tbuckley/cabot-search huggingface dataset:
Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer
Authors: Chaoyang Li, Shuiliang Yu, Fumihiko Nakamura, Shaoman Yin, Jinghua Xu, Amber A. Petrolla, Neena Singh, Alan Tartakoff, Derek W. Abbott, Wei Xin, Man-Sun Sy
Journal: Journal of Clinical Investigation (2009)

The cellular prion protein (PrP) is a highly conserved, widely expressed, glycosylphosphatidylinositol-anchored (GPI-anchored) cell surface glycoprotein. Since its discovery, most studies on PrP have focused on its role in neurodegenerative prion diseases, whereas its function outside the nervous system remains unclear. Here, we report that human pancreatic ductal adenocarcinoma (PDAC) cell lines expressed PrP. However, the PrP was neither glycosylated nor GPI-anchored, existing as pro-PrP and retaining its GPI anchor peptide signal sequence (GPI-PSS). We also showed that the PrP GPI-PSS has a filamin A–binding (FLNa-binding) motif and interacted with FLNa, an actin-associated protein that integrates cell mechanics and signaling. Binding of pro-PrP to FLNa disrupted cytoskeletal organization. Inhibition of PrP expression by shRNA in the PDAC cell lines altered the cytoskeleton and expression of multiple signaling proteins; it also reduced cellular proliferation and invasiveness in vitro as well as tumor growth in vivo. A subgroup of human patients with pancreatic cancer was found to have tumors that expressed pro-PrP. Most importantly, PrP expression in tumors correlated with a marked decrease in patient survival. We propose that binding of pro-PrP to FLNa perturbs FLNa function, thus contributing to the aggressiveness of PDAC. Prevention of this interaction could provide an attractive target for therapeutic intervention in human PDAC.
The Influence of Anticodon-Codon Interactions and Modified Bases on Codon Usage Bias in Bacteria
Authors: W. Ran, P. G. Higgs
Journal: Molecular Biology and Evolution (2010)

Most transfer RNAs (tRNAs) can translate more than one synonymous codon, and most codons can be translated by more than one isoacceptor tRNA. The rates of translation of synonymous codons are dependent on the concentrations of the tRNAs and on the rates of pairing of each anticodon–codon combination. Translational selection causes a significant bias in codon frequencies in highly expressed genes in most bacteria. By comparing codon frequencies in high and low-expression genes, we determine which codons are preferred for each amino acid in a large sample of bacterial genomes. We relate this to the number of copies of each tRNA gene in each genome. In two-codon families, preferred codons have Watson–Crick pairs (GC and AU) between the third codon base and the wobble base of the anticodon rather than GU pairs. This suggests that these combinations are more rapidly recognized by the ribosome. In contrast, in four-codon families, preferred codons do not correspond to Watson–Crick rules. In some cases, a wobble-U tRNA can pair with all four codons. In these cases, A and U codons are preferred over G and C. This indicates that the nonstandard UU combination appears to be translated surprisingly well. Differences in modified bases at the wobble position of the anticodon appear to be responsible for the differences in behavior of tRNAs in two- and four-codon families. We discuss the way changes in the bases in the anticodon influence both the speed and the accuracy of translation. The number of tRNA gene copies and the strength of translational selection correlate with the growth rate of the organism, as we would expect if the primary cause of translational selection in bacteria is the requirement to optimize the speed of protein production.
MiR-29c is downregulated in gastric carcinomas and regulates cell proliferation by targeting RCC2
Authors: Mitsuhiro Matsuo, Chisato Nakada, Yoshiyuki Tsukamoto, Tsuyoshi Noguchi, Tomohisa Uchida, Naoki Hijiya, Keiko Matsuura, Masatsugu Moriyama
Journal: Molecular Cancer (2013)

