tbuckley/cabot-search huggingface dataset:
Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer
Authors: Hyeong-Seok Lim, Han Ju Lee, Keun Seok Lee, Eun Sook Lee, In-Jin Jang, Jungsil Ro
Journal: Journal of Clinical Oncology (2007)

The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer.Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes.Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032)CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.
Graduate Medical Education and Patient Safety
Authors: Stephen R. Workman
Journal: Annals of Internal Medicine (2007)

Letters1 May 2007Graduate Medical Education and Patient SafetyStephen R. Workman, MD, MScStephen R. Workman, MD, MScFrom Dalhousie University, Halifax, B3H 4R2 Nova Scotia, Canada.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-146-9-200705010-00018 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: In the case described in the recent Quality Grand Rounds article by Shojania and colleagues (1), the initial management of the patient reflects the treating clinician's understandable expectation of a rapid recovery from “mild pancreatitis.” This expectation is wrong. Pancreatitis in patients older than 65 years of age would have a statistical mortality rate of 20% (2). In patients older than 80 years, the mortality rate is probably higher—perhaps 40% (3). Usual prognostic criteria do not seem to apply to elderly patients (3, 4). Nor does resolution of pancreatitis, which occurred in this case, guarantee a good ...References1. Shojania KG, Fletcher KE, Saint S. Graduate medical education and patient safety: a busy—and occasionally hazardous—intersection. Ann Intern Med. 2006;145:592-8. [PMID: 17043341] LinkGoogle Scholar2. Goldacre MJ, Roberts SE. Hospital admission for acute pancreatitis in an English population, 1963-98: database study of incidence and mortality. BMJ. 2004;328:1466-9. [PMID: 15205290] CrossrefMedlineGoogle Scholar3. Paajanen H, Jaakkola M, Oksanen H, Nordback I. Acute pancreatitis in patients over 80 years. Eur J Surg. 1996;162:471-5. [PMID: 8817224] MedlineGoogle Scholar4. Fan ST, Choi TK, Lai CS, Wong J. Influence of age on the mortality from acute pancreatitis. Br J Surg. 1988;75:463-6. [PMID: 3390679] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAuthors: Stephen R. Workman, MD, MScAffiliations: From Dalhousie University, Halifax, B3H 4R2 Nova Scotia, Canada.Disclosures: None disclosed. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoGraduate Medical Education and Patient Safety: A Busy—and Occasionally Hazardous—Intersection Kaveh G. Shojania , Kathlyn E. Fletcher , and Sanjay Saint Graduate Medical Education and Patient Safety Kaveh G. Shojania , Kathlyn E. Fletcher , and Sanjay Saint Graduate Medical Education and Patient Safety Matthew N. Fine Graduate Medical Education and Patient Safety Paul F. Griner Metrics 1 May 2007Volume 146, Issue 9Page: 686KeywordsConflicts of interestDeath ratesElderlyGraduate medical educationMotivationPancreatitisSafetyTreatment guidelines ePublished: 1 May 2007 Issue Published: 1 May 2007 Copyright & PermissionsCopyright © 2007 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
VH gene family expression in mice with the xid defect.
Authors: S H Feng, K E Stein
Journal: The Journal of Experimental Medicine (1991)

Preferential use of particular VH gene families in the response to specific antigens has been demonstrated in several systems. The lack of responses to certain types of antigens, therefore, could be the result of deletion of or failure to express some VH genes. Because CBA/N mice, which carry the X-linked immunodeficiency (xid) gene defect, have been shown to be unresponsive to thymus-independent polysaccharide antigens, it was of interest to examine if this unresponsiveness could be accounted for by abnormal expression of particular VH gene families. Using in situ hybridization on B cell colonies, we determined the expression of nine VH gene families in CBA/CaHN females (genotypically normal), CBA/N males (xid) and females (xid), and (CBA/N x CBA/CaHN)F1 males (xid) and females (phenotypically normal). Our results indicate that VH gene family expression, including the S107 family, in CBA/N males and F1 males, is similar to that of CBA/CaHN and F1 females with predominant expression of J558, the largest gene family, in all individuals. Interestingly, CBA/N female mice, which carry two defective X chromosomes, as a group expressed significantly reduced levels of the J558 gene family, and as individuals showed variation in which family was predominantly expressed. We conclude that the unresponsiveness of mice with the xid defect to polysaccharide antigens can not attributed to a failure to express the nine VH gene families that we examined. Our findings do not support previous studies (Primi, D., and P.-A. Cazenave 1986. J. Exp. Med. 165:357), which found an absence of expression of the S107 family in xid mice.
Pretargeted Anti–Carcinoembryonic-Antigen Radioimmunotherapy for Medullary Thyroid Carcinoma
Authors: Andreas Machens, Henning Dralle
Journal: Journal of Clinical Oncology (2006)

