gebhart/patrepeval huggingface dataset:
Activation induces sensitivity toward APO-1 (CD95)-mediated apoptosis in human B cells. (1994)

We have previously described the APO-1 (CD95) cell surface molecule, a novel member of the nerve growth factor/TNF receptor superfamily, identical with the Fas Ag. Triggering of APO-1-induced apoptosis in APO-1+, apoptosis sensitive cells. The data in this study demonstrate that human peripheral blood B cells acquire sensitivity to APO-1-mediated apoptosis on PWM activation. To also study APO-1-mediated apoptosis in an Ag-specific human B cell response, we reconstituted severe combined immunodeficient (SCID) mice i.p. with human PBMC (SCID-hu mice). SCID-hu mice were then injected i.p. with soluble, adjuvant-free tetanus toxoid or diphtheria toxoid, respectively, directly after transfer of the PBMC (day 1) and received an Ag-booster injection on day 14. Two weeks after PBMC transfer human Abs were detected and shown to be Ag specific. SCID-hu mice co-injected with monoclonal anti-APO-1 Ab (IgG3,k) showed significantly suppressed anti-tetanus toxoid or anti-diphtheria toxoid titers, respectively. Sensitivity to anti-APO-1-mediated suppression was only observed in Ag-activated cells from day 0 to day 6 after Ag immunization. Suppression of Ab titers correlated with a decrease of Ag-specific Ig-secreting cells. Re-injection of syngeneic T cells and Ag did not reverse anti-APO-1-induced suppression. These data show a direct suppressive effect of anti-APO-1 on Ag-activated, "specific" B cells. Thus, APO-1-mediated apoptosis in Ag-activated B cells may contribute to the regulation of the humoral immune response.
Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic. (1990)

Both cellular activation signals and exposure to glucocorticoids such as dexamethasone (Dex) cause programmed cell death in T cell hybridomas. When cells were activated in the presence of Dex, however, the degree of killing that was achieved by either stimulus alone was markedly reduced. Dex-induced programmed cell death of normal T cell clones was also prevented by cellular activation. Cyclosporin A (CsA) completely blocked the activation-induced death of T cell hybridomas, but actually enhanced the killing caused by Dex. The addition of CsA to activated T cell hybridomas in the presence of Dex allowed killing to proceed, consistent with ability of CsA to block activation-induced nuclear gene transcription. A number of independent approaches were used to explore the effect of activation on the glucocorticoid signaling/effector pathway. First, RU-486, which binds the glucocorticoid receptor and is a potent competitive antagonist of Dex, did not inhibit activation-induced cell killing. Second, activation of T cell hybridomas did not cause the translocation of the glucocorticoid receptor from the cytoplasm to the nucleus, nor did it prevent the receptor translocation induced by treatment with Dex. Finally, T cell hybridomas were transfected with a plasmid containing the chloramphenicol acetyltransferase (CAT) gene under the control of two tandemly arranged glucocorticoid-responsive elements. Activation of these cells did not induce CAT activity, and did not inhibit the CAT activity induced by Dex. In fact, there was a paradoxical increase in CAT activity when cells were treated with both stimuli. We conclude that cellular activation does not directly utilize the glucocorticoid receptor nor the glucocorticoid pathway when inducing programmed cell death. Furthermore, the ability of activation to inhibit Dex-mediated killing is not due to interference with the classical glucocorticoid signaling pathway, up to and including the initiation of gene transcription. Alternative mechanisms of antagonism, as well as the possible relevance of this phenomenon to the positive selection of self-recognizing thymocytes, are discussed.
Optimal wave-front correction using slope measurements (1983)

In adaptive optical systems that compensate for random wave-front disturbances, a wave front is measured and corrections are made to bring it to the desired shape. For most systems of this type, the local wave-front slope is first measured, the wave front is next reconstructed from the slope, and a correction is then fitted to the reconstructed wave front. Here a more realistic model of the wave-front measurements is used than in the previous literature, and wave-front estimation and correction are analyzed as a unified process rather than being treated as separate and independent processes. The optimum control law is derived for an arbitrary array of slope sensors and an arbitrary array of correctors. Application of this law is shown to produce improved results with noisy measurements. The residual error is shown to depend directly on the density of the slope measurements, but the sensitivity to the precise location of the measurements that was indicated in the earlier literature is not observed.
Macrophage- and dendritic cell—dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF (2003)

