tbuckley/cabot-search huggingface dataset:
Absence of Systemic Immune Response to Adenovectors After Intraocular Administration to Children With Retinoblastoma
Authors: Cristhian J Ildefonso, Lingkun Kong, Ann Leen, Samantha J Chai, Veronica Petrochelli, Murali Chintagumpala, Mary Y Hurwitz, Patricia Chévez-Barrios, Richard L Hurwitz
Journal: Molecular Therapy (2010)

The ocular environment has been shown to induce tolerance to locally administered antigens. We therefore investigated whether there was a systemic immune response against adenoviral vectors injected into the vitreous of retinoblastoma patients enrolled in a phase 1 clinical trial of adenoviral-mediated thymidine kinase gene transfer. Sections of enucleated eyes were immunostained with antibodies against inflammatory cells. A trend toward increasing numbers of plasma cells, T cells, macrophages, and antigen-presenting cells was observed in the injected subjects' eyes, but systemically, there was no significant increase in the number of adenovirus-specific cytotoxic T lymphocytes (CTLs) or in adenovirus neutralizing antibodies. Therefore, in contrast to studies showing significant immunogenicity of Ad-RSVtk following injection into extraocular tumors, injection into the eye produces only a mild local inflammatory response without evidence of systemic cellular or humoral immune responses to adenovirus. The ocular environment has been shown to induce tolerance to locally administered antigens. We therefore investigated whether there was a systemic immune response against adenoviral vectors injected into the vitreous of retinoblastoma patients enrolled in a phase 1 clinical trial of adenoviral-mediated thymidine kinase gene transfer. Sections of enucleated eyes were immunostained with antibodies against inflammatory cells. A trend toward increasing numbers of plasma cells, T cells, macrophages, and antigen-presenting cells was observed in the injected subjects' eyes, but systemically, there was no significant increase in the number of adenovirus-specific cytotoxic T lymphocytes (CTLs) or in adenovirus neutralizing antibodies. Therefore, in contrast to studies showing significant immunogenicity of Ad-RSVtk following injection into extraocular tumors, injection into the eye produces only a mild local inflammatory response without evidence of systemic cellular or humoral immune responses to adenovirus.
Anthocyanidins, novel FAK inhibitors, attenuate PDGF-BB-induced aortic smooth muscle cell migration and neointima formation
Authors: Joe Eun Son, Eunjung Lee, Sung Keun Jung, Jong Eun Kim, Min-Ho Oak, Ki Won Lee, Hyong Joo Lee
Journal: Cardiovascular Research (2013)

Abnormal migration of human aortic smooth muscle cells (HASMCs) causes intimal thickening of the aorta, a pivotal step in atherosclerotic development. Although many studies have demonstrated that high anthocynidins intake confers protective effects against atherosclerosis, the direct molecular targets, and mechanisms of action responsible remain unclear. Here, we investigated the preventive effect of anthocyanidins on atherosclerosis and the underlying mechanisms involved.We analysed six major anthocyanidins, and found that petunidin exhibited the most potent inhibitory effects against platelet-derived growth factor (PDGF)-BB-induced HASMC migration in the Boyden chamber and wound healing assays. Petunidin also suppressed PDGF-BB-induced ex vivo rat aortic sprouting and in vivo rat neointima formation. Western blot analysis showed that petunidin inhibited PDGF-BB-induced phosphorylation of focal adhesion kinase (FAK) at the low concentration of 5 µM, whereas phosphorylation of Src, mitogen-activated protein kinases, and Akt was only slightly inhibited at 20 µM. In vitro and ex vivo FAK activity assays demonstrated that petunidin directly suppresses FAK activity by binding in an ATP non-competitive manner. Moreover, anthocyanidins that reduced HASMC migration also inhibited PDGF-BB-induced FAK phosphorylation, F-actin reduction, and FAK activity, and directly bound with FAK. PDGF-BB-induced migration, F-actin reduction by HASMCs, and ex vivo aortic sprouting were all inhibited by treatment with a commercial FAK inhibitor, PF-228.The results of the present study demonstrate that anthocyanidins can directly bind with and suppress the activity of FAK with atherosclerosis-preventive effects.
Cars: Personal and National Catastrophe
Authors: A. JARRELL RAPER
Journal: Annals of Internal Medicine (1980)

