gebhart/patrepeval huggingface dataset:
Detection of the t(2; 5)(p23; q35) and NPM-ALK Fusion in Non-Hodgkin's Lymphoma by Two-Color Fluorescence In Situ Hybridization (1997)

The non-Hodgkin's lymphoma (NHL) subset commonly referred to as large cell lymphoma (LCL) has historically been characterized by it's marked cytological, immunological, and clinical heterogeneity. One potential defining feature of these lymphomas, the t(2;5)(p23;q35), occurs in 25% to 30% of anaplastic LCLs and is also found in cases with diffuse large cell or immunoblastic morphology. We recently identified nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) as the genes on chromosomes 5 and 2, respectively, that are juxtaposed by this translocation. To provide a complementary approach to the use of classical cytogenetics or polymerase chain reaction-based methods for the detection of this abnormality, we have developed a two-color fluorescent in situ hybridization (FISH) assay for the t(2;5) that may be used for the analysis of both interphase nuclei and metaphase chromosomes. Three overlapping chromosome 5 cosmid clones located immediately centromeric to the NPM gene locus and an ALK P1 clone located telomeric to the chromosome 2 breakpoint were labeled with digoxigenin or biotin, respectively, and used to visualize the derivative chromosome 5 produced by the t(2;5), evident as juxtaposed or overlapping red and green fluorescent signals. This NPM-ALK FISH assay was initially validated by analysis of a series of cytogenetically characterized cell lines, with the presence of the der(5) chromosome showed specifically only in those lines known to contain the t(2;5). The assay was then applied in a blinded fashion to a series of eight cytogenetically t(2;5)-positive clinical specimens and seven known t(2;5)-negative cases, including three NHL and four Hodgkin's disease biopsy samples. Whereas the t(2;5)-negative cases were negative by FISH, all eight t(2;5)-positive cases were positive. One additional case, initially thought to be positive for the translocation by cytogenetics, was proven to not be a classic t(2;5) by interphase and metaphase FISH. These data indicate that the FISH assay described is a highly specific and rapid test that should prove to be a useful adjunct to the currently available methods for detection of the t(2;5).
FISH Detection on DAPI-Banded Chromosomes (2003)

Fluorescence in situ hybridization (FISH) techniques are routinely used in physical mapping studies to determine the regional localization of gene and DNA sequences on human metaphase chromosomes (1). It is often difficult, however, to precisely position the hybridization signals with respect to the conventional chromosome bands. Various approaches have been introduced, including G banding before or after FISH detection (2, 3), cohybridization with Alu or L 1 probes to generate R or G bands (4), use of a combination of various fluorescent dyes, such as quinacrine, Hoechst 33258, or DAPI, with FISH detecting reagents (5, 6), and triple staining with chromomycin, distamycin A, and DAPI (7, 8). Unfortunately, these procedures are not widely used because they are time-consuming and require extensive imaging equipment or careful quality control to be reproducible.
Bifunctional compounds eliciting anti‐inflammatory and anti‐cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning (2005)