Abstract Background Previously, using miRNA microarray, we have found that miR-29c is significantly downregulated in advanced gastric carcinoma. In the present study, we investigated whether miR-29c functions as a tumor-suppressor miRNA in gastric carcinoma cells. For this purpose, we verified the downregulation of miR-29c in gastric carcinoma tissues, and assessed the biological effect of miR-29c on gastric carcinoma cells. Results In miR-29c-transfected cells, both proliferation and colony formation ability on soft agar were significantly decreased. Although apoptosis was not induced, BrdU incorporation and the proportion of cells positive for phospho-histone H3 (S10) were significantly decreased in miR-29c-transfected cells, indicating that miR-29c may be involved in the regulation of cell proliferation. To explain the mechanism of growth suppression by miR-29c, we explored differentially expressed genes (&gt;2-fold) in miR-29c-transfected cells in comparison with negative control transfected cells using microarray. RCC2, PPIC and CDK6 were commonly downregulated in miR-29c-transfected MKN45, MKN7 and MKN74 cells, and all of the genes harbored miR-29c target sequences in the 3’-UTR of their mRNA. RCC2 and PPIC were actually upregulated in gastric carcinoma tissues, and therefore both were identified as possible targets of miR-29c in gastric carcinoma. To ascertain whether downregulation of RCC2 and/or PPIC is involved in the growth suppression by miR-29c, we transfected siRNAs against RCC2 and PPIC into MKN45 and determined cell viability, the rate of BrdU incorporation, and caspase activity. We found that RCC2-knockdown decreased both cell viability and BrdU incorporation without any increase of caspase activity, while PPIC-knockdown did not, indicating that downregulation of RCC2 may be at least partly responsible for the growth suppression by miR-29c. Conclusions Our findings indicate that miR-29c may have tumor-suppressive functions in gastric carcinoma cells, and that its decreased expression may confer a growth advantage on tumor cells via aberrant expression of RCC2.
FGF-16 is a target for adrenergic stimulation through NF- B activation in postnatal cardiac cells and adult mouse heart
Authors: A. G. Sofronescu, K. A. Detillieux, P. A. Cattini
Journal: Cardiovascular Research (2010)

AimsThe fibroblast growth factor (FGF) family plays an important role in cardiac growth and development. However, only FGF-16 RNA levels are reported to increase during the perinatal period and to be expressed preferentially in the myocardium, suggesting control at the transcriptional level and a role for FGF-16 in the postnatal heart. Beyond the identification of two TATA-like elements (TATA1 and TATA2) in the mouse FGF-16 promoter region and the preferential cardiac activity of TATA2, there is no report of Fgf-16 gene regulation. Assessment of promoter sequences, however, reveals putative nuclear factor-kappaB (NF-κB) elements, suggesting that Fgf-16 is regulated via NF-κB activation and thereby implicated in a number of cardiac events. Thus, the Fgf-16 gene was investigated as a target for NF-κB activation in cardiac cells.
The impact of obstructive sleep apnoea on the aorta
Authors: Thomas Gaisl, Daniel J. Bratton, Malcolm Kohler
Journal: European Respiratory Journal (2015)

Obstructive sleep apnoea (OSA) has been shown to be a causal factor in the pathogenesis of vascular dysfunction and hypertension, conditions which can promote dilation and subsequent aortic dissection and rupture. The objective of this review is to summarise the current literature on the possible association between OSA and aortic disease and delineate the underlying mechanisms. Relevant studies were found by searching for terms including “obstructive sleep apnoea” in combination with “aortic aneurysm, dissection, and dilation” in the MEDLINE and EMBASE databases. Observational studies consistently reported that OSA is highly prevalent among patients with aortic aneurysms and aortic dissections. Patients with co-occurring OSA and Marfan's syndrome as well as patients at the more severe end of the spectrum of OSA seem to be especially vulnerable to aortic disease. Several mechanisms are discussed concerning the link between OSA and aortic disease: nocturnal negative intrathoracic pressure surges leading to mechanical stretching of the aorta and ultimately aortic distension; arousal-induced reflex sympathetic activation with subsequent hypertension; and intermittent hypoxia associated with autonomic nervous system activation and consequently increased oxidative stress. Further well controlled studies are needed in order to define the exact role of OSA as a risk factor for aortic disease.
Essential role of Mannose-binding lectin-associated serine protease-1 in activation of the complement factor D
Authors: Minoru Takahashi, Yumi Ishida, Daisuke Iwaki, Kazuko Kanno, Toshiyuki Suzuki, Yuichi Endo, Yoshimi Homma, Teizo Fujita
Journal: The Journal of Experimental Medicine (2009)

