gebhart/patrepeval huggingface dataset:
Improved Learning Complexity in Combinatorial Pure Exploration Bandits (2016)

We study the problem of combinatorial pure exploration in the stochastic multi-armed bandit problem. We first construct a new measure of complexity that provably characterizes the learning performance of the algorithms we propose for the fixed confidence and the fixed budget setting. We show that this complexity is never higher than the one in existing work and illustrate a number of configurations in which it can be significantly smaller. While in general this improvement comes at the cost of increased computational complexity, we provide a series of examples, including a planning problem, where this extra cost is not significant.
Discovery of a Potent and Selective NF-κB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo (2020)

The overexpression of NIK plays a critical role in liver inflammatory diseases. Treatment of such diseases with small-molecule NIK inhibitors is a reasonable but underexplored approach. In this paper, we reported the discovery of a potent and selective NIK inhibitor <b>46</b> (XT2). <b>46</b> inhibited the NIK kinase with an IC<sub>50</sub> value of 9.1 nM in vitro, and it also potently suppressed NIK activities in intact cells. In isogenic primary hepatocytes, treatment of <b>46</b> efficiently suppressed the expressions of NIK-induced genes. <b>46</b> was orally bioavailable in mice with moderate systemic exposure. In a NIK-associated mouse liver inflammation model, <b>46</b> suppressed CCl<sub>4</sub>-induced upregulation of ALT, a key biomarker of acute liver injury. <b>46</b> also decreased immune cell infiltration into the injured liver tissue. Overall, these studies provide examples that an NIK inhibitor is able to suppress toxin-induced liver inflammations, which indicates its therapeutic potentials for the treatment of liver inflammatory diseases.
Cellular Uptake and Subcellular Distribution of Phosphorothioate Oligonucleotides into Cultured Cells (1992)

A phosphorothioate oligonucleotide that has been employed to inhibit HIV-1 viral expression in chronically infected H9 cells was examined for cellular uptake and subcellular distribution. The relationship between extracellular oligonucleotide concentration and the distribution and accumulation into subcellular organelles is important to the design, potential side effects, and understanding of a therapeutically useful antisense oligonucleotide. These studies employed uptake of both 35S- and fluorescence-labeled phosphorothioate oligonucleotides. Experiments with V79, HeLa, H9, and fresh human peripheral blood monocytes indicate that accumulations of oligonucleotide inside cells exceeds the concentration of oligonucleotide in culture media by over 100 times following 1 h of exposure at 37 degrees C. Uptake is more efficient at low concentrations, suggesting a saturable process. The total oligonucleotide that remains in cells begins to reach a plateau after 45-60 min, indicating either that efflux pathways exist or that uptake is saturable. Subcellular fractionation studies with 35S-labeled phosphorothioate demonstrate the oligonucleotide is sequestered into both the nuclei and the mitochondria of cultured HeLa cells in a time-dependent manner. The subcellular fractionation was examined with fluorescence-labeled phosphorothioate by both confocal and fluorescence microscopy, which confirmed the rate and localization of oligonucleotide into cultured cells. Finally, cellular uptake is not uniform for all cells in a nonsynchronous culture.
Beam orientation optimization for intensity modulated radiation therapy using adaptivel2,1-minimization (2011)

Beam orientation optimization (BOO) is a key component in the process of intensity modulated radiation therapy treatment planning. It determines to what degree one can achieve a good treatment plan in the subsequent plan optimization process. In this paper, we have developed a BOO algorithm via adaptive l(2, 1)-minimization. Specifically, we introduce a sparsity objective function term into our model which contains weighting factors for each beam angle adaptively adjusted during the optimization process. Such an objective function favors a small number of beam angles. By optimizing a total objective function consisting of a dosimetric term and the sparsity term, we are able to identify unimportant beam angles and gradually remove them without largely sacrificing the dosimetric objective. In one typical prostate case, the convergence property of our algorithm, as well as how beam angles are selected during the optimization process, is demonstrated. Fluence map optimization (FMO) is then performed based on the optimized beam angles. The resulting plan quality is presented and is found to be better than that of equiangular beam orientations. We have further systematically validated our algorithm in the contexts of 5-9 coplanar beams for five prostate cases and one head and neck case. For each case, the final FMO objective function value is used to compare the optimized beam orientations with the equiangular ones. It is found that, in the majority of cases tested, our BOO algorithm leads to beam configurations which attain lower FMO objective function values than those of corresponding equiangular cases, indicating the effectiveness of our BOO algorithm. Superior plan qualities are also demonstrated by comparing DVH curves between BOO plans and equiangular plans.
Atherectomy of the distal aorta using a "kissing-balloon" technique for the treatment of blue toe syndrome. (1992)

