gebhart/patrepeval huggingface dataset:
Implantable Transvenous Pacing Leads: (2004)

With the dawn of a new millennium, physicians' demands for very thin transvenous leads able to be positioned in nontraditional sites like the Bachmann's bundle, the high and mid-right ventricular septum, and the His bundle have created new and exciting challenges for lead engineers. Bipolar leads can now be as thin and reliable as unipolar leads. Cathode electrodes are very small, porous, and demonstrate high impedance. To optimize stimulation thresholds, steroid-eluting passive- and active-fixation electrodes have become popular for use in the atrium and ventricle. To create thin lead body diameters, new insulation and conductor materials and lead body designs are necessary. Hybrid medical materials having the best features of silicone rubber and polyurethane will allow for reliable insulation. Conductor cables instead of helical coils permit strong thin diameter leads to be designed. Transvenous lead implantation using the traditional stylet may not be possible with thin diameter leads, necessitating the use of sophisticated workstations using steerable catheters to guide these new active-fixation leads to selective sites in the right heart. The pacing lead of the future may be very different from the one used today. Ironically, it will have features and implantation techniques similar to the transvenous leads designed prior to the use of the stylet. We are now approaching full circle in lead development, retracing the footprints of the early implanters of three and a half decades ago.
Metabolic Syndrome and Development of Diabetes Mellitus: Application and Validation of Recently Suggested Definitions of the Metabolic Syndrome in a Prospective Cohort Study (2002)

The World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) recently proposed definitions for the metabolic syndrome. Little is known of their validity, however. The authors assessed the sensitivity and specificity of the definitions of the metabolic syndrome for prevalent and incident diabetes mellitus in a Finnish population-based cohort of middle-aged men (n = 1,005) followed for 4 years since the late 1980s. Four definitions based on the WHO and NCEP recommendations were compared. All definitions identified persons at high risk for developing diabetes during the 4-year follow-up (odds ratios = 5.0-8.8). The WHO definition including waist-hip ratio > 0.90 or body mass index >or= 30 kg/m(2) was the most sensitive (0.83 and 0.67) and least specific (0.78 and 0.80) in detecting the 47 prevalent and 51 incident cases of diabetes. The NCEP definition in which adiposity was defined as waist girth > 102 cm detected only 61% of prevalent and 41% of incident diabetes, although it was the most specific (0.89 and 0.90). The WHO definition seems valid as judged by its relatively high sensitivity and specificity in predicting diabetes. The NCEP definition including waist > 102 cm also identifies persons at high risk for diabetes, but it is relatively insensitive in predicting diabetes.
Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics (2016)

Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed toward understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer. Mol Cancer Ther; 15(7); 1427-35. ©2016 AACR.
Synthesis and properties of mirror-image DNA (1992)

We have investigated the conformations of the hexadeoxyribonucleotide, L-d(CGCGCG) composed of L-deoxyribose, the mirror image molecule of natural D-deoxyribose. In this paper, we report the synthesis of four L-deoxynucleosides and the L-oligonucleotide-ethidium bromide interactions. The L-deoxyribose synthon 9 was synthesized from L-arabinose with an over all yield of 28.5% via the Barton-McCombie reaction. The L-deoxynucleosides were obtained by a glycosylation of appropriate nucleobase derivatives with the 1-chloro sugar 9. After derivatization to nucleoside phosphoramidites, L-deoxycytidine and L-deoxyguanosine were incorporated into a hexadeoxynucleotide, L-d(CGCGCG) by a solid-phase beta-cyanoethylphosphoramidite method. This L-hexanucleotide was resistant to digestion with nuclease P1. The conformations of L-d(CGCGCG) were an exact mirror image of that of the corresponding natural one as described previously, and the conformations of the L-d(CGCGCG)-ethidium bromide complex were also the mirror images of those of the D-d(CGCGCG)-ethidium bromide complex under both low and high salt conditions. These results suggest that ethidium bromide prefers not a right-handed helical sense, but the base-base stacking geometry of the B-form rather than that of the Z-form. Thus, L-DNA would be a useful tool for studying DNA-drug interactions.
Incidence and Clinical Profile of JAK2 V617F Mutation in Myelofibrosis with Myeloid Metaplasia. (2005)

