gebhart/patrepeval huggingface dataset:
Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector (2015)

Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.
Identification of Vascular Endothelial Growth Factor Receptor-1 Tyrosine Phosphorylation Sites and Binding of SH2 Domain-containing Molecules (1998)

Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for Src homology 2 domain-containing molecules. By expressing the intracellular domain of Flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at Tyr-1213 and Tyr-1242 and two minor tyrosine phosphorylation sites at Tyr-1327 and Tyr-1333 in this receptor. This pattern of phosphorylation of Flt-1 was also detected in vascular endothelial growth factor-stimulated cells expressing intact Flt-1. In vitro protein binding studies using synthetic peptides and immunoblotting showed that phospholipase C-gamma binds to both Y(p)1213 and Y(p)1333, whereas Grb2 and SH2-containing tyrosine protein phosphatase (SHP-2) bind to Y(p)1213, and Nck and Crk bind to Y(p)1333 in a phosphotyrosine-dependent manner. In addition, unidentified proteins with molecular masses around 74 and 27 kDa bound to Y(p)1213 and another of 75 kDa bound to Y(p)1333 in a phosphotyrosine-dependent manner. SHP-2, phospholipase C-gamma, and Grb2 could also be shown to bind to the intact Flt-1 intracellular domain. These results indicate that a spectrum of already known as well as novel phosphotyrosine-binding molecules are involved in signal transduction by Flt-1.
Development of Anaplasmamarginale in salivary glands of male Dermacentor andersoni (1993)

Development of the rickettsia, Anaplasma marginale, in salivary glands of male Dermacentor andersoni exposed as nymphs or adult ticks, was studied indirectly by inoculation of susceptible calves with homogenates and directly by examination, using light microscopy and a DNA probe; some unfed ticks were incubated before tissues were collected. Salivary gland homogenates made from ticks in every treatment group caused anaplasmosis when injected into susceptible calves; prepatent periods decreased as the time that ticks had fed increased. Colonies of A marginale were seen only in salivary glands of ticks exposed as adults and not in those exposed as nymphs; the percentage of salivary gland acini infected in these ticks increased linearly with feeding time. However, the probe detected A marginale DNA in salivary glands of ticks from both groups; the amount of DNA detected increased as feeding time was extended. The amount of A marginale DNA appeared to remain constant in gut tissues, but to increase in salivary glands. Salivary glands of adult-infected male ticks that were incubated, but did not feed a second time, became infected with A marginale, and the pattern of infection of acini varied with incubation temperature. Development of A marginale in salivary glands appears to be coordinated with the tick feeding cycle; highest infection rate was observed in ticks exposed as adults.
Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia (2006)

PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.
Characterization of two extreme variants involving the short arm of chromosome 22: are they identical? (1997)

The heteromorphic nature of the short-arms of human acrocentric chromosomes is considered the norm without any dire consequences. We characterized two highly unusual chromosome 22 variants with extremely enlarged short arms by routine and molecular cytogenetic techniques. Routine banding revealed that the two variants were not alike. Therefore, a characterization by fluorescent in situ hybridization (FISH) technique became warranted and revealed their remarkable differences. The first variant apparently had a tandem duplication of bands p11.2-->p13, while the second variant had a loss of the beta-satellite and ribosomal DNA regions with an apparent amplification of the satellite III region. The formation of these extremely enlarged regions can occur by a variety of mechanisms whose clinical significance remains obscure.
Differential, time-dependent effects of perivenous application of fibrin glue on medial thickening in porcine saphenous vein grafts☆ (2006)

Our data indicated that perivenous application of fibrin glue enhances graft thickening and as such does not constitute a strategy for preventing late vein graft failure after CABG.
The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. (1997)

Suppression of elevated CRP in patients with active RA is associated with improvement in functional score, whereas persistent elevation of CRP is associated with functional deterioration. Once abnormal CRP is suppressed, no functional deterioration is likely to occur without re-elevation in CRP. Therefore, elevated CRP provides a convenient short term correlation with functional outcome and can be used as a guide for therapy. A HAQ score is a sensitive indicator of change in early disease.
Pharmacokinetic properties of IgG and various Fc fusion proteins in mice (2015)

Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative study of different antibody-derived Fc fusion proteins. We could confirm that fusion of single-chain Fv (scFv) and single-chain diabody (scDb) molecules to an Fc region yields in fusion proteins with substantially extended half-lives compared with the single-chain versions. However, even fusion proteins with a size similar to that of IgG, e.g., scDb-Fc, did not have a half-life as long as an IgG molecule. Binding to the neonatal Fc receptor (FcRn) under acidic and neutral conditions was similar for IgG and all Fc fusion proteins. However, we observed differences between IgG and the Fc fusion proteins for dissociation of FcRn-bound proteins induced by shifting from acidic to neutral pH, reflecting the physiological release mechanism, further supporting a contribution of the kinetics of pH-dependent release from FcRn to the pharmacokinetic properties of IgG and Fc fusion proteins.
History and Diagnostic Significance of C‐Peptide (2008)

Starting with the epoch-making discovery of proinsulin, C-peptide has played an important interdisciplinary role, both as part of the single-chain precursor molecule and as an individual entity. In the pioneering years, fundamental systematic experiments unravelled new biochemical mechanisms and chemical structures. After the first detection of C-peptide in human serum, it quickly became a most useful independent indicator of insulin biosynthesis and secretion, finding application in a rapidly growing number of clinical investigations. A prerequisite was the development of specific immuno assays for proinsulin and C-peptide. Further milestones were: the chemical synthesis of several C-peptides and the accomplishments in the synthesis of proinsulin; the detection of preproinsulin with its bearings on understanding protein biosynthesis; the pioneering role of insulin, proinsulin, C-peptide, and mini-C-peptides in the development of recombinant DNA technology; and the discovery of the enzymes for the endoproteolytic processing of proinsulin into insulin and C-peptide, completing the pathway of biosynthesis. Today, C-peptide continues to serve as a special diagnostic tool in Diabetology and related fields. Thus, its passive role is well established. Evidence for its active role in physiology and pathophysiology is more recent and is subject of the following contributions.
Spinal Cord Stimulation for Chronic, Intractable Pain (1993)

Over the past two decades, spinal cord stimulation devices and techniques have evolved from single-channel systems, with electrodes requiring laminectomy, into programmable "multichannel" systems with electrodes that may be placed percutaneously. We have reviewed our experience in 320 consecutive patients treated with these devices at our institution between 1972 and 1990. Technical details of treatment as well as patient characteristics have been assessed as predictors of clinical outcome and of hardware reliability by univariate and multivariate statistical methods. Current follow-up has been obtained at intervals from 2 to 20 years (mean, 7.1 yr) postoperatively on 205 patients. All clinical outcome measures have been based on disinterested third-party interview data--standard analog pain ratings, employment status, activities of daily living, and use of analgesics. At 7-year mean follow-up, 52% of the 171 patients who received permanent implants reported at least 50% continued pain relief. A majority had maintained improvements in activities of daily living and analgesic use. Analysis of hardware reliability for 298 permanent implants revealed significantly fewer clinical failures (P < 0.001) and technical failures (in particular, electrode migration and malposition, P = 0.025) as single-channel implants have evolved into programmable, multichannel devices. Our analysis of technical and clinical prognostic factors may be useful to the clinician in selecting patients for this procedure.
Construction of intertypic chimeric dengue viruses by substitution of structural protein genes. (1991)

Dengue virus contains an 11-kilobase positive-strand RNA genome that codes for, in one open reading frame, three structural proteins (capsid, premembrane, and envelope), followed by seven nonstructural proteins. The structural protein genes of a full-length cDNA clone of type 4 dengue virus were replaced with the corresponding genes of dengue 1 or dengue 2 to create intertypic chimeric cDNA. The RNA transcripts made from these templates were infectious when transfected into permissive cells in culture. Progeny of chimeric cDNA produced apparently authentic dengue 1 or dengue 2 structural proteins, together with dengue 4 nonstructural proteins, and as a consequence exhibited type 1 or type 2 serological specificity. Both of the chimeras ultimately grew to the same titer as their type 1 or type 2 parent, but the type 2/type 4 chimera grew very slowly. This chimera also produced small plaques; in contrast, the type 1/type 4 chimera produced normal size plaques. The type 2/type 4 chimera retained the mouse neurovirulence of the dengue 2 virus, which was the source of its structural protein genes. Each of the mice inoculated intracerebrally with the chimera died, but survival time was prolonged. The retardation of replication of the type 2/type 4 chimeric virus suggests that this virus and possibly other intertypic dengue virus chimeras with similar properties should be examined for attenuation in primates and possible usefulness in a live dengue virus vaccine for humans.
Heart failure 1997 (1997)