Atherectomy of the distal aorta using a "kissing-balloon" technique for the treatment of blue toe syndrome.R A Clugston, A C Eisenhauer and R V MatthewsAudio Available | Share
Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. (1995)

Interleukin 12 (IL-12) is an important immunoregulatory cytokine whose receptor is a member of the hematopoietin receptor superfamily. We have recently demonstrated that stimulation of human T and natural killer cells with IL-12 induces tyrosine phosphorylation of the Janus family tyrosine kinase JAK2 and Tyk2, implicating these kinases in the immediate biochemical response to IL-12. Recently, transcription factors known as STATs (signal transducers and activators of transcription) have been shown to be tyrosine phosphorylated and activated in response to a number of cytokines that bind hematopoietin receptors and activate JAK kinases. In this report we demonstrate that IL-12 induces tyrosine phosphorylation of a recently identified STAT family member, STAT4, and show that STAT4 expression is regulated by T-cell activation. Furthermore, we show that IL-12 stimulates formation of a DNA-binding complex that recognizes a DNA sequence previously shown to bind STAT proteins and that this complex contains STAT4. These data, and the recent demonstration of JAK phosphorylation by IL-12, identify a rapid signal-transduction pathway likely to mediate IL-12-induced gene expression.
Comparison of mianserin and dothiepin treatment on the serotonergic system in depressed patients (1990)

Abstract Depressed patients showed a decreased 5‐HT uptake rate and aggregation response and increased platelet ketanserin binding, compared to normal controls. Five weeks treatment with either mianserin or dothiepin improved the biochemical parameters in the patients, although the parameters still had not returned to control levels. There was no difference between the biochemical markers in the mianserin and dothiepin groups at any time during the study.
Expression of Chimeric Receptor CD4ζby Natural Killer Cells Derived from Human Pluripotent Stem Cells Improves In Vitro Activity but Does Not Enhance Suppression of HIV Infection In Vivo (2013)

Cell-based immunotherapy has been gaining interest as an improved means to treat human immunodeficiency virus (HIV)/AIDS. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) could become a potential resource. Our previous studies have shown hESC and iPSC-derived natural killer (NK) cells can inhibit HIV-infected targets in vitro. Here, we advance those studies by expressing a HIV chimeric receptor combining the extracellular portion of CD4 to the CD3ζ intracellular signaling chain. We hypothesized that expression of this CD4ζ receptor would more efficiently direct hESC- and iPSC-derived NK cells to target HIV-infected cells. In vitro studies showed the CD4ζ expressing hESC- and iPSC-NK cells inhibited HIV replication in CD4+ T-cells more efficiently than their unmodified counterparts. We then evaluated CD4ζ expressing hESC (CD4ζ-hESC)- and iPSC-NK cells in vivo anti-HIV activity using a humanized mouse model. We demonstrated significant suppression of HIV replication in mice treated with both CD4ζ-modified and -unmodified hESC-/iPSC-NK cells compared with control mice. However, we did not observe significantly increased efficacy of CD4ζ expression in suppression of HIV infection. These studies indicate that hESC/iPSC-based immunotherapy can be used as a unique resource to target HIV/AIDS.
β-Alanine and β-bends. X-Ray diffraction structures of three linear oligopeptides (1992)

A crystal-state structural analysis of t-Boc-L-Ala-β-Ala-NHMe, t-Boc-Aib-β-Ala-NHMe, and t-Boc-Aib-Aib-β-Ala-NHMe has been performed by X-ray diffraction. While the conformation adopted by t-Boc-L-Ala-β-Ala-NHMe and t-Boc-Aib-β-Ala-NHMe is essentially extended, t-Boc-Aib-Aib-β-Ala-NHMe is folded into two consecutive intramolecularly hydrogen-bonded structures of the i+ 3 →i type (β-bends), with Aib(1)–Aib(2) and Aib(2)–β-Ala(3), respectively, as corner residues. Owing to the presence of the β-aminoacid, the latter β-bend is characterized by an unusual C11 hydrogen-bonded ring. These results indicate that: (i) a β-aminoacid may be incorporated into a β-bend without a major perturbation of the overall geometry of this folded conformation, and (ii) the propensity of the β-Ala residue for β-bend formation is rather low, unless other conformational constraints (e.g. a preceding β-bend) are present in the linear peptide molecule.
Failure of recombinant vaccinia viruses expressing Plasmodium falciparum antigens to protect Saimiri monkeys against malaria (1991)

