gebhart/patrepeval huggingface dataset:
Low level of response to alcohol as a predictor of future alcoholism (1994)

In a heavy-drinking society, a lower sensitivity to modest doses of alcohol is associated with a significant increase in the risk of future alcoholism, perhaps through increasing the chances that a person will drink more heavily and more often.
Education of rural development for agriculture and animal agriculture in Asia and Pacific (2003)

2003年8月28日とかちプラザで開催､日本ユネスコ国内委員会主催の帯広農村開発教育国際セミナー(OASERD)国際連合ユネスコアジア太平洋地域教育開発計画事業(APEID)シンポジウム「地球にやさしい農業をめざして : 緑地回復と持続的農業」講演資料
Pre-clinical translational studies of daratumumab in patients with myeloma or AL amyloidosis undergoing autologous hematopoietic stem cell transplantation (SCT). (2015)

8587 Background: Daratumumab (DARA) is a human IgG1 that binds to CD38 and kills tumor cells expressing CD38 through immune-mediated cytotoxicity. CD38 is expressed on plasma cells in multiple myeloma (MM), AL amyloidosis (AL) and on myeloid progenitor cells. Since SCT remains a standard therapy for MM and AL the effect of DARA on progenitor cells was evaluated. Ability of DARA to induce complement dependent cytotoxicity (CDC) of progenitor cells was assessed in progenitor cell assay (PCA). DARA-mediated antibody-dependent cytotoxicity (ADCC) of progenitor cells, its correlation with FcγRIIIA polymorphism and stem cell potential were examined using NK-cells from post-SCT patients (n = 10, n = 6 MM and n = 4 AL) as effectors against a MM target cell line. Methods: ADCC was performed with post-SCT NK cells and MM.1S cells in the presence of 100 ng/ml DARA or isotype control (ICA). DARA-mediated CDC was evaluated in PCA: unselected or CD34-selected mobilized cells were incubated in complement-rich serum with no antibodies, or DARA or anti-CD59 (BRIC 229) or both. The effects of these antibodies on CFU-GM and BFU-E were evaluated two weeks later. The results were analyzed by two-tailed paired t tests with P < 0.05 as significance level. Results: MedianADCC of MM.1S target cells by primary post-SCT NK cells was 39% and 7% using DARA or ICA, respectively (P < 0.05). Of the 10 NK donors, 6 were V/F or V/V and lysed 60% of targets, while 4 F/F lysed 17% (P< 0.05). In the PCA, there was no decrease in CFU-GM or BFU-E: with unselected mobilized cells, with CD34-selected cells with DARA, or with CD34-selected cells incubated with DARA (500 or 1000 ng/ml) +/- BRIC 229 indicating that DARA did not induce CDC on the CD34-selected progenitor cells. Conclusions: DARA is active in ADCC assays with post-SCT NK cells from patients with MM or AL and its activity correlates with FCGR3A-158V/F polymorphism. DARA did not inhibit progenitor cell growth by CDC in unselected or CD34-selected cells suggesting that administration of DARA may not cause undue harm to the progenitor cells after SCT. These findings support consideration of clinical trials of DARA consolidation post-SCT in MM and AL. CPC: MMRF fellow.
Working with Couples in the Current Environment (1999)

ABSTRACT Couples and families as units of treatment emerged as a major shift from the medical model prevalent up until about forty years ago. No longer was an individual spouse or child singled out and labelled as patient; rather, family interaction became the focus for the early pioneers of family therapy. Now managed care influences decisions formerly made by marriage and family practitioners: whom we treat, diagnoses, length of treatment, methodology, even the education necessary for iicensure. We need to keep the human element and practical knowledge in our profession and realize the limits of trying to be more “scientific.”
Isolation and characterization of an anthracycline-resistant human leukemic cell line. (1985)

