tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
Authors: Joseph Gibbons, Merrill J. Egorin, Ramesh K. Ramanathan, Pingfu Fu, Daniel L. Mulkerin, Stephen Shibata, Chris H.M. Takimoto, Sridhar Mani, Patricia A. LoRusso, Jean L. Grem, Anna Pavlick, Heinz-Josef Lenz, Susan M. Flick, Sherrie Reynolds, Theodore F. Lagattuta, Robert A. Parise, Yanfeng Wang, Anthony J. Murgo, S. Percy Ivy, Scot C. Remick
Journal: Journal of Clinical Oncology (2008)

This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] >or= 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long.The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.
Glomerular Localization and Expression of Angiotensin-Converting Enzyme 2 and Angiotensin-Converting Enzyme
Authors: Minghao Ye, Jan Wysocki, Josette William, Maria José Soler, Ivan Cokic, Daniel Batlle
Journal: Journal of the American Society of Nephrology (2006)

Angiotensin-converting enzyme 2 (ACE2) expression has been shown to be altered in renal tubules from diabetic mice. This study examined the localization of ACE and ACE2 within the glomerulus of kidneys from control (db/m) and diabetic (db/db) mice and the effect of chronic pharmacologic ACE2 inhibition. ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling. ACE, by contrast, was seen only in glomerular endothelial cells. By immunohistochemistry, in glomeruli from db/db mice, strong ACE staining was found more frequently than in control mice (db/db 64.6 +/- 6.3 versus db/m 17.8 +/- 3.4%; P < 0.005). By contrast, strong ACE2 staining in glomeruli from diabetic mice was less frequently seen than in controls (db/db 4.3 +/- 2.4 versus db/m 30.6 +/- 13.6%; P < 0.05). For investigation of the significance of reduced glomerular ACE2 expression, db/db mice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan, a specific angiotensin II type 1 receptor blocker. At the end of the study, glomerular staining for fibronectin, an extracellular matrix protein, was increased in both db/db and db/m mice that were treated with MLN-4760. Urinary albumin excretion (UAE) increased significantly in MLN-4760-treated as compared with vehicle-treated db/db mice (743 +/- 200 versus 247 +/- 53.9 microg albumin/mg creatinine, respectively; P < 0.05), and the concomitant administration of telmisartan completely prevented the increase in UAE associated with the ACE2 inhibitor (161 +/- 56; P < 0.05). It is concluded that ACE2 is localized in the podocyte and that in db/db mice glomerular expression of ACE2 is reduced whereas glomerular ACE expression is increased. The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomerular injury.
Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study
Authors: M. Merlano, E. Russi, M. Benasso, R. Corvò, I. Colantonio, R. Vigna-Taglianti, V. Vigo, A. Bacigalupo, G. Numico, N. Crosetto, M. Gasco, C. Lo Nigro, R. Vitiello, S. Violante, O. Garrone
Journal: Annals of Oncology (2010)
Prediction of Type 2 Diabetes Mellitus With Alternative Definitions of the Metabolic Syndrome
Authors: Anthony J.G. Hanley, Andrew J. Karter, Ken Williams, Andreas Festa, Ralph B. D’Agostino, Lynne E. Wagenknecht, Steven M. Haffner
Journal: Circulation (2005)

Background— In addition to predicting cardiovascular disease (CVD) morbidity and mortality, the metabolic syndrome is strongly associated with the development of type 2 diabetes mellitus (DM), itself an important risk factor for CVD. Our objective was to compare the ability of various metabolic syndrome criteria (including those recently proposed by the International Diabetes Federation), markers of insulin resistance (IR) and inflammation, and impaired glucose tolerance (IGT) in the prediction of DM and to determine whether various proposed modifications to the National Cholesterol Education program (NCEP) metabolic syndrome definition improved predictive ability. Methods and Results— We examined 822 subjects in the Insulin Resistance Atherosclerosis Study aged 40 to 69 years who were nondiabetic at baseline. After 5.2 years, 148 individuals had developed DM. IGT, metabolic syndrome definitions, and IR markers all significantly predicted DM, with odds ratios ranging from 3.4 to 5.4 (all P &lt;0.001), although there were no significant differences in the areas under the receiver operator characteristic (AROC) curves between the definitions. Modifying or requiring obesity, glucose, or IR components in NCEP-defined metabolic syndrome did not significantly alter the predictive ability of the definition under AROC curve criteria (all P &gt;0.05). Similarly, although IR and inflammation variables were significantly associated with incident DM when included in multivariate models with NCEP-defined metabolic syndrome (all P &lt;0.01), expanding the definition by adding these variables as components did not significantly alter the predictive ability of the definition under AROC curve criteria (all P &gt;0.05). Conclusions— The International Diabetes Federation and NCEP metabolic syndrome definitions predicted DM at least as well as the World Health Organization definition, despite not requiring the use of oral glucose tolerance testing or measures of IR or microalbuminuria. Modifications or additions to the NCEP metabolic syndrome definition had limited impact on the prediction of DM.
The relationship of pulmonary valve motion to the motion of surrounding cardiac structures: a two-dimensional and dual M-mode echocardiographic study.
Authors: S E Green, R L Popp
Journal: Circulation (1981)

