gebhart/patrepeval huggingface dataset:
Pharmacokinetics and Clinical Effects of Sublingual Triazolam in Pediatric Dental Patients (2001)

The purpose of this investigation was to describe the pharmacokinetics of sublingual triazolam in children. Nine healthy children (64-98 months old) received 0.25 or 0.375 mg of sublingual triazolam before dental treatment. Plasma triazolam concentrations were measured by gas chromatography/mass spectrometry and analyzed by noncompartmental methods. The peak concentration was 4.9 +/- 2.0 ng/mL (mean +/- SD), time to peak was 75 +/- 32 minutes, the elimination half-life was 91 +/- 32 minutes, and apparent clearance was 17.6 +/- 8.8 mL x kg(-1) x min(-1). Children were tested for gait ataxia, amnesia, and diplopia during a screening session and again after triazolam. Ninety minutes after drug administration, seven of nine children demonstrated ataxia, and three of nine demonstrated amnesia. Peak triazolam concentrations were similar in children with or without ataxia, but they were significantly higher in children with amnesia compared with those without amnesia. Six children demonstrated diplopia 30 and 120 minutes after triazolam; however, peak triazolam concentrations were similar in both groups. Sublingual administration was an acceptable alternative route of triazolam delivery in children.
Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy (2016)

Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK). However, the concomitant oncogenic drivers may affect the sensitivity of crizotinib. Herein, we present a 69-year-old never-smoker Chinese male with advanced lung adenocarcinoma harboring concomitant spectrin beta non-erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. Although the patient received timely and comprehensive treatment, the overall survival was only 8 months. Therefore, c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis. In addition, the novel SPTBN1-ALK fusion gene may become a potential target for anti-tumor therapy.
Efficacy of inactivated poliovirus vaccine in India. (1983)

The immunogenic efficacy of inactivated (Salk) poliovirus vaccine (IPV) was evaluated in infants in India, in view of the high frequency of vaccine failure after immunization with oral (Sabin) poliovirus vaccine (OPV). A total of 150 infants, aged 6-45 weeks, were given 3 doses of IPV, with intervals of 4 or 8 weeks between doses. The effect on the antibody response of child's age, presence of maternal antibody before immunization, and interval between doses was assessed. The overall seroconversion rates to poliovirus types 1, 2, and 3 were 99%, 89%, and 91%, respectively. Seroconversion rates to types 2 and 3, and antibody titres to types 1 and 2, were higher (i) in infants given vaccine doses at 8-week intervals and (ii) in those without detectable maternal antibody. The seroconversion rates in infants without maternal antibody, who were given IPV at 8-week intervals, were 100%, 100%, and 96.2% to poliovirus types 1, 2, and 3, respectively. Thus the immunogenic efficacy of IPV was found to be satisfactory.
The rab7 gtpase resides on a vesicular compartment connected to lysosomes (1995)

Rab GTPases belong to the Ras GTPase superfamily and are key regulators of membrane traffic. Among them, rab7 has been localized on late endosomes of NRK cells but its function remains unknown. In order to investigate its role, we generated stable HeLa cell lines that express either wild type or a GTPase-defective mutant of rab7 in an inducible manner. A morphological analysis of the intracellular localization of these proteins was performed by confocal laser microscopy. Here we show that, in HeLa cells, rab7 is present on a vesicular compartment that extends from the perinuclear area to the cell periphery and shows only a partial colocalization with the cation-independent mannose 6-phosphate receptor, a marker for late endosomes. The topology of this compartment is dependent on the microtubule network since nocodazole treatment results in its scattering throughout the cytoplasm. In addition, we observed that, in contrast to the wild-type protein, a rab7 mutant with a reduced GTPase activity is in part associated with lysosomal membranes. This observation was confirmed by subcellular fractionation in a Percoll gradient. Our data implicate rab7 as the first GTPase functioning on terminal endocytic structures in mammalian cells.
Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. (1991)

Chimeric insulin/insulin-like growth factor-1 receptors and insulin receptor alpha-subunit point mutants were characterized with respect to their binding properties for insulin and insulin-like growth factor-1 (IGF-1) and their ability to translate ligand interaction into tyrosine kinase activation in intact cells. We found that replacement of the amino-terminal 137 amino acids of the insulin receptor (IR) with the corresponding 131 amino acids of the IGF-1 receptor (IGF-1R) resulted in loss of affinity for both ligands. Further replacement of the adjacent cysteine region with IGF-1R sequences fully reconstituted affinity for IGF-1, but only marginally for insulin. Unexpectedly, replacement of the IR cysteine-rich domain alone by IGF-1R sequences created a high affinity receptor for both insulin and IGF-1. The binding characteristics of all receptor chimeras reflected the potential of both ligands to regulate the receptor tyrosine kinase activity in intact cells. Our chimeric receptor data, in conjunction with IR amino-terminal domain point mutants, strongly suggest major contributions of structural determinants in both amino- and carboxyl-terminal IR alpha-subunit regions for the formation of the insulin-binding pocket, whereas, surprisingly, the residues defining IGF-1 binding are present predominantly in the cysteine-rich domain of the IGF-1R.
Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese (2007)

