tbuckley/cabot-search huggingface dataset:
Local Delivery of a Viral Vector Mitigates Neutralization by Antiviral Antibodies and Results in Efficient Transduction of Rabbit Liver
Authors: Bradley L. Hodges, Kristin M. Taylor, Qiuming Chu, Samantha E. Scull, Rebecca G. Serriello, Scott C. Anderson, Fei Wang, Ronald K. Scheule
Journal: Molecular Therapy (2005)

Antiviral antibodies within the human population remain a barrier to the effective clinical use of viral gene transfer vectors. We have asked whether local, balloon catheter-mediated delivery of a viral vector to the rabbit liver using a hepatic vein might mitigate the neutralizing effects of antiviral antibodies. We have compared directly the ability of adenovirus (Ad2) encoding nuclear-localized β-galactosidase to infect the rabbit liver after local and systemic delivery in both the presence and the absence of defined anti-Ad2 antibody titers. In naive rabbits, local delivery resulted in higher β-galactosidase expression compared to systemic delivery. In the presence of passively administered anti-Ad2 antibodies, local delivery resulted in expression levels that were comparable to those obtained in naive rabbits by systemic delivery. Local delivery also resulted in the majority of expression originating from hepatocytes, even in passively immunized animals, a result that could not be duplicated using the systemic approach. Since systemic delivery of adenovirus in naive animal models results in transgene expression levels often regarded as therapeutic, these results predict that local hepatic vein delivery of a viral vector is a clinically practical approach to mitigate neutralizing antiviral antibodies and generate therapeutic levels of transgene expression.
Diagnostic Consistency in Antisocial Personality
Authors: SAMUEL B. GUZE, DONALD W. GOODWIN
Journal: American Journal of Psychiatry (1971)

The authors' study, based on an eight- to nine-year follow-up of convicted male felons, indicates that consistency in the diagnosis of antisocial personality is related to the extent of the original history of delinquent and criminal behavior. Inconsistency appears to be a manifestation of milder antisocial personality.
The Role of Culture in Psychodynamic Psychotherapy: Parallel Process Resulting From Cultural Similarities Between Patient and Therapist
Authors: Carolyn I. Rodriguez, Deborah L. Cabaniss, Melissa R. Arbuckle, Maria A. Oquendo
Journal: American Journal of Psychiatry (2008)

This case illustrates how cultural issues can influence the progression of psychodynamic therapy.During the course of supervision, the resident learns how understanding the cultural similarities and differences between patient and therapist both enhances and hinders the treatment.The supervisor demonstrates the utility of parallel process during supervision in general and as a tool to uncover key cultural issues.The Grand Rounds discussant highlights cultural aspects of the case such as psychotherapy in a second language, assumptions about traditional roles, and demonstrations of closeness. Case Presentation"Ms.B" is a 38-year-old Ecuadorian woman in her first year of medical school who presented with the chief complaint: "I wish I could just accept and love my boyfriend."Ms. B was receiving therapy in a psychopharmacology clinic for 1 year from a psychiatry resident when she began describing worries about conflicts with her boyfriend of 2 months.The psychopharmacology resident referred Ms. B to the psychodynamic therapy clinic for a consultation.Ms. B's past psychiatric history is contributory for recurrent major depression, which had been in remission for 3 years since she began taking fluoxetine.She had no prior suicide attempts or hospitalizations.She reported no other symptoms of axis I pathology.The family history was notable for multiple family members being depressed and one family member attempting suicide.She reported no substance abuse and did not have any medical problems.
Increasing incidence of aortic aneurysms in England and Wales.
Authors: F. G. Fowkes, C. C. Macintyre, C. V. Ruckley
Journal: BMJ (1989)

The numbers of patients being admitted to hospital with aortic aneurysms have increased recently. A study was carried out to try to find out whether this was a true increase in incidence or whether it could be attributable to more accurate diagnosis and better surgical techniques. From analyses of routine statistics it was found that from 1950 to 1984 age standardised mortality rose 20-fold in men to 47.1 per 100,000 population and 11-fold in women to 22.2 per 100,000 and that this was mainly due to more deaths from abdominal aneurysms. Hospital admissions of men with abdominal aneurysms were found to have increased steadily from 1968 to 1983, but the increase for women admitted did not begin until 1978. An increase in both emergency and elective admissions and only a marginal fall in deaths in hospital (from 45% to 39%) suggest that admissions for abdominal aneurysms increased across a wide range of severity of disease. It is concluded for the following reasons that the true incidence of aortic aneurysms, particularly abdominal aneurysms, has been increasing in England and Wales: the trends are not wholly compatible with advances in diagnosis and surgery, there are inconsistencies by age and sex, and increases have occurred in the number of complicated as well as uncomplicated cases.
T&lt;sub&gt;G&lt;/sub&gt; Cell Involvement in the Leukocyte Adherence Inhibition Phenomenon&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn4"&gt;4&lt;/xref&gt;
Authors: S G Taylor, P C Saffold, D P Braun, J E Harris
Journal: JNCI Journal of the National Cancer Institute (1982)

