gebhart/patrepeval huggingface dataset:
Placental/umbilical cord blood transplantation. (1999)

In this article we summarize the clinical outcome of unrelated placental/umbilical cord blood (CB) transplantation, discuss the biological characteristics of CB hematopoietic progenitor/stem cells (HPC) and balance the relative advantages and disadvantages of this therapy as compared with transplantation of other HPC sources. Moreover, we discuss CB banking programs at local, national and international levels. The data reported by the investigators of the New York Placental/Umbilical Cord Blood Program and of the Eurocord group indicate that the clinical outcome of allogeneic unrelated CB transplantation is significantly related to cell dose, being more effective in children than in adults, and is highly dependent on disease stage at transplantation. Furthermore, both studies show lower graft-versus-host disease (GvHD) frequency and severity and prolonged time intervals for platelet engraftment as compared to those of bone marrow and mobilized peripheral blood recipients. Although the data from the New York Placental/Umbilical Cord Blood Program seem to support a negative effect of HLA differences, the latter were not significantly associated with survival in the Eurocord series. Additional observations are therefore necessary to collect conclusive evidence in this regard. Currently available data show that CB contains a higher proportion of primitive HPC and that CB-HPC possess higher proliferation and expansion potentials as compared to adult bone marrow. Furthermore, there is some evidence indicating that CB-HPC are more adequate than HPC from other sources for genetic manipulation and gene therapy. Despite the significant advances in the knowledge of the biology and in the clinical use of CB, a number of problems remain unsolved, including the standardization of banking procedures and unit quality and the development of suitable protocols for transplantation of adult patients.
Enhancement of fibroblast growth factor‐induced diacylglycerol formation and protein kinase C activation by colon tumor‐promoting bile acid in Swiss 3T3 cells (1986)

A small amount (50-200 microM) of deoxycholate (DOC), a colon tumor-promoting bile acid, did not show a direct effect on protein kinase C activity in a cell-free system, but enhanced fibroblast growth factor (FGF)-induced diacylglycerol formation and protein kinase C activation in Swiss 3T3 cells. DOC potentiated both reactions induced by submaximal doses of FGF but showed little effect on the maximal levels of the reactions. DOC alone was inactive in eliciting both reactions in the absence of FGF. DOC did not affect the binding of FGF to the cells. Since it has been described that diacylglycerol serves as a messenger for the activation of protein kinase C in the action of FGF in Swiss 3T3 cells [(1985) FEBS Lett. 191, 205-210], these results suggest that a small amount of DOC increases the sensitivity to FGF of diacylglycerol formation and thereby potentiates protein kinase C activation in this cell line. This action of DOC was in marked contrast to that of 12-O-tetradecanoylphorbol-13-acetate, a potent tumor-promoting phorbol ester, which directly activated protein kinase C in cell-free and intact cell systems.
Synthesis of 3-chloro-5-(4-methylpiperazino)-6,7-dihydro-5H-dibenzo[b,g]thiocin, an eight-membered ring homologue of the neuroleptic agent octoclothepin (1980)

Alkylation of diethyl malonate with 2-(4-chlorophenylthio)benzyl chloride, the following hydrolysis and decarboxylation gave 3-[2-(4-chlorophenylthio)phenyl]propionic acid ( IV ); its chloride was cyclized in low yield by treatment with aluminium chloride to 4-(4-chlorophenylthio)indanone ( V ). The corresponding methylpiperazine derivative VIII was prepared via intermediates VI and VII . A reaction of 3-(2-mercaptophenyl)propionic acid with 5-chloro-2-iodobenzoic acid and the following esterification resulted in the diester XVI which was cyclized by a Dieckmann reaction using sodium hydride in toluene to give ethyl 3-chloro-5-hydroxy-7 H -dibenzo[ b,g ]thiocin-6-carboxylate ( XVII ). The acid hydrolysis afforded the ketone XVIII which was transformed via the intermediates XX and XXI to the title compound II . The product has a mild central depressant activity but it lacks the character of a neuroleptic agent.
Expression of a Synthetic Gene for Human Cap Binding Protein (Human IF-4E) in herichia coli and Fluorescence Studies on Interaction with mRNA Cap Structure Analogues1 (1991)