Letters and Corrections1 January 1980Cars: Personal and National CatastropheA. JARRELL RAPER, M.D.A. JARRELL RAPER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-92-1-125_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: It was an ordinary c onsultation: "Does this patient need antibiotics before dental work?" Her murmur was benign, but at the tender age of 17 years she was crippled, and her mother's haunted eyes told what the family had been through.The automobile accident 3 months ago had been sudden, unexpected, and devastating: left femur, left humerus, nasal bones, mandible (twice), and zygoma all fractured, and multiple facial lacerations of course. She and the rest of her family had suffered through several operations, including tendon transplantation to compensate for a damaged radial nerve. She still has to... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Medical College of Virginia Richmond, VA 23298 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1980Volume 92, Issue 1Page: 125-125KeywordsAntibioticsBoneFemurHumerusLacerationsNervesTendonsTransplantation Issue Published: 1 January 1980 PDF downloadLoading ...
Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor
Authors: Angela M. Whetzel, David T. Bolick, Suseela Srinivasan, Timothy L. Macdonald, Margaret A. Morris, Klaus Ley, Catherine C. Hedrick
Journal: Circulation Research (2006)

Monocyte recruitment and adhesion to vascular endothelium are key early events in atherosclerosis. We examined the role of sphingosine-1-phosphate (S1P) on modulating monocyte/endothelial interactions in the NOD/LtJ (NOD) mouse model of type 1 diabetes. Aortas from nondiabetic and diabetic NOD mice were incubated in the absence or presence of 100 nmol/L S1P. Fluorescently labeled monocytes were incubated with the aortas. Aortas from NOD diabetic mice bound 7-fold more monocytes than nondiabetic littermates (10+/-1 monocytes bound/field for nondiabetic mice vs 74+/-12 monocytes bound/field for diabetic mice, P<0.0001). Incubation of diabetic aortas with 100 nmol/L S1P reduced monocyte adhesion to endothelium by 90%. We found expression of S1P1, S1P2, and S1P3 receptors on NOD aortic endothelial cells. The S1P1 receptor-specific agonist SEW2871 inhibited monocyte adhesion to diabetic aortas. Studies in diabetic S1P3-deficient mice revealed that the S1P3 receptor did not play a pivotal role in this process. S1P reduced endothelial VCAM-1 induction in type 1 diabetic NOD mice, most likely through inhibition of nuclear factor kappaB translocation to the nucleus. Thus, S1P activation of the S1P1 receptor functions in an antiinflammatory manner in type 1 diabetic vascular endothelium to prevent monocyte/endothelial interactions. S1P may play an important role in the prevention of vascular complications of type 1 diabetes.
Incidence of venous thromboembolism in users of combined oral contraceptives
Authors: H. Jick
Journal: BMJ (2000)

This article criticized the report of Lawrenson et al. which estimated the incidence of venous thromboembolism to be at 38 per 100000 women who used combined oral contraceptives.  The report failed to describe how the authors derived their estimate.  In addition they did not provide any details on the validity and specificity of venous thromboembolism diagnosis the presence of medical risk factors and information on the person time at risk for current oral contraceptive users.  This article highlights two aspects of the report: 1) substantially lower estimate of venous thromboembolism than the true incidence; 2) inclusion of both outpatients and inpatients from one of the 5 computer-recorded diagnoses of venous thromboembolism without documentation from clinical records.  Moreover the General Practice Research Database (information source of the report) is said to be uninterpretable for the following reasons: unclear basis of reported incidence and invalidated clinical records of venous thromboembolism diagnosis.  Finally this article emphasizes the necessity of detailed identification of relevant cases and estimating person time at risk to illustrate an accurate estimate of venous thromboembolism prevalence among oral contraceptive users.
Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts
Authors: Jinghai Wu, Robert T. Dauchy, Paul C. Tirrell, Steven S. Wu, Darin T. Lynch, Potjana Jitawatanarat, Christine M. Burrington, Erin M. Dauchy, David E. Blask, Michael W. Greene
Journal: Cancer Research (2011)

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling.
DEVELOPMENTAL PLASTICITY IN NEURAL CIRCUITS FOR A LEARNED BEHAVIOR
Authors: Sarah W. Bottjer, Arthur P. Arnold
Journal: Annual Review of Neuroscience (1997)

▪ Abstract The neural substrate underlying learned vocal behavior in songbirds provides a textbook illustration of anatomical localization of function for a complex learned behavior in vertebrates. The song-control system has become an important model for studying neural systems related to learning, behavior, and development. The song system of zebra finches is characterized by a heightened capacity for both neural and behavioral change during development and has taught us valuable information regarding sensitive periods, rearrangement of synaptic connections, topographic specificity, cell death and neurogenesis, experience-dependent neural plasticity, and sexual differentiation. The song system differs in some interesting ways from some well-studied mammalian model systems and thus offers fresh perspectives on specific theoretical issues. In this highly selective review, we concentrate on two major questions: What are the developmental changes in the song system responsible for song learning and the restriction of learning to a sensitive period, and what factors explain the highly sexually dimorphic development of this system? We discuss the important role of sex steroid hormones and of neurotrophins in creating a male-typical neural song circuit (which can learn to produce complex vocalizations) instead of a reduced, female-typical song circuit that does not produce learned song.
Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors
Authors: H. Richly, B.F. Henning, P. Kupsch, K. Passarge, M. Grubert, R.A. Hilger, O. Christensen, E. Brendel, B. Schwartz, M. Ludwig, C. Flashar, R. Voigtmann, M.E. Scheulen, S. Seeber, D. Strumberg
Journal: Annals of Oncology (2006)
Heart Failure after Myocardial Infarction—Benefit beyond Hemoglobin from Erythropoietin
Authors: P Van der Meer, E Lipsic, RH Henning, K Boddeus, J van der Velden, AA Voors, DJ van Veldhuisen, WH van Gilst, RG Schoemaker
Journal: Journal of the American Society of Nephrology (2005)

