tbuckley/cabot-search huggingface dataset:
Abstract 331: Targeting MCL1 in NPM1-mutant AML
Authors: Haitham Qutob, Amina Abdul-Aziz, Amy Proudfoot, Martin Grundy, Nigel H. Russell, Monica Pallis, Claire H. Seedhouse
Journal: Cancer Research (2014)

Abstract MCL1 and BCL2 are pro-survival molecules which inhibit the apoptosis of AML cells treated with cytotoxic chemotherapy. The nuclear chaperone NPM1 is the most frequently mutated gene in AML. Using siRNA, we established that knockdown of NPM1 reduced expression of both MCL1 (P=0.034) and BCL2 (P=0.025) and increased p53 expression (P=0.03) in NPM1-mutant OCI-AML3 cells. These effects were not seen in cells expressing wildtype NPM1. The differentiating agent ATRA also reduced expression of both MCL1 (P=0.005) and BCL2 (P=0.0005). ATRA (3 days, 500 nM) reduced cell number by 50% in OCI-AML3 cells through growth inhibition, inducing features of differentiation and very little apoptosis. Whereas inhibition of BCL2 using up to 3 µM ABT199 did not augment ATRA-mediated cell reduction in OCI-AML3 cells, RNApolymerase II inhibitors, which preferentially target proteins with a short half-life such as MCL1, and which induce apoptosis, acted additively with ATRA to kill OCI-AML3 cells. Primary AML cells with mutant NPM1 (n=38) expressed higher levels of MCL1 but not of BCL2 than NPM1 wildtype samples (n=61). Primary AML cells frequently co-harbour mutant NPM1 and mutations of the receptor tyrosine kinase FLT3. As FLT3 mutation drives aberrant MCL1, we examined the effects of ATRA on MCL1 in NPM1 mutant samples with and without a FLT3 mutation. ATRA (3 days, 500 nM) induced the downregulation (&amp;gt;20%) of MCL1 in 4/4 primary NPM1 mutant/FLT3 wildtype AML samples compared to 0/3 primary NPM1 mutant/FLT3 mutant AML samples. MCL1 was also downregulated by ATRA in 2/5 double wildtype samples. BCL2 was downregulated by ATRA in 1/4 primary NPMmutant/FLT3 wildtype AML samples, 2/3 primary NPM1 mutant/FLT3 mutant AML samples and 2/5 double wildtype samples. In conclusion, we show that MCL1 levels can be downregulated by mutant NPM1 inhibition and by ATRA in NPM1mutant/FLT3wildtype AML cells. RNA polymerase II inhibitors are clinically available and this work shows that ATRA can enhance their cytotoxic activity. Citation Format: Haitham Qutob, Amina Abdul-Aziz, Amy Proudfoot, Martin Grundy, Nigel H. Russell, Monica Pallis, Claire H. Seedhouse. Targeting MCL1 in NPM1-mutant AML. [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 331. doi:10.1158/1538-7445.AM2014-331
Distribution of joint involvement in women with hand osteoarthritis and associations between joint counts and patient-reported outcome measures
Authors: B Slatkowsky-Christensen, I Haugen, T K Kvien
Journal: Annals of the Rheumatic Diseases (2009)

Objective: This study investigated the association between clinically assessed finger joint involvement (joint counts) and patient outcome measures in hand osteoarthritis (HOA). Methods: Women with HOA (n = 190) (between 50 and 70 years of age, mean 61.6 years) completed a clinical examination, which included assessment of finger joints (carpometacarpal (CMC) joints, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints and distal interphalangeal (DIP) joints) with regard to tenderness/pain, soft tissue swelling, bony enlargement and limited motion, measurement of grip strength and completion of a booklet with questionnaires (Australian/Canadian Osteoarthritis Hand Index (AUSCAN), Arthritis Impact Measurement Scales 2 (AIMS2), Health Assessment Questionnaire (HAQ), Short Form 36 assessment (SF-36) and visual analogue scale for pain (VAS pain)). Results: DIP joints were most frequently affected. Presence of pain in any PIP or DIP finger joint was associated with worse health status. The three other categories of joint findings were generally also associated to worse health status, but associations were mostly not statistically significant. Correlations between tender and swollen joint counts in most finger joint areas and scores of specific outcome measures (AUSCAN, AIMS2 hand + finger), VAS pain and grip strength were mild to moderate, whereas correlations between joint counts and scores of general physical function, general pain and other dimensions of health (AIMS2 and SF-36) were generally low. Conclusions: The association between painful CMC, PIP and DIP joint counts and worse scores for key dimensions of health was moderate.
Aortic Aneurysm in Elderly Patients
Authors: Barbara E. Cammer Paris
Journal: Annals of Internal Medicine (1998)

