gebhart/patrepeval huggingface dataset:
Synergistic Effects of Synthetic Adjuvants on the Humoral Immune Response (1986)

The effect of combinations of adjuvants on the humoral immune response to sheep red blood cells (SRBC) as antigen was investigated. Adjuvants belonging to two categories differing in physicochemical properties were used: surfactants (N,N-dioctadecyl-N',N'-bis-(2-hydroyethyl)propanediamine (CP-20,961), dimethyldioctadecylammonium bromide (DDA), neutrally charged liposomes, polyol (L 101 and L 121) and polyanions [dextran sulfate (DXS), liquoid and suramine]. All adjuvants but suramine augmented humoral responses to 2 X 10(7) SRBC measured by the number of direct anti-SRBC plaque-forming cells (PFC) in the spleen. The response to 2 X 10(6) SRBC was enhanced considerably by L 121 and DXS but hardly or not at all by the other adjuvants. Combinations of two adjuvants were made at distinct ratios (1:3, 2:2, and 3:1) and injected intraperitoneally with 2 X 10(6) SRBC. Low responses (5 X 10(3) PFC per spleen) were induced by combinations of liquoid or suramine with DDA or DXS, and by combinations of CP-20,961, liposomes, L 101 or L 121 with DDA. Combinations of the surfactants DDA, CP-20,961, liposomes, L 101 or L 121 with DXS evoked responses which were significantly higher than the sum of responses supported by the single adjuvants. Ratios of 1:3 or 2:2 (surfactant: DXS) resulted in the most effective combinations. The data obtained suggest that only adjuvants derived from two different physicochemical groups are able to act synergistically.
Nucleotide sequences of the pbpX genes encoding the penicillin‐binding proteins 2x from Streptococcus pneumoniae R6 and a cefotaxime‐resistant mutant, C506 (1989)

Development of penicillin resistance in Streptococcus pneumoniae is due to successive mutations in penicillin-binding proteins (PBPs) which reduce their affinity for beta-lactam antibiotics. PBP2x is one of the high-Mr PBPs which appears to be altered both in resistant clinical isolates, and in cefotaxime-resistant laboratory mutants. In this study, we have sequenced a 2564 base-pair chromosomal fragment from the penicillin-sensitive S. pneumoniae strain R6, which contains the PBP2x gene. Within this fragment, a 2250 base-pair open reading frame was found which coded for a protein having an Mr of 82.35kD, a value which is in good agreement with the Mr of 80-85 kD measured by SDS-gel electrophoresis of the PBP2x protein itself. The N-terminal region resembled an unprocessed signal peptide and was followed by a hydrophobic sequence that may be responsible for membrane attachment of PBP2x. The corresponding nucleotide sequence of the PBP2x gene from C504, a cefotaxime-resistant laboratory mutant obtained after five selection steps, contained three nucleotide substitutions, causing three amino acid alterations within the beta-lactam binding domain of the PBP2x protein. Alterations affecting similar regions of Escherichia coli PBP3 and Neisseria gonorrhoeae PBP2 from beta-lactam-resistant strains are known. The penicillin-binding domain of PBP2x shows highest homology with these two PBPs and S. pneumoniae PBP2b. In contrast, the N-terminal extension of PBP2x has the highest homology with E. coli PBP2 and methicillin-resistant Staphylococcus aureus PBP2'. No significant homology was detected with PBP1a or PBP1b of Escherichia coli, or with the low-Mr PBPs.
Long‐Term Cytokine Production from Engineered Primary Human Stromal Cells Influences Human Hematopoiesis in an In Vivo Xenograft Model (1997)

