tbuckley/cabot-search huggingface dataset:
THE PHARMACOLOGY AND BIOCHEMISTRY OF N-OXIDES
Authors: M.H. BICKEL
Journal: Pharmacological Reviews (1969)

N-Oxides are oxidation products of tertiary amines. They were detected as a new class of chemical compounds before 1900 and were later found to occur as constituents of living matter. In recent years an increasing number of studies by biomedical scientists has been devoted to N-oxides for several reasons. The natural occurrence of N-oxides in plant and animal tissues has posed interesting problems as to the biochemistry and function of these compounds in biological systems. In several cases N-oxides are more active than their corresponding tertiary amines. Hence several N-oxides are important as pharmacological or toxicological agents, e.g. , in the groups of alkaloids, chemotherapeutics, antibiotics, psychotropic drugs, methemoglobin forming compounds, and carcinogenic agents. Certain oncogenic N-oxides act as antimetabolites and have been postulated as inducers of spontaneous cancer. Finally, a large number of tertiary amine drugs produce N-oxides as metabolites or intermediates in drug metabolism.

N-Oxides have been detected in animals, plants, and microorganisms. TrimethylamineN-oxide, which occurs primarily in marine species but also in mammals, including man, has received most attention; however, its biosynthesis and its physiological functions have not yet been fully elucidated. In addition to the pharmacologically active N-oxides of natural origin, many others have been prepared synthetically.

Many findings suggest that N-oxides play an important role in the metabolism of drugs. In addition to N-oxidation of tertiary amines, N-dealkylation of N-oxides has been detected. This suggested a pathway of oxidative N-dealkylation of tertiary amines in which N-oxides would be intermediate metabolites. On the other hand strong evidence for a direct tertiary amine N-dealkylation has also been presented; in this case N-oxides would be by-products. However, N-oxides could also be intermediate metabolites because of the frequently occurring N-oxide reduction which transforms them into the corresponding tertiary amines. With some substrates several or all of these four reactions have been observed to occur simultaneously. Despite many investigations carried out in an attempt to elucidate the mechanisms and enzymatic characteristics of these reactions, our knowledge is stifi incomplete.
Abstract #LB-10: Neurofibromin directly interacts with the N-terminal domain of Focal Adhesion Kinase
Authors: Frederick Kweh, Min Zheng, Elena Kurenova, Margaret Wallace, Vita Golubovskaya, William Cance
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

The neurofibromin is a protein product of neurofibromatosis type 1 (NF1) tumor suppressor gene with a known RAS-GTPase activity, inactivating Ras pathway. Recent studies demonstrated a role of NF-1 in cytoskeletal and focal adhesion organization. In this study, we demonstrate that neurofibromin (NF-1) and Focal Adhesion Kinase (FAK) directly associate both in vivo and in vitro . Confocal microscopy detected NF-1 co-localization with FAK. The pull-down assay demonstrates that the N-terminal domain of FAK and the C-terminal domain of NF-1 directly interact. We show that Nf1+/+ MEF cells adhere less on collagen-treated plates than Nf1-/- MEF cells. Dominant-negative inhibitor of FAK, Adenoviral FAK-CD(C-terminal domain of FAK) caused significantly more detachment in Nf1+/+ MEF cells than in Nf1-/- MEF cells. These results for the first time demonstrate a novel interaction of neurofibromin and FAK. In addition, the results suggest NF-1 and FAK involvement in cell adhesion, cell growth, and other cellular events and pathways.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-10.
Effect of patients' expectations of benefit with standard breast cancer adjuvant chemotherapy on participation in a randomized clinical trial: a clinical vignette study.
Authors: J H Fetting, L A Siminoff, S Piantadosi, M D Abeloff, D J Damron, A M Sarsfield
Journal: Journal of Clinical Oncology (1990)

