gebhart/patrepeval huggingface dataset:
Novel mutations target distinct subgroups of medulloblastoma (2012)

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
The correlation between run-up and repose times of volcanic eruptions (2012)

Volcanoes usually show signs of unrest before an eruption. Establishing physical controls on the duration of precursory activity, that is run-up time, could improve understanding of the dynamics of magma ascent from a shallow magma reservoir to the surface. Another observable indicative of eruption dynamics is the interevent repose time, that is, the time between magmatic eruptions. The repose time could be associated with the mechanism that recharges the magmatic system. Both of these quantities depend on magma viscosity and hence magma composition in addition to other factors. In this work we investigate the interrelationship between run-up time, repose time and silica content by compiling a database of 73 magmatic eruptions from 34 different volcanoes around the world. Run-up and repose time are correlated with ~40 per cent of the variance in the data well explained by a linear correlation. Both of these quantities are significantly correlated with silica content, but although repose times and silica content are highly correlated, run-up times show a weaker correlation with silica content. The data range from basaltic to dacitic with a preponderance of low silica eruptions, so we can investigate the gross influence of viscosity in controlling both run-up and repose time. We also investigate the role of volume erupted finding repose times correlated with the erupted volumes. The trends are clearest when comparing a large range of silica on the global data set and appear to be obscured by other processes for subsets that cover only a small range of silica contents. High silica, and thus by inference high viscosity, systems have longer repose and run-up times and tend to erupt larger quantities of material. The observed interrelationships can provide new insights for constraining physical and probabilistic models for volcanic hazard mitigation.
Regulatory T Cells (Treg) Are Depressed in Patients with Relapsed/Refractory Multiple Myeloma (MM) and Increases towards Normal Range in Responding Patients Treated with Lenalidomide (LEN). (2008)

Abstract CD4+CD25+Foxp3+ regulatory T cells (Tregs) are a group of immune-suppressive T cells responsible for the maintenance of self-tolerance and autoimmunity. Increased Tregs have been implicated in suppression of tumour-immunity, and are associated with poor prognosis in gastric, oesophageal and ovarian cancers. Conversely, reduced Tregs are associated with aggressive disease and poor prognosis in lymphoproliferative disorders such as follicular lymphoma and Hodgkin lymphoma. Meanwhile, conflicting literature exists with regards to the role of Tregs in the pathogenesis of multiple myeloma (MM). Lenalidomide (LEN) is an immunomodulatory drug (ImiD™) that increases T cell numbers and function in vitro but the impact on Tregs in vivo is unknown. As part of an ongoing clinical trial of low-dose lenalidomide, peripheral blood lymphocyte subsets (LSS) and Treg numbers were examined in patients [n=18, median age 67 years (49–77)] with relapsed/refractory MM at baseline and at various time points during treatment with combination LEN (15mg/o/d d1–21q28)-dexamethasone (dex) (20mg/o/d d1–4,9–12,17–20 q28), in order to measure changes induced by LEN-dex treatment. Results were compared to 10 age matched healthy donors. LSS and Tregs were assessed by flow cytometry, with Tregs strictly defined as CD4+CD25hiCD127dimFOXP3+. At baseline, MM patients had depressed B cells (median 0.76 vs. 3.2 ×105/ml; p=0.02) and CD3+ T cells (median 7.2 vs. 12.1 ×105/ml; p&amp;lt;0.001) compared to healthy donors, with an inverse CD4:CD8 T cell ratio (0.7:1 vs. 2.9:1, p=0.008). Tregs in MM patients were markedly reduced at baseline compared to healthy donors [median 0.40 (range: &amp;lt;0.01–1.9) vs. 4.8 (range 2.4–7.1) ×104/ml; p=0.0005]. In 11 patients completing at least 4 treatment cycles, no recovery of B cells (7.6 vs. 2.3 ×105/ml, p=0.053), NK cells (2.1 vs. 2.7×105/ml, p=0.1) or T cells (5.6 at baseline vs. 7.5 × 105/ml, p=0.45) were seen despite all achieving at least a PR (one with IF negative CR). In contrast, median Treg numbers progressively increased towards normal range, from a baseline of 0.3 to 1.3 × 104/ml (p=0.005) and 2.0 × 104/ml (p=0.009) after 4 (n=11) and 6 (n=7) cycles of LEN-dex respectively (figure 1). Patients with relapsed/refractory MM have profoundly disturbed LSS including marked decreased in Treg numbers. Normalisation of Treg numbers in responding patients treated with LENdex suggest that, as in other tumours, Tregs are actively involved in the pathophysiology of MM and their modulation may be an important component of the immunomodulatory mechanisms of LEN. Figure 1: Change in regulatory T cell (Treg) numbers with each cycle of LEN-dex in MM patients Figure 1:. Change in regulatory T cell (Treg) numbers with each cycle of LEN-dex in MM patients
Blood-borne miRNA profile-based diagnostic classifier for lung adenocarcinoma (2016)

