tbuckley/cabot-search huggingface dataset:
Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management
Authors: Elias Jabbour, Hagop Kantarjian
Journal: American Journal of Hematology (2012)

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one-two cases per 100,000 adults and accounts for ∼15% of newly diagnosed cases of leukemia in adults.CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein.Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined.For patients who fail standard-dose imatinib therapy, imatinib dose escalation is a second-line option. Alternative second-line options include 2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs and are candidate for clinical trials. Allogeneic transplantation remains an important therapeutic option for CML-CP harboring the T315I mutation, patients who fail 2nd generation TKIs, and for all patients in advanced phase disease.
Good Clinical Response to Erlotinib in a Patient With Anaplastic Thyroid Carcinoma Harboring an Epidermal Growth Factor Somatic Mutation, L858R, in Exon 21
Authors: Katsuhiro Masago, Masako Miura, Yoshiro Toyama, Yosuke Togashi, Michiaki Mishima
Journal: Journal of Clinical Oncology (2011)
A PROGRAM FOR THE PSYCHIATRIC TRAINING OF GENERAL PRACTITIONERS WHILE UTILIZING THEIR OFFICES AS AN OUTPATIENT FACILITY
Authors: JACKSON A. SMITH, LAVERNE C. STROUGH, CECIL WITTSON, ELAINE MANSFIELD
Journal: American Journal of Psychiatry (1958)

On the basis of 8 months' experience with this small group of 5 physicians, it does appear feasible to instruct general practitioners in the psychiatric management of the chronic alcohol patient. It seems that such a program of instruction presents certain unique problems, primarily the limitation on the time the general practitioner can spend away from his practice. This difficulty can be met in part by brief periods of instruction and by films produced specifically for the general practitioner. This conserves staff time and provides a means of instructing small groups in a scheduled manner. The following advantages to such a program of instruction are seen: the physician's interest is maintained by his treating patients during an extended period of instruction, and he becomes known in his community as one who will accept alcoholic patients and has some instruction in their management. This method of providing treatment in professionally isolated areas appears to have the following advantages as compared to a mobile clinic: the responsible physician is a part of the community and the alcoholic is treated similarly to other patients. The patient may have been previously known to the doctor and there is no stigma attached to visiting a general practitioner in any community. In closing, it appears feasible to train the general practitioner without interrupting his practice, and to use his office as an out-patient and follow-up facility. It is also assumed that after the project ends, the community will still recall that these physicians treat alcoholics and that a continuing service will be provided.
Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134
Authors: Sheng-Ben Liang, Xiu-Zhi Yang, Young Trieu, Zhihua Li, Jessica Zive, Chungyee Leung-Hagesteijn, Ellen Wei, Sergey Zozulya, Christopher C. Coss, James T. Dalton, Ivan George Fantus, Suzanne Trudel
Journal: Clinical Cancer Research (2011)

Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM.The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model.GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134-induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134-treated mice, impairment of glucose tolerance was modest.These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies.
Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group
Authors: Matthias Schwab, Ulrich M. Zanger, Claudia Marx, Elke Schaeffeler, Kathrin Klein, Jürgen Dippon, Reinhold Kerb, Julia Blievernicht, Joachim Fischer, Ute Hofmann, Carsten Bokemeyer, Michel Eichelbaum
Journal: Journal of Clinical Oncology (2008)

To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment.A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity.Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02).DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Crohn's disease: risk of recurrence and reoperation in a defined population.
Authors: S Shivananda, M L Hordijk, A S Pena, J F Mayberry
Journal: Gut (1989)