Patients frequently overestimate the benefit of standard breast cancer adjuvant therapy. This is due in part to vague doctor-patient communication. To examine how the doctor's description and patient's expectations of the benefit of standard therapy affect clinical trial participation, we randomized 282 female cancer patients to one of two versions of a clinical vignette describing a choice between standard cyclophosphamide, methotrexate, and fluorouracil (5FU) (CMF) and a randomized trial comparing CMF with cyclophosphamide, doxorubicin, and 5FU (CAF). The vignettes differed only on whether results with CMF were described verbally or numerically in terms of disease-free survival (DFS). After selecting CMF or the trial, patients estimated their 10-year DFS with CMF. Patients were randomized 3:1 to the verbal vignette. The trial was selected by 110 of 210 (52.4%) verbal vignette patients versus 25 of 72 (34.7%) numeric vignette patients (P = .01). Estimates of 10-year DFS with CMF varied considerably; many were inaccurate. When patients in the verbal vignette group were divided into thirds according to DFS estimate, 22 of 64 (34.4%) in the top third selected the trial versus 38 of 64 (59.4%) and 38 of 65 (58.5%) in the middle and bottom third, respectively (P = .005). Younger age, college education, and previous participation in a trial also predicted trial selection. Multivariate logistic regression suggested that the benefit expected from CMF was more important than how benefit was described in treatment selection. Assuring realistic patient expectations of standard adjuvant therapy benefit is likely to be important during discussion of clinical trials.
Abstract 1041: Endovascular Injury Affects Adipocytokine Profile Of The Periadventitial Adipose Tissue
Authors: Minoru Takaoka, Masataka Sata, Ryozo Nagai
Journal: Circulation (2007)

Background: Adipose tissue secretes not only proinflammatory cytokines but also anti-inflammatory cytokines such as adiponectin. Arteries are surrounded by abundant periadventitial fat tissues, which have been suggested to play a role in maintenance of vascular homeostasis. Here, we investigated whether endovascular injury affects the profile of adipocytokines expressed by perivascular adipose tissue (PAT). Methods and Results: First, the femoral artery of C57BL/6 mice was overstretched by insertion of a large wire. Real-time PCR analysis revealed that wire injury markedly down-regulated adiponectin expression (0.64±0.09 fold, p&lt;0.01) and up-regulated expression of proinflammatory cytokines, TNF alpha, IL-6, PAI-1, and MCP-1 (p&lt;0.01) 1 day after overstretch within PAT. Neutrophils and macrophages accumulated in the adventitia surrounding the injury site at 1 day after the injury. Inflammation was associated temporally with the expression of mRNAs encoding inflammatory adipocytokines. Second, the iliac artery of Wistar rats was dilated percutaneously with a balloon for 1 minute. There were up-regulation of proinflammatory cytokines and down-regulation of adiponectin 1 and 3days after endovascular injury within PAT (p&lt;0.05). Third, abdominal aortas removed from Wistar rat with PAT were dilated with a balloon PTCA catheter for 1 minute ex vivo. After stretching, aortas with PAT were cultured for 6 hours, and we observed increased synthesis of proinflammatory cytokines and decreased synthesis of adiponectin within PAT (p&lt;0.05). Fourth, the stimulation of TNF alpha, which markedly increased in injured arteries, caused significant down-regulation of adiponectin expression and up-regulation of IL-6, PAI-1, and MCP-1 in 3T3L1-derived adipocytes (p&lt;0.01). Conclusions: Angioplasty may induce the changes of perivascular cytokines expression. The accumulation of neutrophils and macrophages at PAT in injured arteries and/or increased proinflammatory expression of injured vascular arteries may reflect these proinflammatory activities of PAT. Increased proinflammatory cytokines and decreased anti-inflammatory cytokine adiponectin in PAT possibly may have a role in vascular remodeling following PTCA-mediated vascular injury.
Dexamethasone (dex) maintenance versus observation (obs) in patients with previously untreated multiple myeloma: A National Cancer Institute Of Canada Clinical Trials Group Study: MY.7
Authors: C. Shustik, A. Belch, S. Robinson, S. Rubin, S. Dolan, M. Kovacs, M. Djurfeldt, L. Shepherd, K. Ding, R. M. Meyer
Journal: Journal of Clinical Oncology (2004)

