gebhart/patrepeval huggingface dataset:
A Therapeutic CD4 Monoclonal Antibody Inhibits TCR-ζ Chain Phosphorylation, ζ-Associated Protein of 70-kDa Tyr319 Phosphorylation, and TCR Internalization in Primary Human T Cells (2002)

The molecular mechanisms mediating the inhibitory effects of a humanized CD4 mAb YHB.46 on primary human CD4(+) T cells were investigated. Preincubation of T cells with soluble YHB.46 caused a general inhibition of TCR-stimulated protein tyrosine phosphorylation events, including a reduction in phosphorylation of p95(vav), linker for activation of T cells, and Src homology 2 domain-containing leukocyte protein of 76-kDa signaling molecules. A marked reduction in activation of the Ras/mitogen-activated protein kinase pathway was also observed. Examination of the earliest initiation events of TCR signal transduction showed that YHB.46 inhibited TCR-zeta chain phosphorylation together with recruitment and tyrosine phosphorylation of the zeta-associated protein of 70-kDa tyrosine kinase, particularly at Tyr(319), as well as reduced recruitment of p56(lck) to the TCR-zeta and zeta-associated protein of 70-kDa complex. These inhibitory events were associated with inhibition of TCR endocytosis. Our results show that the YHB.46 mAb is a powerful inhibitor of the early initiating events of TCR signal transduction.
Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. (2003)

The molecular mechanisms underlying the cell cycle growth-inhibitory and apoptotic effects of flavopiridol (FP) were determined in human breast cancer cells. Treatment with FP caused accumulation in the G(1) phase of the cell cycle and induced apoptosis of SKBR-3 and MB-468 cells. This was associated with down-regulation of the levels of cyclins D1 and B1, as well as with inhibition of cyclin-dependent kinase (cdk) 1, cdk2, and cdk4. FP-induced apoptosis was accompanied by a conformational change and mitochondrial localization of Bax. This resulted in the accumulations of cytochrome c, Smac, and Omi/HtrA2 in the cytosol and induced the poly(ADP-ribose) polymerase cleavage activity of caspase-3. Treatment with FP also attenuated the mRNA and protein levels of XIAP, cIAP-2, Mcl-1, Bcl-x(L), and survivin. In MB-468 cells with overexpression of Bcl-2 (468/Bcl-2), FP-induced Bax conformational change and apoptosis were inhibited, whereas the FP-mediated decline in the levels of IAP proteins, Mcl-11 and Bcl-x(L) remained unaltered. The effects of cotreatment with FP and the nontaxane tubulin-polymerizing agent epothilone (Epo) B were also determined in MB-468 cells. Sequential treatment with Epo B followed by FP induced significantly more apoptosis of MB-468 cells than treatment with the reverse sequence of FP followed by Epo B or treatment with either agent alone (P < 0.05). Treatment with Epo B followed by FP induced more Bax conformational change and was associated with a greater decline in the levels of XIAP, cIAP-2, Mcl-1, and Bcl-x(L). However, MB-468/Bcl-2 cells remained relatively resistant to Epo B followed by FP. Taken together, these findings suggest that the superior sequence-dependent anti-breast cancer activity of Epo B followed by FP may be due to FP-induced Bax conformational change and down-regulation of the antiapoptotic IAP, Bcl-x(L), and Mcl-1 proteins, but this treatment may not overcome the resistance to apoptosis of breast cancer cells conferred by overexpression of Bcl-2.
A Study on Delocalization of MLCT Excited States by Rigid Bridging Ligands in Homometallic Dinuclear Complexes of Ruthenium(II) (1997)