An anthracycline-resistant subline of HL-60 promyelocytic leukemia cells (HL-60/AR) has been isolated in vitro by subculturing in progressively higher concentrations of Adriamycin. The resistant cells are capable of sustaining continuous growth in 10(-6) M Adriamycin which is more than 50 times the 50% inhibitory dose for the parent line. HL-60/AR expressed variable degrees of cross-resistance to daunorubicin, dihydroxyanthracenedione, vincristine, vinblastine, and actinomycin D, but it remained sensitive to methotrexate and 1-beta-D-arabinofuranosylcytosine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of glycoproteins of HL-60/AR revealed two prominent glycoproteins with molecular weights of 160,000 +/- 10,000 and 110,000 +/- 10,000 which were not detected in the sensitive cells. Cellular uptake and retention of daunorubicin was studied in the resistant and sensitive cells utilizing digitized video fluorescence microscopy. The sensitive cells accumulated more drug and showed at least 2-fold greater levels of brightness than the resistant cells. Studies of total intracellular accumulation, utilizing 10(-6) M [14C]-daunorubicin as a marker, showed a 1-h accumulation of 98 +/- 20 pmol/10(6) cells in HL-60/AR versus 255 +/- 25 pmol/10(6) cells in HL-60. Exposure to nontoxic concentrations of the calcium channel blocker Verapamil (10(-5) M) led to enhanced accumulation (175 +/- 8 pmol/10(6) cells) and retention of the drug in HL-60/AR, resulting in increased cytotoxicity in HL-60/AR. These anthracycline-resistant leukemic cells may serve as a valuable experimental model in studying the phenomenon of multiple drug resistance as well as strategies to circumvent it in human myeloid leukemia.
The Combination of IFN- α 2 and IFN- α 8 Exhibits Synergistic Antiproliferative Activity on Renal Cell Carcinoma (RCC) Cell Lines Through Increased Binding Affinity for IFNAR-2 (2007)

Although there are at least 13 interferon-alpha (IFN-alpha) subtypes in humans, interactions between the subtypes remain unknown. To understand IFN-alpha interactions, we examined the antiproliferative activities and the receptor binding affinities of different combinations of IFN-alpha2 and IFN-alpha8 using six renal cell carcinoma (RCC) cell lines. Although IFN-alpha8 was the more potent subtype, synergistic and antagonistic antiproliferative effects were also observed in certain combinations of IFN-alpha2 and IFN-alpha8. To analyze the interactions between IFN-alpha2 and IFN-alpha8, the receptor-binding kinetics of different combinations of IFN-alpha2 and IFN- alpha8 to the IFN-alpha receptors, IFNAR-1 or IFNAR-2, were measured using a surface plasmon resonance-based biosensor. Unexpectedly, the receptor binding kinetics to IFNAR-2 but not to IFNAR-1 were mutually related to antiproliferative activity and increase in the binding speed (K(a)) for IFNAR-2. Moreover, we observed the increased fluorescence intensity (FI) of biotin-labeled IFN-alpha8 to IFNAR-2 by receptor binding inhibition assay with unlabeled IFN-alpha2 but not the other combinations. These findings indicate that the binding manner of IFN-alpha8 for IFNAR-2 is different from that of IFN-alpha2, suggesting that binding of IFN-alpha8 rather than binding of IFN-alpha2 to IFNAR-2 leads to activation and subsequent antiproliferative activity despite the same antiviral activity in RCC.
Long Double-Stranded RNA Induces an Antiviral Response Independent of IFN Regulatory Factor 3, IFN-β Promoter Stimulator 1, and IFN (2009)