Certain organophosphorus (OP) nerve agents (e.g. soman) induce neuroinflammatory processes during acute poisoning. An increased level of typical inflammation markers was also observed in poisoning by alkylating agents such as sulfur mustard (HD). The therapeutic potential of new bifunctional compounds was investigated, eliciting activity of non-steroidal anti-inflammatory drug (NSAID) and anti-cholinesterase (anti-ChE) activity, as an antidotal treatment for both soman and HD poisoning in mice. Three bifunctional compounds were used that include the ChE inhibitor pyridostigmine (PYR) coupled to either ibuprofen (IBU) or diclofenac (DICLO) through an eight (octyl) or ten (decyl) hydrocarbon chain spacer: IBU-PO, IBU-PD and DICLO-PD. These compounds are 15-25 fold less toxic than PYR in mice and exert peripheral and central anti-inflammatory and anti-ChE activity in vivo. IBU-PO (4 mg kg(-1), i.p.), IBU-PD (4 mg kg(-1), i.p.) and PYR (0.13 mg kg(-1), i.p.) reduced to control levels the brain edema in soman-poisoned mice (1.1 LD50, s.c.). Pre-treatment with IBU-PO, IBU-PD and DICLO-PD 4-5 h before soman challenge (2.2-2.3 LD50, s.c.) combined with antidotal treatment (atropine, 11 mg kg(-1), 2-PAM-Cl, 25 mg kg(-1), i.m.) afforded a longer 24 h survival rate (SR) than with PYR pre-treatment. DICLO-PD exhibited the largest protection efficacy (SR = 70% vs 17% with PYR). These results indicate a longer duration of action of bifunctional compounds compared with PYR. DICLO-PD (5% in propyleneglycol) reduced significantly the HD-induced edema in mouse ear-skin (51% increase in biopsy weight compared with 100% without treatment). Quantitative evaluation of ear-skin sections showed that only following DICLO-PD treatment was there a marked decrease in edema. DICLO-PD also elicited a significant decrease in HD-induced vesication as displayed by the reduced sub-epidermal blister level. The data indicate possible use of NSAID-ChEI bifunctional compounds for the medical treatment of both nerve and alkylating chemical agents.
Quantitation of Natural, Recombinant, Cell-Surface and Plasma Tissue Factor. (2004)

Abstract Although it is well established that membrane-anchored cell-surface tissue factor (TF) initiates coagulation when blood contacts damaged tissue, several investigators have reported the existence of a circulating form of TF or TF-like antigen in blood. One report describes the molecular nature of circulating plasma TF as lacking the transmembrane domain, however, the TF activity of this material is a matter of debate. Therefore detection, quantitation and characterization of plasma TF steps towards defining the functional role of circulating TF and its potential contribution to thrombosis and hemostasis. We have developed highly specific and sensitive enzyme-linked (ELISA) and fluorescence-based immunoassays by which all known forms of TF including recombinant (r) truncated (1–218 and 1–242) and full-length (1–263), natural placenta, monocyte in situ as well as plasma TF were detected and quantitated. Immunoblotting confirmed the crossreactivity of anti-TF mAbs with TF from various sources and also revealed that there are significant differences between rTF and TF isolated from natural sources. This could suggest differences in procoagulant activity of rTF and natural TF that has to be investigated. The enzymatic immunoassay of TF was suitable for quantitative analyses of rTF and TF from commercial sources and placenta TF with detection level in the 80 pM range. Since the concentrations of TF on cell surface and in plasma are significantly lower than that found in commercial products, we integrated the double mAb immunoassay into Luminex Multi-Analyte Platform (LMAP) technology and developed a fluorescence-based immunoassay. This new assay was 400-fold more sensitive than ELISA and concentrations as low as 0.2 pM TF could be detected reliably. In addition to higher sensitivity, another advantage of fluorescence-based immunoassay of TF over the existing assays is the ability to determine specific and non-specific binding simultaneously in a single reaction well and such approach enhances assay specificity and reliability. TF on the surface of unstimulated and Lipopolysaccharide-stimulated immortalized human monocytic cells (TIB-202 cell line, ATCC) was quantitated. Unstimulated monocytes displayed between 55-110 TF molecules/cell (3–6 pg TF or 0.1–0.2 pM for 106cells/ml) while stimulated monocytes expressed 8–13 fold more TF as compared to unstimulated cells (730–840 TF molecules/cell, 40–46 pg, 1.2–1.4 pM for 106cells/ml). We also report here that the concentration of TF in plasma of "healthy" individuals (n=92) is in the range of 0.5±1.04 pM (16.2±31.2 pg/ml) and this concentration is substantially lower than that reported by other groups. There are significant variations in the antigen concentration among individuals; in 30% there was no detectable TF antigen (&lt;0.2 pM). Assays of TF set the platform for further analyses of the concentrations of plasma TF in order to establish ranges and variations that occur during specific treatment regimens or due to the presence of certain pathological conditions.
The new World Health Organization classification of lymphomas: the past, the present and the future (2001)

