tbuckley/cabot-search huggingface dataset:
Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice
Authors: Jie Li, Kathleen M. Horak, Huabo Su, Atsushi Sanbe, Jeffrey Robbins, Xuejun Wang
Journal: Journal of Clinical Investigation (2011)

The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) has been observed in proteinopathies, such as desmin-related cardiomyopathy, and implicated in many common diseases, including dilated cardiomyopathy and ischemic heart disease. However, the pathogenic role of PFI has not been established. Here we created inducible Tg mice with cardiomyocyte-restricted overexpression of proteasome 28 subunit α (CR-PA28αOE) to investigate whether upregulation of the 11S proteasome enhances the proteolytic function of the proteasome in mice and, if so, whether the enhancement can rescue a bona fide proteinopathy and protect against ischemia/reperfusion (I/R) injury. We found that CR-PA28αOE did not alter the homeostasis of normal proteins and cardiac function, but did facilitate the degradation of a surrogate misfolded protein in the heart. By breeding mice with CR-PA28αOE with mice representing a well-established model of desmin-related cardiomyopathy, we demonstrated that CR-PA28αOE markedly reduced aberrant protein aggregation. Cardiac hypertrophy was decreased, and the lifespan of the animals was increased. Furthermore, PA28α knockdown promoted, whereas PA28α overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes. Moreover, CR-PA28αOE limited infarct size and prevented postreperfusion cardiac dysfunction in mice with myocardial I/R injury. We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28αOE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury.
FURTHER OBSERVATIONS ON INTRANUCLEAR MICROBODIES
Authors: R. CAPUTO, A. G. BELLONE
Journal: British Journal of Dermatology (1968)

SUMMARY.— The authors have observed the presence of intranuclear micro‐bodies, 0·4—2·5 μ in size, containing osmiophilic particles 200 Å. in size, in 1 of 2 cases of oral leukoplakia and in 1 of 7 cases of bullous erythema multiforme. The different types of intranuclear microbodies so far reported in various dermotoses are classified and their significance is discussed.
Rethinking TB screening: politics, practicalities and the press
Authors: J. Moore-Gillon, P. D. O. Davies, L. P. Ormerod
Journal: Thorax (2010)

Worldwide, tuberculosis (TB) causes 1.3 million deaths each year, and there are at least 9.27 million new cases annually.1 Global population mobility on a scale never seen before means that the UK, along with many other countries with a previously low incidence of the disease, has over the last two decades seen a sharp rise in TB. Indeed most doctors are probably more likely to see a case of TB in the next year than at any other time in their professional lives. In the UK, there are now in excess of 8400 new cases per annum, >70% of them occurring in individuals born outside the country,2 and the picture is similar in the USA, where over half of all cases occur in those born abroad.3 The annual UK rate of TB for those born abroad (87/100 000) is >20 times higher than that for the UK-born population (including UK-born members of ethnic minority groups). For the Black African population in the UK who were born outside this country the rate (at 309/100 000) is 75 times higher than in the UK-born population generally, reflecting the very high TB rates associated with HIV co-infection in sub-Saharan Africa.2

Clearly, current methods of TB screening for new entrants, largely for active TB only, are not working, and debate about how they might be improved has spread beyond health professionals to become the focus of media comment, often hostile, and the subject of political attention and debate.4 We discuss the limitations of current UK screening methods, suggest that the natural history of infection with the TB bacterium means that they cannot succeed and consider alternative approaches.

Since 1971 the UK has had a mechanism (the Port of Arrival Scheme) aimed at screening immigrants from countries with an annual TB incidence …
Early isovolaemic haemofiltration in oliguric patients with septic shock
Authors: Pasquale Piccinni, Maurizio Dan, Stefano Barbacini, Rizzieri Carraro, Emanuela Lieta, Silvio Marafon, Nereo Zamperetti, Alessandra Brendolan, Vincenzo D’Intini, Ciro Tetta, Rinaldo Bellomo, Claudio Ronco
Journal: Intensive Care Medicine (2005)
Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials
Authors: John J Aponte, David Schellenberg, Andrea Egan, Alasdair Breckenridge, Ilona Carneiro, Julia Critchley, Ina Danquah, Alexander Dodoo, Robin Kobbe, Bertrand Lell, Jürgen May, Zul Premji, Sergi Sanz, Esperanza Sevene, Rachida Soulaymani-Becheikh, Peter Winstanley, Samuel Adjei, Sylvester Anemana, Daniel Chandramohan, Saadou Issifou, Frank Mockenhaupt, Seth Owusu-Agyei, Brian Greenwood, Martin P Grobusch, Peter G Kremsner, Eusebio Macete, Hassan Mshinda, Robert D Newman, Laurence Slutsker, Marcel Tanner, Pedro Alonso, Clara Menendez
Journal: The Lancet (2009)
Reconstitution of mutant V2 vasopressin receptors by adenovirus-mediated gene transfer. Molecular basis and clinical implication.
Authors: T Schöneberg, V Sandig, J Wess, T Gudermann, G Schultz
Journal: Journal of Clinical Investigation (1997)