Human hematopoiesis can be supported in beige/nude/ XID (bnx) mice by coinjection of human bone marrow stromal cells engineered to secrete human interleukin 3 (HuIL-3). The major limitation is a total absence of human B cell development in the mice, which could be due to supraphysiological levels of HuIL-3 in the circulation. In an effort to obtain human B lymphoid, as well as T lymphoid and myeloid cell development in the mice, CD34+ cells were coinjected with human marrow stromal cells engineered to secrete human IL-2, IL-7, stem cell factor or FLT3 ligand, +/- IL-3. No single factor other than IL-3 supported sustained human hematopoiesis in the mice, although cytokines were expressed for four to six months post-transplantation. Production of both HuIL-3 and IL-7 in the mice supported extrathymic development of human T lymphocytes, but no B cells, myeloid cells, or clonogenic progenitors were detected. Human B cells were not produced from CD34+ cells in the bnx mice under any condition tested. Another limitation to the bnx/Hu system is a lack of maturation of human red blood cells, although BFU-E are maintained. Stromal cells secreting human erythropoietin and IL-3 were cotransplanted into mice with HuCD34+ cells and an increase in hematocrit from 40%-45% to 80%-85% resulted, with production of human and murine red blood cells. Unfortunately, all mice (n = 9) suffered strokes, displayed paralysis and died within three weeks. The bnx/Hu cotransplantation model provides an interesting system in which to study human hematopoietic cell differentiation under the influence of various cytokines.
Food increases the bioavailability of propafenone. (1987)

The effect of food intake on the bioavailability of propafenone, a new antiarrhythmic agent, was evaluated by comparing its kinetics in 24 healthy volunteers in a fasted state and after a standard breakfast. With food, the maximum plasma drug concentration was reached earlier and was significantly increased. When data from 'slow' metabolizers were excluded, there was an average increase of 147% in the area under the concentration-time curve (AUCo) following the standard breakfast. There was a significant correlation (r = 0.946) between [(AUCo fed - AUCo fasted)/AUCo fasted] and propafenone intrinsic clearance in the fasted state. Food intake, however, does not appear to affect the bioavailability of propafenone in 'slow' metabolizers. Patients should be advised to take propafenone in a constant relationship to food to assure consistent bioavailability.
GM2 Expression in Renal Cell Carcinoma: Potential Role in Tumor-Induced T-Cell Dysfunction (2006)

Multiple mechanisms have been proposed to account for immune escape by tumors. Although gangliosides have long been known to suppress T-cell immunity, few studies have examined the effect of human tumor-derived gangliosides on immune responses. Here, we show that gangliosides isolated from renal cell carcinoma (RCC) cell lines and clear cell tumor tissue can induce apoptosis in peripheral blood T cells. The RCC tissue-derived gangliosides also suppressed IFN-gamma and, in many cases, interleukin-4 production by CD4+ T cells at concentrations (1 ng/mL-100 pg/mL) well below those that induce any detectable T-cell death (4-20 microg/mL). Additional findings show that GM2 expressed by RCC plays a significant role in promoting T-cell dysfunction. This is supported by the demonstration that all RCC cell lines examined (n = 5) expressed GM2 as did the majority of tumors (15 of 18) derived from patients with clear cell RCC. Furthermore, an antibody specific for GM2 (DMF10.167.4) partially blocked (50-60%) T-cell apoptosis induced by coculturing lymphocytes with RCC cell lines or with RCC tissue-derived gangliosides. DMF10.167.4 also partially blocked the suppression of IFN-gamma production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4+ T cells.
Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine (1993)

The clinical performance of a laboratory test can be described in terms of diagnostic accuracy, or the ability to correctly classify subjects into clinically relevant subgroups. Diagnostic accuracy refers to the quality of the information provided by the classification device and should be distinguished from the usefulness, or actual practical value, of the information. Receiver-operating characteristic (ROC) plots provide a pure index of accuracy by demonstrating the limits of a test's ability to discriminate between alternative states of health over the complete spectrum of operating conditions. Furthermore, ROC plots occupy a central or unifying position in the process of assessing and using diagnostic tools. Once the plot is generated, a user can readily go on to many other activities such as performing quantitative ROC analysis and comparisons of tests, using likelihood ratio to revise the probability of disease in individual subjects, selecting decision thresholds, using logistic-regression analysis, using discriminant-function analysis, or incorporating the tool into a clinical strategy by using decision analysis.
Pharmacokinetic and pharmacodynamic surrogate markers: studies with fluoroquinolones in patients (1999)