6510 Background: DEX is an active drug in patients with previously untreated or relapsed multiple myeloma (MM). We conducted a phase III trial comparing DEX vs. prednisone in combination with melphalan as induction therapy; and pulsed monthly DEX vs. OBS as maintenance in previously untreated patients (pts) with MM. No differences in outcomes were observed in induction (ASCO 2001); we now report the results of maintenance therapy. Methods: Patients with symptomatic Durie-Salmon stage I, or stage II/III previously untreated MM were randomized to one of 2 induction regimens given for 12 cycles: arms 1 and 2 -melphalan 9mg/m2 po and prednisone 100 mg po daily for 4 days q 4 weeks; arms 3 and 4 - melphalan as above and DEX 40 mg for 4 days q 4 weeks. At initial randomization, pts were also allocated to receive, if they did not progress, either maintenance with DEX 40mg daily for 4 days q 28 days (arms 2 and 4) or OBS (arms 1 and 3). The primary endpoint was overall survival (OS) with secondary endpoints of progression free survival (PFS), toxicity and quality of life. Results: 307 pts who reached the maintenance phase are included in this analysis; 158 allocated to DEX, 149 to OBS. Pts were balanced in baseline patient and disease-related characteristics, and response to induction therapy. With a median follow-up of 35.3 months, 177 patients have died: (90 DEX and 87 OBS). No benefit in OS was observed (p= 0.74; HR = 0.92, 95% C.I. 0.69–1.24) with median survivals of 3.86 yrs and 3.65 yrs for DEX and OBS respectively. No difference in the cause of death between the two groups was noted. 234 pts have progressed or died (114 DEX, 120 OBS). PFS is superior in patients randomized to receive DEX (p= 0.0001; HR = 0.60, 95% CI 0.47–0.78). Median PFS is 2.76 yrs with DEX and 1.97 yrs with OBS. Conclusion: DEX as monthly pulsed therapy following induction with a melphalan-based regimen improves PFS but not OS in previously untreated patients with MM. These results should be considered in the design of future trials assessing maintenance therapy. No significant financial relationships to disclose.
Molecular characteristics of diverse populations are consistent with the hypothesis of a recent invasion of Drosophila melanogaster by mobile P elements.
Authors: D Anxolabéhère, M G Kidwell, G Periquet
Journal: Molecular Biology and Evolution (1988)

Approximately 100 strains derived from natural populations of Drosophila melanogaster were tested for the presence or absence of P-element sequences by using two molecular probes derived from internal regions of a full-sized P element. Strains that had been collected from several continents at varying times during the past 60 years were examined. The oldest available strains, representing most major geographical regions of the world, exhibited no detectable hybridization to the P-element probes. In contrast, all recently collected natural populations that were tested carried P-element sequences. The earliest appearance of P elements occurred in collections made during the 1950s and early 1960s in the Americas and during the late 1960s on other continents. The youngest strains that were completely devoid of P elements originated in populations sampled during the mid-1960s in America, but as late as 1974 in populations from the USSR. There are differences in the patterns of hybridization to the two P-element probes between populations from different geographical regions. These differences are consistent with the varying P-M phenotypic properties of these populations. Taken together with the results of phenotypic tests reported in earlier studies, the available evidence is consistent with the hypothesis of a worldwide P-element invasion of D. melanogaster during the past 30 years and suggests that the putative invasion of the Americas possibly preceded by approximately a decade that in Europe, Africa, and the rest of the world.
New junior doctor contract will negatively affect women in surgery
Authors: Rhiannon L Harries, H Mohan, P Sinclair
Journal: BMJ (2015)

The Association of Surgeons in Training would like to voice its concerns about the proposed new contract.1 2 Aside from the risks it poses to patient safety and quality of surgical training within the UK, the contract will erode the positive steps made towards the recruitment, retention, …
Abstract MP46: Growth Factors Are Associated With Imaging Markers of Brain Aging in Young Adults
Authors: Claudia L Satizabal, Alexa Beiser, Jayandra J Himali, Rhoda Au, Philip A Wolf, Charles DeCarli, Ramachandran Vasan, Sudha Seshadri
Journal: Circulation (2015)

Metabolic and vascular dysregulation are related to stroke, cognitive decline and dementia. Growth factor biomarkers of these processes, such as Insulin-like Growth Factor 1 (IGF1) and Vascular Endothelial Growth Factor (VEGF) have been associated with risk of neurodegeneration and stroke in middle-aged and older Framingham participants. Additionally, hepatocyte growth factor (HGF) and angiopoietin 2 are novel biomarkers of interest as they have been related to cardiovascular events. As abnormal brain changes probably start years before clinical symptoms, we hypothesize that circulating growth factors are related to MRI endophenotypes of brain aging. We included 1,877 individuals aged 46±8 years from the Framingham Study. Blood samples were collected during 2008-2011, and used to measure IGF1, VEGF, HGF, angiopoietin 2 and its receptor tyrosine kinase (TIE2). Participants underwent brain MRI examination (2009-2013) from which brain volumes and white matter hyperintensities were estimated. We related growth factor levels to brain MRI markers adjusting for age, sex, time between blood draw and MRI, and cardiovascular risk factors. Lower IGF1, as well as higher HGF and angiopoietin 2 levels were associated with higher ventricular volumes indicative of brain shrinkage. Higher TIE2 levels were associated with lower total brain and gray matter volumes, while higher angiopoietin 2 levels were associated with lower white matter volumes. Lower IGF1 levels were also associated with reduced hippocampal volumes. Finally, higher TIE2 levels were associated with larger white matter hyperintensities. Our results suggest that growth factors are associated with neurodegenerative and cerebrovascular markers of brain aging in healthy young adults. Whereas IGF1 seems protective, higher levels of HGF, angiopoietin 2 and TIE2 were associated with greater subclinical brain injury. These associations expand our understanding of the earliest stages of brain aging. We will extend our findings by analyzing cognitive outcomes.
Integrity of acquired chromosomal alterations during the metastatic progression of human hepatocellular carcinoma detected by high-density comprehensive allelotype analysis
Authors: T. Nishimura, N. Nishida, T. Komeda, Y. Fukuda, K. Nakao
Journal: Journal of Clinical Oncology (2004)

