tbuckley/cabot-search huggingface dataset:
Imaging Colon Cancer Response Following Treatment with AZD1152: A Preclinical Analysis of [18F]Fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F]Fluorothymidine Imaging
Authors: Maxim A. Moroz, Tatiana Kochetkov, Shangde Cai, Jiyuan Wu, Mikhail Shamis, Jayasree Nair, Elisa de Stanchina, Inna Serganova, Gary K. Schwartz, Debabrata Banerjee, Joseph R. Bertino, Ronald G. Blasberg
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [18F]-labeled fluoro-2-deoxyglucose, [18F]FDG, and/or 3′-deoxy-3′-[18F]fluorothymidine, [18F]FLT, PET imaging. Experimental design: AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG, and [18F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines. Results: Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts. Conclusions: AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [18F]FDG PET was inadequate in monitoring treatment response, [18F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well. Clin Cancer Res; 17(5); 1099–110. ©2011 AACR.
Direct Interaction of the Cell Division Cycle 37 Homolog Inhibits Endothelial Nitric Oxide Synthase Activity
Authors: M. Brennan Harris, Manuela Bartoli, Sarika G. Sood, Robert L. Matts, Richard C. Venema
Journal: Circulation Research (2006)

Endothelial NO synthase (eNOS) via the production of NO in the endothelium plays a key role in cardiovascular biology and is tightly regulated by co- and posttranslational mechanisms, phosphorylation, and protein–protein interactions. The cell division cycle 37 homolog (Cdc37) is a key heat shock protein 90 (Hsp90) cochaperone for protein kinase clients, and Akt/Hsp90 interaction is dependent on Cdc37. Because both Hsp90 and Akt are key eNOS regulatory proteins, we hypothesized that Cdc37 interacts with eNOS as part of the regulatory complex. In the present study, we demonstrate by coimmunoprecipitation and affinity purification in bovine aortic endothelial cells (BAECs) that Cdc37 is complexed with eNOS, Hsp90, and Akt. In addition, cell fractionation data indicate that Cdc37 is found in caveolae with eNOS. Further analysis by in vitro binding assays reveals a direct interaction between purified Cdc37 and eNOS. Incubation of purified Cdc37 with purified wild-type eNOS decreases eNOS activity in vitro. Overexpression of wild-type Cdc37 in BAECs inhibits eNOS activity and NO release, whereas overexpression of S13A-Cdc37 mutant in BAECs increases eNOS activity and NO release. Taken together, these data suggest that Cdc37 has a direct regulatory interaction with eNOS and may play an important role in mediating the eNOS protein complex formation as well as subsequent eNOS phosphorylation and activation.
Long-Term Outcome of Cognitive Behavior Therapy Versus Relaxation Therapy for Chronic Fatigue Syndrome: A 5-Year Follow-Up Study
Authors: Alicia Deale, Kaneez Husain, Trudie Chalder, Simon Wessely
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study evaluated the long-term outcome of cognitive behavior therapy versus relaxation therapy for patients with chronic fatigue syndrome. METHOD: Sixty patients who participated in a randomized controlled trial of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome were invited to complete self-rated measures and participate in a 5-year follow-up interview with an assessor who was blind to treatment type. RESULTS: Fifty-three patients (88%) participated in the follow-up study: 25 received cognitive behavior therapy and 28 received relaxation therapy. A total of 68% of the patients who received cognitive behavior therapy and 36% who received relaxation therapy rated themselves as “much improved” or “very much improved” at the 5-year follow-up. Significantly more patients receiving cognitive behavior therapy, in relation to those in relaxation therapy, met criteria for complete recovery, were free of relapse, and experienced symptoms that had steadily improved or were consistently mild or absent since treatment ended. Similar proportions were employed, but patients in the cognitive behavior therapy group worked significantly more mean hours per week. Few patients crossed the threshold for “normal” fatigue, despite achieving a good outcome on other measures. Cognitive behavior therapy was positively evaluated and was still used by over 80% of the patients. CONCLUSIONS: Cognitive behavior therapy for chronic fatigue syndrome can produce some lasting benefits but is not a cure. Once therapy ends, some patients have difficulty making further improvements. In the future, attention should be directed toward ensuring that gains are maintained and extended after regular treatment ends.
More Thoughts on the Reporting of Adverse Events in Cancer Clinical Trials
Authors: Martine Extermann
Journal: Journal of Clinical Oncology (2007)

