Miracle-dz/UniFAR-FTUs huggingface dataset:
Frequent p53 alterations but low incidence of ras mutations in UV-B-induced skin tumors of hairless mice.

We have investigated UV-B-induced skin tumors of hairless SKH-HRA mice for alterations in the p53 gene and for mutations in either of the three ras genes. Out of 32 tumors screened, only one contained a ras mutation, i.e. in codon 12 of the K-ras gene. Alterations in the p53 gene were much more abundant, as illustrated immunohistochemically by the accumulation of p53 protein in 75% of the tumor sections examined. Immunoreactivity was observed primarily in the proliferative cell compartment, but no clear correlation between p53 staining in tumor cells and histological parameters for malignancy was observed. Subsequent sequence analysis showed that point mutations in the p53 gene are detectable in 30% (nine out of 30) of the skin tumors examined. The majority of the mutations are located in codons 267 and 272, most likely originating from UV-B-induced photo-adducts at dipyrimidine sites in the non-transcribed strand. Codon 272 corresponds to the human codon 278, which is also a hotspot for p53 mutations in human non-melanoma skin cancers. Codon 267 matches the human codon 273, which does not contain a dipyrimidine site, but represents a CpG hotspot for p53 mutations in internal malignancies. Our results demonstrate that this hairless mouse model for UV-induced skin cancer corresponds closely to human non-melanoma skin cancers with respect to mutations in the p53 gene.
How much immunosuppression is needed after liver transplantation?

To the editor The randomized controlled trial (RCT) by Ramirez et al. (1) compared two immunosuppression regimens after liver transplantation (LT): basiliximab induction, full-dose tacrolimus, and mycophenolate with or without steroids. However, after LT, acute cellular rejection is no longer a major cause of graft loss, while renal impairment, infections, cardiovascular events, and malignancy form a rising burden. Thus, the immunosuppression regimens used in this RCT can be considered “too aggressive. ” Indeed, the systematic use of induction immunosuppression is not supported in the literature and is currently used in only 30.8% of patients in the United States (2). Moreover, previous studies using basiliximab induction or evaluating mycophenolate in LT allowed either to delay the introduction or decrease the exposure to tacrolimus to prevent toxicity (3, 4). However, in the current RCT (1), the mean trough concentrations of tacrolimus within the first month were as high as 11.3 ng/mL in the four immunosuppressant arm (1). In a recent meta-analysis of 32 RCT, tacrolimus trough concentrations 6–10 ng/mL had similar antirejection effects and halved renal impairment rates (5). Furthermore, in a prospective study including 493 LT patients, there was longer graft survival with mean tacrolimus trough concentrations 7–10 ng/mL within the first two wk after liver transplantation, compared with >10 ng/ mL (6). In the current RCT (1), acute cellular rejection rates using protocol biopsies were 5% (1), whereas a previous RCT with less immunosuppression and protocol biopsies had rejection rates 40–50% (7), despite there was a slightly better five-yr graft survival with less immunosuppression (74.4–78.2% vs. 63–75%). The complete suppression of acute cellular rejection early after LT is not needed and could be deleterious in terms of long-term graft tolerance. Indeed, in the current RCT, there was more infection (60%), more new onset diabetes (40%), and more severe cholestatic HCV recurrence (28%) (1), suggesting over immunosuppression. Recent evidence for immunosuppression after LT suggests the use of less drugs and dosage: reduced tacrolimus (i.e., 7–10 ng/mL within the first month after LT) with or without mycophenolate and/or tapering steroids should be sufficient in most patients (5, 6). Basiliximab induction can be used if there is pre-/perioperative renal dysfunction to minimize exposure to tacrolimus early after LT.
Rotational kinematics of the human vestibuloocular reflex. III. Listing's law.

