tbuckley/cabot-search huggingface dataset:
Biochemical and molecular modeling studies of mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic cancer cells
Authors: David Siegel, Philip Reigan, Marie A. Colucci, Jeffery Newsome, Christopher J. Moody, David Ross
Journal: Cancer Research (2006)

3821   Inhibition of NQO1 may result in increased intracellular superoxide, inhibition of cell growth and of the  in-vitro  malignant phenotype in human pancreatic cancer cells. We have designed mechanism-based (suicide) inhibitors of NQO1 based on 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936). The ability of ES936 and a series of structurally related analogs to inhibit purified recombinant human NQO1 (rhNQO1), induce growth inhibition in the human MIAPaCa-2 pancreatic tumor cell line and dock in the active site of NQO1 were examined. ES936 and MAC03/220 were the most efficient inhibitors of rhNQO1 with partition ratios near 4 while MAC03/246 and MAC03/225 were less efficient inhibitors with partition ratios of 44 and 97 respectively. NQO1 inhibition studies in MiaPaCa-2 human pancreatic cancer cells closely paralleled studies with rhNQO1. Treatment of MiaPaCa-2 cells with ES936 or MAC03/220 for 1hr resulted in >99% inactivation of NQO1 at nanomolar concentrations while higher concentrations (micromolar) were required for complete inactivation of NQO1 by the other inhibitors. Growth inhibition studies (MTT) in MiaPaCa-2 cells also paralleled NQO1 inactivation. ES936 and MAC03/220 were more cytotoxic when compared to MAC03/246 and MAC03/225. A molecular docking study of this series of indolequinones in the FADH 2 -site of the human NQO1 crystal structure (PDB: 1KBQ) was performed. These docking studies suggest that NQO1 can accommodate a range of indolequinone substitutions and a variety of different binding modes and interactions. The highest interaction energies in this study were obtained with ES936 and MAC03/220 due to favorable interactions of the indolequinone with Tyr126 or Tyr128, the FADH 2  cofactor and the 4-nitrophenoxy substituent with hydrophobic amino acid residues. Lower interaction energies were calculated for MAC03/246 and MAC03/225. The indolequinone docking studies support the model in which quinones with fused aromatic rings are positioned in the active site so as to optimize π-ring stacking interactions with the reduced isoalloxazine ring system of the FADH 2  cofactor. The ranking of this series of indolequinones from these docking studies supports the biochemical data and suggests that the Affinity molecular docking program can be used as a predictive tool in the rational design of novel indolequinone mechanism-based NQO1 inhibitors (Supported by CA11441).
Treatment for frail elderly patients with diffuse large B-cell lymphoma (DLBCL): A single center experience.
Authors: Pascal Chaïbi, Amale Chebib, Elodie Baudry, Elise Cotto, Francois Piette, Sylvie Berigaud, Melany Siriwardana, Nathalie Mitha, Nelly Koenig, Jean-Philippe Spano
Journal: Journal of Clinical Oncology (2012)