Macrophages and dendritic cells play an important role in regulating B-cell responses, including proliferation to antigens such as trinitrophenyl (TNP)-Ficoll and TNP-Brucella abortus. However, the mechanisms and molecule(s) that regulate these processes are relatively undefined. In this report, we show that human macrophages generated in vitro strongly costimulate proliferation of dense human tonsillar B cells ligated via their B-cell antigen receptor (BCR) but not proliferation via CD40. Similarly, dendritic cells also markedly enhance BCR-activated B-cell proliferation. Soluble molecule(s) are required for human macrophages to costimulate proliferation of B cells triggered via their BCR. Importantly, a TACI (trans-membrane activator and CAML interactor)-Fc fusion protein inhibits both macrophage- and dendritic cell (DC)-dependent BCR-activated B-cell proliferation, indicating a requirement for at least one of the known TACI ligands, BAFF and/or APRIL. Consistent with a major role for BAFF, macrophages release BAFF at levels sufficient to potently costimulate BCR-induced B-cell proliferation. In addition, BAFF is more than 100-fold more potent than APRIL in enhancing BCR-mediated human B-cell proliferation. Furthermore, immunodepletion of APRIL under conditions that prevent APRIL-mediated B-cell costimulation does not block macrophage enhancement of B-cell proliferation. Finally, there is no correlation between the high levels of a proliferation-inducing ligand (APRIL) expressed by macrophages compared with DCs and the similar abilities of macrophages and DCs to enhance BCR-stimulated B-cell proliferation. In summary, our results suggest that macrophage- and DC-derived B-cell-activating factor belonging to the TNF family (BAFF) represents a key molecule by which macrophages and DCs directly regulate human B-cell proliferative responses to T-cell-independent stimuli.
Phase II Trials of High-Dose Interleukin-2 and Lymphokine-Activated Killer Cells in Advanced Breast Carcinoma and Carcinoma of the Lung, Ovary, and Pancreas and Other Tumors (1994)

Treatment with interleukin-2 (IL-2) used alone or in combination with lymphokine-activated killer (LAK) cells is known to be an active therapy for patients with advanced renal cell carcinoma and melanoma. To further explore the activity of IL-2/LAK cell therapy in patients with advanced cancer of various primary sites, the Extramural IL-2/LAK Working Group (IL WG) initiated two phase II trials of high-dose IL-2/LAK therapy: one in patients with advanced breast carcinoma, and one in patients with advanced cancer arising in other sites. Patients with advanced renal cell carcinoma, melanoma, colorectal carcinoma, and lymphoma (Hodgkin's and B-cell non-Hodgkin's) were not eligible for the latter trial, but were treated on other ILWG trials that have been reported previously. Sixty-nine patients received high-dose IL-2 (600,000 IU/kg administered by a 15-min intravenous infusion every 8 h) on days 1–5 and days 11–15. Leukapheresis was performed for collection and ex vivo expansion of LAK cells on days 7–10, and the LAK cells were reinfused on days 11, 12, and 14. The studies were designed to determine whether treatment with IL-2/LAK resulted in at least a 40% response rate, a level of activity that was believed to be sufficient to justify the toxicity and cost of IL-2/LAK therapy. An adequate number of patients with carcinoma of the breast (N = 12), pancreas (N = 8), ovary (N = 7), and lung (non-small cell; N = 6) were accrued to assess response; most of these patients had prior chemotherapy that had failed. In addition, 32 patients with a variety of other tumor types were accrued, but accrual was not adequate to assess response in other primary tumor sites. One patient with adenocarcinoma of the breast had a partial response of 17 weeks' duration. Two patients had minor tumor regression (adenocarcinoma of the lung and spindle cell sarcoma of the lung). We conclude that high-dose IL-2/LAK is not likely to be associated with a response rate exceeding 40% for patients with carcinomas arising in the breast, pancreas, ovary, and lung (non-small cell).
A prospective, randomized study of the use of platelet concentrates irradiated with ultraviolet‐B light in patients with hematologic malignancy (1996)

In this trial, UVB irradiation did not diminish the clinical efficacy of platelet transfusions. There was a small but nonsignificant reduction alloimmunization, but no difference in refractoriness of the two groups was observed. Larger prospective randomized studies are required to confirm these findings and to compare UVB irradiation with white cell reduction.
A Comparative Analysis of Synthetic Quorum Sensing Modulators in Pseudomonas aeruginosa: New Insights into Mechanism, Active Efflux Susceptibility, Phenotypic Response, and Next-Generation Ligand Design (2015)

