tbuckley/cabot-search huggingface dataset:
Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.
Authors: M A Villalona-Calero, S D Baker, L Hammond, C Aylesworth, S G Eckhardt, M Kraynak, R Fram, S Fischkoff, R Velagapudi, D Toppmeyer, B Razvillas, K Jakimowicz, D D Von Hoff, E Rowinsky
Journal: Journal of Clinical Oncology (1998)

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks.Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities.Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose.The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.
Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney
Authors: Jianchun Chen, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2015)

Activation of the EGF receptor (EGFR) or the Hippo signaling pathway can control cell proliferation, apoptosis, and differentiation, and the dysregulation of these pathways can contribute to tumorigenesis. Previous studies showed that activation of EGFR signaling in renal epithelial cells can exacerbate diabetic kidney injury. Moreover, EGFR has been implicated in regulating the Hippo signaling pathway in Drosophila; thus, we examined this potential interaction in mammalian diabetic kidney disease. Yes-associated protein (YAP) is a transcriptional regulator regulated by the Hippo signaling pathway. We found YAP protein expression and phosphorylation were upregulated in diabetic mouse renal proximal tubule epithelial cells, which were inhibited in diabetic proximal tubule EGFR-knockout mice (EGFR(ptKO)) or administration of an EGFR tyrosine kinase inhibitor erlotinib. Furthermore, activation of an EGFR-PI3K-Akt-CREB signaling pathway mediated YAP gene expression and YAP nuclear translocation and interaction with the TEA domain (TEAD) transcription factor complex, which led to upregulated expression of two TEAD-dependent genes, the connective tissue growth factor and amphiregulin genes. In a renal proximal tubule cell line, either pharmacologic or genetic inhibition of EGFR, Akt, or CREB blunted YAP expression in response to high-glucose treatment. Additionally, knocking down YAP expression by specific siRNA inhibited cell proliferation in response to high glucose or exogenous EGF. Therefore, these results link the Hippo pathway to EGFR-mediated renal epithelial injury in diabetes.
Prognostic factors in stage III–IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study
Authors: R. Libé, I. Borget, C.L. Ronchi, B. Zaggia, M. Kroiss, T. Kerkhofs, J. Bertherat, M. Volante, M. Quinkler, O. Chabre, M. Bala, A. Tabarin, F. Beuschlein, D. Vezzosi, T. Deutschbein, F. Borson-Chazot, I. Hermsen, A. Stell, C. Fottner, S. Leboulleux, S. Hahner, M. Mannelli, A. Berruti, H. Haak, M. Terzolo, M. Fassnacht, E. Baudin
Journal: Annals of Oncology (2015)
CHRONIC EPSTEIN-BARR VIRUS INFECTION
Authors: J F Jones, S E Straus
Journal: Annual Review of Medicine (1987)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Celebrating the ACP Centennial: From the <i>Annals</i> Archive—Acute Coronary Syndromes
Authors: Deborah Cotton
Journal: Annals of Internal Medicine (2015)