TO THE EDITOR: In an article in the August 20, 2006, issue of the Journal of Clinical Oncology, Scharf and Colevas described the variability in the reporting of adverse events (AEs) in phase II trials. In the accompanying editorial, Anderson deplored the “inconsistent and incomplete characterization and reporting of high-grade AEs.” Scharf and Colevas do not distinguish between hematologic and nonhematologic AEs. My research has led me to pay considerable attention to AE reporting, and one of the areas in which AEs are reported especially inconsistently is hematologic toxicity. For example, in the same period covered by Scharf and Colevas’s series, two randomized studies published in the same year in this very journal reported on the doxorubicin-cyclophosphamide regimen; one reported an incidence of grade 3/4 neutropenia of 6.3%, the other reported an incidence of 88%. Most likely, the difference lays chiefly on the emphasis that investigators did or did not place on the collection of nadir CBCs. We chose an extreme example, in which the difference is obvious to the reader. However, the frequency of CBCs is rarely reported when toxicity is detailed in publications. The reader might therefore be misled as to the level of toxicity of a given regimen. This heterogeneity in data-gathering also defeats the standardizing purpose of the National Cancer Institute Common Toxicity Criteria (CTC) regarding hematologic toxicity reporting. I would like to suggest several solutions to harmonize the reporting of hematologic toxicity in cancer trials. At the very least, reports should mention how hematologic toxicity was monitored, preferably at the bottom of the toxicity table (eg, weekly CBCs v CBC required only at the beginning of a cycle). Large numbers of patients are usually enrolled onto adjuvant trials, and relatively well-known regimens are administered. In such trials, the requirement of weekly CBCs may safely be traded off for study purposes, in order to ease compliance and free resources to assess key prognostic factors, such as comorbidity and functional status. In contrast, phase II trials explore new single-agent and combination regimens for which only preliminary toxicity information is available from phase I trials. Not controlling weekly CBCs would lead to fictitiously low reports of hematologic toxicity and might provide patients and practitioners with a false sense of security about the infectious risk involved. A compromise solution for large trials could be to mandate weekly CBCs during the first cycle of chemotherapy, since most hematologic toxicities occur during this cycle. If we want to make the tremendous efforts invested into the design of the CTC criteria fruitful, we need to make the reader fully able to assess the quality and meaning of the hematologic toxicity data collection.
Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis
Authors: Tal Teitz, Madoka Inoue, Marcus B. Valentine, Kejin Zhu, Jerold E. Rehg, Wei Zhao, David Finkelstein, Yong-Dong Wang, Melissa D. Johnson, Christopher Calabrese, Marcelo Rubinstein, Razqallah Hakem, William A. Weiss, Jill M. Lahti
Journal: Cancer Research (2013)

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-β pathway in various tumor models. Cytokine TGF-β can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.
Quality of life in patients with chronic respiratory disease: the Spanish version of the Chronic Respiratory Questionnaire (CRQ)
Authors: R Guell, P Casan, M Sangenis, F Morante, J Belda, GH Guyatt
Journal: European Respiratory Journal (1998)

The aim of this study was to translate the Chronic Respiratory Questionnaire (CRQ) into Spanish and to test its measurement properties. The study was performed in 60 patients with chronic obstructive pulmonary disease (forced expiratory volume in one second (FEV1) mean+/-SD 35+/-14% of reference value). A rigorous process of forward and back translation and review produced an easily comprehensible questionnaire, which was administered together with measures of pulmonary function and exercise capacity. The patients were randomly allocated to one of two groups: 30 received respiratory rehabilitation and the other 30 received standard community care only. Weak to moderate statistically significant correlations (0.2-0.38) were found between the domains of the CRQ and pulmonary function and exercise measures. For the three CRQ domains that measure differences between patients at a point in time, Crohnbach's alpha and intraclass correlation coefficients were: fatigue 0.80 and 0.80; emotional function 0.86 and 0.68; and mastery domains 0.84 and 0.67, respectively. Scores remained stable in patients who were deemed clinically stable, and showed large statistically significant improvement (p&lt;0.0001) in patients in the rehabilitation programme. Only low correlations were found between the changes in CRQ and the changes in pulmonary function and exercise capacity. The index of responsiveness was 0.92 for fatigue, and 0.91 for dyspnoea, emotional function and mastery. In conclusion, the Spanish translation of the Chronic Respiratory Questionnaire is likely to be useful for measuring differences between patients, and particularly for measuring the effects of intervention on quality of life in chronic respiratory disease.
IMPROVED SURVIVAL AMONGST PATIENTS TREATED WITH ADJUVANT TAMOXIFEN AFTER MASTECTOMY FOR EARLY BREAST CANCER
Authors: Michael Baum, J.A. Dossett, J.S. Patterson, F.G. Smiddy, A. Wilson, D. Richards, D.M. Brinkley, K. Mcpherson, R.D. Rubens, B.A. Stoll, J.C. Lea, S.H. Ellis
Journal: The Lancet (1983)
Academic medicine: time for reinvention: Medical education, training, and research are under threat because academic medicine is undervalued
Authors: J. P B O'Connor
Journal: BMJ (2004)