The REAL Classification of lymphomas, proposed in 1994, represents a new paradigm in lymphoma classification, consisting of a list of biologic entities defined by clinicopathologic and immunogenetic features. The non-Hodgkin's lymphomas comprise precursor lymphoblastic and mature cell neoplasms of B, T or putative natural killer cell lineage. An individual entity can exhibit a range of morphologic appearances and a range of clinical behavior. The categories in Hodgkin's lymphomas are identical to the widely used Rye classification except for the additional of a new category termed 'lymphocyte-rich classical Hodgkin's lymphoma'. The REAL classification has been validated by a major multi-institutional study involving 1378 cases (The Non-Hodgkin's Lymphoma Classification Project), showing that it is both reproducible and clinically relevant. The new World Health Organization classification of hematopoietic and lymphoid tumors, to be published in 2001, is a joint project of the Society for Hematopathology and European Association of Hematopathologists, under the auspices of the World Health Organization. This classification includes not only lymphoid neoplasms, but also myeloid, histiocytic and mast cell neoplasms. The lymphoma component of the classification is merely an update of the REAL classification, with minor changes necessitated by new information that has become available since its proposal. A conceptual grouping of the non-Hodgkin's lymphomas into four categories (indolent, aggressive, highly aggressive, and localized indolent) is also presented in this review. The next major impetus influencing the approach to lymphoma classification will no doubt be molecular genetics, in particular DNA microarrays, which will yield an enormous amount of new data that will aid in the understanding of lymphomas.
Identification of a Candidate Regulatory Element within the 5′ Flanking Region of the Mouse Igh Locus Defined by Pro-B Cell-Specific Hypersensitivity Associated with Binding of PU.1, Pax5, and E2A (2006)

The Igh locus is controlled by cis-acting elements, including Emu and the 3' IgH regulatory region which flank the C region genes within the well-studied 3' part of the locus. Although the presence of additional control elements has been postulated to regulate rearrangements of the VH gene array that extends to the 5' end of the locus, the 5' border of Igh and its flanking region have not been characterized. To facilitate the analysis of this unexplored region and to identify potential novel control elements, we physically mapped the most D-distal VH segments and scanned 46 kb of the immediate 5' flanking region for DNase I hypersensitive sites. Our studies revealed a cluster of hypersensitive sites 30 kb upstream of the most 5' VH gene. Detection of one site, HS1, is restricted to pro-B cell lines and HS1 is accessible to restriction enzyme digestion exclusively in normal pro-B cells, the stage defined by actively rearranging Igh-V loci. Sequence motifs within HS1 for PU.1, Pax5, and E2A bind these proteins in vitro and these factors are recruited to HS1 sequence only in pro-B cells. Transient transfection assays indicate that the Pax5 binding site is required for the repression of transcriptional activity of HS1-containing constructs. Thus, our characterization of the region 5' of the VH gene cluster demonstrated the presence of a single cluster of DNase I hypersensitive sites within the 5' flanking region, and identified a candidate Igh regulatory region defined by pro-B cell-specific hypersensitivity and interaction with factors implicated in regulating VDJ recombination.
Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage colony-stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma. (2000)

The purpose of our study was to determine the maximally tolerated dose (MTD) and DLT of combined administration of granulocyte macrophage colony-stimulating factor (GM-CSF), low-dose interleukin 2 (IL-2) and IFN-alpha in patients with progressive metastatic melanoma or renal cell carcinoma (RCC). In addition, the activation and expansion of effector cells were measured. Cohorts of three patients were treated with increasing doses of IL-2 (1, 4, and 8 MIU/m2) and GM-CSF (2.5 and 5 microg/kg) with a constant dose of IFNalpha (5 million units) s.c. for 12 days every 3 weeks. An additional six patients were treated at the MTD. Immune activation was monitored during the first cycle. Response was evaluated after two cycles. The MTD was found to be 2.5 microg/kg GM-CSF, 4 MIU/m2 IL-2, and 5 mega units of IFNalpha. DLT was grade 4 fever, chills with hypotension, grade 3 fatigue/malaise, and fluid retention. Dose reduction of IL-2 to 2 MIU/m2 was necessary in three of nine patients who initially received the MTD. Treatment was initiated in the hospital but could be continued at home after 3-4 days. Significant increases in lymphocytes, (activated) T cells (CD4+ and CD8+), NK cells, monocyte DR expression, neutrophils, and eosinophils were found. CD8+ T-cell activation (sCD8) and NK cell expansion was mainly present in patients receiving 2 or 4 MIU/m2 IL-2. Of eight patients with progressive metastatic RCC after nephrectomy, three achieved a complete remission, and 1 of 7 patients with metastatic melanoma achieved a partial remission. In our study, the MTD of combined immunotherapy with GM-CSF, IL-2, and IFNalpha was established; DLT was: (a) grade 4 fever with hypotension needing i.v. fluid support; and (b) grade 3 fluid retention and/or fatigue/malaise. The scheme resulted in considerable expansion and/or activation of various effector cells. The complete responses in RCC patients are promising but need to be confirmed in Phase II studies.
Non-Invasive Epigenetic Detection of Fetal Trisomy 21 in First Trimester Maternal Plasma (2011)

