tbuckley/cabot-search huggingface dataset:
RAS Mutations Affect Tumor Necrosis Factor–Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects
Authors: Pamela K. Kreeger, Roli Mandhana, Shannon K. Alford, Kevin M. Haigis, Douglas A. Lauffenburger
Journal: Cancer Research (2009)

More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. When the dynamics of phosphorylated ERK response to TNFalpha were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-alpha. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-alpha autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFalpha treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence.
Right Ventricular Mechanics and QRS Duration in Patients With Repaired Tetralogy of Fallot
Authors: Anselm Uebing, Derek G. Gibson, Sonya V. Babu-Narayan, Gerhard P. Diller, Konstantinos Dimopoulos, Omer Goktekin, Mark S. Spence, Kai Andersen, Michael Y. Henein, Michael A. Gatzoulis, Wei Li
Journal: Circulation (2007)

Background— Patients after repair of tetralogy of Fallot (ToF) frequently have right ventricular (RV) dysfunction and prolonged QRS duration (QRSd) and thus could be candidates for cardiac resynchronization therapy. We aimed to assess the relationship between QRSd and the timing of RV wall motion, including the RV outflow tract (RVOT), in these patients. Methods and Results— Sixty-seven repaired ToF patients (median age, 34 years; interquartile range, 24 to 43 years) and 35 age-matched control subjects were studied by echocardiography and cardiovascular magnetic resonance (n=55 of 67 ToF patients). Time intervals of the RV cardiac cycle were measured from Doppler recordings. Long-axis M-mode recordings were acquired from the right ventricular (RV) free wall and RV outflow tract (RVOT), and the delay in onset of long-axis shortening was measured. ToF patients showed minor abnormalities of the RV cardiac cycle unrelated to QRSd. RV ejection time was prolonged and correspondingly filling time was reduced compared with control subjects (22.3±2.6 versus 20.0±2.9 s/min, P &lt;0.0001; 29.0±3.8 versus 32.7±3.5 s/min, P &lt;0.0001). Total isovolumic time was normal in ToF patients (8.7±4.0 versus 7.4±2.9 s/min; P =NS). QRSd correlated with the delay in RV free wall motion ( r =0.55, P &lt;0.0001) and more so with the delay in RVOT shortening ( r =0.82, P &lt;0.0001). QRSd also correlated with measures of RVOT abnormality such as long-axis RVOT excursion and akinetic area length ( r =−0.46, P =0.004; r =0.33, P =0.01). Conclusions— QRSd in postoperative ToF patients reflects mainly abnormalities of the RVOT rather than the RV body itself. Thus, prevention and treatment of mechanical asynchrony and malignant arrhythmia should focus on the RV infundibulum. Indications for cardiac resynchronization therapy after ToF repair warrant further investigation.
Treatment of chronic hepatitis C with recombinant human interferon-α2a: Results of a randomized controlled clinical trial
Authors: Giulio Diodati, Paola Bonetti, Franco Noventa, Carla Casarin, Massimo Rugge, Sergio Scaccabarozzi, Alessandro Tagger, Lucio Pollice, Federico Tremolada, Cristina Davite, Giuseppe Realdi, Arturo Ruol
Journal: Hepatology (1994)

Sixty consecutive patients with chronic hepatitis C were included in a randomized controlled trial of recombinant human interferon-alpha 2a vs. no treatment. Treated patients received tapering doses of interferon thrice weekly for 1 yr. Twenty treated cases (66.7%) normalized serum aminotransferase levels within the first 4 mo of treatment, but reactivation or breakthrough frequently occurred afterward (20% in both cases). Only one of the untreated patients showed spontaneous normalization of serum aminotransferase levels. Liver histology did not improve in patients without a biochemical response or with breakthrough during therapy, whereas it did not worsen in long-term responders and reactivating patients. Lack of response does not appear to be related to serum interferon antibodies, although their early appearance is more frequent in patients who showed reactivation later on. No biochemical parameter was found to be predictive for positive response to treatment. Antibody to c100 became negative in 62.5% of long-term responders, whereas no change was recorded in other treated patients or controls. Reactivation and breakthrough often occur during treatment, and further studies are needed to determine the most effective schedule (dose and time) of interferon treatment. Loss of c100 antibody during therapy may be a marker of long-term maintenance of response to interferon therapy.
Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model
Authors: G Scott Ralph, Pippa A Radcliffe, Denise M Day, Janine M Carthy, Marie A Leroux, Debbie C P Lee, Liang-Fong Wong, Lynsey G Bilsland, Linda Greensmith, Susan M Kingsman, Kyriacos A Mitrophanous, Nicholas D Mazarakis, Mimoun Azzouz
Journal: Nature Medicine (2005)
Cd4+Cd25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade
Authors: Patricia A. Taylor, Randolph J. Noelle, Bruce R. Blazar
Journal: The Journal of Experimental Medicine (2001)