Two hundred and ten patients with Crohn's disease (CD) were identified in an epidemiological survey of inflammatory bowel disease in the Leiden Health Care Region of the Netherlands. The survey included all patients with CD seen between 1979-1983. The duration of disease ranged from less than one year to 48 years. Of the 210 patients with CD, 118 (56%) underwent surgical resection. Sixty one had an ileocaecal resection, 14 a proctocolectomy, in seven cases as a two stage procedure; 12 a segmental colectomy with end-to-end anastomosis and eight a subtotal colectomy with ileostomy. Twenty-one of these 118 patients (18%) had recurrences requiring reoperation; in 11 because of recurrence at the anastomotic site. Life table analysis showed that after 10 years 17% of patients required further resection for recurrence and 8% for relapse. By 20 years the rate of recurrence had risen to 56%. Patients over the age of 30 at first resection were at 1.5 fold greater risk of requiring further surgery than younger patients. The initial site of disease played no role in recurrence and there was no evidence that preoperative disease duration, delay in diagnosis, or late surgery had any effect on recurrence rates. This is one of the few community based studies to measure recurrence and relapse. A balanced appraisal is that surgery is not permanently curative, but the need for further resection may be lower than previously suggested.
Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival
Authors: V. Ludovini, S. Gori, M. Colozza, L. Pistola, E. Rulli, I. Floriani, E. Pacifico, F.R. Tofanetti, A. Sidoni, C. Basurto, A. Rulli, L. Crinò
Journal: Annals of Oncology (2008)
Five-year Analysis of a Multi-institutional Prospective Clinical Trial of Delayed Intervention and Surveillance for Small Renal Masses: The DISSRM Registry
Authors: Phillip M. Pierorazio, Michael H. Johnson, Mark W. Ball, Michael A. Gorin, Bruce J. Trock, Peter Chang, Andrew A. Wagner, James M. McKiernan, Mohamad E. Allaf
Journal: European Urology (2015)
An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer
Authors: G. Capri, J. Chang, S.-C. Chen, P. Conte, K. Cwiertka, G. Jerusalem, Z. Jiang, S. Johnston, B. Kaufman, J. Link, J. Ro, J. Schütte, C. Oliva, R. Parikh, A. Preston, J. Rosenlund, M. Selzer, D. Zembryki, S. De Placido
Journal: Annals of Oncology (2009)
Muscle, exercise and arthritis
Authors: M V Hurley
Journal: Annals of the Rheumatic Diseases (2002)

We report the rare case of an 80-year-old male patient with hypertrophic pachymeningoencephalitis that may be associated with temporal arteritis. The patient presented to our neurological department with a 2-week history of latent paresis and ataxia affecting his right hand. He had been diagnosed with temporal arteritis 12 years earlier. Brain MRI showed an enhancement of the left-sided frontoparietal meninges with oedema of the adjacent tissue of the precentral and postcentral cortex. A leptomeningeal biopsy was performed. An autoimmune-mediated immunoglobulin G4-associated hypertrophic pachymeningoencephalitis was diagnosed. The patient received a high-dose corticosteroid therapy and his symptoms gradually improved. Our results suggest that hypertrophic pachymeningoencephalitis may occur as a complication of giant cell arteritis and may cause central neurological deficits by cerebral perifocal oedema.
Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat
Authors: T Mahmud, S Somasundaram, G Sigthorsson, R J Simpson, S Rafi, R Foster, I A Tavares, A Roseth, A J Hutt, M Jacob, J Pacy, D L Scott, J M Wrigglesworth, I Bjarnason
Journal: Gut (1998)

Background —Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent “topical” action and by inhibiting cyclooxygenase. Aims —To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of ( R )- and ( S )-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. Methods —The effects of dinitrophenol, racemic, ( R )-, and ( S )-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats. Results —All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and ( R )-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B 2 concentrations following ( R )-flurbiprofen) while racemic and ( S )- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB 2 , and 6-keto-PGF 1α concentrations by 73–95%). Intestinal inflammation was significantly greater following administration of ( S )-flurbiprofen and racemate than with dinitrophenol and ( R )-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or ( R )-flurbiprofen while both racemic and ( S )-flurbiprofen caused numerous ulcers. Conclusions —Dinitrophenol and ( R )-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.
Focal Adhesion Kinase Is Required for Blood Vessel Morphogenesis
Authors: Dusko Ilic, Branka Kovacic, Susan McDonagh, Fang Jin, Clark Baumbusch, David G. Gardner, Caroline H. Damsky
Journal: Circulation Research (2003)

