gebhart/patrepeval huggingface dataset:
Receptor functions and ligand-dependent transforming potential of a chimeric kit proto-oncogene. (1990)

The c-kit proto-oncogene, the cellular homolog of the transforming gene of a feline retrovirus, encodes a transmembrane tyrosine kinase homologous to receptors for growth factors. To study the cellular function of c-kit, we constructed a chimeric molecule composed of the extracellular portion of the receptor for epidermal growth factor (EGF) and the transmembrane and cytoplasmic domains of p145kit. The hybrid molecule was properly expressed in murine fibroblasts and displayed specific binding of EGF (Kd, 3 x 10(-8) M). Activation of the chimeric receptor by EGF stimulated the tyrosine kinase activity of kit and led to the generation of a potent mitogenic signal. Moreover, cells expressing the chimeric receptor acquired a transformed phenotype once they were stimulated with the heterologous ligand.
A Novel Method for Detection and ex Vivo Expansion of HIV Type 1-Specific Cytolytic T Lymphocytes (1994)

Studies have shown that cytolytic T lymphocyte (CTL) responses may be critical to the clearance of the early viremia in acute HIV-1 infection. It is likely that these cells play an important role in prolonging the asymptomatic phase of the infection. Although HIV-1-specific CTL activity can be detected in direct assays of freshly isolated peripheral blood lymphocytes (PBL) from some infected individuals, this method fails to detect CTL that are present at low frequency and resting, memory CTL. For these reasons, direct CTL assays on PBL from seropositive individuals may underestimate the level of CTL immunity. As part of ongoing investigations of CTL activity in HIV-1-infected individuals, we developed a novel strategy for the detection and ex vivo expansion of HIV-1-specific CTL. This technique involves selective stimulation of PBL from seropositive individuals with autologous Epstein-Barr virus (EBV)-transformed, B-lymphoblastoid cell lines (B-LCL) infected with vaccinia vectors expressing various HIV-1 genes. Prior to their use for in vitro stimulation, B-LCL are treated with psoralen and UV light to inactivate vaccinia virus. After 1 week of stimulation, CTL activity in stimulated cultures is measured in a standard 51Cr release assay. This ex vivo expansion method can selectively increase the bulk culture CTL activity against env, gag and nef, even in some seropositive individuals with low CD4 counts and little evidence of HIV-1-specific CTL in assays of freshly isolated PBL. These expanded CTL are predominantly of the CD8+ phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Surface conductance of a copper wire in a fluid at high pressure (1987)

The three-dimensional flow of heat in a wire carrying a current and immersed in a liquid is solved in detail. Using this exact result the surface conductance of copper in petroleum ether has been measured as a function of pressure to 40 kbars. The measured surface conductance for copper in a fluid is very small, justifying approximations which yield results that are in agreement with a simplified one-dimensional heat-flow problem. Surprisingly, even at 40 kbars pressure a very large fraction of the joule heating within a wire with a length-to-diameter ratio of ∼100 is dissipated through the ends of the wire rather than to the surrounding liquid.
Epstein-Barr Virus Infections: Biology, Pathogenesis, and Management (1993)

Epstein-Barr virus (EBV) encodes genes that ensure its persistence in human B lymphocytes. Some of the genes encourage B-cell proliferation; others are poised to evade or defeat immune recognition. Immune restraints on the virus, however, are typically so effective that most infections are never symptomatic. In contrast, acute infectious mononucleosis, a self-limited lymphoproliferative illness, is common in adolescents and young adults. Unbridled proliferative illnesses arise when cellular immunity is grossly defective. Treatment of EBV-associated syndromes is largely supportive. Antiviral drugs have no proven role except in patients with oral hairy leukoplakia. Vaccine development is technically feasible but is not considered a high priority for developed nations.
Excited State Properties of Rh2(O2CCH3)4: Solution Photochemistry and Photoinitiated DNA Cleavage (2001)

