gebhart/patrepeval huggingface dataset:
Influence of concurrent medications on outcomes of men with prostate cancer included in the TAX327 study. (2010)

4686 Background: Cancer patients (pts) on chemotherapy frequently receive concomitant medications (conmeds) for their coexisting illnesses. Some of these drugs, and/or the medical conditions for which they are prescribed, might influence the outcome of cancer treatment, in particular as some have been reported to have antineoplastic properties in preclinical models. Methods: We selected 14 different conmeds (eg, metformin, digoxin), taken by >20 men in the TAX327 study (N=1006), and analyzed their association with outcome measures including overall survival (OS), PSA response, pain response, and quality of life (QOL) response. The Cochran-Mantel-Haenszel test was used to test response rates, linear regression to test % PSA reduction, and adjusted for stratification by treatment group (D3W=docetaxel 3-weekly; D1W=docetaxel weekly; M=mitoxantrone). Comparative survival was analyzed by Cox proportional hazards; adjusted for treatment group, pain and performance status. The study is hypothesis-generating and p-values were not corrected for multiple significance testing. Results: Men taking verapamil (p=0.011) or digoxin (p=0.046) had worse OS (HR>1) than those not taking. Warfarin users had a greater % PSA reduction (p=0.035) than nonusers. Antidepressant users had lower pain response than nonusers (p=0.028). QOL was better for Cox-2 inhibitor users (p=0.031). Treatment group differences appeared for antidepressants, epoetin, and digoxin on pain response, and for statins on QOL response. Conclusions: Conmeds, or the medical conditions for which they are prescribed, might influence treatment outcome. Here, we report trends to poorer OS for men who received verapamil or digoxin and chemotherapy. Such secondary analysis is limited by the pt numbers, factors contributing to comorbidity, and multiple hypothesis testing. Outcome Conmed n (D3W/D1W/M) D3W Groups D1W M OS Digoxin 10:14:11 0.023 0.3 0.7 Verapamil 16:11:16 0.062 0.14 0.29 PSA response Warfarin 22:23:24 0.047 0.35 0.52 Pain response Antidepressants 27:21:17 0.61 0.018 0.46 Epoetin 16:26:19 0.009 0.79 0.68 Digoxin 10:14:11 0.096 0.38 0.58 QOL response Cox-2 inhibitors 37:34:29 0.27 0.48 0.058 Statins 28:21:33 0.021 0.26 0.36 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Glycosylation properties of the Pichia pastoris-expressed recombinant kringle 2 domain of tissue-type plasminogen activator. (1997)

The oligosaccharide structures present on Asn5 of the Pichia pastoris-expressed recombinant kringle 2 domain of tissue-type plasminogen activator [(r)-[K2tPA]] have been determined by a combination of techniques, including HPLC, FPLC, gel filtration, endoglycosidase digestions and mass spectrometry. The major oligosaccharides identified after their liberation by either hydrazinolysis or by the enzyme peptide:N4-(N-acetyl-beta-glucosaminyl)asparaginyl amidase, were in the oligomer range of (mannose)8(N-acetylglucosamine)2 (Man8GN2) to Man18GN2. The preponderance of these glycans spanned Man9GN2 to Man12GN2, and the major overall product was Man10GN2. An additional (less than 5%) amount of the polypeptide was hyperglycosylated. In contrast with glycoproteins produced in Saccharomyces cerevisiae, our results with specific mannosidase digestions were consistent with previous studies showing that (alpha 1,3)-linked mannose residues were not present in extensions of the core Man8GN2 unit. The results show that the N-linked glycosylation pathways in P. pastoris are substantially different from those found in S. cerevisiae, with shorter Man(alpha 1,6) extensions to the core Man8GN2 and the apparent lack of significant Man(alpha 1,3) additions representing the major processing modality of N-linked glycans in P. pastoris.
Simulations of metal thin film thermal flow processes (1996)

