tbuckley/cabot-search huggingface dataset:
Gene Editing of<i>CCR5</i>in Autologous CD4 T Cells of Persons Infected with HIV
Authors: Pablo Tebas, David Stein, Winson W. Tang, Ian Frank, Shelley Q. Wang, Gary Lee, S. Kaye Spratt, Richard T. Surosky, Martin A. Giedlin, Geoff Nichol, Michael C. Holmes, Philip D. Gregory, Dale G. Ando, Michael Kalos, Ronald G. Collman, Gwendolyn Binder-Scholl, Gabriela Plesa, Wei-Ting Hwang, Bruce L. Levine, Carl H. June
Journal: New England Journal of Medicine (2014)

CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe.We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance.One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
CO2 wedged hepatic venography in the evaluation of portal hypertension
Authors: W Debernardi-Venon
Journal: Gut (2000)

<h3>BACKGROUND/AIMS/METHODS</h3> During hepatic vein catheterisation, in addition to measurement of hepatic venous pressure gradient (HVPG), iodine wedged retrograde portography can be easily obtained. However, it rarely allows correct visualisation of the portal vein. Recently, CO<sub>2</sub> has been suggested to allow better angiographic demonstration of the portal vein than iodine. In this study we investigated the efficacy of CO<sub>2</sub> compared with iodinated contrast medium for portal vein imaging and its role in the evaluation of portal hypertension in a series of 100 patients undergoing hepatic vein catheterisation, 71 of whom had liver cirrhosis. <h3>RESULTS</h3> In the overall series, CO<sub>2</sub> venography was markedly superior to iodine, allowing correct visualisation of the different segments of the portal venous system. In addition, CO<sub>2</sub>, but not iodine, visualised portal-systemic collaterals in 34 patients. In cirrhosis, non-visualisation of the portal vein on CO<sub>2</sub> venography occurred in 11 cases; four had portal vein thrombosis and five had communications between different hepatic veins. Among non-cirrhotics, lack of portal vein visualisation had a 90% sensitivity, 88% specificity, 94% negative predictive value, and 83% positive predictive value in the diagnosis of pre-sinusoidal portal hypertension. <h3>CONCLUSIONS</h3> Visualisation of the venous portal system by CO<sub>2</sub> venography is markedly superior to iodine. The use of CO<sub>2</sub> wedged portography is a useful and safe complementary procedure during hepatic vein catheterisation which may help to detect portal thrombosis. Also, lack of demonstration of the portal vein in non-cirrhotic patients strongly suggests the presence of pre-sinusoidal portal hypertension.
CNS–immune system interactions: Conditioning phenomena
Authors: Robert Ader, Nicholas Cohen
Journal: Behavioral and Brain Sciences (1985)

Abstract Converging data from different disciplines indicate that central nervous system processes are capable of influencing immune responses. This paper concentrates on recent studies documenting behaviorally conditioned suppression and enhancement of immunity. Exposing rats or mice to a conditioned stimulus previously paired with an immunomodulating agent results in alterations in humoral and cell-mediated immune responses to antigenic stimuli, and unreinforced reexposures to the conditioned stimuli result in extinction of the conditioned response. Although the magnitude of such conditioning effects has not been large, the phenomenon has been independently verified under a variety of experimental conditions. The biological impact of conditioned alterations in immune function is illustrated by studies in which conditioning operations were applied in the pharmacotherapy of autoimmune disease in New Zealand mice. In conditioned animals, substituting conditioned stimuli for active drugs delays the onset of autoimmune disease relative to nonconditioned animals using a dose of immunosuppressive drug that, by itself, is ineffective in modifying the progression of disease. The hypothesis that such conditioning effects are mediated by elevations in adrenocortical steroid levels receives no support from available data. Despite its capacity for self-regulation, it appears that the immune system is integrated with other psychophysiological processes and subject to modulation by the brain.
Photosensitive Fluorescent Dye Contributes to Phototoxicity and Inflammatory Responses of Dye-doped Silica Nanoparticles in Cells and Mice
Authors: Yang Zhao, Yan Ye, Xikun Zhou, Jiao Chen, Yuihui Jin, Aaron Hanson, Julia Xiaojun Zhao, Min Wu
Journal: Theranostics (2014)

Dye-doped fluorescent silica nanoparticles provide highly intense and photostable fluorescence signals. However, some dopant dye molecules are photosensitive. A widely-used photosensitive fluorescent dopant, RuBpy, was chosen to systematically investigate the phototoxicity of the dye-doped silica nanoparticles (NPs). We investigated cell viability, DNA damage, and Reactive Oxygen Species (ROS) levels in alveolar macrophages using the dye-doped NPs with or without irradiation. Our results showed that the RuBpy-doped silica NPs could induce significant amount of ROS, DNA damage, apoptosis and impaired proliferation in MH-S cells. In vivo studies in mice showed that RuBpy-doped silica NPs induced significant inflammatory cytokine production and lowered expression in signaling proteins such as ERK1/2 and NF-κB as well as increased lung injury determined by myeloperoxidase and lipid peroxidation. Strikingly, we also found that both RuBpy alone and NPs induced systemic signaling activation in the kidney compared to the liver and lung where showed highly selective signaling patterns, which is more pronounced than RuBpy-doped silica NPs. Moreover, we discovered a critical biomarker (e.g., HMGB1) for silica NPs-induced stress and toxicity and demonstrated differentially-regulated response patterns in various organs. Our results indicate for the first time that the RuBpy-doped silica NPs may impose less inflammatory responses but stronger thermotherapeutic effects on target cells in animals than naked NPs in a time- and dose-dependent manner.
A Transgenic Mouse Model for Early Prostate Metastasis to Lymph Nodes
Authors: Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W. Goodrich, Barbara A. Foster, Irwin H. Gelman
Journal: Cancer Research (2014)

