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81.
The uptake of suspended human albumin microspheres containing 6-mercaptopurine-8-14C by several tumor cell lines has been followed in cell culture. In a preliminary study, HeLa, KB, and human glioblastoma cells have all been shown to phagocytize the drug-containing spheres. We suggest that if studies now in progress confirm the ability of the ingested anticancer agent to survive lysosomal digestion of the albumin spheres, phagocytosis of such spheres may prove to be a method of delivering drug to malignant cells while preventing these agents from producing toxic effects in nonphagocytic tissues. 相似文献
82.
Keith Sumption Theodore J. D. Knight-Jones Melissa McLaws David J. Paton 《Proceedings. Biological sciences / The Royal Society》2020,287(1938)
Foot-and-mouth disease (FMD) is an extremely infectious viral infection of cloven-hoofed animals which is highly challenging to control and can give rise to national animal health crises, especially if there is a lack of pre-existing immunity due to the emergence of new strains or following incursions into disease-free regions. The 2001 FMD epidemic in the UK was on a scale that initially overwhelmed the national veterinary services and was eventually controlled by livestock lockdown and slaughter on an unprecedented scale. In 2020, the rapid emergence of COVID-19 has led to a human pandemic unparalleled in living memory. The enormous logistics of multi-agency control efforts for COVID-19 are reminiscent of the 2001 FMD epidemic in the UK, as are the use of movement restrictions, not normally a feature of human disease control. The UK experience is internationally relevant as few countries have experienced national epidemic crises for both diseases. In this review, we reflect on the experiences and lessons learnt from UK and international responses to FMD and COVID-19 with respect to their management, including the challenge of preclinical viral transmission, threat awareness, early detection, different interpretations of scientific information, lockdown, biosecurity behaviour change, shortage of testing capacity and the choices for eradication versus living with infection. A major lesson is that the similarity of issues and critical resources needed to manage large-scale outbreaks demonstrates that there is benefit to a ‘One Health’ approach to preparedness, with potential for greater cooperation in planning and the consideration of shared critical resources. 相似文献
83.
William C. Hahn Joel S. Bader Theodore P. Braun Andrea Califano Paul A. Clemons Brian J. Druker Andrew J. Ewald Haian Fu Subhashini Jagu Christopher J. Kemp William Kim Calvin J. Kuo Michael T. McManus Gordon B. Mills Xiulei Mo Nidhi Sahni Stuart L. Schreiber Jessica A. Talamas Jonathan Weissman 《Cell》2021,184(5):1142-1155
84.
Ferris M. Pfeiffer Theodore J. Choma Rebecca Kueny 《Computer methods in biomechanics and biomedical engineering》2013,16(13):1459-1467
A validated, using in vitro biomechanical testing, finite element model was used to evaluate the affects of (1) cement augmentation and (2) an intact posterior cortex in osteoporotic bone. The presence of augmentation and/or a posterior cortical cortex increased the stabilization of the pedicle screw 2–5 fold. Placement of cement influenced failure load and toggle; with distal placement having the largest increase in failure load and decrease in cephalad–caudad toggle. The presence of posterior cortex caused a decrease in the amount of toggle, a proximal shift of the center of rotation and an increase in the maximum failure force. 相似文献
85.
Erqi Liu Matthew H. Stenmark Matthew J. Schipper James M. Balter Marc L. Kessler Elaine M. Caoili Oliver E. Lee Edgar Ben-Josef Theodore S. Lawrence Mary Feng 《Translational oncology》2013,6(4):442-446
OBJECTIVES: The full potential of stereotactic body radiation therapy (SBRT), in the treatment of unresectable intrahepatic malignancies, has yet to be realized as our experience is still limited. Thus, we evaluated SBRT outcomes for primary and metastatic liver tumors, with the goal of identifying factors that may aid in optimization of therapy. METHODS: From2005 to 2010, 62 patients with 106 primary and metastatic liver tumors were treated with SBRT to a median biologic effective dose (BED) of 100 Gy (42.6-180). The majority of patients received either three (47%) or five fractions (48%). Median gross tumor volume (GTV) was 8.8 cm3 (0.2-222.4). RESULTS: With a median followup of 18 months (0.46-46.8), freedom from local progression (FFLP) was observed in 97 of 106 treated tumors, with 1- and 2-year FFLP rates of 93% and 82%. Median overall survival (OS) for all patients was 25.2 months, with 1- and 2-year OS of 81%and 52%. Neither BED nor GTV significantly predicted for FFLP. Local failure was associated with a higher risk of death [hazard ratio (HR) = 5.1, P = .0007]. One Child-Pugh Class B patient developed radiationinduced liver disease. There were no other significant toxicities. CONCLUSIONS: SBRT provides excellent local control for both primary and metastatic liver lesions with minimal toxicity. Future studies should focus on appropriate selection of patients and on careful assessment of liver function to maximize both the safety and efficacy of treatment. 相似文献
86.