Quorum sensing (QS) is a chemical signaling mechanism that allows bacterial populations to coordinate gene expression in response to social and environmental cues. Many bacterial pathogens use QS to initiate infection at high cell densities. Over the past two decades, chemical antagonists of QS in pathogenic bacteria have attracted substantial interest for use both as tools to further elucidate QS mechanisms and, with further development, potential anti-infective agents. Considerable recent research has been devoted to the design of small molecules capable of modulating the LasR QS receptor in the opportunistic pathogen Pseudomonas aeruginosa. These molecules hold significant promise in a range of contexts; however, as most compounds have been developed independently, comparative activity data for these compounds are scarce. Moreover, the mechanisms by which the bulk of these compounds act are largely unknown. This paucity of data has stalled the choice of an optimal chemical scaffold for further advancement. Herein, we submit the best-characterized LasR modulators to standardized cell-based reporter and QS phenotypic assays in P. aeruginosa, and we report the first comprehensive set of comparative LasR activity data for these compounds. Our experiments uncovered multiple interesting mechanistic phenomena (including a potential alternative QS-modulatory ligand binding site/partner) that provide new, and unexpected, insights into the modes by which many of these LasR ligands act. The lead compounds, data trends, and mechanistic insights reported here will significantly aid the design of new small molecule QS inhibitors and activators in P. aeruginosa, and in other bacteria, with enhanced potencies and defined modes of action.
Extending the behavioral capabilities of the object-oriented paradigm with an active model of propagation (1990)

Object-oriented design techniques have begun to play a critical role in increasing productivity, assuring correctness, and modeling both the structure and behavior of applications. However, while most object-oriented models support intra-class behavior definition through encapsulation, inter-class relationships and behavior are supported in only a limited sense, i.e., within ISA or inheritance hierarchies. This is a serious draw-back when attempting to model advanced applications such as software-development environments (SDEs) and CAD/CAM. In order to model these critical inter-class relationships and behavior, our goal is to incorporate propagation actions into an object-oriented data model at the design-phase level. This results in increased accuracy in the modeling of information, more complete specification of system behavior, elimination of some side effects, and decreased application coding errors. To meet this goal, this paper presents the active model of propagation (AMP) which supports the specification of inter-class relationships during the design phase to permit system enforced propagation.
213Bi[Dota0, Tyr3]octreotide (Bi-DOTATOC) in peptide receptor radionuclide therapy (PRRT) (1999)

Norenberg, J. P.; Krenning, B. J.; Konings, I. R.; de Jong, M.; Sri-nivasan, A.; Garmestani, K.; Brechbiel, M. W.; Kvols, L. K. Author Information
A Role for the Transcriptional Coactivator PGC-1α in Muscle Refueling (2007)

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1alpha expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, muscle-specific, PGC-1alpha gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1alpha increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to post-exercise recovery. Induction of muscle PGC-1alpha expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1alpha-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1alpha was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase alpha. These findings identify PGC-1alpha as a critical regulator of skeletal muscle fuel stores.
SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression (2014)

Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.
Full‐Mouth Therapy Versus Individual Quadrant Root Planing: A Critical Commentary (2002)

Several studies conducted at one treatment center indicated that FDIS and FRP attained greater therapeutic improvements than PDIS with respect to decreasing probing depths (PD), gaining clinical attachment (CAL), diminishing bleeding upon probing, and reducing the subgingival microflora. However, the magnitude of PD reductions and gains of clinical attachment must be carefully interpreted, because initial PD measurements were usually determined after scaling and root planing, which may have caused the results to be overstated. Furthermore, in studies that addressed the utility of FDIS, it was not possible to determine if benefits induced beyond PDIS were due to FRP or administration of multifaceted intraoral chlorhexidine treatments ora combination of both therapies. One investigation that had protocol limitations indicated that similar results were attained by FRP with and without adjunctive chemotherapy. In contrast, recent studies from 2 other treatment centers indicated that there were no significant differences when the efficacy of quadrant-by-quadrant root planing was compared to FRP or FDIS with regard to PD reduction, gains of clinical attachment, and impact on the magnitude and quality of the immune response. POSSIBLE CLINICAL IMPLICATIONS: Conceptually, full-mouth therapy (FRP or FDIS) could reduce the number of patient visits and facilitate more efficient use of treatment time. In addition, there appears to be no major adverse reactions to full-mouth root planing with or without adjunctive chemotherapy. However, small study populations and non-corroborating data from different treatment centers indicate that additional randomized clinical trials are needed to determine if full-mouth therapy provides clinically relevant improvements beyond PDIS.
SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS (2005)

SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.
Enhancement of Human Immunodeficiency Virus Type 1–Specific CD4 and CD8 T Cell Responses in Chronically Infected Persons after Temporary Treatment Interruption (2000)

Immunologic and virologic outcomes of treatment interruption were compared for 5 chronically human immunodeficiency virus (HIV)-infected persons who have maintained antiretroviral therapy-mediated virus suppression, as compared with 5 untreated controls. After a median interruption of 55 days of therapy accompanied by rebound of virus, reinitiated therapy in 4 of 5 subjects resulted in suppression of 98.86% of plasma virus load by 21-33 days and no significant decrease in CD4 T cell percentage from baseline. Increased T helper responses against HIV-1 p24 antigen (P=. 014) and interferon-gamma-secreting CD8 T cell responses against HIV-1 Env (P=.004) were present during interruption of therapy and after reinitiation of treatment. The remaining subject whose treatment was interrupted did not resume treatment and continued to have a low virus load (<1080 HIV-1 RNA copies/mL) and persistent antiviral cell-mediated responses. In summary, cellular immunity against autologous HIV-1 has the potential to be acutely augmented in association with temporary treatment interruption in chronically infected persons.
Role of CYP27A in cholesterol and bile acid metabolism (2004)

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.
Expression of the gene encoding the 17-kilodalton antigen from Rickettsia rickettsii: transcription and posttranslational modification (1988)

Recently, we reported the molecular cloning and nucleotide sequence analysis of a gene from Rickettsia rickettsii that codes for a 17-kilodalton antigen (17K antigen) and is preceded by sequences closely resembling the -10 and -35 consensus sequences for recognition by Escherichia coli RNA polymerase (Anderson et al., J. Bacteriol. 169:2385-2390, 1987). Experiments described in this report indicate that the start sites for initiating transcription of the 17K antigen gene are identical in the E. coli clone and in intact R. rickettsii. In each case, initiation was shown to begin 9 bases downstream of the presumed Pribnow box sequence (TATACT). A 169-base-pair fragment containing the promoter sequence initiated transcription in both directions when cloned into an E. coli promoter probe vector. The rickettsial fragment was found to contain sequences identical to the -10 region (but not the -35 region) of the E. coli promoter consensus sequence directed away from the 17K antigen gene. The amino-terminal portion (residues 17 to 20) of the deduced amino acid sequence for the 17K antigen contained the tetrapeptide Leu-Gln-Ala-Cys, a sequence that conforms favorably to those described for lipid modification and cleavage by lipoprotein signal peptidase II. The 17K antigen produced by the E. coli clone was shown to be labeled with [3H]palmitate and [3H]glycerol, indicative of lipid modification. In vitro mutagenesis designed to alter the cysteine at residue 20 to a glycine abolished incorporation of [3H]palmitate, suggesting that posttranslational modification occurs via a mechanism similar to that described for other gram-negative bacterial lipoproteins.
Human Pose Estimation Using Body Parts Dependent Joint Regressors (2013)

In this work, we address the problem of estimating 2d human pose from still images. Recent methods that rely on discriminatively trained deformable parts organized in a tree model have shown to be very successful in solving this task. Within such a pictorial structure framework, we address the problem of obtaining good part templates by proposing novel, non-linear joint regressors. In particular, we employ two-layered random forests as joint regressors. The first layer acts as a discriminative, independent body part classifier. The second layer takes the estimated class distributions of the first one into account and is thereby able to predict joint locations by modeling the interdependence and co-occurrence of the parts. This results in a pose estimation framework that takes dependencies between body parts already for joint localization into account and is thus able to circumvent typical ambiguities of tree structures, such as for legs and arms. In the experiments, we demonstrate that our body parts dependent joint regressors achieve a higher joint localization accuracy than tree-based state-of-the-art methods.