gebhart/patrepeval huggingface dataset:
The pathogenesis of COPD and IPF: Distinct horns of the same devil? (2012)

New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases, despite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a "double hit" pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence of pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing factors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise the regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF, mesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling pathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal tissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases (irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD).
Islet cell failure in type 2 diabetes (2006)

The major focus of this Review is on the mechanisms of islet beta cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of beta cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of beta cell mass and for enhanced beta cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of "susceptible" islets and overall risk for T2D is reviewed. The likely mechanisms of beta cell failure are discussed within the two broad categories: those with initiation and those with progression roles.
New nuclear functions of the glycolytic protein, glyceraldehyde‐3‐phosphate dehydrogenase, in mammalian cells (2005)

Recent studies establish that the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is not simply a classical metabolic protein involved in energy production. Instead, it is a multifunctional protein with defined functions in numerous subcellular processes. New investigations establish a primary role for GAPDH in a variety of critical nuclear pathways apart from its already recognized role in apoptosis. These new roles include its requirement for transcriptional control of histone gene expression, its essential function in nuclear membrane fusion, its necessity for the recognition of fraudulently incorporated nucleotides in DNA, and its mandatory participation in the maintenance of telomere structure. Each of these new functions requires GAPDH association into a series of multienzyme complexes. Although other proteins in those complexes are variable, GAPDH remains the single constant protein in each structure. To undertake these new functions, GAPDH is recruited to the nucleus in S phase or its intracellular distribution is regulated as a function of drug exposure. Other investigations relate a substantial role for nuclear GAPDH in hyperglycemic stress and the development of metabolic syndrome. Considerations of future directions as well as the role of GAPDH post-translational modification as a basis for its multifunctional activities is suggested.
Micronuclei frequencies in hospital workers occupationally exposed to low levels of ionizing radiation: influence of smoking status and other factors (2002)

In the context of a medical surveillance program aimed at preventing cancer risk from exposure to ionizing radiation, we investigated chromosomal damage in peripheral lymphocytes from 37 hospital workers exposed to low levels of ionizing radiation and 37 controls. The micronuleus (MN) assay was used as a biomarker of genetic damage. The influence of confounding factors like smoking status, age and gender was investigated by multiple regression analysis. The results indicated that, overall, MN frequency was higher in exposed workers than in controls, although the difference was not statistically significant. Interestingly, smoking status significantly raised MN frequency among the exposed workers but not among controls. This suggests that smoking can influence chromosomal damage induced in humans by ionizing radiation. Among both exposed workers and controls, MN frequency was found to increase with age. Female gender influenced the increase in MN frequency in the exposed group. Our results suggest that the effect of cigarette smoking should be carefully factored into genetic monitoring studies assessing the risks associated with low level radiation exposure.
Bioactivation of Self-Immolative Dendritic Prodrugs by Catalytic Antibody 38C2 (2004)

Self-immolative dendrimers have recently been developed and introduced as a potential platform for a multi-prodrug. These unique structural dendrimers can release all of their tail units, through a self-immolative chain fragmentation, which is initiated by a single cleavage at the dendrimer's core. Incorporation of drug molecules as the tail units and an enzyme substrate as the trigger can generate a multi-prodrug unit that will be activated with a single enzymatic cleavage. We have synthesized the first generation of dendritic prodrugs with doxorubicin and camptothecin as tail units and a retro-aldol retro-Michael focal trigger, which can be cleaved by catalytic antibody 38C2. The bioactivation of the dendritic prodrugs was evaluated in cell-growth inhibition assay with the Molt-3 leukemia cell line in the presence and the absence of antibody 38C2. The dendritic unit was applied as a platform for a heterodimeric prodrug, which achieved a remarkable increase in toxicity with its bioactivation.
Genome-wide screening for trait conferring genes using DNA microarrays (2002)

