tbuckley/cabot-search huggingface dataset:
New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance
Authors: Hagop M. Kantarjian, Moshe Talpaz, Francis Giles, Susan O'Brien, Jorge Cortes
Journal: Annals of Internal Medicine (2006)

Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the BCR-ABL kinase fusion protein and its central role in the pathogenesis of CML provided new opportunities to develop rational molecular targeted therapies. This review provides an update on the underlying pathophysiologies of disease progression and imatinib mesylate resistance, leading to the development of new targeted tyrosine kinase inhibitors for managing CML. Imatinib, a selective inhibitor of BCR-ABL, represents a major success in the era of target-directed cancer chemotherapy. However, patients with advanced CML have been less sensitive to therapy and responses have been short. In addition, treatment resistance is an emerging problem at all disease stages. Insight into factors involved in imatinib resistance and disease progression has highlighted a role for such BCR-ABL–dependent factors as amplification and overexpression of the BCR-ABL gene and the emergence of mutant isoforms of BCR-ABL. However, BCR-ABL–independent factors, including leukemogenic pathways involving kinases other than BCR-ABL, also play a part. In light of the limitations of imatinib against these factors, newer tyrosine kinase inhibitors, including dasatinib (a multitargeted kinase inhibitor of BCR-ABL and Src family kinases) and nilotinib (AMN107, a selective BCR-ABL inhibitor), may provide promising treatment options for patients with CML.
Human herpesvirus 8 (HHV‐8)‐associated peritoneal primary effusion lymphoma (PEL) in two HIV‐negative elderly patients
Authors: Emmanuelle Boulanger, Olivier Hermine, Jean‐Paul Fermand, Isabelle Radford‐Weiss, Nicole Brousse, Véronique Meignin, Antoine Gessain
Journal: American Journal of Hematology (2004)

Human herpesvirus 8 (KSHV/HHV-8) is associated with all forms of Kaposi sarcoma (KS), with a rare high-grade B-cell non-Hodgkin lymphoma characterized by serous effusions in body cavities called primary effusion lymphoma (PEL) and with some forms of multicentric Castleman disease (MCD). Although mostly observed during AIDS, such disorders have also been described with a lower incidence in human immunodeficiency virus-negative patients. We describe here the features of two novel cases of AIDS-unrelated PEL. Two patients, a 78-year-old man (case 1) and a 86-year-old woman (case 2), both of French origin, presented exudative ascitic effusion containing numerous KSHV/HHV-8(+) EBV(-) large lymphomatous cells of B-cell clonal origin, characterized by a CD45(+) CD30(+) CD19(-) CD20(-) immunophenotype. The PEL tumor cells harbored a homogenous and isolated trisomy 12 in case 1 and an aberrant expression of the T-cell lineage antigen CD7 in case 2. Both patients were lymphopenic at the time of PEL diagnosis and rapidly died with progressive lymphoma. Moreover, patient 2 had a previous history of classic KS and MCD clinically improved after treatment with all-trans-retinoid acid and a concomitant metastatic breast adenocarcinoma. Compared to AIDS-related PEL, these two cases displayed distinct features in particular the advanced age of patients, as observed for Mediterranean KS, and the absence of EBV coinfection.
Levels of natural antibodies to endotoxin in bronchial asthma patients undergoing allergen specific immunotherapy (SIT)
Authors: V.A. Beloglazov, A.I. Gordienko, A.A. Bakova, L.N. Znamenskaya, A.V. Rozovenko, L.M. Du Buske
Journal: Journal of Allergy and Clinical Immunology (2003)
Improvement of the Plasma Lipoprotein Pattern After Institution of Insulin Treatment in Diabetes Mellitus
Authors: Carl-David Agardh, Peter Nilsson-Ehle, Bengt Scherstén
Journal: Diabetes Care (1982)

