tbuckley/cabot-search huggingface dataset:
S18 Longitudinal assessment of biomarkers for clinical trials of novel therapeutic agents: the run-in study
Authors: E. W. F. W. Alton, C. Boyd, S. Cunningham, J. C. Davies, S. C. Hyde, J. A. Innes, D. R. Gill, A. Greening, U. Griesenbach, T. Higgins, D. J. Porteous
Journal: Thorax (2010)

We will be undertaking a phase IIB clinical trial of repeated application of liposome-based gene therapy over a one year period in approximately 100 CF patients (Multidose Trial). In preparation for this, we sought to address two key questions. Firstly, could we define the optimal set of patients in which the therapy could both be delivered (good access to the airways via nebulisation), and in whom any therapeutic effect was measurable (one or more abnormal measures of lung disease). Secondly, in this set of ‘can deliver—can measure’ patients, which biomarker(s) could be powered to be the primary outcome measure for the trial. To address both questions, we undertook a study (Run-in), cross-sectionally assessing ‘can deliver’ and longitudinally assessing a large set of candidate biomarkers for ‘can measure’.192 patients from age 10 upwards, with FEV<sub>1</sub> &gt;40% were enrolled at two clinical centres; 154 of these remained in the study after four visits spaced at approximately 4–5 month intervals. Biomarkers assessed cross-sectionally included radionucleotide deposition scans, CT and mucocilary clearance. Longitudinal biomarkers included a large series of serum, sputum and exhaled breath inflammatory markers, lung physiology, exercise-related assays and quality of life assessment. 12 patients were judged too severe for adequate delivery and were excluded. A shortlist of 4 biomarkers was generated based on a) showing a CF/non-CF difference, b) response to course of intravenous antibiotics, and c) coefficients of variation. These four were matched against the remaining 142 patients, and a further seven patients excluded in whom none of these short listed biomarkers was abnormal. 89 patients (3 or 4 biomarkers abnormal) have been definitely included to progress into the Multidose Trial, and a further 46 (1 or 2 biomarkers abnormal) are awaiting the final primary outcome selection. The Run-in study has, therefore, been able to a) select a cohort of ‘optimal’ patients in which to assess gene therapy and b) provide an indication of which may be the more useful biomarkers to use in phase IIB clinical trials of novel therapeutic agents.
Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy
Authors: C PROUD
Journal: Cardiovascular Research (2004)

Cardiac hypertrophy involves increased mass (growth) of the heart and a cardinal feature of this condition is increased rates of protein synthesis. Several signaling pathways have been implicated in cardiac hypertrophy including the phosphatidylinositol 3-kinase (PI3K) and Ras/Raf/MEK/Erk pathways. PI3K lies upstream of the mammalian target of rapamycin (mTOR), an important positive regulator of protein synthesis and cell growth. However, recent data suggest that, in response to certain hypertrophic agents, signaling via Ras and MEK/Erk, as well as mTOR, is required for activation of protein synthesis, indicating new connections between these key signaling pathways.
Randomised study of two doses of cisplatin with cyclophosphamide in epithelial ovarian cancer
Authors: S.B. Kaye, C.R. Lewis, J. Paul, M. Soukop, E.M. Rankin, J. Cassidy, J.A. Davis, N.S. Reed, A. MacLean, J.H. Kennedy, R.P. Symonds, I.D. Duncan, H.K. Gordon, H.C. Kitchener, D.J. Cruickshank, G.A. Swapp, T.K. Sarkar, R.J. Atkinson, S.M. Crawford
Journal: The Lancet (1992)
Laryngeal response patterns to mechanical insufflation-exsufflation
Authors: Tiina Andersen, Magnus Hilland, Astrid Sandnes, Thomas Halvorsen, Ove Fondenes, Ole-Bjørn Tysnes, John-Helge Heimdal, Thor-Andre Ellingsen, Gunvor Mo Norstein, Marit Renså, Tom Karlsen, Ola Røksund
Journal: European Respiratory Journal (2013)

