gebhart/patrepeval huggingface dataset:
Three-Dimensional Computer-Assisted Design of Craniofacial Surgical Procedures (1986)

A computer program is described which aids the clinician in planning craniofacial surgical procedures. It operates on a three-dimensional landmark data base derived by combining posteroanterior and lateral cephalograms from the patient and from the Bolton normative standards. A three-dimensional surgical simulation program based on computerized tomographic (CT) data is also described which can be linked to the cephalometrically based program. After the clinician has selected the number and type of osteotomies to be performed on the patient, an automated optimization program computes the postoperative positions of these fragments which best fit the appropriate normal cephalometric form. The clinician then interactively modifies the design to account for such variables as bone-graft resorption, relapse tendency, occlusal disparities, and the condition of the overlying soft-tissue matrix. Osteotomy movement specifications are easily transferred between the CT-based and the cephalometrically based surgical simulation programs. This allows the automated positioning step to be performed on the cephalometrically based model while the interactive step is performed using the superior image provided by the CT-based model.
Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings (1987)

A detailed immunohistologic and cytogenetic analysis of 12 cases of intermediate lymphocytic lymphoma was performed. The characteristic immunophenotype of intermediate lymphocytic lymphoma was: surface IgM and IgD+, BA1+, B1+, BA2-, B2-, B4+, Leu 14+, Leu 1+, HLA-DR+, and common acute lymphocytic leukemia associated (CALLA) antigen negative. Clonal chromosome abnormalities were identified in ten cases, with structural or numerical abnormalities of chromosomes 11 or 12 in nine cases. Five cases had structural abnormalities involving the long arm of chromosome 11; three of these had translocations with chromosome 14 at band q32. Three cases had trisomy 12, and one case had a translocation involving the long arm of chromosome 12. The tenth case had a translocation involving the long arms of chromosomes 7 and 9. These characteristic immunophenotypic and cytogenetic findings suggest a close lineage relationship between intermediate lymphocytic lymphoma and small lymphocytic (well differentiated) lymphoma/chronic lymphocytic leukemia. Their differing clinical, cytologic, and architectural features suggest, however, that intermediate lymphocytic lymphoma should be considered a separate category of lymphocytic lymphoma in the International Working Formulation.
A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis (2013)

Studies in cell culture and mouse models of cancer have indicated that the soluble sphingolipid metabolite sphingosine 1-phosphate (S1P) promotes cancer cell proliferation, survival, invasiveness, and tumor angiogenesis. In contrast, its metabolic precursor ceramide is prodifferentiative and proapoptotic. To determine whether sphingolipid balance plays a significant role in glioma malignancy, we undertook a comprehensive analysis of sphingolipid metabolites in human glioma and normal gray matter tissue specimens. We demonstrate, for the first time, a systematic shift in sphingolipid metabolism favoring S1P over ceramide, which increases with increasing cancer grade. S1P content was, on average, 9-fold higher in glioblastoma tissues compared with normal gray matter, whereas the most abundant form of ceramide in the brain, C18 ceramide, was on average 5-fold lower. Increased S1P content in the tumors was significantly correlated with increased sphingosine kinase 1 (SPHK1) and decreased sphingosine phosphate phosphatase 2 (SGPP2) expression. Inhibition of S1P production by cultured glioblastoma cells, using a highly potent and selective SPHK1 inhibitor, blocked angiogenesis in cocultured endothelial cells without affecting VEGF secretion. Our findings validate the hypothesis that an altered ceramide/S1P balance is an important feature of human cancers and support the development of SPHK1 inhibitors as antiangiogenic agents for cancer therapy.
β 1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity (2009)