We use EVFLOW, a thin film thermal flow process simulator, to simulate the thermal flow of metal thin films in axisymmetric contacts/vias on patterned wafers, where two dimensional surface evolution is appropriate. The flow processes considered are (1) Al and Au thin film laser melting processes, for which process temperatures are higher than the metal melting points, and (2) conventional Al thermal anneal processes (400–550 °C). Surface tension induced mass transport in the flowing films is calculated by solving the Navier–Stokes and continuity equations for incompressible fluids. Our simulations of Au film profiles during laser melting process predict the experimentally observed trends in void formation and collapse with feature geometry and deposited film thickness. In laser melting processes, the void shrinks and vanishes, resulting in fully filled contacts and planarized metal surfaces. Al film evolution in the thermal anneal process is modeled using a surface layer melting model. The thickness of the liquidlike flowing layer is assumed to be 0.02 μm in this work. The trends in the formation of voids with feature geometry and deposited film thickness predicted by EVFLOW reflect experimental observations. Voids may form during the thermal anneal processes. The surface layer melting model as used in this work will not predict the collapse of voids.
Internal electric field distributions of a dielectric cylinder at resonance wavelengths (1981)

Calculations of the electric field distribution within and around an infinite circular dielectric cylinder, having a relative index of refraction of 1.53 and illuminated with plane-wave radiation of wavelength lambda, have been performed for size parameters ranging from 39 to 51. Results for size parameters that satisfy resonance conditions for various atural modes of oscillation of the cylinder (mode number n = 53; order numbers l = 1-5) clearly illustrate the physical significance of n and l and show that the internally reflected circumferential waves are localized near, but not confined to, the cylinder surface.
Chicken Guanylate-binding Protein (1996)

To gain further insights into the cytokine network of birds, we used polymerase chain reaction technology to clone a cDNA that codes for a chicken homolog of the interferon-induced guanylate-binding proteins (GBPs). In its N-terminal moiety, the 64-kDa chicken GBP contains two sequence blocks of 100 and 19 amino acids, respectively, that are about 70% identical to mammalian GBPs. The first region includes two motifs of the canonical GTP-binding consensus element. The other parts of chicken GBP are poorly conserved, except for a CAAX motif at the extreme C terminus which might signal isoprenylation. Like mammalian GBPs, recombinant chicken GBP specifically bound to agarose-immobilized guanine nucleotides and hydrolyzed GTP to both GDP and GMP. Regulation by interferons was also conserved: chicken GBP RNA was barely detectable in uninduced chicken cells. Low GBP RNA levels were found in cells treated with type I interferon, whereas very high levels were observed in cells treated with supernatant of a chicken T cell line that secretes a gamma-interferon-like activity. Together with recent phylogenetic studies of interferon genes, these results suggest that in spite of low sequence conservation, the various components of the avian interferon system are functionally well conserved.
Why Choose Cardiothoracic Surgery as a Career? (2011)

The future of cardiothoracic surgery faces a lofty challenge with the advancement of percutaneous technology and minimally invasive approaches. Coronary artery bypass grafting (CABG) surgery, once a lucrative operation and the driving force of our specialty, faces challenges with competitive stenting and poor reimbursements, contributing to a drop in applicants to our specialty that is further fueled by the negative information that members of other specialties impart to trainees. In the current era of explosive technological progress, the great diversity of our field should be viewed as a source of excitement, rather than confusion, for the upcoming generation. The ideal future cardiac surgeon must be a "surgeon-innovator," a reincarnation of the pioneering cardiac surgeons of the "golden age" of medicine. Equipped with the right skills, new graduates will land high-quality jobs that will help them to mature and excel. Mentorship is a key component at all stages of cardiothoracic training and career development. We review the main challenges facing our specialty--length of training, long hours, financial hardship, and uncertainty about the future, mentorship, and jobs--and we present individual perspectives from both residents and faculty members.
1,3-Disubstituted Ureas Functionalized with Ether Groups are Potent Inhibitors of the Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties (2007)

Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.
A highly linear CMOS buffer amplifier (1987)

A CMOS buffer amplifier which achieves significant improvements in linearity and drive capability over previously reported high-swing amplifiers is described. The buffer operates from a 5-V supply, is capable of rail-to-rail operation at both the input and output, an exhibits a remarkably high linearity of 0.05% THD while driving 3 V/SUB p-p/ into 100 /spl Omega/ at 20 kHz.
Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes (2009)