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4+CD25+ cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4+ T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte–associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4+CD25+ T cells were found to be potent regulators of alloresponses. Depletion of CD4+CD25+ T cells from the CD4+ responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4+CD25+ T cells to CD4+CD25− cultures restored tolerance induction. These data are the first to indicate that CD4+CD25+ cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.
Influenza vaccine immunogenicity in patients with primary central nervous system malignancy
Authors: R. E. Strowd, K. Swett, M. Harmon, A. F. Carter, A. Pop-Vicas, M. Chan, S. B. Tatter, T. Ellis, M. Blevins, K. High, G. J. Lesser
Journal: Neuro-Oncology (2014)

Patients with central nervous system (CNS) malignancies represent an “at-risk” population for contracting influenza, particularly if they are receiving ongoing chemotherapy, radiation, and/or glucocorticoid treatment. The Centers for Disease Control endorses vaccination for these patients, although data are not available to indicate whether they mount an immunologic response adequate to achieve clinical protection. A pilot prospective cohort study was designed to evaluate the immunogenicity of the standard-dose trivalent inactivated influenza vaccine in patients with malignant CNS tumors. Baseline data collection included diagnosis, chemotherapy, timing of chemotherapy or radiation relative to vaccination, and glucocorticoid dose. Serum samples were collected at baseline, day 14, day 28, and month 3 following vaccination. Samples were tested using hemagglutinin inhibition to determine seroconversion (4-fold rise in titer) and seroprotection (titer >1:40). A total of 38 patients were enrolled (mean age, 54 years ±13.5 years, 60.5% male, 94.7% Caucasian, and 5.3% African American). CNS tumor diagnoses included glioblastoma multiforme (55.2%), other high-grade glioma (13.2%), low-grade glioma (15.8%), and primary CNS lymphoma (15.8%). At enrollment, 20 patients (52.6%) were taking glucocorticoids, 25 (65.8%) were on active chemotherapy, and 3 (7.9%) were undergoing radiation. Seroconversion rates at day 28 for the A/H1N1, A/H3N2, and B strains were 37%, 23% and 23%, respectively. Seroprotection was 80%, 69%, and 74%, respectively. All rates were significantly lower than published rates in healthy adults (P < .001). Influenza vaccine immunogenicity is significantly reduced in patients with CNS malignancies. Future studies are needed to determine the causative etiologies and appropriate vaccination strategies.
Incontinence in Older Women
Authors: Patricia S Goode, Kathryn L Burgio, Holly E Richter, Alayne D Markland
Journal: JAMA (2010)

Urinary incontinence is a common geriatric syndrome that affects at least 1 in 3 older women and can greatly diminish quality of life. Incontinence has been associated with increased social isolation, falls, fractures, and admission to long-term care facilities. Often unreported and thus untreated, it is important to include incontinence as part of the review of systems for all older women. Using the case of Mrs F, we highlight the chronicity of incontinence and discuss the evidence base for evaluation of incontinence in older women, with proper initial diagnosis of the type of incontinence-stress, urgency, or mixed-in order to prescribe optimal treatment. We present an evidence-based discussion of available incontinence treatments including pelvic floor muscle exercises, stress strategies, urge-suppression strategies, fluid management, medications, intravaginal pessaries, intravesical injection of botulinum toxin, percutaneous tibial nerve stimulation, sacral neuromodulation, and surgical procedures for stress incontinence. Special considerations in evaluation and treatment of patients with dementia are presented. Urinary incontinence treatments yield high levels of patient satisfaction and improvements in quality of life.
Echocardiographic Speckle-Tracking Based Strain Imaging for Rapid Cardiovascular Phenotyping in Mice
Authors: Michael Bauer, Susan Cheng, Mohit Jain, Soeun Ngoy, Catherine Theodoropoulos, Anna Trujillo, Fen-Chiung Lin, Ronglih Liao
Journal: Circulation Research (2011)