Abstract The photophysical properties of Rh2(O2CCH3)4(L)2 (L = CH3OH, THF = tetra-hydrofuran, PPh3 = triphenylphosphine, py = pyridine) were explored upon excitation with visible light. All the complexes exhibit a long-lived transient absorption signal (τ = 3.5–5.0 μs) assigned as an electronic excited state of each molecule. An optical transition at −760 nm is observed in the spectra of the transients, whose position is relatively independent of axial ligand. No emission from the Rh2(O2CCH3)4(L)2 (L = CH3OH, THF, PPh3, py) systems was observed at room temperature or at 77 K, but energy transfer from excited Rh2(O2CCH3)4(PPh3)2 to tetracene and perylene takes place to form the 3ππ∗ excited state of each acceptor. Electron transfer from ∗Rh2(O2CCH3)4(PPh3)2 to dimethyl viologen (MV2+) and chloro-p-benzoquinone (Cl-BQ) takes place with quenching rate constants (kq) of 8.0 × 106 M−1s−1 and 1.2 × 106 M−1s−1 in methanol, respectively. A kq value of 2 × 108 M−1s−1 was measured for the quenching of the excited state of Rh2(O2CCH3)4(PPh3)2 by O2 in methanol. The results of the energy and electron transfer experiments are consistent with the production of an excited state of Rh2(O2CCH3)4(PPh3)2 with energy, E00, between 1.34 eV and 1.77 eV. The excited state of Rh2(O2CCH3)4 is not able to undergo hydrogen abstraction chemistry. However, the photoproduced one-electron oxidized complex, Rh2(O2CCH3)4 +, is able to convert isopropanol to acetone and to efficiently cleave DNA with λirr≥ 610 nm.
Small rat islets are superior to large islets in in vitro function and in transplantation outcomes (2005)

Barriers to the use of islet transplantation as a practical treatment for diabetes include the limited number of available donor pancreata. This project was designed to determine whether the size of the islet could influence the success rate of islet transplantations in rats. Islets from adult rats were divided into two groups containing small (diameter <125 microm) or large (diameter >150 microm) islets. An average pancreas yielded three times more small islets than large. Smaller islets were approximately 20% more viable, with large islets containing a scattered pattern of necrotic and apoptotic cells or central core cell death. Small islets in culture consumed twice as much oxygen as large islets when normalized for the same islet equivalents. In static incubation, small islets released three times more insulin under basal conditions than did large islets. During exposure to high glucose conditions, the small islets released four times more insulin than the same islet equivalencies of large islets, and five times more insulin was released by the small islets in response to glucose and depolarization with K+. Most importantly, the small islets were far superior to large islets when transplanted into diabetic animals. When marginal islet equivalencies were used for renal subcapsular transplantation, large islets failed to produce euglycemia in any recipient rats, whereas small islets were successful 80% of the time. The results indicate that small islets are superior to large islets in in vitro testing and for transplantation into the kidney capsule of diabetic rats.
Fibroblast Activation Protein and Its Relationship to Clinical Outcome in Pancreatic Adenocarcinoma (2008)

Fibroblast activation protein is highly expressed in pancreatic adenocarcinoma, with greatest expression immediately adjacent to tumor. Higher FAP expression is associated with worse clinical outcome. The investigation of FAP inhibitors as a therapeutic strategy against pancreatic cancer should be considered.
Estrogen Induces Adenosine Deaminase Gene Expression in MCF-7 Human Breast Cancer Cells: Role of Estrogen Receptor-Sp1 Interactions**This work was supported by the National Institutes of Health (Grant CA-76636), the Welch Foundation, and the Texas Agricultural Experiment Station. (1999)