Accumulated evidence indicates that various types of miRNA are aberrantly expressed in lung cancer and secreted into the bloodstream. For this study, we constructed a serum diagnostic classifier based on detailed bioinformatics analysis of miRNA profiles from a training cohort of 143 lung adenocarcinoma patients and 49 healthy subjects, resulting in a 20 miRNA-based classifier. Validation performed with an independent cohort of samples from lung adenocarcinoma patients (n = 110), healthy subjects (n = 52), and benign pulmonary disease patients (n = 47) showed a sensitivity of 89.1% and specificity of 94.9%, with an area under the curve value of 0.958. Notably, 90.8% of Stage I lung adenocarcinoma cases were correctly diagnosed. Interestingly, this classifier also detected squamous and large cell lung carcinoma cases at relatively high rates (70.4% and 70.0%, respectively), which appears to be consistent with organ site-dependent miRNA expression in cancer tissues. In contrast, we observed significantly lower rates (0-35%) using samples from 96 cases of cancer in other major organs, with breast cancer the lowest. These findings warrant a future study to realize its clinical application as a part of diagnostic procedures for lung cancers, for which early detection and surgical removal is presently the only hope for eventual cure.
Use of restenting should be minimized with intracoronary radiation therapy for in‐stent restenosis (2003)

Restenting at the time of intracoronary radiation therapy (IRT) for in-stent restenosis (ISR) potentially increases the risk of late total occlusion (LTO) of the treated vessel. Prolonged antiplatelet therapy with clopidogrel (6 months) has been shown to be effective in reducing LTO risk. The purpose of this study was to assess the impact of restenting on clinical outcomes following IRT for ISR with 6 months of clopidogrel. We retrospectively evaluated 1,275 patients with 6-months clinical follow-up who were enrolled in radiation trials for ISR using gamma- and beta-emitters conducted at Washington Hospital Center. Patients were analyzed according to whether additional stents were deployed at the time of IRT. The predominant indication for restenting was to optimize the final angiographic result in the event of tissue prolapse or to cover edge dissections. All patients received a minimum of 6 months of clopidogrel. Baseline clinical and angiographic characteristics were similar between the restented and nonrestented groups. Radiation was delivered successfully in all cases. At 6 months, patients treated with additional stents and IRT had a significantly higher rate of target vessel revascularization than patients without additional stents (24.6% vs. 18.7%; P = 0.011). Restenting caused more frequent late thrombosis, late total occlusion, and Q-wave myocardial infarction than no restenting (4.0% vs. 2.2%, P = 0.09; 6.1% vs. 4.3%, P = 0.14; and 1.9% vs. 0.4%, P = 0.009, respectively). Restenting for the treatment of ISR is associated with increased adverse events and should be avoided after intracoronary radiation therapy for in-stent restenosis, as restenting results in a higher recurrence rate and the potential for increased late total occlusion.
Using clock changes in multi-path applications (2002)

This paper studies an alternative to the Watterson (1970) model for multi-path channels. The new model is based on the introduction of random delays. This model is shown to well-represent different kinds of spectra. An application is presented in the case of backscattering from sea surface at small grazing angles of incidence. This clock change-based model allows one to well-describe the physical phenomenon.
A Templating System to Generate Provenance (2017)