Abstract An aberrant tyrosine kinase signalling due to non-receptor tyrosine kinase JAK2 V617F mutation has been highlighted in the pathogenesis of polycythemia vera (PV). In myelofibrosis with myeloid metaplasia (MMM) this mutation has been reported to be present in approximately 50% of the patients and its pathogenetic role is not elucidated. Here we report the results of JAK2 V617F mutation in a retrospective analysis of blood samples from 170 patients with MMM. Search for JAK2 mutation was performed by an allele specific PCR from DNA purified from granulocytes. To evaluate whether the mutation was carried in the homozygous or heterozygous state, digestion of PCR products with BsaXI restriction enzyme was performed. The overall frequency of JAK2 V617F mutation was 60% and homozygosity for the mutation was found in 39.2% of mutant samples. Disease duration was similar in JAK2 mutated and wild type patients. Patients who harboured an homozygous mutation had an higher myeloproliferative severity score (that indexed leukocytosis, thrombocytosis and splenomegaly) than patients who had a wild type or heterozygous genotype. In post-PV MMM, the mutant gene was present in 22/22 (100%) of patients, and the frequency of homozygosity was 59% of the mutated cases. In post-ET MMM (n=13), the mutant gene was present in 46% of the patients, and the frequency of homozygosity was 16% of the mutant samples. In idiopathic MMM (n=135), the incidence of the mutational state was 54.8%, with 35.1% of homozygote mutation. Patients who had received a diagnosis of prefibrotic myelofibrosis (WHO classification) had an incidence of the mutation significantly lower than patients who were diagnosed in the fibrotic stage (6/18, 33% vs 68/112, 60.7%; P=0.001). By considering only patients not receiving cytoreductive or disease modifying agents, patients who had an heterozygote mutation, had a mean Hb value higher than wild type patients (9.4 g/dL vs. 11.4 g/dL; P=0.004). Moreover, patients who had an homozygote mutation had the myeloproliferative severity score higher than both heterozygote and wild type patients (2.26 vs 1.59, P=0.008, and 2.26 vs.1.52, P=0.001, respectively). We conclude that JAK2 V617F mutation is significantly represented in MMM patients. It is a necessary event in the transformation from PV to MMM while not in the transformation from ET to MMM. Patients who harboured an heterozygote state maintained higher Hb values than patients with a wild type genotype, while the homozygote mutation was associated with leukocytosis, thrombocytosis and splenomegaly.
Sensitivity of malignant mesothelioma lacking Merlin to the FAK inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples. (2013)

e18541 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. MPM patients are usually diagnosed at an advanced stage of disease and the prognosis is poor. Median survival after diagnosis is 9 to 12 months and standard-of-care agents such as cisplatin and pemetrexed have only a modest impact on median survival time for MPM patients. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. 40-50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Methods: Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and MPM xenograft growth was measured in vehicle- vs. FAK inhibitor-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples. Results: Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wildtype merlin were less sensitive with EC50 values greater than 1 μM. Accordingly, oral dosing with a FAK inhibitor induced significant tumor growth inhibition in a merlin-negative mesothelioma model in mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients. Conclusions: These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. A potentially pivotal mesothelioma trial is set to initiate in 2013.
Plant adaptation to environmental stress (1993)

Preface. Contributors. Community and ecosystem level. Whole plant responses. Metabolic and genetic responses.
Control of Thickness and Orientation of Solution-Grown Silicon Nanowires (2000)

Bulk quantities of defect-free silicon (Si) nanowires with nearly uniform diameters ranging from 40 to 50 angstroms were grown to a length of several micrometers with a supercritical fluid solution-phase approach. Alkanethiol-coated gold nanocrystals (25 angstroms in diameter) were used as uniform seeds to direct one-dimensional Si crystallization in a solvent heated and pressurized above its critical point. The orientation of the Si nanowires produced with this method could be controlled with reaction pressure. Visible photoluminescence due to quantum confinement effects was observed, as were discrete optical transitions in the ultraviolet-visible absorbance spectra.
Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals: discussion. (1976)

