tbuckley/cabot-search huggingface dataset:
Species Differences in Troxacitabine Pharmacokinetics and Pharmacodynamics
Authors: Henriette Gourdeau, Lorraine Leblond, Bettina Hamelin, Kelly Dong, France Ouellet, Chantal Boudreau, Dominique Custeau, Annie Richard, Marie-Josée Gilbert, Jacques Jolivet
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Troxacitabine is the first unnatural l-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models. Experimental Design: Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of [14C]troxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules. Results: Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring &amp;gt;24 hours exposure for maximum activity. Analysis of the intracellular metabolites of [14C]troxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 μmol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity [treated versus control (T/C) of 27% and tumor regression during treatment]. Conclusions: These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
Isolation of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Using a Novel Cell Separation Strategy
Authors: Wen Xu, Lu Cao, Lei Chen, Jing Li, Xiao-Feng Zhang, Hai-Hua Qian, Xiao-Yan Kang, Yu Zhang, Jian Liao, Le-Hua Shi, Ye-Fa Yang, Meng-Chao Wu, Zheng-Feng Yin
Journal: Clinical Cancer Research (2011)

To establish a sensitive and specific isolation and enumeration system for circulating tumor cells (CTC) in patients with hepatocellular carcinoma (HCC).HCC cells were bound by biotinylated asialofetuin, a ligand of asialoglycoprotein receptor, and subsequently magnetically labeled by antibiotin antibody-coated magnetic beads, followed by magnetic separation. Isolated HCC cells were identified by immunofluorescence staining using Hep Par 1 antibody. The system was used to detect CTCs in 5 mL blood. Blood samples spiked with Hep3B cells (ranging from 10 to 810 cells) were used to determine recovery and sensitivity. Prevalence of CTCs was examined in samples from HCC patients, healthy volunteers, and patients with benign liver diseases or non-HCC cancers. CTC samples were also analyzed by FISH.The average recovery was 61% or more at each spiking level. No healthy, benign liver disease or non-HCC cancer subjects had CTCs detected. CTCs were identified in 69 of 85 (81%) HCC patients, with an average of 19 ± 24 CTCs per 5 mL. Both the positivity rate and the number of CTCs were significantly correlated with tumor size, portal vein tumor thrombus, differentiation status, and the disease extent as classified by the TNM (tumor-node-metastasis) classification and the Milan criteria. HER-2 gene amplification and TP53 gene deletion were detected in CTCs.Our system provides a new tool allowing for highly sensitive and specific detection and genetic analysis of CTCs in HCC patients. It is likely clinically useful in diagnosis and monitoring of HCC and may have a role in clinical decision making.
Identification of the Molecular Mechanisms for Dedifferentiation at the Invasion Front of Colorectal Cancer by a Gene Expression Analysis
Authors: Yoshimasa Oku, Takashi Shimoji, Katsunari Takifuji, Tsukasa Hotta, Shozo Yokoyama, Kenji Matsuda, Takashi Higashiguchi, Toshiji Tominaga, Toru Nasu, Koichi Tamura, Masaaki Matsuura, Satoshi Miyata, Yo Kato, Hiroki Yamaue, Yoshio Miki
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aim of this study is to identify gene expression signatures that accompany dedifferentiation at the cancer invasion front in colorectal cancer. Experimental Design: Two types of colorectal cancer were selected. Both types were well-differentiated adenocarcinomas at the superficial lesion. One type showed a dedifferentiated phenotype at the invasion front (type A, 13 samples); the other showed almost no dedifferentiated cancer cells at the invasion front (type B, 12 samples). Laser microdissection was combined with a cDNA microarray analysis to investigate the superficial lesions and the invasion front in colorectal cancers. Results: Eighty-three genes were differentially expressed between types A and B in the superficial lesions, and the samples of superficial lesions were divided correctly into two clusters by these genes. Interestingly, the samples of the invasion front were also divided into the two same clusters by these genes. The text mining method selected 10 genes involved in potential mechanisms causing dedifferentiation of cancer cells at the invasion front. The potential mechanisms include the networks of transforming growth factor-β, Wnt, and Hedgehog signals. The expression levels of 10 genes were calculated by quantitative reverse transcription-PCR and 8 genes were confirmed to be significantly differentially expressed between two types (P &amp;lt; 0.05). The gene expression profiles of 8 genes divided 12 test cases into two clusters with one misclassification. Conclusions: The molecular mechanisms constructed with 8 genes from three networks of transforming growth factor-β, Wnt, and Hedgehog signals were found to correlate with dedifferentiation at the invasion front of colorectal cancer.
Intracellular sodium and the positive inotropic effect of veratridine and cardiac glycoside in sheep Purkinje fibers.
Authors: D M Brill, J A Wasserstrom
Journal: Circulation Research (1986)

