tbuckley/cabot-search huggingface dataset:
Signals mediating nuclear targeting and their regulation: Application in drug delivery
Authors: David A. Jans, Chee Kai Chan, Stefan Huebner
Journal: Medicinal Research Reviews (1998)

The recent progress with respect to understanding the signals mediating the transport of proteins in both directions through the NPC, and cellular proteins interacting with these signals to effect the transport process has made possible a number of advances in terms of the use of this information in a clinical setting. In particular, our knowledge of the mechanism of regulation of the process, and of how we may exploit the cellular transport machinery itself in a therapeutic situation, especially where there may be transport pathways specific to particular viruses, has advanced considerably. In this context, this review expounds current understanding of the signals conferring targeting to the nucleus, and their practical and potential use in delivering molecules of interest to the nucleus in a clinical context. It also deals with targeting signals conferring nuclear protein export/shuttling between nuclear and cytoplasmic compartments as well as with those conferring nuclear or cytoplasmic retention, and with the specific mechanisms regulating the activity of these signals, and in particular those regulating signal-dependent nuclear protein import. Detailed understanding of the processes of signal-mediated nuclear protein import/export and its regulation enables the considered application and optimization of approaches to target molecules of interest, such as plasmid DNA or toxic molecules, efficiently to the nucleus according to need in a clinical or research context, and enhance the expression or efficiency of their action, respectively. The use of nuclear targeting signals in this context is reviewed, and future possibilities in terms of the application of our growing understanding of nuclear transport and its regulation are discussed. © 1998 John Wiley & Sons, Inc. Med. Res. Rev., 18, No. 4, 189–223, 1998.
Regulation of Antibody Responses via Antibodies, Complement, and Fc Receptors
Authors: Birgitta Heyman
Journal: Annual Review of Immunology (2000)

Antibodies can completely suppress or enhance the antibody response to their specific antigen by several hundredfold. Immunoglobulin M (IgM) enhances antibody responses via the complement system, and complement activation by IgM probably starts the chain of events leading to antibody responses to suboptimal antigen doses. IgG can enhance primary antibody responses in the absence of the complement system and seems to be dependent on Fc receptors for IgG (FcgammaRs). IgE enhances antibody responses via the low-affinity receptor for IgE (FcepsilonRII/CD23). The precise effector mechanisms that cause enhancement are not known, but direct B-cell signaling, antigen presentation, and increased follicular localization are all possibilities. IgG, IgE, and IgM may also suppress antibody responses when used in certain immunization regimes, and it seems reasonable that an important mechanism behind suppression is the masking of antigenic epitopes by antibodies. In addition, FcgammaRIIB, which contains a cytoplasmic inhibitory motif, acts as a negative regulator of antibody responses. This receptor, however, may prevent the antibody responses from exceeding a certain level rather than causing complete suppression.
Regional Localization of <i>ERG</i> , the Channel Protein Responsible for the Rapid Component of the Delayed Rectifier, K <sup>+</sup> Current in the Ferret Heart
Authors: Mulugu V. Brahmajothi, Michael J. Morales, Keith A. Reimer, Harold C. Strauss
Journal: Circulation Research (1997)

Abstract Repolarization of the cardiac action potential varies widely throughout the heart. This could be due to the differential distribution of ion channels responsible for repolarization, especially the K + channels. We have therefore studied the cardiac localization of ERG, a channel protein known to play an important role in generation of the rapid component of the delayed rectifier K + current (I Kr ), an important determinant of the repolarization waveform. Cryosections of the ferret atrium and ventricle were prepared to determine the localization of ERG by fluorescence in situ hybridization (FISH) and immunofluorescence. We found that in the ferret, ERG transcript and protein expression was most abundant in the epicardial cell layers throughout most of the ventricle, except at the base. In the atrium, we found that ERG is most abundant in the medial right atrium, especially in the trabeculae and the crista terminalis of the right atrial appendage. It also is present in areas within the sinoatrial node. In all regions studied, FISH and immunofluorescence showed concordant localization patterns. These data suggest that repolarization mediated by I Kr is not uniform throughout the ferret heart and provide a molecular explanation for heterogeneity in action potential repolarization throughout the mammalian heart.
Regulation of intestinal barrier function by signal transducer and activator of transcription 5b
Authors: X Han, X Ren, I Jurickova, K Groschwitz, B A Pasternak, H Xu, T A Wilson, S P Hogan, L A Denson
Journal: Gut (2008)