Fasting hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is attributed to increased hepatic gluconeogenesis, which has been ascribed to increased transcriptional expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, catalytic (G6Pc). To test this hypothesis, we examined hepatic expression of these 2 key gluconeogenic enzymes in 2 rodent models of fasting hyperglycemia and in patients with T2DM. In rats, high-fat feeding (HFF) induces insulin resistance but a robust beta-cell response prevents hyperglycemia. Fasting hyperglycemia was induced in the first rat model by using nicotinamide and streptozotocin to prevent beta-cell compensation, in combination with HFF (STZ/HFF). In a second model, control and HFF rats were infused with somatostatin, followed by portal vein infusion of insulin and glucagon. Finally, the expression of these enzymes was measured in liver biopsy samples obtained from insulin sensitive, insulin resistant, and untreated T2DM patients undergoing bariatric surgery. Rats treated with STZ/HFF developed modest fasting hyperglycemia (119 +/- 4 vs. 153 +/- 6 mg/dL, P < 0.001) and increased rates of endogenous glucose production (EGP) (4.6 +/- 0.6 vs. 6.9 +/- 0.6 mg/kg/min, P = 0.02). Surprisingly, the expression of PEPCK or G6Pc was not increased. Matching plasma insulin and glucagon with portal infusions led to higher plasma glucoses in the HFF rats (147 +/- 4 vs. 161 +/- 4 mg/dL, P = 0.05) with higher rates of EGP and gluconeogenesis. However, PEPCK and G6Pc expression remained unchanged. Finally, in patients with T2DM, hepatic expression of PEPCK or G6Pc was not increased. Thus, in contrast to current dogma, these data demonstrate that increased transcriptional expression of PEPCK1 and G6Pc does not account for increased gluconeogenesis and fasting hyperglycemia in patients with T2DM.
The human antimouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A. (2000)

Murine monoclonal antibodies (mAbs), when administered to patients, induce a human antimouse immunoglobulin immune response, especially when multiple infusions are required to obtain therapeutic efficacy. In a randomized Phase II clinical study, 83 patients with colorectal carcinoma of stage Dukes C were treated with the murine IgG2a mAb 17-1A (ab1) after curative surgery. The regimen consisted of a single infusion of 500mg of 17-1A within 2 weeks after surgery, followed by 100mg of mAbs four times every 4 weeks. Sera were taken every 2-3 weeks and screened for human antimouse antibodies (HAMA). HAMA were measured by a capture ELISA and an indirect antihuman immunoglobulin ELISA for the analysis of IgG and IgM isotypes. Anti-idiotypic antibodies (ab2) were detected by an inhibition ELISA, and anti-anti-idiotypic antibodies (ab3), recognizing the original antigen, were determined by flow cytometric analysis. About 20% of patients failed to develop HAMA; in the other patients, antibody titers were initially low after the first two infusions and reached their maximum only after a fifth infusion at 18-20 weeks after surgery. An analysis that differentiated between patients who developed recurrences and those who remained tumor-free did not show any difference in antibody titers between the two groups, neither for total HAMA nor for IgG, IgM, or ab2. The formation of ab3 was analyzed in eight patients and proved to be negative in all of them. HAMA remained detectable up to 2 years after the last treatment. In patients who experienced adverse events associated with therapy, HAMA titers tended to rise earlier; this difference, however, was not statistically significant. Thus, neither a beneficial nor a detrimental effect of HAMA formation could be determined for the clinical response to antibody therapy.
Human factor VIII can be packaged and functionally expressed in an adeno‐associated virus background: applicability to haemophilia A gene therapy (1999)