To assess the relationship of late diastolic pulmonary valve motion to motion of adjacent cardiac structures, we performed two-dimensional and dual M-mode echocardiography on 15 pulmonary normotensive (group A) and nine pulmonary hypertensive subjects (group B). Simultaneous pulmonary valve and posterior aortic wall a-waves were less prominent in group B than in group A (p less than 0.001), and their amplitudes were linearly related within each group (r = 0.83). Analysis of two-dimensional studies confirmed a relationship between pulmonary valve and posterior aortic wall late diastolic motion. No subject had independent presystolic motion of the pulmonary valve within the pulmonary artery. Subjects with shallow a-waves had impaired left atrial emptying compared with those with normal a-wave amplitudes (p less than 0.01). We conclude that the pulmonary valve a-wave does not represent independent valvular displacement, but rather, reflects motion of the entire cardiac base. Variations in a-wave morphology may result, at least in part, from the effects of altered ventricular geometry and compliance on left atrial emptying.
Targeting Checkpoint Kinase 1 in Cancer Therapeutics
Authors: Archie N. Tse, Richard Carvajal, Gary K. Schwartz
Journal: Clinical Cancer Research (2007)

Abstract Progression through the cell cycle is monitored by surveillance mechanisms known as cell cycle checkpoints. Our knowledge of the biochemical nature of checkpoint regulation during an unperturbed cell cycle and following DNA damage has expanded tremendously over the past decade. We now know that dysfunction in cell cycle checkpoints leads to genomic instability and contributes to tumor progression, and most agents used for cancer therapy, such as cytotoxic chemotherapy and ionizing radiation, also activate cell cycle checkpoints. Understanding how checkpoints are regulated is therefore important from the points of view of both tumorigenesis and cancer treatment. In this review, we present an overview of the molecular hierarchy of the checkpoint signaling network and the emerging role of checkpoint targets, especially checkpoint kinase 1, in cancer therapy. Further, we discuss the results of recent clinical trials involving the nonspecific checkpoint kinase 1 inhibitor, UCN-01, and the challenges we face with this new therapeutic approach.
Colitis-associated cancer: the dark side of inflammatory bowel disease
Authors: S. Danese, A. Malesci, S. Vetrano
Journal: Gut (2011)

The intrinsic connection between inflammation and cancer promotion is well established and is especially strong in patients with colorectal cancer (CRC), the second most common cause of cancer-related death in Western countries.1 2 The administration of non-steroidal anti-inflammatory drugs in controlled studies reduces the incidence of colon cancer in patients with familial adenoma polyposis, confirming the link between inflammation and colon cancer.3 Several lines of evidence indicate that chronic inflammation predisposes the tissue to cancer by inducing gene mutation, inhibiting apoptosis or stimulating angiogenesis and cell proliferation. Patients with inflammatory bowel disease (IBD) are at increased risk of developing CRC and, in particular, an association between IBD and the development of colitis-associated cancer (CAC) has been reported. Although the severity and extent of disease and the duration of inflammation seem to be major factors associated with the development of CAC in patients with IBD, the molecular determinants of this link have only recently started to be elucidated. Studies have highlighted the presence of leucocyte infiltration and inflammatory mediators in the tumour microenvironment, indicating that immune cells are major players in tumour promotion.2 4

Preclinical models of CAC are helping to clarify the mechanisms underlying cancer-related inflammation. The direct role of the adaptive immune response in promoting CAC is becoming more evident.2 Although T cell responses fuel the inflammatory process and orchestrate the microenvironment surrounding tumours by contributing to the proliferation, migration and survival of cancer cells, activation of the adaptive immune system also …
Mobile teledermatology is here to stay
Authors: A. M. Oakley
Journal: British Journal of Dermatology (2015)

