Miracle-dz/UniFAR-FTUs huggingface dataset:
Somatic Mutations of the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor and Tyrosine Kinase Inhibitor Response to TKIs in Non-small Cell Lung Cancer: An Analytical Database

Background: After the discovery of somatic mutations in the tyrosine kinase domain (exons 18–24) of the epidermal growth factor receptor (EGFR) correlating with responses of non-small cell lung cancer (NSCLC) to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, there has been increasing interest in utilizing this molecular marker for treatment selection. We aimed to analytically catalogue the mutational spectrum of somatic mutations in EGFR and format a database allowing correlation of specific mutations with clinico-pathologic factors and response to TKIs. Methods: A computerized search of MEDLINE (January 1, 2004 to June 30, 2007) was performed to identify articles reporting on NSCLC patients harboring somatic mutations in EGFR. Demographic, clinico-pathologic, mutational, and response data were extracted and tabulated. Results: A total of 202 eligible articles were identified. We report data on 12,244 patients with 3381 somatic EGFR mutations. The majority of mutations have been reported on only one occasion (158 of 254, 62.2%), and only nine mutations occur at a rate of ≥1%. L858R and delE746-A750 account for 32.84% and 24.28% of all mutations, respectively; with 50% of mutations being exon 19 deletions or “deletional-insertions. ” There is a clear association between the presence of mutations and response to TKI. Conclusions: We have generated a free access, nonprofit online analytical database of somatic EGFR mutations in NSCLC. Cumulative information will be made available through a routine update of both database tables and associated graphical representations. Direct updates and submissions through the online site (www.somaticmutations-EGFR.org) are encouraged, as are comments and suggestions.
Guanine Nucleotide Exchange on Heterotrimeric Gi3 Protein Controls Autophagic Sequestration in HT-29 Cells*

Recent results have shown that autophagic sequestration in the human colon cancer cell line HT-29 is controlled by the pertussis toxin-sensitive heterotrimeric Gi3 protein. Here we show that transfection of an antisense oligodeoxynucleotide to the αi3-subunit markedly inhibits autophagic sequestration, whereas transfection of an antisense oligodeoxynucleotide to the αi2-subunit does not change the rate of autophagy in HT-29 cells. Autophagic sequestration was arrested in cells transfected with a mutant of the αi3-subunit (Q204L) that is restricted to the GTP-bound form. In Q204L-expressing cells, 3-methyladenine-sensitive degradation of long lived [14C]valine-labeled proteins was severely impaired and could not be stimulated by nutrient deprivation. Autophagy was also reduced when dissociation of the βγ dimer from the GTP-bound αi3-subunit was impaired in cells transfected with the G203A mutant. In contrast, a high rate of pertussis toxin-sensitive autophagy was observed in cells transfected with an αi3-subunit mutant (S47N) which has an increased guanine nucleotide exchange rate and increased preference for GDP over GTP. Cells that express pertussis toxin-insensitive mutants of either wild-type αi3-subunit (C351S) or S47N αi3-subunit (S47N/C351S) exhibit a high rate of autophagy.
The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma—with special reference to the serum levels of des‐gamma‐carboxy prothrombin

The microvascular invasion of cancer cells (mvi) is a good prognostic factor after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The aim of this study is to predict mvi in patients with HCC who were candidates for OLT. We studied 218 patients with HCC resections who had HCC without any extrahepatic metastases and vascular invasion detected during preoperative evaluation. We analyzed the clinico‐pathological data of these patients to predict the mvi presence. The mvi prediction scoring system was made and the accuracy of this system was examined using independent clinico‐pathologic factors. The size and histological grade of the tumor were significantly correlated with the mvi. The des‐gamma‐carboxy prothrombin (DCP) is a mvi predictor. The sensitivity of our mvi prediction system was 75% and the specificity was 85% in 32 patients who underwent living‐donor liver transplantations for HCC. Our study shows that besides the tumor size and histological grade, a measurement of the serum DCP levels could be a good predictor for mvi. A tumor biopsy and a preoperative measurement of DCP could improve the selection of patients with HCC for OLT. Our scoring system for mvi provides us a precise prediction of the presence of mvi. J. Surg. Oncol. 2007;95:235–240. © 2007 Wiley‐Liss, Inc.
The Relationship Between the Duration of Fecal Shedding and the Production of Contaminated Eggs by Laying Hens Infected with Strains of Salmonella Enteritidis and Salmonella Heidelberg