An artificial gene coding for the human cap binding protein (hCBP: human IF-4E) was chemically synthesized and expressed in Escherichia coli under the control of a trp promoter. The DNA duplex of 662 bp was designed and constructed from 44 oligodeoxynucleotide fragments of typically 30 nucleotides in length. Although the hCBP gene was not directly expressed in E. coli HB101, we succeeded in its high-level expression as a fusion protein connected with a portion of human growth hormone through a tetradecapeptide (Asp-Asp-Pro-Pro-Thr-Val-Glu-Leu-Gln-Gly-Leu-Val-Pro-Arg) that contains the recognition sequence for a site-specific protease alpha-thrombin. Upon induction with 3-indoleacrylic acid, the fusion protein accumulated with a yield of about 20% of the total proteins of the host cell. Upon the treatment of the fusion protein with alpha-thrombin, which recognizes the sequence "Val-Pro-Arg," specific proteolysis at the fused junction occurred efficiently. In this system, nonspecific digestion by alpha-thrombin was not marked. About 15 mg of recombinant hCBP was obtained from a 1-liter culture. Association constants between the recombinant hCBP and mRNA cap structure analogues were determined by fluorescence spectroscopy. The values obtained for the m7GpppA, m7GTP, and m7GMP were almost the same as those reported for the IF-4E isolated from human erythrocyte cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Obesity: What Mental Health Professionals Need to Know (2000)

Although the presence or development of obesity is a daunting problem, it should not be ignored by mental health professionals. Treatment should address not only obesity per se, but also its effects on self-esteem in a hostile cultural climate. Ongoing developments in basic and clinical research are likely to increase the range, efficacy, and acceptability of treatment options in the years ahead.
Dihydrofolate reductase gene amplification and possible rearrangement in estrogen-responsive methotrexate-resistant human breast cancer cells. (1982)

Methotrexate-resistant (MTXR) human breast cancer cells have been obtained which are 1000-fold less sensitive to this drug than the wild type MCF-7 cells from which they were derived. The resistant cells contain approximately a 25-fold increase in the activity of the target enzyme dihydrofolate (DHF) reductase. Enzyme inhibition studies and methotrexate affinity studies fail to reveal any difference in the DHF reductase present in the MTXR cells compared to wild type MCF-7 cells. Cytogenetic analysis demonstrates the presence of elongated marker chromosomes in the resistant cells which are not found in the parental cell line. Analysis of the DNA from MTXR and wild type MCF-7 cells using Southern blot hybridization indicates that the MTXR MCF-7 cells contain more copies of DHF reductase gene sequences than do wild type MCF-7 cells. These experiments also suggest that the amplified DHF reductase gene sequences in MTXR cells may have undergone a uniform structural rearrangement involving the 5' flanking sequences during the process of amplification. MTXR MCF-7 cells respond to estradiol by increasing cell growth, and the level of DHF reductase in the MTXR cells is further induced following administration of estradiol. Radiolabeling studies demonstrate that estrogen stimulates the actual synthesis of DHF reductase in human breast cancer cells.
Computer Simulation of Stepping in the Hind Legs of the Cat: An Examination of Mechanisms Regulating the Stance-to-Swing Transition (2005)

Physiological studies in walking cats have indicated that two sensory signals are involved in terminating stance in the hind legs: one related to unloading of the leg and the other to hip extension. To study the relative importance of these two signals, we developed a three-dimensional computer simulation of the cat hind legs in which the timing of the swing-to-stance transition was controlled by signals related to the force in ankle extensor muscles, the angle at the hip joint, or a combination of both. Even in the absence of direct coupling between the controllers for each leg, stable stepping was easily obtained using either a combination of ankle force and hip position signals or the ankle force signal alone. Stable walking did not occur when the hip position signal was used alone. Coupling the two controllers by mutual inhibition restored stability, but it did not restore the correct timing of stepping of the two hind legs. Small perturbations applied during the swing phase altered the movement of the contralateral leg in a manner that tended to maintain alternating stepping when the ankle force signal was included but tended to shift coordination away from alternating when the hip position signal was used alone. We conclude that coordination of stepping of the hind legs depends critically on load-sensitive signals from each leg and that mechanical linkages between the legs, mediated by these signals, play a significant role in establishing the alternating gait.
Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA). (1998)

