tbuckley/cabot-search huggingface dataset:
CB-05 * THE ROLE OF Emb-5 IN GLIOBLASTOMA MAINTENANCE AND THERAPEUTIC RESISTANCE
Authors: R. D. Rasmussen, K. E. Jensen, M. K. Gajjar, K. Julie la Cour Karottki, J. Bartek, J. Skjoth-Rasmussen, L. Tluckova, P. Hamerlik, J. Bartek
Journal: Neuro-Oncology (2014)

Glioblastoma Multiforme (GBM) is among the most lethal of solid cancers in adults. GBM is associated with a median survival of only approximately 15 months despite aggressive radio- and chemotherapies and recurrence is inevitable. Despite recent advances in our understanding of this deadly disease, the molecular mechanism/genes that cause the high recurrence rates and treatment resistance in GBM are poorly understood. Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Emb-5 is a highly conserved transcription elongation factor and histone chaperone that has been found to counteract H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. We have identified a novel role of Emb-5 in glioblastoma cells. Our data show that siRNA-mediated knockdown of Emb-5 in GBM cells results in decreased proliferation rates and increased levels of DNA damage (measured by gH2AX) as well as delayed DNA repair capacity after exposure to ionizing radiation. Altogether, our data imply an important role of Emb-5 in glioblastoma maintenance and therapeutic resistance. Acknowledgements: The Danish Council for Independent Research/Medical Sciences ID4765/11-105457, Czech Ministry of Health (NT11065-5); DCRC, NovoNordisk Foundation, Lundbeckfonden.
363. Gene Delivery to Human Sweat Glands: A Model for Cystic Fibrosis Gene Therapy
Authors: Haeyul Lee, David R. Koehler, Cho Y. Pang, Ronald H. Levine, Philip Ng, Donna J. Palmer, Paul M. Quinton, Jim Hu
Journal: Molecular Therapy (2005)

Cystic fibrosis (CF) is considered a disease that could be treated by gene therapy, yet the results from past clinical trials showed only transient transgene expression. Gene therapy vectors are mostly studied in cultured cells, rodent models or non-human primates, but it is difficult to test them in human system prior to clinical studies. In this study, we investigated the possibility of using human sweat glands as a model for testing CF gene therapy vectors. In order to deliver genes to human sweat glands ex vivo, we explored various gene delivery methods using a helper-dependent adenovirus vector containing cytokeratin 18 regulatory elements. Gene delivery to sweat glands in skin organ culture by topical application, intra-dermal injection or submerged culture was not effective. We were able to enhance transduction efficiency by isolating and pre-treating sweat glands with dispase, which indicates that the basement membrane is a critical barrier to gene delivery by adenoviral vectors. Using this approach, we showed that the Cftr gene could be efficiently delivered to and expressed by the epithelial cells of sweat glands with our helper dependent adenoviral vector. Based on our study we propose that sweat glands can be used as an alternative model to study functional efficacy of CF gene therapy in humans.
1032-119 Prevalence of mutations in the cardiac myosin-binding protein C gene among tuscan patients with hypertrophic cardiomyopathy
Authors: Francesca Girolami, Iacopo Olivotto, Ilaria Passerini, Daniela Vargiu, Francesca Torricelli, Franco Cecchi, Azienda Ospedaliera Careggi
Journal: Journal of the American College of Cardiology (2004)
Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling.
Authors: L Racioppi, F Ronchese, L A Matis, R N Germain
Journal: The Journal of Experimental Medicine (1993)