Adenosine deaminase (ADA) gene expression is induced by 17beta-estradiol (E2) in MCF-7 human breast cancer cells, whereas the antiestrogens 4'-hydroxytamoxifen and ICI 182,780 exhibit partial estrogen receptor (ER) agonist/antagonist and antagonist activities, respectively. Previous studies have shown that the -211 to +11 region of the ADA gene promoter contains six GC-rich sites (I-VI) that bind Sp1 protein, and these elements are required for high basal expression. In transient transfection studies with pADA211, which contains the -211 to +11 ADA gene promoter linked to a bacterial chloramphenicol acetyl transferase (CAT) reporter gene, E2 and tamoxifen (but not ICI 182,780) induced CAT activity. Ligand-induced transactivation was observed only in cells cotransfected with expression plasmids for wild-type ER or HE11, which does not contain the DNA-binding domain of the ER. Cotransfection with HE15 and HE19, which contain the DNA-binding domain and activation function-1 (AF-1) and AF-2 of the ER, respectively, did not result in E2-induced activity. Subsequent deletion analysis of the ADA gene promoter showed that Sp1 binding site IV (-79 to -73) was primarily responsible for hormone responsiveness. ER activation of ADA gene expression is another example of an E2-induced gene that is dependent on ER/Sp1 interactions with a site-specific GC-rich motif.
Expression and Characterization of the Catalytic Core of Tryptophan Hydroxylase (1998)

Wild type rabbit tryptophan hydroxylase (TRH) and two truncated mutant proteins have been expressed in Escherichia coli. The wild type protein was only expressed at low levels, whereas the mutant protein lacking the 101 amino-terminal regulatory domain was predominantly found in inclusion bodies. The protein that also lacked the carboxyl-terminal 28 amino acids, TRH102-416, was expressed as 30% of total cell protein. Analytical ultracentrifugation showed that TRH102-416 was predominantly a monomer in solution. The enzyme exhibited an absolute requirement for iron (ferrous or ferric) for activity and did not turn over in the presence of cobalt or copper. With either phenylalanine or tryptophan as substrate, stoichiometric formation of the 4a-hydroxypterin was found. Steady state kinetic parameters were determined with both of these amino acids using both tetrahydrobiopterin and 6-methyltetrahydropterin.
Pan-cancer whole-genome analyses of metastatic solid tumours (2019)

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.
Gaps and perspectives of new fluoroquinolones. (1988)

The gaps in the present piperazinyl-substituted fluoroquinolones include: (a) gaps in their antibacterial spectrum, varying from one fluoroquinolone to another for streptococci-pneumococci-enterococci (SPE), some Gram-negative and Gram-positive anaerobes, Nocardia, Pseudomonas maltophilia, Ureaplasma urealyticum, slow-growing mycobacteria; (b) a pH dependence of their antibacterial activity (low activity at acidic pH for piperazinyl-substituted fluoroquinolones); (c) a rapid development of bacterial resistance for some bacteria (staphylococci, pseudomonas) in prolonged treatment of cystic fibrosis, intensive care units; (d) some gaps in the pharmacokinetic parameters such as incomplete oral bioavailability, short half-life, intensive biotransformation, unwanted interactions with other antibiotics or other drugs. The prospects for fluoroquinolones are trying to eliminate these gaps. The 7-piperazinyl or pyrrolidinyl, 1-cyclopropylfluoroquinolones have improved activity on SPE, anaerobes and pseudomonas-acinetobacter. Two categories can be distinguished: (i) with increased activity on SPE, but keeping also the activity on pseudomonas (A-62824, A-62254, A-65846, A-60969, AT-3295, AT-3765); (ii) with increased activity on SPE but with a loss of activity on pseudomonas (CI-934, PD-117558, S-25932). The pharmacokinetic parameters are modified by the N-methylation of the piperazine ring (bioavailability), modification of the hydrophilic or lipophilic character, conditioning half-life, metabolic biotransformation, diffusibility into the spinal fluid, crossing the blood-brain barrier, tubular reabsorption and neuropsychic adverse effects.
Hematologic bone marrow disorders: quantitative chemical shift MR imaging. (1988)

Twenty-one in vivo studies of bone marrow of the lumbar spine were performed with a 0.6-T commercial MR imager and proton chemical shift imaging techniques. Six healthy volunteers served as controls. Multiple measurements in the volunteers demonstrated reproducibility within errors of 5% for fat fraction and 6% for T1 of water. Ten patients who had histologically proved leukemia or aplastic anemia were then examined. The data show that changes in fat fraction represent the underlying reason for many of the changes observed in conventional spin-echo (SE) images of these disorders. Although both conventional and chemical shift images showed differences among the pathologic groups and healthy volunteers, fat fraction determined with chemical shift imaging was the single best discriminator among them. A two-point estimate of fat fraction was also evaluated. This rapid imaging protocol performed almost as well as the complete quantitative analysis in discriminating between pathologic and healthy tissue and showed improved discrimination compared with conventional SE techniques.
Molecular and cellular characterization of SEL‐OB/SVEP1 in osteogenic cells in vivo and in vitro (2005)