Veterans Affairs Medical Center, Cardiology Section (111C). 41 50 Clement Street, San Francisco. CA 941 21, USA.
Protection against cyclophosphamide‐induced alopecia and inhibition of mammary tumor growth by topical 1,25‐dihydroxyvitamin D3 in mice (1998)

Twenty-one-day-old BALB/c mice were shaved on the back to synchronize hair growth. On day 30 or 31, when at least 90% of mice exhibited hair regrowth in the shaved area, 1,25(OH)2D3 was applied topically to the shaved area daily for 5 days. On the 6th day, cyclophosphamide (Cytoxan, CTX) was injected i.p. to induce hair loss in the shaved area. Alopecia was induced in a dose-dependent manner by CTX treatment within 1 to 2 weeks. This effect was reduced significantly if mice were pre-treated with 1,25(OH)2D3, though only slight protection was observed in female mice. Interestingly, this 1,25(OH)2D3-mediated protection against hair loss was attenuated in male mice but became more significant in female mice when they were inoculated with the EMT-6 murine mammary tumor prior to treatment. More importantly, topical treatment with 1,25(OH)2D3 alone was able to inhibit EMT-6 tumor growth in both male and female BALB/c mice. Furthermore, 1,25(OH)2D3 pre-treatment also augmented the anti-tumor effect of CTX. Our results demonstrate that topical application of 1,25(OH)2D3 can protect against CTX-induced alopecia both in tumor-free and in tumor-bearing mice in a sex-dependent manner. Moreover, 1,25(OH)2D3 was shown, either alone or in combination with CTX, to inhibit tumor growth. Int. J. Cancer 75:303–309, 1998. © 1998 Wiley-Liss, Inc.
Models of Inflation Expectations Formation: A Comparison of Household and Economist Forecasts (1983)

THE RECENT APPRECIATION of the critical role played by expectations of inflation in the behavior of macromodels has stimulated empirical studies of the formation of expectations by different groups. Time series survey data on expectations of inflation exist now for economists, households, and businesses. These data have been used as independent variables in explaining wage behavior (Gordon [16], Turnovsky and Wachter [34], and de Menil and Bhatta [5]), prices (Turnovsky and Wachter [34] and Wachtel [36]), interest rates (Gibson [14], Hendershott and Van Horne [19], Pearce [30], and Mishkin [27]), and consumption (Wachtel [36]), generally with a significant improvement in explanatory power. They have also been used as dependent variables in attempts to determine how expectations are formed by Gordon [15], Mullineaux [28], Jacobs and Jones [20], and Figlewski and Wachtel [9] for the economist survey, Van Duyne [35] for the household survey, and Leonard [23] and de Leeuw and McKelvey [4] for businesses. Given their different levels of knowlege of economics and perspectives, one might expect that the models used by the different groups to forecast inflation would
Site-directed mutagenesis of an invariant amino acid residue at the variable-diversity segments junction of an antibody. (1986)

Structural analysis of 21 murine A/J antibodies specific for the hapten p-azobenzenearsonate (Ars), and bearing the major cross reactive idiotype (IdCRI), has revealed an invariant amino acid residue, serine, encoded by the variable-diversity gene segments junction of the heavy chain. To test whether this serine residue is essential for Ars binding, we changed it either to alanine or to threonine by oligonucleotide-directed mutagenesis of a heavy chain gene. Genes containing the mutations were separately introduced into mouse hybridoma cells producing the homologous light chain, and the resulting proteins were tested for antigen binding and idiotypic expression. Whereas the serine to threonine mutant retains full antigen binding activity, the serine to alanine mutant does not bind either to Ars-bovine serum albumin-Sepharose or to the Ars-tyrosine hapten. Both mutants show the same reactivity as wild type towards a series of anti-idiotypic antibodies. These results suggest that a hydroxyl group at the variable-diversity gene segments junction of A/J anti-Ars antibodies is essential for antigen binding.
Impact of Mucosal Eosinophilia and Nasal Polyposis on Quality‐of‐Life Outcomes after Sinus Surgery (2009)

The presence of mucosal eosinophilia at the time of surgery consistently predicted less improvement in both disease-specific and general QOL compared with patients without eosinophilia. The impact of eosinophilia on outcomes was greatest for patients without nasal polyposis, a group that demonstrated the least improvement in QOL measures.
Dominant-Negative Inhibitors of Soluble TNF Attenuate Experimental Arthritis without Suppressing Innate Immunity to Infection (2007)

TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.
Orange-red Flesh in God and Haddock (1959)