High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice.To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models.Herein, we describe a modified echocardiographic technique that uses speckle-tracking based strain analysis for the noninvasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared with conventional echocardiographic measures of LV structure and function, peak longitudinal strain and strain rate were able to detect changes in adult mouse hearts at an earlier time point following myocardial infarction and predicted the later development of adverse LV remodeling. Moreover, speckle-tracking based strain analysis was able to clearly identify subtle improvement in LV function that occurred early in response to standard post-myocardial infarction cardiac therapy.Our results highlight the utility of speckle-tracking based strain imaging for detecting discrete functional alterations in mouse models of cardiovascular disease in an efficient and comprehensive manner. Echocardiography speckle-tracking based strain analysis represents a method for relatively high-throughput and sensitive cardiac phenotyping, particularly in evaluating emerging cardiac agents and therapies in mice.
Are Older French Patients As Willing As Older American Patients to Undertake Chemotherapy?
Authors: Martine Extermann, Gilles Albrand, Hongbin Chen, Sylvie Zanetta, Ronald Schonwetter, Gilbert B. Zulian, Alan Cantor, Jean-Pierre Droz
Journal: Journal of Clinical Oncology (2003)

A view often held in Europe is that older Europeans are less willing than older Americans to undertake chemotherapy. This study assesses whether this view is valid.Three-hundred twenty outpatients aged 70 years and older were interviewed via anonymous questionnaires: French patients with and without cancer and American patients with and without cancer. The response rate was 61% (195 of 320 questionnaires). Ages ranged from 70 to 95 years (29% aged 80 years and older). Two scenarios were presented: a strong chemotherapy (platinum/taxane combination-like) and a milder chemotherapy (weekly vinorelbine-like). The options were to refuse chemotherapy or to accept for a threshold chance of cure, of life prolongation, or of symptom relief. Functional status, education, self-rated health, and depression were controlled for.French noncancer patients (34%) were less willing to accept the strong chemotherapy than French cancer patients (77.8%), American noncancer patients (73.8%), and American cancer patients (70.5%) (P <.001 for each pair). This was also true for the moderate chemotherapy (67.9% v 100%, 95.2%, and 88.5%, respectively; P <.001). Age and sex did not correlate with response, but self-rated health, cancer status, and nationality did. Thresholds varied from patient to patient.Whereas older French people without cancer are more reluctant than older Americans to envision chemotherapy, older cancer patients in both countries have the same amenability to treatment. Chemotherapy options should be fully discussed with older cancer patients, given that most are willing to consider them.
High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3
Authors: Dominic De Nardo, Larisa I Labzin, Hajime Kono, Reiko Seki, Susanne V Schmidt, Marc Beyer, Dakang Xu, Sebastian Zimmer, Catharina Lahrmann, Frank A Schildberg, Johanna Vogelhuber, Michael Kraut, Thomas Ulas, Anja Kerksiek, Wolfgang Krebs, Niklas Bode, Alena Grebe, Michael L Fitzgerald, Nicholas J Hernandez, Bryan R G Williams, Percy Knolle, Manfred Kneilling, Martin Röcken, Dieter Lütjohann, Samuel D Wright, Joachim L Schultze, Eicke Latz
Journal: Nature Immunology (2013)
Systemic AAV6 Delivery Mediating RNA Interference Against SOD1: Neuromuscular Transduction Does Not Alter Disease Progression in fALS Mice
Authors: Chris Towne, Cédric Raoul, Bernard L Schneider, Patrick Aebischer
Journal: Molecular Therapy (2008)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder arising from the selective death of motor neurons. Approximately 20% of familial ALS (fALS) cases are caused by toxic gain-of-function mutations in the superoxide dismutase 1 (SOD1) gene. We as well as others have provided proof-of-principle for the use of RNA interference (RNAi) against mutant SOD1 as a potential therapy for fALS. With the aim of maximizing the delivery of these silencing instructions, we explored the efficacy of intravenous delivery of recombinant adeno-associated virus (rAAV) serotype 6 expressing small hairpin RNAs targeting mutant SOD1 in the G93A SOD1 fALS mouse model. This approach resulted in a systemic transduction profile, corresponding to transduction of the entire skeletal musculature as well as heart and liver. In addition, motor neurons at all levels of the spinal cord and brain stem were transduced, amounting to 3–5% of the lower motor neuron pool. SOD1 protein levels were reduced by >50% in all the muscles that were examined. Crucially, this silencing profile did not alter the course of the disease in this fALS model, thereby providing compelling evidence that SOD1-mediated damage within skeletal muscles does not contribute to death of motor neurons in ALS. Further, this study demonstrates that motor neurons can be transduced across the length of the spinal cord through a single noninvasive delivery of rAAV. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder arising from the selective death of motor neurons. Approximately 20% of familial ALS (fALS) cases are caused by toxic gain-of-function mutations in the superoxide dismutase 1 (SOD1) gene. We as well as others have provided proof-of-principle for the use of RNA interference (RNAi) against mutant SOD1 as a potential therapy for fALS. With the aim of maximizing the delivery of these silencing instructions, we explored the efficacy of intravenous delivery of recombinant adeno-associated virus (rAAV) serotype 6 expressing small hairpin RNAs targeting mutant SOD1 in the G93A SOD1 fALS mouse model. This approach resulted in a systemic transduction profile, corresponding to transduction of the entire skeletal musculature as well as heart and liver. In addition, motor neurons at all levels of the spinal cord and brain stem were transduced, amounting to 3–5% of the lower motor neuron pool. SOD1 protein levels were reduced by >50% in all the muscles that were examined. Crucially, this silencing profile did not alter the course of the disease in this fALS model, thereby providing compelling evidence that SOD1-mediated damage within skeletal muscles does not contribute to death of motor neurons in ALS. Further, this study demonstrates that motor neurons can be transduced across the length of the spinal cord through a single noninvasive delivery of rAAV.
Genome Phylogenetic Analysis Based on Extended Gene Contents
Authors: X. Gu
Journal: Molecular Biology and Evolution (2004)