e18505 Background: DLBCL occurs frequently in elderly pts and recent studies demonstrated that immunochemotherapy with R-mini-CHOP could be a safe and effective treatment for selected pts over 80 years Methods: Since 2008, R-mini-CHOP has been the treatment proposed for elderly pts with DLBCL referred to our oncogeriatric unit, irrespectively of their performance status (PS). We reviewed data of elderly pts treated for DLBCL at our institution from January 2008 to June 2011. Results: 74 pts (50 women, 24 men) were treated for DLBCL. Median age was 85 years (range 71–97), 84 % of pts ≥ 80 years and 16 % of pts ≥ 90 years. 68 pts (92%) had at least one comorbidity. Median number of daily medicines was 4 (range 0 – 12), irrespectively of treatments for DLBCL. Malnutrition was diagnosed in 49 pts. 50 pts (67,5 %) had a poor PS (&gt; 2). Age-adjusted International Pronostic Index (aaIPI) was 0-1 in 9 pts, 2 in 28 pts and 3 in 35 pts. 61 pts were treated with mini-CHOP (cyclophosphamide: 400 mg/m2 D1; doxorubicine: 25 mg/m2 D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m2 by oral route from D1 to D5) plus rituximab (375 mg/m2 D1) every 21 days for 6 cycles. Doxorubicine was replaced by etoposide (150 mg/m2 D1) for 5 pts because of cardiac dysfunction. 8 pts received reduced dose intensity chemotherapy ( without doxorubicine) for the 2 first cycles because of high risk toxicity. Prophylaxis of neutropenia with GCSF was systematic. Median survival was 11 months. 21 pts died during treatment, because of progressive disease (13) or treatment toxicity (6). Complete response (CR) was observed in 44 pts (59,5 %). With a median follow-up of 18 months, 11 relapses were observed. In our population study, aaIPI appears highly predictive of CR, with a CR Rate of 87,5 %, 75 % and 43% respectively for pts with aaIPI 0 - 1, 2 and 3.Hematological toxicity was the most common side effect. Grade 3–4 neutropenia was observed in 28% of the pts and grade 3–4 thrombocytopenia in 12%. 14 pts (19%) experienced at least one episode of febrile neutropenia. Conclusions: In unselected elderly pts with DLBCL, immunochemotherapy with R-mini-CHOP can be effective, but with significant toxicity, even using systematic G-CSF prophylaxis. Prognosis remains poor for pts with aaIPI 3
Practical Implications of the 2016 Revision of the World Health Organization Classification of Lymphoid and Myeloid Neoplasms and Acute Leukemia
Authors: John P. Leonard, Peter Martin, Gail J. Roboz
Journal: Journal of Clinical Oncology (2017)

A major revision of the WHO classification of lymphoid and myeloid neoplasms and acute leukemia was released in 2016. A key motivation for this update was to include new information available since the 2008 version with clinical relevance for the diagnosis, prognosis, and therapy of patients. With > 100 entities described, it is important for the clinician to understand features that may be important in daily practice, whereas researchers need to incorporate the new classification scheme into study development and analysis. In this review, we highlight the key aspects of the 2016 update with particular importance to routine patient care and clinical trial design.
Law, ethics, and emotion: the Charlie Gard case
Authors: Clare Dyer
Journal: BMJ (2017)

The fight over the treatment of terminally ill baby Charlie Gard has been unprecedented, both legally and in its coverage on social media. His parents’ last hope, the European Court of Human Rights, turned them down last week, ruling that the baby should be allowed to die. <b>Clare Dyer</b> looks back at this case and considers where it leaves doctors
Declining Risk of Sudden Death in Heart Failure
Authors: Li Shen, Pardeep S. Jhund, Mark C. Petrie, Brian L. Claggett, Simona Barlera, John G.F. Cleland, Henry J. Dargie, Christopher B. Granger, John Kjekshus, Lars Køber, Roberto Latini, Aldo P. Maggioni, Milton Packer, Bertram Pitt, Scott D. Solomon, Karl Swedberg, Luigi Tavazzi, John Wikstrand, Faiez Zannad, Michael R. Zile, John J.V. McMurray
Journal: New England Journal of Medicine (2017)

The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail.We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization.Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis.Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.).
Assessment of the Natural History of Microscopic Colitis
Authors: CP O'Brien, S O'Donnell, H Barrett, D Royston, S Patchett
Journal: Endoscopy (2006)

Aims: Microscopic (collagenous and lymphocytic) colitis is characterised by chronic diarrhoea, normal endoscopic and radiological findings and typical findings on histology. The natural history of microscopic colitis has been poorly characterised and the aim of our study was to determine the long-term outcome of this condition.
The prognostic impact of primary tumor location in patients undergoing resection for colorectal liver metastasis: A propensity score-matched analysis
Authors: Yuichi Goto, René Adam, Carlos Castro-Benitez, Oriana Ciacio, Gabriella Pittau, Eric Vibert, Antonio Sa-cunha, Daniel Cherqui, Denis Castaing
Journal: Annals of Oncology (2017)
Book: Childfree and Sterilised: Women's Decision and Medical Responses
Authors: Wendy Savage
Journal: BMJ (2000)

