gebhart/patrepeval huggingface dataset:
Differential Antigen Specificity of Hepatitis C Virus–Specific Interleukin 17– and Interferon γ–Producing CD8+ T Cells During Chronic Infection (2012)

A subset of CD8(+) T cells can secrete interleukin 17 (IL-17). However, very little information is currently available about their antigen specificity, tissue distribution, and biological relevance in chronic human viral infection. To address these issues, we comprehensively analyzed peripheral and intrahepatic CD8(+) T-cell responses in a cohort of patients with chronic hepatitis C virus (HCV) infection for the antigen-specific production of IL-17 and interferon (IFN) γ. We found that HCV-specific IL-17-producing and retinoic acid receptor related orphan receptorγt-expressing CD8(+) T cells are detectable in blood and liver and target different epitopes, compared with IFN-γ-producing CD8(+) T cells. Their highest frequency was found in patients with low inflammatory activity, suggesting a protective role in chronic HCV infection.
NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells (2012)

Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflammatory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-κB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5(Δ/Δ)). In this article we show that these animals exhibit slightly decreased CD8(+) T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5(Δ/Δ) macrophages efficiently primed CD8(+) T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5(Δ/Δ) lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines. Hence, loss of NLRC5 expression represents an advantage for evading CD8(+) T cell-mediated elimination by downmodulation of MHC I levels-a mechanism that may be exploited by transformed cells. Our data show that NLRC5 acts as a key transcriptional regulator of MHC I in lymphocytes and support an essential role for NLRs in directing not only innate but also adaptive immune responses.
Kifunensine, a potent inhibitor of the glycoprotein processing mannosidase I. (1990)

Kifunensine, produced by the actinomycete Kitasatosporia kifunense 9482, is an alkaloid that corresponds to a cyclic oxamide derivative of 1-amino mannojirimycin. This compound was reported to be a weak inhibitor of jack bean alpha-mannosidase (IC50 of 1.2 x 10(-4) M) (Kayakiri, H., Takese, S., Shibata, T., Okamoto, M., Terano, H., Hashimoto, M., Tada, T., and Koda, S. (1989) J. Org. Chem. 54, 4015-4016). We also found that kifunensine was a poor inhibitor of jack bean and mung bean aryl-alpha-mannosidases, but it was a very potent inhibitor of the plant glycoprotein processing enzyme, mannosidase I (IC50 of 2-5 x 10(-8) M), when [3H]mannose-labeled Man9GlcNAc was used as substrate. However, kifunensine was inactive toward the plant mannosidase II. Studies with rat liver microsomes also indicated that kifunensine inhibited the Golgi mannosidase I, but probably does not inhibit the endoplasmic reticulum mannosidase. Kifunensine was tested in cell culture by examining its ability to inhibit processing of the influenza viral glycoproteins in Madin-Darby canine kidney cells. Thus, when kifunensine was placed in the incubation medium at concentrations of 1 microgram/ml or higher, it caused a complete shift in the structure of the N-linked oligosaccharides from complex chains to Man9(GlcNAc)2 structures, in keeping with its inhibition of mannosidase I. On the other hand, even at 50 micrograms/ml, deoxymannojirimyucin did not prevent the formation of all complex chains. Thus kifunensine appears to be one of the most effective glycoprotein processing inhibitors observed thus far, and knowledge of its structure may lead to the development of potent inhibitors for other processing enzymes.
The pre-analytical phase of the liquid biopsy (2019)

The term 'liquid biopsy', introduced in 2013 in reference to the analysis of circulating tumour cells (CTCs) in cancer patients, was extended to cell-free nucleic acids (cfNAs) circulating in blood and other body fluids. CTCs and cfNAs are now considered diagnostic and prognostic markers, used as surrogate materials for the molecular characterisation of solid tumours, in particular for research on tumour-specific or actionable somatic mutations. Molecular characterisation of cfNAs and CTCs (especially at the single cell level) is technically challenging, requiring highly sensitive and specific methods and/or multi-step processes. The analysis of the liquid biopsy relies on a plethora of methods whose standardisation cannot be accomplished without disclosing criticisms related to the pre-analytical phase. Thus, pre-analytical factors potentially influencing downstream cellular and molecular analyses must be considered in order to translate the liquid biopsy approach into clinical practice. The present review summarises the most recent reports in this field, discussing the main pre-analytical aspects related to CTCs, cfNAs and exosomes in blood samples for liquid biopsy analysis. A short discussion on non-blood liquid biopsy samples is also included.
PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing (2003)