Our findings suggest that U-PDE9A level and the unmethylation index of PDE9A may be useful biomarkers for non-invasive fetal DS detection during the first trimester of pregnancy, regardless of fetal gender.
Inhibitory effects of human salivary histatins and lysozyme on coaggregation between Porphyromonas gingivalis and Streptococcus mitis (1991)

The effects of histatins on coaggregation between Porphyromonas gingivalis 381 and Streptococcus mitis ATCC 9811 were investigated by using a turbidimetric assay. The coaggregation activity was significantly inhibited by histatins 5 and 8 and strongly by lysozyme. Tritium-labeled histatin 8 bound to P. gingivalis cells but not to S. mitis cells.
Meningioma Transcript Profiles Reveal Deregulated Notch Signaling Pathway (2005)

Meningiomas constitute the second most common central nervous system tumor, and yet relatively little is known about the molecular events that are important for the pathogenesis and malignant progression of these tumors. We have used serial analysis of gene expression to compare the transcriptomes of nonneoplastic meninges and meningiomas of all malignancy grades. A novel finding from this screen is the induction of three components of the Notch signaling pathway: the transcription factor, hairy and enhancer of Split1 (HES1) and two members of the Groucho/transducin-like enhancer of Split family of corepressors, TLE2 and TLE3. TLE corepressors interact and modulate the activity of a wide range of transcriptional regulatory systems, one of which is HES1. We have shown that the transcript and protein levels of HES1, the Notch2 and Notch1 receptors and the Jagged1 ligand are induced in meningiomas of all grades, whereas induction of TLE2 and TLE3 occurs specifically in higher-grade meningiomas. Meningioma cell lines express components of the Notch signaling pathway and an inhibitor of this pathway suppresses meningioma cell survival. These results suggest that deregulated expression of the Notch pathway is a critical event in meningioma pathogenesis and that modulation of this and potentially other signaling pathways by TLE corepressors leads to a more malignant phenotype.
Supporting Multiple Off-Axis Viewpoints at a Tabletop Display (2007)

A growing body of research is investigating the use of tabletop displays, in particular to support collaborative work. People often interact directly with these displays, typically with a stylus or touch. The current common focus of limiting interaction to 2D prevents people from performing actions familiar to them in the 3D world, including piling, flipping and stacking. However, a problem arises when viewing 3D on large displays that are intended for proximal use; the view angle can be extremely oblique and lead to distortion in the perception of the 3D projection. We present a simplified model that compensates for off-axis viewing for a single user and extend this technique for multiple viewers interacting with the same large display. We describe several implications of our approach to collaborative activities. We also describe other display configurations for which our technique may prove useful, including proximal use of a wall or multiple-display configurations.
Abstract LB-153: KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo (2018)