Introduction:  Mechanical insufflation-exsufflation (MI-E) is used to assist cough in neuromuscular diseases. Clinically, the application of MI-E may be challenging in patients with bulbar amyotrophic lateral sclerosis (ALS), possibly related to laryngeal dysfunction.   Aims:  To visualize laryngeal response patterns to MI-E in healthy individuals and in ALS patients.   Methods:  Video recorded transnasal fiberoptic laryngoscopy was applied in 18 healthy individuals and in 18 ALS patients while performing MI-E using Cough Assist® (Respironics, USA) according to a standardized protocol applying pressures of ±20 to ±50 cmH 2 O. Clinical examination by the neurologist determined the bulbar symptoms in ALS patients.   Results:  The laryngeal response to MI-E is heterogenic. Healthy (n=18) and non-bulbar patients (n=6) had the expected and good laryngeal coordination during MI-E. Spastic bulbar patients (n=5) had acceptable coordination, both at glottic and supraglottic levels. Hypotone bulbar patients (n=7) had acceptable coordination at the glottic level, but not at the supraglottic level, resulting in laryngeal adduction during insufflation. In two patients, esophageal opening was observed during supraglottic adduction. Backward movements of epiglottis and the base of the tongue during insufflation and hypopharyngeal obstruction during exsufflation, could be observed in all subgroups.   Conclusions:  Laryngeal dysfunction may compromise the effect of MI-E, particularly if hypotonic bulbar paresis is present. Laryngeal adduction severely reduce the size of the laryngeal inlet, potentially with severe consequences for airflow and thereby the effect of MI-E.
A randomized, double-blinded study comparing six doses of batanopride (BMY-25801) with methylprednisolone in patients receiving moderately emetogenic chemotherapy
Authors: J Rusthoven, J Pater, L Kaizer, K Wilson, D Osoba, J Latreille, B Findlay, W S Lofters, D Warr, F Laberge
Journal: Annals of Oncology (1991)
Neointimal thickening after stent delivery of paclitaxel: change in composition and arrest of growth over six months
Authors: Douglas E Drachman, Elazer R Edelman, Philip Seifert, Adam R Groothuis, Danielle A Bornstein, Kalpana R Kamath, Maria Palasis, Dachuan Yang, Sepideh H Nott, Campbell Rogers
Journal: Journal of the American College of Cardiology (2000)
Interaction of the Heavy and Light Chains of Cardiac Myosin Subfragment-1 With F-Actin
Authors: O.A. Andreev, J. Borejdo
Journal: Circulation Research (1997)

The interaction of the heavy chain (HC) and the light chain (cdLC1) of cardiac S1 (cdS1) with F-actin was studied by cross-linking, Western blotting, and fluorescence polarization methods. Incorporation of cdLC1 in cross-linked products was examined by Western blots using the primary antibody against 71-74 residues of cdLC1. Cross-linking with zero-length, water-soluble reagent yielded three products with apparent molecular masses of 150, 160, and 210 kD. Like in the case of cross-linking of skeletal S1 with actin, these complexes included only HC of S1 and actin. The composition of the products were as follows: 150 kD, one HC of S1 cross-linked through a primary site (on the C-terminal of the 20-kD fragment) to the N-terminus of actin; 160 kD, one HC of S1 cross-linked through a secondary site (on the 50 kD fragment) to the N-terminus of actin; and 210 kD, one HC of S1 cross-linked through primary and secondary sites to two actins. Four additional products with apparent molecular masses of 66, 120, 185, and 235 kD contained cdLC1 and were identified as cdLC1 + actin, cdLC1 + HCS1, cdLC1 + actin + HCS1, and cdLC1 + two actins + HCS1, respectively. The same products were observed when cross-linking was performed in cardiac myofibrils incubated with cdS1. The production of cross-linked complexes of the heavy and light chain with actin decreased with an increase in the molar ratio of cdS1:actin. To test whether the orientation of myosin heads depended on a degree of occupation of thin filaments, myofibrils were irrigated with varying concentrations of cdS1. Fluorescence polarization measurements of cdS1 bound to individual I-bands revealed that the orientation depended on the concentration.
Positive correlation between serum immunoreactivity to<i>Demodex</i>-associated<i>Bacillus</i>proteins and erythematotelangiectatic rosacea
Authors: N. O’Reilly, N. Menezes, K. Kavanagh
Journal: British Journal of Dermatology (2012)