<h3>Background:</h3> Colon epithelial cell (CEC) apoptosis and nuclear factor-κB (NF-κB) activation may compromise barrier function, and it has been reported that signal transducer and activator of transcription 5b (STAT5b)-deficient mice exhibit increased susceptibility to colitis. It is hypothesised that the growth hormone (GH) target STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NF-κB activation. <h3>Methods:</h3> The GH effect upon mucosal injury due to 2,4,6-trinitro-benzenesulfonic acid (TNBS) administration was determined in STAT5b-deficient mice and wild-type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NF-κB activation was determined and related to differences in intestinal permeability and bacterial translocation. RNA interference (RNAi) was used to knock down STAT5b expression in the T84 CEC line, and the effect upon basal and GH-dependent regulation of proapoptotic and inflammatory pathways induced by tumour necrosis factor α (TNFα) was determined. <h3>Results:</h3> GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b-deficient mice. STAT5b deficiency led to activation of a proapoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CECs was increased in STAT5b-deficient mice while tight junction protein abundance was reduced. This was associated with upregulation of CEC Toll-like receptor 2 expression and NF-κB activation. STAT5b knockdown in T84 CEC increased TNFα-dependent NF-κB and caspase-3 activation. GH inhibition of TNFα signalling was prevented by STAT5b knockdown. <h3>Conclusion:</h3> STAT5b maintains colonic barrier integrity by modulating CEC survival and NF-κB activation. STAT5b activation may therefore represent a novel therapeutic target in inflammatory bowel disease.
Two UK people arrested for planning to take relative to Swiss suicide clinic
Authors: N. Hawkes
Journal: BMJ (2013)

Two people have been arrested and questioned by police over claims that they were planning to take a relative to the Dignitas assisted suicide clinic in Switzerland.

Those involved, who have not been named, were described by Sussex police as being a woman aged 65 and a 25 year old man from Chichester, in West Sussex. They are understood to be the wife and son of a 71 year old man with dementia, whose condition police described as vulnerable.

The couple were arrested on 8 August and questioned on suspicion of encouraging or assisting suicide, an offence under the Suicide Act 1961, amended by the Coroners and Justice Act 2009. They were released on bail until 8 October while further inquiries are made. A police spokesman said, “The investigation is looking into what steps, if any, the suspects had made in taking the …
GENERATION OF CYTOTOXIC T LYMPHOCYTES IN VITRO
Authors: H. Robson MacDonald, Howard D. Engers, Jean-Charles Cerottini, K. Theodor Brunner
Journal: The Journal of Experimental Medicine (1974)

Mouse cytotoxic T lymphocytes (CTL) were generated in unidirectional mixed leukocyte cultures (MLC) using normal C57BL/6 spleen cells as responding cells and irradiated DBA/2 spleen cells as stimulating cells. Cytotoxicity was assayed on (51)Cr-labeled P-815 (DBA/2) target cells, and the relative frequency of CTL in individual cell populations was estimated from dose-response curves. Upon inclusion of 2-mercaptoethanol in the culture medium, it was found that significant CTL activity could be detected for as long as 3 wk in primary MLC. Reexposure of MLC cells to the original stimulating alloantigens after 14-41 days in culture resulted in significant cell proliferation and rapid regeneration of high levels of immunologically specific cytotoxicity. CTL activity in these secondary cultures increased dramatically within the first 24 h and reached higher peak levels than those found at the peak of the primary response. Furthermore, proliferation and reappearance of CTL activity could be demonstrated following each of as many as four sequential alloantigenic stimulations of the same initial cell population at 20-day intervals. Interestingly, cells recovered from MLC at the peak of the primary response on day 4 were insensitive to further allogeneic stimulation. Taken together, these results are consistent with the hypothesis that CTL differentiate in MLC to become long-lived memory cells which gradually lose their cytotoxic activity. Upon reexposure to specific alloantigen, such memory CTL rapidly regain their functional activity and proliferate to generate an expanded CTL population.
Management blamed over consultant's malpractice
Authors: J. O'N. Roach
Journal: BMJ (2000)

A government inquiry has blamed poor management within the NHS for allowing the serious malpractice of consultant gynaecologist Rodney Ledward to continue for 16 years. Powerful constraints against “telling tales” and a culture of treating consultants as gods also contributed to the conspiracy of silence surrounding his poor surgical performance.