New HIV therapies are urgently needed to address the growing problem of drug resistance. In this article, we characterize the anti-HIV drug candidate 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457). We show that PA-457 potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). We find that virions from PA-457-treated cultures are noninfectious and exhibit an aberrant particle morphology characterized by a spherical, acentric core and a crescent-shaped, electron-dense shell lying just inside the viral membrane. To identify the determinants of compound activity we selected for PA-457-resistant virus in vitro. Consistent with the effect on Gag processing, we found that mutations conferring resistance to PA-457 map to the p25 to p24 cleavage site. PA-457 represents a unique class of anti-HIV compounds termed maturation inhibitors that exploit a previously unidentified viral target, providing additional opportunities for HIV drug discovery.
A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells (1999)

We have developed an episomal replicating expression vector in which the SV40 gene coding for the large T-antigen was replaced by chromosomal scaffold/matrix attached regions. Southern analysis as well as vector rescue experiments in CHO cells and in Escherichia coli demonstrate that the vector replicates episomally in CHO cells. It occurs in a very low copy number in the cells and is stably maintained over more than 100 generations without selection pressure.
Distinctive expression and function of four GSDM family genes (GSDMA‐D) in normal and malignant upper gastrointestinal epithelium (2008)

Gasdermin (GSDM or GSDMA), expressed in the upper gastrointestinal tract but frequently silenced in gastric cancers (GCs), regulates apoptosis of the gastric epithelium. It has three human homologs, GSDMB, GSDMC, and GSDMD (GSDM family) and they are considered to be involved in the regulation of epithelial apoptosis but not yet known. We investigated the expression pattern of the family genes in the upper gastrointestinal epithelium and cancers. Reverse transcriptase-polymerase chain reaction revealed that, unlike GSDMA expressed in differentiated cells, GSDMB is expressed in proliferating cells and GSDMD in differentiating cells. GSDMC, meanwhile, is expressed in both differentiating and differentiated cells. Colony formation assay showed that GSDMB, closely related to GSDMA, has no cell-growth inhibition activity in gastric cancer cells, and that GSDMC and GSDMD, respectively, exhibit the activity with different strengths from that of GSDMA. Expression analyses of the four family genes in esophageal and GCs suggested that GSDMC and GSDMD as well as GSDMA are tumor suppressors and that GSDMB, which was amplified and overexpressed in some GCs, could be an oncogene. The results of the expression analysis and colony formation assay suggest that each family gene may have a distinct function in the upper gastrointestinal epithelium.
Factors Influencing the Production of Tetanal Toxin (1947)

Summary A modification of our original medium for the production of high levels of tetanal toxin is described. It possesses the advantage of greater simplicity of preparation and composition, and yields equally good, or somewhat better toxin. The earlier statement that our strain Cl. tetani does not withstand lyophilizing is corrected. There is evidence that more than one factor is involved in the stimulation of tetanus toxin production by hog stomach autolysate.
DNA vaccine encoding human immunodeficiency virus‐1 Gag, targeted to the major histocompatibility complex II compartment by lysosomal‐associated membrane protein, elicits enhanced long‐term memory response (2004)

Antigen presentation by major histocompatibility complex type II (MHC II) molecules and activation of CD4+ helper T cells are critical for the generation of immunological memory. We previously described a DNA vaccine encoding human immunodeficiency virus-1 p55Gag as a chimera with the lysosome-associated membrane protein (LAMP/gag). The LAMP/gag chimera protein traffics to the MHC II compartment of transfected cells and elicits enhanced immune responses as compared to a DNA vaccine encoding native gag not targeted to the MHC II compartment. We have now investigated the long-term responses of immunized mice and show that the LAMP/gag DNA vaccine promotes long-lasting B cell- and CD4+ and CD8+ T-cell memory responses induced by DNA encoding non-targeted Gag decay rapidly and elicit very low or undetectable levels of gag DNA is sufficient to generate T-cell memory. Following this initial priming immunization with LAMP/gag DNA, booster immunizations with native gag DNA or the LAMP/gag chimera are equally efficient in eliciting B- and T-cell secondary responses, results in accordance with observations that secondary expansion of CD8+ cells in the boost phase does not require additional CD4+ help. These findings underscore the significance of targeting DNA-encoded vaccine antigens to the MHC II processing compartments for induction of long-term immunological memory.
The Jak-Stat pathway in normal and perturbed hematopoiesis (2000)

The Janus kinase-signal transducer and activator of transcription (Jak-Stat) pathway stands as a paradigm of how diverse extracellular signals can elicit rapid changes in gene expression in specific target cells. This pathway is widely used by members of the cytokine receptor superfamily, including
A faster-acting and more potent form of tissue plasminogen activator. (1994)

