tbuckley/cabot-search huggingface dataset:
Targeting Polo-like Kinase in Cancer Therapy
Authors: Yan Degenhardt, Thomas Lampkin
Journal: Clinical Cancer Research (2010)

Polo-like kinases (Plk) function in mitosis and maintaining DNA integrity. There are four family members, of which Plk1 represents a target for anticancer therapy. Plk1 is only expressed in dividing cells with peak expression during G2/M. Plk1 functions in multiple steps of mitosis, and is overexpressed in many tumor types. Mitotic arrest and inhibition of proliferation, apoptosis, and tumor growth inhibition have been observed in preclinical studies using small interfering RNAs (siRNA) or small molecules that inhibit Plk1. Preclinical studies also show that Plk1 inhibitors may be active against tumors with RAS mutations and that tumor cells with mutations in TP53 are more sensitive to inhibition of Plk1. Several Plk inhibitors are in phase I or II clinical studies. As expected, hematologic toxicity is the primary dose-limiting toxicity. Some patients have achieved clinical response, although in some studies only at doses above the maximum tolerated dose defined in the study. Further evaluation is necessary to discern the clinical utility of Plk1 inhibitors.
Origin of Nogo-A by Domain Shuffling in an Early Jawed Vertebrate
Authors: A. Shypitsyna, E. Malaga-Trillo, A. Reuter, C. A. O. Stuermer
Journal: Molecular Biology and Evolution (2010)

Unlike mammals, fish are able to regenerate axons in their central nervous system. This difference has been partly attributed to the loss/acquisition of inhibitory proteins during evolution. Nogo-A—the longest isoform of the reticulon4 (rtn4) gene product—is commonly found in mammalian myelin where it acts as a potent inhibitor of axonal regeneration. Interestingly, fish RTN4 isoforms were previously reported to lack the most inhibitory Nogo-A–specific region (NSR). Nevertheless, fish axons collapse on contact with mammalian NSR, suggesting that fish possess a functional Nogo-A receptor but not its ligand. To reconcile these findings, we revisited the early evolution of rtn4. Mining of current genome databases established the unequivocal presence of NSR-coding sequences in fish rtn4 paralogues. Further comparative analyses indicate that the common ancestor of fish and tetrapods had an NSR-coding rtn4 gene, which underwent duplication and divergent evolution in bony fish. Our genomic survey also revealed that the cephalochordate Branchiostoma floridae contains a single rtn gene lacking the NSR. Hence, Nogo-A most probably arose independently in the rtn4 gene of a gnathostome ancestor before the split of the fish and tetrapod lineages. Close examination of the NSR uncovered clusters of structural and sequential similarities with neurocan (NCAN), an inhibitory proteoglycan of the glial scar. Notably, the shared presence of transposable elements in ncan and rtn4 genes suggests that Nogo-A originated via insertion of an ncan-like sequence into the rtn4 gene of an early jawed vertebrate with myelinated axons.
Influence of Flow and Pressure on Wave Propagation in the Canine Aorta
Authors: MICHAEL B. HISLAND, MAX ANLIKER
Journal: Circulation Research (1973)

Data on wave speed acquired from 20 anesthetized dogs showed that the thoracic aorta was essentially nondispersive for small artificially generated pressure waves traveling in the downstream or the upstream direction and having frequencies between 40 and 120 Hz. The amplitude of these waves decayed exponentially with the distance traveled. The attenuation was independent of frequency and pressure if the distance was measured in wavelengths. The logarithmic decrement of the downstream waves ranged between 0.7 and 1.0, whereas that of the retrograde waves was between 1.3 and 1.5. The discrepancy in the attenuation for the two directions appeared to be due to the taper of the thoracic aorta. Simultaneous measurements of the transmission times of waves traveling downstream and upstream indicated that small pressure perturbations were convected with a speed that was approximately equal to the mean flow velocity. The speed of such perturbations depended strongly on the aortic pressure level at which they were generated. For normal pressure pulses generated by the heart, the speed of small perturbations at systole might be 30% higher than that at diastole. Theoretical studies have shown that such changes in wave speed due to variations in pressure and flow produce marked nonlinear effects in hemodynamics.
Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells
Authors: Marjolaine Vareille, Elisabeth Kieninger, Marco P Alves, Brigitte S Kopf, Alexander Möller, Thomas Geiser, Sebastian L Johnston, Michael R Edwards, Nicolas Regamey
Journal: Thorax (2012)