Abstract Egg contamination by Salmonella Enteritidis has remained a significant public health problem for nearly two decades, and Salmonella Heidelberg has also been recently implicated in egg-transmitted human illness. Colonization of the intestinal tract is a necessary precursor to the invasion of reproductive organs and subsequent deposition inside eggs laid by infected hens, but the relationship between the persistence of Salmonella in the intestinal tract and the likelihood of egg contamination has been uncertain. In this study, groups of laying hens were inoculated with large oral doses of strains of Salmonella Enteritidis and Salmonella Heidelberg, including variants of the original parent strains that had been reisolated from eggs laid by infected hens in a prior study. The shedding of Salmonella in voided feces was monitored for 6 wk postinoculation, and all eggs laid by infected hens between 5 and 22 days postinoculation were cultured for Salmonella in their contents. The mean duration of fecal shedding was significantly longer for the previously passaged Salmonella strains (26.7 days) than for the original parent strains (17.5 days), and the passaged strains caused a significantly higher frequency of egg contamination (6.4%) than did the parent strains (3.3%). However, the duration of fecal shedding and the frequency of egg contamination were not correlated for any of the Salmonella Enteritidis or Salmonella Heidelberg strains.
Mitochondrial DNA Sequence and Phylogenetic Evaluation of Geographically Disparate Sus scrofa Breeds

Next generation sequencing of mitochondrial DNA (mtDNA) facilitates studies into the metabolic characteristics of production animals and their relation to production traits. Sequence analysis of mtDNA from pure-bred swine with highly disparate production characteristics (Mangalica Blonde, Mangalica Swallow-bellied, Meishan, Turopolje, and Yorkshire) was initiated to evaluate the influence of mtDNA polymorphisms on mitochondrial function. Herein, we report the complete mtDNA sequences of five Sus scrofa breeds and evaluate their position within the phylogeny of domestic swine. Phenotypic traits of Yorkshire, Mangalica Blonde, and Swallow-belly swine are presented to demonstrate their metabolic characteristics. Our data support the division of European and Asian breeds noted previously and confirm European ancestry of Mangalica and Turopolje breeds. Furthermore, mtDNA differences between breeds suggest function-altering changes in proteins involved in oxidative phosphorylation such as ATP synthase 6 (MT-ATP6), cytochrome oxidase I (MT-CO1), cytochrome oxidase III (MT-CO3), and cytochrome b (MT-CYB), supporting the hypothesis that mtDNA polymorphisms contribute to differences in metabolic traits between swine breeds. Our sequence data form the basis for future research into the roles of mtDNA in determining production traits in domestic animals. Additionally, such studies should provide insight into how mtDNA haplotype influences the extreme adiposity observed in Mangalica breeds.
Correlation of Levetiracetam Concentrations Between Serum and Saliva

Purpose More than 100 drugs have been evaluated for salivary therapeutic drug monitoring since the 1970s. The most studied drugs are the anticonvulsants phenytoin, phenobarbital, and carbamazepine, demonstrating strong correlations between serum and saliva concentrations. No published data exist for levetiracetam (LEV) to the authors' knowledge. This study's objective is to determine the correlation between LEV serum and saliva concentrations. Methods Investigators identified subjects seen in neurology clinics at the University of Kentucky. Patients were eligible if they agreed to participate in this study, were taking LEV for a minimum of 4 weeks, and if a serum LEV concentration had been ordered by their physician. Patients spit a minimum of 0.25 mL into a cup to obtain saliva samples. Blood samples were obtained by phlebotomy. Results Serum and saliva LEV concentrations were determined via high-performance liquid chromatography (HPLC) in two separate reference laboratories. Linear regression analysis was used to evaluate correlations. Serum and saliva samples were obtained from 40 patients (22 female, 18 male), ranging from 3 to 57 years of age. The mean ± SD serum LEV concentration for reference laboratory A was significantly lower (P < 0.0001) than reference laboratory B, 23.6 ± 13.8 &mgr;g/mL and 27.0 ± 16.9 &mgr;g/mL, respectively. The mean ± SD saliva to serum concentration fraction was also different for the two laboratories, i.e., 41.0% ± 0.15% for lab A and 36.0% ± 0.15% for lab B (P = 0.001). The correlation coefficients for the two laboratories were similar, 0.87 and 0.86 (both P < 0.0001) for labs A and B, respectively. Conclusion A significant positive correlation exists between LEV saliva and serum concentrations. The ability to monitor LEV therapy using saliva may provide benefits that include facilitating sample collection and improving the quality of life for persons with epilepsy. Patients with poor venous access, such as children and elderly patients, and persons afraid of needles may particularly benefit from this method.
Optimized Multiple Microgrid-Based Clustering of Active Distribution Systems Considering Communication and Control Requirements

