tbuckley/cabot-search huggingface dataset:
Increased Toxicity With Gefitinib, Capecitabine, and Radiation Therapy in Pancreatic and Rectal Cancer: Phase I Trial Results
Authors: Brian G. Czito, Christopher G. Willett, Johanna C. Bendell, Michael A. Morse, Douglas S. Tyler, Nishan H. Fernando, Christopher R. Mantyh, Gerard C. Blobe, Wanda Honeycutt, Daohai Yu, Bryan M. Clary, Theodore N. Pappas, Kirk A. Ludwig, Herbert I. Hurwitz
Journal: Journal of Clinical Oncology (2006)

Purpose Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer. Patients and Methods Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates. Results Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi. Conclusion The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.
DELAYED HYPERSENSITIVITY
Authors: Jonathan W. Uhr, S. B. Salvin, A. M. Pappenheimer
Journal: The Journal of Experimental Medicine (1957)

A general method for induction of the delayed hypersensitive state directed against single protein antigens is described. The method consists of intradermal injection of minute amounts of washed immune precipitates containing the antigen in question. Provided the specific precipitates are formed in the region of antibody excess, maximal sensitivity develops at least 2 to 3 weeks before detectable circulating antibody is formed in guinea pigs against the sensitizing antigen. Neither adjuvant nor killed acid-fast bacteria are required for induction of the delayed hypersensitive state although the degree of sensitization is considerably increased when the sensitizing material is incorporated in Freund's complete adjuvant. Characteristics of the "delayed" as opposed to the "immediate" hypersensitive states in the guinea pig are described and implications of the findings are discussed.
Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine
Authors: Marc Beyer, Matthias Kochanek, Kamruz Darabi, Alexey Popov, Markus Jensen, Elmar Endl, Percy A. Knolle, Roman K. Thomas, Michael von Bergwelt-Baildon, Svenja Debey, Michael Hallek, Joachim L. Schultze
Journal: Blood (2005)
Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning
Authors: Tatsuya Yoshizawa, Yuki Handa, Yoshikatsu Uematsu, Shu Takeda, Keisuke Sekine, Yuko Yoshihara, Toru Kawakami, Kouki Arioka, Hiroshi Sato, Yasushi Uchiyama, Shoichi Masushige, Akiyoshi Fukamizu, Toshio Matsumoto, Shigeaki Kato
Journal: Nature Genetics (1997)
The effect of oral-administered lactulose on colonic nitrogen metabolism and excretion
Authors: Per Brøbech Mortensen
Journal: Hepatology (1992)

The influence of lactulose on organic acid fermentation, nitrogen metabolism and excretion in the colon associated with its mechanism of action on hepatic encephalopathy was investigated. Orally administered lactulose in increasing amounts (0 to 20 to 40 to 80 to 160 gm/day) to 12 healthy volunteers decreased ammonia production in 16.6% fecal homogenates incubated 6 hr and 24 hr at 37 degrees C (mean +/- S.E.M.: from 7 +/- 1 to 0 +/- 0 and from 13 +/- 2 to 0 +/- 0 mmol/L, respectively). Every dose of lactulose was given for 3 days with intervals of 1 to 2 wk, and 24-hr stools were collected on day 3. Fecal concentrations of ammonia decreased (from 50 +/- 9 to 11 +/- 3 mmol/L), but ammonia excretions increased (from 6 +/- 2 to 17 +/- 4 mmol/24 hr). Total fecal concentrations of nitrogen decreased (from 1,043 +/- 78 to 300 +/- 136 mmol/L), but excretions of nitrogen increased fourfold (from 111 +/- 21 to 457 +/- 113 mmoL/24 hr) because of the increase in stool mass. Fecal pH declined (from 6.9 +/- 0.1 to 4.9 +/- 0.1), but total organic acids (short-chain fatty acids and DL-lactate; range = 105 to 148 mmol/L) and osmolality in feces (417 to 450 mOsm/L) did not change, although the colonic fermentation of lactulose had a major impact on the proportions between the nontoxic acetate (increased from 65% +/- 2% to 89% +/- 3%) and the potentially neurotoxic 3-6-carbon fatty acids (decreased from 35% +/- 2% to 11% +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)
Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse
Authors: Dimitri A. Breems, Wim L.J. Van Putten, Peter C. Huijgens, Gert J. Ossenkoppele, Gregor E.G. Verhoef, Leo F. Verdonck, Edo Vellenga, Georgine E. De Greef, Emanuel Jacky, Johannes Van der Lelie, Marc A. Boogaerts, Bob Löwenberg
Journal: Journal of Clinical Oncology (2005)