1. Do slow phase eye velocities generated by the vestibuloocular reflex (VOR) depend on eye position? If the purpose of the VOR is simply to stabilize the retinal image, there can be no such dependence, because eye velocity must always be equal and opposite to head velocity. But if the VOR tolerates some retinal slip to achieve other goals, such as reducing eye velocity or following Listing's law, then one should see specific patterns of dependence. We examined VOR responses of human subjects to yaw, pitch, and roll rotation looking in various directions to quantify how the input-output properties of the VOR vary with eye position. 2. Eye rotation axes during yaw and pitch tilted in the same direction as the gaze line but only one-quarter as far on average. Thus, during yaw head rotation, the axis of eye rotation was roughly aligned with the head axis when the subject looked straight ahead, but tilted up when the gaze direction was up, and down when gaze was down. The amount of tilt varied between subjects, but on average a 30 degrees change in eye position caused a 7.5 degrees tilt in the eye rotation axis. During pitch, the eye axis tilted right when gaze was right and left when gaze was left, also moving 7.5 degrees on average for a 30 degrees change in the gaze direction. 3. During roll stimulation, the axis of eye rotation tilted in the opposite direction to the gaze line, and about one-half as far. On average, when the gaze line moved 30 degrees down, the eye rotation axis tilted 12.0 degrees up; when the gaze moved 30 degrees left, the eye axis tilted 15.3 degrees right. 4. It is often argued that the torsional VOR is weak because head rotation about the line of sight causes little image displacement on the fovea. But the line of sight is collinear with the torsional axis only when the subject looks straight ahead. Does the "weak axis" of the VOR stay collinear with the gaze line when the subject looks eccentrically? We calculated the axis of head rotation for which the VOR response is weakest and found that it does vary with eye position, but does not stay parallel with the gaze direction. When subjects looked straight ahead, the weak axis was roughly collinear with the gaze line; when gaze shifted eccentrically, the weak axis shifted in the same direction but only about one-half as far. (ABSTRACT TRUNCATED AT 400 WORDS)
Characterization of Xylose Uptake in the Yeasts Pichia heedii and Pichia stipitis

The kinetics of xylose uptake were investigated in the efficient xylose fermenter Pichia stipitis and in the more readily genetically manipulated, strictly respiratory yeast Pichia heedii. Both yeasts demonstrated more than one xylose uptake system, differing in substrate affinity. The Km of high-affinity xylose uptake in both organisms was similar to that of the efficient high-affinity glucose uptake system of Saccharomyces cerevisiae. In P. heedii, low-affinity xylose uptake was enhanced with growth on 2% but not 0.05% xylose and high-affinity uptake was reduced. In contrast to glucose uptake, xylose uptake in P. heedii was inhibited by dinitrophenol. Dinitrophenol inhibited both glucose and xylose uptake by P. stipitis. Glucose uptake was not inhibited by a 100-fold molar excess of xylose in P. heedii. It is suggested that xylose uptake in P. heedii is via a carrier system(s) distinct from those for glucose uptake.
Functional rat bladder regeneration through xenotransplantation of the bladder acellular matrix graft.

OBJECTIVE To determine the decreased antigenicity of the bladder acellular matrix graft (BAMG) through xenotransplantation and to assess the in vivo and in vitro functional properties of the rat urinary bladder thus regenerated. MATERIALS AND METHODS After partial cystectomy (> 50%), BAMGs prepared from hamster, rabbit and dog urinary bladders were grafted to male and female Sprague-Dawley rats; 10 control rats underwent partial cystectomy only. Urinary storage and voiding function were monitored in 15 animals using a specially designed 'micturition cage' and cystometry. After 4 months, organ-bath studies and histological techniques were used to evaluate bladder regeneration in vitro in the grafted animals. RESULTS Clinically relevant antigenicity was not evident; no animal died from rejection and all bladder wall components regenerated in all BAMG xenografts. However, the degree and quality of regeneration varied. Muscularization, peak pressure, and bladder capacity were higher in the hamster BAMG-grafted animals, whereas in vitro contractility and compliance were best in the dog BAMG-regenerated bladders. All grafted bladders had significantly better capacity and compliance than the autoregenerated bladders after partial cystectomy alone. CONCLUSIONS The present in vivo and in vitro studies show that BAMG-augmentation cystoplasty can lead to morphological and functional regeneration of the rat bladder, preserving its low-pressure reservoir function. Because BAMG-regenerated bladders show functional innervation that is similar to normal bladders, they can work in coordination with the host bladder components, thus generating adequate intravesical pressure to produce sustained voiding. The decreased antigenicity makes heterologous BAMG transplants feasible without immunosuppression.
The Influence of Concentration/Meditation on Autonomic Nervous System Activity and the Innate Immune Response: A Case Study

Objective In this case study, we describe the effects of a particular individual’s concentration/meditation technique on autonomic nervous system activity and the innate immune response. The study participant holds several world records with regard to tolerating extreme cold and claims that he can influence his autonomic nervous system and thereby his innate immune response. Methods The individual’s ex vivo cytokine response (stimulation of peripheral blood mononuclear cells with lipopolysaccharide [LPS]) was determined before and after an 80-minute full-body ice immersion during which the individual practiced his concentration/meditation technique. Furthermore, the individual’s in vivo innate immune response was studied while practicing his concentration/mediation technique during human endotoxemia (intravenous administration of 2 ng/kg LPS). The results from the endotoxemia experiment were compared with a historical cohort of 112 individuals who participated in endotoxemia experiments in our institution. Results The ex vivo proinflammatory and anti-inflammatory cytokine response was greatly attenuated by concentration/meditation during ice immersion, accompanied by high levels of cortisol. In the endotoxemia experiment, concentration/meditation resulted in increased circulating concentrations of catecholamines, and plasma cortisol concentrations were higher than in any of the previously studied participants. The individual’s in vivo cytokine response and clinical symptoms after LPS administration were remarkably low compared with previously studied participants. Conclusions The concentration/meditation technique used by this particular individual seems to evoke a controlled stress response. This response is characterized by sympathetic nervous system activation and subsequent catecholamine/cortisol release, which seems to attenuate the innate immune response.
Predicting binding affinities of diverse pharmaceutical chemicals to human serum plasma proteins using QSPR modelling approaches

