tbuckley/cabot-search huggingface dataset:
Laninamivir's prolonged intrapulmonary retention: Intrapulmonary pharmacokinetics (PK) and the intracellular disposition to support the long-lasting efficacy after an inhaled administration of its prodrug laninamivir octanoate (LO)
Authors: Hidetoshi Furuie, Kaoru Toyama, Kumiko Koyama, Daisuke Nakai, Hitoshi Ishizuka
Journal: European Respiratory Journal (2013)

Background:  A single inhaled dose of LO, a long-acting neuraminidase inhibitor, exhibits efficacy to patients with influenza virus infection. However, the relation between PK and its long-lasting efficacy has not fully been investigated.   Purpose:  Intrapulmonary PK in healthy volunteers and the intracellular drug disposition in mice were evaluated to support its long-lasting efficacy.   Methods:  Each subject underwent bronchoalveolar lavage (BAL) at specified time intervals from 4 to 240 hrs after an inhaled LO dosing (40mg). Plasma, BAL fluid and alveolar macrophage (AM) were analyzed to determine drug concentrations. Microautoradiographic localization in the respiratory tissues in mice and the drug uptake and release were evaluated using primary cultured airway epithelial cells.   Results:  In healthy volunteers, laninamivir concentration in epithelial lining fluid (ELF) and AM were higher than those in plasma and lasted for 240 hrs. Laninamivir in ELF decreased with a longer half-life (∼ 6 days) and notably exceeded the IC50 values for viral neuraminidase at all time points. In mice, the labeled LO mainly located on the epithelial cells for a long period. LO uptake in epithelial cells increased without saturation and the intracellular laninamivir was released very slowly, which was regarded as a rate-limiting step in the cellular retention.   Conclusion:  ELF concentration profiles and prolonged high intrapulmonary retention of laninamivir support its long lasting efficacy to treat patients with influenza virus infection by the single inhalation.
Efficient Identification of Novel Hla-A*0201–Presented Cytotoxic T Lymphocyte Epitopes in the Widely Expressed Tumor Antigen Prame by Proteasome-Mediated Digestion Analysis
Authors: Jan H. Kessler, Nico J. Beekman, Sandra A. Bres-Vloemans, Pauline Verdijk, Peter A. van Veelen, Antoinette M. Kloosterman-Joosten, Debby C.J. Vissers, George J.A. ten Bosch, Michel G.D. Kester, Alice Sijts, Jan Wouter Drijfhout, Ferry Ossendorp, Rienk Offringa, Cornelis J.M. Melief
Journal: The Journal of Experimental Medicine (2001)

We report the efficient identification of four human histocompatibility leukocyte antigen (HLA)-A(*)0201-presented cytotoxic T lymphocyte (CTL) epitopes in the tumor-associated antigen PRAME using an improved "reverse immunology" strategy. Next to motif-based HLA-A(*)0201 binding prediction and actual binding and stability assays, analysis of in vitro proteasome-mediated digestions of polypeptides encompassing candidate epitopes was incorporated in the epitope prediction procedure. Proteasome cleavage pattern analysis, in particular determination of correct COOH-terminal cleavage of the putative epitope, allows a far more accurate and selective prediction of CTL epitopes. Only 4 of 19 high affinity HLA-A(*)0201 binding peptides (21%) were found to be efficiently generated by the proteasome in vitro. This approach avoids laborious CTL response inductions against high affinity binding peptides that are not processed and limits the number of peptides to be assayed for binding. CTL clones induced against the four identified epitopes (VLDGLDVLL, PRA(100-108); SLYSFPEPEA, PRA(142-151); ALYVDSLFFL, PRA(300-309); and SLLQHLIGL, PRA(425-433)) lysed melanoma, renal cell carcinoma, lung carcinoma, and mammary carcinoma cell lines expressing PRAME and HLA-A(*)0201. This indicates that these epitopes are expressed on cancer cells of diverse histologic origin, making them attractive targets for immunotherapy of cancer.
The Fluctuating Phenotype of the Lymphohematopoietic Stem Cell with Cell Cycle Transit
Authors: Houri K. Habibian, Stefan O. Peters, C.C. Hsieh, Joanne Wuu, Kristin Vergilis, Christina I. Grimaldi, Judith Reilly, Jane E. Carlson, Angela E. Frimberger, F.M. Stewart, Peter J. Quesenberry
Journal: The Journal of Experimental Medicine (1998)