Recent studies with transfected COS-7 cells have shown that functionally inactive mutant V2 vasopressin receptors (occurring in patients with nephrogenic diabetes insipidus) can be functionally rescued by coexpression of a carboxy-terminal V2 receptor fragment (V2-tail) spanning the region where various mutations occur [Schöneberg, T., J. Yun, D. Wenkert, and J. Wess. 1996. EMBO (Eur. Mol. Biol. Organ.) J. 15:1283-1291]. In this study, we set out to characterize the underlying molecular mechanism. Using a coimmunoprecipitation strategy and a newly developed sandwich ELISA system, a direct and highly specific interaction between the mutant V2 vasopressin receptor proteins and the V2-tail polypeptide was demonstrated. To study the potential therapeutic usefulness of these findings, Chinese hamster ovary (CHO) cell lines stably expressing low levels of functionally inactive mutant V2 vasopressin receptors were created and infected with a recombinant adenovirus carrying the V2-tail gene fragment. After adenovirus infection, vasopressin gained the ability to stimulate cAMP formation with high potency and efficacy in all CHO cell clones studied. Moreover, adenovirus-mediated gene transfer also proved to be a highly efficient method for achieving expression of the V2-tail fragment (as well as the wild-type V2 receptor) in Madin-Darby canine kidney tubular cells. Taken together, these studies clarify the molecular mechanisms by which receptor fragments can restore function of mutationally inactivated G protein-coupled receptors and suggest that adenovirus-mediated expression of receptor fragments may lead to novel strategies for the treatment of a variety of human diseases.
Predicting the outcome of ankylosing spondylitis therapy
Authors: Nathan Vastesaeger, Désirée van der Heijde, Robert D Inman, Yanxin Wang, Atul Deodhar, Benjamin Hsu, Mahboob U Rahman, Ben Dijkmans, Piet Geusens, Bert Vander Cruyssen, Eduardo Collantes, Joachim Sieper, Jürgen Braun
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS). Methods ASSERT and GO–RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model. Results Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population. Conclusion Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.
The classification of glomerulonephritis in systemic lupus erythematosus revisited
Authors: Jan J. Weening, Vivette D. D'agati, Melvin M. Schwartz, Surya V. Seshan, Charles E. Alpers, Gerald B. Appel, James E. Balow, J.A.N. A. Bruijn, Terence Cook, Franco Ferrario, Agnes B. Fogo, Ellen M. Ginzler, L.E.E. Hebert, Gary Hill, Prue Hill, J. Charles Jennette, Norella C. Kong, Philippe Lesavre, Michael Lockshin, Lai-Meng Looi, Hirofumi Makino, Luiz A. Moura, Michio Nagata
Journal: Kidney International (2004)
Asporin Is a Fibroblast-Derived TGF-β1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer
Authors: Pamela Maris, Arnaud Blomme, Ana Perez Palacios, Brunella Costanza, Akeila Bellahcène, Elettra Bianchi, Stephanie Gofflot, Pierre Drion, Giovanna Elvi Trombino, Emmanuel Di Valentin, Pino G. Cusumano, Sylvie Maweja, Guy Jerusalem, Philippe Delvenne, Eric Lifrange, Vincent Castronovo, Andrei Turtoi
Journal: PLoS Medicine (2015)

