Miracle-dz/UniFAR-FTUs huggingface dataset:
Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies

Systemic sclerosis (SSc) is a fibrosing connective tissue disease with significantly increased mortality. Therapeutic options to treat fibrosis are limited. The small molecule tyrosine kinase inhibitor imatinib and related drugs such as dasatinib and nilotinib target simultaneously two of the major profibrotic pathways, TGFβ- and PDGF- signaling. Imatinib, dasatinib and nilotinib inhibit collagen synthesis in cultured fibroblasts and have potent anti-fibrotic effects in animal models of different fibrotic diseases. Moreover, several case reports, case series and uncontrolled studies on patients with SSc, mixed connective tissue disease, nephrogenic systemic fibrosis and in particular sclerodermatous graft versus host disease (cGvHD) report regression of fibrosis and good tolerability. However, the results of larger controlled trials, which are currently ongoing, are needed before any conclusions on efficacy and tolerability can be drawn. Until the results of these trials are available, we discourage off-label use of Imatinib in single patients.
Heterogeneity of fetal growth in type 1 diabetic pregnancy.

OBJECTIVE To investigate the frequency of macrosomia in an homogeneous cohort of type 1 diabetic mothers and to analyze the influence of maternal factors and glycemic control on the incidence of fetal macrosomia. MATERIAL AND METHODS Fifty-five consecutive type 1 diabetic first-pregnancies were prospectively studied. Macrosomia was defined by a ponderal index above the 90(th) percentile. Venous cord blood levels of insulin, C peptide and leptin were measured at delivery. The influence of HbA1c levels and other maternal variables on the occurrence of macrosomia and on the ponderal index was assessed using a stepwise regression logistic model. RESULTS The mean (+/- SD) birth weight was 3482 (+/- 497) g at 37.4 +/- 1.0 weeks gestation. Macrosomia occurred in 29 cases (53.7%). Fetal insulin, C peptide and leptin levels were significantly higher in macrosomic than in non macrosomic infants. Maternal age, duration of diabetes, pregravid body mass index, parity, weight gain during pregnancy, presence of a microangiopathy, nephropathy, smoking habits, gestational hypertension or preeclampsia, and HbA1c levels throughout pregnancy did not differed between mothers of macrosomic and non macrosomic infants. In the stepwise analysis none of these covariates was explanatory of the ponderal index. CONCLUSIONS The frequency of macrosomia remains very high in infants of type 1 diabetic mothers despite a reasonable degree of glycemic control. The variability of the fetal growth response to mild hyperglycemia prompts for the identification of other factors involved in the modulation of fetal growth.
Attenuation of morphine withdrawal signs by a D1 receptor agonist in the locus coeruleus of rats

In the present study, the effects of intra-locus coeruleus injection of a dopamine D1 receptor agonist (SKF38393) on naloxone-induced withdrawal signs of morphine-dependent rats were examined. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity for comparison. The D1 agonist and antagonist were injected 15 and 30 min prior to expression of naloxone-induced withdrawal signs, respectively. SKF38393 (2 and 4 μg/site) decreased while SCH23390 (a D1 antagonist) had no effect on the total withdrawal score. On the other hand, SCH23390 (25 ng/site) reversed the SKF38393 effect. It may be concluded that activation of dopamine D1 receptors in the locus coeruleus attenuates naloxone-induced withdrawal.
Investing in evolutionary history: implementing a phylogenetic approach for mammal conservation

Under the impact of human activity, global extinction rates have risen a thousand times higher than shown in the fossil record. The resources available for conservation are insufficient to prevent the loss of much of the world's threatened biodiversity during this crisis. Conservation planners have been forced to prioritize their protective activities, in the context of great uncertainty. This has become known as ‘the agony of choice’. A range of methods have been proposed for prioritizing species for conservation attention; one of the most strongly supported is prioritizing those species that maximize phylogenetic distinctiveness (PD). We evaluate how a composite measure of extinction risk and phylogenetic isolation (EDGE) has been used to prioritize species according to their degree of unique evolutionary history (evolutionary distinctiveness, ED) weighted by conservation urgency (global endangerment, GE). We review PD-based approaches and provide an updated list of EDGE mammals using the 2010 IUCN Red List. We evaluate how robust this method is to changes in phylogenetic uncertainty, knowledge of taxonomy and extinction risk, and examine how mammalian species that rank highly in EDGE score are representative of the collective from which they are drawn.
Retinyl acetate inhibits estrogen-induced mammary carcinogenesis in female ACI rats.