Inhibiting the alpha(4) subunit of the integrin heterodimers alpha(4)beta(1) and alpha(4)beta(7) with the monoclonal antibody natalizumab is an effective treatment for multiple sclerosis (MS). However, the pharmacological action of natalizumab is not understood conclusively. Previous studies suggested that natalizumab inhibits activation, proliferation, or extravasation of inflammatory cells. To specify which mechanisms, cell types, and alpha(4) heterodimers are affected by the antibody treatment, we studied MS-like experimental autoimmune encephalomyelitis (EAE) in mice lacking the beta(1)-integrin gene either in all hematopoietic cells or selectively in T lymphocytes. Our results show that T cells critically rely on beta(1) integrins to accumulate in the central nervous system (CNS) during EAE, whereas CNS infiltration of beta(1)-deficient myeloid cells remains unaffected, suggesting that T cells are the main target of anti-alpha(4)-antibody blockade. We demonstrate that beta(1)-integrin expression on encephalitogenic T cells is critical for EAE development, and we therefore exclude alpha(4)beta(7) as a target integrin of the antibody treatment. T cells lacking beta(1) integrin are unable to firmly adhere to CNS endothelium in vivo, whereas their priming and expansion remain unaffected. Collectively, these results suggest that the primary action of natalizumab is interference with T cell extravasation via inhibition of alpha(4)beta(1) integrins.
Myelination determines the caliber of dorsal root ganglion neurons in culture (1985)

In order to understand the relationship of supporting cells to the differentiation of neurons in culture, we have used morphometry to study myelination of dorsal root ganglion (DRG) neurons by central or peripheral supporting cells. Dissociated DRG cultures from 15-day rat embryos, free of Schwann cells and fibroblasts, were prepared, and supporting cells were added from spinal cord or DRG; myelination commenced after 2 weeks. Control cultures received no supporting cells. At 7, 14, and 24 days, a total of 22 cultures were processed for electron microscopy. Three fascicles from defined points were sampled from each culture. In cultures containing glial cells, smaller fibers (p less than 0.001) were myelinated (mean of median diameter, 1.13 +/- 0.13 (SD) micron) than in cultures containing Schwann cells (1.67 +/- 0.17 micron), although there was no difference (p greater than 0.1) in the degree of myelination expressed as number of myelin lamellae/fiber. A new finding concerned the relationship of axonal diameter to the presence or absence of myelinating cells. In control cultures without supporting cells or in areas where supporting cells were absent, the range of neurite diameter (0.05 to 1.25 micron) and the median diameter (mean of median, 0.24 +/- 0.03 micron) were similar at different times (7, 14, and 24 days), demonstrating a stable population of neurite diameters throughout the period. In myelinated fascicles, a different distribution of neurite diameters was present. Myelinated neurites had a greater median diameter (measured to inner border of myelin) and a different range of fiber diameters compared to bare neurites. For Schwann cells, this range was 0.7 to 3.4 micron, and the mean of median diameters was 1.67 +/- 0.17 micron; for glial cells, the range was 0.6 to 2.4 micron, and the mean of median diameters 1.13 +/- 0.13 micron. Differences between myelinated and bare fibers were all highly significant (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Peroxisome Proliferator-activated Receptor γ Ligands Are Potent Inhibitors of Angiogenesis in Vitro and in Vivo (1999)

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that functions as a transcription factor to mediate ligand-dependent transcriptional regulation. Activation of PPARgamma by the naturally occurring ligand, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), or members of a new class of oral antidiabetic agents, e.g. BRL49653 and ciglitizone, has been linked to adipocyte differentiation, regulation of glucose homeostasis, inhibition of macrophage and monocyte activation, and inhibition of tumor cell proliferation. Here we report that human umbilical vein endothelial cells (HUVEC) express PPARgamma mRNA and protein. Activation of PPARgamma by the specific ligands 15d-PGJ2, BRL49653, or ciglitizone, dose dependently suppresses HUVEC differentiation into tube-like structures in three-dimensional collagen gels. In contrast, specific PPARalpha and -beta ligands do not affect tube formation although mRNA for these receptors are expressed in HUVEC. PPARgamma ligands also inhibit the proliferative response of HUVEC to exogenous growth factors. Treatment of HUVEC with 15d-PGJ2 also reduced mRNA levels of vascular endothelial cell growth factor receptors 1 (Flt-1) and 2 (Flk/KDR) and urokinase plasminogen activator and increased plasminogen activator inhibitor-1 (PAI-1) mRNA. Finally, administration of 15d-PGJ2 inhibited vascular endothelial cell growth factor-induced angiogenesis in the rat cornea. These observations demonstrate that PPARgamma ligands are potent inhibitors of angiogenesis in vitro and in vivo, and suggest that PPARgamma may be an important molecular target for the development of small-molecule inhibitors of angiogenesis.
Array Biosensor for Simultaneous Identification of Bacterial, Viral, and Protein Analytes (1999)