Background Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications. Methods and Findings Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78–0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37–0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. Conclusions Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Randomized Controlled Trial of a Video Decision Support Tool for Cardiopulmonary Resuscitation Decision Making in Advanced Cancer
Authors: Angelo E. Volandes, Michael K. Paasche-Orlow, Susan L. Mitchell, Areej El-Jawahri, Aretha Delight Davis, Michael J. Barry, Kevan L. Hartshorn, Vicki Ann Jackson, Muriel R. Gillick, Elizabeth S. Walker-Corkery, Yuchiao Chang, Lenny López, Margaret Kemeny, Linda Bulone, Eileen Mann, Sumi Misra, Matt Peachey, Elmer D. Abbo, April F. Eichler, Andrew S. Epstein, Ariela Noy, Tomer T. Levin, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2012)

Purpose Decision making regarding cardiopulmonary resuscitation (CPR) is challenging. This study examined the effect of a video decision support tool on CPR preferences among patients with advanced cancer. Patients and Methods We performed a randomized controlled trial of 150 patients with advanced cancer from four oncology centers. Participants in the control arm (n = 80) listened to a verbal narrative describing CPR and the likelihood of successful resuscitation. Participants in the intervention arm (n = 70) listened to the identical narrative and viewed a 3-minute video depicting a patient on a ventilator and CPR being performed on a simulated patient. The primary outcome was participants' preference for or against CPR measured immediately after exposure to either modality. Secondary outcomes were participants' knowledge of CPR (score range of 0 to 4, with higher score indicating more knowledge) and comfort with video. Results The mean age of participants was 62 years (standard deviation, 11 years); 49% were women, 44% were African American or Latino, and 47% had lung or colon cancer. After the verbal narrative, in the control arm, 38 participants (48%) wanted CPR, 41 (51%) wanted no CPR, and one (1%) was uncertain. In contrast, in the intervention arm, 14 participants (20%) wanted CPR, 55 (79%) wanted no CPR, and 1 (1%) was uncertain (unadjusted odds ratio, 3.5; 95% CI, 1.7 to 7.2; P &lt; .001). Mean knowledge scores were higher in the intervention arm than in the control arm (3.3 ± 1.0 v 2.6 ± 1.3, respectively; P &lt; .001), and 65 participants (93%) in the intervention arm were comfortable watching the video. Conclusion Participants with advanced cancer who viewed a video of CPR were less likely to opt for CPR than those who listened to a verbal narrative.
Estimating the reliability of evolutionary trees.
Authors: D Penny, M Hendy
Journal: Molecular Biology and Evolution (1986)

Six protein sequences from the same 11 mammalian taxa were used to estimate the accuracy and reliability of phylogenetic trees using real, rather than simulated, data. A tree comparison metric was used to measure the increase in similarity of minimal trees as larger, randomly selected subsets of nucleotide positions were taken. The ratio of the observed to the expected number of incompatibilities for each nucleotide position (character) is a good predictor of the number of changes required at that position on the minimal (most-parsimonious) tree. This allows a higher weighting of nucleotide positions that have changed more slowly and should result in the minimal length tree converging to the correct tree as more sequences are obtained. An estimate was made of the smallest subset of trees that need to be considered to include the actual historical tree for a given set of data. It was concluded that it is possible to give a reasonable estimate of the reliability of the final tree, at least when several sequences are combined. With the present data, resolving the rodent-primate-lagomorph (rabbit) trichotomy is the least certain aspect of the final tree, followed then by establishing the position of dog. In our opinion, it is unreasonable to publish an evolutionary tree derived from sequence data without giving an idea of the reliability of the tree.
Antibiotics for the common cold: expectations of Germany’s general population
Authors: M S Faber, K Heckenbach, E Velasco, T Eckmanns
Journal: Eurosurveillance (2010)