Two groups of female ACI rats were placed on powdered AIN-76 diets containing retinyl acetate (412,000 i.u. per kg diet) and two groups of rats were placed on placebo diets. Two weeks later one group from each diet was subcutaneously implanted with a 20 mg pellet containing 1 mg of 17 alpha-ethinylestradiol (EE2) mixed with cholesterol, and the remaining groups received 20 mg cholesterol pellet implants. The four groups of animals were maintained on their respective diet for 24 weeks after pellet implantation. The EE2-treated rats were hyperphagic and weighed less than the cholesterol-treated rats. Retinyl acetate had no effect on food consumption or body wt changes. None of the rats that received pellets composed of cholesterol only exhibited mammary carcinomas (MC) or pituitary tumors. All rats with an EE2 implant had pituitary tumors: 88% of the rats on the placebo diet had one or more MC; 70% of the rats on the retinyl acetate diet had one or more MC. The difference between the two EE2-treated groups for incidence of animals with at least one MC was not significant (chi 2). However, the EE2-treated rats on the placebo diet had approximately twice as many MC as the EE2-treated rats on the retinyl acetate diet. Thus, retinyl acetate inhibited estrogen-induced mammary carcinogenesis in female ACI rats, without evidence of gross toxicity.
Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer

Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer. Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n = 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases. Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning. Clin Cancer Res; 23(16); 4744–52. ©2017 AACR.
Inflation, Tax Rules and Investment: Some Econometric Evidence

This paper presents econometric evidence on the effect of tax incentives on business Investment in the United States in the period from 1953 through1978. The analysis emphasizes that the Interaction of inflation and existing tax rules has contributed substantially to the decline of business investment since the late 1960's.Because the investment process is far too complex for any simple econometric model to be convincing, I have estimated three quite different models of investment behavior. The strength of the empirical evidence rests on the fact that all three specifications support the same conclusion. More generally, the analysis and evidence show that theoretical models of macroeconomic equilibrium should specify explicitly the role of distortionary taxes, especially taxes on capital income. The failure to include such tax rules can have dramatic and misleading effects on the qualitative as well as the quantitative properties of macroeconomic theories. This paper was presented as the Fisher-Shultz Lecture at the Fourth World Congress of the Econometric Society, 29 August 1980, in Aix-en-Province. (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of this item.) (This abstract was borrowed from another version of (This abstract was borrowed from another version of this item.)
Bmp2 is required for migration but not for induction of neural crest cells in the mouse

Bone morphogenetic protein (BMP) signaling is essential for neural crest development in several vertebrates. Genetic experiments in the mouse have shown that Bmp2 is essential for the genesis of migratory neural crest cells. Using several markers and a transgenic reporter approach, we now show that neural crest cells are induced in Bmp2 null mutant embryos, but that these cells fail to migrate out of the neural tube. The absence of migratory neural crest cells in these mutants is not due to their elimination by cell death. The neuroectoderm of Bmp2−/− embryos fail to close and create abnormal folds both along the anterior–posterior and medio–lateral axes, which are associated with an apparent medio–lateral expansion of the neural tube. Finally, our data suggest that the molecular cascade downstream of BMP signaling in early neural crest development may be different in mouse and avian embryos. Developmental Dynamics 236:2493–2501, 2007. © 2007 Wiley‐Liss, Inc.
A PET Design Based on SiPM and Monolithic LYSO Crystals: Performance Evaluation