Clonal activation of CD4+ and CD8+ T lymphocytes depends on binding of peptide-major histocompatibility complex (MHC) molecule complexes by their alpha/beta receptors, eventually resulting in sufficient aggregation to initiate second messenger generation. The nature of intracellular signals resulting from such T cell receptor (TCR) occupancy is believed to be independent of the specific structure of the ligand being bound, and to vary quantitatively, not qualitatively, with the concentration of ligand offered and the affinity of the receptor for the peptide-MHC molecule complex. In contrast to the expectations of this model, the analysis of the response of a T helper type 1 clone to mutant E alpha E beta k molecules in the absence or presence of a peptide antigen revealed that peptide inhibited the interleukin 2 (IL-2) response to an otherwise allostimulatory mutant form of this MHC class II molecule. The inhibition was not due to competition for formation of alloantigen, it required TCR recognition of peptide-mutant MHC molecule complexes, and it decreased IL-2 production without affecting receptor-dependent IL-3, IL-2 receptor alpha, or size enlargement responses. This preferential reduction in IL-2 secretion could be correlated with the costimulatory signal dependence of this cytokine response, but could not be overcome by crosslinking the CD28 molecule on the T cell. These results define a new class of TCR ligands with mixed agonist/antagonist properties, and point to a ligand-related variation in the quality of clonotypic receptor signaling events or their integration with other signaling processes. It was also found that a single TCR ligand showed greatly different dose thresholds for the elicitation of distinct effector responses from a cloned T cell population. The observations that changes in ligand structure can result in qualitative alterations in the effects of receptor occupancy and that quantitative variations in ligand density can be translated into qualitative differences in T cell responses have important implications for models of intrathymic selection and control of the results of active immunization.
Abstract 2389: Positive or negative clinical implications of PI3K/Akt/mTOR pathway activation for predicting patient response to targeted therapy using multiplexed protein imaging of tumor tissue.
Authors: Alexandrine Derrien-Colemyn, Soon Park, John Gillespie, Michael Lebowitz, Peter Tunon
Journal: Cancer Research (2013)

Abstract Background: In this ongoing clinical exploratory study, FFPE tissue sections are probed for protein biomarkers along the PI3K/Akt/mTOR pathway. A panel of assays was developed using Layered Immunohistochemistry (L-IHC). L-IHC allows for concurrent measurement of 6-8 proteins (total and/or phosphorylation sites) using a single tissue section. The goal was to discover applications of the technique based on complementary rationales about the implications of pathway activation. Those were: 1) in a scenario where the test indicates drug target activation, analysis for a positive response to an mTOR-targeted tyrosine kinase inhibitor (everolimus and/or temsirolimus) in kidney cancer; or 2) analysis for predicting no response to a HER2-targeted drug (trastuzumab) in breast cancer, assuming a scenario where the test would indicate activation of a functional by-pass pathway. Methods: FFPE pre-treatment tissue samples from patients (pts) with advanced renal cell carcinoma (aRCC) treated with temsirolimus and/or everolimus, and trastuzumab treated HER2-positive breast cancer pts were studied. In L-IHC tissue-transfer layers, the intensity of specific protein biomarker signals in the cancer regions is visually scored. The expression levels are then summed and correlated with the patient's clinical outcome status. Results: In the trastuzumab study, four biomarkers were determined to correlate with patient response. A total of 32 responders and 13 non-responders have been analyzed to date. The sum score for a 4-biomarker panel discriminated between responders and non-responders. The test correctly identified 28/32 responders and 10/13 non-responders for a sensitivity of 87%, specificity of 76%, and an accuracy of 81%. In the mTOR inhibitor study, 35 RCC cases were analyzed, and a composite score based on 6 biomarkers was found to correlate to patient response. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%). Conclusions: These results indicate that multiplexed protein analysis of tumor tissue is capable of providing scenario-specific information, which could help guide targeted therapy with either a positive or a negative clinical significance. Funding source: Supported in part by NCI Grant 5R44CA123994-06 and by 20/20 GeneSystems. Citation Format: Alexandrine Derrien-Colemyn, Soon Park, John Gillespie, Michael Lebowitz, Peter Tunon. Positive or negative clinical implications of PI3K/Akt/mTOR pathway activation for predicting patient response to targeted therapy using multiplexed protein imaging of tumor tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2013-2389
Impaired synthesis of immunoglobulin in patients with chronic lymphocytic leukemia
Authors: Anthony S. Kurec, Frederick R. Davey
Journal: American Journal of Hematology (1987)