9551 Background: It is widely accepted that chromosomal instability is one of the essential features of cancer cells and that significant intratumoral heterogeneity based on the genetic changes may be found in many type of cancer. Therefore, different metastatic lesions in an individual case may well show different genetic changes, reflecting the heterogeneity of the primary tumor, and may serve an important information regarding to the clonal evolution of the tumor. Methods: Tumor tissues of multiple metastatic lesions as well as intrahepatic lesions and non-tumor tissues were obtained from two autopsy cases with hepatocellular carcinoma (HCC) with informed consent. Extracted DNA was subjected to comprehensive allelotype analysis using 400 microsatellite markers that distribute throughout 22 autosomes and X chromosome. Furthermore, the alleles showing imbalance were subjected to comparative multiplex PCR, using a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss.Results:In the first case, allelic imbalances detected in the various metastatic lesions, including two macroscopically distinct lesions of main tumor, intrahepatic metastasis, epiploic lymph node metastasis, pulmonary metastasis and portal vein thrombus (PVT), were almost identical, showing –1p, +1q, -4q, +7, -8p, +8q, +9q, +10, -13q, -17p, +19p, -19q and -X. Additional alterations of +2q and –16q were detected in the PVT and the one portion of the main tumor. In the second case, allelic imbalances detected in three intrahepatic lesions and pulmonary metastasis were completely identical, showing +1, −2q, +4p, −4q, −5, −8p, +8q, +9, −11q, +12, −13q, −14q and −17p. Conclusions: The rate at which chromosomal aberrations accumulate in HCC is significantly slow, retaining the acquired chromosomal alterations during the metastatic progression of the tumor. No significant financial relationships to disclose.
Abstract 15424: The Predictive Value of Abdominal Aortic Calcification on a Plain X-Ray For the Presence of Significant Coronary Artery Stenosis in Asymptomatic Dialysis Patients
Authors: Maurits S Buiten, M K de Bie, J I Rotmans, M J Schalij, T J Rabelink, J W Jukema
Journal: Circulation (2012)

Background Coronary artery disease (CAD) is common in asymptomatic chronic dialysis patients and plays an important role in their poor survival. Early identification of these high risk patients cou...
Abstract 351: Comparative studies on SIRT6 and SIRT7 interactomes: Implications of important roles in cancer via associating with interacting partners
Authors: Namgyu Lee, Jung-Hee Kwon, Sung Jin Park, Kwan Yong Choi
Journal: Cancer Research (2014)

Abstract Sirtuins are NAD+-dependent deacetylases that regulate a range of cellular processes. Although anti-aging effects of sirtuins have been proposed, the proteins interacting with SIRT6 and SIRT7 remain elusive. In the current study, we identified SIRT6- and SIRT7-interacting proteins and compared their interactomes. Our data revealed 129 novel interacting proteins for SIRT6 and 122 for SIRT7 while confirming 7 and 111 previously identified proteins for SIRT6 and SIRT7, respectively. Comparison of the SIRT6 and SIRT7 interactomes under a same experimental condition disclosed 111 shared proteins indicated that functional associations. The functional networks of interactomes exhibited that the binding partners are associated with important biological processes in aging and age-related diseases including cancer. Two proteins, NPM1 and NCL localized in the nucleus and interacted with SIRT6 and SIRT7. NPM1 was identified as a novel substrate and its acetylation level decreased by both SIRT6 and SIRT7. Additionally, in senescent cells, the acetylation level of NPM1 was increased in conjunction with decreased level of SIRT6 and SIRT7, suggesting that acetylation of NPM1 is regulated by SIRT6 and SIRT7 in the aging process. Our findings provide insights on functional relationship between SIRT6 and SIRT7 as well as their roles in DNA repair, chromatin assembly and cancer cell proliferation, and aging. Citation Format: Namgyu Lee, Jung-Hee Kwon, Sung Jin Park, Kwan Yong Choi. Comparative studies on SIRT6 and SIRT7 interactomes: Implications of important roles in cancer via associating with interacting partners. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 351. doi:10.1158/1538-7445.AM2014-351
FoxO3 inactivation promotes human cholangiocarcinoma tumorigenesis and chemoresistance through Keap1‐Nrf2 signaling
Authors: Li Guan, Lei Zhang, Zhicheng Gong, Xiaonan Hou, Yuxiu Xu, Xinhua Feng, Hongyang Wang, Han You
Journal: Hepatology (2016)