Annily Campbell


Cassell, £14.99, pp 256 




ISBN 0 304 33747 1

———————

Rating: ★★ for style, ★★★ for interest

The need for informed consent and involving patients in decisions about their care have become features of health care in this decade, outlined by the General Medical Council in Good Medical Practice and, more recently, in their guidance on consent. As someone who has upheld the rights of women to choose to have an abortion or how to give birth naturally, I am uneasy about the current trend of viewing medicine as another form of consumerism. Shopping around for a doctor who will do what the patient wants regardless of his or her professional opinion as to the risks and benefits of surgery or medical treatment, on the grounds that the patient's autonomy requires unfettered choice, denies the doctor autonomy and undermines the concept of professionalism.

Annily Campbell's meticulous research into 23 women who wanted to be sterilised because they were sure they would never want to have children discusses their difficulties from a feminist view. The theoretical background is well covered but, for me, less interesting than the women's descriptions of the obstacles they faced and the way they reached their decisions. Some of the participants expressed anger that women who embarked on pregnancy even when quite young did not have to justify their decision to bear a child, whereas they, who had decided they did not want to do this, were regarded as abnormal. Only one woman had any regrets, and most had known from an early age that they had no desire to become mothers and had used contraception for some years.

My own view, medically, is that sterilisation is a good option for women (or couples) who have made a mature decision that they do not want any, or any more, children whatever happens. I have not used absolute age or parity limits. If one accepts this how does one, as a professional, decide that the decision is mature? When I followed up over 300 women I had sterilised in New Zealand 1% regretted the decision, but none of these was young or nulliparous.

I did not agree to sterilise one woman aged 18 or recommend vasectomy for a man of 20, and I do not know how they felt about this. I hope they did not feel that I had treated their requests as contemptuously or dismissively as reported by some of the women in this book. As a professional, you must explain why in your opinion the risks outweigh the benefits of any procedure, but the crucial dilemma remains that, while you act on the basis of your training, review of the literature, and experience of patients, the person facing you is an individual who may be quite certain in her own mind that she knows what is best for her. Should her autonomy prevail over yours as a professional who has to do an operation which carries risks, albeit small? There are lessons here for doctors: as Osler said, “Listen to the patient he is telling you the diagnosis.”
Biased activity of soluble guanylyl cyclase: the Janus face of thymoquinone
Authors: Charlotte Detremmerie, Paul M. Vanhoutte, Susan Leung
Journal: Acta Pharmaceutica Sinica B (2017)

The natural compound thymoquinone, extracted from Nigella sativa (black cumin), is widely used in humans for its anti-oxidative properties. Thymoquinone is known for its acute endothelium-independent vasodilator effects in isolated rat aortae and pulmonary arteries, depending in part on activation of adenosine triphosphate-sensitive potassium channels and inhibition of voltage-dependent calcium channels. The compound also improves endothelial dysfunction in mesenteric arteries of ageing rodents and in aortae of rabbits treated with pyrogallol, by inhibiting oxidative stress. Serendipitously, thymoquinone was found to augment contractions in isolated arteries with endothelium of both rats and pigs. The endothelium-dependent augmentation it causes counterintuitively depends on biased activation of soluble guanylyl cyclase (sGC) producing inosine 3ʹ,5ʹ-cyclic monophosphate (cyclic IMP) rather than guanosine 3ʹ,5ʹ-cyclic monophosphate. This phenomenon shows a striking mechanistic similarity to the hypoxic augmentation previously observed in porcine coronary arteries. The cyclic IMP preferentially produced under thymoquinone exposure causes an increased contractility of arterial smooth muscle by interfering with calcium homeostasis. This brief review summarizes the vascular pharmacology of thymoquinone, focussing in particular on how the compound causes endothelium-dependent contractions by biasing the activity of sGC.
Abstract 54: Effect of Salubrinal and PP1 on Cardiomyocytes Protection After Myocardial Infarction in Rats
Authors: Chunlei Liu, Yunyun He, Kunlun He
Journal: Circulation Research (2015)