Rosacea is a chronic inflammatory condition that affects the skin of the face and the eyes. Erythematotelangiectatic rosacea is characterized by flushing, oedema and telangiectasia. Patients with rosacea demonstrate elevated densities of Demodex mites in their skin compared with controls. A bacterium (Bacillus oleronius) isolated from Demodex mites from a patient with papulopustular rosacea has been demonstrated to produce antigenic proteins that may play a role in papulopustular and ocular rosacea.To establish whether there was a correlation between the reactivity of sera from patients with erythematotelangiectatic rosacea to Bacillus antigens, and to characterize the proteins to which these patients showed reactivity.Serum samples from patients with erythematotelangiectatic rosacea and controls were examined for reactivity to Bacillus proteins by Western blot analysis. Proteins to which the sera reacted were excised from gels, trypsin digested, and putative identities were assigned following liquid chromatography-mass spectrometry (LC-MS) analysis.Eighty per cent (21/26) of patients with erythematotelangiectatic rosacea showed serum reactivity to the 62- and 83-kDa proteins of B. oleronius, compared with 40% (9/22) of controls (P = 0·004). The 62-kDa protein was characterized by LC-MS and showed homology to groEL chaperonin, which provokes a strong immune response in mammals. The 83-kDa protein showed homology to aconitate hydratase, of which expression is increased in bacteria under oxidative stress, and which is highly immunogenic.The majority of patients with erythematotelangiectatic rosacea show serum reactivity to two proteins from B. oleronius, suggesting that this bacterium may play a role in the induction of this condition. The two proteins to which patient sera reacted were found to be similar to a heat shock protein and an enzyme involved in regulating the stress response of the bacterium.
Malignant Pheochromocytoma: Effective Treatment with a Combination of Cyclophosphamide, Vincristine, and Dacarbazine
Authors: S D Averbuch, C S Steakley, R C Young, E P Gelmann, D S Goldstein, R Stull, H R Keiser
Journal: Annals of Internal Medicine (1988)

Study Objective: To determine the efficacy and toxicity of combination chemotherapy in patients with advanced, malignant pheochromocytoma. Design: Nonrandomized, single-arm trial. Setting: Governmental medical referral center. Patients: Fourteen patients with malignant pheochromocytoma confirmed by histologic tests. All patients had metastatic disease and elevated urinary catecholamine secretion. Interventions: After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 body surface area on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days. Measurements and Main Results: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete and partial response rate of 57% (median duration, 21 months; range, 7 to more than 34). Complete and partial biochemical responses were seen in 79% of patients (median duration, more than 22 months; range, 6 to more than 35). All responding patients had objective improvement in performance status and blood pressure. Toxicity included expected hematologic, neurologic, and gastrointestinal effects of chemotherapy without serious sequelae. There were four minor hypotensive episodes and one minor hypertensive episode. Conclusions: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine is effective for advanced malignant pheochromocytoma. Urinary catecholamines are useful to ascertain biochemical response to therapy.
Stem cell factor/c-kit system in spermatogenesis
Authors: C Mauduit, S Hamamah, M Benahmed
Journal: Human Reproduction Update (1999)

One of the major unresolved questions with male infertility is the identification of the molecular origin of a great majority of the spermatogenetic arrests currently diagnosed as idiopathic male infertility. During the past years, several families of regulating factors are signalling molecules, and particularly the stem cell factor (SCF)/c-kit system. The SCF and its receptor c-kit are an appropriate example to illustrate the role of signalling molecules in the physiology and pathology of spermatogenesis. The SCF/c-kit regulates primordial germ cell migration, proliferation and apoptosis during fetal gonadal development. The SCF/c-kit also regulates spermatogonia proliferation in the adult animal. In mutant mice, abnormalities of the SCF/c-kit gene expression, such as gene deletion, point mutation, alternative splicing defect, lead to different types of spermatogenesis alterations (e.g. decrease in primordial germ cell migration, decrease in spermatogonia proliferation). More recently, defects in SCF/c-kit gene expression have also been shown in human testicular dysfunctions. Indeed, a reduction in SCF/c-kit expression has been evidenced in oligozoospermia/azoospermia associated with an increase in the germ cell apoptosis process. In addition, c-kit seems to be a good marker of seminoma testicular tumours. This review reports a large number of data - obtained essentially in animal models - that suggest an important role for the SCF/c-kit system in spermatogenesis and, as a corollary, its potential involvement in spermatogenic defects.
DIFFERENTIATING VARIABLES : OBSESSIVE-COMPULSIVE NEUROSIS AND ANOREXIA NERVOSA
Authors: JOHN CLANCY, ALBERT NORRIS
Journal: American Journal of Psychiatry (1961)