With the rapid growth of entire genome data, whole-genome approaches such as gene content become popular for genome phylogeny inference, including the tree of life. However, the underlying model for genome evolution is unclear, and the proposed (ad hoc) genome distance measure may violate the additivity. In this article, we formulate a stochastic framework for genome evolution, which provides a basis for defining an additive genome distance. However, we show that it is difficult to utilize the typical gene content data—i.e., the presence or absence of gene families across genomes—to estimate the genome distance. We solve this problem by introducing the concept of extended gene content; that is, the status of a gene family in a given genome could be absence, presence as single copy, or presence as duplicates, any of which can be used to estimate the genome distance and phylogenetic inference. Computer simulation shows that the new tree-making method is efficient, consistent, and fairly robust. The example of 35 microbial complete genomes demonstrates that it is useful not only to study the universal tree of life but also to explore the evolutionary pattern of genomes.
Malaria control in Nicaragua: social and political influences on disease transmission and control activities
Authors: R Garfield
Journal: The Lancet (1999)

Throughout Central America, a traditional malaria control strategy (depending on heavy use of organic pesticides) became less effective during the 1970s. In Nicaragua, an alternative strategy, based on frequent local epidemiological assessments and community participation, was developed in the 1980s. Despite war-related social instability, and continuing vector resistance, this approach was highly successful. By the end of the contra war, there finally existed organisational and ecological conditions that favoured improved malaria control. Yet the expected improvements did not occur. In the 1990s, Nicaragua experienced its worst recorded malaria epidemics. This situation was partly caused by the country's macroeconomic structural adjustment programme. Volunteers now take fewer slides and provide less treatment, malaria control workers are less motivated by the spirit of public service, and some malaria control stations charge for diagnosis or treatment. To "roll back malaria", in Nicaragua at least, will require the roll-back of some erroneous aspects of structural adjustment.This paper examines the social and political influences on malaria transmission and control activities in Nicaragua. In politically unstable Central America, methods that depend on community participation and planning on the basis of routine surveillance data may be sufficient to control malaria transmission. The Nicaraguan experience in the 1980s and 1990s shows how an integrated approach can prove to be effective where social stability, health education, and strong program administration exists. During the Contra war in the 1980s, implementation of the community-based strategy was limited, resulting in increasing rates of P. vivax transmission in the war zone. The loss of timely epidemiological reporting and the decrease in use of local volunteers for blood slide detection and directly observed therapy resulted in a greater epidemic. More recently, WHO has initiated "Roll Back Malaria" and "Roll Back Structural Adjustment" programs which aim to make more efficient use of limited resources in the health sector to help eradicate malaria. Several components were needed for the strategy: the technical capacity of the national staff needed strengthening, the staff needed to be re-evaluated, additional funds were needed to assure competitive salaries, and malaria control programs needed to be identified for appropriation of funds as essential components to national development planning during structural adjustment. National leadership and the establishment of public service and social solidarity will help mobilize volunteers to work toward the goal of preventing malaria transmission.