Letters15 July 1998Aortic Aneurysm in Elderly PatientsBarbara E. Cammer Paris, MD and Christine Cassel, MDBarbara E. Cammer Paris, MDMount Sinai Medical Center; New York, NY 10029Search for more papers by this author and Christine Cassel, MDMount Sinai Medical Center; New York, NY 10029Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-129-2-199807150-00037 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read Dr. Fiebach's article [1] with a great sense of familiarity. As primary care geriatricians in a multispecialty outpatient practice (average age of patients, 83 years), weighing the risks and benefits of procedures in patients like Dr. S is part of our expertise and daily experience. We were, therefore, particularly surprised by the statement that the gerontologist with whom the author consulted “offered only that his approach was not to look for abdominal aneurysms in octogenarians.”Abdominal aortic aneurysm (AAA) is, for the most part, a disease of the elderly. Elective surgery can improve survival in ...References1. Fiebach NH. Rise and fall. Ann Intern Med. 1997; 127:1037-8. Google Scholar2. Vander der Vliet JA, Boll AP. Abdominal aortic aneurysm. Lancet. 1997; 349:863-6. Google Scholar3. Katz DJ, Stanley JC, Zelenock GB. Operative mortality rates for intact and ruptured abdominal aortic aneurysms in Michigan: an eleven-year statewide experience. J Vasc Surg. 1994; 19:804-17. Google Scholar4. Blum U, Gotz V, Lammer J, Beyersdorf F, Tollner D, Kretschmer G, et al. Endoluminal stent-grafts for infrarenal abdominal aortic aneurysms. N Engl J Med. 1997; 336:13-20. Google Scholar5. Thomas DR, Ritchie CS. Preoperative assessment of older adults. J Am Geriatr Soc. 1995; 43:811-21. Google Scholar Author, Article, and Disclosure InformationAffiliations: Mount Sinai Medical Center; New York, NY 10029 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byRenal perfusion with venous blood extends the permissible suprarenal clamp time in abdominal aortic surgery 15 July 1998Volume 129, Issue 2Page: 166KeywordsAbdominal aortic aneurysmAnesthesiaAneurysmsDeath ratesElderlyGeriatricsLife expectancyOutpatientsPatientsSurgery ePublished: 15 August 2000 Issue Published: 15 July 1998 Copyright & PermissionsCopyright © 1998 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Serodiagnosis of<i>Mycobacterium abscessus</i>complex infection in cystic fibrosis
Authors: Tavs Qvist, Tania Pressler, David Taylor-Robinson, Terese L. Katzenstein, Niels Høiby
Journal: European Respiratory Journal (2015)

Early signs of pulmonary disease with Mycobacterium abscessus complex (MABSC) can be missed in patients with cystic fibrosis (CF). A serological method could help stratify patients according to risk. The objective of this study was to test the diagnostic accuracy of a novel method for investigating IgG activity against MABSC. A prospective study of all patients attending the Copenhagen CF Centre was conducted by culturing for MABSC during a 22-month period and then screening patients with an anti-MABSC IgG ELISA. Culture-positive patients had stored serum examined for antibody kinetics before and after culture conversion. 307 patients had 3480 respiratory samples cultured and were then tested with the anti-MABSC IgG ELISA. Patients with MABSC pulmonary disease had median anti-MABSC IgG levels six-fold higher than patients with no history of infection (434 versus 64 ELISA units; p&lt;0.001). The test sensitivity was 95% (95% CI 74–99%) and the specificity was 73% (95% CI 67–78%). A diagnostic algorithm was constructed to stratify patients according to risk. The test accurately identified patients with pulmonary disease caused by MABSC and was suited to be used as a complement to mycobacterial culture.
Abstract 4192: LIN28 mRNA targets in breast cancer cells
Authors: Harriet K. Kinyamu, Jun Yang, Trevor K. Archer
Journal: Cancer Research (2012)

