gebhart/patrepeval huggingface dataset:
Activity of Thalidomide in AIDS-Related Kaposi’s Sarcoma (2000)

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi’s sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)–seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm 3 (range, 14 to 646 cells/mm 3 ) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.
Purification and characterization of a murine basement membrane collagen-degrading enzyme secreted by metastatic tumor cells. (1983)

A type IV collagen-degrading enzyme activity secreted by a highly metastatic mouse tumor was purified by concanavalin A- and type IV collagen-agarose affinity chromatographies followed by gel filtration on Bio-Gel A-0.5 m. The apparent molecular weight of the enzyme was 160,000 but about 70,000 when Triton X-100 was added to the column buffer. The purified enzyme protein was resolved on sodium dodecyl sulfate-polyacrylamide gel electrophoresis into two polypeptide chains of about 68,000 and 62,000 daltons. The enzyme activity could be increased by preincubation with trypsin and it is possible that the two chains represent latent and active enzyme forms. The enzyme activity was not reduced in the presence of dithiothreitol, it had a pH optimum of 7.6 and was inhibited by EDTA but not N-ethylmaleimide, phenylmethylsulfonyl fluoride, or Trasylol. The inhibition with EDTA was reversible. The pro-alpha 1(IV) and pro-alpha 2(IV) chains of the type IV procollagen substrate were both degraded at a similar rate to form two pairs of degradation fragments corresponding in molecular weights to about 70 and 30% of the original size chains. The presence of Triton X-100 increased slightly the activity of the enzyme and diminished the reduction of its activity upon freezing, indicating that the enzyme is a hydrophobic protein.
Proteases and the emerging role of protease inhibitors in prohormone processing (1994)

Peptide hormones and neurotransmitters constitute a large class of neurohumoral agents that mediate cell-cell communication in neuroendocrine systems. Their biosynthesis requires proteolytic processing of inactive protein precursors into active neuropeptides. Elucidation of the proteolytic components required for prohormone processing is important for identifying key proteases that may control the production of neuropeptides. This article compares the subtilisin-like PC1/3 and PC2 processing enzymes identified through molecular biological approaches, and several candidate processing enzymes identified biochemically, including the 'proopiomelanocortin converting enzyme' (PCE) and the 'prohormone thiol protease' (PTP), as well as others of different classes (aspartyl, cysteine, metallo, and serine proteases). A role for PTP in cellular proenkephalin processing is suggested by blockade of forskolin-stimulated (Met)enkephalin production by Ep453 that is converted intracellularly to E-64c, a selective cysteine protease inhibitor that potently inhibits PTP. A possible role for endogenous protease inhibitors in prohormone processing represents a new aspect of cellular mechanisms that may regulate neuropeptide biosynthesis. Future studies of the enzymology and molecular biology of processing enzymes and endogenous protease inhibitors will be necessary to elucidate mechanisms of prohormone processing.
Crystal-induced neutrophil activation. V. Differential production of biologically active IL-1 and IL-1 receptor antagonist. (1994)

Neutrophils produce IL-1 when stimulated by monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals. Neutrophils also generate the IL-1R antagonist (IL-1Ra), especially when incubated with granulocyte-macrophage CSF (GM-CSF) or TNF-alpha. We studied the simultaneous expression of IL-1 and IL-1Ra by GM-CSF- or TNF-alpha-treated neutrophils activated by MSU or CPPD. Neutrophils incubated with GM-CSF or TNF-alpha produced approximately 300 or 200 times more IL-1Ra than IL-1, respectively. Suboptimal concentrations of MSU or CPPD induced low amounts of IL-1 without affecting IL-1Ra. Interaction of GM-CSF- and TNF-alpha-treated neutrophils with MSU or CPPD up-regulated IL-1 while simultaneously down-regulating IL-1Ra. As a result, the bioactivity of IL-1 secreted was enhanced. Synergistic increases of IL-1 (but not IL-1Ra) mRNA levels were noted in GM-CSF- or TNF-alpha-treated neutrophils exposed to CPPD. Treatment of neutrophils with colchicine before incubation with GM-CSF or TNF alpha, inhibited crystal-induced IL-1 by 50 to 55%, but failed to significantly affect IL-1Ra. The IL-1Ra to IL-1 ratio was significantly increased by 185 to 220%. These results demonstrate that IL-1 and IL-1Ra production by human neutrophils are differentially regulated, that the combined presence of GM-CSF or TNF-alpha and microcrystals favor the production of biologically active IL-1 over that of IL-1Ra, and that colchicine selectively inhibits IL-1 without affecting IL-1Ra production.
Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction (2010)

