tbuckley/cabot-search huggingface dataset:
Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients
Authors: Eduard J. van Beers, Mart N. van der Plas, Erfan Nur, Harm‐Jan Bogaard, Reindert P. van Steenwijk, Bart J. Biemond, Paul Bresser
Journal: American Journal of Hematology (2014)

Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty-four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V'O2 -peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2 -peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R = -0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better.
Parkinson's disease proteins: Novel mitochondrial targets for cardioprotection
Authors: Uma A. Mukherjee, Sang-Bing Ong, Sang-Ging Ong, Derek J. Hausenloy
Journal: Pharmacology & Therapeutics (2015)

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to familial forms of Parkinson's disease (PD), may provide novel therapeutic targets for cardioprotection. In dopaminergic neurons of the substantia nigra, these PD proteins, which include Parkin, PINK1, DJ-1, LRRK2, and α-synuclein, play essential roles in preventing cell death—through maintaining normal mitochondrial function, protecting against oxidative stress, mediating mitophagy, and preventing apoptosis. These rare familial forms of PD may therefore provide important insights into the pathophysiology underlying mitochondrial dysfunction and the development of PD. Interestingly, these PD proteins are also present in the heart, but their role in myocardial health and disease is not clear. In this article, we review the role of these PD proteins in the heart and explore their potential as novel mitochondrial targets for cardioprotection.
Adjuvant chemohormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients
Authors: P.S.G.J. Hupperets, J. Wils, L. Volovics, L. Schouten, M. Fickers, H. Bron, H.C. Schouten, J. Jager, J. Smeets, J. de Jong, G.H. Blijham
Journal: Annals of Oncology (1993)
Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.
Authors: M E Horowitz, E Etcubanas, M L Christensen, J A Houghton, S L George, A A Green, P J Houghton
Journal: Journal of Clinical Oncology (1988)

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.
Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer.
Authors: A Ciarmiello, S Del Vecchio, P Silvestro, M I Potena, M V Carriero, R Thomas, G Botti, G D'Aiuto, M Salvatore
Journal: Journal of Clinical Oncology (1998)

PURPOSE Since we have previously shown that the efflux rate of technetium 99m (99mTc) sestamibi, a transport substrate of P-glycoprotein (Pgp), is directly correlated with Pgp levels in untreated breast carcinoma, we tested whether tumor clearance of 9mTc-sestamibi may be predictive of therapeutic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS Thirty-nine patients with stage III disease, median tumor diameter 5.8 cm (range, 3 to 10) were enrolled onto this prospective clinical trial and underwent 99mTc-sestamibi scan before neoadjuvant chemotherapy. Patients were injected intravenously (i.v.) with 740 MBq of 99mTc-sestamibi; a 15-minute dynamic study was performed, and static planar images were obtained at 0.5, 1, 2, and 4 hours. The time to half clearance of 99mTc-sestamibi was calculated in each patient from decay corrected time-activity curves using a monoexponential fitting. Patients were treated with epirubicin 150 mg/m2 i.v. every 2 weeks for three courses and then underwent surgery within 3 weeks from the completion of chemotherapy. Residual tumor was assessed by pathologic examination of mastectomy specimens. RESULTS Seventeen of 39 patients showed a rapid tumor clearance of 9mTc-sestamibi (time to half clearance [t1/2] &lt; or = 204 minutes) and 15 of these 17 (88%) showed a highly cellular macroscopic residual tumor at histology that indicated lack of tumor response to neoadjuvant chemotherapy. In contrast, only eight of 22 (36%) with prolonged retention of 99mTc-sestamibi (t1/2 &gt; 204 minutes) showed residual macroscopic tumor at histology (Fisher's exact test, P &lt; .01). CONCLUSION A rapid tumor clearance of 99mTc-sestamibi may predict lack of tumor response to neoadjuvant chemotherapy with drugs affected by the multidrug-resistant phenotype in patients with locally advanced breast carcinoma.
The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-co
Authors: O. Nemoto, M. Furue, H. Nakagawa, M. Shiramoto, R. Hanada, S. Matsuki, S. Imayama, M. Kato, I. Hasebe, K. Taira, M. Yamamoto, R. Mihara, K. Kabashima, T. Ruzicka, J. Hanifin, Y. Kumagai
Journal: British Journal of Dermatology (2015)