Abstract LIN28 is a RNA binding protein and a pluripotency factor. It represses tumor suppressing microRNA let-7 and activates let-7 oncogene targets such as HMGA2 and c-Myc. Recent reports show that LIN28 overexpression promotes tumor cell migration and cellular transformation through repression of let-7, and that overexpression is associated with advanced stages of disease, including breast cancer. The molecular function and mode of action of LIN28 in breast cancer is not yet elucidated. To further understand the function of LIN28, we explored LIN28 mRNA targets in breast cancer cells using RNA-protein immunoprecipitation (RIP) followed by RNA sequencing (RIP-Seq). Only 418 genes (1.7% of the human total genes) are enriched more than 1.0 RPKM (reads per kilobase of exon model per million mapped reads) in the LIN28 RIP relative to control RIP. LIN28 mRNA targets in breast cancer cells function in processes that drive tumorigenesis, including cell proliferation, inflammation and metastasis. Therapeutic drugs inhibiting LIN28 could be promising in treatment of cancer. Our experiments also demonstrate that MG132, a proteasome inhibitor, inhibits LIN28 expression and modulates expression of LIN28 mRNA targets in breast cancer cells. Studies are ongoing to reveal the mechanisms by which LIN28 regulates bound targets and how proteasome inhibitors impact this regulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4192. doi:1538-7445.AM2012-4192
Neutrophil-induced injury of rat pulmonary alveolar epithelial cells.
Authors: R H Simon, P D DeHart, R F Todd
Journal: Journal of Clinical Investigation (1986)

The damage to pulmonary alveolar epithelial cells that occurs in many inflammatory conditions is thought to be caused in part by phagocytic neutrophils. To investigate this process, we exposed monolayers of purified rat alveolar epithelial cells to stimulated human neutrophils and measured cytotoxicity using a 51Cr-release assay. We found that stimulated neutrophils killed epithelial cells by a process that did not require neutrophil-generated reactive oxygen metabolites. Pretreatment of neutrophils with an antibody (anti-Mo1) that reduced neutrophil adherence to epithelial cells limited killing. Although a variety of serine protease inhibitors partially inhibited cytotoxicity, we found that neutrophil cytoplasts, neutrophil lysates, neutrophil-conditioned medium, purified azurophilic or specific granule contents, and purified human neutrophil elastase did not duplicate the injury. We conclude that stimulated neutrophils can kill alveolar epithelial cells in an oxygen metabolite-independent manner. Tight adherence of stimulated neutrophils to epithelial cell monolayers appears to promote epithelial cell killing.
Lidocaine-Induced Brugada Syndrome Phenotype Linked to a Novel Double Mutation in the Cardiac Sodium Channel
Authors: Hector M. Barajas-Martínez, Dan Hu, Jonathan M. Cordeiro, Yuesheng Wu, Richard J. Kovacs, Henry Meltser, Hong Kui, Burashnikov Elena, Ramon Brugada, Charles Antzelevitch, Robert Dumaine
Journal: Circulation Research (2008)

Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of I Na generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of I Na by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (−14.1±0.3 mV and −4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.
Involvement of calcium in macrophage leukotriene release during experimental cirrhosis
Authors: L Alric, E Pinelli, G Carrera, J P Vinel, M Beraud, M Duffaut, J P Pascal, B Pipy
Journal: Hepatology (1996)