Abstract The prediction of the plasma protein binding (PPB) affinity of chemicals is of paramount significance in the drug development process. In this study, ensemble machine learning-based QSPR models have been established for a four-category classification and PPB affinity prediction of diverse compounds using a large PPB dataset of 930 compounds and in accordance with the OECD guidelines. The structural diversity of the chemicals was tested by the Tanimoto similarity index. The external predictive power of the developed QSPR models was evaluated through internal and external validations. In the QSPR models, XLogP was the most important descriptor. In the test data, the classification QSPR models rendered an accuracy of >93%, while the regression QSPR models yielded r2 of >0.920 between the measured and predicted PPB affinities, with the root mean squared error <9.77. Values of statistical coefficients derived for the test data were above their threshold limits, thus put a high confidence in this analysis. The QSPR models in this study performed better than any of the previous studies. The results suggest that the developed QSPR models are reliable for predicting the PPB affinity of structurally diverse chemicals. They can be useful for initial screening of candidate molecules in the drug development process.
Angioregressive Pretreatment of Mature Corneal Blood Vessels Before Keratoplasty: Fine-Needle Vessel Coagulation Combined With Anti-VEGFs

Purpose: To evaluate the efficacy and safety of combined feeder vessel coagulation and topical antiangiogenic therapy using bevacizumab in the treatment of mature corneal blood vessels. Methods: Sixteen eyes of 16 patients with mature corneal neovascularization (NV) due to different underlying corneal diseases underwent fine-needle feeder vessel coagulation by diathermy and were treated postoperatively for up to 4 weeks with topical bevacizumab eye drops (containing 5 mg/mL bevacizumab) 5 times a day. Nine patients received an additional subconjunctival bevacizumab injection at the time of cautery. Results: The mean duration of follow-up was 276 ± 147.3 days (range, 29–464 days). Regression of the feeder vessel was observed in 14 eyes. The vascularized area was reduced significantly (P < 0.05). Combined subconjunctival and eye drop antivascular endothelial growth factor treatment was significantly more effective in reducing the vascularized area compared with antivascular endothelial growth factor eye drop therapy alone (P < 0.05). Five patients (5 eyes) needed a second treatment. Thirteen patients (13 eyes) receiving topical bevacizumab treatment combined with feeder vessel coagulation showed stable visual acuity. Two patients had improved visual acuity. One patient had enlarged area of lipid keratopathy despite successful treatment of corneal NV and thus decreased visual acuity. Overall, there was a nonsignificant improvement of best-corrected visual acuity (P > 0.05). Conclusions: In this pilot study, fine-needle feeder vessel coagulation combined with topical bevacizumab application for treatment of mature corneal NV seemed to be a well-tolerated new treatment option to regress corneal NV. This may not only improve corneal transparency but also “preconditions” such a cornea for future keratoplasty.
A new data mining approach for profiling and categorizing kinetic patterns of metabolic biomarkers after myocardial injury

MOTIVATION The discovery of new and unexpected biomarkers in cardiovascular disease is a highly data-driven process that requires the complementary power of modern metabolite profiling technologies, bioinformatics and biostatistics. Clinical biomarkers of early myocardial injury are lacking. A prospective biomarker cohort study was carried out to identify, categorize and profile kinetic patterns of early metabolic biomarkers of planned myocardial infarction (PMI) and spontaneous (SMI) myocardial infarction. We applied a targeted mass spectrometry (MS)-based metabolite profiling platform to serial blood samples drawn from carefully phenotyped patients undergoing alcohol septal ablation for hypertrophic obstructive cardiomyopathy serving as a human model of PMI. Patients with SMI and patients undergoing catheterization without induction of myocardial infarction served as positive and negative controls to assess generalizability of markers identified in PMI. RESULTS To identify metabolites of high predictive value in tandem mass spectrometry data, we introduced a new feature selection method for the categorization of metabolic signatures into three classes of weak, moderate and strong predictors, which can be easily applied to both paired and unpaired samples. Our paradigm outperformed standard null-hypothesis significance testing and other popular methods for feature selection in terms of the area under the receiver operating curve and the product of sensitivity and specificity. Our results emphasize that this new method was able to identify, classify and validate alterations of levels in multiple metabolites participating in pathways associated with myocardial injury as early as 10 min after PMI. AVAILABILITY The algorithm as well as supplementary material is available for download at: www.umit. at/page.cfm? vpath=departments/technik/iebe/tools/bi
Ant-Tree: an ant colony optimization approach to the generalized minimum spanning tree problem