Some 160 women patients gave evidence to the inquiry, many of whom had been scarred physically and emotionally as a result of their treatment.

Mr Ledward was struck off the medical register in 1998 after managers at East Kent Hospitals Trust finally agreed to investigate long …
Measurement of Total Cerebral Blood Flow in the Monkey by External Monitoring of Cesium-131
Authors: DANIEL E. WEINER
Journal: Circulation Research (1967)

A modification of the 42 K fractionation technique has been developed which permits rapid, repeated measurement of cerebral blood flow by external isotope monitoring without jugular or carotid puncture. 131 Cs, an isotope with distribution characteristics similar to those of 42 K, has been used in this study. Cerebral blood flow measurement involves determination of the peak cephalic activity of an intravenously injected bolus of 131 Cs by digital rate counting in a well-scintillation crystal that encloses the head. If the entire fraction of the isotopic bolus entering the head appears in the cerebral circulation before significant venous loss of 131 Cs begins, the ratio of peak cephalic activity to total injected activity will represent the cephalic portion of the cardiac output. Since cerebral capillaries are not very permeable to 131 Cs, activity remaining in the head after decay of peak cephalic activity will represent uptake by noncerebral cephalic tissue, and the peak activity can be corrected to yield only the cerebral cardiac output fraction. Total cerebral blood flow calculated from 131 Cs injection was compared with measured bilateral internal jugular flow obtained by cannulation of the jugular veins. In anesthetized rhesus monkeys, the average ratio (calculated flow/measured flow) was 1.05±0.06.
Faculty Development to Change the Paradigm of Communication Skills Teaching in Oncology
Authors: Anthony L. Back, Robert M. Arnold, Walter F. Baile, James A. Tulsky, Gwyn E. Barley, Roy D. Pea, Kelly A. Fryer-Edwards
Journal: Journal of Clinical Oncology (2009)

Dr B, a faculty oncologist supervising fellows at an outpatient oncology clinic, faces a common teaching quandary. A second-year oncology fellow presents a patient with metastatic lung cancer, which has progressed despite second-line palliative chemotherapy. The fellow concludes his presentation, which was technically impeccable, by saying, “I thought the patient was not getting how bad this is, so it was time to hang crepe. I told him it was a choice between phase I or nothing.” Dr B knows the fellow to be a careful physician who is genuinely concerned about the well-being of his patients. Yet the fellow's comment about hanging crepe raises a red flag for Dr B, because in his experience, blunt disclosures of poor prognoses may lead patients to wonder if their physician is still on their side. In addition, Dr B does not like telling patients that there is nothing more to be done. But he is not sure how to get the fellow to understand this. Should he confront the fellow about this, or just let the comment pass?
Reduced oxidative and nitrosative damage in murine experimental colitis in the absence of inducible nitric oxide synthase
Authors: B Zingarelli, C Szabó, A L Salzman
Journal: Gut (1999)

BACKGROUND Oxidative and nitrosative stress have been implicated in the pathogenesis of inflammatory bowel diseases. AIMS To study the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) in an experimental model of murine enterocolitis. METHODS Trinitrobenzene sulphonic acid (TNBS) was instilled per rectum to induce a lethal colitis in iNOS deficient mice and in wild type controls. The distal colon was evaluated for histological evidence of inflammation, iNOS expression and activity, tyrosine nitration and malondialdehyde formation (as indexes of nitrosative and oxidative stress), myeloperoxidase activity (as index of neutrophil infiltration), and tissue localisation of intercellular adhesion molecule 1 (ICAM-1). RESULTS TNBS administration induced a high mortality and weight loss associated with a severe colonic mucosal erosion and ulceration, increased myeloperoxidase activity, increased concentrations of malondialdehyde, and an intense staining for nitrotyrosine and ICAM-1 in wild type mice. Genetic ablation of iNOS gene conferred to mice a significant resistance to TNBS induced lethality and colonic damage, and notably reduced nitrotyrosine formation and concentrations of malondialdehyde; it did not, however, affect neutrophil infiltration and intestinal ICAM-1 expression in the injured tissue. CONCLUSION Data show that activation of iNOS is required for nitrosative and oxidative damage in experimental colitis.
Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected from five centers in Brazil, 1997-98†
Authors: I.A. Critchley, C. Thornsberry, G. Piazza, M. Jones, M.L. Hickey, A.L. Barth, C. Mendes, F.F. Rossi, H.S. Sader, L.M. Teixeira, D.F. Sahm
Journal: Clinical Microbiology and Infection (2000)
Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells
Authors: Liza B. John, Christel Devaud, Connie P.M. Duong, Carmen S. Yong, Paul A. Beavis, Nicole M. Haynes, Melvyn T. Chow, Mark J. Smyth, Michael H. Kershaw, Phillip K. Darcy
Journal: Clinical Cancer Research (2013)