The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia. Here, we show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy after 18 months. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5. The finding that PIN lesions contain increased numbers of p63/AR-positive, cytokeratin 5-negative basal cells compared with WT or Akap12-/- prostate lobes suggests that these transitional cells may be the source of the lymph node metastases. Taken together, these data suggest that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells.
Radiation Alone for Solid Tumors and the Questionable Development of Therapy-Related Myelodysplastic Syndromes
Authors: C. R. Cogle
Journal: JNCI Journal of the National Cancer Institute (2014)

not be as leukemogenic as combined modality treatment or total body irradiation—an important hypothesis worthy of testing when considering the increased number of cancer survivors after RT. Before rushing to the conclusion that RT alone is free of leukemogenic potential, it is important to address the question from the direction of a solid-tumor patient. Up until this point, oncologists studied t-MN incidence by first finding t-MN patients and then parsing their characteristics based on prior therapy (RT vs chemotherapy vs combined modality vs surgery). In these retrospective analyses, the potential for selection bias is large. In contrast, the real questions are 1) whether solid tumor patients treated with RT alone go on to develop t-MNs at a rate higher than radiation-free counterparts and 2) how post-RT t-MN pathobiology and clinical outcomes compare with those of radiation-free cohorts. Both of these questions require a forward perspective starting from the
A comparison of IgA positive and IgA negative dapsone responsive dermatoses
Authors: LIONEL FRY, VALERIE WALKDEN, FENELLA WOJNAROWSKA, G. HAFFENDEN, R. M. H. McMINN
Journal: British Journal of Dermatology (1980)

SUMMARY A study of thirty-three patients with a clinical diagnosis of dermatitis herpetiformis (DH) referred to our DH clinic over the last 11 years is reported. Twenty-six were referred by other consultant dermatologists. The diagnosis had been made by the clinical features and response of the rash to dapsone. Seventeen patients were found to have IgA in the uninvolved skin (IgA positive) and in sixteen no IgA was found (IgA negative). The duration of the rash prior to referral to the DH clinic was 3 months to 19 years (mean 5.0 years) for the IgA negative patients and 2 months to 22 years (mean 5.2 years) for the IgA positive group. The length of follow-up was 3 months to 11 years (mean 5.0 years) for the IgA negative, and 2–11 years (mean 5.6 years) for the IgA positive group. During follow-up the rash cleared completely and required no treatment in seven of the sixteen IgA negative patients. Thirteen of these sixteen patients no longer required dapsone, but six patients were receiving alternative treatment. In the three patients still taking dapsone IgA has not been found on subsequent biopsy. Of the seventeen IgA positive patients only three were able to stop dapsone during follow-up and in these three the IgA was still detected in the skin. Small intestinal mucosa was abnormal in eight of eleven IgA positive patients, but was normal in all thirteen IgA negative patients in whom jejunal biopsies were performed. An alternative diagnosis to DH has subsequently been made in thirteen of the sixteen IgA negative patients. Although the significance of IgA in the skin in DH is not known it appears to be part of the disease process. Patients who have a rash suggestive of DH and which is dapsone responsive, but in whom IgA is not found in the uninvolved skin, usually turn out to have a dermatosis other than dermatitis herpetiformis. Referral to a unit with expertise in immunofluorescence techniques of skin biopsies would appear to be helpful.
Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees
Authors: Douglas F. Levinson, Jianxin Shi, Kai Wang, Sang Oh, Brien Riley, Ann E. Pulver, Dieter B. Wildenauer, Claudine Laurent, Bryan J. Mowry, Pablo V. Gejman, Michael J. Owen, Kenneth S. Kendler, Gerald Nestadt, Sibylle G. Schwab, Jacques Mallet, Deborah Nertney, Alan R. Sanders, Nigel M. Williams, Brandon Wormley, Virginia K. Lasseter, Margot Albus, Stephanie Godard-Bauché, Madeline Alexander, Jubao Duan, Michael C. O’Donovan, Dermot Walsh, Anthony O’Neill, George N. Papadimitriou, Dimitris Dikeos, Wolfgang Maier, Bernard Lerer, Dominique Campion, David Cohen, Maurice Jay, Ayman Fanous, Peter Eichhammer, Jeremy M. Silverman, Nadine Norton, Nancy Zhang, Hakon Hakonarson, Cynthia Gao, Ami Citri, Mark Hansen, Stephan Ripke, Frank Dudbridge, Peter A. Holmans
Journal: American Journal of Psychiatry (2012)