Only rarely is Atlantic cod found with orange-red coloured skin and flesh. Astaxanthin and zeaxanthin, in the proportion of 2:1, were found to be responsible for the pigmentation of the flesh of such a specimen. Zeaxanthin was the only pigment detected in the flesh of a similarly pigmented haddock.
EGFR Mutations and Lung Cancer (2011)

Epidermal growth factor receptor (EGFR) is a transmembrane protein with cytoplasmic kinase activity that transduces important growth factor signaling from the extracellular milieu to the cell. Given that more than 60% of non-small cell lung carcinomas (NSCLCs) express EGFR, EGFR has become an important therapeutic target for the treatment of these tumors. Inhibitors that target the kinase domain of EGFR have been developed and are clinically active. More importantly, such tyrosine kinase inhibitors (TKIs) are especially effective in patients whose tumors harbor activating mutations in the tyrosine kinase domain of the EGFR gene. More recent trials have suggested that for advanced NSCLC patients with EGFR mutant tumors, initial therapy with a TKI instead of chemotherapy may be the best choice of treatment. Therefore, mutation testing is mandatory to identify these patients, given that selection based only on clinico-pathologic characteristics is inadequate. We review the role of EGFR mutations in the diagnosis and management of NSCLC.
Fixation of osteochondral fractures in rabbit knees. A comparison of Kirschner wires, fibrin sealant, and polydioxanone pins (1992)

We compared fibrin sealant, polydioxanone (PDS) pins and Kirschner wires in the fixation of osteochondral fractures in rabbit knees. Standardised osteochondral fractures of the right medial femoral condyle were made in 56 adult New Zealand white rabbits. There were equal groups of control knees, and those which had Kirschner-wire, fibrin-sealant or PDS-pin fixation. No external immobilisation was used. One animal from each group was killed at two, three and four weeks. The remaining rabbits were killed at six weeks. A fracture which healed with less than 1 mm of displacement was considered a success. There was successful healing in 29% of the control group, in all of the Kirschner-wire group, in 50% of the fibrin-sealant group, and in 86% of the PDS-pin group. The use of PDS pins appears to be a reliable alternative to the use of metal in the fixation of osteochondral fractures in rabbits.
Microarray-based comparison of three amplification methods for nanogram amounts of total RNA (2004)

Gene expression profiling using microarrays requires microgram amounts of RNA, which limits its direct application for the study of nanogram RNA samples obtained using microdissection, laser capture microscopy, or needle biopsy. A novel system based on Ribo-SPIA technology (RS, Ovation-Biotin amplification and labeling system) was recently introduced. The utility of the RS system, an optimized prototype system for picogram RNA samples (pRS), and two T7-based systems involving one or two rounds of amplification (One RA, Standard Protocol, or Two RA, Small Sample Prototcol, version II) were evaluated in the present study. Mouse kidney (MK) and mouse universal reference (MUR) RNA samples, 0.3 ng to 10 mug, were analyzed using high-density Affymetrix Mouse Genome 430 2.0 GeneChip arrays. Call concordance between replicates, correlations of signal intensity, signal intensity ratios, and minimal fold increase necessary for significance were determined. All systems amplified partially overlapping sets of genes with similar signal intensity correlations. pRS amplified the highest number of genes from 10-ng RNA samples. We detected 24 of 26 genes verified by RT-PCR in samples prepared using pRS. Two RA yielded somewhat higher call concordances than did RS and pRS (91.8% vs. 89.3% and 88.1%, respectively). Although all target preparation methods were suitable, pRS amplified the highest number of targets and was found to be suitable for amplification of as little as 0.3 ng of total RNA. In addition, RS and pRS were faster and simpler to use than the T7-based methods and resulted in the generation of cDNA, which is more stable than cRNA.
A Function for Kinesin I in the Posterior Transport of oskar mRNA and Staufen Protein (2000)

The asymmetric localization of messenger RNA (mRNA) and protein determinants plays an important role in the establishment of complex body plans. In Drosophila oocytes, the anterior localization of bicoid mRNA and the posterior localization of oskar mRNA are key events in establishing the anterior-posterior axis. Although the mechanisms that drive bicoid and oskar localization have been elusive, oocyte microtubules are known to be essential. Here we report that the plus end-directed microtubule motor kinesin I is required for the posterior localization of oskar mRNA and an associated protein, Staufen, but not for the anterior-posterior localization of other asymmetric factors. Thus, a complex containing oskar mRNA and Staufen may be transported along microtubules to the posterior pole by kinesin I.