We describe a novel human gene, named SEL-OB/SVEP1, expressed by skeletal tissues in vivo and by cultured osteogenic cells. The mRNA expression was analyzed on frozen tissues retrieved by laser-capture microscope dissection (LCM) and was detected in osteogenic tissues (periosteum and bone) but not in cartilage or skeletal muscle. The SEL-OB/SVEP1 cDNA of 11,139 bp was in silico translated into a 3574AA protein with expected molecular weight of 370 kDa. The protein is composed of multiple domains including complement control protein (CCP) modules with selectin superfamily signature; sushi and other domains, such as vWA, EGF, PTX, and HYR. Stromal osteogenic cells were analyzed for the protein expression using anti-SEL-OB/SVEP1 for immuno-precipitation and Western blot application confirm the presence of high molecular weight protein. Immuno-histochemistry and fluorescence-activated cell sorting (FACS) were applied to detect SEL-OB/SVEP1 on the surface of stromal cells. ELISA quantified the dependence of protein expression on cell density. Bioinformatic analysis of SEL-OB/SVEP1 revealed domains compositions recognized in cell surface molecules and suggested its role in cell adhesion. Analysis of mesechymal osteogenic cells' adhesion in presence of anti-SEL-OB/SVEP1 antibody demonstrated its interference with initial adhesion stages. In summary, present study describes novel SEL-OB/SVEP1 protein with a unique composition of functional domains, restricted pattern of expression in skeletal cells and demonstrated involvement in attachment of mesenchymal cells. The unusual composition of functional domains puts SEL-OB/SVEP1 in the discrete new group of membrane proteins involved in cell adhesion processes. All together makes SEL-OB/SVEP1 an attractive marker for studying the role of stromal osteogenic cells and their interactions within the bone marrow microenvironment creating a network that regulates the skeletal homeostasis.
Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells (2013)

Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells occupy and alter the stromal tissue of the bone marrow as a means of enhancing their survival and growth. However, the nature and magnitude of the changes to the stromal cell tissue remain to be determined. In this study, we used mesenchymal stromal cell and osteoblast-related cell surface marker expression (STRO-1 and alkaline phosphatase, respectively) and flow cytometry to enumerate mesenchymal stromal cell and osteoblast numbers in bone marrow recovered from myeloma patients at the time of diagnosis. Using this approach, we identified an increase in the number of STRO-1 positive colony forming mesenchymal stromal cells and a concomitant decrease in alkaline phophatase osteoblasts. Notably, this increase in mesenchymal stromal cell numbers correlated closely with plasma cell burden at the time of diagnosis. In addition, in comparison with the osteoblast population, the STRO-1+ mesenchymal stromal cell population was found to express higher levels of plasma cell- and osteoclast-activating factors, including RANKL and IL-6, providing a mechanism by which an increase in mesenchymal stromal cells may promote and aid the progression of myeloma. Importantly, these findings were faithfully replicated in the C57BL/KaLwRij murine model of myeloma, suggesting that this model may present a unique and clinically relevant system in which to identify and therapeutically modulate the bone microenvironment and, in turn, alter the progression of myeloma disease.
Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy (1996)