The ant colony optimization is a meta-heuristic inspired by knowledge sharing amongst ants using pheromone, which serves as a kind of collective memory. Since the past few years, there have been several successful applications of this new approach for finding approximate solutions for computationally difficult problems in reasonable times. In this paper, we study the generalized minimum spanning tree problem that involves the design of a minimum weight connected network spanning at least one node out of every disjoint subset of the nodes in a graph. This problem has a wealth of pertinence to a wide range of applications in different areas. As the problem is known as computationally challenging, we adopt the ant colony optimization strategy and present a new solution method, called Ant-Tree, to develop approximate solutions. As an initial attempt, our study aims to provide an investigation of the ant colony optimization approach for coping with tree optimization problems. Through computational experiments, we compare the performances of our approach and the method available in the literature. Numerical results indicate that the proposed method is effective in producing quality approximate solutions.
Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome.

BACKGROUND & AIMS Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients. METHODS Participants underwent 5-day baseline and 5-day treatment periods; gastrointestinal transit (by validated scintigraphy) and bowel function (by daily diaries) were assessed. Treatment effects were compared using analysis of covariance (baseline colonic transit as covariate) with pairwise comparisons of each dose vs placebo. RESULTS There was a significant overall treatment effect on ascending colon emptying half-time (P = .015) and overall colonic transit at 48 hours (P = .02) but not overall transit at 24 hours (P = ns), with a significant acceleration by linaclotide 1000 microg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-microg dose. There were significant overall treatment effects on stool frequency, stool consistency, ease of passage, and time to first bowel movement with a strong dose response for stool consistency (overall, P < .001). No safety issues were identified. CONCLUSIONS In women with constipation-predominant irritable bowel syndrome, linaclotide 1000 microg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.
De facto exchange-rate regimes in Central and Eastern European Countries

This paper attempts to identify implicit exchange rate regimes for currencies of new European Union (EU) countries vis-a-vis the euro. To that end, we apply three sequential procedures that consider the dynamics of exchange rates to data covering the period from 1999:01 to 2012:12. Our results would suggest that implicit bands have existed in many sub-periods for almost all currencies under study. This paper provides new empirical evidence that strengthens the hypothesis of that the implemented policies differ from those announced by the monetary authorities, identifying the existence of de facto fixed monetary systems along large number of sub-periods for different currencies.
Should the lateral chest radiograph be routine in the diagnosis of pneumonia in children? A review of the literature.

OBJECTIVE To assess the evidence of the additive diagnostic value of the lateral chest radiograph to the frontal chest radiograph in children (zero to 18 years) with suspected pneumonia in the emergency department. METHODS The MEDLINE database (1966 to 2001) was searched to identify the highest level of evidence available in support of the lateral. The key words used included chest radiograph, pneumonia and chest x-ray. RESULTS Only four controlled studies were identified that assessed the role of the lateral chest x-ray. Three of these studies were retrospective. In the first study, the addition of the lateral to the frontal chest x-ray in 414 children would have detected an additional nine patients (2.3%) with pneumonia. In the second study, involving 179 patients, a high level of agreement was found between the interpretations based on the frontal chest x-ray alone and those based on both views. A third study of 359 children assessed the criterion validity of a frontal chest x-ray alone. Based upon a radiologist's interpretation of both views as the gold standard, the sensitivity of the frontal view alone was 86%. A fourth study of 158 children with suspected pneumonia revealed that the frontal view alone was diagnostic of pneumonia in 106 of 109 (97%) patients. CONCLUSION There is no randomized controlled trial evidence to support the additive value of the lateral to the frontal chest x-ray in the diagnosis of children with pneumonia. Further prospective studies are required to determine if the addition of the lateral chest x-ray will modify therapy, prevent complications or whether it is cost-efficient.
Nuclear GSK‐3β segregation in desmoid‐type fibromatosis

Desmoid‐type fibromatosis (DF) is a rare benign myofibroblastic neoplasm of the connective tissue that is unable to metastasize but is associated with a high local recurrence rate. Nuclear β‐catenin is the most commonly used histological marker of DF; however, clinical and biological predictive markers guiding the treatment and follow‐up of DF are still lacking. Normally, β‐catenin is regulated by the cytoplasmic multiprotein complex of adenomatous polyposis coli (APC), axin, casein kinase 1α (CK1α), and glycogen synthase kinase 3β (GSK‐3β); this phosphorylates and degrades β‐catenin, which would otherwise translocate to the nucleus. The aim of this study was to analyse the expression and localization of the β‐catenin–protein complex of the Wnt pathway in cells isolated from DF patients.