The cytokine interleukin‐31 (IL‐31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and efficacy of blocking the IL‐31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL‐31 receptor A (IL‐31RA) monoclonal antibody, which binds to IL‐31RA to inhibit subsequent IL‐31 signalling. To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD. In this randomized, double‐blind, placebo‐controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy. No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose‐dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about −50% at week 4 with CIM331 compared with −20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate. A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL‐31.
CASE REPORT OF DISSECTING ANEURYSM OF THE AORTA WITH CARDIAC TAMPONADE
Authors: David R. Sacks
Journal: Annals of Internal Medicine (1945)

Case Reports1 October 1945CASE REPORT OF DISSECTING ANEURYSM OF THE AORTA WITH CARDIAC TAMPONADEDAVID R. SACKSDAVID R. SACKSAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-23-4-661 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAlthough dissecting aneurysm of the aorta with cardiac tamponade is not so rare as to warrant reporting in itself, this case is reported to stress the evolution of certain electrocardiographic changes noted in seriatim which may be of considerable diagnostic value.CASE REPORTOn the morning of September 29, 1942, a white male adult 50 years of age was admitted to the Station Hospital. He appeared critically ill and complained of agonizing pain in the mid chest, back of the neck, throat, teeth, and both arms to the fingertips.The patient stated that while he was standing in the field... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: M.C. Camp Fannin, Texas*Received for publication September 18, 1944. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDISSECTING ANEURYSM OF THE AORTA: TWO CASES WITH UNUSUAL ONSETS*L. FELDMAN, M.D.Dissecting Aneurysm of the Aorta: Its Clinical, Electrocardiographic and Laboratory FeaturesCORONARY INVOLVEMENT IN DISSECTING ANEURYSM OF THE AORTA 1 October 1945Volume 23, Issue 4Page: 661-666KeywordsAneurysmsAortaElectrocardiographyLower back painPharynxThorax ePublished: 1 December 2008 Issue Published: 1 October 1945 PDF downloadLoading ...
Effect of Adriamycin on the Reproductive Integrity of Cultured Leukemia L1210 and P388 Cells 2
Authors: Lee J. Wilkott, Elizabeth Ann Dulmadge, Harris H. Lloyd
Journal: JNCI Journal of the National Cancer Institute (1978)

Proliferating cultured P388 cells exhibited a greater degree of sensitivity to adriamycin than did proliferating cultured L1210 cells, although both leukemia cell populations had approximately the same doubling time. The rate of reduction in viability when cultured L1210 cell populations were exposed to adriamycin (0.0625-2.0 microgram/ml, concentrations that are comparable to tissue drug levels during therapy) was concentration-dependent. Therefore, the results indicated a possible therapeutic advantage to be gained by an increase in drug concentrations (within the limits of acceptable host toxicity) at the target cell site.
Associations among one-year efficacy outcomes following endoscopic thermal vapor ablation (InterVapor™) for heterogeneous emphysema
Authors: Peter Hopkins, Felix J.F. Herth, Gregory Snell, Kim Baker, Christian Witt, Mark H. Gotfried, Arschang Valipour, Manfred Wagner, Franz Stanzel, Jim J. Egan, Steven Kesten, Armin Ernst
Journal: European Respiratory Journal (2012)