Virus infection elicits a robust innate antiviral response dominated by the production of type 1 IFN. In nonprofessional innate immune cells such as fibroblasts, type 1 IFN is rapidly produced following the recognition of viral dsRNA and the subsequent activation of the constitutively expressed transcription factor IFN regulatory factor 3 (IRF3). Although origin, localization, and length are factors in mediating dsRNA recognition and binding by cellular dsRNA-binding proteins, the biological significance of differential dsRNA binding is unclear, since the subsequent signaling pathways converge on IRF3. In this study, we show a dsRNA length-dependent activation of IRFs, IFNs, and IFN-stimulated genes in mouse fibroblasts. The length dependence was exacerbated in fibroblasts deficient in the mitochondria-associated adaptor IFN-beta promoter stimulator 1 and IRF3, suggesting that antiviral gene induction mediated by short and long dsRNA molecules is predominantly IFN-beta promoter stimulator 1 and IRF3 dependent and independent, respectively. Furthermore, we provide evidence of an innate antiviral response in fibroblasts in the absence of both IRF3 and type 1 IFN induction. Even with these key modulators missing, a 60-90% inhibition of virus replication was observed following 24-h treatment with short or long dsRNA molecules, respectively. These data provide evidence of a novel antiviral pathway that is dependent on dsRNA length, but independent of the type 1 IFN system.
Development of group 4 and 5 complexes with N,O chelating supporting ligands as catalysts for the alpha-alkylation of amines (2013)

The use of stoichiometric, catalytic and theoretical methods in the development of an early transition metal catalyst for the α-alkylation of amines is described herein. The investigation is primarily focused on a series of mono(amidate) complexes of tantalum with varying steric and electronic properties. The amidate binding mode and catalytic activity of these complexes is significantly influenced by sterics. Corresponding bis(amidate) complexes are less active as catalysts for the α-alkylation of amines but offers a platform to study the hemi-lability of amidate ligands as well as tantalaziridine formation in these systems. A model 5-membered metallacycle is synthesized and characterized. Isotopic labeling studies with the most active mono(amidate) precatalyst reveal off-cycle reactions and suggest that tantalaziridine formation is rapid and reversible. Preliminary kinetic investigations implicate alkene insertion as the turnover limiting step, consistent with stoichiometric investigations. In addition, the use of radical probes in ligand backbones and an alkene substrate contradicts a one electron mechanism. Quantum chemical calculations are used to develop a theoretical model of the proposed catalytic cycle. The hemi-lability of amidate ligands is highlighted with the optimization of both κ¹(O) and κ²(N,O) minima and transition states. Here, protonolysis is calculated to be the turnover limiting step with small changes in geometry having a significant effect on the potential energy surface. The unlikelihood of a radical mechanism is supported by the computations of triplet species. A survey of established steric parameters has been completed for asymmetric amidate ligands to be used as a predictive tool for catalyst design. The calculated values can be related to the catalytic activity of mono(amidate) and axially chiral tantalum precatalysts. Diamide and diurea proligands featuring a neutral chalcogen atom tether are installed on zirconium and tantalum. The zirconium species form well-defined κ⁴(N,N,O,O) complexes with fluxional behaviour observed for the tantalum species in solution. No evidence of bonding is observed between the chalcogen donor and any metal centre. Fundamental differences in the redox potentials for ligands and complexes are investigated using cyclic voltammetry. The tantalum complexes are found to catalyze the α-alkylation of amines with the zirconium species being competent precatalysts for hydroamination.
Characterization of DNA Probes Immobilized on Gold Surfaces (1997)

We have characterized thiol-derivatized, single-stranded DNA (5‘-HS-(CH2)6-CAC GAC GTT GTA AAA CGA CGG CCA G-3‘, abbreviated HS-ssDNA) attached to gold via a sulfur−gold linkage using X-ray photoelectron spectroscopy (XPS), ellipsometry, and 32P-radiolabeling experiments. We found that hybridization of surface-bound HS-ssDNA is dependent on surface coverage. The buffer concentration of the HS-ssDNA solution was found to have a profound effect on surface coverage, with adsorption greatly reduced at low salt concentration. More precise control over surface coverage was achieved by creating mixed monolayers of the thiol-derivatized probe and a spacer thiol, mercaptohexanol (MCH), by way of a two-step method, where first the gold substrate is exposed to a micromolar solution of HS-ssDNA, followed by exposure to a millimolar solution of MCH. A primary advantage of using this two-step process to form HS-ssDNA/MCH mixed monolayers is that nonspecifically adsorbed DNA is largely removed from the surface. Thus, the majority of surface-bound probes are accessible for specific hybridization with complementary oligonucleotides and are able to discriminate between complementary and noncomplementary target molecules. Moreover, the probe-modified surfaces were found to be stable, and hybridization reactions were found to be completely reversible and specific in a series of experiments where duplex melting was examined.
Inhibition of tumor‐induced angiogenesis by the administration of recombinant interferon‐γ followed by a synthetic lipid‐a subunit analogue (GLA‐60) (1992)