Current treatment with tissue plasminogen activator (tPA) requires an intravenous infusion (1.5-3 h) because the clearance of tPA from the circulation is rapid (t 1/2 approximately 6 min). We have developed a tPA variant, T103N,N117Q, KHRR(296-299)AAAA (TNK-tPA) that has substantially slower in vivo clearance (1.9 vs. 16.1 ml per min per kg for tPA in rabbits) and near-normal fibrin binding and plasma clot lysis activity (87% and 82% compared with wild-type tPA). TNK-tPA exhibits 80-fold higher resistance to plasminogen activator inhibitor 1 than tPA and 14-fold enhanced relative fibrin specificity. In vitro, TNK-tPA is 10-fold more effective at conserving fibrinogen in plasma compared to tPA. Arterial venous shunt models of fibrinolysis in rabbits indicate that TNK-tPA (by bolus) induces 50% lysis in one-third the time required by tPA (by infusion). TNK-tPA is 8- and 13-fold more potent in rabbits than tPA toward whole blood clots and platelet-enriched clots, respectively. TNK-tPA conserves fibrinogen and, because of its slower clearance and normal clot lysis activity, is effective as a thrombolytic agent when given as a bolus at a relatively low dose.
Initial experience with the use of N-butyl 2-cyanoacrylate glue for the fixation of polypropylene mesh in laparoscopic hernia repair. (1998)

The Minimal Access Therapy Training Unit at The Royal Surrey County Hospital Guildford (UK) reports on the initial success with the use of n-butyl 2-cyanoacrylate glue for fixing polypropylene mesh during laparoscopic hernia repair. We report our experience with seven such repairs and describe the prototype glue dispenser and mode of application used to fix the mesh. This is the first reported use of glue in laparoscopic hernia repair.
Leadership from within: rural community revitalisation and the school-community partnership. (2000)

Introduction Recent years have seen an increasing number of rural schools within Australia and overseas playing an active role in the development and sustainability of their communities. This study, which is being funded by the Rural Industries Research and Development Corporation, reports preliminary findings from a rural school in Western Australia dedicated to building an effective and sustainable partnership with its community. It examines the leadership processes involved in establishing and maintaining the partnership, and identifies outcomes for students, the school, and the community as a whole.
Purification and Characterization of a Complex Containing Matriptase and a Kunitz-type Serine Protease Inhibitor from Human Milk (1999)

Matriptase, a trypsin-like serine protease with two potential regulatory modules (low density lipoprotein receptor and complement C1r/s domains), was initially purified from T-47D breast cancer cells. Given its plasma membrane localization, extracellular matrix-degrading activity, and expression by breast cancer cells, this protease may be involved in multiple aspects of breast tumor progression, including cancer invasion. In breast cancer cells, matriptase was detected mainly as an uncomplexed form; however, low levels of matriptase were detected in complexes. In striking contrast, only the complexed matriptase was detected in human milk. The complexed matriptase has now been purified. Amino acid sequences obtained from the matriptase-associated proteins reveal that they are fragments of a Kunitz-type serine protease inhibitor that was previously reported to be an inhibitor of the hepatocyte growth factor activator. In addition, matriptase and its complexes were detected in milk-derived, SV40 T-antigen-immortalized mammary luminal epithelial cell lines, but not in human foreskin fibroblasts or in HT-1080 fibrosarcoma cells. These results suggest that the milk-derived matriptase complexes are likely to be produced by the epithelial components of the lactating mammary gland in vivo and that the activity and function of matriptase may be differentially regulated by its cognate inhibitor, comparing breast cancer with the lactating mammary gland.
Pharmacological Strategies to Increase the Antitumor Activity of Methylating Agents (2002)

Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.
Treatment of linear localized scleroderma with the anti-allergic drug, tranilast (1994)

A 14-year-old boy with linear localized scleroderma had a dramatic improvement in contractures after treatment with N-(3',4'-dimethoxycinnamoyl) anthranilic acid (tranilast, Rizaben). The observation that this anti-allergic drug was effective in localized scleroderma lends further support to the concept that mast cells play a role in increased collagen synthesis in this disease.
Nanostructured bulk thermoelectric materials and their properties (2005)