Background:  The understanding of interactions or associations over the long-term may assist in understanding and predicting changes over time in chronic diseases such as emphysema. The associations among various COPD efficacy endpoints are variable; however, the degree of correlation is often important in examining the consistency of the results across measures not considered redundant.   Objectives:  Determine the correlations of improvements in patient-reported outcomes, exercise capacity and BODE score with lung function and lobar volume reduction (LoVR) measured by CT after 1-year post-InterVapor for heterogeneous emphysema.   Methods:  Single-arm trial of InterVapor in patients with upper lobe emphysema. Patient criteria: FEV 1  15% - 45% predicted, age 40-75 years, RV>150%, TLC>100%, 6 minute walk distance (6MWD)>140 m, DLCO>20%, previous pulmonary rehabilitation. Endpoints included: spirometry, body plethysmography, SGRQ, mMRC dyspnea, 6MWD and LoVR (CT). Pearson correlation coefficients were calculated for associations of changes from baseline to 12 months.   Results:  44 patients received InterVapor. Mean age: 63 years, men 50%, FEV 1  0.86 (31% predicted), RV 237% predicted, DLCO 35% predicted, SGRQ 59 units, 6MWD 300 m, mMRC 2.9.   Conclusion:  Among lung function tests, FEV 1  appeared to correlate the strongest with health outcomes, followed by RV and FRC at one year. The strong correlation of outcomes with LoVR are consistent with the proposed mechanism of action.
The Regulation of Skeletal Muscle Alanine and Glutamine Formation and Release in Experimental Chronic Uremia in the Rat
Authors: Alan J. Garber
Journal: Journal of Clinical Investigation (1978)

The mechanism of the increased alanine and glutamine formation and release from skeletal muscle in experimental uremia was investigated using epitrochlearis preparations from control and chronically uremic rats. In uremic muscle, insensitivity to epinephrine or serotonin suppression of alanine and glutamine release was observed. With control muscles, 1 nm or greater, epinephrine inhibited alanine and glutamine release, whereas with uremic muscles, epinephrine concentrations <1 μM did not alter amino acid release. Decreased alanine and glutamine release with 1 nM serotonin was observed in control muscles, but no inhibition was observed with concentrations <1 μM in uremic muscle. Muscle amino acid levels were the same in control and uremic muscles in the presence or absence of epinephrine or serotonin. The reutilization of released alanine by protein synthesis or oxidation to CO2 was not differentially affected by epinephrine in uremic muscles as compared with control muscle. Dibutyryl-cAMP inhibited amino acid release equally in uremic and control muscles. Epinephrine or serotonin increased cAMP levels two- to four-fold or more in control than in uremic muscle. Basal- and fluoride-stimulated adenylate cyclase activities were equal in uremic and control muscle homogenates and in membrane fractions, but 10 μM epinephrine-stimulated adenylate cyclase was reduced 30-60% with uremia. At any concentration of epinephrine (0.001—100 μM), the stimulation of membrane adenylate cyclase activity was one- to twofold greater with control membranes than with uremic muscle membranes. With either control or uremic muscle, peak adenylate cyclase activity was observed at 1 μM epinephrine.
Airway inflammation in children and adolescents with bronchiolitis obliterans
Authors: Martin Rosewich, Ulrich Zißler, Tanja Kheiri, Johannes Schulze, Eva Herrmann, Ruth Dücker, Ralf Schubert, Stefan Zielen
Journal: European Respiratory Journal (2014)

Background:  Airway inflammation plays a major role in the progression of chronic lung diseases. The features of airway inflammation are not well defined among patients with cases of bronchiolitis obliterans (BO) that began in childhood.   Objectives:  To investigate the sputum cell and cytokine profiles of stable cases of BO regarding lung function and the involvement of small airway disease (SAD)   Methods:  Twenty patients with BO (median age=14.5, range=7-23 years) and 23 healthy controls (median age=16.5 years) were investigated. Lung function parameters and bronchial reversibility testing as well as sputum cell and cytokine profiles (IL-1β, IL-6, IL-8, TNF-α, IL-5, IFN-γ, and NFκB regulation) were analysed using quantitative RT-PCR and cytometric bead assay (CBA) in induced sputum.   Results:  Patients with BO had significantly lower lung function values, including FVC, forced expiratory volume (FEV1), the Tiffeneau index (FEV1/VC) ,  and MEF25, but increased functional residual capacity (RV/TLC) values. Bronchial reversibility was found in five patients (25%). Moreover, airway inflammation (as indicated by total cells, neutrophils, IL-1β, IL-6, IL-8, TNF-α, and NFκB) was significantly increased among patients with BO compared with controls.   Conclusions:  BO is predominantly a neutrophilic disease of the small bronchioles featuring elevated levels of pro-inflammatory cytokines leading to tissue remodelling and fibrosis of the small airways. Future therapies for patients with BO should more efficiently target the small airways.
Augmentation of Response to Chemotherapy by microRNA-506 Through Regulation of RAD51 in Serous Ovarian Cancers
Authors: Guoyan Liu, Da Yang, Rajesha Rupaimoole, Chad V. Pecot, Yan Sun, Lingegowda S. Mangala, Xia Li, Ping Ji, David Cogdell, Limei Hu, Yingmei Wang, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Ilya Shmulevich, Loris De Cecco, Kexin Chen, Delia Mezzanzanica, Fengxia Xue, Anil K. Sood, Wei Zhang
Journal: JNCI Journal of the National Cancer Institute (2015)