FoxO transcription factors have been reported to play pivotal roles in tumorigenesis and drug resistance. The mechanisms underlying the tumor suppression function of FoxOs in human cancers remain largely unknown. Aberrant expression and activation of Nrf2 often correlate with chemoresistance and poor prognosis. Here, we report that FoxO3 directs the basal transcription of Kelch‐like ECH‐associated protein 1 (Keap1), an adaptor protein that bridges Nrf2 to Cul3 for degradation. FoxO3 depletion resulted in Keap1 down‐regulation, thereby activating Nrf2 signaling. We further demonstrated that inhibition of the FoxO3‐Keap1 axis accounts for Nrf2 induction and activation induced by constitutively active AKT signaling or tumor necrosis factor α treatment. Unlike previous findings, FoxO3 silencing led to decreased reactive oxygen species production, therefore protecting cells from oxidative stress‐induced killing in an Nrf2‐dependent manner. Importantly, FoxO3 deficiency strongly potentiated tumor formation in nude mice and rendered cholangiocarcinoma xenografts resistant to cisplatin‐induced cell death by activating Nrf2. Additionally, we found that clinical cholangiocarcinoma samples displayed FoxO3‐Keap1 down‐regulation and Nrf2 hyperactivation, underscoring the essential roles of these proteins in cholangiocarcinoma development. Conclusion : Our results unravel a unique mechanism underlying the tumor suppressor function of FoxO3 through constraining Nrf2 signaling. (H epatology 2016;63:1914‐1927)
International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics
Authors: Marek Jutel, Ioana Agache, Sergio Bonini, A. Wesley Burks, Moises Calderon, Walter Canonica, Linda Cox, Pascal Demoly, Antony J. Frew, Robyn O'Hehir, Jörg Kleine-Tebbe, Antonella Muraro, Gideon Lack, Désirée Larenas, Michael Levin, Bryan L. Martin, Harald Nelson, Ruby Pawankar, Oliver Pfaar, Ronald van Ree, Hugh Sampson, James L. Sublett, Kazunari Sugita, George Du Toit, Thomas Werfel, Roy Gerth van Wijk, Luo Zhang, Mübeccel Akdis, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2016)
Retrospective study of treatment outcomes according to exon difference with EGFR mutations in non-small cell lung cancer patient in Korea
Authors: Ho Sung Lee, Jae Sung Choi, Ki Hyun Seo, Ju Ock Na, Yong Hoon Kim, Mi Hye Oh, Sung Shick Jou
Journal: European Respiratory Journal (2012)

Background/Aims: EGFR mutations in NSCLCs are most important biomarker for EGFR-TKI treatment. About 90% of EGFR mutations are clustered in exons 19 (deletion) and 21 (point mutation at codon 858) and patients with these mutations have great response to EGFR-TKIs. However, the response rates of NSCLC to EGFR-TKIs according to types of EGFR mutation in Korea are still not cleared. This study aimed to evaluate the genomic types of EGFR mutation and compare the influence of each genomic types on the response to EGFR-TKIs and clinical outcomes in patients with NSCLC. Methods: We reviewed medical records from January 2007 to August 2011, and classified genotypes of EGFR mutations which were done by direct sequencing methods. Mutation status was compared with clinicopathological features. Clinical outcomes were assessed based on EGFR genotypes. Results: EGFR gene mutations were identified in 43(20.2%) out of 211 NSCLC patients. EGFR mutations were significantly more frequent in females than in males (37.1% vs. 13.4%, p < 0.001), but not correlated with smoking status (22.% vs. 18.1%, p = 0.311). There are no significant differences between exon 19 deletion and exon 21 point mutation at cordon 858 in progression-free survival (10.9 vs. 9.1 months; p = 0.554), nor in overall survival (21.8 vs. 18.2 months; p = 0.142) and disease control rate (90% vs 85.7%; p = 0.669) with EGFR-TKI treatment. Conclusion: PFS and overall survival were not significantly different between exon 19 deletions and Exon 21 L858R mutations, these results are similar to those of previous studies.