gebhart/patrepeval huggingface dataset:
Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: Data from the JAVELIN Solid Tumor trial. (2017)

9086 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody showing promising efficacy and safety in patients (pts) with non-small cell lung cancer (NSCLC) and other tumors. Here, we present exposure–response (E–R) and PD-L1 expression analyses of second-line (2L) avelumab treatment in pts with NSCLC from a phase 1 trial (NCT01772004). Methods: Pts with NSCLC received 2L avelumab 10 mg/kg IV every 2 weeks (Q2W) until progression or unacceptable toxicity. Serum samples were taken at various time points for pharmacokinetic (PK) analysis. Trough concentrations after first dose (Ctrough first-dose ) were predicted using an identified linear 2-compartment population PK (popPK) model without covariates other than pt body weight. Objective response rate (ORR) was evaluated (RECIST v1.1), and correlated with tumor cell (TC) PD-L1 expression (clone 73-10). Pooled safety data from various tumors in the large phase 1 trial were assessed. Results: In 184 avelumab-treated pts, unselected for PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of Ctrough first-dose (Q1–4). Using ≥1%, ≥5%, ≥50%, and ≥80% PD-L1 staining cutoffs, pts in the upper half of exposure (Ctrough first-dose Q3–4 [n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). PopPK modeling suggested Ctrough first-dose could be optimally increased with alternate avelumab dosing (10 mg/kg weekly vs Q2W, or 20 mg/kg Q2W [simulated median Ctrough first-dose 48 μg/mL vs 18 μg/mL, or 36 μg/mL]). Conclusions: Avelumab has shown clinical activity and acceptable safety in multiple tumors similar to other agents in class. Preliminary analysis of a cohort of pts with 2L advanced NSCLC shows a trend for higher ORR with increasing avelumab Ctrough first-dose quartiles and with higher levels of TC PD-L1 expression. Although this apparent E–R observation may be confounded by single-dose testing or other factors, this analysis provides rationale for studies of more intensive avelumab dosing regimens to assess further clinical benefit in pts with advanced NSCLC. Clinical trial information: NCT01772004.
Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo (1999)

Fgf8 and Fgf4 encode FGF family members that are coexpressed in the primitive streak of the gastrulating mouse embryo. We have analyzed the phenotype of Fgf8(-/-) embryos and discovered that they fail to express Fgf4 in the streak. In the absence of both FGF8 and FGF4, epiblast cells move into the streak and undergo an epithelial-to-mesenchymal transition, but most cells then fail to move away from the streak. As a consequence, no embryonic mesoderm- or endoderm-derived tissues develop, although extraembryonic tissues form. Patterning of the prospective neuroectoderm is greatly perturbed in the mutant embryos. Anterior neuroectoderm markers are widely expressed, at least in part because the anterior visceral endoderm, which provides signals that regulate their expression, is not displaced proximally in the absence of definitive endoderm. Posterior neuroectoderm markers are not expressed, presumably because there is neither mesendoderm underlying the prospective neuroectoderm nor a morphologically normal node to provide the inductive signals necessary for their expression. This study identifies Fgf8 as a gene essential for gastrulation and shows that signaling via FGF8 and/or FGF4 is required for cell migration away from the primitive streak.
의 탈구심적 미학 (2017)

하길종의 감독의 (1975)은 흥행에 크게 성공하면서 `병태 신드롬`을 일으켰을 정도였으며 비평적으로도 큰 찬사를 받았지만, 회의적인 비판 또한 없지 않았다. 또한 구체적인 미학적 검토는 물론 당대 혹은 후대의 영화인들에게 어떻게 받아들여졌는가에 대해서도 구체적으로 검토되지 못했다. 또한 이 영화가 당대 관객들과 만난 구체적인 미적 요소 즉 파토스(pathos)를 불러일으킨 인물과 행위, 공간, 이미지, 서사전략 등은 충분히 설명되지 않았다. 이 글은 이런 맥락에서, 단절적인 서사와 파편적 이미지들로 가득 찬 을 억압에 대응하는 미적 양식의 차원에서 보고자 한다. 미하일 바흐찐(Mikhail Bakhtin, 1895∼1975)은 억압적인 공식문화 혹은 벗어나기가 요원한 지극히 관습적인 문화가 지배적일 때는 웃음과 풍자(인물과 행위), 밀실에서 광장으로(공간), 그로테스크한 물질 혹은 육체성(이미지), 거리낌 없는 말투와 에피소드들의 혼잡한 결집(서사) 등으로 드러난다고 보았다. 즉 구심적 문화에 대항하는 탈구심적 문화가 나타나는데, 이러한 것을 공식문화에 대응하는 민중문화의 특징 그 중에서도 카니발레스크(carnivalesque, 카니발적 양식) 성향으로 보았다. 이 글은 이런 맥락에서 바흐찐의 카니발적 미학 등을 중심으로, 단절된 서사와 분산된 이미지들로 이루어진 이 어떤 통일된 미적 지향을 갖는다는 것을 말하고자 한다.
Evidence for the maintenance of hematopoiesis in a large animal by the sequential activation of stem-cell clones. (1990)