The array biosensor was fabricated to analyze multiple samples simultaneously for multiple analytes. The sensor utilized a standard sandwich immunoassay format: Antigen-specific "capture" antibodies were immobilized in a patterned array on the surface of a planar waveguide and bound analyte was subsequently detected using fluorescent tracer antibodies. This study describes the analysis of 126 blind samples for the presence of three distinct classes of analytes. To address potential complications arising from using a mixture of tracer antibodies in the multianalyte assay, three single-analyte assays were run in parallel with a multianalyte assay. Mixtures of analytes were also assayed to demonstrate the sensor's ability to detect more than a single species at a time. The array sensor was capable of detecting viral, bacterial, and protein analytes using a facile 14-min assay with sensitivity levels approaching those of standard ELISA methods. Limits of detection for Bacillus globigii, MS2 bacteriophage, and staphylococcal enterotoxin B (SEB) were 10(5) cfu/mL, 10(7) pfu/mL, and 10 ng/mL, respectively. The array biosensor also analyzed multiple samples simultaneously and detected mixtures of the different types of analytes in the multianalyte format.
A monolithic 50 kHz 16-bit A/D-D/A converter using sigma-delta modulation (2002)

The converter consists of a third-order sigma-delta modulator, comb and finite impulse response (FIR) filters, a digital noise shaper, and a sixth-order switched-capacitor filter. The converter operates on a single +5-V supply and uses serial I/O to maintain a low pin count. The serial interface allows up to four devices to be connected, thus providing four channels of coherently sampled A/D and D/A I/O. High-level software modeling was used to simulate the system signal-to-noise performance, thereby providing design goal verification.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Advances in Immunotherapy of Multiple Myeloma: From the Discovery of Tumor-Associated Antigens to Clinical Trials (2007)

Tumors aberrantly express tumor-associated antigens that can be specifically recognized by T-cells, thereby providing a scientific rationale for the design and clinical testing of immunotherapeutic strategies targeting these antigens. Multiple myeloma is a fatal hematologic malignancy. Here, we review techniques to discover new tumor-associated antigens in multiple myeloma and the latest immunotherapeutic strategies employed in this disease.
Nitric oxide and proteoglycan biosynthesis by human articular chondrocytes in alginate culture (1994)

Interleukin-1 alpha and beta induced the production of large amounts of nitric oxide by normal, human articular chondrocytes in alginate culture; at the same time the biosynthesis of proteoglycan was strongly suppressed. In a dose-dependent manner, NG-monomethyl-L-arginine both inhibited nitric oxide formation and relieved the suppression of proteoglycan synthesis. However concentrations of NG-monomethyl-L-arginine which completely prevented nitric oxide production only partially restored proteoglycan biosynthesis, even at low doses of interleukin-1 where suppression of proteoglycan synthesis was modest. The organic donor of nitric oxide, S-nitrosyl-acetyl-D,L- penicillamine also inhibited proteoglycan biosynthesis, but not as extensively as interleukin-1. These data suggest that interleukin-1 suppresses synthesis of the cartilaginous matrix through more than one mechanism, at least one of which is dependent upon the production of nitric oxide.
Sindbis virus‐induced silencing of dengue viruses in mosquitoes (2001)

Aedes aegypti were injected intrathoracically with double subgenomic Sindbis (dsSIN) viruses with inserted sequences derived from the genome of one or more of the four dengue (DEN) virus serotypes. Mosquitoes were highly resistant to challenge with homologous DEN viruses from which the effector sequences were derived, and resistance to DEN viruses was independent of the orientation of the effector RNA. dsSIN viruses designed to express RNA derived from the premembrane coding region of DEN-2 prevented the accumulation of DEN2 RNA, and C6/36 cells were highly resistant to DEN-2 virus when challenged at 2, 5 or 8 days after the initial dsSIN virus infections, even though the dsSIN-derived RNA had sharply declined at the later time points. Initiation of resistance occurred prior to or within the first 8 h after challenge with DEN-2 virus. We conclude that DEN viruses are inhibited by a mechanism similar to post-transcriptional gene silencing (PTGS) or RNA interference (RNAi) phenomena described in plants and invertebrates, respectively. The potential occurrence of PTGS or RNAi in mosquitoes and mosquito cells suggests new ways of inhibiting the replication of arthropod-borne viruses in mosquito vectors, studying vector-virus interactions, and silencing endogenous mosquito genes.
Long-term spontaneous regression of malignant melanoma with visceral metastasesReport of a case with immunologic profile (1975)