Editorials17 November 2015Celebrating the ACP Centennial: From the Annals Archive—Acute Coronary SyndromesDeborah Cotton, MD, MPHDeborah Cotton, MD, MPHSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-2093 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail During the 2015 centennial year of the American College of Physicians, publisher of Annals of Internal Medicine, Annals editors will link an article in each issue with an earlier paper from our archives addressing the same disease or clinical question. We hope our readers find this interesting and we welcome comments, especially from physicians who were practicing at the time of publication of the original paper who might offer insight into the impact of the earlier paper on their knowledge or practice.In this issue, Hansen and colleagues, using data from the Danish national health registries, report on the real-world ...References1. Hansen KW, Sorensen R, Madsen M, Madsen JK, Jensen JS, von Kappelgaard LM, et al. Effectiveness of an early versus a conservative invasive treatment strategy in acute coronary syndromes. A nationwide cohort study. Ann Intern Med. 2015;163:737-46. doi:10.7326/M15-0303 LinkGoogle Scholar2. Master AM. Coronary heart disease: angina pectoris, acute coronary insufficiency and coronary occlusion. Ann Intern Med. 1944;20:661-74. doi:10.7326/0003-4819-20-4-661 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoCORONARY HEART DISEASE: ANGINA PECTORIS, ACUTE CORONARY INSUFFICIENCY AND CORONARY OCCLUSION A. M. MASTER Effectiveness of an Early Versus a Conservative Invasive Treatment Strategy in Acute Coronary Syndromes Kim Wadt Hansen , Rikke Sorensen , Mette Madsen , Jan Kyst Madsen , Jan Skov Jensen , Lene Mia von Kappelgaard , Poul Erik Mortensen , Theis Lange , and Soren Galatius Effectiveness of an Early Versus a Conservative Invasive Treatment Strategy in Acute Coronary Syndromes Kim Wadt Hansen , Rikke Sorensen , Mette Madsen , Jan Kyst Madsen , Jan Skov Jensen , Lene Mia von Kappelgaard , Poul Erik Mortensen , Theis Lange , and Soren Galatius Metrics 17 November 2015Volume 163, Issue 10Page: 798KeywordsArmed forcesAutopsyCardiovascular therapyChartsCoronary arteriesCoronary heart diseaseElectrocardiographyResearch laboratoriesSigns and symptomsStable coronary artery disease ePublished: 17 November 2015 Issue Published: 17 November 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Registration of dynamic multiview 2D ultrasound and late gadolinium enhanced images of the heart: Application to hypertrophic cardiomyopathy characterization
Authors: Julián Betancur, Antoine Simon, Edgar Halbert, François Tavard, François Carré, Alfredo Hernández, Erwan Donal, Frédéric Schnell, Mireille Garreau
Journal: Medical Image Analysis (2015)
Factors Affecting B-Cell Growth and Differentiation
Authors: Tadamitsu Kishimoto
Journal: Annual Review of Immunology (1985)

Since the discovery of T-B interactions in the antibody response, the mechanism of the regulatory functions of T cells in the B-cell response has been studied extensively in immunology. The possibility that helper functions of T cells may be mediated by soluble products released from T cells was originally proposed by Dutton and his colleagues in 1971 (1). In their experiment with murine splenic B cells, they showed that anti-SRBC (sheep red blood cell) response in T cell-depleted splenic lymphocytes could be reconstituted by culture supernatants of mixed lymphocyte reactions. This was confirmed by Schimpl & Wecker (2) and several other investi­ gators (3-5) who showed the active soluble factor(s) in culture supernatants of mitogens or antigen-stimulated T cells. Schimpl & Wecker demonstrated that cell-free supernatants from alloantigen-stimulated or concanavalin A (Con A}-stimulated T cells could fully substitute for T cells in the response in vitro to unrelated antigens such as SRBC. They postulated that T cells stimulated by their specific antigen released a substance, T cell-replacing factor (TRF), which was able to stimulate B cells to proliferate and/or differentiate only when B cells carried antigens on their receptors. Essentially the same result was reported by Kishimoto & Ishizaka with rabbit B cells (3). They demonstrated that anti-DNP (dinitrophenyl) antibody response could be induced in DNP-primed B cells by the stimulation with DNP-heterologous carrier conjugate and a cell-free supernatant from carrier-primed T cells stimulated with the primed carrier antigen. In a series of experiments, they also demonstrated that the factor(s)
Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation
Authors: Laura Eisenmenger, Marie-Claire Porter, Christopher J. Carswell, Andrew Thompson, Simon Mead, Peter Rudge, John Collinge, Sebastian Brandner, Hans R. Jäger, Harpreet Hyare
Journal: JAMA Neurology (2015)

Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses.To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation.Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012.Correlation of regional and total brain scores with disease duration.Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus.Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials.
A randomized phase I/II study of continuous versus intermittent intravenous interferon gamma in patients with metastatic melanoma.
Authors: M S Ernstoff, T Trautman, C A Davis, S D Reich, P Witman, J Balser, S Rudnick, J M Kirkwood
Journal: Journal of Clinical Oncology (1987)