Veratridine is a sodium channel toxin that exerts a powerful positive inotropic effect and prolongs the action potential duration in the heart. To determine the basis of the inotropic action of veratridine and to examine the effects of dissimilar methods of raising intracellular sodium activity on contractility, we measured twitch tension and intracellular sodium activity using sodium-sensitive microelectrodes in stimulated sheep Purkinje fibers exposed to veratridine and in voltage-clamped fibers exposed to veratridine and cardiac glycoside. In stimulated fibers, veratridine (0.1-1 microM) produced coincident increases in intracellular sodium activity, action potential duration, and tension. In voltage-clamped fibers, veratridine (1-2 microM) and acetylstrophanthidin (0.1 microM) raised intracellular sodium activity and tension to a comparable degree. Tetrodotoxin (10 microM) abolished the mechanical, electrophysiological, and ionic changes produced by veratridine. The relationship between intracellular sodium activity and tension in voltage-clamped fibers (n = 6) was indistinguishable for veratridine and acetylstrophanthidin and could be fitted either with a linear function with slopes of 122.8% and 124.2%, respectively, or with a power function with slopes of 4.60 and 4.54, respectively, where the slope represents the exponential power of intracellular sodium activity to which tension is proportional. These results indicate that the positive inotropic action of veratridine is entirely accounted for by accumulation of intracellular sodium, which increases intracellular calcium available for contraction by sodium-calcium exchange. This study is the first direct demonstration that veratridine or any other sodium channel toxin affects intracellular sodium activity and suggests that the inotropic potency of veratridine and cardiac glycoside rely on the same mechanism, namely, elevation of intracellular sodium.
Overexpression of sarcoplasmic reticulum Ca2+–ATPase improves cardiac contractile function in hypothyroid mice
Authors: W Bluhm
Journal: Cardiovascular Research (1999)

Objective: Prolonged cardiac contraction and relaxation in hypothyroidism are in part related to diminished expression of the gene coding for the calcium pump of the sarcoplasmic reticulum (SERCA2a). Therefore, we examined whether or not transgenic SERCA2a gene expression in mice may compensate for the cardiac effects of hypothyroidism. Methods: SERCA2a mRNA and protein were analyzed from hearts of euthyroid and hypothyroid mice of wild-type or SERCA2a transgene status. Contractile function was studied in isolated left ventricular papillary muscles. Results: We found significant decreases of SERCA2a mRNA and protein levels in hearts of hypothyroid wild-type mice in comparison with euthyroid wild-type mice (controls). Papillary muscles from hypothyroid wild-type mice showed significant increases in time to peak contraction and relaxation times compared with controls. In contrast, SERCA2a mRNA and protein levels were significantly higher in hypothyroid SERCA2a transgenic mice than in hypothyroid wild-type mice. The transgene led to a functional improvement by compensating for the prolonged contraction and relaxation of papillary muscles. Conclusions: Our murine model of hypothyroidism revealed decreases in SERCA2a gene expression accompanied by prolonged contraction and relaxation of papillary muscles, and an improvement of the contractile phenotype due to compensated SERCA2a gene expression in SERCA2a transgenic mice.
Why do sperm carry RNA? Relatedness, conflict, and control
Authors: David J. Hosken, David J. Hodgson
Journal: Trends in Ecology & Evolution (2014)

Classically, sperm were seen as transcriptionally inactive vehicles for delivering the paternal haplotype to an egg. Yet, it has become apparent that sperm also carry thousands of different RNAs, and the functions of most of these are unknown. Here, we make four novel suggestions for sperm RNA function. First, they could act as relatedness markers facilitating sperm cooperation. Second, they could act as paternally imposed suppressors of haploid interests. Third, they could act as a nuptial gift, providing the female with resources that entice her to fertilise ova using the sperm of the gift-provider. Fourth, they could represent the contents of a Trojan horse, delivered by males to manipulate female reproduction. We discuss these ideas and suggest how they might be tested.
Intergenerational conflict over grandparental investment
Authors: Tim W. Fawcett, Pieter van den Berg, Franz J. Weissing, Justin H. Park, Abraham P. Buunk
Journal: Behavioral and Brain Sciences (2010)