PROV-TEMPLATEIS a declarative approach that enables designers and programmers to design and generate provenance compatible with the PROV standard of the World Wide Web Consortium. Designers specify the topology of the provenance to be generated by composing templates, which are provenance graphs containing variables, acting as placeholders for values. Programmers write programs that log values and package them up in sets of bindings, a data structure associating variables and values. An expansion algorithm generates instantiated provenance from templates and sets of bindings in any of the serialisation formats supported by PROV. A quantitative evaluation shows that sets of bindings have a size that is typically 40 percent of that of expanded provenance templates and that the expansion algorithm is suitably tractable, operating in fractions of milliseconds for the type of templates surveyed in the article. Furthermore, the approach shows four significant software engineering benefits: separation of responsibilities, provenance maintenance, potential runtime checks and static analysis, and provenance consumption. The article gathers quantitative data and qualitative benefits descriptions from four different applications making use of PROV-TEMPLATE. The system is implemented and released in the open-source library ProvToolbox for provenance processing.
Maturational Effects of Gonadotropins on the Cumulus-Oocyte Complex of the Rat (1979)

The temporal relationship between maturational events in the cumulus oophorus and the oocyte of adult rats was examined. The time of preovulatory surge of LH was estimated from analysis of the critical period. Cyclic rats were killed on the afternoon and night of proestrus; hCG-treated rats were injected during the early morning hours of proestrus and were killed up to 13 h later. At necropsy, the ovaries were removed and the oocytes with their cumuli were isolated from the large preovulatory follicles. The intercellular mucification and tissue dissociation characteristic of cumuli around ovulated oocytes began to appear 4.24 ± 0.15 h after endogenous LH secretion or 4.31 ± 0.25 h after hCG. Transformation of the cumulus started at its periphery and spread centripetally. By 5.70 ± 0.21 and 7.17 ± 0.34 h, respectively, the cumuli had completed their differentiation. Maturation of the oocytes began before and ended after maturation of the cumuli. Timing of the maturational events preceding spontaneous cyclic ovulation and hCG-induced ovulation was similar. Small differences were attributed to differences in circulating levels of gonadotropin as a function of time. It was concluded that cumulus maturation is induced by the ovulatory surge of LH.
Robust seed-based stroke width transform for text detection in natural images (2015)

Text detection in natural scene images is challenging due to the significant variations of the appearance of the text itself and its interaction with the context. The popular stroke width transform (SWT) algorithm is highly efficient but sensitive to the defects of the edges extracted from the input image when searching for the matching edge pixels for computing potential stroke width. In this paper, we propose a novel seed-based variant of SWT that enhances significantly the robustness of the original algorithm to complicated image contextual interference and varied text appearance. We first search for the seed segment of strokes, which is defined as a consecutive sequence of neighbouring rays (pairs of edge pixels) with regular length and satisfying certain constraints, and grow from them to localize more stroke segments. We then exploit the principal width and direction information of stroke captured by the stroke segments detected to rectify inaccurate stroke width and recover missed stroke parts, which are resulted from erroneous and noisy edges in complex natural images. The stroke segments detected are also exploited to improve the accuracy of candidate character localization. The experimental results on public datasets demonstrated the effectiveness of the proposed method.
Accurate stress extraction for nearly incompressible materials by the displacement formulation of the p-version FEM (1996)

Direct methods for computing the pointwise stresses for nearly incompressible elastic materials fail to provide meaningful results when applied to the displacement formulation of the finite element method (FEM). A new extraction method for accurate computation of pointwise stresses for nearly incompressible elastic materials is presented. It is based on the complementary energy principle applied over a local domain in the postprocessing phase in conjunction with the p-version finite element solution. It is shown that accurate pointwise stresses are obtained, that the relative error in the pointwise stresses converges at a rate which is as fast as the relative error measured in the energy norm or faster, and importantly, the extracted stresses are virtually independent of Poisson's ratio. Numerical results for two problems, one having a smooth solution and the other containing a singular point, are provided.
Using copropagating P-waves to extract nonlinear elastic characteristics of rock (2016)