The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that usually are short lived. Therefore, a clinically useful prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies at relapse of AML.A prognostic score is presented based on the multivariate analysis of 667 AML patients in first relapse among 1,540 newly diagnosed non-M3 AML patients (age 15 to 60 years) entered onto three successive Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research Collaborative Group trials.Four clinically relevant parameters are included in this index (ie, length of relapse-free interval after first complete remission, cytogenetics at diagnosis, age at relapse, and whether previous stem-cell transplantation was performed). Using this stratification system, three risk groups were defined: a favorable prognostic group A (overall survival [OS] of 70% at 1 year and 46% at 5 years), an intermediate-risk group B (OS of 49% at 1 year and 18% at 5 years), and a poor-risk group C (OS of 16% at 1 year and 4% at 5 years).The prognostic index estimates the outcome of AML patients in first relapse using four commonly applied clinical parameters and might identify patients who are candidates for salvage and investigational therapy.
Peroxisome Proliferator-Activated Receptor (PPAR) α and PPARβ/δ, but not PPARγ, Modulate the Expression of Genes Involved in Cardiac Lipid Metabolism
Authors: Andries J. Gilde, Karin A.J.M. van der Lee, Peter H.M. Willemsen, Giulia Chinetti, Feike R. van der Leij, Ger J. van der Vusse, Bart Staels, Marc van Bilsen
Journal: Circulation Research (2003)

Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPARα in FA-mediated expression has been demonstrated, the role of the PPARβ/δ and PPARγ isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPARα (Wy-14,643), PPARβ/δ (L-165041, GW501516), or PPARγ (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPARα and PPARβ/δ ligands, but not to PPARγ ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPARα and PPARβ/δ, but not by PPARγ ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPARβ/δ, the FA-induced expression of genes was mimicked by the PPARβ/δ ligand only, indicating that FA also act as ligands for the PPARβ/δ isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPARγ ligands. However, addition of PPARα and PPARβ/δ ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPARα, PPARβ/δ, but not PPARγ, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPARβ/δ in cardiac disease.
Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations
Authors: Anne M Molloy, Sean Daly, James L Mills, Peadar N Kirke, Alexander S Whitehead, Dorothy Ramsbottom, Mary R Conley, Donald G Weir, John M Scott
Journal: The Lancet (1997)
Improving Prescribing Practices Late in Life
Authors: Greg A. Sachs
Journal: JAMA Internal Medicine (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer
Authors: Sana Intidhar Labidi-Galy, Vanja Sisirak, Pierre Meeus, Michael Gobert, Isabelle Treilleux, Agathe Bajard, Jean-Damien Combes, Julien Faget, François Mithieux, Alexandre Cassignol, Olivier Tredan, Isabelle Durand, Christine Ménétrier-Caux, Christophe Caux, Jean-Yves Blay, Isabelle Ray-Coquard, Nathalie Bendriss-Vermare
Journal: Cancer Research (2011)

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance.
The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia☆
Authors: Y ABDALLAH, D GLIGORIEVSKI, S KASSECKERT, L DIETERICH, M SCHAFER, C KUHLMANN, T NOLL, H SAUER, H PIPER, C SCHAFER
Journal: Cardiovascular Research (2006)

The autonomous proliferative response of endothelial cells to hypoxia has been shown to be dependent on activation of NAD(P)H oxidase, on the cytosolic Ca2+ load, and, consequently, on nuclear translocation of extracellular signal-regulated kinase (ERK)1/2 during transient hypoxia. The aim of the present study was to investigate whether poly(ADP-ribose) polymerase (PARP) is a downstream signal of NAD(P)H oxidase, mediating cytosolic Ca2+ load and hence nuclear translocation of ERK1/2 and endothelial cell proliferation.Porcine aortic endothelial cells were incubated under hypoxic conditions for 40 min. Cytosolic [Ca2+] and reactive oxygen species (ROS) formation were measured in fura-2- and DCF-loaded cells, respectively. PARP activation was detected by immunocytochemistry, and endothelial cell proliferation was determined 24 h after 60 min of transient hypoxia.Inhibition of NAD(P)H oxidase with antisense oligonucleotide against the p22(phox) subunit, MEK/ERK signalling with UO 126 (30 microM), or PARP with PJ 34 (10 microM) leads to a marked reduction in hypoxia-induced cytosolic Ca2+ load and activation of PARP. Hypoxia-induced translocation of ERK1/2 and endothelial cell proliferation were also prevented when NAD(P)H oxidase or PARP were inhibited; however, hypoxic ROS formation was not affected in the presence of PARP inhibitor.PARP represents a downstream effector of NADP(H) oxidase and acts as a necessary intermediate step for the hypoxic proliferative response of endothelial cells.
High-Field Magnetic Resonance Imaging of Suicidality in Patients With Major Depressive Disorder
Authors: Zhiyun Jia, Xiaoqi Huang, Qizhu Wu, Tijiang Zhang, Su Lui, Junran Zhang, Nabin Amatya, Weihong Kuang, Raymond C.K. Chan, Graham J. Kemp, Andrea Mechelli, Qiyong Gong
Journal: American Journal of Psychiatry (2010)

