tbuckley/cabot-search huggingface dataset:
Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine
Authors: Karin J. Metzner, Xia Jin, Fred V. Lee, Agegnehu Gettie, Daniel E. Bauer, Michele Di Mascio, Alan S. Perelson, Preston A. Marx, David D. Ho, Leondios G. Kostrikis, Ruth I. Connor
Journal: The Journal of Experimental Medicine (1999)

The role of CD8(+) T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Deltanef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8(+) T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8(+) T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8(+) T cell depletion was associated with a 1-2 log increase in SIVmac239Deltanef plasma viremia. Control of SIVmac239Deltanef replication was temporally associated with the recovery of CD8(+) T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8(+) T cells. Overall, our results indicate that CD8(+) T cells play an important role in controlling replication of live, attenuated SIV in vivo.
Serious Cytomegalovirus Disease in the Acquired Immunodeficiency Syndrome (AIDS)
Authors: MARK A. JACOBSON
Journal: Annals of Internal Medicine (1988)

Life-threatening opportunistic cytomegalovirus infection is a complication of the acquired immunodeficiency syndrome (AIDS) that occurs in 7.4% or more of patients with AIDS. Cytomegalovirus retinitis, colitis, esophagitis, and gastritis are the commonest manifestations of severe cytomegalovirus end-organ disease. Extensive trials with intravenous ganciclovir, a nucleoside analogue with myelosuppressive toxicity, have shown that ganciclovir halts the progression of cytomegalovirus retinitis and gastrointestinal disease. Since relapse is common when therapy is discontinued, most patients with AIDS need lifelong maintenance therapy. The clinical response to ganciclovir therapy is usually accompanied by diminished shedding of the virus. Based on limited data, foscarnet, a pyrophosphate analogue, also appears to have some efficacy in treating cytomegalovirus infection. Unlike ganciclovir, foscarnet does not cause myelosuppression. An important direction for future clinical research is the development of more effective and less toxic therapy, as well as orally bioavailable drugs for maintenance therapy.
Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure.
Authors: T Eschenhagen, U Mende, M Nose, W Schmitz, H Scholz, A Haverich, S Hirt, V Döring, P Kalmár, W Höppner
Journal: Circulation Research (1992)

In human heart failure the positive inotropic and cAMP-elevating effects of both beta-adrenoceptor agonists and phosphodiesterase inhibitors are diminished. This has been explained at least in part by an increase in the inhibitory signal-transducing G protein (Gi) and unchanged stimulatory G protein (Gs). In the present study we determined the mRNA expression pattern of the alpha subunits of Gi-1, Gi-2, Gi-3, and Gs in myocardial tissue samples of patients undergoing heart transplantation. Northern blot analysis of total RNA extracted from left ventricles with 32P-labeled cDNAs demonstrated expression of Gi alpha-2, Gi alpha-3, and Gs alpha mRNA. In contrast, Gi alpha-1 mRNA was not detectable. To investigate whether the increased ratio of Gi/Gs might be due to altered gene expression, we compared mRNA levels of Gi alpha-2, Gi alpha-3, and Gs alpha in left ventricular myocardium from failing hearts with idiopathic dilated cardiomyopathy (n = 8) and ischemic cardiomyopathy (n = 6) and from nonfailing hearts from transplant donors (n = 8). Compared with nonfailing control hearts, the Gi alpha-2 mRNA was increased by 75 +/- 26% (p less than 0.05) in idiopathic dilated cardiomyopathy hearts and 90 +/- 26% (p less than 0.05) in ischemic cardiomyopathy hearts. Gi alpha-3 and Gs alpha mRNA levels were similar in the three groups. The results suggest that as in other mammalian species, Gi alpha-2 and Gi alpha-3 mRNA are the predominant Gi alpha mRNA subtypes in human ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review
Authors: M. Z. Braganza, C. M. Kitahara, A. Berrington de Gonzalez, P. D. Inskip, K. J. Johnson, P. Rajaraman
Journal: Neuro-Oncology (2012)