Abstract The cause of hypogammaglobulinemia in patients with chronic lymphocytic leukemia (CLL) is unknown. Experiments were performed to determine if sera, monocytes, or non‐T cells from patients with CLL suppress the proliferative response and synthesis of immunoglobulin (Ig) following incubation with pokeweed mitogen (PWM) in cocultures with lymphocytes from normal individuals. The data indicate that sera and monocytes from patients with CLL did not suppress the proliferative response or synthesis of Ig by normal non‐T cells. When various numbers of normal non‐T cells and CLL non‐T cells were cocultured with a constant number of normal T cells, the proliferative response and the concentration of supernatant Ig decreased as the proportion of CLL non‐T cells increased. Since similar results were obtained when irradiated non‐T cells from normal individuals were substituted for non‐T cells from patients with CLL, we believe that the decrease in proliferative response and diminished synthesis of Ig is not the result of the suppressor non‐T cells but is related to the dilution of normal B cells by inert non‐ T cells. We conclude that these experiments serve as an in vitro model for patients with CLL and suggest that the hypogammaglobulinemia observed in this disease is related to the diluting out of normal B cells by the accumulation of neoplastic B cells in the peripheral blood, bone marrow, and lymphoid tissue of these patients.
Famciclovir for Genital Herpes
Authors: Barry D. Goldman
Journal: JAMA (1997)

<h3>To the Editor.</h3> —I read with great interest the article on the use of famciclovir in recurrent genital herpes by Dr Sacks and colleagues.<sup>1</sup>Interestingly, no mention was made on the number of clinical episodes (the development of vesicular and ulcerative lesions) of genital herpes aborted by famciclovir, although the incidence of aborted clinical episodes was mentioned as a parameter in the "Methods" section. This well-designed study<sup>1</sup>should have been able to detect any effect, since treatment was patient initiated and patients were selected to have prodomal symptoms. Abortive viral shedding was found. However, it is not clear whether the ability of famciclovir to abort clinical episodes was studied and found to be insignificant vs placebo or simply was not studied.
Macrophage/microglial-mediated primary demyelination and motor disease induced by the central nervous system production of interleukin-3 in transgenic mice.
Authors: C S Chiang, H C Powell, L H Gold, A Samimi, I L Campbell
Journal: Journal of Clinical Investigation (1996)

Activated macrophage/microglia may mediate tissue injury in a variety of CNS disorders. To examine this, transgenic mice were developed in which the expression of a macrophage/microglia activation cytokine, interleukin-3 (IL-3), was targeted to astrocytes using a murine glial fibrillary acidic protein fusion gene. Transgenic mice with low levels of IL-3 expression developed from 5 mo of age, a progressive motor disorder characterized at onset by impaired rota-rod performance. In symptomatic transgenic mice, multi-focal, plaque-like white matter lesions were present in cerebellum and brain stem. Lesions showed extensive primary demyelination and remyelination in association with the accumulation of large numbers of proliferating and activated foamy macrophage/microglial cells. Many of these cells also contained intracisternal crystalline pole-like inclusions similar to those seen in human patients with multiple sclerosis. Mast cells were also identified while lymphocytes were rarely, if at all present. Thus, chronic CNS production of low levels of IL-3 promotes the recruitment, proliferation and activation of macrophage/microglial cells in white matter regions with consequent primary demyelination and motor disease. This transgenic model exhibits many of the features of human inflammatory demyelinating diseases including multiple sclerosis and HIV leukoencephalopathy.
Transplantation of kidneys from donors with hepatitis C antibody into recipients with pre-transplantation anti-HCV
Authors: Jose M. Morales, Jose M. Campistol, Gregorio Castellano, Amado Andres, Francisco Colina, Antonio Fuertes, Guadlupe Ercilla, Miguel Bruguera, Jordi Andreu, Pablo Carretero, Jose L. Rodicio, Andrew S. Levey, Brian J.G. Pereira
Journal: Kidney International (1995)
Review: Screening and treating asymptomatic adults with carotid artery stenosis lead to no net benefit
Authors: David C. Anderson
Journal: Annals of Internal Medicine (2014)

Source Citation Jonas DE, Feltner C, Amick HR, et al. Screening for asymptomatic carotid artery stenosis: A systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;161:336-46. 25004169
Recording of Tetanus Immunizations
Authors: Donald M. Crosiar
Journal: JAMA (1962)