Editor—As surgical trainees teaching anatomy at a leading university, we welcome the recent editorial highlighting the current crisis faced by academic medicine.1

This crisis has serious consequences beyond research and its practical application.2 Basic medical sciences must inform evidence based medicine to optimise clinical management. All doctors need a firm and comprehensive basic science education. As experts, academic medical staff are integral in providing this education.

Non-academics should possess skills such as the critical appraisal of papers to lessen the gulf between academics and other doctors. Otherwise a two tier profession is created with a generation of doctors devoid of specialist intellectual interests and less inclined to think as they practise.

The crisis threatens postgraduate medical education. Trainees wishing to undertake a formal research period or pursue an academic career are denied designated posts approved for training. Basic science jobs such as anatomy demonstrating are not officially recognised by the surgical royal colleges as training posts.3 Specialist training reforms have left academia undervalued in the target based culture that dictates medical practice.

Trainees wishing to undertake research, teaching, and writing should be encouraged to develop and nurture these skills throughout their career. Academic consultants are desperately needed in the United Kingdom: 10% of posts are unfilled.4 Recruitment problems will remain if research is poorly paid with insecure funding.

We believe that a change in infrastructure and in attitude towards the value of academic medicine must accompany improved funding and facilities. The profession and society at large should encourage and reward innovation, scientific imagination, and creative thinking among doctors if a system of medical education of international renown and a vibrant first class research community are to be maintained in the United Kingdom.
Biphasic Vasodilator Action of Troglitazone on the Renal Microcirculation
Authors: Shuji Arima, Kentaro Kohagura, Kazuhisa Takeuchi, Yoshihiro Taniyama, Akira Sugawara, Yukio Ikeda, Michiaki Abe, Ken Omata, Sadayoshi Ito
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Recent studies have demonstrated that thiazolidinediones, novel antidiabetic compounds that improve the insulin sensitivity, lower BP and decrease urinary protein excretion. However, neither the target vasculature nor the underlying mechanism for their actions is well understood. In this study, the action of troglitazone (Tro), a thiazolidinedione compound, on the glomerular afferent (Af-Arts) and efferent (Ef-Arts) arterioles, crucial vascular segments to the control of glomerular hemodynamics, were directly examined. Rabbit Af-Arts or Ef-Arts were microdissected from the superficial cortex and perfused at constant pressure. Increasing doses of Tro (10−8 to 10−5 M) were added to both the bath and lumen of preconstricted arterioles. In Af-Arts, Tro caused dose-dependent and biphasic dilation. Tro at 10−5 M increased the diameter by 28 ± 6% (n = 8, P < 0.01) until 20 min, with the diameter remaining at this level for 60 min, and then Tro began to dilate Af-Arts again. At 120 min, Tro at 10−5 M further increased the diameter by 23 ± 4% (n = 6). Disrupting the endothelium had no effect on either dilation (n = 7 or n = 5). Pretreatment with SKF 96365 (50 μM), which inhibits both voltage- and receptor-operated calcium channels, abolished the early-phase dilation without affecting the late-phase dilation; 20 or 120 min after adding Tro at 10−5 M, the diameter increased by 4 ± 2% (n = 7) or 28 ± 3% (n = 6), respectively. In contrast to Af-Arts, Tro caused monophasic dilation in Ef-Arts; Tro at 10−5 M did not cause significant dilation until 80 min, and at 120 min the diameter increased by 37 ± 4% (n = 5). These results suggest that in the Af-Art Tro has biphasic endothelium-independent vasodilator action, which is partly mediated by an inhibition of calcium influx. This vasodilator action may play a role in the BP-lowering effect of Tro. In addition, by dilating the postglomerular Ef-Art, Tro may decrease the glomerular capillary pressure and hence the excretion of urinary protein.
Theophylline again? Reasons for believing
Authors: B. G. Cosio, J. B. Soriano
Journal: European Respiratory Journal (2009)