For the structurally rigid homometallic dinuclear complexes (ttp)Ru(tpy-tpy)Ru(ttp)4+ and (ttp)Ru(tpy-ph-tpy)Ru(ttp)4+, we have obtained ground-state absorption spectra and transient-absorption difference spectra at room temperature and luminescence spectra and lifetimes in the temperature interval from room temperature to the rigid matrix (90 K); the solvent was acetonitrile or butyronitrile (tpy is 2,2‘:6‘,2‘‘-terpyridine, ttp is 4‘-p-tolyl-2,2‘:6‘,2‘‘-tpy, and ph is 1,4-phenylene). The gathered spectroscopic data indicate that after absorption of visible light, formation of the luminescent metal-to-ligand charge transfer (MLCT) excited states takes place, which involves the bridging ligand (BL). Since we found that (ttp)Ru(tpy-tpy)Ru(ttp)4+ is a good luminophore (λmax = 720 nm, Φ = 4.7 × 10-3, and τ = 570 ns) while both (ttp)Ru(tpy-ph-tpy)Ru(ttp)4+ (λmax = 656 nm, Φ = 1.1 × 10-4, and τ = 4 ns) and the reference mononuclear complex Ru(ttp)22+ (λmax = 640 nm, Φ = 3.2 × 10-5, and τ = 0.9 ns) are not, we have explored the effects brought about by the delocalization and energy content of the luminescent state. The study of the temperature dependence of the luminescence lifetimes indicates that two main nonradiative paths, i and ii, are responsible for deactivation of the luminescent state. Path i directly connects the luminescent and ground states; within the frame of the “energy-gap law”, vibronic analysis of low-temperature luminescence profiles enables one to correlate the delocalization of the M → BL CT state and the extent of structural distortions occurring at the accepting ligand. Thermally activated decay via a metal-centered (MC, of dd orbital origin) excited state characterizes path ii, with a MLCT−MC energy separation ΔE = 3800, 2300, and 1600 cm-1 for (ttp)Ru(tpy-tpy)Ru(ttp)4+, (ttp)Ru(tpy-ph-tpy)Ru(ttp)4+, and Ru(ttp)22+, respectively. At room temperature, for this limited series of complexes it is found that nonradiative processes governed by the “energy-gap law” play a minor role as compared to thermally activated processes, the ratios of the rate constants being knract/knrdir ≈ 16, 1900, and 7000 for (ttp)Ru(tpy-tpy)Ru(ttp)4+, (ttp)Ru(tpy-ph-tpy)Ru(ttp)4+, and Ru(ttp)22+, respectively.
Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. (2001)

Recent evidence suggests that one mechanism whereby cytotoxic drugs, such as doxorubicin, kill tumors is the induction or up-regulation of Fas ligand (FasL) expression on the tumor cell surface. The ensuing engagement of Fas by FasL on adjacent cells leads to apoptosis. However, despite cytotoxic drug-induced FasL expression, Fas-sensitive tumors frequently resist chemotherapy, suggesting that they may possess a mechanism that prevents or inactivates Fas-FasL interactions. In the present work, we addressed the involvement of the FasL/Fas signaling pathway in doxorubicin-induced apoptosis and the ability of matrix metalloproteinases (MMPs) to proteolytically cleave FasL in tumor cells. Doxorubicin-induced apoptosis was inhibited by expression of soluble Fas or incubation of the tumor cells with MMP-7 but not with MMP-2 or MMP-9. Resistance to doxorubicin was also induced by expression in the tumor cells of constitutively active MMP-7 but not of a catalytically inactive mutant. Conversely, inhibition of MMP-7 expression in tumor cells by transfection of MMP-7 cDNA in antisense orientation resulted in sensitization to doxorubicin. MMP-7 efficiently cleaved recombinant FasL in vitro and reduced cell surface FasL expression. Our observations provide evidence that one mechanism whereby MMP-7 may promote tumor survival and resistance to doxorubicin is by cleaving FasL and reducing its effectiveness in triggering Fas-mediated apoptosis.
Detecting differential usage of exons from RNA-seq data (2012)

RNA-seq is a powerful tool for the study of alternative splicing and other forms of alternative isoform expression. Understanding the regulation of these processes requires sensitive and specific detection of differential isoform abundance in comparisons between conditions, cell types, or tissues. We present DEXSeq, a statistical method to test for differential exon usage in RNA-seq data. DEXSeq uses generalized linear models and offers reliable control of false discoveries by taking biological variation into account. DEXSeq detects with high sensitivity genes, and in many cases exons, that are subject to differential exon usage. We demonstrate the versatility of DEXSeq by applying it to several data sets. The method facilitates the study of regulation and function of alternative exon usage on a genome-wide scale. An implementation of DEXSeq is available as an R/Bioconductor package.
Novel structural arrangement of nematode cystathionine β-synthases: characterization of Caenorhabditis elegans CBS-1 (2012)