To the Editor:—  Every patient who has received a tetanus toxoid series should have a small tattoo mark placed in an appropriate spot, such as in the left axilla, to indicate that the individual has been immunized. If the patient has damage to the left axilla, the mark could be placed in the opposite axilla. Since records are lost and memories are short, this would provide a fool-proof way of identifying an individual who has had his immunizations completed, as surely as, or more surely than we can identify the same by inquiring if he or she has served in the Armed Forces.  Also, such information could be further extended to indicate vaccinations against other organisms by the use of color coding, i.e., black pigment for toxoid series completed, red for diphtheria, green for polio, and so forth. The site of the identifying marks could be decided upon by common
Case 13-1961
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. Kibbee
Journal: New England Journal of Medicine (1961)

Presentation of Case A two-year-old girl was brought to the hospital because of fever. Two months previously a furuncle in the right inguinal region was incised and drained. Subsequently, there were elevations of the temperature to 101 to 103°F., and another furuncle in the same region was incised and drained one month before admission. Despite antibiotic therapy the white-cell count, which was 23,800, with 69 per cent neutrophils, remained elevated, as did the temperature. The patient constantly flexed the right hip and resisted attempts to extend the right knee. Tenderness was present in the right inguinal region. Splinting in the . . .
836. Suitability of Anti-Retroviral Genes for Gene Therapy of AIDS
Authors: Matthias Schweizer, Sabine Fengler, Silke Schuele, Sylvia Raupp, Carsten Muenk, Dorothee M. von Laer, Klaus Cichutek
Journal: Molecular Therapy (2005)

Although a number of genes able to inhibit HIV-1 replication have been described, a valid comparison of their potency was difficult up to now due to the lack of a standardised assay system. In order to develop such an assay, we established an HIV-1 challenge system based on a permissive human T cell line. The cells were transduced using an optimised MLV vector transferring the marker gene egfp in additon to the therapeutic gene.
Planned Parenthood v Casey. The impact of the new undue burden standard on reproductive health care
Authors: J. Benshoof
Journal: JAMA (1993)

The recent US Supreme Court decision in Planned Parenthood v Casey, by changing the legal standard by which restrictions on abortion are evaluated, will have a profound effect on access to reproductive health care in the United States. This article reviews the Pennsylvania antiabortion restrictions at issue in Casey and discusses the ways in which the new constitutional standard fundamentally weakens the legal protections previously afforded women and physicians in the 1973 case, Roe v Wade. While the majority opinion reaffirmed a woman's right to choose an abortion, the opinion opens the door to a multitude of new restrictive abortion laws, which diminish, and in some cases completely block, a woman's ability to exercise that right. The effect of weakened legal protection will fall most heavily on young, poor, minority, and rural women, who will be unable to overcome obstacles imposed by mandatory waiting periods, biased counseling, and parental notification requirements. The restrictions are also likely to exacerbate the shortage of physicians providing abortion services by making the procedure more costly and the providers' jobs more dangerous. Finally, the medical community can help to ensure women access to comprehensive and competent reproductive health care.
Immunization with a Lentiviral Vector Stimulates both CD4 and CD8 T Cell Responses to an Ovalbumin Transgene
Authors: Helen M. Rowe, Luciene Lopes, Yasuhiro Ikeda, Ranbir Bailey, Isabelle Barde, Martin Zenke, Benjamin M. Chain, Mary K. Collins
Journal: Molecular Therapy (2005)

Lentiviral vectors encoding antigens are promising vaccine candidates because they transduce dendritic cells (DC) in vivo and prime CTL responses. Here we examine their stimulation of antigen-specific CD4+ T cells, critical for protective immunity against tumors or infectious disease. We constructed lentiviral vectors (lentivectors) expressing ovalbumin, which was secreted (OVA), cytoplasmic (OVAcyt), or fused to either invariant chain (Ii-OVA) or transferrin receptor (TfR-OVA) sequences, targeting the MHC class II presentation pathway. Murine DC infected with the various lentivectors could stimulate OT-I (CD8+, OVA TCR transgenic) T cells and all except OVAcyt could also stimulate OT-II (CD4+, OVA TCR transgenic) T cells in vitro. Direct injection of the OVA-, Ii-OVA-, or TfR-OVA-expressing vectors into mice resulted in a CD4+ T cell response, as shown by expansion of adoptively transferred OT-II T cells and upregulation of CD44 on these cells. The Ii-OVA vector was the most potent inducer of IFN-γ-secreting CD4+ and CD8+ T cells and was the only vector to protect mice completely from challenge with OVA-expressing tumor cells. Therefore directly injected lentivectors can stimulate CD4+ T cells; both CD4+ and CD8+ responses can be enhanced by targeting the antigen to the MHC class II pathway.
The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes
Authors: Hajime Higuchi, Masayuki Adachi, Soichiro Miura, Gregory J. Gores, Hiromasa Ishii
Journal: Hepatology (2001)