Thirty patients with documented metastatic melanoma were randomly assigned to receive recombinant DNA-produced gamma-interferon (specific activity approximately, 20 MU/mg) intravenously (IV) over either two or 24 hours at dosages of 3, 30, 300, 1,000, or 3,000 micrograms/m2. Objective toxicity resembled that of alpha-interferon and included fever, chills, myalgias, headache, and fatigue. Neutropenia, elevations in liver enzymes, tachyarrhythmias, and CNS changes also were noted. Dose-limiting toxicity included neutropenia, liver enzyme abnormality, constitutional symptoms, and a change in mental status. The incidence of toxicity was qualitatively similar in both two- and 24-hour treatment arms, but was quantitatively more severe in the 24-hour continuous infusion arm. Maximum tolerated dose was 1,000 micrograms/m2 in both schedules. Pharmacokinetic studies showed a half-life of six to nine hours. One patient had a complete response after two cycles of therapy and an additional patient entered partial remission after three cycles. Recombinant gamma-interferon (rIRN-gamma) is tolerated at dosages of 1,000 micrograms/m2 administered daily either by two or 24 hour infusion for 14 days in patients with metastatic melanoma. The responses documented in this early trial warrant further evaluation for the treatment of metastatic melanoma.
Duplication and Adaptive Evolution of a Key Centromeric Protein in<i>Mimulus</i>, a Genus with Female Meiotic Drive
Authors: Findley R. Finseth, Yuzhu Dong, Arpiar Saunders, Lila Fishman
Journal: Molecular Biology and Evolution (2015)

The fundamental asymmetry of female meiosis creates an arena for genetic elements to compete for inclusion in the egg, promoting the selfish evolution of centromere variants that maximize their transmission to the future egg. Such "female meiotic drive" has been hypothesized to explain the paradoxically complex and rapidly evolving nature of centromeric DNA and proteins. Although theoretically widespread, few cases of active drive have been observed, thereby limiting the opportunities to directly assess the impact of centromeric drive on molecular variation at centromeres and binding proteins. Here, we characterize the molecular evolutionary patterns of CENH3, the centromere-defining histone variant, in Mimulus monkeyflowers, a genus with one of the few known cases of active centromere-associated female meiotic drive. First, we identify a novel duplication of CENH3 in diploid Mimulus, including in lineages with actively driving centromeres. Second, we demonstrate long-term adaptive evolution at several sites in the N-terminus of CENH3, a region with some meiosis-specific functions that putatively interacts with centromeric DNA. Finally, we infer that the paralogs evolve under different selective regimes; some sites in the N-terminus evolve under positive selection in the pro-orthologs or only one paralog (CENH3_B) and the paralogs exhibit significantly different patterns of polymorphism within populations. Our finding of long-term, adaptive evolution at CENH3 in the context of centromere-associated meiotic drive supports an antagonistic, coevolutionary battle for evolutionary dominance between centromeric DNA and binding proteins.
Identifying Breast Cancer Patients at High Risk for Bone Metastases
Authors: Marco Colleoni, Anne O’Neill, Aron Goldhirsch, Richard D. Gelber, Marco Bonetti, Beat Thürlimann, Karen N. Price, Monica Castiglione-Gertsch, Alan S. Coates, Jurij Lindtner, John Collins, Hans-Jörg Senn, Franco Cavalli, John Forbes, Anne Gudgeon, Edda Simoncini, Hernan Cortes-Funes, Andrea Veronesi, Martin Fey, Carl-Magnus Rudenstam
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates. PATIENTS AND METHODS: We evaluated data from 6,792 patients who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1993. Median follow-up was 10.7 years. A total of 1,275 patients (18.7%) presented with node-negative disease, whereas 3,354 patients (49.4%) had one to three and 2,163 patients (31.9%) had four or more involved axillary lymph nodes. We also assessed the incidence of subsequent bone metastases in the cohort of 1,220 patients who had a first event in local or regional sites or soft tissue alone. Median follow-up for this cohort was 7.7 years from first recurrence. RESULTS: For the entire population with operable disease, the cumulative incidence of bone metastases at any time was 8.2% at 2 years from randomization and 27.3% at 10 years. The highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at 2 years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at 2 years from first recurrence and 36.7% at 10 years). CONCLUSION: Treatments to prevent bone metastases may have a major impact on the course of breast cancer and may be most efficiently studied in populations with several involved axillary nodes at the time of presentation and in populations with local or regional recurrence or recurrence in soft tissue.
Novel Variant of Miller Fisher Syndrome Occurring With Tumor Necrosis Factor α Antagonist Therapy
Authors: Gokulan Ratnarajan, Alexander Thompson, Caroline Dodridge, Allyson Parry, John Elston
Journal: JAMA Neurology (2015)