The findings in this study identify potential therapeutics [i.e. N2 peptide or 21G6 F(ab')(2)] that prevent specific IgM binding to ischaemic antigens in the heart, resulting in a significant reduction in cardiac I/R injury.
Disruption of virus movement confers broad-spectrum resistance against systemic infection by plant viruses with a triple gene block. (1994)

White clover mosaic virus strain O (WClMV-O), species of the Potexvirus genus, contains a set of three partially overlapping genes (the triple gene block) that encodes nonvirion proteins of 26 kDa, 13 kDa, and 7 kDa. These proteins are necessary for cell-to-cell movement in plants but not for replication. The WClMV-O 13-kDa gene was mutated (to 13*) in a region of the gene that is conserved in all viruses known to possess triple-gene-block proteins. All 10 13* transgenic lines of Nicotiana benthamiana designed to express the mutated movement protein were shown to be resistant to systemic infection by WClMV-O at 1 microgram of WClMV virions per ml, whereas all plants from susceptible control lines became systemically infected. Of the 13* transgenic lines, 3 selected for their abundant seed supply were shown to be resistant to systemic infection when challenged by inoculation with three different WClMV strains (O, M, and J) or with WClMV-O RNA at 10 micrograms/ml. Most plants were also resistant to systemic infection at inoculum concentrations up to 250 micrograms of WClMV virions per ml. In addition, the three 13* transgenic plant lines were found to be resistant to systemic infection with two other members of the Potexvirus group, potato virus X and narcissus mosaic virus, and the Carlavirus potato virus S but not to be resistant to tobacco mosaic virus of the Tobamovirus group. These results indicate that virus resistance can be engineered into transgenic plants by expression of dominant negative mutant forms of triple-gene-block movement proteins.
Prognostic Gene-Expression Signatures in Adult Acute Myeloid Leukemia with Normal Karyotype. (2005)

Abstract Acute myeloid leukemia (AML) encompasses a large number of morphologically similar but molecularly distinct variants. Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value. However, despite recent successes in detecting novel molecular markers like FLT3 (fms-related tyrosine kinase 3) mutation, treatment stratification is still difficult, especially for the 40–45% of patients with intermediate-risk, normal karyotype disease. To better characterize AML at the molecular level, and to address the need for improved risk stratification, we recently profiled gene expression in a large series of adult AML patients (Bullinger et al., N Engl J Med350:1605, 2004). By unsupervised analysis we identified new prognostically-relevant AML subgroups, and using a supervised learning algorithm we constructed a gene-expression based outcome predictor, which accurately predicted overall survival across all patients, including for the subset of AML cases normal karyotype. Having demonstrated the presence at diagnosis of normal karyotype signatures correlating with clinical outcome, we have now sought to refine a prognostic signature specific for normal karyotype disease. Towards this goal, we have now profiled 119 samples of adult AML patients with normal karyotype using 42k cDNA microarrays from the Stanford Functional Genomics Facility. By semi-supervised analysis using the supervised principal component method (Bair et al., PLoS Biology2:511, 2004), we built a cross-validated gene-expression based outcome predictor in a randomly partitioned training set (n=60 samples). This outcome signature, comprising only 16 genes, significantly predicted outcome class for normal karyotype samples in the independent test set (n=59 samples; P=0.001). In multivariate analysis, the 16-gene signature was a strong [odds ratio=0.35 (0.13 to 0.91); P=0.01] factor in predicting overall survival, independent of known prognostic factors including FLT3 mutations and preceeding malignancy. Our findings support the utility of expression profiling for improved risk stratification and clinical management of the clinically important subclass of AML patients with normal karyotype disease.
Studies of Glycogen Synthesis and the Krebs Cycle by Mass Isotopomer Analysis with [U-13C]Glucose in Rats (1989)