Mice with the MRL background have a genetic propensity for autoimmune lupus nephritis. The lpr mutation on the MRL, but not the C3H background, induces rapid and fatal renal injury in which macrophages (M phi) are prominent. We previously established that CSF-1 accompanies M phi accumulation in the kidney of MRL-lpr mice. Furthermore, CSF-1 introduced into the kidney incites renal injury in mice with the lpr mutation, but not congenic strains. Notably, CSF-1 induces more severe tissue injury in MRL-lpr than in C3H-lpr mice. We hypothesized that M phi from the MRL background respond more readily to CSF-1 than normal strains. We establish herein the following: 1) glomerular M phi and bone marrow M phi (BMM phi) from MRL-lpr mice proliferate similarly to CSF-1; 2) MRL BMM phi proliferate more vigorously to CSF-1 than normal strains (C3H, BALB/c) or another strain with lpr (C3H-lpr); and 3) modulation of CSF-1 receptor expression by CSF-1 is more rapid in MRL than C3H BMM phi. We used a gene transfer strategy to deliver CSF-1 into the kidney to evaluate M phi response to CSF-1. We genetically modified tubular epithelial cells to produce CSF-1 (CSF-1-TECs) and placed these cells with BMM phi under the renal capsule. CSF-1-TEC + BMM phi caused a greater accumulation of M phi in the implant site and interstitium of MRL +/+ than C3H +/+ mice. Furthermore, CSF-1-TEC + BMM phi caused a lesion consisting of M phi in MRL +/+ mice, extending from the implant into the adjacent cortex. We suggest that the response of MRL M phi to CSF-1 is responsible for the notable accumulation of M phi in the MRL-lpr kidney.
A review of remdesivir for COVID-19 in pregnancy and lactation (2021)

Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts, underscoring the need for effective prevention and treatment strategies. However, despite progress in innovative and flexible trial designs during the COVID-19 pandemic, regressive policies excluding pregnant and breastfeeding people from biomedical research persist. Remdesivir, a broad-spectrum antiviral, was the first drug licensed for the treatment of COVID-19, based on data showing it reduced the time to recovery in hospitalized patients. Pregnant and breastfeeding people were specifically excluded from all clinical trials of remdesivir in COVID-19, but data are accumulating from post-marketing registries, compassionate use programmes and case series/reports. In this review we synthesize these data and highlight key knowledge gaps to help inform clinical decision-making about its use in pregnancy and lactation.
Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-alpha in rodents. (1987)

Treatment of healthy rats and mice with a single intravenous injection of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) caused a dose-dependent gastrointestinal inflammation. Within 30 min gastric emptying was blocked and tissue edema occurred in the small and large intestine. In the cecum hemorrhage occurred after 4 h at doses greater than or equal to 250 micrograms/kg. The cecum exhibited an acute inflammatory response following rHuTNF-alpha treatment similar to that seen in tumor necrosis at the same dose. The vascular endothelium became swollen, increased numbers of neutrophils and other leukocytes attached to and penetrated the endothelium, and finally hemorrhage occurred. Treatment of rats with daily injections of rHuTNF-alpha (250 micrograms/kg per d) for 3 wk failed to produce cachexia. Within 24-48 h rats became resistant to the hemorrhagic effect of rHuTNF-alpha, however, the cytokine still caused a transitory block of gastric emptying after 10 d of treatment. Treatment at 5- or 10-d intervals produced results similar to the initial injection. These results suggest that maximum hemorrhagic response will occur when rHuTNF-alpha is administered at intervals of 5-10 d rather than daily.
Fraction Collection from Capillary Liquid Chromatography and Off-line Electrospray Ionization Mass Spectrometry Using Oil Segmented Flow (2010)

Off-line analysis and characterization of samples separated by capillary liquid chromatography (LC) has been problematic using conventional approaches to fraction collection. We demonstrate collection of nanoliter fractions by forming plugs of effluent from a 75 mum inner diameter LC column segmented by an immiscible oil such as perfluorodecalin. The plugs are stored in tubing that can then be used to manipulate the samples. Off-line electrospray ionization mass spectrometry (ESI-MS) was used to characterize the samples. ESI-MS was performed by directly pumping the segmented plugs into a nanospray emitter tip. Critical parameters including the choice of oils, ESI voltage, and flow rates that allow successful direct infusion analysis were investigated. Best signals were obtained under conditions in which the oil did not form an electrospray but was siphoned away from the tip. Off-line analysis showed preservation of the chromatogram with no loss of resolution. The method was demonstrated to allow changes in flow rate during the analysis. Specifically, decreases in flow rate were used to allow extended MS analysis time on selected fractions, similar to "peak parking".