Despite a great deal of recent progress in the treatment of heart failure ([1][1]), the prognosis of this condition continues to be poor and new approaches to its treatment are most welcome. One such new approach was originally based on the recognition that anemia is a strong predictor of outcome ([
Modulation of Endothelial Cell K <sub>Ca</sub> 3.1 Channels During Endothelium-Derived Hyperpolarizing Factor Signaling in Mesenteric Resistance Arteries
Authors: Kim A. Dora, Nicola T. Gallagher, Alister McNeish, Christopher J. Garland
Journal: Circulation Research (2008)

Arterial hyperpolarization to acetylcholine (ACh) reflects coactivation of K(Ca)3.1 (IK(Ca)) channels and K(Ca)2.3 (SK(Ca)) channels in the endothelium that transfers through myoendothelial gap junctions and diffusible factor(s) to affect smooth muscle relaxation (endothelium-derived hyperpolarizing factor [EDHF] response). However, ACh can differentially activate K(Ca)3.1 and K(Ca)2.3 channels, and we investigated the mechanisms responsible in rat mesenteric arteries. K(Ca)3.1 channel input to EDHF hyperpolarization was enhanced by reducing external [Ca(2+)](o) but blocked either with forskolin to activate protein kinase A or by limiting smooth muscle [Ca(2+)](i) increases stimulated by phenylephrine depolarization. Imaging [Ca(2+)](i) within the endothelial cell projections forming myoendothelial gap junctions revealed increases in cytoplasmic [Ca(2+)](i) during endothelial stimulation with ACh that were unaffected by simultaneous increases in muscle [Ca(2+)](i) evoked by phenylephrine. If gap junctions were uncoupled, K(Ca)3.1 channels became the predominant input to EDHF hyperpolarization, and relaxation was inhibited with ouabain, implicating a crucial link through Na(+)/K(+)-ATPase. There was no evidence for an equivalent link through K(Ca)2.3 channels nor between these channels and the putative EDHF pathway involving natriuretic peptide receptor-C. Reconstruction of confocal z-stack images from pressurized arteries revealed K(Ca)2.3 immunostain at endothelial cell borders, including endothelial cell projections, whereas K(Ca)3.1 channels and Na(+)/K(+)-ATPase alpha(2)/alpha(3) subunits were highly concentrated in endothelial cell projections and adjacent to myoendothelial gap junctions. Thus, extracellular [Ca(2+)](o) appears to modify K(Ca)3.1 channel activity through a protein kinase A-dependent mechanism independent of changes in endothelial [Ca(2+)](i). The resulting hyperpolarization links to arterial relaxation largely through Na(+)/K(+)-ATPase, possibly reflecting K(+) acting as an EDHF. In contrast, K(Ca)2.3 hyperpolarization appears mainly to affect relaxation through myoendothelial gap junctions. Overall, these data suggest that K(+) and myoendothelial coupling evoke EDHF-mediated relaxation through distinct, definable pathways.
Experiences and Attitudes of Patients With Terminal Cancer and Their Family Caregivers Toward the Disclosure of Terminal Illness
Authors: Young Ho Yun, Yong Chol Kwon, Myung Kyung Lee, Woo Jin Lee, Kyung Hae Jung, Young Rok Do, Samyong Kim, Dae Seog Heo, Jong Soo Choi, Sang Yoon Park
Journal: Journal of Clinical Oncology (2010)