Plasma lipids and lipoproteins were studied in 26 nonobese diabetic patients, either newly diagnosed or unsatisfactorily controlled by oral antidiabetic treatment. Measurements were performed before and 3-4 mo after the institution of insulin treatment. In a subgroup of seven patients, the activities of lipoprotein lipase (LPL) and hepatic lipase (HL) in postheparin plasma and the elimination rate of exogenous triglyceride were also monitored. After beginning insulin treatment, diabetic control was improved as demonstrated by decreasing levels of HbA1. Mean plasma cholesterol and triglyceride levels decreased by about 10% (P less than 0.01) and 40% (P less than 0.05), respectively. The decrease in plasma cholesterol was largely accounted for by a fall in LDL cholesterol levels (-8%, P less than 0.05), while plasma HDL cholesterol concentrations increased by about 12% (P less than 0.01). The elimination rate of exogenous triglycerides increased significantly. There was a suggestive, but not significant, increase in LPL activity while the HL activity remained unchanged. It is concluded that the improved diabetic control after institution of insulin treatment results in a significant improvement of the plasma lipoprotein profile. Since the improvement of the lipoprotein pattern is not strictly correlated to the amelioration of indices reflecting glucose transport, we suggest that the plasma lipoprotein pattern may provide an additional tool for monitoring the degree of control in diabetes mellitus.
Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity
Authors: Mark T. Gladwin, Alan N. Schechter, James H. Shelhamer, Lewis K. Pannell, Deirdre A. Conway, Borys W. Hrinczenko, James S. Nichols, Margaret E. Pease-Fye, Constance T. Noguchi, Griffin P. Rodgers, Frederick P. Ognibene
Journal: Journal of Clinical Investigation (1999)

Nitric oxide (NO) inhalation has been reported to increase the oxygen affinity of sickle cell erythrocytes. Also, proposed allosteric mechanisms for hemoglobin, based on S-nitrosation of β-chain cysteine 93, raise the possibilty of altering the pathophysiology of sickle cell disease by inhibiting polymerization or by increasing NO delivery to the tissue. We studied the effects of a 2-hour treatment, using varying concentrations of inhaled NO. Oxygen affinity, as measured by P50, did not respond to inhaled NO, either in controls or in individuals with sickle cell disease. At baseline, the arterial and venous levels of nitrosylated hemoglobin were not significantly different, but NO inhalation led to a dose-dependent increase in mean nitrosylated hemoglobin, and at the highest dosage, a significant arterial-venous difference emerged. The levels of nitrosylated hemoglobin are too low to affect overall hemoglobin oxygen affinity, but augmented NO transport to the microvasculature seems a promising strategy for improving microvascular perfusion.
Mucosal peptic activity during Helicobacter pylori infection in pediatric patients.
Authors: J Yahav, G Oderda, A Diver-Haber, N Keller, A Jonas
Journal: Gut (1992)

Intramucosal peptic activity may participate in the genesis of acute and chronic superficial gastritis. The proteolytic activity of homogenates of gastric mucosa (antrum and body) and duodenum were measured at pH 2.0 (total peptic activity) after exposure to pH 8.0 (pepsinogen) and the activated pepsinogen (pepsin) was calculated in pediatric patients investigated for the presence of Helicobacter pylori (H pylori), 122 antral, 77 stomach body, and 74 duodenal biopsies were examined in 43 H pylori positive patients, 51 controls, and 28 H pylori negative gastritis patients. Activated pepsinogen was significantly reduced in the stomach of H pylori positive patients only. Pepsinogen values were similar in all the anatomical areas tested in all patients. In 13 H pylori positive patients reinvestigated three months after antibiotic therapy, antral mucosal activated pepsinogen activity increased significantly (mean pretreatment 1.56 (1.0) U/mg protein versus mean post-treatment 2.72 (1.7) U/mg protein) and reached values comparable with controls. The decreased activated pepsinogen activity in association with normal pepsinogen content observed in the antrum of H pylori positive gastritis patients indicate local pepsin inactivation or alternately enhanced removal into the gastric lumen or backflow into the circulation.
PREDICTORS OF STENT THROMBOSIS WITH DRUG-ELUTING STENT IN JAPANESE POPULATION: KICS REGISTRY
Authors: Masahide Nagano, Seiji Hokimoto, Michio Mizobe, Kenichi Tsujita, Koichi Kaikita, Kazuko Nakagawa, Hisao Ogawa
Journal: Journal of the American College of Cardiology (2013)
A Proposed New Role for the Insurance Industry in Biomedical Research Funding
Authors: Kahn Cr
Journal: New England Journal of Medicine (1984)