Adeno-associated virus (AAV) is a single-stranded DNA parvovirus displaying several attractive features applicable to haemophilia A gene therapy, including nonpathogenicity and potential for long-term transgene expression from either integrated or episomal forms. We have generated and characterized two B-domain-deleted (BDD) fVIII mutants, deleted in residues Phe756 to Ile1679 (fVIIIdelta756-1679) or Thr761 to Asn1639 (fVIIIdelta761-1639). [35S]metabolic labelling experiments and immunoprecipitation demonstrated intact BDD-fVIII of the predicted size in both lysates and supernatants (Mr approximately 155 kD for fVIIIdelta756-1679 and Mr approximately 160 kD for fVIIIdelta761-1639) after transient transfection into COS-1 cells. Functional fVIII quantification appeared maximal using fVIIIdelta761-1639, as evaluated by Coatest and clotting assay (98+/-20mU/ml/1x10(6) cells and 118+/-29 mU/ml/1x10(6) respectively, collection period 48 h). To bypass potential size limitations of rAAV/fVIII vectors, we expressed fVIIIdelta761-1639 using a minimal human 243 bp cellular small nuclear RNA (pHU1-1) promoter, and demonstrated VIII activity approximately 30% of that seen using CMV promoter. This BDD-fVIII (rAAV(pHU1-1) fVIIIdelta761-1639) can be efficiently encapsidated into rAAV (107% of wild type), as demonstrated by replication centre and DNAase sensitivity assays. A concentrated recombinant viral stock resulted in readily detectable factor VIII expression in COS-1 cells using a maximally-achievable MOI approximately 35 (Coatest 15 mU/ml; clotting assay 25+/-20 mU/ml/1x10(6) cells). These data provide the first evidence that rAAV is an adaptable virus for fVIII delivery, and given the recent progress using this virus for factor IX delivery in vivo, provide a new approach towards definitive treatment of haemophilia A.
Molecular analysis of the Escherichia coli phoP-phoQ operon (1992)

The phoP-phoQ operon of Salmonella typhimurium is a member of the family of two-component regulatory systems and controls expression of the phoN gene that codes for nonspecific acid phosphatase and the genes involved in the pathogenicity of the bacterium. The phoP-phoQ operon of Escherichia coli was cloned on a plasmid vector by complementation of a phoP mutant, and the 4.1-kb nucleotide sequence, which includes the phoP-phoQ operon and its flanking regions, was determined. The phoP-phoQ operon was mapped at 25 min on the standard E. coli linkage map by hybridization with the Kohara mini set library of the E. coli chromosome (Y. Kohara, K. Akiyama, and K. Isono, Cell 50:495-508, 1987). The predicted phoP and phoQ gene products consist of 223 and 486 amino acids with estimated molecular masses of 25,534 and 55,297 Da, respectively, which correspond well with the sizes of the PhoP and PhoQ proteins identified by the maxicell method. The amino acid sequences of PhoP and PhoQ of E. coli were 93 and 86% identical, respectively, to those of S. typhimurium.
Chemiluminescent Probe for the in Vitro Detection of Protease Activity (2007)

A strategy involving the use of a self-immolative linker has been investigated for the chemiluminescent sensing of proteases. The reactive linker enabled the release of a 1,2-dioxetane light precursor. As a proof of principle, caspase-3, a key peptidase involved in apoptosis has been targeted. An in vitro assay has been carried out and proved the decomposition of the linker and the selectivity for caspase-3.
Fluorescent choleretic and cholestatic bile salts take different paths across the hepatocyte: transcytosis of glycolithocholate leads to an extensive redistribution of annexin II. (1994)