Peripheral T-cell lymphomas (PTCL) have been generally reported to have a worse prognosis than B-cell lymphomas (BCL). Because of their heterogeneity and scarcity, the outcomes of the different histological subtypes have not been compared. From October 1987 to March 1993, 1,883 patients with diffuse aggressive non-Hodgkin's lymphomas (NHL) included in the LNH87 protocol could be assessed for both morphology and immunophenotyping. Among them, 288 (15%) had PTCL and 1,595 (85%) had BCL. According to the Kiel classification, most PTCL were classified as angioimmunoblastic (AIL; 23%), pleomorphic medium and large T-cell (PML; 49%), or anaplastic large cell (ALCL; 20%) lymphomas. Comparing PTCL with BCL patients, the former had more disseminated disease (78% v 58%), B symptoms (57% v 40%), bone marrow involvement (31% v 17%), skin involvement (21% v 4%), and increased beta2-microglobulin (50% v 34%), whereas BCL patients had more bulky disease (41% v 26%). According to the International Prognostic Index (IPI), PTCL and BCL scores were, respectively: 0 factors, 13% and 15%; 1 factor, 17% and 22%; 2 factors, 24% and 25%; >/=3 factors, 45% and 37% (P = .09). For BCL and PTCL, respectively, complete remission rates were 63% and 54% (P = .004); the 5-year overall survival (OS) rates were 53% and 41% (P = .0004) and event-free survival (EFS) rates were 42% and 33% (P < . 0001). Comparison of the different histological subtypes of lymphoma showed that the 5-year OS rate for T-ALCL (64%) was superior to those of other PTCL (35%) as well as diffuse large B-cell (53%) NHL. When multivariate analysis was applied using the IPI score as one factor, nonanaplastic PTCL remained an independent parameter (P = . 0004). Although the poor prognosis of non-ALCL PTCL could be due in part to the presence of adverse prognostic factors at diagnosis, this study shows that the T-cell phenotype is an independent significant factor, which should be incorporated into the definition of prognostic groups.
Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products. (1993)

Nonenzymatic glycation of proteins occurs at an accelerated rate in diabetes and can lead to the formation of advanced glycation end products of proteins (AGEs), which bind to mononuclear phagocytes (MPs) and induce chemotaxis. We have isolated two cell surface-associated binding proteins that mediate the interaction of AGEs with bovine endothelial cells. One of these proteins is a new member of the immunoglobulin superfamily of receptors (termed receptor for AGEs or RAGE); and the second is a lactoferrin-like polypeptide (LF-L). Using monospecific antibodies to these two AGE-binding proteins, we detected immunoreactive material on Western blots of detergent extracts from human MPs. Radioligand-binding studies demonstrated that antibody to the binding proteins blocked 125I-AGE-albumin binding and endocytosis by MPs. Chemotaxis of human MPs induced by soluble AGE-albumin was prevented in a dose-dependent manner by intact antibodies raised to the AGE-binding proteins, F(ab')2 fragments of these antibodies and by soluble RAGE. When MP migration in response to N-formyl-Met-Leu-Phe was studied in a chemotaxis chamber with AGE-albumin adsorbed to the upper surface of the chamber membrane, movement of MPs to the lower compartment was decreased because of interaction of the glycated proteins with RAGE and LF-L on the cell surface. The capacity of AGEs to attract and retain MPs was shown by implanting polytetrafluoroethylene (PTFE) mesh impregnated with AGE-albumin into rats: within 4 d a florid mononuclear cell infiltrate was evident in contrast to the lack of a significant cellular response to PTFE with adsorbed native albumin. These data indicate that RAGE and LF-L have a central role in the interaction of AGEs with human mononuclear cells and that AGEs can serve as a nidus to attract MPs in vivo.
RF sensor for multiphase flow measurement through an oil pipeline (2006)