CBSs (cystathionine β-synthases) are eukaryotic PLP (pyridoxal 5 *-phosphate)-dependent proteins that maintain cellular homocysteine homoeostasis and produce cystathionine and hydrogen sulfide. In the present study, we describe a novel structural arrangement of the CBS enzyme encoded by the cbs-1 gene of the nematode Caenorhabditis elegans. The CBS-1 protein contains a unique tandem repeat of two evolutionarily conserved catalytic regions in a single polypeptide chain. These repeats include a catalytically active C-terminal module containing a PLP-binding site and a less conserved N-terminal module that is unable to bind the PLP cofactor and cannot catalyse CBS reactions, as demonstrated by analysis of truncated variants and active-site mutant proteins. In contrast with other metazoan enzymes, CBS-1 lacks the haem and regulatory Bateman domain essential for activation by AdoMet (S-adenosylmethionine) and only forms monomers. We determined the tissue and subcellular distribution of CBS-1 and showed that cbs-1 knockdown by RNA interference leads to delayed development and to an approximately 10-fold elevation of homocysteine concentrations in nematode extracts. The present study provides the first insight into the metabolism of sulfur amino acids and hydrogen sulfide in C. elegans and shows that nematode CBSs possess a structural feature that is unique among CBS proteins.
Purified monocyte-derived angiogenic substance (angiotropin) induces controlled angiogenesis associated with regulated tissue proliferation in rabbit skin. (1988)

Angiotropin is a differentiation factor for microvascular endothelial cells isolated from serum-free cultures of lectin-activated, porcine monocytes. We used an ear lobe model in rabbits, single intradermal injection of angiotropin to induce phenotypical changes of the endothelial cells in capillaries and postcapillary venules, vascular engorgement, and subsequent angiogenesis in dose-dependent manner. The vascular changes are associated with epidermal and stromal cell proliferation. Angiogenesis and tissue proliferation occur in the absence of tissue necrosis and do not lead to scar formation. Angiotropin-induced angiogenesis is not inhibited by local dexamethasone although it involves a defined turnover of inflammatory cells. Proliferation is transient and regressive events follow. The overall tissue reaction resembles changes found in the undamaged skin margin of a primary healing wound during the inflammatory/proliferative phase. From these observations we conclude that angiotropin is an important secretory product of activated peripheral macrophages that triggers inflammatory and proliferative reactions in wound healing by activating microvascular endothelial cells.
Changes in serum immunoreactive erythropoietin during the menstrual cycle and normal pregnancy (1983)

Immunoreactive erythropoietin was estimated in samples of serum collected during the follicular and luteal phases of the menstrual cycle in seven women and in sera collected sequentially throughout normal pregnancy in these and three other women. Estimates of serum erythropoietin during the follicular and luteal phases of the menstrual cycle were almost identical. During pregnancy in all 10 subjects serum erythropoietin increased at some time after 8 weeks gestation. These changes were not related to other endocrine values, to indicators of haematological and renal function or to infant birthweight except that changes in serum erythropoietin and placental lactogen were related (P less than 0.00001). In one other woman treated over 17 weeks of pregnancy with continuous intravenous infusion of salbutamol, erythropoietin levels were within the range found in normal pregnancies.
Interactive Data Compression (2005)

Let X and Y be two random variables with probability distribution p(x,y), joint entropy H(X,Y) and conditional entropies H(X \ Y) and H(Y \ X) . Person P/sub x/ knows X and person P/sub Y/ knows Y. They communicate over a noiseless two-way channel so that both know X and Y. It is proved that, on the average, at least H(X \ Y) + H(Y \ X) bits must be exchanged and that H(X,Y) + 2 bits are sufficient. If p(x.y) > 0 for all (x.y), then at least H(X,Y) bits must be communicated on the average. However, if p (x,y) is uniform over its support set, the average number of bits needed is close to H(X \ Y) + H (Y \ X). Randomized protocols can reduce the amount of communication considerably but only when some probability of error is acceptable.
Adapting to source properties in processing data integration queries (2004)

An effective query optimizer finds a query plan that exploits the characteristics of the source data. In data integration, little is known in advance about sources' properties, which necessitates the use of adaptive query processing techniques to adjust query processing on-the-fly. Prior work in adaptive query processing has focused on compensating for delays and adjusting for mis-estimated cardinality or selectivity values. In this paper, we present a generalized architecture for adaptive query processing and introduce a new technique, called adaptive data partitioning (ADP), which is based on the idea of dividing the source data into regions, each executed by different, complementary plans. We show how this model can be applied in novel ways to not only correct for underestimated selectivity and cardinality values, but also to discover and exploit order in the source data, and to detect and exploit source data that can be effectively pre-aggregated. We experimentally compare a number of alternative strategies and show that our approach is effective.
Telomerase activity and in situ telomerase RNA expression in malignant and non-malignant lymph nodes. (1997)