A new small animal PET based on SiPM and monolithic LYSO crystals has been developed. Eight detector modules form the PET ring, each mounting an array of 12 × 12 SiPMs coupled to a readout providing the summed signals of the pixels on each of the 12 rows and 12 columns of the SiPM array. This design makes it possible to accurately determine the centroid of the scintillation light distribution with about 1.6 mm full width at half maximum (FWHM) resolution without correction for the 1 mm source size, and the photon depth of interaction (DOI) with nearly 2 mm FWHM. This single ring PET system has a homogeneous spatial resolution across the entire 80 mm transaxial field of view (FOV) of about 1 mm FWHM. The noise equivalent count rate (NECR) peak is estimated to occur at around 39.2 MBq with a rate of approximately 82.7 kcps for the mouse-like phantom and 22 kcps at 48.1 MBq for the rat-like phantom. Following the NEMA protocol, the peak absolute sensitivity in the center of the FOV is 2.8% for a 30% peak energy window. A pilot test injecting NaF to a mouse of 20 grams is also presented. Finally, the PET ring has been tested in front of a high field 15.2 T Magnetic Resonance (MR). No significant variation on energy and spatial resolution across the FOV has been observed due to the presence of the magnetic field.
Drug‐Associated Hospital Admissions in Older Medical Patients

A survey of drug‐related admissions of patients aged 50 years and older was conducted at the Health Sciences Centre, Winnipeg to determine the interrelationship of risk factors, and isolate the effect of age. All nonelective medical admissions were prospectively assessed to determine the role of drug therapy as a contributory factor. Of the 863 eligible admissions, 162 exhibited at least one drug‐related adverse patient event (DRAPE) at the time of hospitalization. This accounted for 19% of the admissions (23% of 718 admissions that involved prescription drugs). Although adverse drug reactions were responsible for many DRAPEs (48%), intentional noncompliance (27%), treatment failure (19%), alcohol (14%), and medication error (10%) were also frequent contributing causes. Drugs commonly implicated in DRAPEs were systemic steroids, digoxin, nonsteroidal anti‐inflammatory agents, α‐methyldopa, calcium channel blockers, β‐blockers, theophylline, furosemide, sympathomimetics, thiazides, and benzodiazepines. The risk of a DRAPE was related to the number of diseases prior to admission (r = 0.81; P < .026) and the number of drugs used (r = 0.77; P < .001). Age was not correlated with the risk of a DRAPE. Females had significantly more adverse drug reactions, although sex was not a predictor for overall DRAPE risk.
HLA-C*01 is a Risk Factor for Crohn's Disease

Background:A dysregulated mucosal immune response to the intestinal environment in a genetically susceptible host is hypothesized to be critical to the pathogenesis of Crohn's disease (CD). Therefore, we examined CD-susceptibility genes involved in the immune response through a genome-wide association study and consecutive genotyping of human leukocyte antigens (HLAs) and killer cell immunoglobulin-like receptors. Methods:An initial genome-wide association study was performed with 275 CD patients and 2369 controls from a Korean population. To validate the loci identified in the genome-wide association study, replication genotyping was performed in a different cohort of 242 CD patients and 1066 controls. Finally, high-resolution genotyping of HLA and killer cell immunoglobulin-like receptor was performed. Results:Four susceptibility loci, a promoter region in tumor necrosis factor (ligand) superfamily member (TNFSF15) and 3 independent regions in HLAs, showed significant associations with CD. Among them, rs114985235 in the intergenic region between HLA-B and HLA-C showed the strongest association, with an increased risk of CD (P = 8.71 × 10−23; odds ratio, 2.25). HLA typing in this region showed HLA-C*01 to be responsible for the association of CD among 43 HLA-B and HLA-C genotypes identified in the Korean population. However, the interaction of HLA-C with killer cell immunoglobulin-like receptor had little effect on the development of CD. Conclusions:We newly identified HLA-C*01 as a prominent CD-susceptibility HLA allotype in the Korean population. In addition, these results confirm that genetic variations in immune response genes, such as HLAs and TNFSF15, are important host factors for the pathogenesis of CD.
Nontraumatic Osteonecrosis After Chemotherapy for Testicular Cancer: A Systematic Review

