tbuckley/cabot-search huggingface dataset:
Circulating Tumor Cells as Biomarkers in Prostate Cancer
Authors: Daniel C. Danila, Martin Fleisher, Howard I. Scher
Journal: Clinical Cancer Research (2011)

Abstract Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment effects and to identify therapeutic targets in a tumor at the time treatment is being considered. This review focuses on establishing analytically valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The FDA Critical Path provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision-making. CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment, as an efficacy-response surrogate biomarker of survival, is currently being tested in large phase III trials, with the novel antiandrogen therapies abiraterone acetate and MDV3100. Molecular determinants can be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTCs from more patients, the potential clinical uses of CTCs in determining prognosis and monitoring treatment effects, and CTCs as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice. Clin Cancer Res; 17(12); 3903–12. ©2011 AACR.
Dynamics of Actin Evolution in Dinoflagellates
Authors: Sunju Kim, Tsvetan R. Bachvaroff, Sara M. Handy, Charles F. Delwiche
Journal: Molecular Biology and Evolution (2010)

Dinoflagellates have unique nuclei and intriguing genome characteristics with very high DNA content making complete genome sequencing difficult. In dinoflagellates, many genes are found in multicopy gene families, but the processes involved in the establishment and maintenance of these gene families are poorly understood. Understanding the dynamics of gene family evolution in dinoflagellates requires comparisons at different evolutionary scales. Studies of closely related species provide fine-scale information relative to species divergence, whereas comparisons of more distantly related species provides broad context. We selected the actin gene family as a highly expressed conserved gene previously studied in dinoflagellates. Of the 142 sequences determined in this study, 103 were from the two closely related species, Dinophysis acuminata and D. caudata, including full length and partial cDNA sequences as well as partial genomic amplicons. For these two Dinophysis species, at least three types of sequences could be identified. Most copies (79%) were relatively similar and in nucleotide trees, the sequences formed two bushy clades corresponding to the two species. In comparisons within species, only eight to ten nucleotide differences were found between these copies. The two remaining types formed clades containing sequences from both species. One type included the most similar sequences in between-species comparisons with as few as 12 nucleotide differences between species. The second type included the most divergent sequences in comparisons between and within species with up to 93 nucleotide differences between sequences. In all the sequences, most variation occurred in synonymous sites or the 5′ UnTranslated Region (UTR), although there was still limited amino acid variation between most sequences. Several potential pseudogenes were found (approximately 10% of all sequences depending on species) with incomplete open reading frames due to frameshifts or early stop codons. Overall, variation in the actin gene family fits best with the "birth and death" model of evolution based on recent duplications, pseudogenes, and incomplete lineage sorting. Divergence between species was similar to variation within species, so that actin may be too conserved to be useful for phylogenetic estimation of closely related species.
Worsening heart failure, a critical event during hospital admission for acute heart failure: results from the <scp>VERITAS</scp> study
Authors: Gad Cotter, Marco Metra, Beth A. Davison, Stefanie Senger, Robert C. Bourge, John G.F. Cleland, Guillaume Jondeau, Henry Krum, Christopher M. O'Connor, John D. Parker, Guillermo Torre‐Amione, Dirk J. van Veldhuisen, Olga Milo, Isaac Kobrin, Maurizio Rainisio, John J.V. McMurray, John R. Teerlink
Journal: European Journal of Heart Failure (2014)
Kindler syndrome: a focal adhesion genodermatosis
Authors: J.E. Lai-Cheong, A. Tanaka, G. Hawche, P. Emanuel, C. Maari, M. Taskesen, S. Akdeniz, L. Liu, J.A. McGrath
Journal: British Journal of Dermatology (2008)

Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament–hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of β1 and β3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.
Absence of a <i>NPR-A</i> Gene Functional Deletion Allele in a Postmyocardial Infarction Cohort From New Zealand
Authors: Barry R. Palmer, Chris M. Frampton, A. Mark Richards, Vicky A. Cameron, Tomohiro Nakayama
Journal: Circulation Research (2004)