To test if hematopoiesis can be maintained by the sequential activation of stem-cell clones, we performed autologous marrow transplantations with limited numbers of cells in cats heterozygous for the X chromosome-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) and observed the G6PD phenotypes of erythroid and granulocyte/macrophage progenitors over time. The animals were the female offspring of Geoffroy male and domestic female cats. In repeated studies of marrow from control animals (n = 5) or experimental animals prior to transplantation (n = 3), the percent of progenitors with domestic-type G6PD did not vary. After transplantation, the peripheral blood counts, marrow morphologies, frequencies of progenitors, and progenitor cell cycle kinetics returned to normal. However, abrupt and significant fluctuations were seen in the G6PD type of progenitors from each cat during the 1-1.5 years of observation. These data cannot be explained if there were either a large or constant population of active stem cells and thus imply, in a large-animal system, that hematopoiesis was maintained through clonal succession. A stochastic model was developed to estimate the numbers of active clones and their mean lifetimes.
Collaboration with Robotic Drawers (2015)

In this video, we explored how everyday household robots should behave when performing collaborative tasks with human users. We ran a Wizard of Oz study (N=20) that utilized a set of robotic drawers. The participants were asked to assemble a cube by working together with the drawers which contained the tools needed to accomplish the task. We conducted a between-subjects test with the drawers while varying one of two variables (expressivity and proactivity) to yield a 2x2 factorial design.
Improving the Clinical Patency of Prosthetic Vascular and Coronary Bypass Grafts: The Role of Seeding and Tissue Engineering (2002)

In patients requiring coronary or peripheral vascular bypass procedures, autogenous vein is currently the conduit of choice. If this is unavailable, then a prosthetic material is used. Prosthetic graft is liable to fail due to occlusion of the graft. To prevent graft occlusion, seeding of the graft lumen with endothelial cells is undertaken. Recent advances have also looked at developing a completely artificial biological graft engineered from the patient's cells with properties similar to autogenous vessels. This review encompasses the developments in the two principal technologies used in developing hybrid coronary and peripheral vascular bypass grafts, that is, seeding and tissue engineering.
Amorphous silicon thin-film transistors and arrays fabricated by jet printing (2002)

Phase-change wax-based printed masks, in place of conventional photolithography, were used to fabricate hydrogenated amorphous silicon thin-film transistors (TFTs). Wax-mask features with a minimum feature size of ∼20 μm were achieved using an acoustic-ink-printing process. Both discrete and matrix addressing structured bottom-gate TFTs with source–drain contacts overlapping the channel were created using a four-mask process. The TFTs had current–voltage characteristics comparable to photolithographically patterned devices, with mobility of 0.6–0.9 cm2/V s, threshold voltage of 2–3 V, and on/off ratios exceeding 107 for devices with channel lengths below 50 μm.
Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. (1992)

We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 of the 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes.
Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma (2012)

Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.
Learning from text: Matching readers and texts by latent semantic analysis (1998)

This study examines the hypothesis that the ability of a reader to learn from text depends on the match between the background knowledge of the reader and the difficulty of the text information. Latent Semantic Analysis (LSA), a statistical technique that represents the content of a document as a vector in high‐dimensional semantic space based on a large text corpus, is used to predict how much readers will learn from texts based on the estimated conceptual match between their topic knowledge and the text information. Participants completed tests to assess their knowledge of the human heart and circulatory system, then read one of four texts that ranged in difficulty from elementary to medical school level, then completed the tests again. Results show a nonmonotonic relation in which learning was greatest for texts that were neither too easy nor too difficult. LSA proved as effective at predicting learning from these texts as traditional knowledge assessment measures. For these texts, optimal assignment of text on the basis of either prereading measure would have increased the amount learned significantly.
Viral Vectors for Cancer Immunotherapy (2006)