Saimiri sciurus monkeys were immunized at multiple sites with recombinant vaccinia viruses expressing Plasmodium falciparum antigen genes and boosted 4 weeks later. Control monkeys were immunized with a thymidine kinase-negative vaccinia virus mutant. Two weeks later, all of the monkeys were challenged by intravenous inoculation of P. falciparum (Indochina strain) parasites. A group of unimmunized monkeys was challenged in parallel. All of the monkeys that received vaccinia virus recombinants or the control virus produced good anti-vaccinia virus antibody responses. However, those that received a single construct containing ring-infected erythrocyte surface antigen (RESA) given at eight sites did not produce significant antibody to any of the three major RESA repeat epitopes after immunization but were primed for an enhanced antibody response after challenge infection with P. falciparum. Most of the monkeys produced detectable antibodies to the RESA epitopes after challenge infection. One group of monkeys was immunized with four constructs (expressing RESA, two merozoite surface antigens [MSA-1 and MSA-2], and a rhoptry protein [AMA-1]), each given at two sites. While these monkeys failed to produce significant antibody against MSA-2 or AMA-1 after immunization, they produced enhanced responses against these antigens after challenge infection. Immunization involved an allelic form of MSA-2 different from that present in the parasite challenge strain, so that the enhanced responses seen after challenge infection indicated the presence of T-cell epitopes common to both allelic forms. No groups of monkeys showed any evidence of protection against challenge, as determined by examination of the resulting parasitemias.
Dermatan sulfate: new functions from an old glycosaminoglycan (2002)

Glycosaminoglycans constitute a considerable fraction of the glycoconjugates found on cellular membranes and in the extracellular matrix of virtually all mammalian tissues. Their ability to bind and alter protein-protein interactions or enzymatic activity has identified them as important determinants of cellular responsiveness in development, homeostasis, and disease. Although heparan sulfate tends to be emphasized as the most biologically active glycosaminoglycan, dermatan sulfate is a particularly attractive subject for further study because it is expressed in many mammalian tissues and it is the predominant glycan present in skin. Dermatan and dermatan sulfate proteoglycans have also been implicated in cardiovascular disease, tumorigenesis, infection, wound repair, and fibrosis. Growing evidence suggests that this glycosaminoglycan, like the better studied heparin and heparan sulfate, is an important cofactor in a variety of cell behaviors.
In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin. (1997)

We evaluated the TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunotoxin in both murine and nonhuman primate models. TXU-PAP caused dose-limiting cardiac toxicity in BALB/c mice. In a SCID mouse model of invariably fatal human T-lineage acute lymphoblastic leukemia (ALL), TXU-PAP therapy resulted in a marked improvement of leukemia-free survival without any side effects. Whereas 100% of control mice treated with PBS, unconjugated TXU antibody, or B43-PAP (an immunotoxin that does not react with T-lineage ALL cells) died of disseminated human leukemia within 80 days (median survival, 37 days), 80 +/- 13% of SCID mice treated with 15 microgram of TXU-PAP (median survival, >120 days) and 100% of mice treated with 30 microgram of TXU-PAP (median survival, > 120 days) remained alive and free of leukemia for >120 days. In cynomolgus monkeys, TXU-PAP showed favorable pharmacokinetics with an elimination half-life of 8.1-8.7 h. The monkeys treated with TXU-PAP at dose levels of 0.05 mg/kg/day x 5 days and 0.10 mg/kg/day x 5 days tolerated the therapy very well, without any significant clinical compromise or side effects, and at necropsy, no gross or microscopic lesions were found. This study provides a basis for further evaluation of TXU-PAP as an investigational biotherapeutic agent in the treatment of T-lineage ALL.
Artificial control of gene expression in mammalian cells by modulating RNA interference through aptamer–small molecule interaction (2006)