Nakayama et al 1 have described an interesting polymorphism in the NPR-A gene in a Japanese population.An 8-nucleotide deletion in the 5Ј untranslated region (UTR) of the gene was found to be associated with essential hypertension and left ventricular hypertrophy in a study of 200 hypertensive (HT) and 200 normotensive (NT) subjects.The polymorphism occurred at a frequency of 4% in the HT patients and in a single NT subject (0.5%) who was subsequently found to have left ventricular hypertrophy.Carriers of the functional deletion (D) allele had higher plasma BNP levels, a strong marker of cardiac stress, than those with the wild-type allele.Expression of NPR-A from the D allele was reduced compared with the wild-type allele and it is suggested that the deletion interferes with binding of regulatory factors to the 5Ј UTR of the gene. 1 We screened 498 patients from the Christchurch Post-Myocardial Infarction (PMI) Study 2-4 who had acute myocardial infarction for the NPR-A D allele.DNA samples were amplified using the polymerase chain reaction primers hNPR-Af 5Јacgcgcctgatgcctgg-gac3Ј and hNPR-Ar 5Јcagtaccacggctaccgtcaggtt3Ј and the wild-type (I ) and D amplimers (216 and 208 bp, respectively) were resolved on 3% agarose, 0.5 ϫ TBE gels and visualized using ethidium bromide and a Bio-Rad Fluor-S imaging system (Hercules, Calif).Patient DNA samples with (nϭ3) and without (nϭ3) the functional deletion from the Japanese study were used as controls. 1The New Zealand patients were 75% male, with a mean age of 62.4 (Ϯ0.5) years, 15.0% had a history of previous myocardial infarction, 52.0% had or were being treated for hypertension, 60.4% were past or present smokers, 11.4% had diabetes, 1.6% had had congestive heart failure, 52.7% were being treated with ␤-blockers, and 31.7% were being treated with an angiotensin-converting enzyme inhibitor; 83.3% were of European ethnicity, 3.8% Maori, 1.2% other (Indian, Middle Eastern, Pacific Islanders), and 11.7% not stated.None of the 498 New Zealand patients carried the NPR-A D allele.However, patient DNA samples with the functional deletion mutation from the original Japanese study 1 were positive in our assay, indicating that any positive samples in our New Zealand sample population would have been detected had they been present.The upper 95% confidence limit for the prevalence of carriers of the D allele is 0.60% in this PMI patient cohort.These findings suggest that this functional deletion polymorphism is rare outside Japanese populations.This conclusion is supported by the report of Knowles et al, 5 who studied the structure of the entire NPR-A gene from 34 unrelated individuals of black, white, and unknown ethnicities, finding 10 polymorphic sites in noncoding regions of the gene, but not the 5Ј UTR 8 bp I/D polymorphism.
Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel
Authors: Per Svenningsen, Claus Bistrup, Ulla G Friis, Marko Bertog, Silke Haerteis, Bettina Krueger, Jane Stubbe, Ole Nørregaard Jensen, Helle C Thiesson, Torben R Uhrenholt, Bente Jespersen, Boye L Jensen, Christoph Korbmacher, Ole Skøtt
Journal: Journal of the American Society of Nephrology (2008)

Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in <i>Xenopus laevis</i> oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in <i>Xenopus laevis</i> oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC γ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.
Targeted Intraoperative Radiotherapy Impairs the Stimulation of Breast Cancer Cell Proliferation and Invasion Caused by Surgical Wounding
Authors: Barbara Belletti, Jayant S. Vaidya, Sara D'Andrea, Frank Entschladen, Mario Roncadin, Francesca Lovat, Stefania Berton, Tiziana Perin, Ezio Candiani, Sonia Reccanello, Andrea Veronesi, Vincenzo Canzonieri, Mauro G. Trovò, Kurt S. Zaenker, Alfonso Colombatti, Gustavo Baldassarre, Samuele Massarut
Journal: Clinical Cancer Research (2008)

After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment.We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed.WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients.Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.
Low-Complexity Regions in Plasmodium falciparum: Missing Links in the Evolution of an Extreme Genome
Authors: M. M. Zilversmit, S. K. Volkman, M. A. DePristo, D. F. Wirth, P. Awadalla, D. L. Hartl
Journal: Molecular Biology and Evolution (2010)

Over the past decade, attempts to explain the unusual size and prevalence of low-complexity regions (LCRs) in the proteins of the human malaria parasite Plasmodium falciparum have used both neutral and adaptive models. This past research has offered conflicting explanations for LCR characteristics and their role in, and influence on, the evolution of genome structure. Here we show that P. falciparum LCRs (PfLCRs) are not a single phenomenon, but rather consist of at least three distinct types of sequence, and this heterogeneity is the source of the conflict in the literature. Using molecular and population genetics, we show that these families of PfLCRs are evolving by different mechanisms. One of these families, named here the HighGC family, is of particular interest because these LCRs act as recombination hotspots, both in genes under positive selection for high levels of diversity which can be created by recombination (antigens) and those likely to be evolving neutrally or under negative selection (metabolic enzymes). We discuss how the discovery of these distinct species of PfLCRs helps to resolve previous contradictory studies on LCRs in malaria and contributes to our understanding of the evolution of the of the parasite's unusual genome.
Evaluation of an Amitriptyline-Perphenazine Combination in Chronic Schizophrenia
Authors: ROBERT E. BECKER
Journal: American Journal of Psychiatry (1970)