DESPITE the explosion in biotechnology, over the past 10 to 15 years there has been a gradual decline in the support of biomedical research in the United States. This is true whether support is considered in terms of constant dollars or the fraction of total health-care costs devoted to research. Thus, in 1970 about 3.9 per cent of all health-care dollars were devoted to research and development, whereas by 1982 the figure had declined to only 2.9 per cent, or $9.2 billion for research and development, as compared with a total health-care budget of $317 billion.1 By any industrial standard, . . .
Sudden Infant Death Syndrome: Resurgent Research Offers Hope
Authors: Jody W. Zylke
Journal: JAMA (1989)

A SYNDROME of apparently healthy infants dying suddenly and inexplicably was described almost a century ago and has been the subject of systematic study for more than 40 years. But understanding of crucial aspects of sudden infant death syndrome (SIDS)—what causes it, which infants are at risk, and how to prevent it—is still limited. Leaders in the field are hoping to change this by providing direction and opportunities for intensified research. The opportunities are in the form of additional funding. According to L. Stanley James, MD, chair of neonatology at Columbia Presbyterian Medical Center in New York City, "the government is now having a special rejuvenation of SIDS research, and over the next 5 years, they are going to be putting in $30 to $40 million." The direction is supplied through a 5-year research plan recently proposed by a panel of experts under the direction of the National Institute of
Abstract B20: Breast cancer progression suppressor miR-290 targets breast cancer biomarker Arid4b
Authors: Natalie Goldberger, Renard Walker, Chang Hee Kim, Kent Hunter
Journal: Cancer Research (2012)

Abstract Several microRNAs (miRNAs) have been classified as metastasis regulators in breast cancer, yet few studies have examined how germline variations may promote metastasis via miRNA dysregulation. To explore this concept, highly metastatic MMTV-PyMT mice were crossed with 25 AKXD (AKR/J × DBA/2J) recombinant inbred strains to produce F1 progeny with varying metastatic indices. All mammary tumors in the F1 progeny were evaluated by miRNA microarray and correlated with metastatic index to produce miR-290 (containing mature miR-290-3p and miR-290-5p) as one of the top candidates. Further analysis showed miR-290-3p was downregulated in normal lung and breast tissue from highly metastatic AKR/J strains versus less metastatic DBA/2J strains, thereby supporting a germline component to miR-290 regulation. Next, when miR-290 was ectopically expressed in Mvt-1 and 6DT1, and orthotopically injected into FVB/N mice, a significant reduction in both mammary tumor burden and the number of pulmonary metastases was observed. Computational analysis identified breast cancer biomarker Arid4b as a top target of miR-290-3p, which was confirmed by luciferase reporter assay. In conclusion, these results suggest germline genetic changes may reduce miR-290 expression, in turn increasing Arid4b expression, to create a predisposition towards breast cancer progression. Citation Format: Natalie Goldberger, Renard Walker, Chang Hee Kim, Kent Hunter. Breast cancer progression suppressor miR-290 targets breast cancer biomarker Arid4b [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B20.
Medical Malpractice and the Tort System-Reply
Authors: Peter D. Jacobson
Journal: JAMA (1990)

<h3>In Reply.—</h3> I appreciate the concerns expressed by Drs Kalenak and Meyerowitz. These letters raise specific malpractice issues that I did not address in my article, but also suggest the need to consider that medical malpractice litigation is only one aspect of the broader relationship between law and medicine. Both Drs Kalenak and Meyerowitz raise the issue of the contingency fee system as a potential cause of medical malpractice claims and awards. Although I have not conducted the analysis suggested by Dr Kalenak myself, recent work by Sloan et al<sup>1</sup>and earlier work by Danzon<sup>2</sup>provide some insight. Both studies, using multiple regression techniques on different data sets, concluded that neither attorneys per capita nor limitations on contingency fee arrangements had statistically significant effects on claim frequency or award severity. As to attorney density, Danzon concluded that for every 10% increase in attorney density, malpractice award severity rose
Usability of the Medicare Health Web Site
Authors: Sara J. Czaja, Joseph Sharit, Sankaran N. Nair
Journal: JAMA (2008)