Abstract Selection on grandparental investment is more complex than Coall &amp; Hertwig (C&amp;H) propose. Patterns of investment are subject to an intergenerational conflict over how resources should be distributed to maximize fitness. Grandparents may be selected to distribute resources unevenly, while their descendants will be selected to manipulate investment in their own favor. Here we outline the evolutionary basis of this conflict.
CRF and CRF Receptors: Role in Stress Responsivity and Other Behaviors
Authors: Tracy L. Bale, Wylie W. Vale
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Since corticotropin-releasing factor (CRF) was first characterized, a growing family of ligands and receptors has evolved. The mammalian family members include CRF, urocortinI (UcnI), UcnII, and UcnIII, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein. These family members differ in their tissue distribution and pharmacology. Studies have provided evidence supporting an important role of this family in regulation of the endocrine and behavioral responses to stress. Although CRF appears to play a stimulatory role in stress responsivity through activation of CRFR1, specific actions of UcnII and UcnIII on CRFR2 may be important for dampening stress sensitivity. As the only ligand with high affinity for both receptors, UcnI's role may be promiscuous. Regulation of the relative contribution of the two CRF receptors to brain CRF pathways may be essential in coordinating physiological responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of CRF family members.
Failure to demonstrate a hormonal inhibitor of proximal sodium reabsorption
Authors: Fred S. Wright, Barry M. Brenner, Cleaves M. Bennett, Robert I. Keimowitz, Robert W. Berliner, Robert W. Schrier, Pierre J. Verroust, Hugh E. De Wardener, Heinz Holzgreve
Journal: Journal of Clinical Investigation (1969)

Recently, it has been reported that a humoral inhibitor of proximal sodium reabsorption could be detected in plasma, and dialysates of plasma, of rats and dogs undergoing saline diuresis. We have repeated these studies using similar techniques and protocols. Fractional sodium reabsorption by the proximal tubule (as estimated in free-flow micropuncture studies from tubule fluid-to-plasma inulin ratios) was found not to be lower during infusion of "natriuretic" plasma than during subsequent infusion of "hydropenic" plasma. Similarly, infusion of natriuretic plasma failed to prolong reabsorptive half-time of the shrinking drop beyond that seen during hydropenic plasma infusion. No increase in urine volume or rate of sodium excretion was observed during the period of natriuretic plasma infusion, nor did natriuretic plasma result in an increase in these measures in rats undergoing water diuresis. It also has been reported that dialysates of natriuretic plasma, but not of hydropenic plasma, when placed directly into the tubule lumen, inhibit proximal sodium reabsorption. In double blind studies carried out independently in Bethesda, London, and Cologne, we failed to detect the presence of a dialyzable inhibitor in natriuretic plasma. Finally, in contrast to other recent reports, we were unable to detect inhibitory activity in plasma obtained from dogs during the "escape" phase of chronic deoxycorticosterone acetate administration.
Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor
Authors: Raymond J. Andersen, Nasrin R. Mawji, Jun Wang, Gang Wang, Simon Haile, Jae-Kyung Myung, Kate Watt, Teresa Tam, Yu Chi Yang, Carmen A. Bañuelos, David E. Williams, Iain J. McEwan, Yuzhou Wang, Marianne D. Sadar
Journal: Cancer Cell (2010)
No role for routine CT scans in paediatric empyemas
Authors: J Massie, N Pillarisetti, S Ranganathan
Journal: Thorax (2008)

In the paper by Jaffe et al , the authors describe the CT findings of 31 patients with thoracic empyema who had three investigations (chest radiography, CT scan and ultrasound scan).1 They correctly conclude that routine CT scanning has no role for children with empyema treated with uro-kinase and percutaneous chest drainage. It is interesting to note that CT scanning is becoming popular as nearly half the subjects had a chest CT scan on referral. They …
Understanding Cardiomyopathy Phenotypes Based on the Functional Impact of Mutations in the Myosin Motor
Authors: Jeffrey R. Moore, Leslie Leinwand, David M. Warshaw
Journal: Circulation Research (2012)