The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs.No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families.Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.
P200 Snoring and carotid atheroma: no association
Authors: R. H. Mason, Z. Mehta, P. M. Rothwell, J. R. Stradling
Journal: Thorax (2010)

<h3>Background</h3> Obstructive Sleep apnoea (OSA) has increasingly been linked to cardiovascular endpoints including hypertension, stroke, myocardial infarction, and carotid atherosclerosis. Snoring is strongly associated with OSA. More recently, the snoring component of OSA, by producing local arterial trauma, has been independently linked to the presence of carotid but not femoral atheroma,1 and to acute carotid trauma in an animal model.2 The aim of this study was to identify whether this relationship could be established retrospectively in a high vascular risk cohort of individuals with a recent cerebrovascular event (TIA or stroke). <h3>Method</h3> Participants with a recent TIA or stroke in the Oxford Vascular Study (OXVASC) completed an entry questionnaire which included frequency of snoring (never, rarely (1–2/year), occasionally (4–8/year), sometimes (1–2/month), often (1–2/week), usually (3–5/week) and always (every night). A subset of 316 individuals (aged 62–84 years), with both a completed snoring questionnaire and carotid Doppler data, were included. This information was used to retrospectively assess a potential relationship between presence and severity of snoring, and degree of carotid artery stenosis and plaque type (echogenic/echolucent/mixed, calcified/non-calcified and smooth/irregular). <h3>Results</h3> 160 out of 316 participants were male, mean (SD) age 73.2 (11.22). No significant association could be identified between intensity of self-reported snoring and degree of carotid stenosis or plaque morphology. <h3>Conclusions</h3> No significant association could be identified between snoring and carotid atheroma. There are no obvious explanations for the discrepancy between this study and previous work, except that the original study measured snoring objectively during a one night in hospital study, whereas in our study snoring was subjectively assessed and perhaps better represents the usual situation at home. Furthermore, the femoral artery may not be an appropriate ‘control’ artery with which to compare the carotid for atheroma.
Primary CNS Lymphoma of T-Cell Origin: A Descriptive Analysis From the International Primary CNS Lymphoma Collaborative Group
Authors: Tamara N. Shenkier, Jean-Yves Blay, Brian Patrick O’Neill, Philip Poortmans, Eckhard Thiel, Kristoph Jahnke, Lauren E. Abrey, Edward Neuwelt, Richard Tsang, Tracy Batchelor, Nancy Harris, Andrés J.M. Ferreri, Maurilio Ponzoni, Peter O’Brien, James Rubenstein, Joseph M. Connors
Journal: Journal of Clinical Oncology (2005)

Purpose To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). Patients and Methods A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. Results We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (≤ 60 v &gt; 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. Conclusion This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.
Viral Infection in the Renal Transplant Recipient
Authors: Camille N. Kotton, Jay A. Fishman
Journal: Journal of the American Society of Nephrology (2005)

Viruses are among the most common causes of opportunistic infection after transplantation and the most important. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Viral infection, both symptomatic and asymptomatic, causes the “direct effects” of invasive disease and “indirect effects,” including immune suppression predisposing to other opportunistic infections and oncogenesis. Rapid and sensitive microbiologic assays for many of the common viruses after transplantation have replaced, for the most part, serologic testing and in vitro cultures for the diagnosis of infection. Furthermore, quantitative molecular tests allow the individualization of antiviral therapies for prevention and treatment of infection. This advance is most prominent in the management of cytomegalovirus, Epstein-Barr, hepatitis B, and hepatitis C viruses. Diagnostic advances have not been accompanied by the development of specific and nontoxic anti-viral agents or effective antiviral vaccines. Vaccines, where available, should be given to patients as early as possible and well in advance of transplantation to optimize the immune response. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections.
Neonatal vesiculopustular eruption of the face: a sign of trisomy 21-associated transient myeloproliferative disorder
Authors: R. Moriuchi, A. Shibaki, K. Yasukawa, T. Onozuka, T. Sato, M. Kaneda, A. Iguchi, R. Kobayashi, H. Shimizu
Journal: British Journal of Dermatology (2007)

Journal Article Neonatal vesiculopustular eruption of the face: a sign of trisomy 21‐associated transient myeloproliferative disorder Get access R. Moriuchi, R. Moriuchi Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar A. Shibaki, A. Shibaki Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Correspondence: Akihiko Shibaki. E‐mail: ashibaki@med.hokudai.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Yasukawa, K. Yasukawa Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Onozuka, T. Onozuka Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar T. Sato, T. Sato Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar M. Kaneda, M. Kaneda Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar A. Iguchi, A. Iguchi Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar R. Kobayashi, R. Kobayashi Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar H. Shimizu H. Shimizu Departments of Dermatology and Paediatrics, Hokkaido University Graduate School of Medicine, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 6, 1 June 2007, Page 1373, https://doi.org/10.1111/j.1365-2133.2007.07877.x Published: 01 June 2007