tbuckley/cabot-search huggingface dataset:
137. Localization of Regions in CD46 That Interact with Adenovirus
Authors: Anuj Gaggar, Dmitry M. Shayakhmetov, M. Kathryn Liszewski, John P. Atkinson, Andre Lieber
Journal: Molecular Therapy (2005)

Understanding how a pathogen interacts with its cellular receptor is a fundamental aspect of virus-host interactions. Delineating these interactions can help to understand viral tropism and can provide novel targets for antiviral therapeutics. CD46, or membrane cofactor protein (MCP), is a ubiquitously expressed transmembrane protein belonging to the regulators of complement activation (RCA) family. In addition to its role in preventing complement damage to normal cells, this protein has been described as a cellular receptor for a variety of pathogens, including Neisseria and Streptococcus strains, as well as measles virus (especially the Edmonston strain), human herpesvirus 6, bovine viral diarrhea virus, and different human group B adenovirus serotypes. For several of these pathogens the binding sites within CD46 have been described, however, it is still unknown how adenovirus interacts with CD46. In this study, we used competition experiments with known CD46 ligands, CD46-specific antibodies, and a set of CD46 mutants to localize the binding domain for the group B adenovirus serotypes 35 and 11 (Ad35 and Ad11, respectively). Our results demonstrated that Ad35 competes with measles virus for binding to CD46 but not with complement protein C3b. We further show that Ad binding to CD46 is a protein-protein interaction and that N-glycosylations do not critically contribute to infection with Ad35 fiber containing Ad vectors. Our data demonstrate that the virus binding site is localized within the CD46 CCP2 domain. Moreover, we found that native conformation of CCP2 domain is crucial for Ad35 binding. Amino acid substitutions at the positions 130-135 or 152-156 completely abolish the adenovirus receptor function of CD46. These regions localize to the same planar face of CD46 and likely form an extended adenovirus binding surface since no single amino acid substitution within these areas eliminate virus binding. Finally, we demonstrate that the infection with a virus possessing human group B serotype Ad11 fibers is also mediated by the CCP2 domain of CD46. The identification of the Ad35 binding domain within CD46 is important for a better understanding of virus cell interaction and may help in the identification of the domains within the Ad fiber knob that are involved in CD46 binding. The data obtained in this study might help in the design of anti-viral therapeutics against adenovirus serotypes that utilize CD46 as a primary cellular attachment receptor.
Enhancement of initial stability of press-fit femoral stems using injectable calcium phosphate cement: an in vitro study in dog bones
Authors: E.M. Ooms, N. Verdonschot, J.G.C. Wolke, W.Van de Wijdeven, M.M.M. Willems, M.F.T. Schoenmaker, J.A. Jansen
Journal: Biomaterials (2003)
Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice
Authors: Zhipeng Meng, Xiaoqiong Wang, Yichao Gan, Yunfeng Zhang, Hong Zhou, Carl Van Ness, Jun Wu, Guiyu Lou, Hua Yu, Chao He, Rongzhen Xu, Wendong Huang
Journal: Journal of Hepatology (2012)
Tracheal Allotransplantation after Withdrawal of Immunosuppressive Therapy
Authors: Pierre Delaere, Jan Vranckx, Geert Verleden, Paul De Leyn, Dirk Van Raemdonck
Journal: New England Journal of Medicine (2010)

Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the tracheal allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At 4 months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.
Identifying dysfunctional miRNA-mRNA regulatory modules by inverse activation, cofunction, and high interconnection of target genes: A case study of glioblastoma
Authors: Y. Xiao, Y. Ping, H. Fan, C. Xu, J. Guan, H. Zhao, Y. Li, Y. Lv, Y. Jin, L. Wang, X. Li
Journal: Neuro-Oncology (2013)