The records of patients with the diagnosis of anorexia nervosa and obsessive-compulsive neurosis were examined with respect to certain variables. These were compared with 2 patients who had features of both conditions. The results are described.
Postoperative Chemoradiotherapy and Cetuximab for High-Risk Squamous Cell Carcinoma of the Head and Neck: Radiation Therapy Oncology Group RTOG-0234
Authors: Paul M. Harari, Jonathan Harris, Merrill S. Kies, Jeffrey N. Myers, Richard C. Jordan, Maura L. Gillison, Robert L. Foote, Mitchell Machtay, Marvin Rotman, Deepak Khuntia, William Straube, Qiang Zhang, Kian Ang
Journal: Journal of Clinical Oncology (2014)

Purpose To report results of a randomized phase II trial (Radiation Therapy Oncology Group RTOG-0234) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) with high-risk pathologic features. Patients and Methods Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and/or extracapsular nodal extension and/or two or more nodal metastases. Patients were randomly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m 2 or docetaxel 15 mg/m 2 once per week. Results Between April 2004 and December 2006, 238 patients were enrolled. With a median follow-up of 4.4 years, 2-year overall survival (OS) was 69% for the cisplatin arm and 79% for the docetaxel arm; 2-year disease-free survival (DFS) was 57% and 66%, respectively. Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors. Grade 3 to 4 myelosuppression was observed in 28% of patients in the cisplatin arm and 14% in the docetaxel arm; mucositis was observed in 56% and 54%, respectively. DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial (Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck), which had a hazard ratio of 0.76 for the cisplatin arm versus control (P = .05) and 0.69 for the docetaxel arm versus control (P = .01), reflecting absolute improvement in 2-year DFS of 2.5% and 11.1%, respectively. Conclusion The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity. The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial.
Comparison of central venous, oesophageal and mouth occlusion pressure with water-filled catheters for estimating pleural pressure changes in healthy adults
Authors: A Flemale, C Gillard, JP Dierckx
Journal: European Respiratory Journal (1988)

The validity of the central venous and water-filled oesophageal catheter technique as a measure of pleural pressure changes was tested in ten healthy subjects in different body positions during inspiratory efforts with occluded airways, by comparing the simultaneous changes in mouth pressure (delta Pm) taken to represent pleural pressure changes, in central venous pressure (delta Pcv) and in oesophageal pressure (delta Poes). delta Pcv/delta Pm values were close to unity in the sitting and left lateral positions, whereas in the supine and right lateral position, substantial deviations from unity were found in some instances. delta Poes/delta Pm values were close to unity in all positions, except some rare instances. No appreciable phase difference between delta Pm/delta Poes and delta Pm/delta Pcv was found when the amplitude ratios were close to unity. We conclude that valid measurements of pleural pressure changes can be obtained in most instances with the central venous and the water-filled oesophageal catheter system according to the occlusion test procedure.
ONTOGENY OF B LYMPHOCYTES
Authors: Michael C. Gelfand, David H. Sachs, Rose Lieberman, William E. Paul
Journal: The Journal of Experimental Medicine (1974)

The frequency of lymphocytes bearing complement receptors in the spleens of 2-wk old mice appears to be controlled by two independent genes. The presence of a "high" allele at either locus leads to intermediate or high frequency of CRL at 2 wk of age. One of the genes controlling complement receptor lymphocyte (CRL) frequency (CRL-1) is linked to the H-2 complex. Thus, in progeny of (AKR x DBA/2)F(1) x DBA/2, all mice with a low frequency of CRL at 2 wk of age are homozygous for the H-2 type of the low CRL parent (DBA/2). Furthermore, in the B10 series of congenic mice, CRL frequency at 2 wk of age is similar to the frequency in the donor of the H-2 region. Thus, C57BL/10, B10.BR, and B10-D2 mice are all of the low CRL type while B10.A mice are intermediate in CRL frequency at 2 wk. C57BR and DBA/2, the donors of the H-2 complex of the B10.BR and B10.D2, respectively, are of low CRL type while the A/WySn, the donor of the H-2 complex in the B10.A, is an intermediate CRL strain. Similarly in the A/WySn series of congenic mice, A.CA, A.SW, and A.BY are all low CRL strains while the A/WySn is intermediate. Studies of CRL frequency in mice with recombinant H-2 chromosomes (B10.A(2R), (4R), and (5R); B6/TL(+); and A/TL(-)) indicate that CRL-1 is to the right of the Ss-Slp genes and to the left of Tla.
Informed Non-Dissent: A Better Option Than Slow Codes When Families Cannot Bear to Say “Let Her Die”
Authors: Alexander A. Kon
Journal: The American Journal of Bioethics (2011)