A provisional diagnosis of acute autoimmune ophthalmoparesis was made.Investigations included a normal full blood cell count and renal, liver, thyroid, and bone profiles, as well as negative anti-acetylcholine receptor and anti-Musk antibody test results.The erythrocyte sedimentation rate was 43 mm/h (to convert to mm/h, multiply by 1) and C-reactive protein level was 26 mg/L (to convert to nmol/L, multiply by 9.524) attributable to her active bowel disease.Magnetic resonance imaging of the brain and magnetic resonance venogram were normal.The anti-GQ1b IgG antibody titer was 6400, supporting the diagnosis of an isolated autoimmune acute ophthalmoparesis variant of MFS occurring with TNFα antagonist therapy.Treatment with intravenous immunoglobulin or plasmapheresis was considered; however, it was not given because of the relatively mild symptoms, potential risks of treatment, and likely lack of impact on long-term recovery.Instead, occlusion was used to eliminate diplopia with reading glasses for near tasks.Two weeks later, the ophthalmoparesis was unchanged but the eyelid twitches and hops had reduced and the pupillary light responses had improved.By 10 weeks after presentation, all symptoms and signs had resolved and anti-GQ1b IgG antibody titer had reduced to 200.Discussion | Tumor necrosis factor α antagonists have been reported to be associated with, or cause, central and peripheral nervous system demyelination including multiple sclerosis-like symptoms, 5 as well as 2 cases clinically compatible with MFS, 6 neither of whom had anti-GQ1b antibodies.The temporal association of infliximab therapy suggests that TNF antagonism may have caused or permitted the development of MFS in this case, although the mechanism involved is unclear.This case extends the spectrum of TNF antagonistassociated neurological disorders and provides further evidence that these are immune mediated.Clinicians should be vigilant for the potential broad-ranging, although uncommon, neurological adverse effects of these drugs.
A three-miRNA signature as promising non-invasive diagnostic marker for gastric cancer
Authors: Vivian Yvonne Shin, Enders K. O. Ng, Vivian W. Chan, Ava Kwong, Kent-Man Chu
Journal: Molecular Cancer (2015)

Despite the declining incidence of gastric cancer, mortality rate remains high due to late presentation. We aimed to evaluate the sensitivity of miRNA as a diagnostic marker for gastric cancer in the circulation.Plasma samples from 3 independent groups comprise 123 gastric cancer patients and 111 healthy controls for miRNA profiling from microarray screening.Microarray data showed that 25 miRNAs were upregulated in gastric cancer patients and 6 highly expressed miRNAs (miR-18a, miR-140-5p, miR-199a-3p, miR-627, miR-629 and miR-652) were selected for validation. In an independent validation set, levels of miR-627, miR-629 and miR-652 were significantly higher in gastric cancer patients than healthy controls (P <0.0001). An algorithm with improved sensitivity and specificity as gastric cancer classifier was adopted and validated in another random set of 15 plasma samples. Results showed that combination of 3 miRNAs obtained the highest area under curve, with a cut-off at 0.373, with a sensitivity of 86.7% and a specificity of 85.5%.This study revealed a three-miRNA signature as a promising classifier for gastric cancer, and greatly enhances the feasibility of circulating miRNAs as non-invasive diagnostic marker for this disease.
The Pharmacological and Physiological Role of Cyclic GMP in Vascular Smooth Muscle Relaxation
Authors: L J Ignarro, P J Kadowitz
Journal: The Annual Review of Pharmacology and Toxicology (1985)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Scare over oral contraceptives
Authors: J L Armstrong, M Reid, A Bigrigg
Journal: BMJ (1995)

EDITOR,--The Department of Health's recent press release concerning the safety of some third generation contraceptive pills has important consequences for women using oral contraception.1 To document their views and any change in behaviour of women taking the contraceptive pill after this warning, a survey was carried out at a large family planning clinic.

After the announcement a telephone helpline was established at the clinic. This took 2348 calls on the first seven …
The Cpf1 CRISPR-Cas protein expands genome-editing tools
Authors: Robert D. Fagerlund, Raymond H. J. Staals, Peter C. Fineran
Journal: Genome biology (2015)

CRISPR-Cas systems have immense biotechnological utility. A recent study reveals the potential of the Cpf1 nuclease to complement and extend the existing CRISPR-Cas9 genome-editing tools.
Review of K. R. Monroe, R. B. Miller, and J. Tobis.<i>Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical and Political Issues</i>.<sup>1</sup>Review of C. B. Cohen.<i>Renewing the Stuff of Life: Stem Cells, Ethics, and Public Policy</i>.<sup>2</sup>Review of R. Korobkin with S. R. Munzer.<i>Stem Cell Century: Law and Policy for a Breakthrough Technology</i>.<sup>3</sup>
Authors: Insoo Hyun
Journal: The American Journal of Bioethics (2008)