significant survival advantage of patients with progressive medullary thyroid carcinoma treated with pretargeted anti–carcinoembryonic-antigen radioimmunotherapy over an untreated control group matched on calcitonin doubling time (median, 110 months v 61 months; P .030). This survival advantage doubled for biologic responders relative to these controls (median, 159 months v 61 months; P .010), and was still evident when biologic responders were compared with biologic nonresponders (median, 159 months v 109 months; P .035). In delineating clinical risk, Chatal et al relied on calcitonin doubling times, with cut-offs set at 2 years and 5 years. In clinical practice, however, a risk classification based on calcitonin doubling times may not really be helpful because of the need for protracted expectant observation. Anti–carcinoembryonic-antigen radioimmunotherapy is targeted on membrane-bound carcinoembryonic antigen. There is some evidence to suggest that serum levels of carcinoembryonic antigen from patients with medullary thyroid carcinoma may correspond to the expression of carcinoembryonic antigen in the cancer cells. 2,3 In addition, the duration of response to pretargeted anti–carcinoembryonic-antigen radioimmunotherapy was previously shown to correlate with the duration of the blood carcinoembryonic antigen response. 4 The suitability of serum levels of carcinoembryonic antigen for risk stratification of patients with medullary thyroid carcinoma before initial operation has emerged only recently. 5 Preoperative serum levels of carcinoembryonic antigens greater than 30 ng/mL almost always conflicted with surgical curability and were associated with an approximately 70% rate of involvement of the central and lateral lymph node compartment on the side of the primary tumor. This rate of involvement increased to approximately 90% when the preoperative serum level of carcinoembryonic antigen exceeded 100 ng/mL. In this setting, involvement of the lateral lymph node compartment on the side opposite to the primary tumor, and distant metastases were seen in three quarters of the patients at the time of operation. 5 These data suggest that pretherapeutic serum levels of carcinoembryonic antigen, which are available within a few days, may predict the chance of patients with medullary thyroid carcinoma to benefit from anti– carcinoembryonic-antigen radioimmunotherapy. We wonder if Chatal et al have the data to break down their patients with medullary thyroid carcinoma by pretherapeutic serum level of carcinoembryonic antigen and response to pretargeted anti– carcinoembryonic-antigen radioimmunotherapy. This piece of information would further elucidate the effectiveness of this novel therapeutic modality in select subgroups of patients with medullary thyroid carcinoma.
The Iron Transport Protein NRAMP2 Is an Integral Membrane Glycoprotein That Colocalizes with Transferrin in Recycling Endosomes
Authors: Samantha Gruenheid, François Canonne-Hergaux, Susan Gauthier, David J. Hackam, Sergio Grinstein, Philippe Gros
Journal: The Journal of Experimental Medicine (1999)

The natural resistance associated macrophage protein (Nramp) gene family is composed of two members in mammals, Nramp1 and Nramp2. Nramp1 is expressed primarily in macrophages and mutations at this locus cause susceptibility to infectious diseases. Nramp2 has a much broader range of tissue expression and mutations at Nramp2 result in iron deficiency, indicating a role for Nramp2 in iron metabolism. To get further insight into the function and mechanism of action of Nramp proteins, we have generated isoform specific anti-Nramp1 and anti-Nramp2 antisera. Immunoblotting experiments indicate that Nramp2 is present in a number of cell types, including hemopoietic precursors, and is coexpressed with Nramp1 in primary macrophages and macrophage cell lines. Nramp2 is expressed as a 90–100-kD integral membrane protein extensively modified by glycosylation (&amp;gt;40% of molecular mass). Subcellular localization studies by immunofluorescence and confocal microscopy indicate distinct and nonoverlapping localization for Nramp1 and Nramp2. Nramp1 is expressed in the lysosomal compartment, whereas Nramp2 is not detectable in the lysosomes but is expressed primarily in recycling endosomes and also, to a lower extent, at the plasma membrane, colocalizing with transferrin. These findings suggest that Nramp2 plays a key role in the metabolism of transferrin-bound iron by transporting free Fe2+ across the endosomal membrane and into the cytoplasm.
Tolerance of nebulised gentamicin in adult bronchiectasis - A single centre study
Authors: Jonathan Miller, Hilary Tedd, Sunny Syba, Helen Groves, Anthony De Soyza
Journal: European Respiratory Journal (2012)