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.
SYNTHESIS OF SUBSTITUTED DINITROPHENYL KETONES AND PHENYLACETIC ACIDS. PART IV (1948)

2 :4-Dinitro-6-chlorophenylacetone and 2 :4-dinitro. 6-chlorophenyIacetic acid have been prepared by the ketonic and acid hydrolysis of 2 :4-dinitro-6-chlorophenylacetoacetic ester. The ketone has been characterised by preparation of suitable derivatives. The reduction of 2 :4-dinitro-6-chloropbenyl­acetoacetic ester by iron powder and water has also been carried out.
Vascular Permeability Factor (VPF)/Vascular Endothelial Growth Factor (VEGF) Receptor-1 Down-modulates VPF/VEGF Receptor-2-mediated Endothelial Cell Proliferation, but Not Migration, through Phosphatidylinositol 3-Kinase-dependent Pathways (2001)

Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) achieves its multiple functions by activating two receptor tyrosine kinases, Flt-1 (VEGF receptor-1) and KDR (VEGF receptor-2), both of which are selectively expressed on primary vascular endothelium. To dissect the respective signaling pathways and biological functions mediated by these receptors in primary endothelial cells with these two receptors intact, we developed a chimeric receptor system in which the N terminus of the epidermal growth factor receptor was fused to the transmembrane domain and intracellular domain of KDR (EGDR) and Flt-1 (EGLT). We observed that KDR, but not Flt-1, was responsible for VPF/VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration. Moreover, Flt-1 showed an inhibitory effect on KDR-mediated proliferation, but not migration. We also demonstrated that the inhibitory function of Flt-1 was mediated through the phosphatidylinositol 3-kinase (PI-3K)-dependent pathway because inhibitors of PI-3K as well as a dominant negative mutant of p85 (PI-3K subunit) reversed the inhibition, whereas a constitutively activated mutant of p110 introduced the inhibition to HUVEC-EGDR. We also observed that, in VPF/VEGF-stimulated HUVECs, the Flt-1/EGLT-mediated down-modulation of KDR/EGDR signaling was at or before intracellular Ca(2+) mobilization, but after KDR/EGDR phosphorylation. By mutational analysis, we further identified that the tyrosine 794 residue of Flt-1 was essential for its antiproliferative effect. Taken together, these studies contribute significantly to our understanding of the signaling pathways and biological functions triggered by KDR and Flt-1 and describe a unique mechanism in which PI-3K acts as a mediator of antiproliferation in primary vascular endothelium.
Gastrin receptor characterization: affinity cross-linking of the gastrin receptor on canine gastric parietal cells (1987)

We applied affinity cross-linking methods to label the gastrin receptor on isolated canine gastric parietal cells in order to elucidate the nature of its chemical structure. 125I-labeled Leu15-gastrin and 125I-labeled gastrin2(-17) bound to intact parietal cells and their membranes with equal affinity, and half-maximal inhibition of binding was obtained at an incubation concentration of 3.2 X 10(-10) M unlabeled gastrin. 125I-gastrin2(-17) was cross-linked to plasma membranes or intact parietal cells by incubation in disuccinimidyl suberate. The membrane pellets were solubilized with or without dithiothreitol and applied to electrophoresis on 7.5% sodium dodecyl sulfate polyacrylamide gels. Autoradiograms revealed a band of labeling at Mr 76,000 and labeling of this band was inhibited in a dose-dependent fashion by addition of unlabeled gastrin to the incubation mixture. Dithiothreitol in concentrations as high as 100 mM did not alter the electrophoretic mobility of the labeled band. After taking into account the molecular weight of 125I-gastrin2(-17), our results suggest that the gastrin receptor on parietal cells is a single protein of Mr 74,000 without disulfide-linked subunits.
Triboelectric–Pyroelectric–Piezoelectric Hybrid Cell for High‐Efficiency Energy‐Harvesting and Self‐Powered Sensing (2015)