Journal Article Mobile teledermatology is here to stay Get access A. M. Oakley A. M. Oakley Department of Dermatology Waikato Hospital Hamilton New Zealand https://orcid.org/0000-0002-9461-2790 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 4, 1 April 2015, Pages 856–857, https://doi.org/10.1111/bjd.13722 Published: 01 April 2015
BINDING OF AGGREGATED γ-GLOBULIN TO ACTIVATED T LYMPHOCYTES IN THE GUINEA PIG
Authors: John A. van Boxel, David L. Rosenstreich
Journal: The Journal of Experimental Medicine (1974)

Heat-aggregated guinea pig γ-globulin was shown to bind to the surface membrane of a subclass of guinea pig T lymphocytes. Cells of this subpopulation were identified as T lymphocytes because these cells did not stain for surface Ig (a B-cell marker) but did form spontaneous E-rosettes with rabbit erythrocytes (a T-cell marker). A strikingly high proportion of such aggregate-binding (Agg+), E-rosette-forming (E-rosette+), but surface Ig-negative (Ig-) cells were found in an inflammatory exudate. Thus purified peritoneal exudate lymphocytes (PELs) are known to consist of over 90% T cells, and 59% of these cells bound aggregates. 10% of these Agg+ Ig- E-rosette+ cells were found in draining lymph node cell populations and none in thymus cell populations. The high frequency amongst PELs suggested that these Aggregate+ Ig- E-rosette+ cells might be activated T cells as these are known to occur in high proportion in PEL populations. Confirmatory evidence for this postulate was provided by the striking increase (from 10% to 46%) of Ig- E-rosette+ cells that bound aggregates when lymph node cells were activated by antigen stimulation in vitro.
Polymerase chain reaction assay for the detection of Helicobacter pylori in gastric biopsy specimens: comparison with culture, rapid urease test, and histopathological tests.
Authors: R Fabre, I Sobhani, P Laurent-Puig, N Hedef, N Yazigi, C Vissuzaine, I Rodde, F Potet, M Mignon, J P Etienne
Journal: Gut (1994)

Ulcer recurrence is probably related to residual Helicobacter pylori (H pylori). Histological examination and culture are considered to be the most specific tests. CLO test is a rapid but less specific test, which is usually used as an alternative test to culture. The aim of this study was to investigate the efficiency of a simplified polymerase chain reaction (PCR) assay as a procedure for the diagnosis of gastric H pylori infection of patients. Biopsy specimens were obtained from antral mucosa of 58 patients at endoscopy and submitted to four tests for detection of H pylori. The bacteria were found in 53%, 43%, 48%, and 50% of patients according to the results of PCR, CLO test, culture, and histological examination. Twenty three patients had both negative histology and negative culture and PCR was negative in all of these. Thirteen patients were not classified because only histology or culture was positive and 10 of these had a positive PCR test. When the diagnosis of H pylori was established by agreement with both histology and culture or three positive tests out of four, 29 patients were H pylori positive (28 having had three positive tests and one displaying positive histology and culture), and 26 were negative, and three undetermined. PCR proved the most sensitive and specific test. These results suggest the simplified PCR assay may be a valuable test for the detection of H pylori.
Effect of aging on anorectal function.
Authors: J J Bannister, L Abouzekry, N W Read
Journal: Gut (1987)

Measurements of anorectal function were conducted on 37 elderly (66-87 years) and 48 young (19-55 years) normal subjects. Elderly subjects had decreased anal pressures compared with younger subjects, required lower rectal volumes to inhibit anal sphincter tone and had increased rectal pressures upon balloon distension. The rectal volume required to cause the desire to defecate and the maximum tolerated volume were lower in the elderly, but the corresponding rectal pressures were similar, indicating the sensations were mediated by tension, or pressure receptors. Rectal contractions were generated at similar degrees of rectal distension. A lower proportion of elderly, compared with young subjects could defecate a sphere 18 mm in diameter within 20 seconds. The degree of perineal descent was greater in the elderly female subjects compared with the young women, although there was no difference in this measurement between men. The anorectal angle was similar in young and old. The changes in anorectal function in the elderly would tend to make them more susceptible to faecal incontinence.
Subsets of Human Dendritic Cell Precursors Express Different Toll-like Receptors and Respond to Different Microbial Antigens
Authors: Norimitsu Kadowaki, Stephen Ho, Svetlana Antonenko, Rene de Waal Malefyt, Robert A. Kastelein, Fernando Bazan, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2001)

Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c+ immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-α. CD11c+ imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-α, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-α and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment
Authors: Jurjen S. Lagas, Robert A.B. van Waterschoot, Vicky A.C.J. van Tilburg, Michel J. Hillebrand, Nienke Lankheet, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Imatinib, a BCR-ABL tyrosine kinase inhibitor, is a substrate of the efflux transporters P-glycoprotein (P-gp; ABCB1) and ABCG2 (breast cancer resistance protein), and its brain accumulation is restricted by both transporters. For dasatinib, an inhibitor of SCR/BCR-ABL kinases, in vivo interactions with P-gp and ABCG2 are not fully established yet. Experimental Design: We used Abcb1a/1b−/−, Abcg2−/−, and Abcb1a/1b;Abcg2−/− mice to establish the roles of P-gp and ABCG2 in the pharmacokinetics and brain accumulation of dasatinib. Results: We found that oral uptake of dasatinib is limited by P-gp. Furthermore, relative brain accumulation, 6 hours after administration, was not affected by Abcg2 deficiency, but absence of P-gp resulted in a 3.6-fold increase after oral and 4.8-fold higher accumulation after i.p. administration. Abcb1a/1b;Abcg2−/− mice had the most pronounced increase in relative brain accumulation, which was 13.2-fold higher after oral and 22.7-fold increased after i.p. administration. Moreover, coadministration to wild-type mice of dasatinib with the dual P-gp and ABCG2 inhibitor elacridar resulted in a similar dasatinib brain accumulation as observed for Abcb1a/1b;Abcg2−/− mice. Conclusions: Brain accumulation of dasatinib is primarily restricted by P-gp, but Abcg2 can partly take over this protective function at the blood-brain barrier. Consequently, when both transporters are absent or inhibited, brain uptake of dasatinib is highly increased. These findings might be clinically relevant for patients with central nervous system Philadelphia chromosome–positive leukemia, as coadministration of an inhibitor of P-gp and ABCG2 with dasatinib might result in better therapeutic responses in these patients.
Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function
Authors: M LINDSEY, D GOSHORN, C SQUIRES, G ESCOBAR, J HENDRICK, J MINGOIA, S SWETERLITSCH, F SPINALE
Journal: Cardiovascular Research (2004)

To evaluate the effects of aging on left ventricular (LV) geometry, collagen levels, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) abundance, and myocardial fibroblast function.Young (3-month-old; n=28), middle-aged (MA; 15-month-old; n=17), and old (23-month-old; n=16) CB6F1 mice of both sexes were used in this study. Echocardiographic parameters were measured; collagen, MMP, and TIMP levels were determined for both the soluble and insoluble protein fractions; and fibroblast function was evaluated.LV end-diastolic dimensions and wall thickness increased in both MA and old mice, accompanied by increased soluble protein and decreased insoluble collagen. Immunoblotting revealed differential MMP/TIMP profiles. Compared to MA levels, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-14 increased, and TIMP-3 and TIMP-4 decreased in the insoluble fraction of old mice, suggesting increased extracellular matrix (ECM) degradative capacity. Fibroblast proliferation was blunted with age.This study, for the first time, identified specific differences in cellular and extracellular processes that likely contribute to age-dependent ECM remodeling.
Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors
Authors: V.M. Macaulay, M.R. Middleton, A.S. Protheroe, A. Tolcher, V. Dieras, C. Sessa, R. Bahleda, J.-Y. Blay, P. LoRusso, D. Mery-Mignard, J.-C. Soria
Journal: Annals of Oncology (2012)
Points: Academic boycotts of South Africans
Authors: F P Retief
Journal: BMJ (1987)

recognised or treated properly.As there is no widely accepted treatment for myalgic encephalomyelitis as an "organic" disorder it is important to recognise and treat any reversible illness, particularly if patients face "a long period of physical incapacity ... from ten to twenty years."'Physical and psychological assessment of patients with suspected myalgic encephalomyelitis may help to prevent more suicides in patients with this disorder.' 1 Ramsay AM.Post-viral fatigue syndrome: the saga of Royal Free disease.
Recognition of Left Ventricular Outflow Obstruction
Authors: J. DAVID BRISTOW
Journal: Circulation (1965)

The purpose of this report is to summarize the syndromes of obstruction to left ventricular outflow. Emphasis is placed upon the correlations between clinical, hemodynamic, and angiographic features that permit an accurate diagnosis. An exact definition of the problem in each patient has become of great importance because of rapid advances in cardiac surgery, which now offers specific treatment for each of the syndromes described.