The aim of the present study was to assess the mechanism of 5-lipoxygenase metabolites (LT) secretion by peritoneal macrophages in rats wih CC14 induced cirrhosis. After stimulation with calcium ionophore A23187 or opsonized zymosan, [3H] arachidonic acid labeled macrophages from cirrhotic rats presented a significantly greater secretion of LT than macrophages from healthy controls. In addition, the phorbol ester TPA (protein kinase C activator) increased LT production only in macrophages from cirrhotic animals and not in controls. Although Ca2+ is thought to be involved in 5 lipoxygenase activation, the role of Ca2+ in LT production was studied. The use of a Ca2+-free medium as well as the addition of TMB-8 (an inhibitor of intra-cellular Ca2+ movements and of plasma membrane Ca2+ fluxes) resulted in a fall in LT production greater for macrophages from cirrhotic animals than for controls. The measurement of cytosolic Ca2+ concentration by cytofluorimetry showed that Fluo-3 loaded macrophages from cirrhotic rats had a greater cytosolic CA2+ concentration than macrophages from control animals both in basal conditions and after A23187 stimulation. Study of 45Ca2+ uptake suggest, that extra-cellular Ca2+ is implicated in the elevated cytosolic Ca2+ observed in macrophages from cirrhotic animals as compared to healthy controls. The greater Ca2+ concentration observed in macrophages from cirrhotic rats was not related to a difference in phospholipase C activation because inositol phosphate production did not differ between macrophages from healthy and cirrhotic animals. Taken together these results suggest that as compared to healthy animals, the greater LT production during cirrhosis could be dependent upon a difference in 5-lipoxygenase activation related to a rise in cytosolic Ca2+ concentration independently of inositol phosphates generation.
Characteristics and survival of 26 patients with paraneoplastic arthritis
Authors: J Morel, V Deschamps, E Toussirot, E Pertuiset, C Sordet, P Kieffer, J M Berthelot, H Champagne, X Mariette, B Combe
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To date, only a few series of patients with paraneoplastic arthritis have been published. The charts of patients with cancer-associated arthritis were collected in order to describe characteristics of this rheumatism. <h3>Methods:</h3> A questionnaire was created for this study and validated by experts based on specific criteria of inclusion and exclusion. Histology of neoplasia was included. <h3>Results:</h3> In all, 16 males and 10 females with a mean (range) age of 57.5 years (28–85) were recruited from 17 nationwide centres in France. Patients presented with symmetric polyarthritis involving wrists and hands (85%) and extra-articular symptoms were frequent (84%). There was no specific biologic or radiographic feature. The mean (range) delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0–21.2). Tumours were usually diagnosed after articular symptoms occurred (88.5%). Twenty patients had a solid cancer, and six a haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). Tumours were diagnosed at an early stage, which may explain the good median survival of 1.21 years (range 0.64–present) with a mean follow-up of 1.9 years (range 0.16–10). The percentage of articular symptoms resolution was significantly higher in patients with solid tumours, as compared to patients with haemopathy (p = 0.007). In cases of tumour relapse, rheumatic symptoms did not recur for 75% of patients. <h3>Conclusions:</h3> Underlying neoplasia should be considered in male patients with new onset polyarthritis, smokers, and particularly in patients chronically ill. Additional investigations should then be performed to diagnose cancer at an early stage.
Cell proliferation of myeloma plasma cells: Comparison of the blood and marrow compartments
Authors: Shaji Kumar, S. Vincent Rajkumar, Philip R. Greipp, Thomas E. Witzig
Journal: American Journal of Hematology (2004)

Abstract The plasma cell labeling Index (PCLI), a measure of marrow plasma cells in S phase of the cell cycle, provides a good estimate of the proliferative capacity of the malignant clonal plasma cells. Multiple studies have also demonstrated its prognostic value in multiple myeloma (MM). Clonal plasma cells have been demonstrated in the peripheral blood of patients with multiple myeloma. The labeling index of these circulating cells can also be determined by a method similar to that employed for marrow plasma cells. The goal of this study was to compare the proliferation kinetics of plasma cells in the marrow to that in the circulation. The PCLI was estimated on peripheral blood (PBLI) and bone marrow aspirates (BMLI) using a slide‐based bromodeoxyuridine (BrdU) immunofluorescence microscopy technique. One hundred seventeen patients who had simultaneous estimation of the PBLI and BMLI and who had ≥90% of the blood cIg + cells identified as monoclonal plasma cells were studied. The PBLI was generally lower than the BMLI (median difference 0.4) and correlated with the BMLI (ρ = 0.491, P &lt; 0.0001). Twenty‐seven patients with PBLI higher than BMLI had a poorer prognosis, with median survival of 2 months from the time of the labeling index determination, compared to 12 months for the remaining 90 patients ( P = 0.01). Myeloma plasma cells circulating in the peripheral blood are capable of proliferation, albeit at a slower rate compared to those in the marrow. These differences reflect a more favorable microenvironment in the marrow likely resulting from the differences in the cytokine levels and supporting stromal cells in the marrow. Am. J. Hematol. 77:7–11, 2004. © 2004 Wiley‐Liss, Inc.
The Book on Fractures by Lamb—An Explanation.
Authors: Fred. R. Belknap
Journal: JAMA (1907)