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G0 to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2–4-h intervals of culture over 24–48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2–4-h intervals, with engraftment nadirs occurring in late S and early G2. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.
CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status
Authors: Audrey L. Kinter, Margaret Hennessey, Alicia Bell, Sarah Kern, Yin Lin, Marybeth Daucher, Maria Planta, Mary McGlaughlin, Robert Jackson, Steven F. Ziegler, Anthony S. Fauci
Journal: The Journal of Experimental Medicine (2004)

Human immunodeficiency virus (HIV) disease is associated with loss of CD4(+) T cells, chronic immune activation, and progressive immune dysfunction. HIV-specific responses, particularly those of CD4(+) T cells, become impaired early after infection, before the loss of responses directed against other antigens; the basis for this diminution has not been elucidated fully. The potential role of CD25(+)CD4(+) regulatory T cells (T reg cells), previously shown to inhibit immune responses directed against numerous pathogens, as suppressors of HIV-specific T cell responses was investigated. In the majority of healthy HIV-infected individuals, CD25(+)CD4(+) T cells significantly suppressed cellular proliferation and cytokine production by CD4(+) and CD8(+) T cells in response to HIV antigens/peptides in vitro; these effects were cell contact dependent and IL-10 and TGF-beta independent. Individuals with strong HIV-specific CD25(+) T reg cell function in vitro had significantly lower levels of plasma viremia and higher CD4(+): CD8(+) T cell ratios than did those individuals in whom this activity could not be detected. These in vitro data suggest that CD25(+)CD4(+) T reg cells may contribute to the diminution of HIV-specific T cell immune responses in vivo in the early stages of HIV disease.
Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer
Authors: S. Fogli, R. Danesi, A. Gennari, S. Donati, P.F. Conte, M. Del Tacca
Journal: Annals of Oncology (2002)

BackgroundThe objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2′,2′-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer.Patients and methodsThe drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model.ResultsPaclitaxel administration significantly increased the epirubicinol area under the concentration–time curve, from 357 ± 146 (epirubicin) to 603 ± 107 (EP) and 640 ± 81 h × νg/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 µmol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP.ConclusionsPaclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine.
PTP1B Contributes to the Oncogenic Properties of Colon Cancer Cells through Src Activation
Authors: Shudong Zhu, Jeffrey D. Bjorge, Donald J. Fujita
Journal: Cancer Research (2007)

Abstract Src-specific activity has been reported to be elevated in a high percentage of colon cancer cell lines and tumors, but the underlying mechanisms are largely unknown. In this study, we report that, in the seven cancer cell lines tested, Src-specific activity was elevated (5.2- to 18.7-fold) relative to normal colon cells (FHC). This activation of Src correlated with reduced phosphorylation at Y530 of Src, whereas there was no significant change in the level of phosphorylation at Y419. The membrane tyrosine phosphatase activity for a Src family-specific phosphopeptide substrate FCP (Fyn COOH-terminal peptide phosphorylated by Csk) was greatly increased in the cancer cells and was attributed to PTP1B in most of the cell lines. Membrane PTP1B protein levels were also greatly increased. Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src. It also increased anchorage-independent cell growth and this increase was blocked by the Src inhibitor PP2 and Src small interfering RNA (siRNA). Down-regulating PTP1B activity by PTP1B inhibitor CinnGEL 2Me or knocking down PTP1B using siRNA also reduced Src kinase activity and colony formation ability of colon cancer cells. PTP1B siRNA reduced tumor growth in nonobese diabetic/severe combined immunodeficient mice. This study suggests that (a) PTP1B can act as an important activator of Src in colon cancer cells via dephosphorylation at Y530 of Src and (b) elevated levels of PTP1B can increase tumorigenicity of colon cancer cells by activating Src. [Cancer Res 2007;67(21):10129–37]
American Society of Clinical Oncology Statement on Minimum Standards and Exemplary Attributes of Clinical Trial Sites
Authors: Robin Zon, Neal J. Meropol, Robert B. Catalano, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2008)

To describe both minimum requirements for a site conducting quality clinical trials and attributes of an exemplary site.Minimum requirements and exemplary attributes were selected based on literature review, prevailing regulatory requirements, and consensus among a group of community and academic clinical researchers.To provide guidance to oncologists who wish to conduct patient-oriented research, recommendations are made to assist in the development and implementation of high-quality research programs with the priority of protecting the welfare and rights of trial participants. A quality research site complies with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the accepted international ethical and scientific quality standards for designing, conducting, recording, and reporting trials involving human participants. Recognizing that many research sites conduct clinical trials in compliance with accepted GCP standards, supplemental attributes of an exemplary research site that exceed the GCP criteria are also described. These attributes include diversification of clinical trial mix, high accrual activity, participation in the trial development process, maintenance of high educational standards, quality assurance, multidisciplinary involvement in the clinical trial process, and promotion of clinical trial awareness programs.Meeting the minimum criteria ensures conduct of quality clinical trials; however, some sites may wish to incorporate value-added attributes to exceed GCP compliance. These attributes are proposed as performance goals rather than requirements, recognizing that all sites conducting research will not necessarily meet each attribute but may still conduct high-quality clinical trials.
Pathology of Ovarian Cancers in <b> <i>BRCA1</i> </b> and <b> <i>BRCA2</i> </b> Carriers
Authors: Sunil R. Lakhani, Sanjiv Manek, Frederique Penault-Llorca, Adrienne Flanagan, Laurent Arnout, Samantha Merrett, Lesley McGuffog, Dawn Steele, Peter Devilee, Jan G. M. Klijn, Hanne Meijers-Heijboer, Paolo Radice, Silvana Pilotti, Heli Nevanlinna, Ralf Butzow, Hagay Sobol, Jocylyne Jacquemier, Dominique Stoppa Lyonet, Susan L. Neuhausen, Barbara Weber, Teresa Wagner, Robert Winqvist, Yves-Jean Bignon, Franco Monti, Fernando Schmitt, Gilbert Lenoir, Susanne Seitz, Ute Hamman, Paul Pharoah, Geoff Lane, Bruce Ponder, D. Timothy Bishop, Douglas F. Easton
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer. Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated. Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21–2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P &amp;lt; 0.0001), had a higher percentage solid component (P = 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers. Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively aggressive and may be expected to have poor prognosis, although this may be treatment dependent.
P131 Fitness to fly assessment in patients with neuromuscular disease
Authors: J. Humphreys, S. Agarwal, I. Cliff, S. Mathew, N. Mustfa
Journal: Thorax (2010)

<h3>Introduction</h3> Patients with neuromuscular disorders (NMD) can develop ventilatory impairment due to respiratory muscle weakness but despite disability, many travel by air. The British Thoracic Society (BTS) recommends hypoxic challenge test (HCT) in those who have baseline oxygen saturation (SpO2) at sea level between 92–95%.1 However, this recommendation is based on very limited evidence. <h3>Objectives</h3> To determine if baseline pulse oximetry at sea level provides a safe guide to predict hypoxia during flying and preclude a HCT in NMD patients. <h3>Methods</h3> HCT performed on 12 NMD patients (11 Motor Neuron Disease and 1 Duchene9s Muscular Dystrophy) attending ventilation clinic were retrospectively reviewed. HCT was performed to assess their fitness to fly irrespective of their baseline SpO<sub>2</sub>. A fall in PaO<sub>2</sub>&lt;6.6 kPa was considered positive, PaO<sub>2</sub> between 6.6 and 7.4 kPa was considered borderline and &gt;7.4 kPa was considered negative.1 Spirometry and sniff nasal inspiratory pressure (SNIP) were also recorded. <h3>Results</h3> There were nine male and three female patients, age range 27–72 years (median 63 years). Four patients were positive for HCT and two had borderline results. Only two patients among this group met the criteria for HCT as per BTS recommendation. Six patients were negative for HCT and only one met the criteria for HCT. There was no difference in median FEV<sub>1</sub> (1.85 vs 2.04 L/s) and median FVC (2.5 vs 2.41 l) between patient with positive or borderline HCT and patients with negative HCT. SNIP was lower in those who were positive or borderline than those who were negative (median 28.5 vs 43 cmH<sub>2</sub>O). <h3>Conclusions</h3> Patients with NMD and respiratory muscle weakness are prone to develop hypoxia irrespective of their baseline oxygen saturation, FEV<sub>1</sub> and FVC. SNIP may be better at predicting the risk of hypoxia during air travel.
Differential requirement of the epidermal growth factor receptor for G protein-mediated activation of transcription factors by lysophosphatidic acid
Authors: Regina A Oyesanya, Susie Greenbaum, David Dang, Zendra Lee, Abir Mukherjee, Jinhua Wu, Paul Dent, Xianjun Fang
Journal: Molecular Cancer (2010)

The role of the epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in provoking biological actions of G protein-coupled receptors (GPCRs) has been one of the most disputed subjects in the field of GPCR signal transduction. The purpose of the current study is to identify EGFR-mediated mechanisms involved in activation of G protein cascades and the downstream transcription factors by lysophosphatidic acid (LPA).In ovarian cancer cells highly responsive to LPA, activation of AP-1 by LPA was suppressed by inhibition of EGFR, an effect that could be reversed by co-stimulation of another receptor tyrosine kinase c-Met with hepatocyte growth factor, indicating that LPA-mediated activation of AP-1 requires activity of a RTK, not necessarily EGFR. Induction of AP-1 components by LPA lied downstream of Gi, G12/13, and Gq. Activation of the effectors of Gi, but not Gq or G12/13 was sensitive to inhibition of EGFR. In contrast, LPA stimulated another prominent transcription factor NF-kappaB via the Gq-PKC pathway in an EGFR-independent manner. Consistent with the importance of Gi-elicited signals in a plethora of biological processes, LPA-induced cytokine production, cell proliferation, migration and invasion require intact EGFR.An RTK activity is required for activation of the AP-1 transcription factor and other Gi-dependent cellular responses to LPA. In contrast, activation of G12/13, Gq and Gq-elicited NF-kappaB by LPA is independent of such an input. These results provide a novel insight into the role of RTK in GPCR signal transduction and biological functions.
Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region
Authors: Ching-Hon Pui, Paul S Gaynon, James M Boyett, Judith M Chessells, André Baruchel, Willem Kamps, Lewis B Silverman, Andrea Biondi, Dörthe O Harms, Etienne Vilmer, Martin Schrappe, Bruce Camitta
Journal: The Lancet (2002)
A new myeloproliferative syndrome
Authors: Jill R. Schofield, William A. Robinson
Journal: American Journal of Hematology (1995)

Abstract We report here two cases of a previously undescribed myeloprollferative disorder. Both were young adult males who presented with generalized lymphadenopathy, splenomegaly, leukocytosis, polycythemia, and persistent thrombocytopenia. The leukocyte alkaline phosphatase (LAP) score was low in both cases, and the bone marrow was hypercellular without dysplasia or fibrosis, but lacked the Philadelphia chromosome, BCR gene rearrangement, or other karyotypic abnormalities. The clinical course was indolent in each case. One patient died from an unusual ‘blast crisis’ after 12 years, while the second patient remains in a complete hematologic remission on hydroxyurea and alpha interferon 4 years from diagnosis. Interestingly, changes in therapy in this patient have consistently resulted in precise and concerted fluctuations in his blood counts, with the red and white cells cycling together and the platelets and mean corpuscular volume (MCV) changing concomitantly but in the opposite direction. This unique myeloproliferative disorder is distinguishable from all previously described forms of chronic myeloid leukemia and other myeloproliferative syndromes. ©1995 Wiley‐Liss, Inc.
Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo
Authors: Daniel Hawiger, Kayo Inaba, Yair Dorsett, Ming Guo, Karsten Mahnke, Miguel Rivera, Jeffrey V. Ravetch, Ralph M. Steinman, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2001)

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon gamma and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.