The nonreceptor tyrosine kinase focal adhesion kinase (FAK) is a point of convergence for signals from extracellular matrix, soluble factors, and mechanical stimuli. Targeted disruption of the fak gene in mice leads to death at embryonic day 8.5 (E8.5). FAK −/− embryos have severely impaired blood vessel development. Gene expression and in vitro differentiation studies revealed that endothelial cell differentiation was comparable in FAK −/− and wild-type E8.5 embryos. We examined the role of FAK in blood vessel morphogenesis using an in vitro tubulogenesis assay and three different culture systems: FAK +/+ and FAK −/− embryoid bodies, FAK +/+ and FAK −/− endothelial cells, and human umbilical vein endothelial cells expressing antisense FAK, a dominant-negative fragment of FAK, or wild-type FAK. In all of these systems, endothelial cells deficient in FAK expression or function displayed a severely reduced ability to form tubules in Matrigel. These studies demonstrate clearly that the vascular defects in FAK −/− mice result from the inability of FAK-deficient endothelial cells to organize themselves into vascular networks, rather than from defects in tissue-specific differentiation.
PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria
Authors: Michael Föller, Daniela S. Kempe, Krishna M. Boini, Ganesh Pathare, Balasaheb Siraskar, Paola Capuano, Ioana Alesutan, Mentor Sopjani, Gerti Stange, Nilufar Mohebbi, Madhuri Bhandaru, Teresa F. Ackermann, Martin S. Judenhofer, Bernd J. Pichler, Jürg Biber, Carsten A. Wagner, Florian Lang
Journal: Journal of the American Society of Nephrology (2011)

Insulin and IGF1-dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB/SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3. Because insulin and IGF1 increase renal tubular calcium and phosphorus reabsorption, we examined GSK3 regulation of phosphate transporter activity and determined whether PKB/SGK inactivates GSK3 to enhance renal phosphate and calcium transport. Overexpression of GSK3 and the phosphate transporter NaPi-IIa in Xenopus oocytes decreased electrogenic phosphate transport compared with NaPi-IIa-expressing oocytes. PKB/SGK serine phosphorylation sites in GSK3 were mutated to alanine to create gsk3(KI) mice resistant to PKB/SGK inactivation. Compared with wildtype animals, gsk3(KI) animals exhibited greater urinary phosphate and calcium clearances with higher excretion rates and lower plasma concentrations. Isolated brush border membranes from gsk3(KI) mice showed less sodium-dependent phosphate transport and Na-phosphate co-transporter expression. Parathyroid hormone, 1,25-OH vitamin D levels, and bone mineral density were decreased in gsk3(KI) mice, suggesting a global dysregulation of bone mineral metabolism. Taken together, PKB/SGK phosphorylation of GSK3 increases phosphate transporter activity and reduces renal calcium and phosphate loss.
Coronary Artery Calcium Score Combined With Framingham Score for Risk Prediction in Asymptomatic Individuals
Authors: Philip Greenland, Laurie LaBree, Stanley P. Azen, Terence M. Doherty, Robert C. Detrano
Journal: JAMA (2004)

ContextGuidelines advise that all adults undergo coronary heart disease (CHD) risk assessment to guide preventive treatment intensity. Although the Framingham Risk Score (FRS) is often recommended for this, it has been suggested that risk assessment may be improved by additional tests such as coronary artery calcium scoring (CACS).ObjectivesTo determine whether CACS assessment combined with FRS in asymptomatic adults provides prognostic information superior to either method alone and whether the combined approach can more accurately guide primary preventive strategies in patients with CHD risk factors.Design, Setting, and ParticipantsProspective observational population-based study, of 1461 asymptomatic adults with coronary risk factors. Participants with at least 1 coronary risk factor (&gt;45 years) underwent computed tomography (CT) examination, were screened between 1990-1992, were contacted yearly for up to 8.5 years after CT scan, and were assessed for CHD. This analysis included 1312 participants with CACS results; excluded were 269 participants with diabetes and 14 participants with either missing data or had a coronary event before CACS was performed.Main Outcome MeasureNonfatal myocardial infarction (MI) or CHD death.ResultsDuring a median of 7.0 years of follow-up, 84 patients experienced MI or CHD death; 70 patients died of any cause. There were 291 (28%) participants with an FRS of more than 20% and 221 (21%) with a CACS of more than 300. Compared with an FRS of less than 10%, an FRS of more than 20% predicted the risk of MI or CHD death (hazard ratio [HR], 14.3; 95% confidence interval [CI]; 2.0-104; P = .009). Compared with a CACS of zero, a CACS of more than 300 was predictive (HR, 3.9; 95% CI, 2.1-7.3; P&lt;.001). Across categories of FRS, CACS was predictive of risk among patients with an FRS higher than 10% (P&lt;.001) but not with an FRS less than 10%.ConclusionThese data support the hypothesis that high CACS can modify predicted risk obtained from FRS alone, especially among patients in the intermediate-risk category in whom clinical decision making is most uncertain.
yrGATE: a web-based gene-structure annotation tool for the identification and dissemination of eukaryotic genes.
Authors: Matthew D Wilkerson, Shannon D Schlueter, Volker Brendel
Journal: Genome biology (2006)