Nontraumatic osteonecrosis is a well-documented late complication of chemotherapy for hematologic malignancies, with prolonged corticosteroid exposure implicated. Reports of this treatment complication in patients treated with chemotherapy for solid tumors are sparse. We reviewed our institutional experience and the published medical literature to explore an association between chemotherapy for testicular cancer and the occurrence of nontraumatic osteonecrosis. Two databases of men with testicular cancer were reviewed. Search of the medical literature included MEDLINE, CANCERLIT, and EMBASE. Two of 107 men with testicular cancer treated with chemotherapy at our center were identified with nontraumatic osteonecrosis. Literature review identified 14 reports describing patients with 39 solid tumors with osteonecrosis after chemotherapy. Of 38 adults, 28 had testicular cancer and 6 had breast cancer. All patients with testicular cancer had received cisplatin, vinblastine, and bleomycin, or bleomycin, etoposide, and cisplatin. Twenty-seven of 28 had received corticosteroids. Diagnosis was subacute in three and delayed a mean of 26 months (range, 12–47 months) in 26. The femoral head was involved in 26 patients, with bilateral involvement in 18. Crude incidence was 1.5% (95% CI, 0.9–2.1). Nontraumatic osteonecrosis is an infrequent but disabling late complication of cancer chemotherapy reported most commonly in adult patients with testicular cancer. Corticosteroid exposure makes this association plausible.
Demagnetization Analysis of Permanent Magnets According to Rotor Types of Interior Permanent Magnet Synchronous Motor

This paper shows a study on the demagnetization performance analysis of permanent magnet according to three kinds of rotor types of an interior permanent magnet synchronous motor (IPMSM). It is very important to consider demagnetization performance as well as motor performance such as rated torque, output current, and efficiency when designing IPMSM. Three kinds of rotor types according to permanent magnet arrangement; single layer type, v shape type, and double layer type are generally used for IPMSM. In the paper, the magnetic equivalent circuits according to each rotor type are proposed in order for initial design of thickness of permanent magnets considering demagnetization by lumped constant related to magnetic circuit. The volume of permanent magnets per pole and back EMF of each rotor type is assumed to equal for the comparison of demagnetization of IPMSMs with same performance each other. Next, distribution of demagnetization in the permanent magnet is analyzed by using finite element method (FEM) for the verification of the results by magnetic equivalent circuit.
Gender Differences in Cardiac Repolarization Following Intravenous Sotalol Administration

Background: Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate-corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. Methods: A total of 15 healthy volunteers, 9 female and 6 male (age: 32 ± 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. Results: The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 ± 13 vs 438 ± 13 ms, P < .001), while it was less significant in males (395 ± 23 vs 413 ± 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 ± 8 vs 21 ± 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. Conclusion: Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females.
A regulatory gene network that directs micromere specification in the sea urchin embryo.

Micromeres and their immediate descendants have three known developmental functions in regularly developing sea urchins: immediately after their initial segregation, they are the source of an unidentified signal to the adjacent veg(2) cells that is required for normal endomesodermal specification; a few cleavages later, they express Delta, a Notch ligand which triggers the conditional specification of the central mesodermal domain of the vegetal plate; and they exclusively give rise to the skeletogenic mesenchyme of the postgastrular embryo. We demonstrate the key components of the zygotic regulatory gene network that accounts for micromere specificity. This network is a subelement of the overall endomesoderm specification network of the Strongylocentrotus purpuratus embryo. A central role is played by a newly discovered gene encoding a paired class homeodomain transcription factor which in micromeres acts as a repressor of a repressor: the gene is named pmar1 (paired-class micromere anti-repressor). pmar1 is expressed only during cleavage and early blastula stages, and exclusively in micromeres. It is initially activated as soon as the micromeres are formed, in response to Otx and beta-Catenin/Tcf inputs. The repressive nature of the interactions mediated by the pmar1 gene product was shown by the identical effect of introducing mRNA encoding the Pmar1 factor, and mRNA encoding an Engrailed-Pmar1 (En-Pmar1) repressor domain fusion. In both cases, the effects are derepression: of the delta gene; and of skeletogenic genes, including several transcription factors normally expressed only in micromere descendants, and also a set of downstream skeletogenic differentiation genes. The spatial phenotype of embryos bearing exogenous mRNA encoding Pmar1 factor or En-Pmar1 is expansion of the domains of expression of the downstream genes over most or all of the embryo. This results in transformation of much of the embryo into skeletogenic mesenchyme cells that express skeletogenic markers. The normal role of pmarl is to prevent, exclusively in the micromeres, the expression of a repressor that is otherwise operative throughout the embryo. This function accounts for the localization of delta transcription in micromeres, and thereby for the conditional specification of the vegetal plate mesoderm. It also explains why skeletogenic differentiation gene batteries normally function only in micromere descendants. More generally, the regulatory network subelement emerging from this work shows how the specificity of micromere function depends on continuing global regulatory interactions, as well as on early localized inputs.