Acute ethanol intoxication induces oxidative stress and apoptosis in primary cultured hepatocytes. Oxidative stress can trigger mitochondrial cytochrome c release initiating the mitochondrial pathway of apoptosis. Based on this information, we formulated the hypothesis that ethanolinduced oxidative stress causes mitochondrial dysfunction resulting in apoptosis. In the present study, we found that the mitochondrial membrane permeability transition (MPT) is essential for induction of mitochondrial cytochrome c release and caspase activation of ethanol. The short–term incubation with ethanol (50 mmol/L) induced the MPT, cytochrome c release, caspase activation, and apoptosis of cultured rat hepatocytes. Hepatocyte apoptosis was prevented by caspase inhibitors ( i.e., Z–VAD–fmk, DEVD–cho, and DMQD–cho). An MPT inhibitor, cyclosporin A, also prevented ethanol–induced cytochrome c release, caspase activation, and apoptosis, suggesting that acute ethanol–induced apoptosis is MPT dependent. Ethanol–induced MPT was also attenuated by N'N'–dimethylthiourea (DMTU, a scavenger of hydrogen peroxide, 10 mmol/L) and N –acetyl–cysteine (NAC, an antioxidant, 5 mmol/L). Preventing hepatocyte MPT by DMTU or NAC attenuated cytochrome c release as well as caspase activation, suggesting that ethanol–induced oxidative stress mediates the MPT. Thus, acute ethanol induces MPT via oxidative stress, and the MPT mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol.
NORMAL AND PATHOLOGICAL FRAGMENTATION OF RED BLOOD CELLS; THE PHAGOCYTOSIS OF THESE FRAGMENTS BY DESQUAMATED ENDOTHELIAL CELLS OF THE BLOOD STREAM; THE CORRELATION OF THE PEROXIDASE REACTION WITH PHAGOCYTOSIS IN MONONUCLEAR CELLS
Authors: Charles A. Doan, Florence R. Sabin
Journal: The Journal of Experimental Medicine (1926)

1. There is constantly some breaking down of red cells in the circulation by fragmentation. 2. The fragments of red cells, as well as whole red cells, are phagocytized and destroyed by clasmatocytes or endothelial phagocytes. 3. When there is an increase in fragmentation in abnormal or pathological states, desquamated endothelial cells of the blood stream, as well as the clasmatocytes of the tissues, increase proportionately and take in these fragments. These cells are to be distinguished from eosinophilic leucocytes by the nature of their granules, by the type of motility of the cells, and by a negative peroxidase test. 4. The desquamated endothelial cells, clasmatocytes, in the circulating blood are positive to the peroxidase test only when they have taken in positive material. 5. The monocytes show marked variations of the oxidase reaction in different species and to different techniques. With the Sato and Sekiya technique most monocytes of human blood are positive, while most of them in rabbit blood are negative, but both positive and negative reactions are found in both human and rabbit blood.
Mishandling Misconduct: The NSABP Lumpectomy Trial-Reply
Authors: Drummond Rennie
Journal: JAMA (1994)

<h3>In Reply.</h3> —Dr Lerner is trying to kill the messenger. He alleges, first, that I apologized for the article by Lee-Feldstein et al<sup>1</sup>and the Baue<sup>2</sup>Editorial. I didn't. I'm proud of both. My Editorial was not meant to be "scientific," just a factual account of the NSABP's failure to be frank. Second, that I have no expertise in breast cancer. I agree, which is precisely the reason why I requested Dr Baue, a surgeon with such expertise, to write his Editorial. Third, that I got my facts from the papers. As the references show, I also got them from the Office of Research Integrity report, Washington news sheets, and NSABP/NCI press releases, as well as from my calls to the NCI. But we were all forced to glean the main facts of the case from the newspapers. Why? Because the NSABP has chosen not to publish their