Click to increase image sizeClick to decrease image size Acknowledgments The views expressed are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. This article is not subject to U.S. copyright law.
Upper Limit of Autoregulation of Cerebral Blood Flow in the Baboon
Authors: SVEND STRANDGAARD, ERIC T. MACKENZIE, DIPANKAR SENGUPTA, JACK O. ROWAN, NIELS A. LASSEN, A. MURRAY HARPER
Journal: Circulation Research (1974)

The upper limit of autoregulation of cerebral blood flow was studied in ten young baboons. Blood pressure was increased by infusing angiotensin, and cerebral blood flow was measured by the intracarotid 133 xenon injection method. Autoregulation was maintained until blood pressure was 30-40% above resting values. At this blood pressure level, cerebrovascular resistance reached a maximum. Any additional increase in blood pressure resulted in an increase in cerebral blood flow and a decrease in cerebrovascular resistance; this situation is designated the "breakthrough of autoregulation." In four baboons subjected to unilateral sympathetic denervation, autoregulation of cerebral blood flow was studied bilaterally; no difference in the upper limit of autoregulation was found between the intact and the sympathectomized hemisphere. The breakthrough of autoregulation supposedly plays an important role in the pathogenesis of acute hypertensive encephalopathy. The old concept of hypertensive cerebral vasospasm has been revised in recent years, and it is now generally recognized that acute hypertensive encephalopathy is caused by focal overdistention of brain arterioles with lesions of the blood-brain barrier. However, whether this condition is associated with a high cerebral blood flow in the clinical syndrome has not been investigated.
Reflections on a genocide
Authors: R H James
Journal: BMJ (1994)

EDITOR, - John Hall graphically recorded the horror of Rwanda but reflected little on its cause.1 Like most of the British press he failed to look at the global problem. He could be compared with a reporter describing the horror of the bombing of Dresden by Britain without mentioning German military expansionism or the holocaust.

Although they comprise only 15% of the population Tutsis have ruled Rwanda and Burundi and the Hutus (85% of …
Lactic Acidosis as a Result of Iron Deficiency
Authors: Clement A. Finch, Philip D. Gollnick, Michael P. Hlastala, Louise R. Miller, Erick Dillmann, Bruce Mackler
Journal: Journal of Clinical Investigation (1979)

Iron-deficient rats have an impaired work performance, even when their anemia is corrected by exchange transfusion. Muscle activity is associated with a higher blood lactate concentration than is observed in iron-replete animals. The accumulation of lactate is a result of excessive production as lactate clearance from the blood was shown to be unaffected. By adjusting the work load to a lower level, it was possible to divide iron-deficient animals into two groups, one capable of continued treadmill running and another in which animals stopped before 20 min. In the former, blood lactate concentration reached a plateau at moderate levels, whereas it continued to increase in the latter until the animal stopped running. Levels of α-glycerophosphate oxidase in skeletal muscle mitochondria were found to be much lower in the second group (P < 0.001). Lactate infusion into normal animals was shown to interfere with work performance, and maintenance of a normal pH in iron-deficient and iron-replete animals did not prevent the impairment in work associated with high blood lactate concentrations. Additional evidence was obtained that energy substrate (blood glucose and free fatty acids, muscle glycogen) was adequate in irondeficient animals. Oxygen tension in their vena caval blood was higher than in controls. Furthermore, the in situ behavior of electrically stimulated gastroenemius and soleus muscles appeared similar to that of control animals. Because the stimulation of the single muscle in the iron-deficient animal did not result in appreciable elevation of blood lactate and did not show impaired contractility further supported the hypothesis that the elevation of blood lactate caused the decreased work performance. It is concluded that iron deficiency by a depletion in the iron-containing mitochondrial enzyme, α-glycerophosphate oxidase, impairs glycolysis, resulting in excess lactate formation, which at high levels leads to cessation of physical activity.