To the Editor: The use of Internet-based applications to support health management tasks has grown enormously. 1 Studies investigating these applications have focused on prevalence of or reasons for use.We evaluated the ability of a sample of older adults to use the Medicare.govWeb site to make decisions concerning eligibility for services and prescription drug plans. MethodsTwo hundred eighteen people responded to newspaper advertisements and flyers in community and senior centers in the greater Miami area through telephone contact.Participants were required to be aged at least 50 years; be cognitively unimpaired (Mini-Mental State Examination 2 score >26); have had computer experience (assessed via questionnaire 3 ); be English speaking; and not have depressive symptoms or severe visual or hearing impairments.Following screening, 201 were eligible for participation, 64 of whom expressed lack of interest or did not report for the study.Participants were enrolled consecutively; 112 completed the protocol and were compensated $50 (Table 1).To characterize the sample, data were collected on age, education, and race/ethnicity (based on self-report using fixed categories 4 ).
OC-100 The clonal origins of gastric adenocarcinoma
Authors: T Ventayol Garcia, M Rodriguez-Justo, T Graham, M Novelli, N Wright, S McDonald
Journal: Gut (2012)

<h3>Introduction</h3> We have previously shown that entire fields of dysplasia in the human stomach are derived from a single mutated, metaplastic gland.<sup>1</sup> This suggests that intestinal metaplasia (IM) can be considered a field defect among which dysplasia can arise and this would indicate that adenocarcinomas derived from such dysplasia would also be clonal. Recent work published by our laboratory has indicated that familial adenomatous polyposis–associated colorectal adenomas as well as some sporadic lesions<sup>2</sup> and dysplasia within Barrett9s oesophagus<sup>3</sup> are polyclonal. There is therefore a need to ascertain the clonality of gastric adenocarcinomas (GA). <h3>Methods</h3> Here we screened a large cohort of GA patients for mutations in genes accounting for nearly 90% of reported mutations in GA in order assess mutation frequencies. The screening was then followed by laser capture microdissection PCR sequencing and loss of heterozygosity (LOH) analysis of the mutated specimens in order to assess clonality of GA from dysplasia and IM. <h3>Results</h3> From the 51 patients cohort we have found 18 patients (35.3%) presenting mutations, but only one out of the 51 patients (1.9%) presented two independent mutations in a single cancer. We found 3 mutations in APC (6.3%), one in CDKN2A (2.2%), 13 in TP53 (27.7%), one in CTNNB1 (2.2%) and one in K-RAS (2.4%), but none in PIK3CA or PTEN. Our mutation frequencies are comparable to previous reports, however we observed that most functional mutations occurred as a single event despite screening multiple genes. Analysis of the multiple laser capture microdissected areas revealed multiple genotypes within the same cancer in three out of the five patients. Moreover, current LOH data shows LOH of chromosome 17 in IM and throughout the cancers in all different genotypes, suggesting that chromosome 17 LOH might have been the first hit mutation followed by mutations in TP53, and in one patient a subsequent CTNNB1 mutation. <h3>Conclusion</h3> This suggests that cancer progression may have been initiated by LOH in intestinal metaplasia and that GA cells might become genetically diverse as the cells evolve in the tumour. Therefore, IM is likely to represent a field defect for gastric cancer. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Gutierrez-Gonzalez L</b>, Graham TA, Rodriguez-Justo M, <i>et al.</i> The clonal origins of dysplasia from intestinal metaplasia in the human stomach. <i>Gastroenterology</i> 2011;<b>140</b>:1251–60. 2. <b>Thirlwell C</b>, <i>et al.</i> Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. <i>Gastroenterology</i> 2010;<b>138</b>:1441–54. 3. <b>Leedham SJ</b>, <i>et al.</i> Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett9s oesophagus. <i>Gut</i> 2008;<b>57</b>:1041–8.
Tolerability of high-dose topical tretinoin: the Veterans Affairs Topical Tretinoin Chemoprevention Trial
Authors: A. Geng, M.A. Weinstock, R. Hall, D. Eilers, M. Naylor, J. Kalivas
Journal: British Journal of Dermatology (2009)