Over the last decade, immunotherapy approaches for the treatment of cancer have been investigated with renewed vigour, perhaps catalyzed by the clinical successes seen with monoclonal antibody and cytokine based therapies. The identification of tumor-associated antigens (TAAs) in multiple cancer types has enabled the development of targeted immunotherapies and allayed some of the safety concerns associated with the induction of deleterious autoimmune reactions. In addition to the TAA or therapeutic gene, the antigen delivery system is equally as important for the development of a successful cancer vaccine. One approach to induce a potent and targeted antitumor response is to use viruses to deliver the TAA to cells of the immune system. A diverse array of oncolytic viruses and recombinant viral vectors encoding numerous therapeutic genes or TAAs have been tested in pre-clinical studies and produced results which, in some cases, justify their clinical development as potential cancer immunotherapies. Within the last 5-10 years, many such recombinant vectors have made the transition from pre-clinical research to clinical development and it is these, which are given most weight in this review.
Cloning and expression of the cDNA for human antithrom, bin III (1982)

A partial cDNA clone for human antithrombin III (ATIII) was obtained by screening a cDNA library prepared from size fractionated liver RNA with a pool of eight 16-base long synthetic DNA fragments whose sequence was determined from protein sequence data. A fragment of the partial cDNA clone was used to enrich RNA for ATIII messages, and cDNA clones encoding the entire ATIII structural gene were identified. The complete nucleotide and predicted amino acid sequences of human ATIII and its 32 residue signal peptide are reported, and provide further opportunity to compare the ATIII primary structure with corresponding regions from homologous proteins, alpha 1-antitrypsin and ovalbumin. Plasmids in which the structural genes for mature and pre-ATIII were linked to the E. coli trp promoter-operator support the synthesis of human antithrombin III and pre-antithrombin III in bacteria.
Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. (1996)

Docetaxel is an active agent in MBC. Its activity as a single agent is comparable to many combination chemotherapy regimens and is not affected by prior adjuvant chemotherapy. Studies are ongoing to improve its therapeutic index and to incorporate docetaxel in combination chemotherapy regimens.
Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice. (1985)

Immunization of mice with a combination of passively administered syngeneic IgG (anti-p-azophenylarsonate [anti-Ars]) antibody and a soluble, multivalent form of the antibody's corresponding antigen (Limulus polyphemus hemocyanin conjugated with Ars [Lph-Ars]) resulted in specific autoanti-IgG Fc (rheumatoid factor) production. The response was rapid and only anti-IgG of the IgM isotype is found. Because immunization with either the IgG antibody or the antigen alone did not result in rheumatoid antibody production, immune complexes appear to be the active form of the immunogens. Antibody/antigen ratios that resulted in maximal anti-IgG antibody responses were the same as those required for peak in vitro immunoprecipitation, i.e., equivalence. Previous exposure of the mice to the exogenously supplied antigen was not required for the response. The response to immune complexes is specific because mice immunized with IgG2a-containing complexes produced autoanti-IgG2a, while mice immunized with IgG1-containing complexes produced anti-IgG1 with little reactivity to other IgG isotypes. IgG2a blocked in its complement-fixing capacity was more effective in eliciting the anti-IgG2a response than native IgG2a, suggesting a possible role for the complement system in modulating the anti-IgG2a response. Induction of rheumatoid factor production by immune complexes could be induced in xid mice but not in nu/nu mice, indicating T lymphocyte dependence of the response. In contrast, the B lymphocyte activator lipopolysaccharide was able to elicit vigorous rheumatoid factor production in both nu/nu and normal mice, demonstrating that nu/nu mice contain B cells capable of making the response. Rheumatoid antibody produced in the immune complex- or LPS-induced responses is Fc specific and has relatively low affinity for IgG that is not bound to antigen.
Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper‐reactivity in sensitized mice exposed to aerosolized allergen (2001)

Simultaneous induction of eosinophilic inflammation in the nose and lungs was found in a mouse model of respiratory allergy. These findings support the viewpoint that upper and lower airway disease represent a continuum of inflammation involving one common airway and provide evidence for the concept of global airway inflammation after inhalation of allergen.
Forage Quality, Evaluation, and Utilization (1994)

Forage ouality, evaluation and Utilization , Forage ouality, evaluation and Utilization , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی
Cloning and Functional Analysis of the ndk1 Gene Encoding Nucleoside-diphosphate Kinase in Schizosaccharomyces pombe (1995)