Several relevant studies of fluoroquinolones are reviewed, and the pneumonia model is used to predict clinical efficacy. In vitro pharmacokinetic and pharmacodynamic relationships help the clinician understand the pharmacologic effects of an antimicrobial agent. The clinical translation of in vitro determinants has proved challenging, however. Surrogate markers that define specific relationships between pharmacokinetic and pharmacodynamic characteristics of antimicrobials have been used to predict positive patient outcomes. Studies have shown that the ratio of the area under the serum concentration-time curve from 0 to 24 hours to the minimum inhibitory concentration, also known as the area under the inhibitory curve, is uniquely suited as a surrogate for identifying fluoroquinolone concentrations that correlate with clinical efficacy. In patients, appropriate dosage levels can be readily examined with the nosocomial pneumonia model. Modeling patient responses to infection has become a useful way of interpreting the clinical effects of fluoroquinolone therapy.
Stimulation of Synthesis of Free Chondroitin Sulfate Chains by β-D-Xylosides in Cultured Cells (1974)

Previous studies have shown that D-xylose partially overcomes the puromycin inhibition of chondroitin sulfate synthesis in cultured chick embryo chondrocytes. Likewise, D-xylose stimulates chondroitin sulfate synthesis by limb bud mesenchyme cells previously treated with BrdU or limb bud cartilage cells treated with puromycin. The studies reported here show that p-nitrophenyl-beta-D-xylopyranoside and 4-methyl-umbelliferyl-beta-D-xylopyranoside cause a much greater stimulation than does D-xylose and are active at much lower concentrations. In contrast to D-xylose, the xylosides strikingly stimulate chondroitin sulfate synthesis in predifferentiated mesenchyme cells. The xylosides stimulate synthesis of chondroitin sulfate by rat glial cell tumor cells (RC-6), a mouse neuroblastoma (C1300, NB41A), and two strains of cultured rat hepatoma cells (HTC, H(4)). These results indicate that certain types of nonconnective tissue cells contain the enzymic machinery for synthesis of chondroitin sulfate which is normally not utilized because of limited synthesis of core protein and/or xylosyltransferase. The beta-xylosides may be used as a probe of the capacity of various cell types to synthesize sulfated glycosaminoglycans.
Mechanistic considerations in chemopreventive drug development (1994)

This overview of the potential mechanisms of chemopreventive activity will provide the conceptual groundwork for chemopreventive drug discovery, leading to structure-activity and mechanistic studies that identify and evaluate new agents. Possible mechanisms of chemopreventive activity with examples of promising agents include carcinogen blocking activities such as inhibition of carcinogen uptake (calcium), inhibition of formation or activation of carcinogen (arylalkyl isothiocyanates, DHEA, NSAIDs, polyphenols), deactivation or detoxification of carcinogen (oltipraz, other GSH-enhancing agents), preventing carcinogen binding to DNA (oltipraz, polyphenols), and enhancing the level or fidelity of DNA repair (NAC, protease inhibitors). Chemopreventive antioxidant activities include scavenging reactive electrophiles (GSH-enhancing agents), scavenging oxygen radicals (polyphenols, vitamin E), and inhibiting arachidonic acid metabolism (glycyrrhetinic acid, NAC, NSAIDs, polyphenols, tamoxifen). Antiproliferation/antiprogression activities include modulation of signal transduction (glycyrrhetinic acid, NSAIDs, polyphenols, retinoids, tamoxifen), modulation of hormonal and growth factor activity (NSAIDs, retinoids, tamoxifen), inhibition of aberrant oncogene activity (genistein, NSAIDs, monoterpenes), inhibition of polyamine metabolism (DFMO, retinoids, tamoxifen), induction of terminal differentiation (calcium, retinoids, vitamin D3), restoration of immune response (NSAIDs, selenium, vitamin E), enhancing intercellular communication (carotenoids, retinoids), restoration of tumor suppressor function, induction of programmed cell death (apoptosis) (butyric acid, genistein, retinoids, tamoxifen), correction of DNA methylation imbalances (folic acid), inhibition of angiogenesis (genistein, retinoids, tamoxifen), inhibition of basement membrane degradation (protease inhibitors), and activation of antimetastasis genes. A systematic drug development program for chemopreventive agents is only possible with continuing research into mechanisms of action and thoughtful application of the mechanisms to new drug design and discovery. One approach is to construct pharmacological activity profiles for promising agents. These profiles are compared among the promising agents and with untested compounds to identify similarities. Classical structure-activity studies are used to find optimal agents (high efficacy with low toxicity) based on good lead agents. Studies evaluating tissue-specific and pharmacokinetic parameters are very important. A final approach is design of mechanism-based assays and identification of mechanism-based intermediate biomarkers for evaluation of chemopreventive efficacy.
Characterization of the Macrolide P-450 Hydroxylase from Streptomyces venezuelae Which Converts Narbomycin to Picromycin, (1998)