The effect of the administration of recombinant interferon-gamma (rIFN-gamma) and a synthetic lipid A subunit analog (GLA-60) on angiogenesis induced by B16-BL6 melanoma was examined in syngeneic C57BL/6 mice. Intravenous administration of rIFN-gamma followed by GLA-60 (referred to as rIFN-gamma/GLA-60) induced endogenous production of tumor necrosis factor (TNF). This treatment on day 3 after tumor inoculation caused a marked decrease in the number of vessels oriented towards the tumor mass (angiogenic response) and tumor size over a period of 9 days. In contrast, neither rIFN-gamma nor GLA-60 alone, nor GLA-60/rIFN-gamma (reverse sequence of administration), which is unable to induce the production of TNF in the serum, had any effect. Sera induced by the treatment with rIFN-gamma/GLA-60, and recombinant TNF, inhibited the in vitro growth of lung endothelial cells which is considered to be one of the essential events in tumor neovascularization. Multiple i.v. treatments with rIFN-gamma/GLA-60 on days 5, 8 and 11 after s.c. implantation of tumor significantly inhibited primary tumor growth by the amputation time (day 20) and lung metastasis of B16-BL6 cells on day 34, while other treatment modalities had no such effect. Our results indicate that inhibition of lung-tumor metastasis by rIFN-gamma/GLA-60 treatment may be partly due to the inhibition of tumor-associated angiogenesis.
Roots. Use of the HPRT gene and the HAT selection technique in DNA‐mediated transformation of mammalian cells: First steps toward developing hybridoma techniques and gene therapy (1992)

In 1956, I decided to apply my experience in microbial genetics to developing analogous systems for human cell lines, including the selection of mutants with either a loss or gain of a biochemical function. For instance, mutants resistant to azahypoxanthine showed a loss of the HPRT enzyme (hypoxanthine phosphoribosyl transferase), whereas gain of the same enzyme was accomplished by blocking de novo purine biosynthesis with aminopterin, while supplying hypoxanthine and thymine (HAT selection). Using HAT selection, we: (i) genetically transformed HPRT- mutant cells to HPRT+ wild type by using DNA extracted from HPRT+ cells, and (ii) selected HPRT+ hybrid cells by fusing HPRT- D98/AH2 cells with skin cells. These approaches, which we dubbed in 1962 as a 'first step toward gene therapy', contributed to the later development of (i) cell fusion techniques, (ii) the development of monoclonal antibodies, (iii) routine transformation of mammalian cells with cloned genes, and (iv) methods for creating transgenic organisms.
Immunoprevention of HER-2/ neu Transgenic Mammary Carcinoma through an Interleukin 12-Engineered Allogeneic Cell Vaccine (2004)