The complement system is an essential component of innate immunity, participating in the pathogenesis of inflammatory diseases and in host defense. In the lectin complement pathway, mannose-binding lectin (MBL) and ficolins act as recognition molecules, and MBL-associated serine protease (MASP) is a key enzyme; MASP-2 is responsible for the lectin pathway activation. The function of other serine proteases (MASP-1 and MASP-3) is still obscure. In this study, we generated a MASP-1– and MASP-3–deficient mouse model (Masp1/3−/−) and found that no activation of the alternative pathway was observed in Masp1/3−/− serum. Mass spectrometric analysis revealed that circulating complement factor D (Df) in Masp1/3−/− mice is a zymogen (pro-Df) with the activation peptide QPRGR at its N terminus. These results suggested that Masp1/3−/− mice failed to convert pro-Df to its active form, whereas it was generally accepted that the activation peptide of pro-Df is removed during its secretion and factor D constitutively exists in an active form in the circulation. Furthermore, recombinant MASP-1 converted pro-Df to the active form in vitro, although the activation mechanism of pro-Df by MASP-1 is still unclear. Thus, it is clear that MASP-1 is an essential protease of both the lectin and alternative complement pathways.
John Murray Harper
Authors: J McBlane
Journal: BMJ (2002)

Former general practitioner Helensburgh (b Glasgow 1922; q Glasgow 1946), d 16 March 2002.

After national service in the Royal Army Medical Corps in Palestine and Egypt, John entered general practice in Helensburgh until he retired in 1992. A GP of the old school, he had the great gift of making patients feel better. A devoted family man, he spent much of his retirement caring for his wife, Jean, but he was also able to enjoy golf, rugby, and cricket, and he had a lifelong interest in the paintings of the Scottish colourists. Predeceased by his wife and son John, he leaves two daughters.
Where CD4<b>+</b>CD25<b>+</b> T reg cells impinge on autoimmune diabetes
Authors: Zhibin Chen, Ann E. Herman, Michael Matos, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2005)

Foxp3 is required for the generation and activity of CD4(+)CD25(+) regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in the draining lymph nodes, nor accelerate the onset of T cell infiltration of the pancreatic islets. However, this insulitis was immediately destructive, causing a dramatic progression to overt diabetes. Microarray analysis revealed that T reg cells in the insulitic lesion adopted a gene expression program different from that in lymph nodes, whereas T reg cells in draining or irrelevant lymph nodes appeared very similar. Thus, T reg cells primarily impinge on autoimmune diabetes by reining in destructive T cells inside the islets, more than during the initial activation in the draining lymph nodes.
Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms’ tumor: a Children’s Cancer Group report
Authors: A.M. Abu-Ghosh, M.D. Krailo, S.C. Goldman, R.S. Slack, V. Davenport, E. Morris, J.H. Laver, G.H. Reaman, M.S. Cairo
Journal: Annals of Oncology (2002)
The efficacy and safety of inhaled fluimucil-antibiotic-IT in the treatment of exacerbations of COPD and chronic bronchitis with bronchiectasis
Authors: Valentina Kapustina, Svetlana Ovcharenko
Journal: European Respiratory Journal (2013)

Introduction : In severe exacerbations of COPD and chronic bronchitis accompanied by difficult expectorated purulent sputum there is a need in both antibiotic and mucolytic treatment.  Aims : To investigate the efficacy and safety of an original combination drug - inhaled Thiamphenicol Glycinate Acetylcysteinate (Fluimucil-antibiotic-IT) 500 mg daily.  Methods : 15 patients with acute exacerbation of COPD (phenotype of airways disease) and 10 patients with acute exacerbation of chronic bronchitis with bronchiectasis were recruited (60% male, with mean age of 59.4±16.0 and %FEV1 64.3±11.5%). Nebulized Fluimucil-antibiotic-IT was administrated 250 mg BID for 6 days. At baseline and after 6 days respiratory symptoms severity, inflammation markers, sputum culture were assessed and adverse events were collected.  Results : After 6 days of treatment it was noted decrease the severity of sputum production (4 vs 1.5, p Conclusions : Fluimucil-antibiotic-IT is effective and safe combination treatment of COPD and chronic bronchitis exacerbations.
ETIOLOGY OF YELLOW FEVER
Authors: Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1919)