Starved rats were infused intragastrically via indwelling duodenal cannulae with glucose at a rate of 30 mg/min/kg. The infusate contained [U-13C]glucose at an enrichment of 32 or 17%. At the end of the infusion, after 160 min, glucose and lactate were isolated from arterial and portal blood and from liver, and liver glycogen was isolated and hydrolyzed to glucose. The enrichment in glucose and lactate and the isotopomer distribution in glucose of masses from 180 to 186 were determined by gas chromatography-mass spectrometry (GC-MS). From analysis of these data we determined (a) gluconeogenesis proceeds at half the basal rate in the presence of a large infused glucose load, (b) one-quarter of the hepatic pyruvate pool is derived from nonglucose carbon, (c) half of the labeled molecules in liver glycogen are of mass 186 from the infused glucose and half are of masses 181-183, (d) the contribution of the indirect path from pyruvate when corrected for synthesis from unlabeled pyruvate ranges from 55 to 65%, (e) the rate of pyruvate carboxylase averages 90% that of citrate synthase, and (f) the rate of exchange of oxaloacetate with fumarate is about three times the rate of flux in the Krebs cycle (four times in the "forward" direction), and the enrichment in carbon 1 of oxaloacetate was 2.3 times that in carbon 4. In the Appendix a method to obtain the isotopomer distribution of newly formed glucose and glycogen glucose is described. An algorithm to correct for the contribution of natural abundance of 13C and the presence of 12C in commercial [U-13C]glucose is presented. A novel mathematical analysis to obtain the parameters of the Krebs cycle from the isotopomer distribution is developed in the Appendix. Equations to calculate the relative rates of pyruvate carboxylase (y), and the equilibration of oxaloacetate with fumarate from the isotopomer distribution are derived. Mass isotopomer analysis provides a novel and powerful tool for the study of carbohydrate metabolism and the operation of the Krebs cycle.
Enhancement of sleep slow waves: underlying mechanisms and practical consequences (2014)

Even modest sleep restriction, especially the loss of sleep slow wave activity, is invariably associated with slower EEG activity during wake, the occurrence of local sleep in an otherwise awake brain, and impaired performance due to cognitive and memory deficits. Recent studies not only confirm the beneficial role of sleep in memory consolidation, but also point to a specific role for sleep slow waves. Thus, the implementation of methods to enhance sleep slow waves without unwanted arousals or lightening of sleep could have significant practical implications. Here we first review the evidence that it is possible to enhance sleep slow waves in humans using transcranial direct-current stimulation and transcranial magnetic stimulation. Since these methods are currently impractical and their safety is questionable, especially for chronic long-term exposure, we then discuss novel data suggesting that it is possible to enhance slow waves using sensory stimuli. We consider the physiology of the K-complex, a peripheral evoked slow wave, and show that, among different sensory modalities, acoustic stimulation is the most effective in increasing the magnitude of slow waves, likely through the activation of non-lemniscal ascending pathways to the thalamo-cortical system. In addition, we discuss how intensity and frequency of the acoustic stimuli, as well as exact timing and pattern of stimulation, affect sleep enhancement. Finally, we discuss automated algorithms that read the EEG and, in real-time, adjust the stimulation parameters in a closed-loop manner to obtain an increase in sleep slow waves and avoid undesirable arousals. In conclusion, while discussing the mechanisms that underlie the generation of sleep slow waves, we review the converging evidence showing that acoustic stimulation is safe and represents an ideal tool for slow wave sleep enhancement.
Historicism and 'Presentism' in Early Modern Studies (2000)

Historicism and ‘Presentism’ in Early Modern Studies Robin Headlam Wells Robin Headlam Wells Search for other works by this author on: Oxford Academic Google Scholar The Cambridge Quarterly, Volume XXIX, Issue 1, 2000, Pages 37–60, https://doi.org/10.1093/camqtly/XXIX.1.37 Published: 01 January 2000
Fluorescent dyes alter intracellular targeting and function of cell‐penetrating tetrapeptides (2004)

Fluorescent labels are commonly used to investigate the mechanisms of cellular uptake and intracellular distribution of cell-penetrating peptides. However, labels such as fluorescein and rhodamine are relatively large and very lipophilic and may significantly alter physicochemical properties of small peptides. To minimize the impact of the fluorescent probe on a tetrapeptide, we substituted one of the amino acids (Lys4) in a tetrapeptide ([Dmt1]DALDA, Dmt-D-Arg-Phe-Lys-NH2 where Dmt = 2',6'-dimethyltyrosine) with two different fluorescent amino acids (beta-dansyl-L-alpha,beta-diaminopropionic acid (dnsDap4) or beta-anthraniloyl-L-alpha,beta-diaminopropionic acid (atnDap4)). Initial studies with confocal laser scanning microscopy (CLSM) showed very different localization patterns for the two fluorescent analogs, with [Dmt1,atnDap4]DALDA showing mitochondrial localization and [Dmt1,dnsDap4]DALDA showing diffuse cytoplasmic localization. Studies with isolated mouse liver mitochondria suggested that [Dmt1,dnsDap4]DALDA targeted the mitochondrial matrix resulting in mitochondrial depolarization, opening of the permeability transition pore, mitochondrial swelling, and rapid release of the peptide into the cytoplasm. In contrast, [Dmt1,atnDap4]DALDA was retained in the inner mitochondrial membrane and did not induce mitochondrial swelling. Furthermore, [Dmt1,atnDap4]DALDA protected mitochondria against Ca2+-induced swelling. Importantly, the unlabeled parent peptide [Dmt1]DALDA behaved like [Dmt1,atnDap4]DALDA and was mitoprotective. These findings suggest that experimental results obtained with fluorescent labels must be interpreted with caution, and the use of multiple fluorophores, together with confirmation using the original or radiolabeled molecule, is recommended.
Leptin and Adipocytokines: Bridging the Gap Between Immunity and Atherosclerosis (2007)