This article has been retracted Vareille M, Kieninger E, Alves MP, <i>et al</i>. Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells. <i>Thorax</i> 2012 Jun;67:517-25. This article has been retracted. In our article recently published in <i>Thorax</i>, we described a novel mechanism explaining the increased susceptibility of patients with cystic fibrosis (CF) to rhinovirus infections, namely defective interferon type I and III production by CF airway epithelial cells. In experiments performed after publication of the article we were unable to consistently replicate our findings of deficient interferon type I and III production by CF airway epithelial cells upon rhinovirus infection. In the light of these results, we carried out detailed investigations of the data reported in the above manuscript and regrettably found evidence of deliberate manipulation of experimental data by the first author Dr M. Vareille. This manipulation was accompanied in some instances by absence of original data files. The manipulation/original data absence involved data presented in most, if not all of the figures, thus we wish to fully retract the paper and apologise to the readers of <i>Thorax</i> and to the scientific community for the inconvenience this has caused. We also checked data published by our group in manuscripts on which Dr Vareille was a co-author and found that data published in these manuscripts had not been manipulated. These two manuscripts, whose data and conclusions we stand by are: Edwards MR, Regamey N, Vareille M, Kieninger E, Gupta A, Shoemark A, Saglani S, Sykes A, Macintyre J, Davies J, Bossley C, Bush A, Johnston SL. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 2013 Jul;6:797-806. doi: 10.1038/mi.2012.118. Epub 2012 Dec 5. PMID:23212197 and Kieninger E, Vareille M, Kopf BS, Blank F, Alves MP, Gisler FM, Latzin P, Casaulta C, Geiser T, Johnston SL, Edwards MR, Regamey N. Lack of an exaggerated inflammatory response on virus infection in cystic fibrosis. Eur Respir J. 2012 Feb;39:297–304. doi: 10.1183/09031936.00054511. Epub 2011 Jun 30. PMID:21719483. Dr. Vareille has received a letter from the Secretary General of the University of Bern condemning her scientific misconduct as a severe offence against the rules of scientific integrity. Her current employers have also been informed. All co-authors of the publication including Dr. Vareille concur with the retraction statement.
MPs call for regular scrutiny of Better Care Fund after numerous concerns
Authors: A. O'Dowd
Journal: BMJ (2015)

MPs have called for yearly evaluations of the controversial Better Care Fund, which is designed to shift care from hospitals into the community by encouraging integrated health and social care, to ensure that its shortcomings are monitored.

MPs on the parliamentary Public Accounts Committee voiced many concerns about the fund in their Planning for the Better Care Fund report, published on 26 February.1

England’s Better Care Fund is intended to help older and disabled people to be cared for more in the community than in hospitals by creating a single, pooled budget to incentivise the NHS and local government to work more closely together.

The fund is now intended to pool £5.3bn (€7.2bn; $8.2bn) of existing NHS and local authority funding from April, but controversy has arisen about the level …
Characterization of a kidney proximal tubule cell line, LLC-PK1, expressing endocytotic active megalin.
Authors: R Nielsen, H Birn, S K Moestrup, M Nielsen, P Verroust, E I Christensen
Journal: Journal of the American Society of Nephrology (1998)

Reabsorption and cellular handling of glomerular filtered vitamins, peptides, and hormones in the proximal tubule are essential, but thus far, poorly elucidated processes. The multiligand receptor megalin, initially described as a Heymann nephritis antigen and later identified as a member of the LDL receptor gene family, mediates reabsorption of several molecules, such as transcobalamin-vitamin B12 and albumin, in the proximal tubule. Consequently, a differentiated cell line of proximal tubular origin expressing megalin is an important requisite for examination of the above-mentioned processes. This study shows, using electron microscopy, that the cell line LLC-PK1, originating from the proximal tubule, maintained differentiated morphology and had a well developed endocytotic apparatus. Furthermore, by immunoblotting and immunohisto- and cytochemistry, megalin was identified in the endocytotic compartments of these cells. Megalin was situated mainly in the endosomes and in the dense apical tubules, but it was also identified in coated pits and in the brush border. The ability of megalin to mediate internalization and degradation of labeled receptor-associated protein (RAP) in a RAP-inhibitable manner was demonstrated. By autoradiography, the endocytosed, iodinated RAP was located in endosomes and lysosomes in the apical part of the cells. Moreover, the LLC-PK1 cells assembled in a monolayer with a hindrance toward diffusion of labeled mannitol, inulin, and dextran at a satisfactory level for the study of proximal tubule handling of smaller proteins. This study reveals a proximal tubule cell line expressing megalin in a functional manner well suited for binding, uptake, and transcellular transport studies.
Calcium-activated transient outward chloride current and phase 1 repolarization of swine ventricular action potential
Authors: G LI, X DU, Y SIOW, K O, H TSE, C LAU
Journal: Cardiovascular Research (2003)