By the inoculation of guinea pigs intraperitoneally with the emulsions of kidneys from wild rats and mice captured in Guayaquil, it was found that 67 per cent of the wild rats tested harbored in their kidneys a leptospira which produced in guinea pigs symptoms and lesions identical with those produced by Leptospira icterohamorrhagia derived either from patients suffering from infectious jaundice in Japan or Europe, or from wild rats caught in New York. Immune sera were prepared in rabbits by injecting different strains of the Guayaquil leptospira. These sera had a marked agglutinating and disintegrating influence upon the homologous strains, and also, but often to a less pronounced degree, upon the strains of Leptospira icterohœmorrhagiœ from other sources. Pfeiffer's phenomenon was also found to be positive, and protection was demonstrated against infection with virulent cultures of strains of Leptospira icterohœmorrhagiœ. The same sera had no effect, or at most a very slight one, upon Leptospira icteroides. Guinea pigs inoculated with icteroides strains were not noticeably protected by the use of the immune sera prepared with the Guayaquil rat strains. Guinea pigs inoculated with killed cultures of the Guayaquil strains of leptospira proved to be resistant to a subsequent infection with heterologous as well as homologous strains of Leptospira icterohœmorrhagiœ. It is concluded, therefore, that the leptospira isolated from the kidneys of wild rats and mice in Guayaquil belongs to the group of Leptospira icterohœmorrhagiœ, and differs from Leptospira icteroides in its immunity reactions. No positive transmission was obtained with kidney material from bats and an opossum.
Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells.
Authors: J G Krueger, J T Wolfe, R T Nabeya, V P Vallat, P Gilleaudeau, N S Heftler, L M Austin, A B Gottlieb
Journal: The Journal of Experimental Medicine (1995)

Skin irradiation with ultraviolet B (UVB) is a common and often durable treatment for psoriasis and other inflammatory skin disorders. We studied the effects of UVB on keratinocytes and leukocytes in psoriatic tissue and in culture. In nine patients treated repetitively, most of the cellular and molecular changes that typify the psoriatic epidermis reverted to normal. Keratinocyte hyperplasia, assessed by expression of the Ki-67 cell cycle antigen, decreased by 70%, and residual cell proliferation was appropriately confined to the basal layer. Epidermal thickening was reduced by 60%, and a granular layer reformed. Expression of keratin 16, as well as suprabasal integrin alpha 3 and insulin-like growth factor-1 receptors, was eliminated, whereas filagrin increased markedly. UVB also depleted &amp;gt; 90% of the CD3+, CD8+, and CD25+ T cells from the psoriatic epidermis, whereas dermal T cells were only minimally depressed. The latter finding parallels the known inability of these doses of UVB to penetrate the dermis. In tissue culture, UVB was antiproliferative and cytotoxic toward T cells and keratinocytes, but the T cells were 10-fold more sensitive. Furthermore, low doses of UVB induced apoptosis in lymphocytes but not keratinocytes, as detected by the TUNEL (TdT-mediated dUTP-biotin nick end labeling) technique. The selective effects of UVB on intraepidermal T cells in situ and in culture support the hypothesis that epidermal alterations in psoriasis can be normalized by a depletion of activated intraepidermal T cells.
Safety and Efficacy of Surgical Ventricular Restoration in Unstable Patients With Recent Anterior Myocardial Infarction
Authors: Marisa Di Donato, Alessandro Frigiola, Melika Benhamouda, Lorenzo Menicanti
Journal: Circulation (2004)