Although exposure to moderate-to-high doses of ionizing radiation is the only established environmental risk factor for brain and CNS tumors, it is not clear whether this relationship differs across tumor subtypes, by sex or age at exposure, or at the low-to-moderate range of exposure. This systematic review summarizes the epidemiologic evidence on the association between ionizing radiation exposure and risk of brain/CNS tumors. Articles included in this review estimated radiation exposure doses to the brain and reported excess relative risk (ERR) estimates for brain/CNS tumors. Eight cohorts were eligible for inclusion in the analysis. Average age at exposure ranged from 8 months to 26 years. Mean dose to the brain ranged from 0.07 to 10 Gy. Elevated risks for brain/CNS tumors were consistently observed in relation to ionizing radiation exposure, but the strength of this association varied across cohorts. Generally, ionizing radiation was more strongly associated with risk for meningioma compared with glioma. The positive association between ionizing radiation exposure and risk for glioma was stronger for younger vs older ages at exposure. We did not observe an effect modification on the risk for meningioma by sex, age at exposure, time since exposure, or attained age. The etiologic role of ionizing radiation in the development of brain/CNS tumors needs to be clarified further through additional studies that quantify the association between ionizing radiation and risk for brain/CNS tumors at low-to-moderate doses, examine risks across tumor subtypes, and account for potential effect modifiers.
Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal Antibody
Authors: Robert H. Vonderheide, Keith T. Flaherty, Magi Khalil, Molly S. Stumacher, David L. Bajor, Natalie A. Hutnick, Patricia Sullivan, J. Joseph Mahany, Maryann Gallagher, Amy Kramer, Stephanie J. Green, Peter J. O'Dwyer, Kelli L. Running, Richard D. Huhn, Scott J. Antonia
Journal: Journal of Clinical Oncology (2007)

The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.
Lack of Evidence for Elevated Breakdown Rate of Skeletal Muscles in Weight-Losing, Tumor-Bearing Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: G Svaninger, K Bennegard, L Ekman, M Ternell, K Lundholm
Journal: JNCI Journal of the National Cancer Institute (1983)

Protein degradation was measured as tyrosine release rate from proteins of extensor digitorum longus (EDL) muscles and as urinary excretion of 3-methylhistidine in freely fed adult nongrowing C57BL/6J mice with sarcomas, to study protein degradation in cancer-induced wasting of skeletal muscles. Whole muscle protein breakdown rate was unchanged, whereas protein synthesis was depressed, leading to an increased net degradation of skeletal muscles with loss of soluble, myofibrillar, and collagen proteins. Starvation for 24 hours elevated whole muscle protein breakdown in mice with and without sarcomas. Subsequent refeeding for 24 hours normalized the degradation. Adaptation to anorexia in pair-fed controls was achieved by a decrease in muscle protein turnover evaluated by urinary excretion of 3-methylhistidine over 5 days. The measurement of "catabolic decrease" of muscle protein breakdown protected the muscle mass in mice without tumors, but it was ineffective in tumor-bearing animals. The unchanged rate of breakdown of proteins in whole EDL muscles from tumor-bearing mice was accompanied by increased maximum cathepsin D activity and by elevated autolytic activity at acid pH in some muscles. Therefore, cathepsin D activity and net protease activities did not reflect whole muscle protein degradation in tumor-induced malnutrition. The results demonstrate that wasting of skeletal muscles in experimental cancer was not dependent on increased degradation but was dependent on depressed protein synthesis.
HER3 Comes of Age: New Insights into Its Functions and Role in Signaling, Tumor Biology, and Cancer Therapy
Authors: Marcia R. Campbell, Dhara Amin, Mark M. Moasser
Journal: Clinical Cancer Research (2010)