Although expression of telomerase by activated lymphocytes may limit its usefulness, measurement of enzyme activity combined with detection of hTR using in situ hybridisation may assist in the histopathological diagnosis of lymph nodes.
A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880). (1985)

5,6-Dihydro-5-azacytidine (DHAC; NSC 264880) is an analogue of 5-azacytidine that does not possess the hydrolytically unstable 5,6-imino bond of the parent compound. Thus, unlike 5-azacytidine, DHAC is stable in aqueous solution and may be administered by prolonged i.v. infusion, potentially avoiding acute toxicities associated with bolus administration of 5-azacytidine. In this study, patients with advanced cancer were treated with DHAC administered as a 24-h constant i.v. infusion every 28 days. Treatment began at a dose of 1 g/sq m and was escalated to the maximum-tolerated dose of 7 g/sq m, where the limiting toxicity was pleuritic chest pain. Other toxicities included nausea and vomiting, which were not limiting. There was no evidence for myelosuppression, nephrotoxicity, or hepatotoxicity. DHAC was measured in plasma, urine, and ascites by a sensitive and specific reverse-phase high-performance liquid chromatography assay capable of detecting 50 ng of drug per ml. Steady-state plasma levels were achieved with 8 h and ranged from 10.0 to 20.5 micrograms of DHAC per ml at the maximum-tolerated dose. Total-body clearance of 311 +/- 76 ml/min/sq m and postinfusion half-lives between 1 and 2 h were observed. Between 8 and 20% of the administered dose was excreted unchanged in urine. While ascites DHAC levels in a patient with ovarian cancer were comparable to plasma levels, postinfusion elimination was slower from this compartment than from plasma. No correlation was observed between DHAC plasma levels and duration or intensity of dose-limiting pleuritic chest pain. One patient with progressive Hodgkin's lymphoma demonstrated stabilization of disease for seven treatment cycles, and two patients with aggressive lymphoma demonstrated dramatic, although transient, disease responses. A dose of 7 g/sq m is recommended for Phase II trials of DHAC using this schedule.
Review Does polyethylene oxide possess a low thrombogenicity? (1993)

Because of the 'bland' nature of polyethylene oxide towards proteins and cells, considerable effort has been devoted to preparing surfaces rich in polyethylene oxide, using block copolymers, surface immobilization or other methods. It is clear that these modifications result in reduced levels of cell (including platelet) adhesion and protein adsorption, when compared to unmodified and typically hydrophobic substrates. It is far less clear whether the reduced adhesion or adsorption is due specifically to the thermodynamic effects of polyethylene oxide or to the increase in surface hydrophilicity after its immobilization. Even more so, it is unclear whether the reduction in such parameters is evidence of a reduced thrombogenicity.
Regulatory Aspects of Noninvasive Glucose Measurements (2002)

The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act (the Act) established three regulatory classes for medical devices. Section 513 of the Act specifies three classes based upon the degree of control and Food and Drug Administration (FDA) oversight that is necessary to assure that the various types of devices are safe and effective. High-risk devices are placed into the most regulated device class, Class III. Under Section 515 of the Act, all devices placed in Class III are subject to premarket approval (PMA) requirements. PMA by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Advisory panel review is required of virtually all original submissions. Manufacturing facilities of devices requiring PMA approval are also subject to preapproval inspection to assure data integrity and compliance with good manufacturing practices. An approved PMA is granted for marketing a particular medical device for a particular intended use. FDA considers noninvasive and minimally invasive glucose devices that are intended to measure, monitor, or predict blood glucose levels in diabetics to be high-risk medical devices. These devices will have a significant potential impact on the medical care of people with diabetes. The technology offers potential improvements in the quality of life, enhanced blood glucose control through increased frequency of testing, or access to testing, in a broader range of patients. However, the technology is not yet well understood, and the information obtained from these devices is often different from the information that has been the traditional base for the management of diabetes. As a result, FDA requires both analytical and clinical studies to support the intended claims for these new devices.
Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study (2008)