To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression.We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2(+) tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach.In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8(+) T cells following antigen-specific stimulation with PD-L1(+) tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2(+) tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1(+) CD11b(+) myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen.This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer.
Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer
Authors: Atsushi Aruga, Nobuhiro Takeshita, Yoshihito Kotera, Ryuji Okuyama, Norimasa Matsushita, Takehiro Ohta, Kazuyoshi Takeda, Masakazu Yamamoto
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and there are only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response, and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus on their fluctuations during long-term vaccination until the disease had progressed. Experimental Design: Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. HLA-A*2402–restricted epitope peptides, lymphocyte antigen 6 complex locus K, TTK protein kinase, insulin-like growth factor-II mRNA-binding protein 3, and DEP domain containing 1 were vaccinated subcutaneously once a week at doses of 0.5, 1, or 2 mg and continued until disease progression. The adverse events were assessed by Common Terminology Criteria for Adverse Events and the immune response was monitored by an enzyme-linked immunospot assay or by flow cytometry. The clinical effects observed were tumor response, progression-free survival (PFS), and overall survival (OS). Results: Four-peptide vaccination was well tolerated. No grade 3 or 4 adverse events were observed. Peptide-specific T-cell immune responses were observed in seven of nine patients and clinical responses were observed in six of nine patients. The median PFS and OS were 156 and 380 days. The injection site reaction and CTL induction seemed to be prognostic factors of both PFS and OS. Conclusions: Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations. Clin Cancer Res; 19(8); 2224–31. ©2013 AACR.
Sympathetic activation: a mechanism for morphine induced pain and rises in liver enzymes after cholecystectomy?
Authors: I C Roberts-Thomson, J R Jonsson, D B Frewin, G C Coates
Journal: Gut (1990)

In patients with biliary type pain after cholecystectomy, morphine often precipitates pain and may induce rises in plasma concentrations of liver enzymes because of exaggerated or prolonged rises in intrabiliary pressure. In this study, changes in plasma concentrations of catecholamines and histamine were determined after the administration of morphine in patients with and without a two-fold or greater rise in the plasma concentration of aspartate aminotransferase at four hours. Those showing rises in aminotransferase had higher concentrations of noradrenaline at 40 and 60 minutes after morphine and higher concentrations of dopamine at 40 minutes after morphine. The two groups had similar concentrations of adrenaline and histamine. Attempts to inhibit rises in aminotransferase after morphine by pretreatment with histamine, serotonin and alpha-receptor blockers were largely unsuccessful, although inhibition was observed with phenoxybenzamine in two of five patients. Higher plasma concentrations of noradrenaline and dopamine before and soon after induction of pain in patients showing rises in aminotransferase are consistent with sympathetic activation but heterogeneity appears to exist in the response to alpha-receptor blockade.
HDL Cholesterol, Apolipoproteins, and Cardiovascular Risk in Hemodialysis Patients
Authors: Günther Silbernagel, Bernd Genser, Christiane Drechsler, Hubert Scharnagl, Tanja B. Grammer, Tatjana Stojakovic, Vera Krane, Eberhard Ritz, Christoph Wanner, Winfried März
Journal: Journal of the American Society of Nephrology (2014)

High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m(2). The primary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confirmation in future studies.
Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy
Authors: Jan Senderek, Michael Krieger, Claudia Stendel, Carsten Bergmann, Markus Moser, Nico Breitbach-Faller, Sabine Rudnik-Schöneborn, Astrid Blaschek, Nicole I Wolf, Inga Harting, Kathryn North, Janine Smith, Francesco Muntoni, Martin Brockington, Susana Quijano-Roy, Francis Renault, Ralf Herrmann, Linda M Hendershot, J Michael Schröder, Hanns Lochmüller, Haluk Topaloglu, Thomas Voit, Joachim Weis, Friedrich Ebinger, Klaus Zerres
Journal: Nature Genetics (2005)