The post-polyketide synthase (PKS) biosynthetic tailoring of macrolide antibiotics usually involves one or more oxidation reactions catalyzed by cytochrome P450 monooxygenases. As the specificities of members from this class of enzymes vary significantly among PKS gene clusters, the identification and study of new macrolide P450s are important to the growing field of combinatorial biosynthesis. We have isolated the cytochrome P450 gene picK from Streptomyces venezuelae which is responsible for the C-12 hydroxylation of narbomycin to picromycin. The gene was located by searching regions proximal to modular PKS genes with a probe for macrolide P450 monooxygenases. The overproduction of PicK with a C-terminal six-His affinity tag (PicK/6-His) in Escherichia coli aided the purification of the enzyme for kinetic analysis. PicK/6-His was shown to catalyze the in vitro C-12 hydroxylation of narbomycin with a kcat of 1.4 s-1, which is similar to the value reported for the related C-12 hydroxylation of erythromycin D by the EryK hydroxylase. The unique specificity of this enzyme should be useful for the modification of novel macrolide substrates similar to narbomycin, in particular, ketolides, a promising class of semisynthetic macrolides with activity against erythromycin-resistant pathogens.
Loss of heterozygosity on chromosome arms 3p and 6q in microdissected adenocarcinomas of the uterine cervix and adenocarcinoma in situ (2002)

The authors have identified three chromosomal regions that may harbor TSGs involved in the development/progression of adenocarcinomas of the uterine cervix, 3p12-14.2, 3p21.3-pter, and 6q22-25.2. Deletions also were detected in adenocarcinoma in situ, suggesting the genes may be inactivated early in cervical tumorigenesis.
Diagnosis versus Detection of Caries (2004)

Caries diagnosis is the art or act of identifying a disease from its signs and symptoms. This is distinct from the detection of the signs and symptoms themselves. The diagnosis forms the basis for making informed treatment decisions. Hence, if there is no diagnostic step expressed in terms of the probability of present and future occurrence of disease, practitioners may resort to treatments guided by previous experiences with similar clinical manifestations. This paper reviews various methodological aspects of caries diagnostic testing. It is concluded that rather than continuing to search for the truth of the diagnosis, it may be more informative to consider the consequences of the diagnosis. This view is supported by results from caries-preventive trials in which the activity of carious lesions has been monitored longitudinally over years.
Rapid Neural Coding in the Retina with Relative Spike Latencies (2008)

Natural vision is a highly dynamic process. Frequent body, head, and eye movements constantly bring new images onto the retina for brief periods, challenging our understanding of the neural code for vision. We report that certain retinal ganglion cells encode the spatial structure of a briefly presented image in the relative timing of their first spikes. This code is found to be largely invariant to stimulus contrast and robust to noisy fluctuations in response latencies. Mechanistically, the observed response characteristics result from different kinetics in two retinal pathways ("ON" and "OFF") that converge onto ganglion cells. This mechanism allows the retina to rapidly and reliably transmit new spatial information with the very first spikes emitted by a neural population.
Effect of modification of carbohydrate side chains on the reactivity of antibodies with core-protein epitopes of the MUC1 gene product. (1993)