The FL2000 study was undertaken to evaluate the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first-line treatment of follicular lymphoma patients with a high tumor burden. Patients were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide, and prednisolone) plus interferon-alpha2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m(2) rituximab and interferon for the same time period (R-CHVP+I arm). After a median follow-up of 5 years, event-free survival estimates were, respectively, 37% (95% confidence interval [CI], 29%-44%) and 53% (95% CI, 45%-60%) in the CHVP+I and R-CHVP+I arm (P = .001). Five-year overall survival estimates were not statistically different in the CHVP+I (79%; 95% CI, 72%-84%) and R-CHVP+I (84%; 95% CI, 78%-84%) arms. In a multivariate regression analysis, event-free survival was significantly influenced by both the Follicular Lymphoma International Prognostic Index score (hazard ratio = 2.08; 95% CI, 1.6%-2.8%) and the treatment arm (hazard ratio = 0.59; 95% CI, 0.44%-0.78%). With a 5-year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. This study's clinical trial was registered at the National Institutes of Health website as no. NCT00136552.
A naturally occurring secreted human ErbB3 receptor isoform inhibits heregulin-stimulated activation of ErbB2, ErbB3, and ErbB4. (2001)

A variety of receptor-mediated signaling pathways are controlled by both positive and negative extracellular regulators. In this study, we demonstrate that a naturally occurring secreted form of the human ErbB3 receptor, p85-soluble ErbB3 (sErbB3), is a potent negative regulator of heregulin (HRG)-stimulated ErbB2, ErbB3, and ErbB4 activation. We show that p85-sErbB3 binds to HRG with an affinity comparable to that of full-length ErbB3 and competitively inhibits high affinity HRG binding to ErbB2/ErbB3 heterodimers on the cell surface of breast carcinoma cells with an IC(50) of 0.5 nM. p85-sErbB3 inhibits HRG-induced phosphorylation of ErbB2, ErbB3, and ErbB4 in breast carcinoma-derived cell lines and can also block HRG-stimulated activation of mitogen-activated protein kinase, Akt, and association of ErbB3 with the phosphatidylinositol 3'-kinase p85 regulatory subunit. Cell growth assays show that exogenous addition of a 100-fold molar excess of p85-sErbB3 inhibits HRG-stimulated cell growth by as much as 90%. Whereas several potential mechanisms of p85-sErbB3 inhibition of ErbB receptor activation exist, our results suggest that at least one means of inhibition is competition for HRG binding. The IC(50) for both p85-sErbB3- and 2C4 (a monoclonal antibody specific for ErbB2)-mediated inhibition of HRG binding is approximately 0.5 nM, although the mechanism of inhibition by these two proteins is distinct. Together these results suggest that p85-sErbB3 is a naturally occurring negative regulator of HRG-stimulated signal transduction that may have important therapeutic applications in human malignancies associated with HRG-mediated cell growth such as breast and prostate cancer.
Interpretation of the dissolution of insoluble peptide sequences based on the acid‐base properties of the solvent (2006)

The dissolution process of model insoluble peptide sequences was investigated in view of the electron acceptor (AN) and electron donor (DN) solvent properties. The Alzheimer's disease-inducing (1-42) Abeta-amyloid peptide and its (1-21) fragment, the (66-97) transmembrane bradykinin B2 receptor sequence, and the strongly aggregated VVLGAAIV were selected as models of insoluble peptides. Solvents presenting similar AN and DN values failed, despite their polarities, to dissociate peptide chains (free in solution or bound to a polymer). The maximum solubility of these aggregated sequences was attained in solvents presenting the highest possible (AN-DN) values (in positive or negative mode). The AN-DN values ranged from approximately -20 to +80 and, notably, the lowest dissociation power was ascribed to solvents presenting values of approximately +40. The strong hydrogen bond donor water is located in this region, indicating that, for dissociation of specific insoluble segments, the solvent should appropriately combine its acid/base strength with the potential for van der Waals interactions. We also observed a sequence-dependent pH effect on peptide solubility confirmed through circular dichroism spectroscopy. This approach also revealed a complex but, in many cases, consistent influence of peptide conformation on its solubility degree, even when structure-inducing solvents were added. In conclusion, the random method of selecting solvents to dissolve insoluble and intractable peptide sequences, still in use by some, could be partially supplanted by the strategy described herein, which may be also applicable to other solute dissociation processes.