Peripheral blood mononuclear cells (PBMC), T-cells, non-T-cells, TG cells, and TM cells were tested for leukocyte adherence inhibition (LAI) reactivity to purified protein derivative (PPD) in normal human volunteers to determine the reactive cell subfractions. T-cells were separated by sheep red blood cell rosetting and TM and TG cells by rosetting with anti-ox red blood cell (ORBC) IgM- and IgG-treated ORBC. Fresh PBMC, T-cells, and TG cells gave positive LAI reactivity to PPD in PPD-positive donors only. PBMC that had undergone 24-hour incubation or extensive washing, non-T-cells, and TM cells were unreactive. All cell subfractions were negative in PPD-negative donors. Indirect LAI assay was performed on the spent media from overnight incubation of unstimulated PBMC and also following a 1-hour incubation of the various cell subfractions obtained from a PPD-reactive donor with PPD. Positive reactions, indicating the release of an LAI factor (LAIF), were obtained with the spent media and with the T-cell and TG cell subfractions following PPD stimulation, whereas non-T-cell and TM cell subfractions yielded no reactivity. Incubation of sensitized T-cells with PPD in the presence of cycloheximide and preincubation of T-cells for 24 hours with cycloheximide before PPD exposure failed to inhibit LAI reactivity. These data suggest that T-cells, specifically TG cells, can release LAIF upon specific antigen stimulation with PPD, whereas non-T-cell and TM cell subpopulations fail to respond to the same stimulus. LAIF may also be released into the culture media with prolonged (overnight) incubation in artificial media or with extensive washing. Inhibition of protein synthesis during antigen exposure or up to 24 hours before antigen exposure does not appear to inhibit LAI reactivity.
Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy
Authors: Nagato Sato, Takumi Yamabuki, Atsushi Takano, Junkichi Koinuma, Masato Aragaki, Ken Masuda, Nobuhisa Ishikawa, Nobuoki Kohno, Hiroyuki Ito, Masaki Miyamoto, Haruhiko Nakayama, Yohei Miyagi, Eiju Tsuchiya, Satoshi Kondo, Yusuke Nakamura, Yataro Daigo
Journal: Cancer Research (2010)

Dickkopf-1 (DKK1) is an inhibitor of Wnt/beta-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer.
Measles Virus Infects Human Dendritic Cells and Blocks Their Allostimulatory Properties for CD4+ T Cells
Authors: Isabelle Grosjean, Christophe Caux, Chantal Bella, Ingrid Berger, Fabian Wild, Jacques Banchereau, Dominique Kaiserlian
Journal: The Journal of Experimental Medicine (1997)

Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a+ DC derived from cord blood CD34+ progenitors and Langerhans cells isolated from human epidermis to support MV replication. Here we show that both cultured CD1a+ DC and epidermal Langerhans cells can be infected in vitro by both vaccine and wild type strains of MV. DC infection with MV resulted within 24–48 h in cell–cell fusion, cell surface expression of hemagglutinin, and virus budding associated with production of infectious virus. MV infection of DC completely abrogated the ability of the cells to stimulate the proliferation of naive allogeneic CD4+ T cell as early as day 2 of mixed leukocyte reaction (MLR) (i.e., on day 4 of DC infection). Mannose receptor–mediated endocytosis and viability studies indicated that the loss of DC stimulatory function could not be attributed to the death or apoptosis of DC. This total loss of DC stimulatory function required viral replication in the DC since ultraviolet (UV)-inactivated MV or UV-treated supernatant from MV-infected DC did not alter the allostimulatory capacity of DC. As few as 10 MV- infected DC could block the stimulatory function of 104 uninfected DC. More importantly, MV-infected DC, in which production of infectious virus was blocked by UV treatment or paraformaldehyde fixation, actively suppressed allogeneic MLR upon transfer to uninfected DC–T-cultures. Thus, the mechanisms which contribute to the loss of the allostimulatory function of DC include both virus release and active suppression mediated by MV-infected DC, independent of virus production. These data suggest that carriage of MV by DC may facilitate virus spreading to secondary lymphoid organs and that MV replication in DC may play a central role in the general immune suppression observed during measles.
East Africans in Sweden Have a High Risk for Type 1 Diabetes
Authors: Anders Hjern, Ulf Söderström, Jan Åman
Journal: Diabetes Care (2012)