We have used fluorescent derivatives of the choleretic bile salts cholate and chenodeoxycholate, the cholestatic salt lithocholate, and the therapeutic agent ursodeoxycholate to visualize distinct routes of transport across the hepatocyte and delivery to the canalicular vacuole of isolated hepatocyte couplets. The cholate and chenodeoxycholate derivatives produced homogeneous intracellular fluorescence and were rapidly transported to the vacuole, while the lithocholate analogue accumulated more slowly in the canalicular vacuole and gave rise to punctate fluorescence within the cell. Fluorescent ursodeoxycholate showed punctate intracellular fluorescence against a high uniform background indicating use of both pathways. Inhibition of vesicular transport by treatment with colchicine and Brefeldin A had no effect on the uptake of any of the compounds used, but it dramatically impaired delivery of both the lithocholate and the ursodeoxycholate derivatives to the canalicular vacuole. We conclude that while the chenodeoxycholate and cholate analogues traverse the hepatocyte by a cytoplasmic route, lithocholate and ursodeoxycholate analogues are transported by vesicle-mediated transcytosis. Treatment of couplets with glycine derivatives of lithocholate and ursodeoxycholate, but not cholate or chenodeoxycholate, led to a marked relocalization of annexin II, which initially became concentrated at the basolateral membrane, then moved to a perinuclear distribution and finally to the apical membrane as the incubation progressed. This suggests that lithocholate and ursodeoxycholate treatment leads to a rapid induction of transcytosis and that annexin II exchange occurs upon membrane fusion at all stages of the hepatocyte transcytotic pathway. These results indicate that isolated hepatocyte couplets may provide an inducible model system for the study of vesicle-mediated transcytosis.
Performance of subcutaneously implanted needle-type glucose sensors employing a novel trilayer coating (1993)

A miniature, needle-type glucose sensor based on a new trilayer membrane configuration has been prepared and evaluated both in vitro and in vivo. The perfluorinated ionomer, Nafion, was used as a protective, biocompatible, outer coating, and poly(o-phenylenediamine) as an inner coating to reduce interference by small, electroactive compounds. Glucose oxidase immobilized in a bovine serum albumin matrix was sandwiched between these coatings. The entire sensor assembly of Pt working electrode and Ag/AgCl reference electrode was 0.5 mm in diameter and could be inserted subcutaneously through an 18-gauge needle. The sensor current closely followed the plasma glucose level during a glucose tolerance test in active dogs, with a delay of 3 min, corresponding to the known lag time for subcutaneous glucose levels. The sensor remained functional after 1 week of implantation, but failed after 2 weeks due to degradation of the reference electrode. In vitro tests in pH 7.4 buffer or whole blood show the sensors have good selectivity, sensitivity of about 25 nA/mM, precision of 2-5%, and a 90% response time of 33 s. Stabilization following polarization requires 10-30 min in vitro and 30-40 min in vivo.
Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA (2005)

MicroRNAs are small RNA molecules that regulate messenger RNA (mRNA) expression. MicroRNA 122 (miR-122) is specifically expressed and highly abundant in the human liver. We show that the sequestration of miR-122 in liver cells results in marked loss of autonomously replicating hepatitis C viral RNAs. A genetic interaction between miR-122 and the 5' noncoding region of the viral genome was revealed by mutational analyses of the predicted microRNA binding site and ectopic expression of miR-122 molecules containing compensatory mutations. Studies with replication-defective RNAs suggested that miR-122 did not detectably affect mRNA translation or RNA stability. Therefore, miR-122 is likely to facilitate replication of the viral RNA, suggesting that miR-122 may present a target for antiviral intervention.
Effectiveness of the Slip Circle, “COMBINATOR”, Model for Combined Tire Cornering and Braking Forces When Applied to a Range of Tires (1998)

&lt;div class="htmlview paragraph"&gt;The slip circle, COMBINATOR, model was developed to predict combined driving or braking and cornering performance of tires from straight-line torqued data and free-rolling cornering data only. In the original COMBINATOR paper, limited verification was presented. In the current paper, the model is shown to be broadly applicable to tires of all types. This is demonstrated through successful modeling of heavy-duty tires as large as 425/65R22.5 and by modeling of racing tires. The heavy duty tire models and summarized data are available from SAE Cooperative Research on electronic media.&lt;/div&gt;
Extrachromosomal MicroDNAs and Chromosomal Microdeletions in Normal Tissues (2012)

We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200 to 400 base pairs long, are derived from unique nonrepetitive sequence, and are enriched in the 5'-untranslated regions of genes, exons, and CpG islands. Chromosomal loci that are enriched sources of microDNA in the adult brain are somatically mosaic for microdeletions that appear to arise from the excision of microDNAs. Germline microdeletions identified by the "Thousand Genomes" project may also arise from the excision of microDNAs in the germline lineage. We have thus identified a previously unknown DNA entity in mammalian cells and provide evidence that their generation leaves behind deletions in different genomic loci.