Accumulating evidence demonstrates that complex diseases may arise from cooperative effects of multiple dysfunctional miRNAs. Thus, identifying abnormal functions cooperatively regulated by multiple miRNAs is useful for understanding the pathogenesis of complex diseases. In this study, we proposed a multistep method to identify dysfunctional miRNA-mRNA regulatory modules (dMiMRMs) in a specific disease, in which a group of miRNAs cooperatively regulate a group of target genes involved in a specific function. We identified dysfunctional miRNAs, which were differentially expressed and inversely regulated most of their target genes, by integrating paired miRNA and mRNA expression profiles and miRNA target information. Then, we identified cooperative functional units, in each of which a pair of miRNAs cooperatively repressed function-enriched and highly interconnected target genes. Finally, the cooperative functional units were assembled into dMiMRMs. We applied our method to glioblastoma (GBM) and identified GBM-associated dMiMRMs at the population, subtype, and individual levels. We identified 5 common dMiMRMs using all GBM samples, 3 of which were associated with the prognosis in patients with GBM and were better predictors of prognosis than were miRNAs or mRNAs alone. By applying our approach to GBM subtypes, we found consistent dMiMRMs across GBM subtypes, and some subtype-specific dMiMRMs were observed. Furthermore, personalized dMiMRMs were identified, suggesting significant individual differences in different patients with GBM. Our method provides the capability to identify miRNA-mediated dysfunctional mechanisms underlying complex diseases.
Penicillin‐allergic patients react to penicillin‐modified “self”
Authors: S. J. D. Bell, W. J. Pichler
Journal: Allergy (1989)

Penicillin G (PNG) has been demonstrated to elicit T‐cell responsiveness in vitro in allergic patients by means of a lymphocyte transformation test (LTT). As it was not clear how, or in what form, the stimulatory PNG determinants were inducing cellular proliferation, we compared the immune response elicited by different PNG preparations. Peripheral blood lymphocytes (PBL) of patients with proven PNG allergy were isolated, and proliferative responsiveness to soluble PNG alone, soluble PNG‐protein conjugates (BPO‐HSA, BPO‐PL, BPO‐HEX), and non‐reactive penicilloate salts, was evaluated. An autologous mixed lymphocyte culture (MLC) using penicilloylated stimulator cells, was used to test responsiveness to membrane‐bound PNG. We found that the addition of either 1000 μg/ml of potentially‐reactive PNG to cell cultures, or of penicilloylated autologous cells was stimulatory, whereas non‐reactive PNG salt, and soluble PNG conjugates were not stimulatory. Considering current and earlier findings, it appears that T cell immunity in these patients is directed towards PNG‐modified “self”, as PNG‐modified autologous cells are potent stimulators in PNG‐allergic individuals.
Evaluation of <sup>111</sup>In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
Authors: Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
Journal: Theranostics (2011)