We have developed, in conjunction with Solartron ISA, an electromagnetic cavity resonator based sensor for multiphase flow measurement through an oil pipeline. This sensor is non-intrusive and transmits low power (10 mW) radio frequencies (RF) in the range of 100–350 MHz and detects the pipeline contents using resonant peaks captured instantaneously. The multiple resonances from each captured RF spectrum are analysed to determine the phase fractions in the pipeline. An industrial version of the sensor for a 102 mm (4 inch) diameter pipe has been constructed and results from this sensor are compared to those given by simulations performed using the electromagnetic high frequency structure simulator software package HFSS.
Expression of tau protein in non-neuronal cells: microtubule binding and stabilization (1992)

The microtubule-associated protein tau is a developmentally regulated family of neuronal phosphoproteins that promotes the assembly and stabilization of microtubules. The carboxy-terminal half of the protein contains three copies of an imperfectly repeated sequence; this region has been found to bind microtubules in vitro. In addition, a fourth copy of the repeat has been found in adult-specific forms of tau protein. To examine the structure and function of tau protein in vivo, we have transiently expressed fetal and adult forms of tau protein and tau protein fragments in tissue culture cells. Biochemical analysis reveals full-length products with heterogeneity in post-translational modification synthesized in the cells. Immunofluorescent staining of transfected cells shows that, under our conditions, sequences on both sides of the repeat region are required for in vivo microtubule co-localization. These additional regions may be required either for enhancing microtubule contacts or for proper protein folding in the cell. In our expression system, the bundling of cellular microtubules occurs only in transfections using four-repeat tau constructs; any four-repeat construct capable of binding is also able to induce bundling. Our data suggest that the presence of bundles is correlated with enhanced microtubule stability; factors that increase stability such as higher levels of tau protein expression or the presence of the fourth repeat, increase the fraction of transfected cells showing bundles. Finally, the presence of tau protein in the cell allows all interphase microtubules to become acetylated, a post-translational modification usually reserved for a subset of stable cellular microtubules.
X-ray Crystal Structure of Human Dopamine Sulfotransferase, SULT1A3 (1999)

Humans are one of the few species that produce large amounts of catecholamine sulfates, and they have evolved a specific sulfotransferase, SULT1A3 (M-PST), to catalyze the formation of these conjugates. An orthologous protein has yet to be found in other species. To further our understanding of the molecular basis for the unique substrate selectivity of this enzyme, we have solved the crystal structure of human SULT1A3, complexed with 3'-phosphoadenosine 5'-phosphate (PAP), at 2.5 A resolution and carried out quantitative structure-activity relationship (QSAR) analysis with a series of phenols and catechols. SULT1A3 adopts a similar fold to mouse estrogen sulfotransferase, with a central five-stranded beta-sheet surrounded by alpha-helices. SULT1A3 is a dimer in solution but crystallized with a monomer in the asymmetric unit of the cell, although dimer interfaces were formed by interaction across crystallographic 2-fold axes. QSAR analysis revealed that the enzyme is highly selective for catechols, and catecholamines in particular, and that hydrogen bonding groups and lipophilicity (cLogD) strongly influenced K(m). We also investigated further the role of Glu(146) in SULT1A3 using site-directed mutagenesis and showed that it plays a key role not only in defining selectivity for dopamine but also in preventing many phenolic xenobiotics from binding to the enzyme.
Effects of nucleotides and nucleotide:analogs on human serum sialyltransferase. (1979)