We propose a dynamic method to detect the nonlinear elastic hysteretic characteristics of rock. The method is easily implemented and requires injecting two co-propagating longitudinal waves into the rock and receiving them. One of the waves is a high energy low-frequency longitudinal wave that loads strain in the rock, and a other is the low energy high-frequency longitudinal wave that is used to detect the elastic modulus variation induced by the loaded strain. Analyzing the relationship between elastic modulus variation and the loaded strain, we quantify the nonlinear elastic characteristics of the rock, including the nonlinear coefficients and slow dynamics, and evaluate hysteretic loops. A typical sandstone experiment is displayed and results show the nonlinear coefficients are independent of input amplitude of the longitudinal waves, but slow dynamics are a function of the input amplitude of the low fequency longitudinal waves. Presentation Date: Thursday, October 20, 2016 Start Time: 10:35:00 AM Location: 150 Presentation Type: ORAL
Assessment of Cystine Solubility in Urine and of Heterogeneous Nucleation (1983)

Factors affecting cystine solubility were sought in an effort to derive a reliable method for estimating urinary saturation with respect to cystine. In synthetic solutions, cystine solubility was measured from the maximum ambient cystine concentration reached after incubation with an excess of solid cystine. It rose progressively as the ionic strength increased from addition of mineral electrolytes. The increment in cystine solubility between ionic strength of 0.005 and 0.3 ranged from 13 mg./1. for potassium chloride to 70 mg./1. for calcium chloride. Urinary macromolecules (less than 5,000 daltons, obtained by ultrafiltration), at concentrations normally expected to be found in urine, increased cystine solubility by as much as 45 mg./1. Because of these actions of electrolytes and macromolecules, cystine solubility in urine (from control subjects and patients with cystinuria) exceeded solubility in synthetic solution containing 5 mM sodium cacodylate by 68 to 89 mg./1. Thus, the saturation of cystine in individual urine samples cannot be estimated by comparing the original cystine concentration with a defined cystine solubility curve. It may be more accurately measured as the ratio of original cystine concentration and the directly determined cystine solubility in urine. The estimated assessment of urinary saturation with respect to cystine was shown to deviate from the empirically derived measure from -33 to +44 per cent. In conclusion, cystine is more soluble in urine because of the effects of electrolytes and macromolecules. Thus, urinary saturation of cystine cannot be estimated from solubility curves but must be empirically derived from the direct assessment of cystine solubility in individual urine samples.
Chemical synthesis, absolute configuration, and stereochemistry of formation of 10‐hydroxywarfarin: A major oxidative metabolite of (+)‐(r)‐warfarin from hepatic microsomal preparations (1990)

The synthesis of a diastereomerically pure 10-hydroxywarfarin [4-hydroxy-3-(2-hydroxy-3-oxo-1-phenylbutyl)-2H-1 benzopyran-2-one] was accomplished in three steps from racemic warfarin. The relative configuration of the synthetic product was established by conversion to a cyclic derivative followed by NMR and X-ray diffraction analysis. Absolute stereochemistry was determined by enzymatic conversion of either of the pure enantiomers of warfarin to a 10-hydroxy metabolite of known relative configuration. Metabolic formation of 10-hydroxywarfarin was studied using hepatic microsomal preparations from female rats and man. The formation of 10-hydroxywarfarin catalyzed by hepatic microsomes from both dexamethasone-treated rats and man was highly stereoselective [(R)/(S): 3.4-9.0] for (R)-warfarin. In contrast, little stereoselectivity was observed in reactions catalyzed by untreated rat liver microsomes. The resultant stereochemistry at the site of oxidation was also found to be highly dependent on substrate stereochemistry. (R)-Warfarin gave (9R;10S)-10-hydroxywarfarin with only a trace of the (9R;10R) isomer irrespective of which enzyme preparation was used for catalysis, while (S)-warfarin gave (9S;10R)-10-hydroxywarfarin with only a trace of the (9S;10S) isomer, again irrespective of which enzyme preparation was used for catalysis.
The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis (2017)