A case of a 58-year-old woman with viscerally metastatic malignant melanoma is presented 12 years after spontaneous and complete regression of disease. Diagnosis of primary and metastatic lesions was confirmed by review of tissue sections. The presence and subsequent absence of visceral metastases were documented by open liver biopsies. Sections of metastatic lesions revealed extensive necrosis of tumor and infiltration of lymphocytes and plasma cells. Skin testing showed a strongly positive delayed hypersensitivity response to dinitrochlorobenzene (DNCB), to a standard battery of bacterial and fungal antigens, and to two of four preparations of allogeneic melanoma antigens. Values for cell- and serum-mediated cytotoxicity against melanoma cells and the response of the patient's lymphocytes to phytohemagglutinin were slightly above the normal range. A review of the literature reveals 13 other cases of long-term spontaneous regression of melanoma. None of these, however, had biopsy evidence of visceral disease. In each of the 13 cases, regression was associated with an event that might be inferred to have altered the patient's hormonal or immune status. This patient also provides evidence of a complete, spontaneous, and long-term remission of metastatic disease associated with the spontaneous development of host immunity.
Relationship of Oxidative Stress and Fibrinolysis in Diabetes Mellitus (1996)

This study attempted to verify the existence of a relationship between oxidative stress documented by malondialdehyde (MDA) and superoxide dismutase (SOD) and fibrinolysis analysed by tissue plasminogen activator (tPA) and its inhibitor (PAI-1) in diabetes mellitus. Forty-seven patients with Type 1 (n = 27) and Type 2 (n = 20) diabetes were examined together with 20 non-diabetic controls. The following were analysed: plasma MDA concentration, SOD activity in erythrocytes, tPA activity and antigen, PAI-1 activity and antigen, fasting blood glucose, fructosamine, glycated haemoglobin (HbAlc), and urine albumin. SOD activity was decreased in patients with diabetes. This contrasted with an increased plasma MDA concentration especially in Type 2 diabetes as compared with Type 1 or healthy persons (p < 0.001). tPA activity was increased in both groups of patients with diabetes as compared to healthy persons (p < 0.001), PAI-1 activity was higher in Type 2 diabetes with vascular changes than in the remaining subgroups (p < 0.001). Multivariate analysis revealed a significant positive relationship between plasma MDA concentrations and PAI-1 antigen (r = 0.53, p < 0.001) and a negative relationship between SOD and tPA activities (r = -0.53, p < 0.01). We conclude that oxidative stress may modulate fibrinolytic properties in diabetes mellitus.
Apoptosis Signal-Regulating Kinase 1/p38 Signaling Pathway Negatively Regulates Physiological Hypertrophy (2008)

These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.
Yeast-Based Genetic System for Functional Analysis of Poxvirus mRNA Cap Methyltransferase (2003)

Structural differences between poxvirus and human mRNA capping enzymes recommend cap formation as a target for antipoxviral drug discovery. Genetic and pharmacologic analysis of the poxvirus capping enzymes requires in vivo assays in which the readout depends on the capacity of the viral enzyme to catalyze cap synthesis. Here we have used the budding yeast Saccharomyces cerevisiae as a genetic model for the study of poxvirus cap guanine-N7 methyltransferase. The S. cerevisiae capping system consists of separate triphosphatase (Cet1), guanylyltransferase (Ceg1), and methyltransferase (Abd1) components. All three activities are essential for cell growth. We report that the methyltransferase domain of vaccinia virus capping enzyme (composed of catalytic vD1-C and stimulatory vD12 subunits) can function in lieu of yeast Abd1. Coexpression of both vaccinia virus subunits is required for complementation of the growth of abd1Delta cells. Previously described mutations of vD1-C and vD12 that eliminate or reduce methyltransferase activity in vitro either abolish abd1Delta complementation or elicit conditional growth defects. We have used the yeast complementation assay as the primary screen in a new round of alanine scanning of the catalytic subunit. We thereby identified several new amino acids that are critical for cap methylation activity in vivo. Studies of recombinant proteins show that the lethal vD1-C mutations do not preclude heterodimerization with vD12 but either eliminate or reduce cap methyltransferase activity in vitro.
Enhancing the anti-tumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition (2004)