Background: Chemoresistance is a major challenge in cancer treatment.miR-506 is a potent inhibitor of the epithelial-tomesenchymal transition (EMT), which is also associated with chemoresistance.We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. Methods:We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents.We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity.All statistical tests were two-sided.Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001;TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04).MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51.Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36 ± 0.05g vs 0.07 ± 0.02g, P < .001;control miRNA plus olaparib vs miR-506 plus olaparib: 0.32 ± 0.13g vs 0.05 ± 0.02g, P = .045,respectively), thus recapitulating the clinical observation.Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy. MTT AssayTwenty-four hours after transfection with 20 nm miR-506, miR-Ctrl, or anti-miR-LNA, cells were seeded onto 96-well
Molecular Biology of Burkitt’s Lymphoma
Authors: Jonathan L. Hecht, Jon C. Aster
Journal: Journal of Clinical Oncology (2000)

The diagnostic category of Burkitt’s lymphoma encompasses a closely related group of aggressive B-cell tumors that includes sporadic, endemic, and human immunodeficiency virus–associated subtypes. All subtypes are characterized by chromosomal rearrangements involving the c-myc proto-oncogene that lead to its inappropriate expression. This review focuses on the roles of c-myc dysregulation and Epstein-Barr virus infection in Burkitt’s lymphoma. Although the normal function of c-Myc remains enigmatic, recent data indicate that it has a central role in several fundamental aspects of cellular biology, including proliferation, differentiation, metabolism, apoptosis, and telomere maintenance. We discuss new insights into the molecular mechanisms of these c-Myc activities and their potential relevance to the pathogenesis of Burkitt’s lymphoma and speculate on the role of Epstein-Barr virus.
Phase I trial of weekly paclitaxel in advanced lung cancer.
Authors: W Akerley, M Glantz, H Choy, V Rege, S Sambandam, P Joseph, L Yee, B Rodrigues, P Wingate, L Leone
Journal: Journal of Clinical Oncology (1998)

PURPOSE We conducted a phase I study in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose (MTD) of paclitaxel using an extended weekly schedule. PATIENTS AND METHODS Patients with stage IIIB/IV NSCLC were treated with paclitaxel administered weekly over 3 hours for 6 weeks of an 8-week cycle. Doses were modified for granulocyte counts less than 1,800/microL or neurotoxicity greater than grade I. Groups of three patients were entered at each dose level. The dose was escalated to the next level if less than 50% of patients developed unacceptable toxicity and received more than 80% of the intended first-cycle dose. RESULTS Twenty-six patients were entered through six dose levels (100, 125, 135, 150, 175, and 200 mg/m2/wk). Four of six patients at the 175-mg/m2 dose level and only one of six patients at the 200-mg/m2 level received all scheduled doses of paclitaxel during cycle 1. Neutropenia was dose-limiting. Fourteen patients were treated with subsequent cycles of paclitaxel. Grade II to III neuropathy developed in five of 24 patients. It occurred more commonly with greater duration of therapy, but improved following dose reduction. Nine of 26 (35% +/- 10%) patients demonstrated an objective response. CONCLUSION The MTD of paclitaxel using a weekly schedule is 175 mg/m2/wk for 6 of 8 weeks. Neutropenia limits dosing acutely, but neuropathy is limiting with sustained therapy. This schedule of paclitaxel results in a twofold to threefold increase in dose-intensity with less toxicity than anticipated from conventional dosing. Further evaluation of this schedule is warranted to assess efficacy and toxicity of prolonged administration.