An optimized communication and control infrastructure, based on the microgrid building block concept, for active distribution systems is essential to facilitate powerful control framework under the smart grid paradigm. In this paper, a novel methodology for designing a communication and control infrastructure is presented. The new design takes into account both communication system and distribution system-related aspects. The proposed design facilitates systematic and optimized clustering of the distribution system into a set of virtual microgrids with optimized communication requirements while considering the power quality aspects, characteristics of distributed generation units, distributed energy storage units, and distributed reactive sources. The new design facilitates robust infrastructure for smart distribution systems operation and control, e.g., self-healing control and optimized system-level operation, by using virtual microgrids as building blocks in future distribution systems. The motivations, conceptual design, problem formulation and solution algorithms are presented in this paper. The well-known PG&E 69-bus distribution system is selected as a test case and through several sensitivity studies, the effect of optimization coefficients on the design, and the robustness of the algorithm are investigated. Finally, the algorithm is tested on the IEEE 123-bus distribution system.
Neuroprotective Effects of Creatine and Cyclocreatine in Animal Models of Huntington’s Disease

The gene defect in Huntington’s disease (HD) may result in an impairment of energy metabolism. Malonate and 3-nitropropionic acid (3-NP) are inhibitors of succinate dehydrogenase that produce energy depletion and lesions that closely resemble those of HD. Oral supplementation with creatine or cyclocreatine, which are substrates for the enzyme creatine kinase, may increase phosphocreatine (PCr) or phosphocyclocreatine (PCCr) levels and ATP generation and thereby may exert neuroprotective effects. We found that oral supplementation with either creatine or cyclocreatine produced significant protection against malonate lesions, and that creatine but not cyclocreatine supplementation significantly protected against 3-NP neurotoxicity. Creatine and cyclocreatine increased brain concentrations of PCr and PCCr, respectively, and creatine protected against depletions of PCr and ATP produced by 3-NP. Creatine supplementation protected against 3-NP induced increases in striatal lactate concentrations in vivo as assessed by 1H magnetic resonance spectroscopy. Creatine and cyclocreatine protected against malonate-induced increases in the conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid, biochemical markers of hydroxyl radical generation. Creatine administration protected against 3-NP-induced increases in 3-nitrotyrosine concentrations, a marker of peroxynitrite-mediated oxidative injury. Oral supplementation with creatine or cyclocreatine results in neuroprotective effects in vivo, which may represent a novel therapeutic strategy for HD and other neurodegenerative diseases.
Acute Hypoxia Increases S100β Protein in Association with Blood Flow Redistribution away from Peripheral Circulations in Fetal Sheep

We investigated in fetal sheep during late gestation the effects of acute hypoxemia on fetal plasma S100β protein concentrations and how these relate to fetal redistribution of blood flow and acid-base status. Under general anesthesia, five Welsh Mountain sheep fetuses were instrumented with vascular catheters, and transit-time flow transducers were implanted around a femoral artery and an umbilical artery. At least 5 d after surgery, fetuses were subjected to 1 h of normoxia, 0.5 h of hypoxemia, and 1 h of recovery. Hypoxemia induced significant falls in fetal pHa, arterial oxygen pressure, acid-base excess, and [HCO3−], without alteration to arterial partial pressure of carbon dioxide. An increase in arterial blood pressure, a fall in heart rate, an increase in femoral vascular resistance, and a decrease in umbilical vascular resistance occurred in all fetuses. During hypoxemia, plasma S100β increased significantly and remained elevated until the end of the protocol. Within individual fetuses, plasma S100β correlated with femoral vascular resistance and pH. In contrast, no relationship was found between S100β and umbilical vascular resistance. This study reports for the first time that a controlled period of fetal hypoxemia with associated acidemia leads to persistent elevations in plasma S100β concentrations that strongly correlate with hemodynamic changes that are known to occur during fetal blood flow redistribution. These findings open up a new role for changes in fetal S100β concentrations as a possible early marker of fetal hypoxia with associated acidemia in perinatal medicine.
I2 average current mode control for switching converters