This study evaluated the ability of cytokine-engineered allogeneic (H-2(q)) HER-2/neu-positive cells to prevent tumor development in mammary cancer-prone virgin female BALB/c (H-2(d)) mice transgenic for the transforming rat HER-2/neu oncogene (BALB-neuT mice). Repeated vaccinations with cells engineered to release interleukin (IL)-2, IL-12, IL-15, or IFN-gamma showed that IL-12-engineered cell vaccines had the most powerful immunopreventive activity, with >80% of 1-year-old BALB-neuT mice free of tumors. On the contrary all of the untreated mice and all of the mice vaccinated with IL-12-engineered cells lacking either HER-2/neu or allogeneic antigens developed mammary carcinomas within 22 or 33 weeks, respectively. Whole mount, histology, immunohistochemistry, and gene expression profile analysis showed that vaccination with IL-12-engineered cells maintained 26-week mammary glands free of neoplastic growth, with a gene expression profile that clustered with that of untreated preneoplastic glands. The IL-12-engineered cell vaccine elicited a high production of IFN-gamma and IL-4 and a strong anti-HER-2/neu antibody response. Immune protection was lost or markedly impaired in BALB-neuT mice lacking IFN-gamma or antibody production, respectively. The protection afforded by the IL-12-engineered cell vaccine was equal to that provided by the systemic administration of recombinant IL-12 in combination with HER-2/neu H-2(q) cell vaccine. However, IL-12-engineered cell vaccine induced much lower circulating IL-12 and IFN-gamma, and therefore lower potential side effects and systemic toxicity.
Distance-adaptive spectrum resource allocation in spectrum-sliced elastic optical path network [Topics in Optical Communications (2010)

The rigid nature of current wavelength-routed optical networks brings limitations on network utilization efficiency. One limitation originates from mismatch of granularities between the client layer and the wavelength layer. The recently proposed spectrum-sliced elastic optical path network (SLICE) is expected to mitigate this problem by adaptively allocating spectral resources according to client traffic demands. This article discusses another limitation of the current optical networks associated with worst case design in terms of transmission performance. In order to address this problem, we present a concept of a novel adaptation scheme in SLICE called distance-adaptive spectrum resource allocation. In the presented scheme the minimum necessary spectral resource is adaptively allocated according to the end-to-end physical condition of an optical path. Modulation format and optical filter width are used as parameters to determine the necessary spectral resources to be allocated for an optical path. Evaluation of network utilization efficiency shows that distance-adaptive SLICE can save more than 45 percent of required spectrum resources for a 12-node ring network. Finally, we introduce the concept of a frequency slot to extend the current frequency grid standard, and discuss possible spectral resource designation schemes.
Quality of Transmission Awareness in Converged Electronic and Optical Networks with OpenFlow (2013)

OpenFlow, as a unified operator-friendly manageable network control approach, has benefits of supporting the convergence of electronic packet and optical circuit networks as well as quality-of-transmission (QoT) awareness. We experimentally present the QoT-awareness in converged OpenFlow networks with (i) QoT-aware wavelength reassignment (ii) QoT-aware path re-routing if the QoT is below the requirement. The experimental work validates efficient networking approach and provides a key direction for next generation software defined networks.
Regulation of Epithelial Sodium Channels by the Cystic Fibrosis Transmembrane Conductance Regulator (1996)

Cystic fibrosis airway epithelia exhibit enhanced Na+ reabsorption in parallel with diminished Cl- secretion. We tested the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) directly affects epithelial Na+ channel activity by co-incorporating into planar lipid bilayers immunopurified bovine tracheal CFTR and either heterologously expressed rat epithelial Na+ channel ( alpha,b eta,gamma-rENaC) or an immunopurified bovine renal Na+ channel protein complex. The single channel open probability (Po) of rENaC was decreased by 24% in the presence of CFTR. Protein kinase A (PKA) plus ATP activated CFTR, but did not have any effect on rENaC. CFTR also decreased the extent of elevation of the renal Na+ channel Po following PKA-mediated phosphorylation. Moreover, the presence of CFTR prohibited the inward rectification of the gating of this renal Na+ channel normally induced by PKA-mediated phosphorylation, thus down-regulating inward Na+ current. This interaction between CFTR and Na+ channels occurs independently of whether or not wild-type CFTR is conducting anions. However, the nonconductive CFTR mutant, G551D CFTR, cannot substitute for the wild-type molecule. Our results indicate that CFTR can directly down-regulate single Na+ channel activity, thus accounting, at least in part, for the observed differences in Na+ transport between normal and cystic fibrosis-affected airway epithelia.
Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation (2019)

Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.