We report a DNA microarray-based method for genome-wide monitoring of competitively grown transformants to identify genes whose overexpression confers a specific cellular phenotype. Whereas transcriptional profiling identifies differentially expressed genes that are correlated with particular aspects of the cellular phenotype, this functional genomics approach determines genes that result in a specific physiology. This parallel gene-trait mapping method consists of transforming a strain with a genomic library, enriching the cell population in transformants containing the trait conferring gene(s), and finally using DNA microarrays to simultaneously isolate and identify the enriched gene inserts. Various methods of enrichment can be used; here, genes conferring low-level antibiotic resistance were identified by growth in selective media. We demonstrated the method by transforming Escherichia coli cells with a genomic E. coli library and selecting for transformants exhibiting a growth advantage in the presence of the anti-microbial agent Pine-Sol. Genes conferring Pine-Sol tolerance (19 genes) or sensitivity (27 genes) were identified by hybridizing, on DNA microarrays containing 1,160 E. coli gene probes, extra-chromosomal DNA isolated from transformed cells grown in the presence of various levels of Pine-Sol. Results were further validated by plating and sequencing of individual colonies, and also by assessing the Pine-Sol resistance of cells transformed with enriched plasmid library or individual resistance genes identified by the microarrays. Applications of this method beyond antibiotic resistance include identification of genes resulting in resistance to chemotherapeutic agents, genes yielding resistance to toxic products (recombinant proteins, chemical feedstocks) in industrial fermentations, genes providing enhanced growth in cell culture or high cell density fermentations, genes facilitating growth on unconventional substrates, and others.
Cadherin switching in ovarian cancer progression (2003)

The roles of the cadherins in the progression of ovarian cancer to the late stages of the disease state when malignant cells have disseminated within the peritoneal cavity remain poorly understood. In view of these observations, we have undertaken a comprehensive survey of the cadherin subtypes present in normal ovarian surface epithelium and peritoneum and in the tumors and peritoneal effusions of women diagnosed with Stage I or Stage II primary ovarian cancer using a degenerate cloning strategy for sequences highly conserved among this family of cell adhesion molecules. On the basis of the nucleotide sequences of the resultant PCR products, multiple cadherin subtypes (E-, N-, P-cadherin, and cadherin-4, -6, and -11) were found to be present in these normal and malignant tissues and cells. P-cadherin was determined to be the predominant cadherin subtype in normal peritoneum, peritoneal effusions and Stage II tumor masses. An increase in P-cadherin mRNA and protein expression levels in ovarian tumor masses with progression to later stages of the disease state was confirmed by Northern and Western blot analysis, respectively. In addition, we have determined that the cadherin-associated protein, known as beta-catenin, is expressed in normal peritoneum, ovarian tumors and malignant cell effusions obtained from women with Stage I or Stage II cancer. Immunoprecipitation studies demonstrated that P-cadherin was capable of interacting with beta-catenin in these normal and malignant tissues and cells. Collectively, these findings suggest that the regulated expression of P-cadherin/beta-catenin complexes in ovarian tumor cells may represent a key step in disease progression.
Structural Properties of a Carbon-Nanotube Crystal (1994)

Carbon nanotubes of uniform size may soon be available in macroscopic quantities. Here we examine the ordered condensed phase of these tubes. As the tube diameter varies, the structural properties show a clear transition between two regimes with qualitatively different behavior. Tubes 10 \AA{} and less in diameter behave as rigid cylinders. For diameters over 25 \AA{}, the tubes flatten against each other under the van der Waals attraction, forming a honeycomb structure. This structure exhibits an anomalous rigidity, which does not decrease as expected with increasing tube diameter. Based on reported tube sizes, both regimes should be experimentally accessible.
Four workshops in alternate concepts in controlled fusion. Part B. Extended summaries (1977)

A review has been completed of fourteen alternate fusion reactor concepts that could lead to more practical power plants. These concepts are in addition to the Tokamak and mirror concepts which are presently receiving the bulk of the U.S. R and D effort. The concept characterizations were assembled by means of workshops and are presented in two sets of summaries. Part A is a concise executive summary written in nontechnical language and suitable for reading by executives who do not require a discussion of scientific details. A longer, more technical summary is presented in Part B. The objective is a presentation of the facts in a neutral tone without overselling or overcriticizing any concept. The concepts reviewed were limited to those employing magnetic confinement techniques for pure fusion power production.
Reviews of Books (1994)

Journal Article Reviews of Books Get access Révolution française et ‘vandalisme révolutionnaire’. Actes du colloque international de Clermont-Ferrand, 15–17 décembre 1988. Paris: Universitas. 1992. x + 461 pp. £45. ISBN 2 7400 0001 4. GWYNNE LEWIS GWYNNE LEWIS University of Warwick Search for other works by this author on: Oxford Academic Google Scholar French History, Volume 8, Issue 1, March 1994, Pages 106–108, https://doi.org/10.1093/fh/8.1.106 Published: 01 March 1994
Stereoselective cyclooxygenase inhibition in cellular models by the enantiomers of ketoprofen (1993)