A triboelectric-pyroelectric-piezoelectric hybrid cell, consisting of a triboelectric nanogenerator and a pyroelectric-piezoelectric nanogenerator, is developed for highly efficient mechanical energy harvesting through multiple mechanisms. The excellent performance of the hybrid cell enhances the energy-harvesting efficiency significantly (by 26.2% at 1 kΩ load resistance), and enables self-powered sensing, which will lead to a variety of advanced applications.
Acid‐citrate‐dextrose‐phosphoenolpyruvate medium as a rejuvenant for blood storage (1983)

Stored, depleted RBC were rejuvenated with respect to their levels of adenosine triphosphate (ATP), 2,3‐diphosphoglycerate (2,3‐DPG), and P50 by acid‐citrate‐dextrose per‐servatives containing phosphoenolpyruvate (PEP) without sucrose. The restorations of P50 and 2,3‐DPG were dependent on the phosphoenolpyruvate concentration. Erythrocyte P50 and 2,3‐DPG, even after treatment with these preservatives, decreased with increasing storage period, but the P50 and 2,3‐DPG of five‐week‐old blood were still higher than the corresponding values of fresh blood. ATP concentration was also increased by treating stored blood with preservatives containing phosphoenolpyruvate, but the elevated ATP of five‐week‐old blood was only about 50 percent of fresh blood. The ATP level could not be raised further by increasing phosphoenolpyruvate concentration but was improved by supplementation with adenine and nucleosides. Incubation of stored blood with 15 mM phosphoenolpyruvate was sufficient to restore ATP, 2,3‐DPG and P50 of three‐week‐old blood to nearly normal. The results of these studies indicate that sucrose is not necessary for PEP to be effective as a preservative additive.
Microfabrication of a mechanically controllable break junction in silicon (1995)

We present a detailed description of the fabrication and operation at room temperature of a novel type of tunnel displacement transducer. Instead of a feedback system it relies on a large reduction factor assuring an inherently stable device. Stability measurements in the tunnel regime infer an electrode stability within 3 pm in a 1 kHz bandwidth. In the contact regime the conductance takes on a discrete number of values when the constriction is reduced atom by atom. This reflects the conduction through discrete channels.
Individual differences in the orientation of the cytolytic T cell response against mouse tumor P815 (1995)

We reported previously that the mouse tumor P815 expresses four distinct antigens (A, B, C, D) recognized by syngeneic cytolytic T lymphocytes (CTL). A fifth P815 antigen (E) was identified by means of a CTL clone derived from tumor-infiltrating lymphocytes. We compared a number of mice for the orientation of their CTL response with respect to the various P815 antigens. Lymphocytes from mice inoculated subcutaneously with living P815 cells were stimulated in vitro with tumor cells and the resulting CTL were tested against targets expressing either antigens A and B or antigens C, D and E. Many mice had an asymmetrical response, some producing CTL directed almost exclusively against antigens A, B and others producing CTL directed almost exclusively against C, D. E. When mice were inoculated into two separate sites, different orientations in the responses of the two local lymph nodes were often observed, suggesting that individual differences in the orientation of the anti-P815 CTL response do not result from preexisting differences between the animals. Asymmetrical CTL responses persisted in mice that were given a second injection of tumor cells. A possible interpretation of our results is that the major component of the CTL response is made of the progeny of a very small number of CTL precursors that happen to be the first to be stimulated by the tumor antigens.
Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF- through an ERK1/2-dependent pathway (2009)

Antibodies specific to moesin, which are frequently detectable in the serum of patients with aplastic anemia (AA), can induce tumor necrosis factor-alpha (TNF-alpha) secretion from monocytes and a human monocytic leukemia cell line THP-1. We investigated the mechanisms responsible for TNF-alpha secretion from monocytic cells induced by the auto-antibodies that are purified from the sera of AA patients. TNF-alpha induction by anti-moesin antibodies depended on the amount of cell surface moesin expressed by THP-1 cells. F(ab')(2) fragments prepared from the anti-moesin antibodies were able to stimulate THP-1 cells to secrete TNF-alpha and this stimulatory effect was enhanced by cross-linking of moesins with anti-human IgG F(ab')(2) fragment antibodies. Anti-moesin antibodies as well as their F(ab')(2) fragments induced the phosphorylation of ERK1/2 in monocytic cells and this effect was suppressed by the addition of an ERK1/2 inhibitor. Moreover, anti-moesin antibody treatment induced the phosphorylation of moesin proteins in the monocytes and THP-1 cells within 30 min. These results indicate that anti-moesin antibodies induce TNF-alpha secretion from monocytes through the activation of the ERK1/2 pathway provoked by direct binding to moesin on the cells.
Cutaneous gene transfer for skin and systemic diseases (2002)