The human epidermal growth family (HER) of tyrosine kinase receptors underlies the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now seems to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 seems to underlie resistance to epidermal growth factor receptor (EGFR)- or HER2-targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depends entirely on the development and power of predictive tools.
Lung Cancer That Harbors an <i>HER2</i> Mutation: Epidemiologic Characteristics and Therapeutic Perspectives
Authors: Julien Mazières, Solange Peters, Benoit Lepage, Alexis B. Cortot, Fabrice Barlesi, Michéle Beau-Faller, Benjamin Besse, Hélène Blons, Audrey Mansuet-Lupo, Thierry Urban, Denis Moro-Sibilot, Eric Dansin, Christos Chouaid, Marie Wislez, Joachim Diebold, Enriqueta Felip, Isabelle Rouquette, Julie D. Milia, Oliver Gautschi
Journal: Journal of Clinical Oncology (2013)

HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC. We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments. HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively. This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
Cochlear Implants: System Design, Integration, and Evaluation
Authors: Fan-Gang Zeng, Stephen Rebscher, William Harrison, Xiaoan Sun, Haihong Feng
Journal: IEEE Reviews in Biomedical Engineering (2008)

As the most successful neural prosthesis, cochlear implants have provided partial hearing to more than 120000 persons worldwide; half of which being pediatric users who are able to develop nearly normal language. Biomedical engineers have played a central role in the design, integration and evaluation of the cochlear implant system, but the overall success is a result of collaborative work with physiologists, psychologists, physicians, educators, and entrepreneurs. This review presents broad yet in-depth academic and industrial perspectives on the underlying research and ongoing development of cochlear implants. The introduction accounts for major events and advances in cochlear implants, including dynamic interplays among engineers, scientists, physicians, and policy makers. The review takes a system approach to address critical issues in cochlear implant research and development. First, the cochlear implant system design and specifications are laid out. Second, the design goals, principles, and methods of the subsystem components are identified from the external speech processor and radio frequency transmission link to the internal receiver, stimulator and electrode arrays. Third, system integration and functional evaluation are presented with respect to safety, reliability, and challenges facing the present and future cochlear implant designers and users. Finally, issues beyond cochlear implants are discussed to address treatment options for the entire spectrum of hearing impairment as well as to use the cochlear implant as a model to design and evaluate other similar neural prostheses such as vestibular and retinal implants.
Stroke Rehabilitation: Strategies to Enhance Motor Recovery
Authors: Michael W. O'Dell, Chi-Chang David Lin, Victoria Harrison
Journal: Annual Review of Medicine (2008)

Recent evidence indicates that the brain can remodel after stroke, primarily through synaptogenesis. Task-specific and repetitive exercise appear to be key factors in promoting synaptogenesis and are central elements in rehabilitation of motor weakness following stroke. Expert medical management ensures a patient is well enough to participate in rehabilitation with minimal distractions due to pain or depression. Contraint-induced motor therapy and body-weight-supported ambulation are forms of exercise that "force use" of an impaired upper extremity. Technologies now in common use include robotics, functional electrical stimulation, and, to a lesser degree, transcranial magnetic stimulation and virtual reality. The data on pharmacological interventions are mixed but encouraging; it is hoped such treatments will directly stimulate brain tissue to recovery. Mitigation of factors preventing movement, such as spasticity, might also play a role. Research evaluating these motor recovery strategies finds them generally good at the movement level but somewhat less robust when looking at functional performance. It remains unclear whether inconsistent evidence for functional improvement is a matter of poor treatment efficacy or insensitive outcome measures.
How high does intracellular sodium rise during acute myocardial ischaemia? A view from NMR spectroscopy
Authors: J. S Ingwall
Journal: Cardiovascular Research (1995)

Journal Article How high does intracellular sodium rise during acute myocardial ischaemia? A view from NMR spectroscopy Get access Joanne S Ingwall Joanne S Ingwall NMR Laboratory, Brigham and Women's Hospital, 221 Longwood Avenue, Room 209, Boston, MA 02115, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 2, February 1995, Page 279, https://doi.org/10.1016/S0008-6363(96)88584-1 Published: 01 February 1995
CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis
Authors: Young Mo Kang, Xiaoyu Zhang, Ulf G. Wagner, Hongyu Yang, Robert D. Beckenbaugh, Paul J. Kurtin, Jörg J. Goronzy, Cornelia M. Weyand
Journal: The Journal of Experimental Medicine (2002)

The assembly of inflammatory lesions in rheumatoid arthritis is highly regulated and typically leads to the formation of lymphoid follicles with germinal center (GC) reactions. We used microdissection of such extranodal follicles to analyze the colonizing T cells. Although the repertoire of follicular T cells was diverse, a subset of T cell receptor (TCR) sequences was detected in multiple independent follicles and not in interfollicular zones, suggesting recognition of a common antigen. Unexpectedly, the majority of shared TCR sequences were from CD8 T cells that were highly enriched in the synovium and present in low numbers in the periphery. To examine their role in extranodal GC reactions, CD8 T cells were depleted in human synovium-SCID mouse chimeras. Depletion of synovial CD8 T cells caused disintegration of the GC-containing follicles. In the absence of CD8 T cells, follicular dendritic cells disappeared, production of lymphotoxin-alpha1beta2 markedly decreased, and immunoglobulin (Ig) secretion ceased. Immunohistochemical studies demonstrated that these CD8 T cells accumulated at the edge of the mantle zone. Besides their unique localization, they were characterized by the production of interferon (IFN)-gamma, lack of the pore-forming enzyme perforin, and expression of CD40 ligand. Perifollicular IFN-gamma+ CD8 T cells were rare in secondary lymphoid tissues but accounted for the majority of IFN-gamma+ cells in synovial infiltrates. We propose that CD8+ T cells regulate the structural integrity and functional activity of GCs in ectopic lymphoid follicles.
Epidemiological and genetic investigations of human-to-human transmission of zoonotic influenza viruses
Authors: S Herfst, R Fouchier
Journal: Eurosurveillance (2014)

Preview this article: Epidemiological and genetic investigations of human-to-human transmission of zoonotic influenza viruses, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/19/25/art20840-en-1.gif
Trends in Cause of Death After Percutaneous Coronary Intervention
Authors: Daniel B. Spoon, Peter J. Psaltis, Mandeep Singh, David R. Holmes, Bernard J. Gersh, Charanjit S. Rihal, Ryan J. Lennon, Issam D. Moussa, Robert D. Simari, Rajiv Gulati
Journal: Circulation (2014)

The impact of changing demographics on causes of long-term death after percutaneous coronary intervention (PCI) remains incompletely defined.We evaluated trends in cause-specific long-term mortality after index PCI performed at a single center from 1991 to 2008. Deaths were ascertained by scheduled prospective surveillance. Cause was determined via telephone interviews, medical records, autopsy reports, and death certificates. Competing-risks analysis of cause-specific mortality was performed using 3 time periods of PCI (1991-1996, 1997-2002, and 2003-2008). Final follow-up was December 31, 2012. A total of 19 077 patients survived index PCI hospitalization, of whom 6988 subsequently died (37%, 4.48 per 100 person-years). Cause was determined in 6857 (98.1%). Across 3 time periods, there was a 33% decline in cardiac deaths at 5 years after PCI (incidence: 9.8%, 7.4%, and 6.6%) but a 57% increase in noncardiac deaths (7.1%, 8.5%, and 11.2%). Only 36.8% of deaths in the recent era were cardiac. Similar trends were observed regardless of age, extent of coronary disease, or PCI indication. After adjustment for baseline variables, there was a 50% temporal decline in cardiac mortality but no change in noncardiac mortality. The decline in cardiac mortality was driven by fewer deaths from myocardial infarction/sudden death (P<0.001) but not heart failure (P=0.85). The increase in noncardiac mortality was primarily attributable to cancer and chronic diseases (P<0.001).This study found a marked temporal switch from predominantly cardiac to predominantly noncardiac causes of death after PCI over 2 decades. The decline in cardiac mortality was independent of changes in baseline clinical characteristics. These findings have implications for patient care and clinical trial design.
Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy
Authors: Jaspal Kaeda, Derville O'Shea, Richard M. Szydlo, Eduardo Olavarria, Francesco Dazzi, David Marin, Susan Saunders, Jamshid S. Khorashad, Nicholas C. P. Cross, John M. Goldman, Jane F. Apperley
Journal: Blood (2006)