Objective: It is unknown whether 4-aminopyridine- (4-AP-) sensitive transient outward K+ current (Ito1) and/or Ca2+-activated transient outward Cl− current (ICa.Cl or Ito2) contribute(s) to phase 1 repolarization of pig ventricular action potential (AP). The purpose of the present study was to determine ionic contribution of the phase 1 repolarization of AP in pig ventricle. Methods: We used whole-cell patch techniques to record APs and membrane currents, and Western immunoblotting analysis to detect expression of Ito1 protein (Kv4.2 or Kv4.3) in pig ventricular myocytes. Results: A transient outward current (Ito) was activated upon depolarization voltage steps to between −10 and +60 mV from −50 mV in pig ventricular cells, and the Ito was resistant to 4-AP application, but sensitive to the inhibition by ryanodine (10 μmol/l) and the Ca2+ channel blockade, and the Cl− channel blocker 4,4′-diisothiocyanostilben-2,2′disulfonic acid (DIDS, 150 μmol/l). The current was diminished by external Cl− (Cl−o) replacement and showed a 'bell-shaped' I–V relationship at room temperature, typical of Ito2. No difference in Ito2 was observed in the regional cells from epicardium, midmyocardium, and endocardium of left ventricle. APs showed significant phase 1 and 'spike and dome' in pig ventricular myocytes. The phase 1 and 'spike and dome' of APs were not affected by 4-AP (3 mmol/l), but abolished by replacing Cl−o and by application of 100 μmol/l DIDS, suggesting Ito2 contribution. Western immunoblotting analysis showed no evidence for the expression of 4-AP-sensitive Ito1 channel protein (Kv4.2 or Kv4.3) in pig ventricular cells. Conclusion: The results indicate that 4-AP-sensitive Ito1 is not expressed, and only Ca2+-activated Ito2 is present in pig cardiac cells, which contributes importantly to the phase 1 repolarization of ventricular APs in this species.
Antipsychotics, mood stabilisers, and risk of violent crime
Authors: Seena Fazel, Johan Zetterqvist, Henrik Larsson, Niklas Långström, Paul Lichtenstein
Journal: The Lancet (2014)

Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden.We used linked Swedish national registers to study 82,647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006-09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden's national crime register.In 2006-09, 40,937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6·5%) were convicted of a violent crime during the study period. In the same period, 41,710 women were prescribed these drugs, of whom 604 (1·4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0·55, 95% CI 0·47-0·64) and by 24% in patients prescribed mood stabilisers (0·76, 0·62-0·93). However, we identified potentially important differences by diagnosis-mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0·60, 95% CI 0·39-0·92).In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered.The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare.
Glucagon and intravenous glucose tolerance
Authors: R. J. Jarrett
Journal: BMJ (1967)

Bence Jones protein indicates further dedifferentiation " (misprinted as " differentia- tion " under Fig. 2).5 Irrespective of the proportion catabolized, Bence Jones proteinuria seems to carry a worse prognosis.I hope this has clarified the issue.-Iam, etc.,
Rap1 Integrates Tissue Polarity, Lumen Formation, and Tumorigenic Potential in Human Breast Epithelial Cells
Authors: Masahiko Itoh, Celeste M. Nelson, Connie A. Myers, Mina J. Bissell
Journal: Cancer Research (2007)

Abstract Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here, we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their nonmalignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to the formation of acinar structures with correct polarity, and dramatically reduced tumor incidence despite the persistence of genomic abnormalities and baseline growth. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy. [Cancer Res 2007;67(10):4759–66]
'Conversion' from ulcerative colitis to Crohn's disease associated with corticosteroid treatment.
Authors: A D Dwarakanath, J Nash, J M Rhodes
Journal: Gut (1994)

<h3>Introduction</h3> Motivating behavioural change during client consultations is of crucial importance across all health professions to address the growing burden of chronic conditions. Yet health professionals often lack the skills and confidence to use evidence-based counselling interventions to support clients’ behavioural change and mobilise clients’ resources and self-efficacy for change to address their long-term needs. <h3>Aims</h3> This pre–post pilot study will develop a motivational interviewing (MI) virtual client training tool for health professionals and test the effectiveness of the educational content and usability of the virtual client interaction. <h3>Methods and analysis</h3> Postgraduate students across a range of health disciplines will be recruited. Data assessing attitudes towards preventive healthcare will be collected using a modified version of the Preventive Medicine Attitudes and Activities Questionnaire. Conversations with the virtual client will be analysed using the Motivational Interviewing Treatment Integrity code to assess changes in MI skills. The System Usability Scale will be used to assess the usability of the virtual client training tool. <h3>Ethics and dissemination</h3> This protocol was approved by the Flinders University Social and Behavioural Research Ethics Committee in May 2019. The results of the pilot study will inform the development of an avatar-based mobile application consisting of MI teaching and interactions with a generic virtual client that can be easily adapted to multiple scenarios.
Role of HER2 in wound-induced breast carcinoma proliferation
Authors: Elda Tagliabue, Roberto Agresti, Maria Luisa Carcangiu, Cristina Ghirelli, Daniele Morelli, Manuela Campiglio, Maritza Martel, Riccardo Giovanazzi, Marco Greco, Andrea Balsari, Sylvie Ménard
Journal: The Lancet (2003)
CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells
Authors: Yaohe Wang, Rathi Gangeswaran, Xingbo Zhao, Pengju Wang, James Tysome, Vipul Bhakta, Ming Yuan, C.P. Chikkanna-Gowda, Guozhong Jiang, Dongling Gao, Fengyu Cao, Jennelle Francis, Jinxia Yu, Kangdong Liu, Hongyan Yang, Yunhan Zhang, Weidong Zang, Claude Chelala, Ziming Dong, Nick Lemoine
Journal: Journal of Clinical Investigation (2009)

