tbuckley/cabot-search huggingface dataset:
<i>MDR1</i> Synonymous Polymorphisms Alter Transporter Specificity and Protein Stability in a Stable Epithelial Monolayer
Authors: King Leung Fung, James Pan, Shinobu Ohnuma, Paul E. Lund, Jessica N. Pixley, Chava Kimchi-Sarfaty, Suresh V. Ambudkar, Michael M. Gottesman
Journal: Cancer Research (2013)

The drug efflux function of P-glycoprotein (P-gp) encoded by MDR1 can be influenced by genetic polymorphisms, including two synonymous changes in the coding region of MDR1. Here we report that the conformation of P-gp and its drug efflux activity can be altered by synonymous polymorphisms in stable epithelial monolayers expressing P-gp. Several cell lines with similar MDR1 DNA copy number were developed and termed LLC-MDR1-WT (expresses wild-type P-gp), LLC-MDR1-3H (expresses common haplotype P-gp), and LLC-MDR1-3HA (a mutant that carries a different valine codon in position 3435). These cell lines express similar levels of recombinant mRNA and protein. P-gp in each case is localized on the apical surface of polarized cells. However, the haplotype and its mutant P-gps fold differently from the wild-type, as determined by UIC2 antibody shift assays and limited proteolysis assays. Surface biotinylation experiments suggest that the non-wild-type P-gps have longer recycling times. Drug transport assays show that wild-type and haplotype P-gp respond differently to P-gp inhibitors that block efflux of rhodamine 123 or mitoxantrone. In addition, cytotoxicity assays show that the LLC-MDR1-3H cells are more resistant to mitoxantrone than the LLC-MDR1-WT cells after being treated with a P-gp inhibitor. Expression of polymorphic P-gp, however, does not affect the host cell's morphology, growth rate, or monolayer formation. Also, ATPase activity assays indicate that neither basal nor drug-stimulated ATPase activities are affected in the variant P-gps. Taken together, our findings indicate that "silent" polymorphisms significantly change P-gp function, which would be expected to affect interindividual drug disposition and response.
Tamoxifen, Radiation Therapy, or Both for Prevention of Ipsilateral Breast Tumor Recurrence After Lumpectomy in Women With Invasive Breast Cancers of One Centimeter or Less
Authors: Bernard Fisher, John Bryant, James J. Dignam, D. Lawrence Wickerham, Eleftherios P. Mamounas, Edwin R. Fisher, Richard G. Margolese, Lois Nesbitt, Soonmyung Paik, Thomas M. Pisansky, Norman Wolmark
Journal: Journal of Clinical Oncology (2002)

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of ≤ 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of .05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P = .28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P = .039). Survival in the three groups was 93%, 94%, and 93%, respectively (P = .93). CONCLUSION: In women with tumors ≤ 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.
Connexin45 Expression Is Preferentially Associated With the Ventricular Conduction System in Mouse and Rat Heart
Authors: Steven R. Coppen, Emmanuel Dupont, Stephen Rothery, Nicholas J. Severs
Journal: Circulation Research (1998)

Cardiac myocytes are electrically coupled by gap junctions, clusters of low-resistance intercellular channels composed of connexins. Variations in the quantities and spatial distribution of different connexin types have been implicated in regional differentiation of electrophysiological properties in the heart. Although independent studies have demonstrated that connexin43 is abundant in working ventricular myocardium and that connexin40 is preferentially expressed in the atrioventricular conduction system of a number of species, information on the spatial distribution of connexin45 in the heart is limited to data obtained using an antibody raised to a single peptide sequence. In the present study, we report on the production and characterization of a new anti-connexin45 antibody and its application to the investigation of connexin45 expression in mouse and rat myocardium. The affinity-purified antiserum, raised in guinea pig to residues 354 to 367 of human connexin45, recognized a single 45-kD band on Western blots of HeLa cells transfected to express connexin45 and gave punctate immunolabeling at the cell borders, demonstrated by freeze-fracture cytochemistry to represent gap junctions. Only low levels of connexin45 mRNA were detected on Northern blots of mouse and rat cardiac tissues, and connexin45 protein levels were below the limit of detection on Western blots. Confocal microscopy of immunolabeled ventricular tissue revealed that the major part of the working myocardium was immunonegative for connexin45. A clearly defined zone containing connexin45-expressing cells was, however, localized to the endocardial surface, overlapping with connexin40-expressing myocytes of the conduction system. As these results contrast with the prevailing view that connexin45 is widely distributed in working ventricular myocytes, we compared the immunolabeling pattern obtained with a commercially supplied anti-connexin45 antiserum raised against the same peptide that was used in previous studies. The commercial connexin45 antiserum gave widespread labeling throughout the ventricular myocardium, but this labeling was inhibited by a six-amino acid peptide matching part of the connexin43 sequence, indicating cross-reaction of the commercial connexin45 antiserum with connexin43 in the tissue. Further evidence for such cross-reactivity came from observations on connexin43-transfected cells, which gave positive immunolabeling with the commercial anti-connexin45 antiserum. Our demonstration of a specific association of connexin45 with connexin40-expressing myocytes in rat and mouse ventricle raises the possibility that connexin45 contributes to the modulation of electrophysiological properties in the ventricular conduction system and highlights the need for reappraisal of the distribution and role of connexin45 in other species.
Prevalence of C282Y and H63D Mutations in the Hemochromatosis (<i>HFE</i>) Gene in the United States
Authors: Karen K. Steinberg, Mary E. Cogswell, Joy C. Chang, Samuel P. Caudill, Geraldine M. McQuillan, Barbara A. Bowman, Laurence M. Grummer-Strawn, Eric J. Sampson, Muin J. Khoury, Margaret L. Gallagher
Journal: JAMA (2001)

Context Population-based estimates of the prevalence of disease-associated mutations, such as hemochromatosis ( HFE ) gene mutations, are needed to determine the usefulness of genetic screening. Objective To estimate the prevalence of the HFE mutations C282Y and H63D in the US population. Design Cross-sectional population-based study of samples in the DNA bank from phase 2 of the Third National Health and Nutrition Examination Survey conducted from 1992 to 1994. Setting and Participants Genotyped samples of cells from a total of 5171 participants, cross-classified by sex, age, and race/ethnicity in the analysis. Main Outcome Measures Estimates of the prevalence of C282Y and H63D mutations. Results The prevalence of C282Y homozygosity is estimated to be 0.26% (95% confidence interval [CI], 0.12%-0.49%); 1.89% (95% CI, 1.48%-2.43%) for H63D homozygosity; and 1.97% (95% CI, 1.54%-2.49%) for compound heterozygosity. The prevalence estimates for C282Y heterozygosity (C282Y/wild type) are 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican-Americans. The prevalence estimates of the C282Y mutation in the US population are 5.4% (95% CI, 4.7%-6.2%) and 13.5% (95% CI, 12.5%-14.8%) for the H63D mutation. Conclusions Estimates of prevalence of HFE mutations are within the expected range for non-Hispanic whites and blacks but the estimated prevalence of the C282Y mutation among Mexican-Americans is less than expected. Mutation data now need to be linked to clinically relevant indices, such as transferrin saturation level.
The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy
Authors: D van der Heijde, G Burmester, J Melo-Gomes, C Codreanu, E Martin Mola, R Pedersen, B Freundlich, D J Chang
Journal: Annals of the Rheumatic Diseases (2007)

To determine if adding etanercept (ETN) to methotrexate (MTX) or MTX to ETN for 52 weeks in rheumatoid arthritis (RA) patients with moderate disease activity provides higher efficacy.All patients (n = 227) received open-label ETN 25 mg subcutaneously twice-weekly and MTX orally up to 20 mg weekly for 52 weeks and had completed a 3-year study in which patients received MTX, ETN or combination therapy. Endpoints were based on Disease Activity Score (DAS) and European League Against Rheumatism (EULAR) responses.Patients previously receiving combination therapy (Combination group; n = 96) had a lower disease activity at baseline. The mean DAS for those previously receiving MTX (ETN-added group; n = 55) and previously receiving ETN (MTX-added group; n = 76) were in the moderate disease activity range at baseline; Combination patients had a low disease activity. The greatest increase in DAS remission rates from baseline to week 52 was in the ETN-added group (23.6% to 41.8%, p<0.01), although Combination (37.6% to 50.0%, p<0.01) and MTX-added (26.7% to 36.8%, p = NS) also demonstrated improvements. DAS low disease activity and EULAR responses showed similar results. No new safety issues were identified.RA patients who were partial responders to long-term MTX or etanercept monotherapy obtained a higher efficacy with combination therapy. Responses achieved by patients with combination therapy after 3 years in the previous study were sustained or improved during the fourth year of treatment. This trial supports the higher therapeutic effect of combination treatment with etanercept and MTX in RA patients with moderate disease activity despite monotherapy with one of the two agents.
More information, more choice: an Italian database for oncology patients
Authors: A. Bogliolo, W. Russell-Edu, G. Alloro, R. Ballarini, G. Bocchini, L. Cecere, A. Codonesu, G. Cognetti, M. Montella, R. Ricci, P. Seroppi, A. Trocino, R. Truffelli, F. Cognetti, I. Truccolo
Journal: Annals of Oncology (2005)
Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma
Authors: Robert J. Motzer, Thomas E. Hutson, Piotr Tomczak, M. Dror Michaelson, Ronald M. Bukowski, Olivier Rixe, Stéphane Oudard, Sylvie Negrier, Cezary Szczylik, Sindy T. Kim, Isan Chen, Paul W. Bycott, Charles M. Baum, Robert A. Figlin
Journal: New England Journal of Medicine (2007)

Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted.We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety.The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001).Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).
MDR1-Pgp 170 expression in human bronchus
Authors: E Lechapt-Zalcman, I Hurbain, R Lacave, F Commo, T Urban, M Antoine, B Milleron, JF Bernaudin
Journal: European Respiratory Journal (1997)

MDR1 P-glycoprotein (Pgp 170), a member of the adenosine triphosphate (ATP) binding cassette transporters, acts as an efflux pump for various hydrophobic agents, particularly for xenobiotics such as benzo(a)pyrene. It has also been shown to regulate cell-volume activated chloride channels. Pgp 170 could, therefore, be of particular importance in cellular mechanisms of defence in the airways and in the control of mucus layer composition. For these reasons, we evaluated the precise localization of Pgp 170 in human adult airways. Fresh non-neoplastic bronchial specimens were collected from 33 patients (26 smokers, four exsmokers and three nonsmokers) who underwent surgery for lung carcinoma. The presence of MDR1 messenger ribonucleic acid (mRNA) was demonstrated by reverse transcriptase chain reaction (RT-PCR) in bronchial epithelial cells collected by gentle scraping from either smokers, exsmokers or nonsmokers. Immunodetection of Pgp 170 using a panel of monoclonal antibodies (MRK16, JSB1, C219, C494) was performed either on cryostat or paraffin-embedded sections of histologically normal bronchial tissue. Pgp 170 was constantly detected with intense labelling at the apical surface of ciliated epithelial cells from the surface epithelium or ciliated collecting ducts, and on apical and lateral surfaces of serous cells from bronchial glands. No staining of mucus-secreting cells was observed. Pgp 170 was also demonstrated at the luminal surface of endothelial cells of bronchial capillaries. In conclusion, the expression of MDR1 P-glycoprotein in bronchial structures, particularly at the epithelial apical surface, suggests important roles for this transmembrane protein in human airways.
Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice
Authors: S. Alberti, G. Schuster, P. Parini, D. Feltkamp, U. Diczfalusy, M. Rudling, B. Angelin, I. Björkhem, S. Pettersson, J.-′«. Gustafsson
Journal: Journal of Clinical Investigation (2001)

The nuclear oxysterol-receptor paralogues LXRα and LXRβ share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRα has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRβ in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRβ–/– and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRβ–/– mice compared with LXRβ+/+ mice, when fed standard chow. The mRNA levels for cholesterol 7α-hydroxylase, oxysterol 7α-hydroxylase, sterol 12α-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRβ–/– mice — in contrast to LXRα–/– mice — maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRβ has no complete overlapping function compared with LXRα in the liver.
Polymorphisms in the type IV collagen 3 gene and the risk of COPD
Authors: K. M. Kim, S. H. Park, J. S. Kim, W. K. Lee, S. I. Cha, C. H. Kim, Y. M. Kang, T. H. Jung, I. S. Kim, J. Y. Park
Journal: European Respiratory Journal (2008)

A number of genome-wide linkage analyses have identified the 2q33.3–2q37.2 region as the most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesised that the type IV collagen α3 ( COL4A3 ) gene, which is one of the genes located in the 2q33.3–2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of COL4A3 -1162T&gt;C, IVS2+12C&gt;A, P141L, G162E, H451R, P574L and *315C&gt;A polymorphisms with the risk of COPD was investigated in a case–control study of 311 COPD patients and 386 controls. The presence of at least one 451R allele was associated with a significantly higher risk of COPD compared with the 451 H/H genotype (adjusted odds ratio 1.48, 95% confidence interval (1.03–2.14)). When the subjects were stratified according to age and COPD severity, the 451R allele was associated with a significantly higher risk of COPD only in younger individuals with severe COPD (3.02 (1.37–6.67)). In conclusion, these findings suggest that the type IV collagen α3 gene contributes to the genetic susceptibility to chronic obstructive pulmonary disease.
Mutations in the hemochromatosis gene and response to interferon in chronic hepatitis C
Authors: M. Sampietro, N. Corbetta, M. Amato, A. Casatta, L. Lupica, M. Mattioli, M. Del Vitto, V. Molteni, A.L. Fracanzani, S. Fargion, G. Fiorelli
Journal: Journal of Hepatology (1998)
Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial
Authors: Frédéric A Houssiau, David D'Cruz, Shirish Sangle, Philippe Remy, Carlos Vasconcelos, Radmila Petrovic, Christoph Fiehn, Enrique de Ramon Garrido, Inge-Magrethe Gilboe, Maria Tektonidou, Daniel Blockmans, Isabelle Ravelingien, Véronique le Guern, Geneviève Depresseux, Loïc Guillevin, Ricard Cervera
Journal: Annals of the Rheumatic Diseases (2010)

Background Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment. Methods A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months. Results The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out. Conclusions Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.
<i>TP53</i> and <i>KRAS</i> Mutation Load and Types in Lung Cancers in Relation to Tobacco Smoke: Distinct Patterns in Never, Former, and Current Smokers
Authors: Florence Le Calvez, Anush Mukeria, Jay D. Hunt, Olaf Kelm, Rayjean J. Hung, Philippe Tanière, Paul Brennan, Paolo Boffetta, David G. Zaridze, Pierre Hainaut
Journal: Cancer Research (2005)

Abstract TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (Plinear trend &amp;lt; 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.