The effects and efficacy of surgical ventricular restoration (SVR) in ischemic cardiomiopathy caused by chronic anterior myocardial infarction (MI) are well established. Normally, SVR is delayed at least 3 months after MI to allow the healing of infarcted tissue. Some patients have instability <30 days after anterior MI, with increased risk for morbidity and mortality.Objectives- This study tests the safety and efficacy of SVR in the setting of subacute complicated anterior MI, in terms of early and late outcome.74 patients (62+/-10 years) were submitted to SVR at < or =30 days after anterior MI for clinical instability and were retrospectively selected from a series of 430 patients undergoing SVR at our center, between 1998 and 2001. The surgical indications included: angina (60%); New York Heart Association class 4 (62%); clinical signs of heart failure (18%); life-threatening arrhythmias (12%); and cardiogenic shock in 4% (or 3) patients. Follow-up is available for 93% of patients. All patients had coronary artery bypass grafting (CABG) (3.1+/-1.2) with internal mammary artery (IMA) utilization. An endoventricular patch was used in 17 patients (23%); direct ventriculotomy closure was used in the remaining patients. Operative mortality was 5.4% (4/74). Hemodynamic parameters improved significantly in patients with dilated hearts and reduced ejection fraction. Mitral regurgitation that resulted was significantly reduced. Survival at 3 years was 87% in the overall population and 85% in patients 70 years or older.This study reports the largest series of patients with complicated, recent anterior MI treated with SVR. The results show that SVR is feasible, has acceptable in-hospital mortality, and has good early and late outcome. Further experience is needed to establish whether SVR, which excludes the infarcted region, can prevent the long-term adverse remodeling of LV dilated hearts after anterior infarction.
Robust tumor immunity to melanoma mediated by interleukin-9–producing T cells
Authors: Rahul Purwar, Christoph Schlapbach, Sheng Xiao, Hong Soon Kang, Wassim Elyaman, Xiaodong Jiang, Anton M Jetten, Samia J Khoury, Robert C Fuhlbrigge, Vijay K Kuchroo, Rachael A Clark, Thomas S Kupper
Journal: Nature Medicine (2012)
Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb®) in human breast carcinoma cells
Authors: A. Vazquez-Martin, C. Oliveras-Ferraros, R. Colomer, J. Brunet, J.A. Menendez
Journal: Annals of Oncology (2008)
Time for a Level Playing Field: Inequalities in Regulatory/Approval Processes—The Example of Bevacizumab in Epithelial Ovarian Cancer
Authors: Paul J. Hoskins, Michael Fung-Kee-Fung, Dianne Miller, Walter Gotlieb
Journal: Journal of Clinical Oncology (2015)

][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] It has clinical benefit, defined as a 3-month or greater increase in progression-free survival (PFS) in renal, colorectal, and epithelial ovarian cancer (EOC; Fig 1).Most oncologists would regard this degree of benefit as valuable. 20evacizumab has also been approved in metastatic non-small-cell lung cancer, despite lesser benefit.However, although the same information is used by regulatory bodies for evaluation of this drug, there is a discordance in national approval rates in EOC: Canada, de facto, and the United Kingdom (despite European Union approval) are nonapprovers.Submission was made to Health Canada for the inclusion of bevacizumab in the first-line treatment of EOC, but the request was withdrawn by Roche (Basel, Switzerland) after initial review because of the resultant supplementary questions.Within Canada, Health Canada also seems to have applied different standards for ovarian as opposed to colorectal and lung cancers, despite similar outcomes.Additionally complicating interpretation is that multiple levels of approval may be needed.The initial stage (licensing or market authorization) looks at efficacy and safety; this is the role of Health Canada and the European Medicines Agency (EMA).Bevacizumab did not pass this stage in Canada.In the United Kingdom, after EMA approval, a subsequent regulatory process that now involves cost information as well as the data has to be navigated before funding approval.NICE (the National Institute for Health Care and Excellence) has this funding role in the United Kingdom and did not approve bevacizumab.In total, worldwide approval of bevacizumab in EOC has been given, in addition to the European Union, in 66 and 21 countries in the first-line setting and in platinum-sensitive relapse, respectively.How can there be such a marked regulatory/funder discordance both between countries and also within an individual country?It cannot be based on a lack of real benefit, given that the same studies were used in the successful and unsuccessful applications, and the outcomes for ovarian cancer were at least as good as those for bowel and superior to those in non-small-cell lung cancer (and bevacizumab was approved for both of these entities in Canada).Why this inconsistency?
Can We Model Nitric Oxide Biotransport? A Survey of Mathematical Models for a Simple Diatomic Molecule with Surprisingly Complex Biological Activities
Authors: Donald G. Buerk
Journal: Annual Review of Biomedical Engineering (2001)

Nitric oxide (NO) is a remarkable free radical gas whose presence in biological systems and whose astonishing breadth of physiological and pathophysiological activities have only recently been recognized. Mathematical models for NO biotransport, just beginning to emerge in the literature, are examined in this review. Some puzzling and paradoxical properties of NO may be understood by modeling proposed mechanisms with known parameters. For example, it is not obvious how NO can survive strong scavenging by hemoglobin and still be a potent vasodilator. Recent models do not completely explain how tissue NO can reach effective levels in the vascular wall, and they point toward mechanisms that need further investigation. Models help to make sense of extremely low partial pressures of NO exhaled from the lung and may provide diagnostic information. The role of NO as a gaseous neurotransmitter is also being understood through modeling. Studies on the effects of NO on O2 transport and metabolism, also reviewed, suggest that previous mathematical models of transport of O2 to tissue need to be revised, taking the biological activity of NO into account.