Advanced bulk thermoelectric materials have been developed by fabricating composites of uniformly distributed thermoelectric nanoparticles within a high surface area semiconductor matrix. In this composite structure, constituents of the thermoelectric materials' figure of merit can be decoupled and controlled independently, and consequently, one can achieve a high thermoelectric figure of merit. The produced composites exhibited extremely low thermal conductivity and relatively high electrical conductivity. However, the Seebeck coefficient was relatively low, probably due to poor quality of the thermoelectric particles. In an in-plane test geometry (van der Pauw configuration), the electrical resistivity of the composite sample decreased continuously as temperature increased, a typical semiconductor behavior. In the perpendicular-to-the-plane (cross-plane) test geometry, electrical resistance of the sample increased continuously with increasing temperature, probably a semi-metallic behavior. This anisotropy in the electrical resistance was reproducible. We also observed relatively strong high frequency AC-signals in the in-plane test geometry samples.
Alleviating the latency and bandwidth problems in WWW browsing (1997)

This work addresses three problems that are associated with Web browsing: (a) low bandwidth available to the end user who is connected via slow modems or outdoor wireless networks, (b) long and variable latencies in document access, and (c) temporary disconnections of mobile users. Three techniques are used with a variety of heuristics in order to overcome these problems: (a) pro ling user and group access patterns and using these pro les in order to pre-fetch documents, (b) ltering HTTP requests and responses in order to reduce data transmission over bottleneck links, and (c) hoarding documents based on user pro les in order to support limited web browsing even during disconnection. In this paper, we describe the design and implementation of a WWW proxy-based system that incorporates the above techniques. We describe our experiences with the proxy system, and present performance results that show an improvement in the experience of Web browsing using this system. 1
Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. (1994)

p185c-neu and epidermal growth factor receptor (EGFR) associate into an active heterodimer, and overexpression of these two receptors leads to a transformed phenotype. However, the association of EGFR and kinase-deficient Neu proteins (point mutant N757 or cytoplasmic domain deletion mutant N691stop) results in a defective or inactive heterodimeric complex. In this report we explore the biological consequences of heterodimerization between EGFR and wild-type (WT) or kinase-deficient mutant Neu proteins in living cells. We show that co-expression of EGFR and kinase-deficient Neu proteins abolished the synergistic transformation and tumorigenicity. Moreover, the normal responses of EGFR to ligand were significantly suppressed, e.g., loss of EGF-dependent transformation, reduced rate of receptor endocytosis and turnover, diminished DNA synthesis, and decreased EGF binding affinity. These results provide the first evidence that kinase-deficient Neu proteins suppress normal EGFR function and display a dominant negative mutant phenotype. Together with the stimulatory effects observed in cells forming active heterodimers, these studies provide a role for heterodimerization of EGFR and Neu/c-erbB2 in interreceptor activation and synergistic signaling which may be responsible for the transition from normal receptor function into oncogenesis.
Respiratory Sinus Arrhythmia and its Association with Pain in Women with Fibromyalgia Syndrome (2015)

The results of VHR indices during the supine position and the DBT women with FMS suggest impairment of neurocardiac integrity associated with pain and the impact of FMS on the quality of life.
3‐Heptylamino‐5‐Phenylpyridazine Derivatives as Analogues of Acyl‐CoA: Cholesterol Acyltransferase Inhibitors Containing the N‐Heptyl‐N′‐Arylureidic Moiety (2006)

A series of novel Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors 8a-f was synthesized; the substances were characterized by the presence of a 2,5-dimethylpyrazin-3-yl moiety at one end and a 3-heptylamino-5-phenylpyridazine system at the other one, linked through linear alkyl spacers of different length. The new derivatives were designed based on the hypothesis that the 3-amino-5-phenylpyridazine moiety could mimic the aryl substituted urea, which was present in a number of ACAT inhibitors previously described. The choice of the 2,5-dimethylpyrazin-3-yl substituent was supported by a preliminary investigation, which indicated that this moiety is the most powerful in conferring ACAT inhibitory properties to the new series. The pharmacological results proved the idea to be sound. Finally, compounds 9a-c, lacking the phenylpyridazine moiety were prepared and tested to further strengthen our hypothesis.
MARROW GRAFTS BY COMBINED MARROW AND LEUKOCYTE INFUSIONS IN UNRELATED DOGS SELECTED BY HISTOCOMPATIBILITY TYPING (1968)

Consistent and rapid bone marrow grafts were produced in lethally irradiated dogs by infusions of marrow cells and peripheral blood leukocytes obtained from single living donors. Canine histocompatibility typing by lymphocyte cytotoxic antisera was evaluated in selecting donor-recipient pairs of unrelated dogs for marrow grafting. Significantly longer survival was observed in recipients that received marrow grafts from matched donors (P > 0.01 < 0.02).