Abstract The pharmacological activity of rac ‐ketoprofen and its enantiomers was investigated in vitro using different cellular models. The effect of these compounds on arachidonic acid metabolism was assessed by measuring the inhibition of prostanoid generation under the action of several agonists. Thus, we have evaluated the inhibition of (1) thromboxane B 2 synthesis in rabbit platelets and human polymorphonuclear leukocytes (PMNs), (2) prostaglandin E 2 synthesis in three cultured cells, namely human umbilical vein endothelial cells (HUVEC), human keratinocytes, and mouse macrophage‐like P388D1 cells. The IC 50 values found for (+)‐(S)‐ketoprofen were in the range between 0.1 n M and 0.8 μ M , being slightly lower in all models than those found for rac ‐ketoprofen (0.4 n M –3 μ M ). On the other hand, (−)‐(R)‐ketoprofen showed inhibition of cyclooxygenase only at concentrations two or three orders of magnitude higher than those required for the (+)‐(S) enantiomer. These results, obtained with cell types of relevance for inflammatory processes and with compounds of high optical purity, demonstrate that the prostanoid biosynthesis inhibition caused by the drug rac ‐ketoprofen is exclusively due to its dextrorotatory enantiomer. © 1993 Wiley‐Liss, Inc.
Primary Genetic Investigation of a Hyperlipidemia Model: Molecular Characteristics and Variants of the Apolipoprotein E Gene in Mongolian Gerbil (2014)

The objective of this work was to establish a novel Mongolian gerbil (Meriones unguiculatus) hyperlipidemia model and to investigate its susceptibility genetic basis. Two rodent (gerbil and rat) hyperlipidemia models were induced by feeding a high fat/high-cholesterol (HF/HC) diet. There were significant increases of serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in gerbils within a 4-week modeling period. About 10-30% of >8-month-old individuals developed hyperlipidemia spontaneously. The apolipoprotein E (ApoE) gene was cloned by merging a sequence of rapid amplification of cDNA ends (RACE) and nested polymerase chain reaction products. The results revealed an open reading frame of 948 bp, encoding a protein of 298 amino acids. The gene without a 5'-UTR region in the first intron was highly homologous to human Apo-A-I and rat Apo-A-IV. The distribution of expression of the ApoE gene in liver, brain, heart, lung, kidney, and adrenal gland was detected by an ABC immunohistochemical procedure. Three single nucleotide polymorphisms (SNPs; C97T, G781T, and A1774T) were first found using PCR-single-strand conformation polymorphism (PCR-SSCP) in a closed population containing 444 animals. Correlation analysis confirmed that new SNPs, age, and gender were associated significantly (P < 0.05) with hyperlipidemia.
2-methoxyestradiol enhances p53 protein transduction therapy-associated inhibition of the proliferation of oral cancer cells through the suppression of NFkappaB activity. (2004)

Protein transduction therapy using poly-arginine peptide can deliver the biologically active proteins. A previous study showed that 11 poly-arginine fused p53 protein (11R-p53) effectively penetrated across the plasma membrane and inhibited the proliferation of oral cancer cells. However, the intracellular half-life of the delivered protein was less than 36 h. Previous studies also showed that 2-methoxyestradiol (2-ME), an endogenous non-toxic estrogenic metabolite, induces the stabilization of the wild-type p53 protein in human cancer cells posttranscriptionally. In the present study, we examined whether 2-ME induced the stabilization of 11R-p53 and had an inhibitory effect on the proliferation of oral cancer cells. The application of 2-ME significantly enhanced the inhibitory effect of 11R-p53 on the proliferation of oral cancer cells. However, 2-ME had no effect on the intracellular half-life of 11R-p53 in oral cancer cells. Of interest is the finding that 2-ME suppressed the transcriptional activity of NFkappaB, which has an important role in tumorigenesis, but did not affect p53 transcriptional activity. These results suggest that 2-ME synergistically enhances the 11R-p53-induced inhibition of the proliferation of oral cancer cells through the suppression of NFkB transcription.
Secreted Immunodominant Mycobacterium tuberculosis Antigens Are Processed by the Cytosolic Pathway (2010)