Abstract Antibodies blocking the PD-1/PD-L1 axis present significant breakthroughs in the treatment of hitherto untreatable cancers. However, despite the highly encouraging progress that has been made, multiple tumour types demonstrate limited response to these therapies. The emerging picture is that combination with other therapies is required to improve response rates and/or the durability of response. Additional benefit could be achieved by combining an anti-PD-L1 approach with another modulator of T cell activation. ICOS is a co-stimulatory molecule expressed on activated T cells such as TEff and TReg cells present in the tumour microenvironment (TME). ICOS agonism has been demonstrated to improve TEff cell survival and IFNγ release, resulting in the activation of T cell-dependent eradication of the tumour. In addition, the high expression of ICOS observed on TReg cells in the TME allows these highly immunosuppressive cells to be selectively depleted when using the appropriate antibody format. With the aim of targeting both ICOS and PD-L1, we have developed a bispecific mAb² (KY1055) as a human IgG1 format that consists of fully human Fab arms targeting ICOS and a modified Fc (Fcab) containing binding sites to PD-L1. We demonstrate potent (single digit nM) binding to ICOS via the Fab and to PD-L1 via the Fcab. Furthermore, in vitro studies reveal that KY1055 can bridge together ICOS- and PD-L1-expressing cells and can activate ICOS signalling through this cross-presentation. Functionality of the Fcab was validated by demonstrating that it blocks the PD-1-PD-L1 inhibitory pathway, resulting in the up-regulation of IFNγ in monocyte:T cell co-culture assays. We also demonstrate the ability of KY1055 to deplete ICOShigh cells in vitro by ADCC. In vivo, we confirm the anti-tumour efficacy of KY1055 in several syngeneic models that are poorly responsive to the respective monotherapies and further demonstrate improved anti-tumour efficacy when combined with anti-CTLA4 and anti-PD-1 in vivo. Finally, we demonstrate that KY1055 depletes TRegs and improves the TEff : TReg ratio in vivo in a CT26 model of tumour growth. Altogether, these data warrant further development of KY1055 for the treatment of solid tumours. Citation Format: Richard C. Sainson, Nahida Parveen, Gwenoline Borhis, Miha Kosmac, Tracey OKell, Emma Taggart, Joana Carvalho, Matthew McCourt, Hanif Ali, Hannah Craig, Aksana Labokha. KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-153.
Synthesis and toxicity of full-length and truncated bacterial CryIVD mosquitocidal proteins expressed in lepidopteran cells using a baculovirus vector (1992)

Full-length (72K) and truncated (61K) CryIVD mosquitocidal proteins of Bacillus thuringiensis (Bt) were expressed in Spodoptera frugiperda cells and larvae of Trichoplusia ni using a baculovirus vector to investigate the role of CryIVD peptides in toxicity as well as to evaluate further the baculovirus/lepidopteran system for expressing Bt proteins. The cryIVD genes were inserted into the Autographa californica multinucleocapsid nuclear polyhedrosis virus (AcMNPV) under control of the polyhedrin promoter by recombination in S. frugiperda cells between a transfer vector carrying the Bt genes and vDA26Z, a recombinant AcMNPV carrying the Escherichia coli beta-galactosidase gene under control of the DA26 promoter. Recombinant AcMNPVs carrying the genes were detected as blue occlusion body-negative plaques in monolayers of S. frugiperda cells grown in the presence of X-Gal. Infection of S. frugiperda cells and T. ni larvae with plaque-purified recombinant virus, expressing either the full-length or truncated CryIVD protein, resulted in the synthesis of proteins of the expected size, as confirmed by immunoblot analyses, and their crystallization into cuboidal inclusions in the cytoplasm. Infected cells and purified inclusions from the virus (AcCryIVD) expressing the full-length protein were highly toxic to mosquito larvae, but similar preparations from the virus (AcCryIVD-C) expressing the truncated protein with a 9.6K deletion at the N terminus were non-toxic. Proteolysis with trypsin of CryIVD proteins produced by Bt and the recombinant AcMNPVs yielded peptides corresponding in size, showing that synthesis of mosquitocidal Bt proteins in lepidopteran cells occurred. The lack of toxicity of the truncated CryIVD protein, which like the toxic full-length protein yielded a 34K protein on proteolysis that has been implicated in toxicity, indicates that by itself this protein is non-toxic. These results demonstrate the utility of the baculovirus system for expression of mosquitocidal Bt proteins and for investigation of their mode of action.