Physicians mention patients' expectations as a reason for prescribing antibiotics for common (viral) upper respiratory tract infections despite clinical evidence against their use and the physicians' better judgement. We aimed to assess the prevalence of such expectations and factors of influence (knowledge and attitudes) in Germany's general population. In November 2008, 1,778 persons registered with a large market research company were invited to complete an online questionnaire on expectations concerning prescription of antibiotics and on knowledge and attitudes regarding the effectiveness and use of antibiotics for upper respiratory tract infections. A total of 1,076 persons aged 15-78 years participated (response: 61%), of whom 91.8% reported using antibiotics 'only if absolutely necessary'. Prescription of antibiotics was expected by 113 (10.5%) of the 1,076 respondents for the common cold and by 997 (92.7%) for pneumonia. In a logistic regression analysis, predictors for expecting a prescription for antibiotics for the common cold included the following opinions: 'common cold or flu can effectively be treated with antibiotics' (prevalence: 37.6%; odds ratio (OR): 9.6; 95% confidence interval (CI): 3.8 to 24.3) and 'antibiotics should be taken when having a sore throat to prevent more serious illness' (prevalence 8.6%; OR: 7.6; 95% CI: 3.9 to 14.5). Among those expecting a prescription (n=113), 80 (71%) reported that they would trust their physician when he or she deems a prescription unnecessary; a further eight (7%) would be unsatisfied, but would accept the decision. Our results suggest that only a minority expects antibiotics for the treatment of cold symptoms. Physicians should be educated that their decisions not to prescribe antibiotics for the common cold, even when against patients' expectations, are apparently accepted by the majority.
Management of large polyps within the Solent bowel cancer screening programme
Authors: G. Longcroft-Wheaton, R. Duane-Moore, W. Edwards, P. Bhandari
Journal: Gut (2011)

<h3>Introduction</h3> The introduction of the bowel cancer screening programme has resulted in a rise in the number of large polyps being encountered during endoscopy. The exact frequency and management of these polyps remains unclear. This study aims to assess the incidence of large polyps and their management in the BCSP and to extrapolate this to the national scenario within the programme. <h3>Methods</h3> The bowel cancer screening database was interrogated to identify all cases over the last 3 years where lesions greater than 2 cm were identified. In each case the polyp morphology and histology was noted. The case files were retrieved and the treatment given to the patient recorded. <h3>Results</h3> The Solent BCSP covers a catchment population of 763 000.In total 1573 colonoscopies were performed over a 3 year period. <h3>Polyp burden</h3> There were 2454 polyps in total (1072 per million per annum). 193 polyps &gt;2 cm were seen during this period. This amounts to 84 per million per annum and represents 7.9% of the total polyp burden. 122/193 were pedunculated polyps (53 per million per annum) and 71/193 were flat polyps &gt;2 cm (31 per million per annum) representing 2.9% of all polyps. It is flat lesions &gt;3 cm which we believe are very challenging. The frequency of these was 32/193 (14 per million per annum), just 1.3% of the polyps encountered. <h3>Polyp cancers</h3> The overall risk of cancer in polyps &gt;2 cm was 13%. Size did not correlate to risk of malignancy. <h3>Polyp management</h3> 24/193 polyps were not resected endoscopically. 17 were referred to surgery due to suspected malignancy and were found to have cancer at surgery. 7 benign adenomas were sent to surgery. 4 benign polyps were referred to surgery due to technical inability of the endoscopist, 1 due to coexisting cancer, 1 due to co-existing ulcerative colitis and 1 due to patient choice. <h3>Conclusion</h3> (1) The majority of polyps in the BCSP are small (2) Flat adenomas &gt;2 cm are infrequent and those &gt;3 cm are rare, representing 1.3% of the total polyp burden (3) The management of most of the large lesions in this series was endoscopic, due in part to a strong local EMR service within the Solent area (4) Our data shows that the number of patients with large and flat lesions in the BCS programme is low and a good outcome can be achieved in a specialist centre.
Interaction of protamine sulfate with thrombin
Authors: Richard J. Cobel‐Geard, Houria I. Hassouna
Journal: American Journal of Hematology (1983)

Protamine sulfate (salmine), a basic protein with a molecular weight of 4,626 +/- 109, is a known antiheparin agent which in the absence of heparin demonstrates an anticoagulant activity. To date, much work has been done to elucidate the interaction of heparin with thrombin and its physiologic inhibitor, Antithrombin III (ATIII). Little is known, however, about the mechanism of anticoagulant action of protamine sulfate and its mode of thrombin inactivation. We provide information about the interaction of protamine sulfate with purified, labeled thrombin and ATIII through binding experiments in which protamine is shown to inhibit the inactivation of thrombin by ATIII. Furthermore, we show in clotting assays that protamine sulfate has an inhibitory effect on thrombin in the conversion of fibrinogen to fibrin, and that this inhibition is concentration dependent, partial, and reversible.