3029 Background: Molecular inhibition of the ErbB signaling pathway is under active investigation as a promising anti-cancer treatment strategy. Pre-clinical studies suggest that enhanced anti-tumor activity may be achieved by maximizing ErbB signaling inhibition. Using high throughput screening with cDNA microarrays, we identified HDAC inhibitors as having strong potential to enhance the effects of anti-ErbB agents. Methods: Microarray: Total RNA was isolated from cells after 12 and 24 hours exposure to HDAC inhibitor SAHA (suberoylanilide hydroxamic acid). cDNA probes were prepared from experimental and appropriate reference RNA samples, labeled, and hybridized to 20K human cDNA. Data was validated using quantitative real time RT-PCR. Cell Proliferation: Exponentially growing cells were incubated in medium containing vehicle control, CI-1033 (pan-ErbB tyrosine kinase inhibitor), SAHA, or both drugs in combination for 72 hours. Cells were then stained with 0.5% crystal violet and cell viability was determined using relative absorbance. Apoptosis: Caspase activity was analyzed by fluorescence spectroscopy using a fluorescein labeled pan-caspase inhibitor. Results: Array studies using SAHA in prostate and breast cancer cell lines show decreased transcript expression (> 50%) of EGFR and ErbB2. Findings from the array data were validated using real time RT-PCR and western blot analysis. Enhanced proliferative inhibition was seen in prostate (DU145, PC3), breast (SKBr3, MCF7), and head and neck tumor cells (UM-SCC6) when SAHA was combined with CI-1033. Combining HDAC inhibition with EGFR blockade demonstrated strong abrogation of EGFR and AKT signaling following EGF stimulation, as well as a supra-additive increase in caspase activity (p<0.05). Conclusions: These results suggest that used cooperatively, anti-ErbB agents and HDAC inhibitors may offer a unique and potentially potent strategy of dual targeted therapy. Based on emerging preclinical data, we are currently designing Phase I clinical trials which combine HDAC inhibitors with ErbB blockade. No significant financial relationships to disclose.
Identification of Potential Sites for Tryptophan Oxidation in Recombinant Antibodies Using tert-Butylhydroperoxide and Quantitative LC-MS (2011)

Amino acid oxidation is known to affect the structure, activity, and rate of degradation of proteins. Methionine oxidation is one of the several chemical degradation pathways for recombinant antibodies. In this study, we have identified for the first time a solvent accessible tryptophan residue (Trp-32) in the complementary-determining region (CDR) of a recombinant IgG1 antibody susceptible to oxidation under real-time storage and elevated temperature conditions. The degree of light chain Trp-32 oxidation was found to be higher than the oxidation level of the conserved heavy chain Met-429 and the heavy chain Met-107 of the recombinant IgG1 antibody HER2, which have already been identified as being solvent accessible and sensitive to chemical oxidation. In order to reduce the time for simultaneous identification and functional evaluation of potential methionine and tryptophan oxidation sites, a test system employing tert-butylhydroperoxide (TBHP) and quantitative LC-MS was developed. The optimized oxidizing conditions allowed us to specifically oxidize the solvent accessible methionine and tryptophan residues that displayed significant oxidation in the real-time stability and elevated temperature study. The achieved degree of tryptophan oxidation was adequate to identify the functional consequence of the tryptophan oxidation by binding studies. In summary, the here presented approach of employing TBHP as oxidizing reagent combined with quantitative LC-MS and binding studies greatly facilitates the efficient identification and functional evaluation of methionine and tryptophan oxidation sites in the CDR of recombinant antibodies.