The role of the adipose tissue in immunity has recently emerged, and there is now ample evidence that this role is elucidated by a number of cytokine-like hormones produced by adipocytes - called adipokines. The most relevant adipokines are leptin, adiponectin and visfatin, and all have marked effects on metabolic and immune function. The discovery of adipokines has led to the development of a novel concept that the pathogenesis of atherosclerosis can be associated with low-degree inflammation associated with slow (auto)immune attack of the endothelial wall of arteries. This model considers therefore adipokines as the bridge between atherosclerosis, inflammation and immunity. We review here the most recent advances on adipokine research, with a particular emphasis on the model that considers atherosclerotic lesions as effects of the (auto)immune-mediated damage of the endothelium that is sustained by low-degree chronic inflammation typical of obesity and metabolic syndrome.
Identification of highly conserved regulatory domains and protein-binding sites in the promoters of the rat and human genes encoding the stress-inducible 78-kilodalton glucose-regulated protein. (1988)

The gene encoding GRP78 has been shown to be constitutively expressed in many cell types and is inducible by the calcium ionophore A23187. To understand the regulation of GRP78 transcription, we analyzed the components that control its basal-level expression. By transfecting deletions into cells, we have identified a 54-nucleotide cis-acting regulatory element important for high basal-level expression and a contiguous 50-nucleotide element for both basal-level expression and A23187 induction. Using DNase footprinting assays with both rat and human GRP78 promoters, we demonstrated that the protein factors present in the HeLa cell nuclear extracts bind to the regulatory regions identified by the deletion studies. This domain contains a palindromic sequence and is highly conserved among GRP genes in Caenorhabditis elegans, chicks, rats, and humans.
C‐reactive protein as a prognostic marker for men with androgen‐independent prostate cancer (2008)

C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (<or=8 mg/L) or abnormal (>8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy.
Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants (1990)

To study the roles of viral genes in the establishment and maintenance of herpes simplex virus (HSV) latency, we have developed a polymerase chain reaction assay that is both quantitative and sensitive. Using this assay, we analyzed the levels of viral DNA in trigeminal ganglia of mice inoculated corneally with HSV mutants that are defective for virus replication at one or more sites in mice and for reactivation upon ganglionic explant. Ganglia from mice infected with thymidine kinase-negative mutants, which replicate at the site of inoculation and establish latency but do not replicate acutely in ganglia or reactivate upon explant, contained a range of levels of HSV DNA that overlapped with the range found in ganglia latently infected with wild-type virus. On average, these mutant-infected ganglia contained one copy of HSV DNA per 100 cell equivalents (ca. 10(4) molecules), which was 50-fold less than the average for wild-type virus. Ganglia from mice infected with a ribonucleotide reductase deletion mutant, which is defective for acute replication and reactivation upon ganglionic explant, also contained on average one copy of HSV DNA per 100 cell equivalents. We also detected substantial numbers of HSV DNA molecules (up to ca. 10(3] in ganglia of mice infected with an ICP4 deletion mutant and other replication-negative mutants that are severely impaired for viral DNA replication and gene expression. These results raise the possibility that such mutants can establish latency, which could have important implications for mechanisms of latency and for vaccine and antiviral drug development.
Is thrombolytic therapy really better than conventional treatment in acute inferior myocardial infarction? (1995)

In general, no letter should contain more than six references (also typed with double spacing
Embryonic Stem Cells Proliferate and Differentiate when Seeded into Kidney Scaffolds (2009)

The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.
[Plaque surgery for Peyronie's disease: heterologous grafts]. (2003)

Surgical treatment of Induratio Penis Plastica includes conservative procedures (phalloplasty), substitutive procedures (prosthesis) and combined procedures (phalloplasty plus prosthesis). Our policy for conservative treatment is based on radical removal of the plaque and replacement with biological patches. During a 15 year experience we employed lyophilized dura mater, autologous dermal graft, preputial skin, cadaveric dermal graft (AlloDerm), venous graft and porcine SIS (Small Intestine Submucosa) graft. Our experience confirms the superiority of venous grafts, but preliminary results with SIS grafts are encouraging.