We cloned the ndk1 gene encoding a subunit of nucleoside-diphosphate kinase (NDK) from Schizosaccharomyces pombe, by using polymerase chain reaction. The deduced ndk1 gene product has 151 amino acid residues and is approximately 60% identical with both Saccharomyces cerevisiae and mammalian NDKs. The gene product exhibited NDK activity and cross-reacted with antibodies raised against rat NDK. Disruption of ndk1 greatly reduced the cellular NDK activity but caused no obvious phenotype in cell growth and sexual development of the organism. However, a mutated allele of ndk1 could inhibit sexual development in a dominant-negative manner. This allele carried a point mutation in cysteine 116, which locates next to the putative active center histidine 117, and the mutant gene product showed no NDK activity. Gene expression inducible in response to mating pheromone signaling was decreased in cells carrying the dominant-negative allele. Cases have been reported in higher eukaryotes in which NDK appears to play a more sophisticated role than a simple catalyst in cell physiology, and the results of this study suggest that S. pombe NDK may also perform such a role in regulation of sexual development in the fission yeast.
Risk Factors, Outcome, and Treatment in Subtypes of Ischemic Stroke: The German Stroke Data Bank (2001)

Our results foster the concept of ischemic stroke as a polyetiologic disease with marked differences between subtypes regarding risk factors and outcome. Therefore, studies involving risk factors of ischemic stroke should differentiate between etiologic stroke subtypes.
The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. (2001)

TAFI (thrombin activatable fibrinolysis inhibitor) down regulates fibrinolysis after activation by relatively high concentrations of thrombin generated during coagulation via thrombin mediated factor XI activation and subsequent activation of the intrinsic pathway. It is this secondary burst of thrombin that is severely diminished in haemophilia A, a deficiency of coagulation factor VIII. We therefore investigated the role of TAFI in haemophilia A by measuring the clot lysis times of tissue factor induced fibrin formation and tPA mediated fibrinolysis. In haemophilia A plasma clot lysis times were normal at relatively high tissue factor concentrations but severely decreased at moderate to low tissue factor concentrations, indicating that the thrombin generation via the extrinsic pathway was insufficient to activate TAFI. Addition of factor VIII, TAFI or thrombomodulin restored the clot lysis times at low tissue factor concentrations. This confirms the hypothesis that the bleeding disorder in haemophilia A is not merely a defect in the initial clot formation but is in fact a triple defect: reduced thrombin formation via the extrinsic pathway at low tissue factor concentrations, a reduced secondary burst of thrombin generation via the intrinsic pathway and a defective down regulation of the fibrinolytic system by the intrinsic pathway.
The Diversity of Anti-Microbial Secondary Metabolites Produced by Fungal Endophytes: An Interdisciplinary Perspective (2013)

Endophytes are microbes that inhabit host plants without causing disease and are reported to be reservoirs of metabolites that combat microbes and other pathogens. Here we review diverse classes of secondary metabolites, focusing on anti-microbial compounds, synthesized by fungal endophytes including terpenoids, alkaloids, phenylpropanoids, aliphatic compounds, polyketides, and peptides from the interdisciplinary perspectives of biochemistry, genetics, fungal biology, host plant biology, human and plant pathology. Several trends were apparent. First, host plants are often investigated for endophytes when there is prior indigenous knowledge concerning human medicinal uses (e.g., Chinese herbs). However, within their native ecosystems, and where investigated, endophytes were shown to produce compounds that target pathogens of the host plant. In a few examples, both fungal endophytes and their hosts were reported to produce the same compounds. Terpenoids and polyketides are the most purified anti-microbial secondary metabolites from endophytes, while flavonoids and lignans are rare. Examples are provided where fungal genes encoding anti-microbial compounds are clustered on chromosomes. As different genera of fungi can produce the same metabolite, genetic clustering may facilitate sharing of anti-microbial secondary metabolites between fungi. We discuss gaps in the literature and how more interdisciplinary research may lead to new opportunities to develop bio-based commercial products to combat global crop and human pathogens.
Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD) (2017)

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a <i>DUX4</i> gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable <i>DUX4</i> mRNAs. In addition, an open chromatin structure is required for <i>DUX4</i> gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of <i>DUX4</i> mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the <i>DUX4</i> mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD.
Antiparallel side-by-side dimeric motif for sequence-specific recognition in the minor groove of DNA by the designed peptide 1-methylimidazole-2-carboxamide netropsin. (1992)

The designed peptide 1-methylimidazole-2-carboxamide netropsin (2-ImN) binds specifically to the sequence 5'-TGACT-3'. Direct evidence from NMR spectroscopy is presented that this synthetic ligand binds DNA as a 2:1 complex, which reveals that the structure is an antiparallel dimer in the minor groove of DNA. This is in contrast to the 1:1 complexes usually seen with most crescent-shaped minor groove binding molecules targeted toward A+T-rich tracts but reminiscent of a dimeric motif found for distamycin at high concentrations. These results suggest that sequence-dependent groove width may play an important role in allowing an expanded set of DNA binding motifs for synthetic peptides.