The constant frequency average current mode control is a widely used control scheme for the converters requiring precise current control, but its transient response is relatively slow, while the switching loss and driving loss significantly diminish the light load efficiency. To solve these issues, the I2 control average current mode is proposed. By combining the fast direct current feedback and integral feedback, the I2 control achieves both wide bandwidth and accurate current control. As a particular embodiment of this concept, by adopting constant on-time modulation, constant on-time I2 control needs no artificial ramp, and has fast dynamic response. Moreover, due to the decrease of switching frequency, constant on-time I2 control improves the efficiency in discontinuous-conduction-mode. The concept of I2 control can be extended to other modulations. Small signal model using describing function based equivalent circuit model is proposed. The model is accurate up to 1/2 switching frequency. Based on model, the design guidelines are discussed. The proposed control is verified with simulation and hardware measurement results.
Antibiotic prescribing practices among Norwegian dentists

Objective. There is little information on antibiotic prescribing habits among dentists in general. In 1992 we reported a study among Norwegian dentists, and the present investigation was undertaken to find out if the patterns of antibiotic prescription had changed since then. Material and methods. A total of 470 randomly selected dentists (10% of total) received a questionnaire and a letter describing the survey and 313 responded. Results. Results indicated that 35% did not issue any prescriptions in a typical week, while 3% issued ≥5. Fifty percent reported that they might prescribe antibiotics when treating periodontal diseases, but only 3.4% reported the use of microbial diagnosis before selecting an antibiotic; 71% of the respondents reported use of antibiotics occasionally to prevent general complications of dental treatment; 80% prescribed antibiotics for prophylactic use if the patient revealed a history of endocarditis, while 5% reported never doing so. Conclusion. These findings are in concert with the results obtained 11 years ago, but indicating that dentists who had attended postgraduate courses on antibiotics prescribed such drugs more frequently. This was not statistically significant. However, it is of great concern that 5% never prescribed antibiotics when treating patients with a history of endocarditis, and that 20% did not know that amoxicillin was a penicillin. Such lack of knowledge may cause fatal results of therapy.
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.

CONTEXT Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure. OBJECTIVE To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure. DESIGN, SETTING, AND PARTICIPANTS The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment. INTERVENTION Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy. MAIN OUTCOME MEASURES Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema. RESULTS During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups. CONCLUSION Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00071331
Expression of extracellular matrix molecules typical of articular cartilage in the human scapholunate interosseous ligament

The scapholunate interosseous ligament (SLIL) connects the scaphoid and lunate bones and plays a crucial role in carpal kinematics. Its rupture leads to carpal instability and impairment of radiocarpal joint function. As the ligament is one of the first structures affected in rheumatoid arthritis, we conducted an immunohistochemical study of cadaveric tissue to determine whether it contains known autoantigens for rheumatoid arthritis. We immunolabelled the ligament from one hand in 12 cadavers with monoclonal antibodies directed against a wide range of extracellular matrix (ECM) molecules associated with both fibrous and cartilaginous tissues. The labelling profile has also enabled us to comment on how the molecular composition of the ligament relates to its mechanical function. All regions of the ligament labelled for types I, III and VI collagens, chondroitin 4 and 6 sulphates, keratan sulphate, dermatan sulphate, versican, tenascin and cartilage oligomeric matrix protein (COMP). However, both entheses labelled strongly for type II collagen, aggrecan and link protein and were distinctly fibrocartilaginous. In some regions, the ligament attached to bone via a region of hyaline cartilage that was continuous with articular cartilage. Labelling for cartilage molecules in the midsubstance was most evident dorsally. We conclude that the SLIL has an ECM which is typical of other highly fibrocartilaginous ligaments that experience both tensile load and shear. The presence of aggrecan, link protein, COMP and type II collagen could explain why the ligament may be a target for autoantigenic destruction in some forms of rheumatoid arthritis.
Bingkai Identitas dalam Konflik Geopolitik: Intervensi Militer Rusia di Ukraina

Tulisan ini bertujuan untuk menelaah konflik antara Rusia dengan Ukraina yang berakhir dengan lepasnya wilayah Krimea. Rusia membela diri dengan menyatakan bahwa aneksasi terhadap Krimea adalah upaya membebaskan wilayah tersebut bertujuan untuk melindungi mayoritas warga etnisnya dari dampak ketidakstabilan politik yang terjadi di Ukraina akibat munculnya gerakan revolusioner. Dengan analisis secara khusus yang menitik beratkan pada kesamaan identitas dari warga Ukraina di Krimea dengan orang-orang Rusia, tulisan ini secara umum berargumen bagaimana secara historis kesamaan identitas dapat menjadi faktor yang mendukung tindakan opresif yang dilakukan oleh suatu negara dalam meraih ambisi geopolitiknya. Tulisan ini mengungkap bagaimana suatu identitas yang dimiliki bersama oleh negara dengan negara lainnya dapat digunakan sebagai isu krusial untuk menjustifikasi tindakan unilateral terhadap negara lain.