The product of the MUC1 gene, the polymorphic epithelial mucin (PEM), contains a large domain consisting of tandem repeats of 20 amino acids. Each repeat contains five potential sites for O-glycosylation, suggesting that this region forms a scaffold for the attachment of the O-linked carbohydrate which makes up more than 50% of the molecule. A number of monoclonal antibodies have been shown to recognize core-protein epitopes within the tandem repeat domain. One such antibody, SM3, reacts with the mucin expressed by breast carcinomas but shows little or no reaction with normal resting or lactating breast. Using primary mammary epithelial cells (HuME), an immortalized cell line derived from HuME (MTSV1-7) and a breast carcinoma cell line (BT20) the influence of the carbohydrate side chains on the binding of antibodies to core-protein epitopes has been investigated. We unequivocally show that the masking of the SM3 epitopes in normal breast epithelial cells is due to the carbohydrate side chains. In addition we demonstrate that the binding of two other antibodies (HMFG1, HMFG2) to core-protein epitopes is influenced by the carbohydrate side chains. The binding of HMFG-1 is particularly affected by sialic acid whereas the binding of HMFG2 is influenced by the length of the oligosaccharide side chains. Furthermore, inhibited elongation of O-linked carbohydrate side chains does not seem to interfere with the cell trafficking of the mucin to the cell surface.
Transversus Abdominis Plane Block With Liposomal Bupivacaine for Pain After Cesarean Delivery in a Multicenter, Randomized, Double-Blind, Controlled Trial (2020)

TAP block using LB plus bupivacaine HCl as part of a multimodal analgesia protocol incorporating intrathecal morphine resulted in reduced opioid consumption after cesarean delivery in the PCA set. Results suggest that with correct TAP block placement and adherence to a multimodal postsurgical analgesic regimen, there is an opioid-reducing benefit of adding LB to bupivacaine TAP blocks after cesarean delivery (ClinicalTrials.gov identifier: NCT03176459).
Integrins and tumor invasion (1990)

Cell-extracellular matrix interactions are important in the process of tumor cell invasion and metastasis. In particular, the interactions of tumor cells with basement membranes of tissue epithelial, as well as vascular endothelial, cells are likely to represent key steps in the metastatic process. The interactions between cells and the connective tissue matrix are mediated by a large family of cell surface receptors, the integrins, which represent multiple receptors for extracellular matrix and basement membrane components. Here, I review recent progress in elucidating the roles of integrins in tumor cell invasion. Altered expression of this large family of receptors on invasive tumor cells, as compared with non-invasive cells, may represent a fundamental step in the progressive expression of the invasive phenotype.
BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR (2009)

BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
The Human β Globin Locus Introduced by YAC Transfer Exhibits a Specific and Reproducible Pattern of Developmental Regulation in Transgenic Mice (1997)

The human beta globin locus spans an 80-kb chromosomal region encompassing both the five expressed globin genes and the cis-acting elements that direct their stage-specific expression during ontogeny. Sequences proximal to the genes and in the locus control region, 60 kb upstream of the adult beta globin gene, are required for developmental regulation. Transgenic studies have shown that altering the structural organization of the locus disrupts the normal pattern of globin gene regulation. Procedures for introducing yeast artificial chromosomes (YACs) containing large genetic loci now make it possible to define the sequences required for stage-restricted gene expression in constructs that preserve the integrity of the beta globin locus. We demonstrate that independent YAC transgenic lines exhibit remarkably similar patterns of globin gene expression during development. The switch from gamma to beta globin predominant expression occurs between day 11.5 and 12.5 of gestation, with no more than twofold differences in human beta globin mRNA levels between lines. Human beta globin mRNA levels were twofold to fourfold lower than that of mouse betamaj, revealing potentially significant differences in the regulatory sequences of the two loci. These findings provide an important basis for studying regulatory elements within the beta globin locus.