Benton Harbor, Mich., April 13, 1907. <h3>To the Editor:</h3> —InThe Journalof April 13, 1907, p. 1281, appears a letter from D. S. Lamb, Washington, D. C., relative to letters coming to him from various parts of the country requesting copies of "New Methods of Reducing Fractures and Dislocations." I think I may be able to explain where Mr. Lamb's letters came from, and why. A traveling contortionist gave an exhibition in this city about two years ago, and among other things, he told the physicians who were present that if they would write the curator of the National Medical Museum, giving name, they could get gratis a book on new methods of reducing fractures and dislocations, published by the United States government. So far as I know no reply was ever received to the letter written from here. [Dr. V. M. Griswold, Fredonia, N. Y., sends similar information
Association Between Twin Pregnancy and Hyperglycemia in a Multiethnic Community in New Zealand
Authors: David Simmons, Manisha Yapa
Journal: Diabetes Care (2002)

Human placental lactogen is higher in twin pregnancies than singleton pregnancies. Theoretically, this should increase insulin resistance and risk for gestational diabetes mellitus (GDM) (1). However, twin pregnancy has been found to be associated with a higher incidence of GDM in some studies (2,3) but not others (4,5). Polynesians have a high incidence of GDM (6), and we have investigated whether, in our multiethnic population, twin pregnancies are associated with a greater risk of GDM.

Locally, a universal screening policy using a nonfasting 50-g glucose challenge test (GCT) at 24–28 weeks is advocated (6), and if the fasting glucose is ≥5.5 mmol/l and/or the 2-h post–oral glucose tolerance test (OGTT) 75-g load is ≥9.0 mmol/l, GDM is diagnosed (7). If a suspicion of GDM occurs (e.g., previous GDM or evidence of macrosomia), then direct referral …
MicroRNA Expression and Outcome in Resected NSCLC—Letter
Authors: Shun-ichiro Kageyama, Yusuke Takagi, Takeshi Sawada, Natsuko Kageyama-Yahara, Masahiko Shibuya
Journal: Cancer Research (2011)

We read with considerable interest the report by Voortman and colleagues describing the prognostic and predictive values of 7 micro RNAs for the survival of patients who participated in the International Adjuvant Lung Cancer Trial (IALT; ref. 1). Although a statistically significant effect was undetectable in this large cohort, the tendencies identified in most of the analyses were similar to those found in smaller studies. We would like to bring the following methodologic issues to the attention of the authors.First, the authors examined only 1 section per patient and the samples were macrodissected. Normal tissues contain high levels of micro RNAs of interest. Other methods such as microdissection can be used to efficiently avoid influencing micro RNA detection (2). Using multiple section slices also helps to standardize the results.Second, the authors used small nucleolar RNA U66 as the endogenous normalization control. However, some recent reports suggest that homeostatic RNA might not be the optimal normalization control for cancer data sets because of a significant association with survival (3). Several studies reported that differences in the normalization method affect the result of micro RNA microarray expression profiling (4, 5). Although the standard method has not been established yet, the accurate normalization is essential for proper data interpretation.This study is challenging because samples were collected from 28 centers in 14 countries. To minimize effects derived from differences in the quality of samples, sample preparation methods including the removal of normal tissues and micro RNA normalization are critically important. If these are carried out with more accuracy, the results might reflect the power of the large cohort. Moreover, a clear standard should be immediately established.No potential conflicts of interest were disclosed.See the Response, p. 5358