The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen- related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus trafficking to the nucleus of human pancreatic cancer cells. Similar to CEACAM6 overexpression, treatment with a Src-selective inhibitor significantly reduced adenovirus replication in these cancer cells and normal human epithelial cells. In a mouse xenograft tumor model, siRNA-mediated knockdown of CEACAM6 also significantly enhanced the antitumor effect of an oncolytic adenovirus. We propose that CEACAM6-associated signaling pathways could be potential targets for the development of biomarkers to predict the response of patients to adenovirus-based therapies, as well as for the development of more potent adenovirus-based therapeutics.
Adiponectin Specifically Increased Tissue Inhibitor of Metalloproteinase-1 Through Interleukin-10 Expression in Human Macrophages
Authors: Masahiro Kumada, Shinji Kihara, Noriyuki Ouchi, Hideki Kobayashi, Yoshihisa Okamoto, Koji Ohashi, Kazuhisa Maeda, Hiroyuki Nagaretani, Ken Kishida, Norikazu Maeda, Azumi Nagasawa, Tohru Funahashi, Yuji Matsuzawa
Journal: Circulation (2004)

Background— Vascular inflammation and subsequent matrix degradation play an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipose-specific plasma protein, accumulated to the injured artery and attenuated vascular inflammatory response. Clinically, high plasma adiponectin level was associated with low cardiovascular event rate in patients with chronic renal failure. The present study was designed to elucidate the effects of adiponectin on matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in human monocyte-derived macrophages. Methods and Results— Human monocyte-derived macrophages were incubated with the physiological concentrations of human recombinant adiponectin for the time indicated. Adiponectin treatment dose-dependently increased TIMP-1 mRNA levels without affecting MMP-9 mRNA levels. Adiponectin also augmented TIMP-1 secretion into the media, whereas MMP-9 secretion and activity were unchanged. Time course experiments indicated that TIMP-1 mRNA levels started to increase at 24 hours of adiponectin treatment and were significantly elevated at 48 hours. Adiponectin significantly increased interleukin-10 (IL-10) mRNA expression at the transcriptional level within 6 hours and significantly increased IL-10 protein secretion within 24 hours. Cotreatment of adiponectin with anti–IL-10 monoclonal antibody completely abolished adiponectin-induced TIMP-1 mRNA expression. Conclusions— Adiponectin selectively increased TIMP-1 expression in human monocyte-derived macrophages through IL-10 induction. This study identified, for the first time, the adiponectin/IL-10 interaction against vascular inflammation.
Inpatient resource utilisation in younger (2–5 yrs) and older (6–14 yrs) asthmatic children in Finland
Authors: E. Valovirta, V. Sazonov Kocevar, M. Kaila, M. Kajosaari, A. Koivikko, K. Korhonen, O. Linna, M. Mäkelä, K. Remes, R.H. Ben-Joseph
Journal: European Respiratory Journal (2002)

Asthma is the most common chronic disorder among Finnish children, however, the economic burden of paediatric asthma in Finland has not yet been comprehensively evaluated. The objective of this study was to compare inpatient resource utilisation between younger (2–5 yrs) and older children (6–14 yrs) with asthma in Finland. A national database of inpatient resource utilisation was applied to determine use of hospital services among children with asthma in 1999. Regional estimates of charges were combined with hospitalisation episodes to determine total inpatient cost. The results indicate that younger asthmatic children consume 3‐times more inpatient resources per capita. Incidence of first admissions because of asthma was 3‐times higher in younger children. Hospitalisation and rehospitalisation rates were also 3‐ and 4‐times higher, respectively. The total annual inpatient cost of asthma in children aged 2–5 and 6–14 yrs was E 1.98 million with each group accounting for E 1.12 million and E 0.86 million, respectively. Regional and age-related differences in hospitalisation rates and costs were likely related to variable clinical practice on the primary level, difficulties with diagnosis and compliance among younger children.