About 300 carcinogens and non-carcinogens of a wide variety of chemical types have been tested for mutagenicity in the simple Salmonella/microsome test. The test uses bacteria as sensitive indicators of DNA damage, and mammalian liver extracts for metabolic conversion of carcinogens to their active mutagenic forms. There is a high correlation between carcinogenicity and mutagenicity: 90% (157/175) of the carcinogens were mutagenic in the test, including almost all of the known human carcinogens that were tested. Despite the severe limitations inherent in defining non-carcinogenicity, few "non-carcinogens" showed any degree of mutagenicity [McCann et al. (1975) Proc. Nat. Acad. Sci. USA 72, 5135-5139]. In the present paper, carcinogens negative in the test andapparent false positives are discussed. We also discuss evidence that chemical carcinogens and radiation, likely to initiate most human cancer and genetic defects do so by damage to DNA. The Salmonella test can play a central role in a program of prevention: to identify mutagenic chemicals in the environment (all indications are there are many) and to aid in the development of non-mutagenic products to prevent future human exposure.
Compiling standard ML to Java bytecodes (1998)

MLJ compiles SML'97 into verifier-compliant Java byte-codes. Its features include type-checked interlanguage working extensions which allow ML and Java code to call each other, automatic recompilation management, compact compiled code and runtime performance which, using a 'just in time' compiling Java virtual machine, usually exceeds that of existing specialised bytecode interpreters for ML. Notable features of the compiler itself include whole-program optimisation based on rewriting, compilation of polymorphism by specialisation, a novel monadic intermediate language which expresses effect information in the type system and some interesting data representation choices.
Cell and molecular regulation of the mouse blastocyst (2006)

Animals use diverse strategies to specify tissue lineages during development. A common strategy is to partition maternally supplied and localized lineage determinants into progenitor cells. The mouse embryo appears to use a different, more regulative strategy to specify the first three lineages: the epiblast (EPI: future embryo), the trophectoderm (TE: future placenta), and the primitive endoderm (PE: future yolk sac). These lineages are specified during two successive differentiation steps leading to formation of the blastocyst. Here, we review classic and contemporary models of early lineage specification in the mouse, and describe recent efforts to understand the molecular regulation of these events. We describe evidence that trophectoderm differentiation bears resemblance to the process of epithelialization and describe the importance of apical/basal protein complexes in regulating this process. Next, we present a revised model of PE specification, and describe evidence that PE cells in the inner cell mass sort out to occupy their ultimate position on the surface of the EPI. Finally, we describe factors that reinforce these lineages and three distinct stem cell types that can be isolated from them. Together, these mechanisms guide the differentiation of the first lineages of the mouse and thereby set up tissues that will be important for the first steps of embryonic body patterning.
Microbial Synthesis of Purine 2′-Amino-2′-deoxyribosides (1985)

The microbial synthesis of some purine 2′-amino-2′-deoxyribonucleosides from purine bases and 2′-amino-2′-deoxyuridine is described. Various bacteria, especially Erwinia herbicola, Salmonella schottmuelleri, Enterobacter aerogenes and Escherichia coli, were able to transfer the aminoribosyl moiety of 2′-amino-2′-deoxyuridine to purine bases (transaminoribosylation) in the presence of inorganic phosphate. The optimum conditions for the reaction were pH 7.0 and 63°C. No reaction was observed in the absence of inorganic phosphate and the optimum concentration of it was around 30 mm. Adenine, guanine, 2-chlorohypoxanthine and hypoxanthine were transformed to the corresponding 2′-amino-2′-deoxyribonucleosides by the catalytic activity of the wet cell paste of Enterobacter aerogenes AJ 11125. The enzymatically synthesized purine 2′-amino-2′-deoxyribonucleosides were isolated and identified by physicochemical means. 2′-Amino-2′-deoxyadenosine strongly inhibited the growth of Hela cells in tissue culture, and the ED50 was 2.5μ/ml.
Metabolic-flux and network analysis in fourteen hemiascomycetous yeasts (2004)