The purpose of this study was to demonstrate the valence of cyclic RGD peptides, P-RGD (PEG(4)-c(RGDfK): PEG(4) = 15-amino-4,710,13-tetraoxapentadecanoic acid), P-RGD(2) (PEG(4)-E[c(RGDfK)](2), 2P-RGD(4) (E{PEG(4)-E[c(RGDfK)](2)}(2), 2P4G-RGD(4) (E{PEG(4)-E[G(3)-c(RGDfK)](2)}(2): G(3) = Gly-Gly-Gly) and 6P-RGD(4) (E{PEG(4)-E[PEG(4)-c(RGDfK)](2)}(2)) in binding to integrin α(v)β(3), and to assess the impact of peptide and linker multiplicity on biodistribution properties, excretion kinetics and metabolic stability of their corresponding (111)In radiotracers. Five new RGD peptide conjugates (DOTA-P-RGD (DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid), DOTA-P-RGD(2), DOTA-2P-RGD(4), DOTA-2P4G-RGD(4), DOTA-6P-RGD(4)), and their (111)In complexes were prepared. The integrin α(v)β(3) binding affinity of cyclic RGD conjugates were determined by a competitive displacement assay against (125)I-c(RGDyK) bound to U87MG human glioma cells. Biodistribution, planar imaging and metabolism studies were performed in athymic nude mice bearing U87MG human glioma xenografts. The integrin α(v)β(3) binding affinity of RGD conjugates follows the order of: DOTA-6P-RGD(4) (IC(50) = 0.3 ± 0.1 nM) ~ DOTA-2P4G-RGD(4) (IC(50) = 0.2 ± 0.1 nM) ~ DOTA-2P-RGD(4) (IC(50) = 0.5 ± 0.1 nM) > DOTA-3P-RGD(2) (DOTA-PEG(4)-E[PEG(4)-c(RGDfK)](2): IC(50) = 1.5 ± 0.2 nM) > DOTA-P-RGD(2) (IC(50) = 5.0 ± 1.0 nM) >> DOTA-P-RGD (IC(50) = 44.3 ± 3.5 nM) ~ c(RGDfK) (IC(50) = 49.9 ± 5.5 nM) >> DOTA-6P-RGK(4) (IC(50) = 437 ± 35 nM). The fact that DOTA-6P-RGK(4) had much lower integrin α(v)β(3) binding affinity than DOTA-6P-RGD(4) suggests that the binding of DOTA-6P-RGD(4) to integrin α(v)β(3) is RGD-specific. This conclusion is consistent with the lower tumor uptake for (111)In(DOTA-6P-RGK(4)) than that for (111)In(DOTA-6P-RGD(4)). It was also found that the G(3) and PEG(4) linkers between RGD motifs have a significant impact on the integrin α(v)β(3)-targeting capability, biodistribution characteristics, excretion kinetics and metabolic stability of (111)In-labeled cyclic RGD peptides. On the basis of their integrin α(v)β(3) binding affinity and tumor uptake of their corresponding (111)In radiotracers, it was conclude that 2P-RGD(4), 2P4G-RGD(4) and 6P-RGD(4) are most likely bivalent in binding to integrin α(v)β(3), and extra RGD motifs might contribute to the long tumor retention times of (111)In(DOTA-2P-RGD(4)),( 111)In(DOTA-2P4G-RGD(4)) and (111)In(DOTA-6P-RGD(4)) than that of (111)In(DOTA-3P-RGD(3)) at 72 h p.i. Among the (111)In-labeled cyclic RGD tetramers evaluated in the glioma model, (111)In(DOTA-2P4G-RGD(4)) has very high tumor uptake with the best tumor/kidney and tumor/liver ratios, suggesting that (90)Y(DOTA-2P4G-RGD(4)) and (177)Lu(DOTA-2P4G-RGD(4)) might have the potential for targeted radiotherapy of integrin α(v)β(3)-positive tumors.
ABO blood groups and rheumatic heart disease.
Authors: A L Macafee
Journal: Annals of the Rheumatic Diseases (1965)

Buckwalter, Naifeh, and Auer (1962) reviewed the literature on the relationship of the blood groups to rheumatic fever.There is a significant increase in the frequency of ABO (H) non-secretors in rheu- matic fever patients as compared with controls, and there is a significant deficiency of patients of blood group 0. This paper reports the ABO distribution in 431 additional cases.
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin
Authors: Patricia Collin-Osdoby
Journal: Circulation Research (2004)