The author describes a controlled study of an amitriptyline-perphenazine combination given to 58 chronic schizophrenic patients. There was no evidence of the combination's increased effectiveness over perphenazine used alone. He discusses the possibility of therapeutic incompatibility between perphenazine and amitriptyline at some dosage levels and concludes that there is no evidence that supports using a perphenazine-amitriptyline combination.
Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
Authors: Asa Abeliovich, Yvonne Schmitz, Isabel Fariñas, Derek Choi-Lundberg, Wei-Hsien Ho, Pablo E Castillo, Natasha Shinsky, Jose Manuel Garcia Verdugo, Mark Armanini, Anne Ryan, Mary Hynes, Heidi Phillips, David Sulzer, Arnon Rosenthal
Journal: Neuron (2000)
Metabolic Signatures of Exercise in Human Plasma
Authors: Gregory D. Lewis, Laurie Farrell, Malissa J. Wood, Maryann Martinovic, Zoltan Arany, Glenn C. Rowe, Amanda Souza, Susan Cheng, Elizabeth L. McCabe, Elaine Yang, Xu Shi, Rahul Deo, Frederick P. Roth, Aarti Asnani, Eugene P. Rhee, David M. Systrom, Marc J. Semigran, Ramachandran S. Vasan, Steven A. Carr, Thomas J. Wang, Marc S. Sabatine, Clary B. Clish, Robert E. Gerszten
Journal: Science Translational Medicine (2010)

Measurement by mass spectrometry of 200 blood metabolites reveals that individuals who are more fit respond more effectively to exercise, as shown by larger exercise-induced increase in glycerol.
Anticraving Medications for Relapse Prevention: A Possible New Class of Psychoactive Medications
Authors: Charles P O'Brien
Journal: American Journal of Psychiatry (2005)

Psychiatrists have gradually developed a list of medications that are effective in the treatment of addictive disorders. Although alcoholism has received the most attention, nicotine, heroin, and cocaine have all been shown to be influenced by heredity. Of course, the immediate goal is the reduction of drug craving and the prevention of relapse to compulsive drug taking. A medication that can aid in the maintenance of the opiate-free state is naltrexone, a specific opiate antagonist. Naltrexone is also a good example of an anticraving medication used in the treatment of alcoholism. Clinicians currently have two types of medication to aid in the treatment of tobacco use disorder, arguably the most important addiction. Bupropion and nicotine replacement can be given in a coordinated fashion to provide the best available results. At present, no medication is approved by the Food and Drug Administration for the indication of cocaine addiction. Recently, however, five different medications, already approved for other purposes, have been found to be effective among cocaine addicts. Despite clinical trials that show benefit, anticraving medications are not well known and are underused by clinicians. Addiction is a heterogeneous condition, with variability in reactivity to the drug of abuse and to the medications available to treat it. Recent developments in pharmacogenetics may result in improved selection of medications based on genotype.
Aromatase Inhibitors and Postmenopausal Breast Cancer Patients with Tamoxifen-Induced Endometrial Pathology
Authors: Leilani Morales, Robert Paridaens, Dirk Timmerman, Patrick Neven
Journal: Clinical Cancer Research (2006)

To the Editor: We have read with great interest the recently published article by Gerber et al. ([1][1]) on the potential endometrial benefit of anastrozole given to postmenopausal breast cancer patients with tamoxifen-induced endometrial pathology. Their study showed that the switch to anastrozole
Ovarian cancer immunotherapy: opportunities, progresses and challenges
Authors: Bei Liu, John Nash, Carolyn Runowicz, Helen Swede, Richard Stevens, Zihai Li
Journal: Journal of Hematology & Oncology (2010)

Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer.
β-Lactam Monotherapy vs β-Lactam–Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia
Authors: Nicolas Garin, Daniel Genné, Sebastian Carballo, Christian Chuard, Gerhardt Eich, Olivier Hugli, Olivier Lamy, Mathieu Nendaz, Pierre-Auguste Petignat, Thomas Perneger, Olivier Rutschmann, Laurent Seravalli, Stephan Harbarth, Arnaud Perrier
Journal: JAMA Internal Medicine (2014)

The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia.Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation.Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7.After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.clinicaltrials.gov Identifier: NCT00818610.
The effect of montelukast on respiratory symptoms and lung function in wheezy infants
Authors: Anna S. Pelkonen, Kristiina Malmström, Seppo Sarna, Merja Kajosaari, Timo Klemola, L. Pekka Malmberg, Mika J. Mäkelä
Journal: European Respiratory Journal (2012)

Our aim was to investigate the effectiveness of montelukast in recurrently wheezy infants. We randomised 113, 6–24-month-old children with recurrent wheezing to receive either placebo or montelukast daily for an 8-week period. The primary end-point was symptom-free days. The secondary aims were to evaluate the effect of montelukast on rescue medication, on lung function, airway responsiveness and exhaled nitric oxide fraction ( F eNO ). Clinical response and F eNO were determined, the functional residual capacity (FRC) and specific airway conductance (sG aw ) were measured using an infant whole-body plethysmograph, the maximal flow at functional residual capacity ( V ′ max,FRC ) was recorded using the squeeze technique and airway responsiveness was evaluated by performing a dosimetric methacholine challenge test. There was no significant difference in changes in weekly symptom-free days between the montelukast and the placebo group (3.1–3.7 days versus 2.7–3.1 days, p = 0.965). No significant differences were detected in the secondary end-points, i.e. use of rescue medication, FRC, s G aw , V ′ max,FRC , F eNO or airway responsiveness between groups. Montelukast therapy did not influence the number of symptom-free days, use of rescue medication, lung function, airway responsiveness or airway inflammation in recurrently wheezy, very young children .