To investigate the prevalence of type 1 diabetes in children with an origin in Sub-Saharan Africa in Sweden.Nationwide register study based on retrieved prescriptions of insulin during 2009 in children aged 0-18 years. The study population consisted of 35,756 children in families with an origin in Sub-Saharan Africa and 1,666,051 children with native Swedish parents.The odds ratio (OR) for insulin medication in Swedish-born children in families originating in East Africa was 1.29 (95% CI 1.02-1.63) compared with offspring of native Swedish parents, after adjustment for age and sex, and less common in children who themselves were born in East Africa: 0.50 (0.34-0.73). Offspring of parents from other parts of Sub-Saharan Africa had a comparatively low risk for insulin medication.This study indicates that Swedish-born children with an origin in East Africa have a high risk of type 1 diabetes.
Akt2 and Akt3 play a pivotal role in malignant gliomas
Authors: H. Mure, K. Matsuzaki, K. T. Kitazato, Y. Mizobuchi, K. Kuwayama, T. Kageji, S. Nagahiro
Journal: Neuro-Oncology (2009)

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.
Molecular Mechanisms of Prion Pathogenesis
Authors: Adriano Aguzzi, Christina Sigurdson, Mathias Heikenwaelder
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Prion diseases are infectious neurodegenerative diseases occurring in humans and animals with an invariably lethal outcome. One fundamental mechanistic event in prion diseases is the aggregation of aberrantly folded prion protein into large amyloid plaques and fibrous structures associated with neurodegeneration. The cellular prion protein (PrPC) is absolutely required for disease development, and prion knockout mice are not susceptible to prion disease. Prions accumulate not only in the central nervous system but also in lymphoid organs, as shown for new variant and sporadic Creutzfeldt-Jakob patients and for some animals. To date it is largely accepted that prions consist primarily of PrPSc, a misfolded and aggregated beta-sheet-rich isoform of PrPC. However, PrPSc may or may not be completely congruent with the infectious moiety. Here, we discuss the molecular mechanisms leading to neurodegeneration, the role of the immune system in prion pathogenesis, and the existence of prion strains that appear to have different tropisms and biochemical characteristics.
Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates
Authors: Brian C. Beard, Grant D. Trobridge, Christina Ironside, Jeannine S. McCune, Jennifer E. Adair, Hans-Peter Kiem
Journal: Journal of Clinical Investigation (2010)

HSC transplantation using genetically modified autologous cells is a promising therapeutic strategy for various genetic diseases, cancer, and HIV. However, for many of these conditions, the current efficiency of gene transfer to HSCs is not sufficient for clinical use. The ability to increase the percentage of gene-modified cells following transplantation is critical to overcoming this obstacle. In vivo selection with mutant methylguanine methyltransferase (MGMTP140K) has been proposed to overcome low gene transfer efficiency to HSCs. Previous studies have shown efficient in vivo selection in mice and dogs but only transient selection in primates. Here, we report efficient and stable MGMTP140K-mediated multilineage selection in both macaque and baboon nonhuman primate models. Treatment consisting of both O6-benzylguanine (O6BG) and N,N′-bis(2-chloroethyl)-N-nitroso-urea (BCNU) stably increased the percentage of transgene-expressing cells from a range of initial levels of engrafted genetically modified cells, with the longest follow-up after drug treatment occurring over 2.2 years. Drug treatment was well tolerated, and selection occurred in myeloid, lymphoid, and erythroid cells as well as platelets. Retrovirus integration site analysis before and after drug treatments confirmed the presence of multiple clones. These nonhuman primate studies closely model a clinical setting and should have broad applications for HSC gene therapy targeting human diseases of malignant, genetic, and infectious nature, including HIV.
Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial
Authors: Andrew Appelboam, Adam Reuben, Clifford Mann, James Gagg, Paul Ewings, Andrew Barton, Trudie Lobban, Mark Dayer, Jane Vickery, Jonathan Benger
Journal: The Lancet (2015)