Recent studies have uncovered extensive presence and functions of small noncoding RNAs in gene regulation in eukaryotes. In particular, RNA interference (RNAi) has been the subject of significant investigations for its unique role in post-transcriptional gene regulation and utility as a tool for artificial gene knockdown. Here, we describe a novel strategy for post-transcriptional gene regulation in mammalian cells in which RNAi is specifically modulated through RNA aptamer-small molecule interaction. Incorporation of an RNA aptamer for theophylline in the loop region of a short hairpin RNA (shRNA) designed to silence fluorescent reporter genes led to dose-dependent inhibition of RNAi by theophylline. shRNA cleavage experiments using recombinant Dicer demonstrated that theophylline inhibited cleavage of an aptamer-fused shRNA by Dicer in vitro. Inhibition of siRNA production by theophylline was also observed in vivo. The results presented here provide the first evidence of specific RNA-small molecule interaction affecting RNAi, and a novel strategy to regulate mammalian gene expression by small molecules without engineered proteins.
Combining intracellular antibodies to restore function of mutated p53 in cancer (2015)

TP53 is a tumor suppressor gene that is mutated in 50% of cancers, and its function is tightly regulated by the E3 ligase, Mdm2. Both p53 and Mdm2 are localized in the cell nucleus, a site that is impervious to therapeutic regulation by most antibodies. We identified a cell-penetrating lupus monoclonal anti-DNA antibody, mAb 3E10, that targets the nucleus, and we engineered mAb 3E10 to function as an intranuclear transport system to deliver therapeutic antibodies into the nucleus as bispecific single chain Fv (scFv) fragments. Bispecific scFvs composed of 3E10 include PAb421 (3E10-PAb421) that binds p53 and restores the function of mutated p53, and 3G5 (3E10-3G5) that binds Mdm2 and prevents destruction of p53 by Mdm2. We documented the therapeutic efficacy of these bispecific scFvs separately in previous studies. In this study, we show that combination therapy with 3E10-PAb421 and 3E10-3G5 augments growth inhibition of cells with p53 mutations compared to the effect of either antibody alone. By contrast, no enhanced response was observed in cells with wild-type p53 or in cells homozygous null for p53.
Antigenic specificity of the cytolytic T lymphocyte (CTL) response to murine sarcoma virus-induced tumors. II. Analysis of the clonal progeny of CTL precursors stimulated in vitro with syngeneic tumor cells. (1980)

Abstract A sensitive limiting dilution mixed leukocyte-tumor cell microculture (micro MLTC) system is described that permitted the study of frequency and specificity of cytolytic T lymphocyte precursor cells (CTL-P) reactive against syngeneic Moloney leukemia virus- (MLV) induced tumor cells. Optimal microculture conditions were found to depend on the addition of secondary mixed leukocyte culture (MLC) supernatant as a nonspecific stimulant, and on the presence of accessory cells in the form of irradiated syngeneic spleen cells. After priming of C57BL/6 and BALB/c mice with the Moloney sarcoma-leukemia virus complex, the mean CTL-P frequency in regressor spleens was found to be approximately 1/600 and 1/1300, respectively. In reciprocal experiments, the clonal progeny of the individual CTL-P reactive in micro MLTC against syngeneic (MB1-2 in C57BL/6 and LSTRA in BALB/c) tumor cells was tested for cytolytic activity on both syngeneic and allogeneic tumor cells. In a total of 576 microcultures set up in each system, the majority of the positive microcultures lysed syngeneic but not allogeneic tumor target cells; however, of 198 positive B6 cultures, 13 (7%) appeared clearly to be “double-reactors,” lysing both syngeneic and allogeneic tumor cells to a similar degree. No such “double-reactors” were observed in the 119 positive BALB/c cultures. CTL-P with selective specificity for allogeneic tumor target cells appeared either to be absent or present at very low frequencies in both strains tested. These studies provide direct evidence for the existence of limited heterogeneity at the clonal level in the response of CTL-P to MLV-induced tumor cells. Furthermore, the system used should be amenable to a more detailed analysis of the fine specificity of individual clones.
Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137 (2013)