So, what is new for theophylline in asthma? Theophylline has been used over the last 70 years for treating patients with asthma. It is well known as a bronchodilator and the current asthma guidelines recommend it as an add-on therapy in noncontrolled asthmatics 1. More than a decade ago, Evans et al. 2 showed that adding theophylline is equally effective as doubling inhaled corticosteroid (ICS) doses for asthma control. In a recent issue of the European Respiratory Journal , Spears et al. 3 reported significant improvements in both lung function and asthma control score in smoking asthmatics who are treated with a combination of low-dose theophylline and beclomethasone compared with each drug alone. The potential relevance of this small, self-labelled pilot trial is that to our knowledge, it is the first to test an effect of this mechanism in smokers. Worldwide, one in every four asthmatics still smokes; interestingly, the prevalence of smoking in asthmatics mirrors the population prevalence of smoking in that geographic population 4. Every smoker should quit but anyone with asthma or any other respiratory condition should be offered all options and help to achieve full smoking cessation.

So, what is the point? Something has changed in our scientific knowledge of the mechanism of action of theophylline in recent years. Since Ito et al. 5 described in vitro a novel …
An essential role for SKAP-55 in LFA-1 clustering on T cells that cannot be substituted by SKAP-55R
Authors: Eun-Kyeong Jo, Hongyan Wang, Christopher E. Rudd
Journal: The Journal of Experimental Medicine (2005)

Lymphocyte function-associated antigen (LFA)-1 clustering, which is needed for high avidity binding to intercellular adhesion molecule (ICAM)-1 and -2, regulates T cell motility and T cell–antigen-presenting cell (APC) conjugation. In this study, down-regulation of SKAP-55 by small interfering RNAs (siRNAs) identified an essential role for this adaptor molecule in the T cell receptor (TCR)–mediated ”inside-out signaling” that is needed for LFA-1 clustering and T cell–APC conjugation. In contrast, down-regulation of SKAP-55 had no effect on TCR–CD3 clustering. Furthermore, the expression of the related protein SKAP-55R failed to compensate for the loss of SKAP-55 in LFA-1 clustering, indicating that SKAP-55 has a unique function that cannot be replaced by this closely related protein. Our findings therefore indicate that SKAP-55, unlike SKAP-55R, is specifically tailored as an essential component of the inside-out signaling events that couple the TCR to LFA-1 clustering and T cell–APC conjugation.
A Randomized Study and Open-Label Extension Evaluating the Long-Term Efficacy of Pramlintide as an Adjunct to Insulin Therapy in Type 1 Diabetes
Authors: Fred Whitehouse, Davida F. Kruger, Mark Fineman, Larry Shen, James A. Ruggles, David G. Maggs, Christian Weyer, Orville G. Kolterman
Journal: Diabetes Care (2002)

OBJECTIVE—To assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—In a 52-week, double-blind, placebo-controlled, multicenter study, 480 patients with type 1 diabetes were randomized to receive preprandial injections of placebo or 30 μg pramlintide q.i.d., in addition to existing insulin regimens. At week 20, pramlintide-treated patients were re-randomized to 30 or 60 μg pramlintide q.i.d. if decreases from baseline in HbA1c were &amp;lt;1% at week 13. Of the 342 patients who completed the 52-week study, 236 individuals (∼70%) elected to participate in a 1-year open-label extension in which all patients received 30 or 60 μg pramlintide q.i.d.. RESULTS—Treatment with pramlintide led to a mean reduction in HbA1c of 0.67% from baseline to week 13 that was significantly (P &amp;lt; 0.0001) greater than the placebo reduction (0.16%), and a significant placebo-corrected treatment difference was sustained through week 52 (P = 0.0071). The greater HbA1c reduction was associated with an average weight loss, rather than weight gain, and was not accompanied by an increased overall event rate of severe hypoglycemia. In the open-label extension, mean HbA1c levels decreased rapidly in patients receiving pramlintide for the first time and remained at reduced levels in patients who continued pramlintide treatment. The most common adverse events reported by the pramlintide group were mild nausea and anorexia, which both occurred during the initial weeks of treatment and dissipated over time. CONCLUSIONS—Mealtime pramlintide treatment as an adjunct to insulin improved long-term glycemic control without inducing weight gain or increasing the overall risk of severe hypoglycemia in patients with type 1 diabetes.