Objective: Suicide is a major social and public health problem, but its neurobiology in major depressive disorder is poorly understood. The purpose of this study was to use magnetic resonance diffusion tensor imaging to characterize abnormalities of white matter integrity in major depressive disorder patients with and without a history of suicide attempts. Method: Participants were 52 patients with major depressive disorder, with (N=16) and without (N=36) a history of suicide attempts, and 52 healthy comparison subjects matched for age, gender, education, and ethnicity. Diffusion tensor imaging in a 3.0 Tesla magnetic resonance scanner was performed. Whole-brain voxel-based analysis was used to compare fractional anisotropy across the three groups and analyze the correlation with symptom severity. A region-of-interest analysis was applied to the bilateral hippocampus, thalamus, and lentiform nucleus Results: Fractional anisotropy was decreased in the left anterior limb of the internal capsule in suicide attempters relative to both nonattempters and healthy comparison subjects, in the right frontal lobe relative to comparison subjects only, and in the right lentiform nucleus relative to nonattempters only. There was no significant correlation with symptom severity. Conclusions: Decreased fractional anisotropy in the left anterior limb of the internal capsule appears to characterize patients with major depressive disorder who have a history of attempting suicide. Longitudinal studies are required to validate this as a potential marker that may inform the development of strategies for reducing suicide.
The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms
Authors: S. Caponi, N. Funel, A.E. Frampton, F. Mosca, L. Santarpia, A.G. Van der Velde, L.R. Jiao, N. De Lio, A. Falcone, G. Kazemier, G.A. Meijer, H.M. Verheul, E. Vasile, G.J. Peters, U. Boggi, E. Giovannetti
Journal: Annals of Oncology (2012)
Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer—Gynaecological Cancer Group)
Authors: P.O. Witteveen, J. van der Velden, I. Vergote, C. Guerra, C. Scarabeli, C. Coens, G. Demonty, N. Reed
Journal: Annals of Oncology (2009)
Measurement of the High–Molecular Weight Form of Adiponectin in Plasma Is Useful for the Prediction of Insulin Resistance and Metabolic Syndrome
Authors: Kazuo Hara, Momoko Horikoshi, Toshimasa Yamauchi, Hirokazu Yago, Osamu Miyazaki, Hiroyuki Ebinuma, Yasushi Imai, Ryozo Nagai, Takashi Kadowaki
Journal: Diabetes Care (2006)

The high-molecular weight (HMW) form of adiponectin, an adipocyte-derived insulin-sensitizing hormone, has been reported to be the most active form of this hormone. We investigated whether measurement of plasma HMW adiponectin levels, using our newly developed enzyme-linked immunosorbent assay system for selective measurement of human HMW adiponectin level, may be useful for the prediction of insulin resistance and metabolic syndrome.A total of 298 patients admitted for diabetes treatment or coronary angiography served as study subjects. Receiver operator characteristic (ROC) curves for the HMW ratio (HMWR; ratio of plasma level of HMW adiponectin to that of total adiponectin) and plasma total adiponectin levels were plotted to predict the presence of insulin resistance and metabolic syndrome.The area under the ROC curve (AUC) of the HMWR values to predict the presence of insulin resistance was significantly larger than that of plasma total adiponectin level in total subjects (0.713 [95% CI 0.620-0.805] vs. 0.615 [0.522-0.708], P = 0.0160). The AUC for the HMWR values to predict the presence of metabolic syndrome was significantly larger than that for plasma total adiponectin levels in men (0.806 [0.747-0.865] vs. 0.730 [0.660-0.800], P = 0.0025) and in women (0.743 [0.659-0.828] vs. 0.637 [0.532-0.742], P = 0.0458).The HMWR value has better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level.
The differences in atrioventricular conduction of premature beats in young and adult goats.
Authors: W B Gough, E N Moore
Journal: Circulation Research (1975)

Atrioventricular (AV) conduction was studied in anesthetized, open-chest, 1-35-day-old goats. Atrial, bundle of His, and ventricular bipolar electrograms were recorded, and the functional refractory periods of the AV conduction system and the ventricles were determined. Supraventricular premature excitation invaded the ventricles during their vulnerable period. This AV conduction property is different from that of the adult goat heart; thus, the existence of a lateral accessory bypass tract was investigated. Electrocardiographic leads I, aVF, and V10 revealed no delta waves indicative of ventricular preexcitation. Bundle of His electrograms showed that: (1) bundle of His excitation always preceded the onset of ventricular depolarization, (2) no shortening occurred in the bundle of His to ventricular activation time following early atrial premature beats, and (3) the functional refractory period of the AV node was less than that of the ventricle. The ventricular epicardial excitation sequence indicated no involvement of a lateral bypass tract in the AV conduction of basic or premature beats. Interruption of the bundle of His caused complete AV block. Therefore, no functional lateral accessory bypass tracts are present in the young goat heart, and the AV node and the ventricular specialized conduction system of the young goat are capable of conducting premature atrial excitation to the ventricles within plus or minus 10 msec of the expiration of the ventricular functional refractory period.
Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
Authors: Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude
Journal: BMJ (2015)

<b>Objectives</b> To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. <b>Design</b> Double blind randomised placebo controlled trial. <b>Setting</b> 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. <b>Participants</b> 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. <b>Interventions</b> Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. <b>Main outcome measures</b> The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. <b>Results</b> The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. <b>Conclusions</b> Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.