Abstract The properties of human serum cytidine 5′-monophosphate (CMP)-N-acetylneuraminic acid:glycoprotein sialyltransferase (EC 2.4.99.1) were studied. Optimal enzyme activity was observed in an assay medium buffered with 0.1 m cacodylate at pH 6.5 and using desialyzed fetuin as an acceptor. Neither Mn2+ nor Mg2+ were required for optimal enzyme activity, and when present, they inhibited the enzyme activity at concentrations greater than 2 and 5 mm, respectively. Enzyme inhibition was also observed in the presence of detergents such as Triton X-100, deoxycholate, and sodium dodecyl sulfate. Two sulfhydryl agents, N-ethylmaleimide and p-chloromercuriphenylsulfonic acid, showed inhibitory activity toward sialyltransferase. The effects of nucleotides and nucleotide:analogs on sialyltransferase were also studied. It was found that cytidine nucleotides, which act as competitive inhibitors, showed the greatest inhibitory activity. Like cytidine nucleotides its analogs (5′-fluorocytidine monophosphoric acid, cytosine-β-d-arabinofuranoside-5′-triphosphate, cytosine-β-d-arabinofuranoside-5′-monophosphoric acid, and cytidine 3′:5′-cyclic monophosphoric acid) acted as competitive inhibitors but were not as effective in enzyme inhibition, although 5′-fluorocytidine monophosphoric acid was nearly as potent in its inhibitory capacity as CMP. The apparent K1 for CMP was 50 µm, and for 5′-fluorocytidine monophosphoric acid it was 70 µm. Enzyme inhibition was also observed with ribodialdehyde CMP, and to a lesser extent with 5′-(trans-4-N-acetylcyclohexyl)cytidylic acid hydrochloride and its cis counterpart which were synthesized as analogs of CMP:N-acetylneuraminic acid. A noncompetitive inhibition was observed for both adenosine and uridine nucleotides. The extent of inhibition for all nucleotides and their analogs increased with an increasing number of phosphate groups in the compound (K1= 16, 19, and 50 µm for cytidine 5′-triphosphate, cytidine 5′-diphosphate, and CMP, respectively). These studies are important in assessing the activity of potential inhibitors of glycoconjugate biosynthesis and should aid in the design of more active and specific agents which may be useful in the chemotherapy of cancer.
Trk receptor inhibition induces apoptosis of proliferating but not quiescent human osteoblasts. (2002)

Prostate cancer frequently metastasizes to the skeleton, producing painful osteoblastic lesions, which are associated with significant morbidity and mortality. This bone tropism involves the bidirectional paracrine interactions between prostate cancer cells and osteoblasts. These interactions enhance prostate cancer cell survival and proliferation of osteoblasts. Therefore, agents that can induce apoptosis of prostate cancer cells and proliferating osteoblasts would be highly advantageous. Previously, we have documented that the unique survival pathway for prostate cancer cells involves a neurotrophin/Trk receptor autocrine pathway. The indocarbazole compounds, CEP-701 and CEP-751, are potent inhibitor of this Trk receptor survival signaling and thus selectively induces apoptosis of prostate cancer cells in various in vitro and in vivo models. In this study, we documented the effects of CEP-751 on the conditionally immortalized osteoblastic cell line, hFOB, in vitro. At the permissive temperature of 34 degrees C, these cells express large T antigen, inducing their continuous proliferation, whereas at 39 degrees C, T antigen is degraded and the cells stop proliferating without undergoing apoptosis. Trk receptors are expressed in hFOB cells, as determined both by reverse transcription-PCR and Western blots. These osteoblasts were shown to produce nerve growth factor and brain-derived neurotrophic factor but not neurotrophin-3, as measured by ELISA. hFOB osteoblasts, cultured at 34 degrees C, secreted significantly (P < 0.01) more brain-derived neurotrophic factor and nerve growth factor into the medium than hFOB cells cultured at 39 degrees C. Because the Trk/neurotrophin axis is present in both proliferating and quiescent (i.e., nonproliferating) osteoblasts, the effects of 48 h of exposure to various doses of CEP-751 on cell viability and apoptosis of hFOB cells were assessed by trypan blue exclusion assays and 4',6-diamidino-2-phenylindole nuclear staining. Cell viability and apoptosis of hFOB cells at 34 degrees C were significantly and dose-dependently decreased compared with untreated proliferating cells. In contrast, even the highest concentration of CEP-751 (200 nM) did not affect cell viability and apoptosis of quiescent hFOB cells cultured at 39 degrees C. This trk inhibition-induced cytotoxicity was confirmed using early-passage, proliferating normal (i.e., non-SV40-transformed) human osteoblasts, which also express Trk receptor protein. These combined results demonstrate that proliferating osteoblasts acquire a sensitivity to trk inhibition- induced apoptosis not shared with normally quiescent osteoblasts.