from Iceland, Norway, Iceland, Scotland, the Netherlands, Germany, France (Paris), and Caucasian populations in Canada and the USA. The compiled data further show that dissimilarities in apoE allele frequencies among Caucasian populations are comparable to dissimilarities between some Caucasian and Asian populations. Notably, the frequency of ϵ4 appears to be higher in northern regions of Europe (the Nordic countries, Scotland, Germany, and the Netherlands) than in southern regions (Switzerland, Tyrol, France [Nancy], Italy, and Spain). © 1992 Wiley‐Liss, Inc.
Differences in Vital Signs Between Elderly and Nonelderly Patients Prior to Ward Cardiac Arrest

Objectives:Vital signs and composite scores, such as the Modified Early Warning Score, are used to identify high-risk ward patients and trigger rapid response teams. Although age-related vital sign changes are known to occur, little is known about the differences in vital signs between elderly and nonelderly patients prior to ward cardiac arrest. We aimed to compare the accuracy of vital signs for detecting cardiac arrest between elderly and nonelderly patients. Design:Observational cohort study. Setting:Five hospitals in the United States. Patients:A total of 269,956 patient admissions to the wards with documented age, including 422 index ward cardiac arrests. Interventions:None. Measurements and Main Results:Patient characteristics and vital signs prior to cardiac arrest were compared between elderly (age, 65 yr or older) and nonelderly (age, < 65 yr) patients. The area under the receiver operating characteristic curve for vital signs and the Modified Early Warning Score were also compared. Elderly patients had a higher cardiac arrest rate (2.2 vs 1.0 per 1,000 ward admissions; p < 0.001) and in-hospital mortality (2.9% vs 0.7%; p < 0.001) than nonelderly patients. Within 4 hours of cardiac arrest, elderly patients had significantly lower mean heart rate (88 vs 99 beats/min; p < 0.001), diastolic blood pressure (60 vs 66 mm Hg; p = 0.007), shock index (0.82 vs 0.93; p < 0.001), and Modified Early Warning Score (2.6 vs 3.3; p < 0.001) and higher pulse pressure index (0.45 vs 0.41; p < 0.001) and temperature (36.4°C vs 36.3°C; p = 0.047). The area under the receiver operating characteristic curves for all vital signs and the Modified Early Warning Score were higher for nonelderly patients than elderly patients (Modified Early Warning Score area under the receiver operating characteristic curve 0.85 [95% CI, 0.82–0.88] vs 0.71 [95% CI, 0.68–0.75]; p < 0.001). Conclusions:Vital signs more accurately detect cardiac arrest in nonelderly patients compared with elderly patients, which has important implications for how they are used for identifying critically ill patients. More accurate methods for risk stratification of elderly patients are necessary to decrease the occurrence of this devastating event.
Switching CA/OS CFAR using neural network for radar target detection in non-homogeneous environment

This paper presents the switching CA/OS CFAR using neural network for improving the radar target detection in non-homogeneous environment. This method uses one of between CA-CFAR and OS-CFAR as output threshold depends on the nearest value with the output of neural network. The neural network used in this research is the Multi-Layer Perceptron (MLP) consisted of two hidden layers. The input of neural network was as many as 3 consisted of CA and OS CFAR and Cell Under Test (CUT) value. The pattern of those inputs will be classified and recognized by the neural network by the training to calculate the preliminary threshold. That threshold will be compared to CA and OS CFAR to select the best final threshold. The method was examined with three simulated common radar cases including homogeneous background, multi target and clutter wall environment. The experiments show that the proposed method is capable to select properly based on the best performance of both CA and OS CFAR in homogeneous and non-homogeneous environments.
Medical versus surgical treatment of asymptomatic carotid stenosis: the ever-changing nature of evidence-based medicine.

Randomized trials have shown that prophylactic carotid endarterectomy (CEA) in patients with asymptomatic carotid stenosis (ACS) moderately reduces stroke risk compared with medical management alone provided that the procedural morbidity and mortality does not exceed 3%. These results provided “evidence-supported” armor to increasingly perform CEA on patients with ACS despite opposition questioning the marginal benefit from surgery and its cost-effectiveness. These trials were conducted in the 1980s to early 2000s, a time when aspirin was the sole antiplatelet therapy, and before the emergence of statins, angiotensin-converting enzyme inhibitors, and new antihypertensive agents. Medical therapy has changed dramatically since, and the annual rates of stroke in medically treated patients with ACS have fallen from 2% to 2.5% to <1% in recent years with the advent of modern medical therapy and its increased use, improved management of vascular risk factors, and decline in smoking.1,2 Conversely, stroke risk after carotid revascularization remained unchanged over the last 2 decades. That medical treatment is now as effective as CEA in the majority of patients with ACS is …