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are inherited diseases with a high incidence of death due to electric abnormalities or outflow tract obstruction. In many of the families afflicted with either disease, causative mutations have been identified in various sarcomeric proteins. In this review, we focus on mutations in the cardiac muscle molecular motor, myosin, and its associated light chains. Despite the &gt;300 identified mutations, there is still no clear understanding of how these mutations within the same myosin molecule can lead to the dramatically different clinical phenotypes associated with HCM and DCM. Localizing mutations within myosin's molecular structure provides insight into the potential consequence of these perturbations to key functional domains of the motor. Review of biochemical and biophysical data that characterize the functional capacities of these mutant myosins suggests that mutant myosins with enhanced contractility lead to HCM, whereas those displaying reduced contractility lead to DCM. With gain and loss of function potentially being the primary consequence of a specific mutation, how these functional changes trigger the hypertrophic response and lead to the distinct HCM and DCM phenotypes will be the future investigative challenge.
Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired Pneumonia
Authors: Yann-Erick Claessens, Marie-Pierre Debray, Florence Tubach, Anne-Laure Brun, Blandine Rammaert, Pierre Hausfater, Jean-Marc Naccache, Patrick Ray, Christophe Choquet, Marie-France Carette, Charles Mayaud, Catherine Leport, Xavier Duval
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Clinical decision making relative to community-acquired pneumonia (CAP) diagnosis is difficult. Chest radiograph is key in establishing parenchymal lung involvement. However, radiologic performance may lead to misdiagnosis, rendering questionable the use of chest computed tomography (CT) scan in patients with clinically suspected CAP.Objectives: To assess whether early multidetector chest CT scan affects diagnosis and management of patients visiting the emergency department with suspected CAP.Methods: A total of 319 prospectively enrolled patients with clinically suspected CAP underwent multidetector chest CT scan within 4 hours. CAP diagnosis probability (definite, probable, possible, or excluded) and therapeutic plans (antibiotic initiation/discontinuation, hospitalization/discharge) were established by emergency physicians before and after CT scan results. The adjudication committee established the final CAP classification on Day 28.Measurements and Main Results: Chest radiograph revealed a parenchymal infiltrate in 188 patients. CAP was initially classified as definite in 143 patients (44.8%), probable or possible in 172 (53.8%), and excluded in 4 (1.2%). CT scan revealed a parenchymal infiltrate in 40 (33%) of the patients without infiltrate on chest radiograph and excluded CAP in 56 (29.8%) of the 188 with parenchymal infiltrate on radiograph. CT scan modified classification in 187 (58.6%; 95% confidence interval, 53.2–64.0), leading to 50.8% definite CAP and 28.8% excluded CAP, and 80% of modifications were in accordance with adjudication committee classification. Because of CT scan, antibiotics were initiated in 51 (16%) and discontinued in 29 (9%), and hospitalization was decided in 22 and discharge in 23.Conclusions: In CAP-suspected patients visiting the emergency unit, early CT scan findings complementary to chest radiograph markedly affect both diagnosis and clinical management.Clinical trial registered with www.clinicaltrials.gov (NCT 01574066).
Dermatological Findings in Early Detection of Complex Regional Pain Syndrome
Authors: Rameez Kabani, Alain Brassard
Journal: JAMA Dermatology (2014)

Complex regional pain syndrome (CRPS) is a chronic pain condition usually affecting the extremities. It mostly occurs in 3 distinct stages with intense pain being the hallmark feature in every stage. Skin abnormalities are common, and often necessary, in the clinical findings required to diagnose CRPS.A man in his 30s presented to the dermatology clinic with complaints of recurrent redness, swelling, and burning pain in his left arm. Based on this clinical presentation with normal findings from a neurological examination and unremarkable findings on diagnostic imaging, the diagnosis of CRPS was made.It is important for dermatologists to understand and recognize CRPS as a neurological disorder with major dermatologic implications. The ability of dermatologists to identify and direct patients with this syndrome is a critical factor in determining the likelihood of favorable outcomes following diagnosis of CRPS. This report outlines and reviews a neurological condition presenting with clinically significant cutaneous changes. We illustrate the bias that dermatologists may have in exclusively associating patient complaints with dermatological implications. This stresses the necessity for dermatologists to perform comprehensive medical histories and physical examinations to minimize diagnostic error and improve patient care.
Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival
Authors: Max S. Topp, Peter Kufer, Nicola Gökbuget, Mariele Goebeler, Matthias Klinger, Svenja Neumann, Heinz-A. Horst, Thorsten Raff, Andreas Viardot, Mathias Schmid, Matthias Stelljes, Markus Schaich, Evelyn Degenhard, Rudolf Köhne-Volland, Monika Brüggemann, Oliver Ottmann, Heike Pfeifer, Thomas Burmeister, Dirk Nagorsen, Margit Schmidt, Ralf Lutterbuese, Carsten Reinhardt, Patrick A. Baeuerle, Michael Kneba, Hermann Einsele, Gert Riethmüller, Dieter Hoelzer, Gerhard Zugmaier, Ralf C. Bargou
Journal: Journal of Clinical Oncology (2011)

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.