Knowledge of how the immune system recognizes and attempts to control cancer growth and development has improved dramatically. The advent of immunotherapies for cancer has resulted in robust clinical responses and confirmed that the immune system can significantly inhibit tumor progression. Until recently, metastatic melanoma was a disease with limited treatment options and a poor prognosis. CD137 (also known as 4-1BB) a member of the tumor necrosis factor (TNF) receptor superfamily, is an activation-induced T cell costimulator molecule. Growing evidence indicates that anti-CD137 monoclonal antibodies possess strong antitumor properties, the result of their powerful capability to activate CD8+ T cells, to produce interferon (IFN)-γ, and to induce cytolytic markers. Combination therapy of anti-CD137 with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Of importance, targeting CD137 eliminates established tumors, and the fact that anti-CD137 therapy acts in concert with other anticancer agents and/or radiation therapy to eradicate nonimmunogenic and weakly immunogenic tumors is an additional benefit. Currently, BMS-663513, a humanized anti-CD137 antibody, is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, ovarian cancer, and B-cell malignancies. In this review, we discuss the basis of the therapeutic potential of targeting CD137 in cancer treatment, focusing in particular, on BMS-663513 as an immune costimulatory monoclonal antibody for melanoma immunotherapy.
Vitamin C in human health and disease is still a mystery? An overview (2003)

Ascorbic acid is one of the important water soluble vitamins. It is essential for collagen, carnitine and neurotransmitters biosynthesis. Most plants and animals synthesize ascorbic acid for their own requirement. However, apes and humans can not synthesize ascorbic acid due to lack of an enzyme gulonolactone oxidase. Hence, ascorbic acid has to be supplemented mainly through fruits, vegetables and tablets. The current US recommended daily allowance (RDA) for ascorbic acid ranges between 100-120 mg/per day for adults. Many health benefits have been attributed to ascorbic acid such as antioxidant, anti-atherogenic, anti-carcinogenic, immunomodulator and prevents cold etc. However, lately the health benefits of ascorbic acid has been the subject of debate and controversies viz., Danger of mega doses of ascorbic acid? Does ascorbic acid act as a antioxidant or pro-oxidant? Does ascorbic acid cause cancer or may interfere with cancer therapy? However, the Panel on dietary antioxidants and related compounds stated that the in vivo data do not clearly show a relationship between excess ascorbic acid intake and kidney stone formation, pro-oxidant effects, excess iron absorption. A number of clinical and epidemiological studies on anti-carcinogenic effects of ascorbic acid in humans did not show any conclusive beneficial effects on various types of cancer except gastric cancer. Recently, a few derivatives of ascorbic acid were tested on cancer cells, among them ascorbic acid esters showed promising anticancer activity compared to ascorbic acid. Ascorbyl stearate was found to inhibit proliferation of human cancer cells by interfering with cell cycle progression, induced apoptosis by modulation of signal transduction pathways. However, more mechanistic and human in vivo studies are needed to understand and elucidate the molecular mechanism underlying the anti-carcinogenic property of ascorbic acid. Thus, though ascorbic acid was discovered in 17th century, the exact role of this vitamin/nutraceutical in human biology and health is still a mystery in view of many beneficial claims and controversies.
Studies on Wound Healing: Effects of Calcium D-Pantothenate on the Migration, Proliferation and Protein Synthesis of Human Dermal Fibroblasts in Culture (1999)

The effect of calcium D-pantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts from three different donors was investigated. The migration of cells into a wounded area was dose-dependently stimulated by Ca D-pantothenate. The number of cells that migrated across the edge of the wound increased from 32 +/- 7 cells/mm without Ca D-pantothenate to 76 +/- 2 cells/mm with 100 mg/ml Ca D-pantothenate. Moreover, the mean migration distance per cell increased from 0.23 +/- 0.05 mm to 0.33 +/- 0.02 mm. The mean migration speed was calculated to be 10.5 mm/hour without and 15 mm/hour with Ca D-pantothenate. Cell proliferation was also dose-dependently stimulated. The final cell densities were 1.2 to 1.6-fold higher in cultures containing 100 mg/ml Ca D-pantothenate. The protein synthesis was modulated, since two unidentified proteins were more strongly expressed in pantothenate supplemented cultures. In conclusion, Ca D-pantothenate accelerates the wound healing process by increasing the number of migrating cells, their distance and hence their speed. In addition, cell division is increased and the protein synthesis changed. These results suggest that higher quantities of pantothenate are locally required to enhance wound healing.