Purpose We investigated the experiences of cancer patients and their family caregivers who became aware that the cancer was terminal, how they became aware, and how they felt about disclosure of the information. Patients and Methods In this cohort study, we administered questionnaires to 619 consecutive patients determined by physicians to be terminally ill and to their family caregivers. Results A total of 481 patients and 381 family caregivers completed the questionnaire. A majority of patients (58.0%) and caregivers (83.4%) were aware of the patient's terminal status. Approximately 28% of patients and 23% of caregivers reported that they guessed it from the patient's worsening condition. The patient group was more likely than the caregiver group (78.6% v 69.6%) to prefer that patients be informed of their terminal status. Patients informed of their terminal diagnosis had a significantly better quality of life and fewer symptoms and had a lower rate of emotional distress than patients who guessed it from their worsening condition. Younger patients and patients who paid the treatment costs themselves were significantly more likely to want to be told when their illness was terminal. If the patient paid the treatment cost and was employed at the time of the cancer diagnosis, the family caregivers were more likely to prefer disclosure of terminal illness. Conclusion Most patients with terminal cancer and their family caregivers preferred disclosure, and patients who knew of their terminal diagnosis had a lower rate of emotional distress and a higher health-related quality of life.
Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group
Authors: C. Tom Kouroukis, Andrew Belch, Michael Crump, Elizabeth Eisenhauer, Randy D. Gascoyne, Ralph Meyer, Reinhard Lohmann, Pedro Lopez, Jean Powers, Robert Turner, Joseph M. Connors
Journal: Journal of Clinical Oncology (2003)

A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC).Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m(2) weekly for the first three administrations and was increased to 80 mg/m(2) for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more.Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life.Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.
Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions.
Authors: P J Ossanna, S T Test, N R Matheson, S Regiani, S J Weiss
Journal: Journal of Clinical Investigation (1986)

Triggered human neutrophils were able to maintain released elastase in an active form in the presence of purified alpha-1-proteinase inhibitor (alpha-1-PI), serum or bronchoalveolar lavage fluid (BAL). The accumulation of free elastase activity was associated with a decrease in the ability of the alpha-1-PI to inhibit porcine pancreatic elastase, an increase in proteinase activity associated with alpha-2-macroglobulin, and the oxidation of alpha-1-PI to a molecule containing four methionine sulfoxide residues. Neutrophils used both hypochlorous acid and long-lived N-chloroamines to oxidize the alpha-1-PI, but hypochlorous acid was preferentially used for suppressing the activity of the antiproteinase over short distances whereas the N-chloroamines were effective even when the phagocytes and alpha-1-PI were physically separated. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of purified alpha-1-PI, serum, or BAL that had been incubated with triggered neutrophils revealed that the released neutrophil elastase was not complexed with the antiproteinase and that a portion of the alpha-1-PI had undergone proteolysis. These data suggest that the presence of free neutrophil elastase as well as inactive, oxidized, and proteolyzed alpha-1-PI in fluids recovered from inflammatory sites in vivo could be directly mediated by triggered neutrophils alone.
Cadherin-13, a Mediator of Calcium-Dependent Cell-Cell Adhesion, Is Silenced by Methylation in Chronic Myeloid Leukemia and Correlates With Pretreatment Risk Profile and Cytogenetic Response to Interferon Alfa
Authors: Jose Roman-Gomez, Juan A. Castillejo, Antonio Jimenez, Francisco Cervantes, Concepcion Boque, Lourdes Hermosin, Angel Leon, Albert Grañena, Dolors Colomer, Anabel Heiniger, Antonio Torres
Journal: Journal of Clinical Oncology (2003)

Purpose: Cadherin-13 (CDH13) is a newly characterized cadherin molecule responsible for selective cell recognition and adhesion, the expression of which is decreased by methylation in a variety of human cancers, indicating that the CDH13 gene functions as a tumor suppressor gene. Although defective progenitor-stromal adhesion is a well-recognized feature of chronic myeloid leukemia (CML), the role of CDH13 abnormalities has not been evaluated in this disease. Patients and Methods: We examined the methylation status of the CDH13 promoter in 179 chronic phase (CP)-CML patients and in 52 advanced-phase samples and correlated it with mRNA expression using methylation-specific polymerase chain reaction (PCR) and reverse transcriptase PCR. Results: Aberrant de novo methylation of the CDH13 promoter region was observed in 99 (55%) of 179 of CP-CML patients, and 90 of the patients failed to express CDH13 mRNA (P &lt; .0001). Advanced-stage samples (n = 52) showed concordant methylation results with their corresponding CP tumors, indicating that CDH13 methylation was not acquired during the course of the disease. Nevertheless, absence of CDH13 expression was more frequently observed among Sokal high-risk patients (P = .01) and was also independently associated with a shorter median progression-free survival time (P = .03) and poor cytogenetic response to interferon alfa treatment (P = .0001). Conclusion: Our data indicate that the silencing of CDH13 expression by aberrant promoter methylation occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.
Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma
Authors: Hung Huynh, Pierce K.H. Chow, Nallasivam Palanisamy, Manuel Salto-Tellez, Boon Cher Goh, Chi Kuen Lee, Anaji Somani, How Sung Lee, Ramnarayanan Kalpana, Kun Yu, Puay Hoon Tan, Jeanie Wu, Richie Soong, Ming Hui Lee, Henley Hor, Khee Chee Soo, Han Chong Toh, Patrick Tan
Journal: Journal of Hepatology (2008)