Exposure to Mycobacterium tuberculosis can result in lifelong but asymptomatic infection in most individuals. Although CD8(+) T cells are elicited at high frequencies over the course of infection in both humans and mice, how phagosomal M. tuberculosis Ags are processed and presented by MHC class I molecules is poorly understood. Broadly, both cytosolic and noncytosolic pathways have been described. We have previously characterized the presentation of three HLA-I epitopes from M. tuberculosis and shown that these Ags are processed in the cytosol, whereas others have demonstrated noncytosolic presentation of the 19-kDa lipoprotein as well as apoptotic bodies from M. tuberculosis-infected cells. In this paper, we now characterize the processing pathway in an additional six M. tuberculosis epitopes from four proteins in human dendritic cells. Addition of the endoplasmic reticulum-Golgi trafficking inhibitor, brefeldin A, resulted in complete abrogation of Ag processing consistent with cytosolic presentation. However, although addition of the proteasome inhibitor epoxomicin blocked the presentation of two epitopes, presentation of four epitopes was enhanced. To further examine the requirement for proteasomal processing of an epoxomicin-enhanced epitope, an in vitro proteasome digestion assay was established. We find that the proteasome does indeed generate the epitope and that epitope generation is enhanced in the presence of epoxomicin. To further confirm that both the epoxomicin-inhibited and epoxomicin-enhanced epitopes are processed cytosolically, we demonstrate that TAP transport and new protein synthesis are required for presentation. Taken together, these data demonstrate that immunodominant M. tuberculosis CD8(+) Ags are processed and presented using a cytosolic pathway.
Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen (2003)

We generated fully human mAbs (HmAbs) to carcinoembryonic antigen (CEA) using the KM mouse, which carries a human chromosome 14 fragment containing the entire Ig H chain loci and human kappa L chain segments in the mouse genome. Forty-six hybridoma clones producing HmAbs to CEA were thus obtained by fusing the P3-U1 mouse myeloma cells with splenocytes of the KM mice immunized with CEA. Among them, 22 clones produced HmAbs that reacted with CEA but not with 3 other CEA-related cell adhesion molecule (CEACAM) family members, CEACAM1, CEACAM6 and CEACAM8. In 12 HmAbs examined, 8 were IgG4, 2 were IgG3, 1 was IgG2, and the other was IgG1. The affinity constants for CEA of these HmAbs were comparable to those of the previously prepared mouse anti-CEA mAbs (MmAbs). BIAcore analyses revealed that 1 and 2 of the 22 HmAbs react with 2 epitopes defined by MmAbs on the domain N and the domain A1 or B1 of CEA, respectively. In the presence of human complement in vitro, 2 HmAbs tested showed substantial cytotoxicity, namely, 50-65%, against CEA-expressing tumor cells. With human lymphokine-activated killer cells in vitro, 3 HmAbs tested exhibited 40-65% Ab-dependent cell-mediated cytotoxicity against the tumor cells. Moreover, one of the HmAbs induced a significant inhibition of tumor growth when administered to mice xenografted with the CEA-expressing cells. Considering their lack of immunogenicity to humans, these CEA-specific HmAbs may be useful for immunotherapeutic approaches as well as for immunodiagnosis.
Phenotype vs Genotype in the Evolution of Astrocytic Brain Tumors (2000)

Astrocytic brain tumors are the most frequent human gliomas and they include a wide range of neoplasms with distinct clinical, histopathologic, and genetic features. Diffuse astrocytomas are predominantly located in the cerebral hemispheres of adults and have an inherent tendency to progress to anaplastic astrocytoma and (secondary) glioblastoma. The majority of glioblastomas develop de novo (primary glioblastomas), without an identifiable less-malignant precursor lesion. These subtypes of glioblastoma evolve through different genetic pathways, affect patients at different ages, and are likely to differ in their responses to therapy. Primary glioblastomas occur in older patients and typically show epidermal growth factor receptor (EGFR) overexpression, PTEN mutations, p16 deletions, and, less frequently, MDM2 amplification. Secondary glioblastomas develop in younger patients and often contain TP53 mutations as their earliest detectable alteration. Morphologic variants of glioblastoma were shown to have intermediate clinical and genetic profiles. The giant cell glioblastoma clinically and genetically occupies a hybrid position between primary (de novo) and secondary glioblastomas. Gliosarcomas show identical gene mutations in the gliomatous and sarcomatous tumor components, which strongly supports the concept that there is a monoclonal origin for gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.
Correspondence Between a Mammalian Spliceosome Component and an Essential Yeast Splicing Factor (1993)

None of the mammalian splicing factors that have been cloned corresponds to the yeast pre-messenger RNA splicing factors, the PRP proteins. Here, a generalizable strategy was used to isolate a complementary DNA encoding the mammalian spliceosome-associated protein (SAP) SAP 62. It is demonstrated that SAP 62 is the likely functional homolog of the yeast PRP11 protein. Both PRP11 and SAP 62 associate stably with the spliceosome, contain a single zinc finger, and display significant amino acid sequence similarity. Unlike PRP11, SAP 62 contains 22 proline-rich heptapeptide repeats at the carboxyl-terminus.