Background: British Thoracic Society non CF bronchiectasis (nCFBr) guidelines suggest that long-term nebulised antibiotics should be considered in patients with more than 3 exacerbations per year. Nebulised gentamicin reduces bacterial load and exacerbations in nCFBr. Adverse effects can occur with aerosolized delivery of antimicrobials and so limit their use. We studied the tolerability of nebulised gentamicin in a real world population  Methods: We measured spirometry in nCFBr patients challenged with 80mg of nebulised gentamicin, at baseline, 1min, 5min, and 10min post nebulised gentamicin. Long term tolerability and benefits were assessed  Results: Forty-two patients (19male:23female) were enrolled Feb 2010-Dec 2011. Mean age was 60yrs (range 17-77). Colonisation with  P.aeruginosa ,  H.influenzae  and  S.aureus  was seen in 17(40%), 11(26%) and 4(9%) patients respectively. Mean baseline FEV1 was 1.48L/min (56% pred), range 0.3-3.75L/min (16-108% pred). Mean FEV1 was preserved at 1min (1.45L/min), 5min (1.52L/min) and 10min (1.53L/min) post nebulised gentamicin. There was no difference between pre-dose and 10min post-dose FEV1 (p>0.05). One patient was unable to tolerate the nebulised challenge due to fall in FEV1 and symptoms. Long-term, 8 patients (19%) were unable to tolerate nebulised gentamicin due to side effects. It was stopped in 5 patients (12%) as they did not report benefits  Conclusions: These data show nebulised gentamicin is well tolerated in acute challenges even in patients with severe airflow obstruction but long-term adherence declines. We aim to present microbiological data. The utility of acute challenge tests remain unclear in predicting longer term tolerability.
Short-term Modulation of Cell Proliferation and Apoptosis and Preventive/Therapeutic Efficacy of Various Agents in a Mammary Cancer Model
Authors: Konstantin Christov, Clinton J. Grubbs, Anne Shilkaitis, M. Margaret Juliana, Ronald A. Lubet
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The methylnitrosourea (MNU)-induced mammary cancer model in rats is similar to estrogen receptor–positive breast cancer in women. In prevention studies using this model, tumor incidence and multiplicity were typically primary end points. The ability of various agents administered for a short period to modulate cell proliferation [proliferation index (PI)] and apoptosis [apoptotic index (AI)] in mammary cancers was compared with their efficacy in long-term prevention and therapy studies. Experimental Design: Rats were injected with MNU to induce mammary cancers. For the prevention studies, agents were administered by gavage or in the diet beginning 5 days after MNU. For proliferation (PI) and apoptosis (AI) experiments, animals with a palpable mammary cancer were treated with the agents for only 4 to 7 days. PI was determined following 5-bromodeoxyuridine labeling whereas AI was determined using the terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling assay. Therapeutic efficacy was evaluated by measuring cancer size over a 6-week period. Results: Treatments with differing chemopreventive efficacy and mechanism(s) of action were examined: (a) hormonal treatments [tamoxifen, vorozole (an aromatase inhibitor), and ovariectomy]; (b) retinoid X receptor agonists (targretin, 9-cis retinoic acid, and UAB30); (c) inducers of drug-metabolizing enzymes (indole-3-carbinol, 5,6 benzoflavone, and diindoylmethane); (d) agents that alter signal transduction (R115777, a farnesyltransferase inhibitor); Iressa (an epidermal growth factor receptor inhibitor); sulindac and celecoxib (cyclooxygenase 1/2 and cyclooxygenase 2 inhibitors); and (e) diverse agents including meclizine, vitamin C, and sodium phenylbutyrate. Correlations between inhibition of PI, increase of AI, and chemopreventive efficacy were observed. Although most agents with moderate or low preventive efficacy suppressed PI, they minimally affected AI. Conclusions: The data confirmed that the short-term effects of various agents on cell proliferation and apoptosis in small mammary cancers can predict their preventive/therapeutic efficacy. Thus, these biomarkers can be used to help determine the efficacy of compounds in phase II clinical prevention trials.
Cell-wall determinants of the bactericidal action of group IIA phospholipase A2 against Gram-positive bacteria
Authors: Amy K. Foreman-Wykert, Yvette Weinrauch, Peter Elsbach, Jerrold Weiss
Journal: Journal of Clinical Investigation (1999)

We have shown previously that a group IIA phospholipase A2 (PLA2) is responsible for the potent bactericidal activity of inflammatory fluids against many Gram-positive bacteria. To exert its antibacterial activity, this PLA2 must first bind and traverse the bacterial cell wall to produce the extensive degradation of membrane phospholipids (PL) required for bacterial killing. In this study, we have examined the properties of the cell-wall that may determine the potency of group IIA PLA2 action. Inhibition of bacterial growth by nutrient deprivation or a bacteriostatic antibiotic reversibly increased bacterial resistance to PLA2-triggered PL degradation and killing. Conversely, pretreatment of Staphylococcus aureus or Enterococcus faecium with subinhibitory doses of β-lactam antibiotics increased the rate and extent of PL degradation and/or bacterial killing after addition of PLA2. Isogenic wild-type (lyt+) and autolysis-deficient (lyt–) strains of S. aureus were equally sensitive to the phospholipolytic action of PLA2, but killing and lysis was much greater in the lyt+ strain. Thus, changes in cell-wall cross-linking and/or autolytic activity can modulate PLA2 action either by affecting enzyme access to membrane PL or by the coupling of massive PL degradation to autolysin-dependent killing and bacterial lysis or both. Taken together, these findings suggest that the bacterial envelope sites engaged in cell growth may represent preferential sites for the action and cytotoxic consequences of group IIA PLA2 attack against Gram-positive bacteria.
Quality of Life in the Intergroup Exemestane Study: A Randomized Trial of Exemestane Versus Continued Tamoxifen After 2 to 3 Years of Tamoxifen in Postmenopausal Women With Primary Breast Cancer
Authors: Lesley J. Fallowfield, Judith M. Bliss, Lucy S. Porter, Miranda H. Price, Claire F. Snowdon, Stephen E. Jones, R. Charles Coombes, Emma Hall
Journal: Journal of Clinical Oncology (2006)

To compare and describe the quality of life (QOL) of women allocated to tamoxifen or exemestane within the Intergroup Exemestane Study (IES).Postmenopausal women with primary breast cancer who were disease free after 2 to 3 years were randomly assigned to switch from tamoxifen to exemestane or continue with tamoxifen until 5 years of treatment were completed. A subset of IES centers participated in a QOL substudy. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) were administered before random assignment and at predefined follow-up times. The primary end point was the FACT-B composite Trial Outcome Index (TOI). Secondary end points included total FACT-B+ES score, total ES score, and severity of individual endocrine symptoms. This analysis reports QOL up to 24 months.Five hundred eighty-two patients from eight countries were enrolled onto the substudy. Completion and return of questionnaires was excellent, with 85% available for analysis. QOL was generally good and stable over 2 years, with no clinically meaningful differences found between groups in TOI or ES. Prevalence of severe endocrine symptoms at trial entry was high for vasomotor complaints and sexual problems, which persisted for both groups during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < .001).The switch from tamoxifen to exemestane neither increased nor decreased endocrine symptoms present after 2 to 3 years of tamoxifen; the switch also did not initiate significant reports of new symptoms. Results indicate that the clinical benefits of exemestane over tamoxifen are achieved without significant detrimental effect on QOL.
Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer
Authors: Jennifer M. Bailey, Benjamin J. Swanson, Tomofumi Hamada, John P. Eggers, Pankaj K. Singh, Thomas Caffery, Michel M. Ouellette, Michael A. Hollingsworth
Journal: Clinical Cancer Research (2008)

We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression.We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth. We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice.Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts.These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.
Regulatory substances produced by lymphocytes. VI. Cell cycle specificity of inhibitor of DNA synthesis action in L cells.
Authors: A B Wagshal, B V Jegasothy, B H Waksman
Journal: The Journal of Experimental Medicine (1978)

IDS inhibits DNA synthesis and mitosis of L cells only when present during the late G1 phase of the cell cycle, as shown with L cells synchronized by a variety of methods. This corresponds well with earlier findings that IDS inhibits DNA synthesis in mitogen-stimulated lymphocytes when present between 16 and 24 h after adding mitogen. In both cell types, the inhibition produced by IDS appears to be totally the result of elevation of cAMP level. Thus, inhibitors of cAMP phosphodiesterase work synergistically with IDS, and activators of cAMP phosphodiesterase overcome the inhibition by IDS. This paper shows that IDS raises cAMP levels in L cells only within a narrow interval of the cell cycle, around 6-8 h after mitosis. This cell cycle specificity, which may be related to appearance of receptors for IDS only at discrete times, may be important in limiting IDS action to suppression, as elevated cAMP levels have a variety of other effects during other phases of the cell cycle.
Evidence for a Role of the PD-1:PD-L1 Pathway in Immune Resistance of HPV-Associated Head and Neck Squamous Cell Carcinoma
Authors: Sofia Lyford-Pike, Shiwen Peng, Geoffrey D. Young, Janis M. Taube, William H. Westra, Belinda Akpeng, Tullia C. Bruno, Jeremy D. Richmon, Hao Wang, Justin A. Bishop, Lieping Chen, Charles G. Drake, Suzanne L. Topalian, Drew M. Pardoll, Sara I. Pai
Journal: Cancer Research (2013)

Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We show membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor-associated macrophages is geographically localized to sites of lymphocyte fronts, whereas the majority of CD8+ tumor-infiltrating lymphocytes express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.