Topical tretinoin is a medication commonly used for acne that has potential application in the long-term treatment of photodamaged skin. However, there are few published data regarding the tolerability of high-dose tretinoin with long-term use. To assess the long-term tolerability of tretinoin 0.1% cream. A randomized, multicentre, double-blind, controlled trial for chemoprevention of keratinocyte carcinomas (i.e. basal cell or squamous cell carcinomas) using topical tretinoin cream to the face and ears was conducted. All participants were veterans and had a history of two or more keratinocyte carcinomas over the previous 5 years. Participants were examined (by a study dermatologist) and interviewed every 6 months (for up to 5.5 years to May 2004). Treatment comprised tretinoin 0.1% cream or vehicle control cream once daily, then twice daily as tolerated. Participants were instructed to step down application frequency to once daily or less if twice daily was not tolerated. The main outcome measures were reported side-effects, frequency of cream application and attendance at study visits. Appropriate data were available for four of the six clinical sites of this trial. Data from 736 randomized participants (mean age 71 years; 97% men) from four clinical sites were analysed. The tretinoin group more commonly reported one or more side-effects at the 6-month follow-up than the control group (61% vs. 42%, P < 0.0001). Side-effects decreased over time in both groups, but to a greater extent in the tretinoin group, and the difference became nonsignificant at 30 months. Burning was the most common side-effect (39% tretinoin vs. 17% control, P < 0.0001). There was no difference in severity of side-effects among those affected. Of the participants who reported burning in either group, most reported mild burning; only 11% of those with burning in the tretinoin group reported it as severe (mild 62% tretinoin vs. 70% placebo; severe 11% vs. 5%; P = 0.4). Itching (24% vs. 16%, P = 0.01) and other local cutaneous reactions (12% vs. 6%, P = 0.01) were also more commonly reported by the tretinoin group at 6 months. There was no difference in numbness (2% vs. 2%, P = 0.9). Participants in the tretinoin group were less likely to apply cream twice daily at 6 months (29% vs. 43%, P = 0.0002). This difference persisted over the entire duration of follow-up. There was little difference between groups in attendance at study visits or completion of telephone interviews (92% vs. 95%, P = 0.06). No unexpected adverse events were reported. Overall, the tolerability level of topical tretinoin was high in this study population, with almost 40% of the tretinoin group reporting no side-effects, and the majority (67%) tolerating at least once-daily dosing at 6-month follow-up. High-dose topical tretinoin is feasible for long-term use in this population.
Probing the Contribution of <i>I</i> <sub>Ks</sub> to Canine Ventricular Repolarization
Authors: Paul G.A. Volders, Milan Stengl, Jurren M. van Opstal, Uwe Gerlach, Roel L.H.M.G. Spätjens, Jet D.M. Beekman, Karin R. Sipido, Marc A. Vos
Journal: Circulation (2003)

In large mammals and humans, the contribution of IKs to ventricular repolarization is still incompletely understood.In vivo and cellular electrophysiological experiments were conducted to study IKs in canine ventricular repolarization. In conscious dogs, administration of the selective IKs blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, IKs block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of IKs in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated IKs activation to promote APD95 shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by IKr block, IKs block exaggerated repolarization instability with further prolongation of APD.Ventricular repolarization in conscious dogs is importantly dependent on IKs. IKs function becomes prominent during beta-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during IKr block, when it limits repolarization instability by time-dependent activation. Unstimulated IKs does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal IKs and the sympathetic nervous system in vivo.