Vascular calcification often occurs with advancing age, atherosclerosis, various metabolic disorders such as diabetes mellitus and end-stage renal disease, or in rare genetic diseases, leading to serious clinical consequences. Such mineralization can occur at various sites (cardiac valves, arterial intima or media, capillaries), involve localized or diffuse widespread calcification, and result from numerous causes that provoke active inflammatory and osteogenic processes or disordered mineral homeostasis. Although valuable research has defined many key factors and cell types involved, surprising new insights continue to arise that deepen our understanding and suggest novel research directions or strategies for clinical intervention in calcific vasculopathies. One emerging area in vascular biology involves the RANKL/RANK/OPG system, molecules of the tumor necrosis factor-related family recently discovered to be critical regulators of immune and skeletal biology. Evidence is accumulating that such signals may be expressed, regulated, and function in vascular physiology and pathology in unique ways to promote endothelial cell survival, angiogenesis, monocyte or endothelial cell recruitment, and smooth muscle cell osteogenesis and calcification. Concerted research efforts are greatly needed to understand these potential roles, clarify whether RANKL (receptor activator of nuclear factor kappaB ligand) promotes and osteoprotegerin (OPG) protects against vascular calcification, define how OPG genetic polymorphisms relate to cardiovascular disease, and learn whether elevated serum OPG levels reflect endothelial dysfunction in patients. Overall, the RANKL/RANK/OPG system may mediate important and complex links between the vascular, skeletal, and immune systems. Thus, these molecules may play a central role in regulating the development of vascular calcification coincident with declines in skeletal mineralization with age, osteoporosis, or disease.
Genetic Risk, Number of Previous Depressive Episodes, and Stressful Life Events in Predicting Onset of Major Depression
Authors: Kenneth S. Kendler, Laura M. Thornton, Charles O. Gardner
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The association between stressful life events and the onset of major depression decreases as the number of previous depressive episodes increases. How do genetic risk factors for major depression impact on this “kindling” phenomenon? In particular, do those at high genetic risk exhibit an increase in the speed of kindling, or are they “prekindled”? METHOD: Using discrete-time survival analysis, the authors examined the interaction between genetic risk, number of previous depressive episodes, and life event exposure in the prediction of episodes of major depression in female-female twin pairs from a population-based registry. The twins were interviewed four times over a 9-year period, producing 92,521 person-months of exposure. RESULTS: The decline in the association between stressful life events and risk for major depression as the number of previous depressive episodes increased was strongest in those at low genetic risk and was weak to absent in those at high genetic risk. In the absence of previous depressive episodes, those at high genetic risk frequently experienced depressive episodes without major environmental stressors. CONCLUSIONS: Genetic risk factors for depression produce a “prekindling” effect rather than increase the speed of kindling. The “kindled” state, wherein depressive episodes occur with little provocation, may be reached by two pathways: many previous depressive episodes, perhaps driven by multiple adversities, and high genetic risk.
A nomogram for individualized estimation of survival among patients with brain metastasis
Authors: J. S. Barnholtz-Sloan, C. Yu, A. E. Sloan, J. Vengoechea, M. Wang, J. J. Dignam, M. A. Vogelbaum, P. W. Sperduto, M. P. Mehta, M. Machtay, M. W. Kattan
Journal: Neuro-Oncology (2012)

Purpose: An estimated 24%–45% of patients with cancer develop brain metastases. Individualized estimation of survival for patients with brain metastasis could be useful for counseling patients on clinical outcomes and prognosis. Methods: De-identified data for 2367 patients with brain metastasis from 7 Radiation Therapy Oncology Group randomized trials were used to develop and internally validate a prognostic nomogram for estimation of survival among patients with brain metastasis. The prognostic accuracy for survival from 3 statistical approaches (Cox proportional hazards regression, recursive partitioning analysis [RPA], and random survival forests) was calculated using the concordance index. A nomogram for 12-month, 6-month, and median survival was generated using the most parsimonious model. Results: The majority of patients had lung cancer, controlled primary disease, no surgery, Karnofsky performance score (KPS) ≥ 70, and multiple brain metastases and were in RPA class II or had a Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 1.25–2.5. The overall median survival was 136 days (95% confidence interval, 126–144 days). We built the nomogram using the model that included primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. The potential use of individualized survival estimation is demonstrated by showing the heterogeneous distribution of the individual 12-month survival in each RPA class or DS-GPA score group. Conclusion: Our nomogram provides individualized estimates of survival, compared with current RPA and DS-GPA group estimates. This tool could be useful for counseling patients with respect to clinical outcomes and prognosis.
Nephrolithiasis: site of the initial solid phase
Authors: David A. Bushinsky
Journal: Journal of Clinical Investigation (2003)

Most cases of nephrolithiasis are associated with the relatively common metabolic abnormality of idiopathic hypercalciuria (1). These patients generally absorb an excess amount of dietary calcium leading to increased urine calcium excretion and supersaturation with respect to calcium oxalate and calcium phosphate; they subsequently form stones. Other patients with nephrolithiasis, who have had an intestinal bypass procedure, absorb oxalate in excess leading to increased urine oxalate excretion and supersaturation with respect to calcium oxalate; they also subsequently form stones. In these and other causes of nephrolithiasis, the site of the initial solid phase has long been the subject of debate. Over 65 years ago, A. Randall demonstrated that interstitial crystals located at, or adjacent to, the papillary tip, Randall’s plaques, were common in stone formers (2). He found that these crystals were composed not of calcium oxalate, the most common solid phase found in patients with nephrolithiasis, but of calcium phosphate (3). He believed that the calcium phosphate crystals formed in the papillary interstitium and then eroded into the urinary space, serving as a heterogeneous nucleation surface for calcium oxalate. B. Finlayson later argued that, due to rapid flow of the renal ultrafiltrate through the tubule, there was insufficient time for formation of a lumen-obstructing solid phase (4), which also suggested that an intratubular site of stone formation was unlikely. However, other investigators found that calcium oxalate crystals adhered to cultured tubular cells (5), where they could either be endocytosed or remain on the cell surface, serving as a nidus for growth into larger, clinically significant, calculi.
Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma
Authors: B. Fouty, T. Moss, V. Solodushko, M. Kraft
Journal: European Respiratory Journal (2006)