In a quantitative comparative study, we elucidated the glucose metabolism in fourteen hemiascomycetous yeasts from the Genolevures project. The metabolic networks of these different species were first established by (13)C-labeling data and the inventory of the genomes. This information was subsequently used for metabolic-flux ratio analysis to quantify the intracellular carbon flux distributions in these yeast species. Firstly, we found that compartmentation of amino acid biosynthesis in most species was identical to that in Saccharomyces cerevisiae. Exceptions were the mitochondrial origin of aspartate biosynthesis in Yarrowia lipolytica and the cytosolic origin of alanine biosynthesis in S. kluyveri. Secondly, the control of flux through the TCA cycle was inversely correlated with the ethanol production rate, with S. cerevisiae being the yeast with the highest ethanol production capacity. The classification between respiratory and respiro-fermentative metabolism, however, was not qualitatively exclusive but quantitatively gradual. Thirdly, the flux through the pentose phosphate (PP) pathway was correlated to the yield of biomass, suggesting a balanced production and consumption of NADPH. Generally, this implies the lack of active transhydrogenase-like activities in hemiascomycetous yeasts under the tested growth condition, with Pichia angusta as the sole exception. In the latter case, about 40% of the NADPH was produced in the PP pathway in excess of the requirements for biomass production, which strongly suggests the operation of a yet unidentified mechanism for NADPH reoxidation in this species. In most yeasts, the PP pathway activity appears to be driven exclusively by the demand for NADPH.
The Epidemiology of Myasthenia Gravis (2003)

Population-based studies of the epidemiology of myasthenia gravis (MG) have been conducted for over 50 years. Over that time, there has been a clear trend towards an increase in the reported prevalence of the disease. In recent years, there has also been an interest in determining a reasonably accurate estimate of the number of MG patients in the United States. Current estimates place the prevalence at a high value of about 20 per 100,000. The year 2000 U.S. population estimate is slightly less than 280 million. A crude estimate of the number of MG patients derived from the population estimate and the reported prevalence from selected populations indicates that there are between 53,000 and 59,900 patients in the United States at this time. The age and ethnic distributions in the United States are evolving from those that were present when the majority of the population-based studies were done, and the distribution of severity of the disease may also have changed. Future studies of the epidemiology of MG should take these factors into account, and further research into the economic and quality-of-life impact of the disease in the population is needed.
Changes of Hepatitis B Virus Dna in Liver and Serum Caused by Recombinant Leukocyte Interferon Treatment: Analysis of Intrahepatic Replicative Hepatitis B Virus Dna (1985)

Twenty patients with HBeAg-positive chronic liver disease were given large doses of recombinant leukocyte interferon for 4 weeks. Changes of hepatitis B virus DNA in livers and sera were analyzed by the molecular hybridization technique in paired biopsies obtained before and 2 weeks after treatment. Serum hepatitis B virus DNA was examined before, during and after the treatment until 4 weeks post-interferon. Analysis of hepatic hepatitis B virus DNA revealed species that appeared to represent various forms of replicative hepatitis B virus DNA, i.e., relaxed circular, linear, supercoiled and single-stranded hepatitis B virus DNA, respectively. No evidence of integration of hepatitis B virus DNA in genomic DNA was obtained. Of 15 cases which were positive for hepatic hepatitis B virus DNA before treatment and in which paired biopsies were obtained, hepatic hepatitis B virus DNA became negative in 4, decreased in 5 and unchanged in 6. Among several types of replicative viral DNA in liver tissue, supercoiled hepatitis B virus DNA tended to remain after other forms were reduced. A close correlation between hepatic and serum hepatitis B virus DNA was found in 37 liver biopsy samples and corresponding sera. These results indicate that interferon treatment reduces serum hepatitis B virus levels by inhibiting viral replication in the liver and that persistence or reappearance of hepatitis B virus in serum after interferon is associated with replication.
In Pancreatic Carcinoma, Dual EGFR/HER2 Targeting with Cetuximab/Trastuzumab Is More Effective than Treatment with Trastuzumab/Erlotinib or Lapatinib Alone: Implication of Receptors' Down-regulation and Dimers' Disruption (2012)

We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb)-trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2(low) human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras-mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab')(2) fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization.