tbuckley/cabot-search huggingface dataset:
The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.
Authors: B Rehermann, P Fowler, J Sidney, J Person, A Redeker, M Brown, B Moss, A Sette, F V Chisari
Journal: The Journal of Experimental Medicine (1995)

Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.
Daily practice assessment of liver injury in patients with psoriasis on methotrexate
Authors: R.J.B. Driessen, P.C.M. Van De Kerkhof, E.M.G.J. De Jong
Journal: British Journal of Dermatology (2009)

Journal Article Daily practice assessment of liver injury in patients with psoriasis on methotrexate Get access R.J.B. Driessen, R.J.B. Driessen Department of Dermatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6525 GL Nijmegen, the Netherlands E‐mail: R.Driessen@derma.umcn.nl Search for other works by this author on: Oxford Academic Google Scholar P.C.M. Van De Kerkhof, P.C.M. Van De Kerkhof Department of Dermatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6525 GL Nijmegen, the Netherlands E‐mail: R.Driessen@derma.umcn.nl Search for other works by this author on: Oxford Academic Google Scholar E.M.G.J. De Jong E.M.G.J. De Jong Department of Dermatology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6525 GL Nijmegen, the Netherlands E‐mail: R.Driessen@derma.umcn.nl Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 162, Issue 1, 1 January 2010, Pages 211–213, https://doi.org/10.1111/j.1365-2133.2009.09498.x Published: 01 January 2010
The routine six week postnatal vaginal examination.
Authors: T Noble
Journal: BMJ (1993)

80% of the women appreciated having someone to listen to their problems; there was little change in the physical outcome of the pregnancy.21In addition, I suspect that midwives and doctors are haunted by the fear that they might miss something (or at least be accused of missing something) if they don't conform to the expected ritual.Current moves to demedicalise and decentralise childbirth, potentially providing more continuity of care, are neces- sitating radical changes in the organisation of maternity care.22They should be seen as an opportunity to discard outdated rituals, rather than simply to transfer them from doctors to midwives.The time saved could be channelled into prospective trials of more promising interventions, such as programmes of smoking cessation, and increasing the time available for training in counselling about the many new screening tests becoming available in early pregnancy.
14 Cross-genotype-reactivity of the immunodominant HCV-CD8 T-cell epitope NS3-1073: Significance for the development of peptide-based vaccines against HCV
Authors: P. Fytili, G. Dalekos, M. Cornberg, V. Schlaphoff, W. Zauner, K. Zachou, M.P. Manns, C. Klade, H. Wedemeyer
Journal: Journal of Hepatology (2006)
Nutritional Mechanisms and Temporal Control of Migratory Energy Accumulation in Birds
Authors: F Bairlein, E Gwinner
Journal: Annual Review of Nutrition (1994)

INTRODUCTION   187ENERGY RESERVES   189~ONAL MECHANISMS TO ACHIEVE MIGRATORY FUELING ......... 191Food Intake and Assimilation   192Seasonal Shifts in Food Selection   192TEMPORAL CONTROL OF MIGRATION AND MIGRATORY FATrENING ..... 199The Circannaal Component   199Synchronization by Photoperiod   200Species. and Population.Specific Programs   201Body Reserves and Migratory Activity   205CONCLUSIONS   206
Products of Cells Cultured From Gliomas. V. Cytology and Morphometry of Two Cell Types Cultured From Glioma2
Authors: Paul E. McKeever, Terry W. Hood, James Varani, James A. Taren, William H. Beierwaltes, Richard Wahl, Monica Liebert, Phu K. Nguyen
Journal: JNCI Journal of the National Cancer Institute (1987)

Explants of cells of a human glioma were evaluated with the nuclear fluorochrome 4',6-diamidino-2-phenylindole, by phase-contrast illumination, and by Giemsa staining correlated with double immunofluorescence for glial fibrillary acidic protein (GFAP) and fibronectin (FN). FN-positive (FN+) cells lacked GFAP detectable by immunofluorescence. Their mean nuclear-to-cytoplasmic ratio was large (0.192). Actual mean areas of nuclei (1,252 microns2) and cytoplasm (8,376 microns2) of FN+ cells compared with mean areas of fibroblasts suggested that the high nuclear-to-cytoplasmic ratio of FN+ cells was due to their microscopically evident reduced cytoplasmic spreading rather than to larger nuclei. Some FN+ cells showed marked variation in nuclear and nucleolar size and shape. Others had abnormal mitoses or hyperchromatic nuclei. GFAP-positive (GFAP+) cells lacked FN detectable by immunofluorescence. GFAP+ cells were smaller and less round than FN+ cells. Their usual location was growing on a layer of FN+ cells. The mean nuclear-to-cytoplasmic ratio (0.245) of GFAP+ cells was the highest in the study, surpassing the ratio of the continuous glioma line LM (0.176). Mean areas of nuclei (289 microns2) and of cytoplasm (1,350 microns2) of GFAP+ cells suggested that their high nuclear-to-cytoplasmic ratio was due to their microscopically evident reduced cytoplasmic spreading. Reduced spreading was associated with extension of long, thin cytoplasmic processes. The majority of GFAP+ cells showed marked cytoplasmic basophilia, nuclear hyperchromasia, and clumped chromatin. Features observed in both FN+ and GFAP+ cells from this high-grade astrocytoma are features associated with malignant transformation in more thoroughly studied tumor systems.
Efficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX
Authors: Baoli Hu, Daniele M. Gilkes, Jiandong Chen
Journal: Cancer Research (2007)

Abstract The p53 tumor suppressor plays a key role in protection against malignant transformation. MDM2 and MDMX are important regulators of the transcriptional activity and stability of p53 by binding to its NH2 terminus. Recent studies suggest that inhibition of both MDM2 and MDMX is necessary for robust activation of p53 in certain tumor cells. However, small-molecule MDM2 inhibitors such as Nutlin fail to inhibit MDMX despite significant homology between the two proteins. The therapeutic efficacy of such compounds may be compromised by MDMX overexpression. To evaluate the feasibility and biological effects of simultaneously disrupting p53 binding to MDM2 and MDMX, we used phage display to identify a novel peptide that can inhibit p53 interactions with MDM2 (IC50 = 10 nmol/L) and MDMX (IC50 = 100 nmol/L). Expression of a scaffold protein (thioredoxin) displaying this peptide sequence by adenovirus disrupts both MDM2 and MDMX interaction with p53, resulting in efficient p53 activation, cell cycle arrest, and apoptosis of tumor cells overexpressing MDM2 and MDMX. Intratumoral injection of the adenovirus also induces growth suppression of tumor xenografts in mice in a p53-dependent fashion. These results show the therapeutic potential of targeting both MDM2 and MDMX in cancer, and provide a novel structural motif for the design of potent p53 activators. [Cancer Res 2007;67(18):8810–7]
The Infant Nasopharyngeal Microbiome Impacts Severity of Lower Respiratory Infection and Risk of Asthma Development
Authors: Shu Mei Teo, Danny Mok, Kym Pham, Merci Kusel, Michael Serralha, Niamh Troy, Barbara J. Holt, Belinda J. Hales, Michael L. Walker, Elysia Hollams, Yury A. Bochkov, Kristine Grindle, Sebastian L. Johnston, James E. Gern, Peter D. Sly, Patrick G. Holt, Kathryn E. Holt, Michael Inouye
Journal: Cell Host & Microbe (2015)
Precocious and enhanced functional maturation of B lineage cells in New Zealand Black mice during embryonic development.
Authors: H Jyonouchi, P W Kincade
Journal: The Journal of Experimental Medicine (1984)

Previous reports suggest that large numbers of immunoglobulin-secreting cells appear in tissues of NZB strain mice from the time of birth. In this study, we investigated the development of B lineage cells during embryonic life and found that they were present 2-3 d earlier and in higher numbers in NZB embryos than several other strains of mice. That is, liver cell suspensions from NZB embryos contained larger numbers of surface Ig (sIg)- cells that could form B cell colonies in mitogen-dependent semisolid agar culture. Sephadex G-10-adherent cell depletion diminished numbers of colonies and this was partially restored by addition of humoral factors. The latter were partially purified from serum of very young NZB mice. These findings document that abnormal changes take place in B lineage cells and possibly also in cells that regulate their maturation in NZB strain mice at a very early stage of development.
Ideal Cardiovascular Health and Mortality From All Causes and Diseases of the Circulatory System Among Adults in the United States
Authors: Earl S. Ford, Kurt J. Greenlund, Yuling Hong
Journal: Circulation (2012)

Background— Recently, the American Heart Association developed a set of 7 ideal health metrics that will be used to measure progress toward their 2020 goals for cardiovascular health. The objective of the present study was to examine how well these metrics predicted mortality from all causes and diseases of the circulatory system in a national sample of adults in the United States. Methods and Results— We used data from 7622 adults ≥20 years of age who participated in the National Health and Nutrition Examination Survey from 1999 to 2002 and whose mortality through 2006 was determined via linkage to the National Death Index. For the dietary and glycemic metrics, we used alternative measures. During a median follow-up of 5.8 years, 532 deaths (186 deaths resulting from diseases of the circulatory system) occurred. About 1.5% of participants met none of the 7 ideal cardiovascular health metrics, and 1.1% of participants met all 7 metrics. The number of ideal metrics was significantly and inversely related to mortality from all causes and diseases of the circulatory system. Compared with participants who met none of the ideal metrics, those meeting ≥5 metrics had a reduction of 78% (adjusted hazard ratio, 0.22; 95% confidence interval, 0.10–0.50) in the risk for all-cause mortality and 88% (adjusted hazard ratio, 0.12; 95% confidence interval, 0.03–0.57) in the risk for mortality from diseases of the circulatory system. Conclusion— The number of ideal cardiovascular health metrics is a strong predictor of mortality from all causes and diseases of the circulatory system.
Complicated Puzzle in Cetuximab-Based Chemotherapy: Skin Toxicity and Resection Rate in Patients With Initially Unresectable Colorectal Liver Metastases
Authors: Yu Sunakawa, Takehiro Takahashi, Wataru Ichikawa, Ken Shimada, Yasutsuna Sasaki
Journal: Journal of Clinical Oncology (2013)

We read the excellent article written by Ye et al 1 in Journal of Clinical Oncology.It was reported that the addition of cetuximab to fluorouracil, leucovorin, and irinotecan or modified fluorouracil, leucovorin, and oxaliplatin was associated with facilitated radical resections of liver metastases, providing improved longterm survival in patients with initially unresectable colorectal liver metastases (wild-type KRAS).The authors are to be congratulated on successfully indicating that cetuximab combined with chemotherapy improved the resectability of liver metastases and prolonged survival compared with chemotherapy alone.However, we question whether the cetuximab-induced skin toxicity was associated with R0 resection rates for liver metastases.In Table 3 of their article, 1 based on subgroup analysis, patients with grade 2 to 3 acne-like rash experienced no significant benefit compared with those with grade 0 to 1 acne-like rash in terms of progression-free survival (PFS) and overall survival (OS), although the authors mentioned that patients with grade 2 to 3 skin reactions experienced greater benefit than those with grade 0 to 1 skin reactions in terms of response rate and OS, without statistical significance.In particular, the median PFS of 9.6 months in patients with grade 2 to 3 acne-like rash seems to be worse compared with the PFS of 11.1 months in patients with grade 0 to 1 acne-like rash.In this study's subgroup analysis, the resection rate for liver metastases, which is the primary end point, has yet to be indicated according to skin toxicity.We have reported that there was no trend toward a correlation between response rate of systemic chemotherapy and resection rate for liver metastases in patients with initially unresectable colorectal liver metastases. 2 The resection rate seemed to have reached a plateau at an objective response rate of approximately 60% in the era of combination chemotherapy with monoclonal antibody.The association of treatment efficacy with cetuximab-induced skin toxicity has been previously described in several reports. 3-6In recent pooled analysis, the occurrence of skin rash was significantly associated with reduced risk of death in patients treated with cetuximab or panitumumab. 7Subgroup analysis with small sample size and short follow-up may be reasons why this study was not able to demonstrate that patients with high-grade skin toxicity have better PFS and OS than patients with low-grade skin toxicity.However, the question remains of whether cetuximab-induced skin toxicity is correlated with resection rates for liver metastases in patients with KRAS wild-type synchronous unresectable liver-limited metastases from colorectal cancer.We would be grateful to Ye et al 1 for conducting such a challenging study, and we suggest that the authors indicate the primary end point according to cetuximab-induced skin toxicity.
Correlation Between Docetaxel Clearance and Estimated Cytochrome P450 Activity by Urinary Metabolite of Exogenous Cortisol
Authors: Noboru Yamamoto, Tomohide Tamura, Yoshikazu Kamiya, Ikuo Sekine, Hideo Kunitoh, Nagahiro Saijo
Journal: Journal of Clinical Oncology (2000)

PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6β-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method. PATIENTS AND METHODS: Thirty patients with advanced non–small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6β-OHF and FC were measured. More than 2 days later, 60 mg/m 2 of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed. RESULTS: After cortisol administration, the total amount of 24-hour urinary 6β-OHF (T6β-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 ± 4,076 μg/d (mean ± SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 ± 6.4 L/h/m 2 and 2.66 ± 0.91 mg/L 8729· h, respectively. An excellent correlation between docetaxel CL and T6β-OHF was observed (r = .867). In multivariate analysis, T6β-OHF (P &lt; .001), alpha-1-acid glycoprotein (P &lt; .004), AST (P = .007), and age (P = .022) significantly correlated with docetaxel CL. CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6β-OHF after cortisol administration.
Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis
Authors: L. Plantier, B. Crestani, S. E. Wert, M. Dehoux, B. Zweytick, A. Guenther, J. A. Whitsett
Journal: Thorax (2011)

<h3>Background</h3> Bronchiolisation of distal airspaces is an unexplained feature of idiopathic pulmonary fibrosis (IPF). The authors sought to identify mechanisms driving the differentiation of mucus cells during the bronchiolisation process. <h3>Methods</h3> Pathways governing airway mucus cell differentiation include SRY (sex determining region Y)-box 2 (SOX2), Notch, forkhead box A3(FOXA3)/SAM pointed domain containing ETS transcription factor (SPDEF), epidermal growth factor (EGF) and the EGF-related neuregulins NRG1α and NRG1β. Immunostaining for components of those pathways and mucins were performed on lung tissue obtained from patients with IPF (n=20), chronic obstructive pulmonary disease (n=13), idiopathic pulmonary artery hypertension (n=5) and from organ donors (n=6). NRG1α and NRG1β were quantified in bronchoalveolar lavage fluid (BALF) of patients with early IPF (n=20), controls (n=9), and patients with other interstitial pneumonias (n=13). <h3>Results</h3> In IPF, the bronchiolised and enlarged distal airspaces stained for SOX2 are consistent with epithelial differentiation characteristic of conducting airway epithelium. IPF mucus cells expressed MUC5B but low levels of MUC5AC and MUC2, a profile typical of submucosal glands. Singularly, SPDEF, a transcription factor associated with mucus metaplasia, was rarely detected in mucus cells in IPF. The Notch target, HES1, was present in mucus cells from all groups. NRG1α was detected in serous cells within normal submucosal glands and in epithelial cells lining honeycombing areas in IPF, and was not detected in other patients. NRG1α concentrations were elevated in BALF from patients with early IPF. <h3>Conclusion</h3> Expression of SOX2 and MUC5B and lack of SPDEF in atypically differentiated cells of bronchiolised distal airspaces are consistent with abnormal programming of airway epithelial cells in IPF. NRG1α may contribute to bronchiolisation of the distal lung seen in IPF.
Overexpression of Transcription Factor Sp2 Inhibits Epidermal Differentiation and Increases Susceptibility to Wound- and Carcinogen-Induced Tumorigenesis
Authors: Tae-Hyung Kim, Shannon L. Chiera, Keith E. Linder, Carol S. Trempus, Robert C. Smart, Jonathan M. Horowitz
Journal: Cancer Research (2010)

Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within 2 weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional effect.
Estrogen Alone in Postmenopausal Women and Breast Cancer Detection by Means of Mammography and Breast Biopsy
Authors: Rowan T. Chlebowski, Garnet Anderson, JoAnn E. Manson, Mary Pettinger, Shagufta Yasmeen, Dorothy Lane, Robert D. Langer, F. Allan Hubbell, Anne McTiernan, Susan Hendrix, Robert Schenken, Marcia L. Stefanick
Journal: Journal of Clinical Oncology (2010)

As the influence of estrogen alone on breast cancer detection is not established, we examined this issue in the Women's Health Initiative trial, which randomly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen (CEE; 0.625 mg/d) or placebo.Screening mammography and breast exams were performed at baseline and annually. Breast biopsies were based on clinical findings. Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic (ROC) analyses of mammogram performance.After a 7.1-year mean follow-up, fewer invasive breast cancers were diagnosed in the CEE than in the placebo group, but the difference was not statistically significant. Use of CEE alone increased mammograms with short-interval follow-up recommendations (cumulative, 39.2% v 29.6.3%; P < .001) but not abnormal mammograms (ie, those suggestive of or highly suggestive of malignancy; cumulative, 7.3% v 7.0%; P = .41). Breast biopsies were more frequent in the CEE group (cumulative, 12.5% v 10.7%; P = .004) and less commonly diagnosed as cancer (8.9% v 15.8%, respectively, with positive biopsies; P = .04). Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use.CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies, respectively. Although the breast biopsies on CEE were less commonly diagnosed as cancer, breast cancer detection was not substantially compromised. These findings differ from estrogen-plus-progestin use, for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen.