tbuckley/cabot-search huggingface dataset:
Identification of an Unintended Consequence of Nrf2-Directed Cytoprotection against a Key Tobacco Carcinogen plus a Counteracting Chemopreventive Intervention
Authors: Joseph D. Paonessa, Yi Ding, Kristen L. Randall, Rex Munday, Dayana Argoti, Paul Vouros, Yuesheng Zhang
Journal: Cancer Research (2011)

NF-E2-related factor 2 (Nrf2) is a major cytoprotective gene and is a key chemopreventive target against cancer and other diseases. Here we show that Nrf2 faces a dilemma in defense against 4-aminobiphenyl (ABP), a major human bladder carcinogen from tobacco smoke and other environmental sources. Although Nrf2 protected mouse liver against ABP (which is metabolically activated in liver), the bladder level of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP), the predominant ABP-DNA adduct formed in bladder cells and tissues, was markedly higher in Nrf2(+/+) mice than in Nrf2(-/-) mice after ABP exposure. Notably, Nrf2 protected bladder cells against ABP in vitro. Mechanistic investigations showed that the dichotomous effects of Nrf2 could be explained at least partly by upregulation of UDP-glucuronosyltransferase (UGT). Nrf2 promoted conjugation of ABP with glucuronic acid in the liver, increasing urinary excretion of the conjugate. Although glucuronidation of ABP and its metabolites is a detoxification process, these conjugates, which are excreted in urine, are known to be unstable in acidic urine, leading to delivery of the parent compounds to bladder. Hence, although higher liver UGT activity may protect the liver against ABP, it increases bladder exposure to ABP. These findings raise concerns of potential bladder toxicity when Nrf2-activating chemopreventive agents are used in humans exposed to ABP, especially in smokers. We further show that 5,6-dihydrocyclopenta[c][1,2]-dithiole-3(4H)-thione (CPDT) significantly inhibits dG-C8-ABP formation in bladder cells and tissues but does not seem to significantly modulate ABP-catalyzing UGT in liver. Thus, CPDT exemplifies a counteracting solution to the dilemma posed by Nrf2.
Hair greying is associated with active hair growth
Authors: H.I. Choi, G.I. Choi, E.K. Kim, Y.J. Choi, K.C. Sohn, Y. Lee, C.D. Kim, T.J. Yoon, H.J. Sohn, S.H. Han, S. Kim, J.H. Lee, Y.H. Lee
Journal: British Journal of Dermatology (2011)

Background Hair greying is an obvious sign of ageing in humans. White (nonpigmented) hair is thicker than black (pigmented) hair. The growth rate of white hair is also significantly higher than that of black hair. However, the mechanism underlying this is largely unknown. Objectives To examine the association between hair greying and hair growth patterns by evaluating expression of the genes or proteins related to hair growth in white and black hairs. Methods Morphological characteristics were observed in eyebrow and scalp hairs. The differential expression of genes was analysed in black and white hairs from human scalp by a microarray analysis. Reverse transcription–polymerase chain reaction (RT-PCR) and immunohistochemistry for genes and proteins related to hair growth were performed in black and white hairs. Results Keratin and keratin-associated protein (KRTAP) genes in white hair were upregulated at least two-fold in comparison with black hair in a microarray analysis. Upregulation of selected keratin genes and KRTAP4 isoform genes in white hair was validated by RT-PCR. Immunoreactivity for KRT6, KRT14/16 and KRT25 was increased in the hair follicle of white hair compared with black hair. Gene expression of fibroblast growth factor 5 (FGF5) was downregulated in white hair compared with black hair. However, gene expression of FGF7 was upregulated in white hair compared with black hair. Conclusions Expression of genes and proteins associated with active hair growth is upregulated in white (nonpigmented) hair compared with black (pigmented) hair. These results suggest that hair greying is associated with active hair growth.
Role of the CHADS2Score in the Evaluation of Thromboembolic Risk in Patients With Atrial Fibrillation Undergoing Transesophageal Echocardiography Before Pulmonary Vein Isolation
Authors: Sarinya Puwanant, Brandon C. Varr, Kevin Shrestha, Sarah K. Hussain, W.H. Wilson Tang, Ruvin S. Gabriel, Oussama M. Wazni, Mandeep Bhargava, Walid I. Saliba, James D. Thomas, Bruce D. Lindsay, Allan L. Klein
Journal: Journal of the American College of Cardiology (2009)
Performance of the preliminary definition of improvement in juvenile chronic arthritis patients treated with methotrexate
Authors: N. Ruperto, A. Ravelli, F. Falcini, L. Lepore, R. De Sanctis, F. Zulian, A. Buoncompagni, M. L. Sardella, C. Strano, M. Alessio, S. Viola, A. Martini
Journal: Annals of the Rheumatic Diseases (1998)

To investigate the performance of the core set of outcome measures and the preliminary definition of improvement (PDI) in the assessment of response to methotrexate (MTX) treatment in children with juvenile chronic arthritis (JCA).Data were obtained from an open label, non-controlled trial designed to investigate the efficacy of MTX in children with JCA. All patients had the core set of variables assessed at baseline and after six months of treatment. Variables in the core set are: (1) physician global assessment of disease activity; (2) parent or patient (if appropriate in age) global assessment of overall well being; (3) functional ability; (4) number of joints with active arthritis; (5) number of joints with limited range of motion; (6) erythrocyte sedimentation rate. The PDI specifies that to be classified as improved, a patient must show at least 30% improvement from baseline in three of any six variables in the core set, with no more than one of the remaining variables worsening by more than 30%.A total of 111 JCA patients were included in the study. According to the PDI, after six months of MTX treatment 73 patients (66%) were classified as improved and 38 (34%) as not improved. Among the core set variables, parent assessment detected the highest percentage of patients improved (72%) and functional assessment the lowest (37%).The PDI identifies about two thirds of patients with JCA treated with low dose MTX as improved. This proportion is similar to that expected to improve based upon a previous controlled study of low dose, oral MTX and provides preliminary evidence of the definition's validity.
Re-defining normal: bone mineral density in elite female athletes
Authors: P Cutti, R Steele, I Shrier, D Garza, W Meeuwisse, L Bacharach, G Matheson
Journal: British Journal of Sports Medicine (2011)

Background College age female athletes are susceptible to decreased bone mineral density (BMD) which puts them at an elevated risk for poor bone health in the future. Objective The primary purpose of this study was to compare site-specific and total body BMD of college-age female athletes across sports of varying impact level. Secondary objectives included (1) evaluating the relationship between BMD and menstrual, family bone health, and personal bone health histories; (2) to determine the best clinical predictors of BMD in this population. Design Cross-sectional. Setting NCAA Division I female athletes screened at university sports medicine centre. Participants 265 (20.1±1.19 years, 66.5±10.9 kg, 1.7±0.09 m) college-age female athletes from 14 different sporting teams. Interventions Personal and family health questionnaire, Total Body (TB), anteroposterior Spine (APS), Dual Femur (DF) BMD and Body Composition scans using GE Lunar iDXA. Main outcome measurements Athletes were separated into three sport impact categories. BMD measurements were compared across the impact levels. Both stepwise regression and classification and regression tree analysis were conducted to determine significant predictors of BMD. Results Athletes participating in low and moderate impact sports had significantly lower TB and site-specific BMD values when compared to high impact athletes (TB: High=1.24, Mod=1.18, Low=1.15; APS High=1.33, Mod=1.25, Low=1.21; DF High=1.25, Mod=1.12, Low=1.11). The BMD values for each secondary exposure were lower in those with history of abnormal menses (TB-1.19, APS- 1.24, DF- 1.17), previous stress fracture/reaction (TB-1.19, APS- 1.27, DF- 1.17), and poor family bone health (TB-1.18, APS- 1.26, DF- 1.16). Classification and regression trees (CART) analysis shows highest TB mean BMD was found in high impact athletes with LBM&gt;50.9 kg. Conclusion There is an ordinal relationship between sport impact level and BMD. Using CART analysis, gynaecological age, impact level and LBM are the best predictors of mean BMD.
Psychiatric Disorders in Preschool Offspring of Parents With Bipolar Disorder: The Pittsburgh Bipolar Offspring Study (BIOS)
Authors: Boris Birmaher, David Axelson, Benjamin Goldstein, Kelly Monk, Catherine Kalas, Mihaela Obreja, Mary Beth Hickey, Satish Iyengar, David Brent, Wael Shamseddeen, Rasim Diler, David Kupfer
Journal: American Journal of Psychiatry (2010)

The authors evaluated lifetime prevalence and specificity of DSM-IV psychiatric disorders and severity of depressive and manic symptoms at intake in preschool offspring of parents with bipolar I and II disorders.A total of 121 offspring ages 2-5 years from 83 parents with bipolar disorder and 102 offspring of 65 demographically matched comparison parents (29 with non-bipolar psychiatric disorders and 36 without any lifetime psychopathology) were recruited for the study. Parents with bipolar disorder were recruited through advertisements and adult outpatient clinics, and comparison parents were ascertained at random from the community. Participants were evaluated with standardized instruments. All staff were blind to parental diagnoses.After adjustment for within-family correlations and both biological parents' non-bipolar psychopathology, offspring of parents with bipolar disorder, particularly those older than age 4, showed an eightfold greater lifetime prevalence of attention deficit hyperactivity disorder (ADHD) and significantly higher rates of having two or more psychiatric disorders compared to the offspring of the comparison parents. While only three offspring of parents with bipolar disorder had mood disorders, offspring of parents with bipolar disorder, especially those with ADHD and oppositional defiant disorder, had significantly more severe current manic and depressive symptoms than comparison offspring.Preschool offspring of parents with bipolar disorder have an elevated risk for ADHD and have greater levels of subthreshold manic and depressive symptoms than children of comparison parents. Longitudinal follow-up is warranted to evaluate whether these children are at high risk for developing mood and other psychiatric disorders.
What are “normal movements” in any population?
Authors: R. S. W. Masters, R. C. J. Polman
Journal: Behavioral and Brain Sciences (1996)

Abstract It is the contention of Latash &amp; Anson (L&amp;A) that in atypical populations, such as those with cognitive, central neurological, or peripheral disorders, the central nervous system (CNS) is capable of producing more effective, though often less “normal,” movement patterns ifleft to its own devices. It is the aim of this commentary to extend their argument to other populations by pointing out the many parallels with development of movement patterns in sport.
Cabozantinib Overcomes Crizotinib Resistance in ROS1 Fusion–Positive Cancer
Authors: Ryohei Katayama, Yuka Kobayashi, Luc Friboulet, Elizabeth L. Lockerman, Sumie Koike, Alice T. Shaw, Jeffrey A. Engelman, Naoya Fujita
Journal: Clinical Cancer Research (2014)

Abstract Purpose: ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase I trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non–small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib-resistance mechanisms in ROS1-rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required. Experimental Design: The sensitivity of CD74–ROS1–transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor–resistant mutations in CD74–ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high-throughput drug screening with small-molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74–ROS1–mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74–ROS1. Results: We identified multiple novel crizotinib-resistance mutations in the ROS1 kinase domain, including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74–ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations. Conclusions: We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Clin Cancer Res; 21(1); 166–74. ©2014 AACR.
Comparison of bismuth citrate and 5-aminosalicylic acid enemas in distal ulcerative colitis: a controlled trial.
Authors: R D Pullan, S Ganesh, V Mani, J Morris, B K Evans, G T Williams, J Rhodes
Journal: Gut (1993)

An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.
Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer
Authors: Catia Moutinho, Anna Martinez-Cardús, Cristina Santos, Valentin Navarro-Pérez, Eva Martínez-Balibrea, Eva Musulen, F. Javier Carmona, Andrea Sartore-Bianchi, Andrea Cassingena, Salvatore Siena, Elena Elez, Josep Tabernero, Ramon Salazar, Albert Abad, Manel Esteller
Journal: JNCI Journal of the National Cancer Institute (2013)

A major problem in cancer chemotherapy is the existence of primary resistance and/or the acquisition of secondary resistance. Many cellular defects contribute to chemoresistance, but epigenetic changes can also be a cause. A DNA methylation microarray was used to identify epigenetic differences in oxaliplatin-sensitive and -resistant colorectal cancer cells. The candidate gene SRBC was validated by single-locus DNA methylation and expression techniques. Transfection and short hairpin experiments were used to assess oxaliplatin sensitivity. Progression-free survival (PFS) and overall survival (OS) in metastasic colorectal cancer patients were explored with Kaplan–Meier and Cox regression analyses. All statistical tests were two-sided. We found that oxaliplatin resistance in colorectal cancer cells depends on the DNA methylation–associated inactivation of the BRCA1 interactor SRBC gene. SRBC overexpression or depletion gives rise to sensitivity or resistance to oxaliplatin, respectively. SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%; n = 39 of 131), where it predicted shorter PFS (hazard ratio [HR] = 1.83; 95% confidence interval [CI] = 1.15 to 2.92; log-rank P = .01), particularly in oxaliplatin-treated case subjects for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13 to 3.40; log-rank P = .01). In a validation cohort of unresectable colorectal tumors treated with oxaliplatin (n = 58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; 95% CI = 1.01 to 3.60; log-rank P = .045). These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.
Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia
Authors: Gunnar Cario, Martin Stanulla, Bernard M. Fine, Oliver Teuffel, Nils v. Neuhoff, André Schrauder, Thomas Flohr, Beat W. Schäfer, Claus R. Bartram, Karl Welte, Brigitte Schlegelberger, Martin Schrappe
Journal: Blood (2004)
Tobacco Smoke Stimulates the Transcription of Amphiregulin in Human Oral Epithelial Cells: Evidence of a Cyclic AMP-Responsive Element Binding Protein–Dependent Mechanism
Authors: Baoheng Du, Nasser K. Altorki, Levy Kopelovich, Kotha Subbaramaiah, Andrew J. Dannenberg
Journal: Cancer Research (2005)

Abstract Activation of epidermal growth factor receptor (EGFR)–mediated signaling has been implicated in the pathogenesis of tobacco smoke–induced cancers. Recently, elevated levels of amphiregulin, a ligand of the EGFR, were found in the oral mucosa of smokers. The main objective of this study was to elucidate the mechanism by which tobacco smoke induces amphiregulin. Treatment of a nontumorigenic human oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke stimulated amphiregulin (AR) transcription resulting in increased amounts of amphiregulin mRNA and protein. Tobacco smoke stimulated the cyclic AMP (cAMP)→protein kinase A (PKA) pathway leading to increased cAMP-responsive element binding protein–dependent activation of AR transcription. These inductive effects of tobacco smoke were dependent on the aryl hydrocarbon receptor (AhR). In fact, α-naphthoflavone, an AhR antagonist, blocked tobacco smoke–mediated induction of binding of cAMP-responsive element binding protein to the AR promoter and thereby suppressed the induction of amphiregulin. Notably, treatment of MSK-Leuk1 cells with tobacco smoke or exogenous amphiregulin stimulated DNA synthesis. An inhibitor of EGFR tyrosine kinase or a neutralizing antibody to amphiregulin abrogated the increase in DNA synthesis mediated by tobacco smoke. Taken together, these findings suggest that tobacco smoke stimulated a signaling pathway comprised of AhR→cAMP→PKA resulting in enhanced AR transcription and increased DNA synthesis. The ability of tobacco smoke to induce amphiregulin and thereby enhance DNA synthesis is likely to contribute to the procarcinogenic effects of tobacco smoke.
Evaluation of albumin as a reference marker of dilution in bronchoalveolar lavage fluid from asthmatic and control subjects.
Authors: C Ward, M Duddridge, J Fenwick, P V Gardiner, A Fleetwood, D J Hendrick, E H Walters
Journal: Thorax (1993)

BACKGROUND--Standardised expression of results of bronchoalveolar lavage (BAL) is problematical in the absence of a validated "denominator" of epithelial lining fluid dilution. The suitability of albumin in BAL fluid has been investigated in groups of clinically stable asthmatic and control subjects. METHODS--Absolute levels of albumin in BAL fluid were measured in a preliminary study of 21 asthmatic and 10 control subjects. In a more complex study designed to investigate the origin of albumin sampled at BAL in nine asthmatic and seven control subjects, radiolabelled albumin was injected intravenously five minutes before BAL. RESULTS--In the preliminary study levels of albumin in BAL fluid were very similar, with a geometric mean value of 44 (95% CI 35-54) micrograms/ml BAL supernatant for the asthmatic subjects and 41 (95% CI 33-52) micrograms/ml for the controls. The majority of control and asthmatic subjects in the radiolabel study exhibited minimal flux of albumin from the circulation into the BAL aspirate. This finding was not uniform, however, and in a third of the asthmatic subjects an albumin flux equivalent to &gt; 20% of the measurable albumin was found in two or more aliquots of a 3 x 60 ml lavage. CONCLUSIONS--The results of this investigation into the source of albumin sampled at BAL suggest that, in general, albumin would be a reasonable reference solute for normalising the degree of dilution of BAL fluid in the groups studied. The origin of albumin was not always restricted to the bronchopulmonary segment under investigation, however, with significant leakage from the blood compartment in some individuals despite the consistency of absolute levels observed in the preliminary study.
Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas
Authors: E. Regnier-Rosencher, H. Lazareth, L. Gressier, M.F. Avril, E. Thervet, N. Dupin
Journal: British Journal of Dermatology (2013)

Vemurafenib, a selective BRAF (v-raf murine sarcoma viral oncogene homologue B1) kinase inhibitor, is a new targeted biotherapy that improves survival in patients with metastatic melanomas harbouring the BRAF V600E mutation. However, this drug has significant dermatological adverse effects. We report a new severe cutaneous reaction to this drug associated with acute kidney injury (AKI). Four patients presented a generalized grade 3 (Common Terminology Criteria for Adverse Events) erythematous eruption with hyperkeratosis pilaris, 5-14 days after the introduction of vemurafenib. These symptoms were associated with AKI in all cases and transitory hypereosinophilia in two cases. Vemurafenib treatment was stopped in three patients and the dose was reduced in the fourth, leading to a gradual improvement of skin symptoms and renal function. Positron-emission tomography scans showed a complete response in three cases and a major response in one case. Vemurafenib was reintroduced at a lower dose, without a relapse of the rash, but renal function again deteriorated. Thus, we report a cluster of four cases of AKI associated with similar, severe, grade 3 cutaneous drug reactions related to vemurafenib.