The Valsalva manoeuvre is an internationally recommended treatment for supraventricular tachycardia, but cardioversion is rare in practice (5-20%), necessitating the use of other treatments including adenosine, which patients often find unpleasant. We assessed whether a postural modification to the Valsalva manoeuvre could improve its effectiveness.We did a randomised controlled, parallel-group trial at emergency departments in England. We randomly allocated adults presenting with supraventricular tachycardia (excluding atrial fibrillation and flutter) in a 1:1 ratio to undergo a modified Valsalva manoeuvre (done semi-recumbent with supine repositioning and passive leg raise immediately after the Valsalva strain), or a standard semi-recumbent Valsalva manoeuvre. A 40 mm Hg pressure, 15 s standardised strain was used in both groups. Randomisation, stratified by centre, was done centrally and independently, with allocation with serially numbered, opaque, sealed, tamper-evident envelopes. Patients and treating clinicians were not masked to allocation. The primary outcome was return to sinus rhythm at 1 min after intervention, determined by the treating clinician and electrocardiogram and confirmed by an investigator masked to treatment allocation. This study is registered with Current Controlled Trials (ISRCTN67937027).We enrolled 433 participants between Jan 11, 2013, and Dec 29, 2014. Excluding second attendance by five participants, 214 participants in each group were included in the intention-to-treat analysis. 37 (17%) of 214 participants assigned to standard Valsalva manoeuvre achieved sinus rhythm compared with 93 (43%) of 214 in the modified Valsalva manoeuvre group (adjusted odds ratio 3·7 (95% CI 2·3-5·8; p<0·0001). We recorded no serious adverse events.In patients with supraventricular tachycardia, a modified Valsalva manoeuvre with leg elevation and supine positioning at the end of the strain should be considered as a routine first treatment, and can be taught to patients.National Institute for Health Research.
Measles Virus Nucleocapsid Protein Binds to FcγRII and Inhibits Human B Cell Antibody Production
Authors: Kissia Ravanel, Claire Castelle, Thierry Defrance, T. Fabian Wild, Dominique Charron, Vincent Lotteau, Chantal Rabourdin-Combe
Journal: The Journal of Experimental Medicine (1997)

Despite the development of an efficient specific immune response during measles virus (MV) infection, an immunosuppression occurs contributing to secondary infections. To study the role of nucleocapsid protein (NP) in MV-induced immunosuppression, we produced recombinant MV NP. Purified recombinant NP exhibited biochemical, antigenic, and tridimensional structure similar to viral NP. By flow cytometry, we showed that viral or recombinant NP bound to human and murine B lymphocytes, but not to T lymphocytes. This binding was specific, independent of MHC class II expression, and dependent of the B lymphocyte activation state. The murine IIA1.6 B cell line, deficient in the Fc receptor for IgG (FcγRII) expression, did not bind NP efficiently. Transfected IIA1.6 cells expressing either murine FcγRIIb1 or b2, or human FcγRIIa, b1*, or b2 isoforms efficiently bound NP. Furthermore, this binding was inhibited up to 90% by monoclonal antibodies 2.4G2 or KB61 specific for murine and human FcγRII, respectively. Finally, the in vitro Ig synthesis of CD40- or Ig-activated human B lymphocytes in the presence of interleukin (IL)-2 and IL-10 was reduced by 50% in the presence of recombinant NP. These data demonstrate that MV NP binds to human and murine FcγRII and inhibits in vitro antibody production, and therefore suggests a role for NP in MV-induced immunosuppression.
Bortezomib Sensitizes Human Astrocytoma Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis
Authors: Athanassios P. Kyritsis, Fanny Tachmazoglou, Jasti S. Rao, Vinay K. Puduvalli
Journal: Clinical Cancer Research (2007)

To the Editors: We read with interest the June 1, 2007, article by Koschny et al. (1) reporting that bortezomib sensitized primary human astrocytoma cells for tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis. The authors isolated primary glioma cells from 13 astrocytoma and oligoastrocytoma patients and compared the levels of TRAIL-induced apoptosis, long-term tumor cell survival, caspase, and caspase target cleavage. They reported that although the isolated primary tumor cells from the glioma patients were highly TRAIL resistant, coadministration of TRAIL with the proteasome inhibitor bortezomib sensitized all primary glioma cells to TRAIL-induced apoptosis. The effect of bortezomib was due to enhanced TRAIL DISC formation, down-regulation of cFLIP, and activation of the intrinsic apoptosis pathway. Up-regulation of the death receptors TRAIL-R1 and TRAIL-R2 was at least partially responsible for this effect. They concluded that overcoming TRAIL resistance by bortezomib administration might provide a therapeutic option for glioma patients.We have reported in established glioma cell lines that the apoptosis in response to TRAIL was unrelated to TRAIL-R2 expression but is related to activation of the extrinsic [cleavage of caspase-8, caspase-3, and poly(ADP)ribose polymerase] and mitochondrial apoptotic pathways and down-regulation of the FLIP levels. In addition, TRAIL induced caspase-dependent cleavage of Akt (a pathway also implicated in the resistance to TRAIL-induced apoptosis), neutralizing its antiapoptotic effects (2).The contribution of the up-regulation of the TRAIL-R1 and TRAIL-R2 in the induction of apoptosis during TRAIL treatment is not clear yet. Interestingly, we have constructed a recombinant replication-deficient adenovirus vector carrying the TRAIL-R2 cDNA, which is currently being purified and characterized. It would be interesting to see in primary astrocytoma cells from glioma patients, as the ones described by Koschny et al. (1), if this adenovirus has an additional effect to the combination of bortezomib and TRAIL.