Abstract Your Gene structure Annotation Tool for Eukaryotes (yrGATE) provides an Annotation Tool and Community Utilities for worldwide web-based community genome and gene annotation. Annotators can evaluate gene structure evidence derived from multiple sources to create gene structure annotations. Administrators regulate the acceptance of annotations into published gene sets. yrGATE is designed to facilitate rapid and accurate annotation of emerging genomes as well as to confirm, refine, or correct currently published annotations. yrGATE is highly portable and supports different standard input and output formats. The yrGATE software and usage cases are available at http://www.plantgdb.org/prj/yrGATE .
<i>In Vitro</i>Systems for the Study of Human Placental Endocrine Function*
Authors: GUY E. RINGLER, JEROME F. STRAUSS
Journal: Endocrine Reviews (1990)

AMONG endocrine organs, the placenta is unique with respect to the diversity of its hormonal products and the mechanisms that control its secretory activity. The placenta elaborates protein, glycoprotein, and steroidal hormones, as well as cytokines and growth factors. It possesses receptors for a variety of these factors, as well as for thyronines, steroids, and protein hormones. At present count, the human placenta produces more than 30 hormones and has receptors for almost as many regulatory factors (1–3). Consequently, it has frequently been the starting material from which hormones and receptors have been purified. Although the placenta functions in concert with the maternal organism and the fetus in the production of some hormones (e.g., estrogens), the study of isolated placental tissue has been important in the elucidation of placental function as well as the biology of secretory cells in general. Our purpose is to review the existing in vitro systems for study of endocrine functions of human placental tissue. For additional information, the reader may wish to consult a recent monograph dealing with placental perfusion (4) and earlier reviews by Stromberg et al. (5) and Loke and Whyte (6) for insight into the history of the development of various trophoblast tissue culture methods, and two recent volumes, one focusing on cellular approaches to the study of the placenta (7), the other on placental protein hormones (8).
Fragile histidine triad protein expression in nonsmall cell lung cancer and correlation with Ki-67 and with p53
Authors: C. Mascaux, B. Martin, J.M. Verdebout, A.P. Meert, V. Ninane, J.P. Sculier
Journal: European Respiratory Journal (2003)

Fragile histidine triad (FHIT) is a tumour suppressor gene, which is altered in a variety of epithelial tumours, including lung cancer. Biochemical and functional pathways of its tumourigenicity are not yet understood. Its role in tumour proliferation is particularly controversial. The purpose of this study was to correlate the expression of FHIT protein in nonsmall cell lung cancer (NSCLC) with tumour proliferation as estimated by Ki-67 antigen and with p53, a suppressor gene. FHIT, Ki-67 and p53 expression were evaluated by immunohistochemistry in 119 resected NSCLC. Altogether, 58 tumours were negative (expression &lt;10%) for FHIT. The median expression in tumours was 15% positive cells, in comparison with 100% in normal matched lung tissue. The expression was as strong as in normal tissue in only 19 cases. FHIT expression was significantly lower in squamous cell carcinoma (SCC) (5%) than in adenocarcinoma (ADC) (64%). The median expression of Ki-67 was 20% and 69% of tumours were positives (expression &gt;10%). Ki-67 expression was significantly higher in SCC (33.3%) than in ADC (10%). The loss of FHIT protein was not correlated with the expression of p53 (median: 7.5%, 58% of positive tumours for a cut-off of 10% of positive cells) or Ki-67. But percentage of labelled cells for p53 and Ki-67 were significantly correlated. The results suggest that for fragile histidine triad, the pathway of tumourigenesis is independent of p53 and of tumoural proliferation, as reported previously in vitro .