Tissue damage frequently occurs. The immune system senses it and enforces homeostatic responses that lead to regeneration and repair. The synthesis of acute phase molecules is emerging as a crucial event in this program. The prototypic long pentraxin PTX3 orchestrates the recruitment of leukocytes, stabilizes the provisional matrix in order to facilitate leukocyte and stem progenitor cells trafficking, promotes swift and safe clearance of dying cells and of autoantigens, limiting autoimmunity and protecting the vasculature. These non-redundant actions of PTX3 are necessary for the resolution of inflammation. Recent studies have highlighted the mechanisms by which PTX3 adapts the functions of innate immune cells, orchestrates tissue repair and contributes to select the appropriate acquired immune response in various tissues. Conversely, PTX3 continues to be produced in diseases where the inflammatory response does not resolve. It is therefore a valuable biomarker for more precise and personalized stratification of patients, often independently predicting clinical evolution and outcome. There is strong promise for novel therapies based on understanding the mechanisms with which PTX3 plays its homeostatic role, especially in regulating leukocyte migration and the resolution of inflammatory processes.
Characterization of putative Wnt3a-Inducible Enhancers (2015)

The Wnt signaling pathway has been previously shown to play a major role in regulating bone metabolism and it is emerging as a target for the therapeutic intervention of bone thinning disorders such as osteoporosis. Several Wnt proteins have been shown to be expressed in bone and mutations in Wnt pathway members such as Wnt co-receptor Lrp5 and Wnt inhibitor Sost have been shown to be associated with low or high bone mass disorders, however, very little is known about specific roles played by different Wnt ligands in bone development, repair and remodeling. To identify downstream targets of Wnt signaling we sequence RNA synthesized by Wnt3a treated osteoblasts and found 214 genes to be significantly up-regulated by >2-fold in the presence of Wnt3a ligand. Computational analysis of ChipSeq data in the loci of these 214 genes predicted 163 putative Wnt-inducible enhancers. In this project, we sought to functionally validate these putative enhancer elements that may account for the Wnt3a-dependent activation of these 214 transcripts. Candidate enhancers were cloned, transfected into osteoblast-like cell lines, and examined for transgene expression in the presence and absence of recombinant Wnt3a protein. Preliminary data suggests that several noncoding elements may have enhancer properties both in the absence or presence of Wnt3a, in vitro.
Antibiofilm Activity of Acidic Phospholipase Isoform Isolated from <em>Bothrops erythromelas</em> Snake Venom (2020)

Introduction: Bacterial resistance is a worldwide public health problem, requiring new therapeutic options. An alternative approach to this problem is the use of animal toxins, such as phospholipases (PLA2) isolated from snake venom, which have important biological activities. Bothrops erythromelas is one of the snake species in the Northeast of Brazil that attracts great medical-scientific interest. Here we aimed to purify and characterize a PLA2 from B. erythromelas, searching for heterologous activities against bacterial biofilm. Methods: Venom extraction and quantification were followed by RP-HPLC in C18 column, MALDI-ToF mass spectrometry and sequencing by Edman degradation. All experiments were monitored by specific activity using 4-nitro-3 (octanoyloxy) benzoic acid (4N3OBA) substrate. In addition, hemolytic tests and anti-bacterial tests including action against Escherichia coli, Staphylococcus aureus and Acinetobacter baumannii, were carried out. Moreover, tests of antibiofilm action against A. baumannii were also performed. Results: PLA2, after one purification step, presented 31 N-terminal amino acid residues, and molecular weight of 13656.4 Da with enzymatic activity confirmed in 0.06 &amp;micro;M concentration. Antibacterial activity against S. aureus (IC50 = 30.2 &amp;micro;M) and antibiofilm activity against A. baumannii (IC50 = 1.1 &amp;micro;M) were observed. Conclusions: This is the first time that PLA2 purified from B. erythromelas venom has appeared as an alternative candidate in studies of new antibacterial medicines.
Chapter 15 Economic Considerations (2016)

Economic Considerations"Every time we obtain a sample . . .we make sure there is a piece of paper . . .I take all the risks and put $25 million of investment into the research.I don't want the patient then saying, 'Yeah, but it came from me.' " -