Corticosteroids are the first line of therapy for asthma. Whether they alter the progression of airway remodelling in asthma is, as yet, unknown. To determine whether corticosteroids could alter the fibroblast cell cycle the current authors studied the effect of dexamethasone on cultured airway fibroblasts obtained from nine mild-to-moderate, steroid-naïve asthmatics (forced expiratory volume in one second 78+/-4% predicted), and seven normal controls. Fibroblasts were cultured from endobronchial biopsies obtained via bronchoscopy. Cells were exposed to dexamethasone (10(-9)-10(-7) M) and studied at 72 h to determine differences in progression through the cell cycle. In asthmatic fibroblasts, dexamethasone, at concentrations of 10(-8)M and 10(-7)M, nearly doubled the number of cells in the S phase (17.8+/-3.0% and 18.4+/-3.1%, respectively) compared with untreated fibroblasts (10.3+/-1.4%). There was no significant effect in normal control fibroblasts. Dexamethasone induced hyperphosphorylation of the tumour suppressor, retinoblastoma (RB) in asthmatic fibroblasts; fibroblasts from normal controls had significantly less hyperphosphorylation of RB. No difference in protein expression of the CCAAT/enhancer binding protein alpha between the two groups was detected. This study suggests that dexamethasone can stimulate G1-S phase cell cycle transition in human airway fibroblasts obtained from asthmatics. Whether this leads to enhanced airway remodelling in some individuals remains to be determined.
Clinical significance and outcome of polymicrobial Staphylococcus aureus bacteremia
Authors: Seong Yeon Park, Ki-Ho Park, Kyung Mi Bang, Yong Pil Chong, Sung-Han Kim, Sang-Oh Lee, Sang-Ho Choi, Jin-Young Jeong, Jun Hee Woo, Yang Soo Kim
Journal: Journal of Infection (2012)
Benefits of combining inspiratory muscle with ‘whole muscle’ training in children with cystic fibrosis: a randomised controlled trial
Authors: Elena Santana-Sosa, Laura Gonzalez-Saiz, Iris F Groeneveld, José R Villa-Asensi, María I Barrio Gómez de Aguero, Steven J Fleck, Luis M López-Mojares, Margarita Pérez, Alejandro Lucia
Journal: British Journal of Sports Medicine (2013)

Background The purpose of this study (randomised controlled trial) was to assess the effects of an 8-week combined ‘whole muscle’ (resistance+aerobic) and inspiratory muscle training (IMT) on lung volume, inspiratory muscle strength (PI max ) and cardiorespiratory fitness (VO 2 peak) (primary outcomes), and dynamic muscle strength, body composition and quality of life in paediatric outpatients with CF (cystic fibrosis, secondary outcomes). We also determined the effects of a detraining period. Methods Participants were randomly allocated with a block on gender to a control (standard therapy) or intervention group (initial n=10 (6 boys) in each group; age 10±1 and 11±1 years). The latter group performed a combined programme (IMT (2 sessions/day) and aerobic+strength exercises (3 days/week, in-hospital)) that was followed by a 4-week detraining period. All participants were evaluated at baseline, post-training and detraining. Results Adherence to the training programme averaged 97.5%±1.7%. There was a significant interaction (group×time) effect for PI max , VO 2peak and five-repetition maximum strength (leg-press, bench-press, seated-row) (all (p&lt;0.001), and also for %fat (p&lt;0.023) and %fat-free mass (p=0.001), with training exerting a significant beneficial effect only in the intervention group, which was maintained after detraining for PI max and leg-press. Conclusion The relatively short-term (8-week) training programme used here induced significant benefits in important health phenotypes of paediatric patients with CF. IMT is an easily applicable intervention that could be included, together with supervised exercise training in the standard care of these patients.