Objective: salubrinal, an inhibitor of ER-stress, has potent effect on cell injury. In this study, we investigated the effect of salubrinal and its dervative-PP1 on cell protection aganinst myocardial infarction ( MI). Methods: Male wistar rats were randomly divided into 5 groups:i) sham-operated; ii) vehicle (MI+ DMSO); iii) MI + salubrinal; iv) MI + PP1; v) MI + metoprolol. After 24 hours treatment, heart tissue was havested and stained by 2,3,5-triphenyltetrazolium chloride (TTC). Serum was havested for the detection of CK-MB, cTNT, CRP. The changes in histomophology were observed using hematoxylin and eosin (HE) staining. The expression of mRNA and protein involved in apoptosis, autophagy, ER stress was analyzed using real-time reverse transcription-polymerase chain reaction and western blotting, respectively. Results: Salubrinal and PP1 decreased the infarction area and the level of CK-MB, cTNT, CRP. The mechanism analysis demonsted that salubrinal and PP1 have a cell protection through a ER-stress related pathway, showing upregualtion of PERK, eIF2α, ATF4, GRP78, GADD34, p62 , LC3IIand down regualtion of chop, caspase12 as detected by real-time PCR and western blotting. Conclusions: The current study suggested that salubrinal and PP1 have a cell protection effect involed in ER stress related autophay and apoptosis.This may implicated that salubrinal and PP1 may be a potent compound for the treatment of MI.
Gemcitabine cisplatin regimen in patients with advanced or metastatic pancreatic cancer (AMPC)
Authors: El Hakim Boudjella Abdelkader, Fethia Braneci, Nacera Caid, Radia Benemla, Louiza Saoudi, Soumia Rekkache, Radia Ramoul, Farida Smaili
Journal: Annals of Oncology (2017)
Low Bax/Bcl-2 Ratio and NOTCH1 Mutations Represent Powerful and Synergistic Adverse Prognostic Factors within Trisomy 12 Chronic Lymphocytic Leukemia (CLL)
Authors: Giovanni Del Poeta, Maria Ilaria Del Principe, Massimiliano Postorino, Michele Dal Bo, Maria Francesca Rossi, Francesco Buccisano, Luca Maurillo, Davide Rossi, Livio Pupo, Benedetta Mariotti, Adriano Venditti, Paolo de Fabritiis, Maria Cantonetti, Gianluca Gaidano, Francesco Lo Coco, Valter Gattei, Sergio Amadori
Journal: Blood (2016)
Evaluation of Chest Pain in the Emergency Department
Authors: Richard V. Aghababian
Journal: Annals of Internal Medicine (1995)

Letters15 August 1995Evaluation of Chest Pain in the Emergency DepartmentRichard V. AghababianRichard V. AghababianSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-123-4-199508150-00015 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:As President of the American College of Emergency Physicians, I must comment on the editorial by Kaul and Abbott [1]. The authors are apparently unfamiliar with the capabilities of most emergency physicians. The authors state that “emergency department physicians, by the nature of their training are generalists, and not experts in cardiovascular medicine.” I point out that emergency medicine has been recognized as a medical specialty by the American Board of Medical Specialties and that graduates of emergency residency programs have completed at least 36 months of training.The authors correctly note that reports published in the ...References1. Kaul S, Abbott RD. Evaluation of chest pain in the emergency department (Editorial). Ann Intern Med. 1994; 121:976-8. Google Scholar2. Aufderheide TP, Keelan MH. Milwaukee prehospital chest pain project, phase I: feasibility and accuracy of prehospital thrombolytic candidate selection. Am J Cardiol. 1992; 69:991-6. Google Scholar3. Gibler WB, Young GP, Hedges JR, et al. The Emergency Medicine Cardiac Research Group: acute myocardial infarction in chest pain patients with nondiagnostic ECG. Serial CK-MB sampling in the emergency department. Ann Emerg Med. 1992; 21:504-12. Google Scholar4. Graff LG, ed. Observation Medicine. Boston: Andover Medical; 1993. Google Scholar Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 August 1995Volume 123, Issue 4Page: 314-318KeywordsAcute myocardial infarctionCreatineElectrocardiographyEmergency departmentEmergency medicineIschemiaMyocardial infarctionPatientsResidencyShock ePublished: 15 August 2000 Issue Published: 15 August 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
CanStem111P trial: A phase III study of napabucasin plus nab-paclitaxel (nab-PTX) with gemcitabine (gem) in adult patients with metastatic pancreatic adenocarcinoma (mPDAC)
Authors: T. Bekaii-Saab, D. Goldstein, C.P. Li, T. Okusaka, B. O’Neil, M. Reni, J. Tabernero, S. Qin, E. Van Cutsem, L. Borodyansky, C.J. Li
Journal: Annals of Oncology (2017)
Use of next-generation sequencing (NGS) to detect a novel ALK fusion and a high frequency of other actionable alterations in colorectal cancer (CRC).
Authors: Jeffrey S. Ross, Doron Lipson, Christine E Sheehan, Geoff Otto, Roman Yelensky, Alex Parker, Mirna Jarosz, Frank Juhn, Tina Brennan, Sean Downing, Amy Donahue, Sohail Balasubramanian, Gary A. Palmer, Vincent A. Miller, Philip Stephens, Maureen T. Cronin
Journal: Journal of Clinical Oncology (2012)

3533 Background: We hypothesized that NGS could identify genomic alterations that guide selection of targeted therapies and discover novel drug targets for primary and metastatic CRC. Methods: DNA was extracted and sequenced from 4 X 10 μ FFPE sections from 40 (32 primary and 8 metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage unknown) using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions (64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions (1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of CRCs respectively, with both mutated more frequently than reported in COSMIC. Alterations associated with potential sensitivity to targeted therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS (TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 Mb tandem duplication generated a novel C2orf44-ALK gene fusion starting at the canonical exon 20 recombination site previously reported for the majority of ALK gene fusions. cDNA sequencing identified an 90-fold increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results in ALK kinase domain overexpression and contains the same intracellular domain as other ALK fusions including the ALK inhibitor sensitive EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from FFPE CRC samples uncovered an unexpectedly high frequency of genomic alterations, many of which may be clinically actionable by informing treatment decisions, including a novel ALK gene fusion. This previously unrecognized subset of CRC patients may be candidates for clinical trials of crizotinib or other ALK inhibitors.
RNA Editing in Pathogenesis of Cancer
Authors: Bora E. Baysal, Shraddha Sharma, Seyedsasan Hashemikhabir, Sarath Chandra Janga
Journal: Cancer Research (2017)

Several adenosine or cytidine deaminase enzymes deaminate transcript sequences in a cell type or environment-dependent manner by a programmed process called RNA editing. RNA editing enzymes catalyze A>I or C>U transcript alterations and have the potential to change protein coding sequences. In this brief review, we highlight some recent work that shows aberrant patterns of RNA editing in cancer. Transcriptome sequencing studies reveal increased or decreased global RNA editing levels depending on the tumor type. Altered RNA editing in cancer cells may provide a selective advantage for tumor growth and resistance to apoptosis. RNA editing may promote cancer by dynamically recoding oncogenic genes, regulating oncogenic gene expression by noncoding RNA and miRNA editing, or by transcriptome scale changes in RNA editing levels that may affect innate immune signaling. Although RNA editing markedly increases complexity of the cancer cell transcriptomes, cancer-specific recoding RNA editing events have yet to be discovered. Epitranscriptomic changes by RNA editing in cancer represent a novel mechanism contributing to sequence diversity independently of DNA mutations. Therefore, RNA editing studies should complement genome sequence data to understand the full impact of nucleic acid sequence alterations in cancer. Cancer Res; 77(14); 3733-9. ©2017 AACR.
Retrospective Study Evaluating Hematological Remission Rates and Survival in Chinese Adults with Relapsed or Refractory (r/r) Philadelphia Chromosome Negative (Ph-) B-Precursor Acute Lymphoblastic Leukemia (ALL)
Authors: Jun Ma, Ting Liu, Jie Jin, Jianda Hu, Qifa Liu, Jianxiang Wang, Zhixiang Shen, Xin Du, Bin Jiang, Xianhua Meng
Journal: Blood (2016)