Recent progress in molecular genetics has illuminated the basis for a wide variety of inherited and acquired diseases. Gene therapy offers an attractive therapeutic approach capitalizing upon these new mechanistic insights. The skin is a uniquely attractive tissue site for development of new genetic therapeutic approaches both for its accessibility as well as for the large number of diseases that are amenable in principle to cutaneous gene transfer. Amongst these opportunities are primary monogenic skin diseases, chronic wounds and systemic disorders characterized by low or absent levels of circulating polypeptides. For cutaneous gene therapy to be effective, however, significant progress is required in a number of domains. Recent advances in vector design, administration, immune modulation, and regulation of gene expression have brought the field much nearer to clinical utility.
Host‐induced gene silencing inhibits the biotrophic pathogen causing downy mildew of lettuce (2014)

Host-induced gene silencing (HIGS) is an RNA interference-based approach in which small interfering RNAs (siRNAs) are produced in the host plant and subsequently move into the pathogen to silence pathogen genes. As a proof-of-concept, we generated stable transgenic lettuce plants expressing siRNAs targeting potentially vital genes of Bremia lactucae, a biotrophic oomycete that causes downy mildew, the most important disease of lettuce worldwide. Transgenic plants, expressing inverted repeats of fragments of either the Highly Abundant Message #34 (HAM34) or Cellulose Synthase (CES1) genes of B. lactucae, specifically suppressed expression of these genes, resulting in greatly reduced growth and inhibition of sporulation of B. lactucae. This demonstrates that HIGS can provide effective control of B. lactucae in lettuce; such control does not rely on ephemeral resistance conferred by major resistance genes and therefore offers new opportunities for durable control of diverse diseases in numerous crops.
Hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood progenitor cells evaluated in vitro and in vivo (1996)

The hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood (UCB) samples was evaluated in vitro and in vivo. Phenotypic analysis shows that approximately 1% of cord blood mononuclear cells express high levels of CD34 antigen on their surface (CD34hi), but none of a panel of lineage antigens (Lin-), suggesting that they are hematopoietic progenitor cells that have not yet committed to a specific lineage. Approximately 1% of CD34hi/Lin- cells are primitive hematopoietic progenitors that produce B lymphoid and multiple myeloid progeny for up to 7 weeks in stromal cell cultures. Twenty-one percent (+/- 13%) of CD34hi/Lin- cells also express low levels of the Thy-1 antigen and are threefold to fourfold enriched over CD34hi/Lin- cells in primitive hematopoietic potential as measured by long-term culture and phenotypic analysis. One-week liquid cultures of CD34-enriched UCB progenitor cells in the presence of interleukin (IL)-3, IL-6, and stem cell factor (SCF) results in a two-fold to threefold expansion of progenitors capable of reinitiating long-term stromal cell cultures. Only the CD34hi/Thy-1+/Lin- cell population was capable of maintaining progenitors with secondary transfer potential in long-term stromal cell cultures and is thus postulated to contain all of the primitive hematopoietic stem cells in UCB. The in vivo transplantation potential of UCB was also measured. Ex vivo manipulated UCB progenitor cells were used to engraft irradiated human thymus fragments implanted in severe combined immunodeficiency (SCID) mice. Thymic engraftment with >5% donor-derived cells and a normal CD4/CD8 distribution was observed in 19 of 23 tissues tested. UCB cells from in vitro expansion cultures engrafted with efficiencies comparable to nonexpanded cells. Similar results were obtained for UCB engraftment of human bone fragments implanted in SCID mice. In all cases, engraftment was achieved in competition with endogenous competitor stem cells and across major histocompatibility barriers. Taken together, this data demonstrates that human UCB is a rich source of multipotent hematopoietic progenitors that can be cryopreserved, enriched by physical methods, and expanded in a limited fashion without measurable loss of long-term culture or in vivo engrafting potential as measured in these assays.
Expression of ras proto-oncogene proteins in normal human tissues. (1987)

The expression of ras proto-oncogenes in normal human tissues was studied by immunohistochemical staining and by immunoblotting using monoclonal antibodies. We detected p21ras protein in almost every fetal and adult tissue, but the level varied significantly among cell types. In some cell lineages, immature cells capable of proliferation contain more p21ras than do mature cells. By contrast, certain fully differentiated cells, such as neurons and the epithelial cells of endocrine glands, express abundant p21ras. Among mammalian tissues the highest level of ras protein was detected in brain. Crude synaptosomal membrane preparations from rat brain contain substantially more p21ras than do plasma membranes from rat liver. The observed distribution of p21ras suggests a role for these proteins both in cellular proliferation and in certain specialized cellular functions.