Benjamin Lemasson Thomas L. Chenevert Theodore S. Lawrence Christina Tsien Pia C. Sundgren Charles R. Meyer Larry Junck Jennifer Boes Stefanie Galbán Timothy D. Johnson Alnawaz Rehemtulla Brian D. Ross Craig J. Galbán 《Translational oncology》2013,6(6):766-774
Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high-grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas. 相似文献
87.
Brett D. Welch Ping Yuan Sayantan Bose Christopher A. Kors Robert A. Lamb Theodore S. Jardetzky 《PLoS pathogens》2013,9(8)
Paramyxoviruses cause a wide variety of human and animal diseases. They infect host cells using the coordinated action of two surface glycoproteins, the receptor binding protein (HN, H, or G) and the fusion protein (F). HN binds sialic acid on host cells (hemagglutinin activity) and hydrolyzes these receptors during viral egress (neuraminidase activity, NA). Additionally, receptor binding is thought to induce a conformational change in HN that subsequently triggers major refolding in homotypic F, resulting in fusion of virus and target cell membranes. HN is an oligomeric type II transmembrane protein with a short cytoplasmic domain and a large ectodomain comprising a long helical stalk and large globular head domain containing the enzymatic functions (NA domain). Extensive biochemical characterization has revealed that HN-stalk residues determine F specificity and activation. However, the F/HN interaction and the mechanisms whereby receptor binding regulates F activation are poorly defined. Recently, a structure of Newcastle disease virus (NDV) HN ectodomain revealed the heads (NA domains) in a “4-heads-down” conformation whereby two of the heads form a symmetrical interaction with two sides of the stalk. The interface includes stalk residues implicated in triggering F, and the heads sterically shield these residues from interaction with F (at least on two sides). Here we report the x-ray crystal structure of parainfluenza virus 5 (PIV5) HN ectodomain in a “2-heads-up/2-heads-down” conformation where two heads (covalent dimers) are in the “down position,” forming a similar interface as observed in the NDV HN ectodomain structure, and two heads are in an “up position.” The structure supports a model in which the heads of HN transition from down to up upon receptor binding thereby releasing steric constraints and facilitating the interaction between critical HN-stalk residues and F. 相似文献
88.
Background
Agent-based models are valuable for examining systems where large numbers of discrete individuals interact with each other, or with some environment. Diabetic Veterans seeking eye care at a Veterans Administration hospital represent one such cohort.Objective
The objective of this study was to develop an agent-based template to be used as a model for a patient with diabetic retinopathy (DR). This template may be replicated arbitrarily many times in order to generate a large cohort which is representative of a real-world population, upon which in-silico experimentation may be conducted.Methods
Agent-based template development was performed in java-based computer simulation suite AnyLogic Professional 6.6. The model was informed by medical data abstracted from 535 patient records representing a retrospective cohort of current patients of the VA St. Louis Healthcare System Eye clinic. Logistic regression was performed to determine the predictors associated with advancing stages of DR. Predicted probabilities obtained from logistic regression were used to generate the stage of DR in the simulated cohort.Results
The simulated cohort of DR patients exhibited no significant deviation from the test population of real-world patients in proportion of stage of DR, duration of diabetes mellitus (DM), or the other abstracted predictors. Simulated patients after 10 years were significantly more likely to exhibit proliferative DR (P<0.001).Conclusions
Agent-based modeling is an emerging platform, capable of simulating large cohorts of individuals based on manageable data abstraction efforts. The modeling method described may be useful in simulating many different conditions where course of disease is described in categorical stages. 相似文献89.
Dipankar Ray Shirish Shukla Uday Sankar Allam Abigail Helman Susmita Gurjar Ramanand Linda Tran Michael Bassetti Pranathi Meda Krishnamurthy Matthew Rumschlag Michelle Paulsen Lei Sun Thomas P. Shanley Mats Ljungman Mukesh K. Nyati Ming Zhang Theodore S. Lawrence 《PloS one》2013,8(2)
The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (−/−) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTPSer178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT. 相似文献
90.
Prion diseases are fatal neurodegenerative disorders characterized by misfolding of the cellular prion protein (PrPc) into the disease-associated isoform (PrPSc) that has increased β-sheet content and partial resistance to proteolytic digestion. Prion diseases from different mammalian species have varying propensities for transmission upon exposure of an uninfected host to the infectious agent. Chronic Wasting Disease (CWD) is a highly transmissible prion disease that affects free ranging and farmed populations of cervids including deer, elk and moose, as well as other mammals in experimental settings. The molecular mechanisms allowing CWD to maintain comparatively high transmission rates have not been determined. Previous work has identified a unique structural feature in cervid PrP, a rigid loop between β-sheet 2 and α-helix 2 on the surface of the protein. This study was designed to test the hypothesis that the rigid loop has a direct influence on the misfolding process. The rigid loop was introduced into murine PrP as the result of two amino acid substitutions: S170N and N174T. Wild-type and rigid loop murine PrP were expressed in E. coli and purified. Misfolding propensity was compared for the two proteins using biochemical techniques and cell free misfolding and conversion systems. Murine PrP with a rigid loop misfolded in cell free systems with greater propensity than wild type murine PrP. In a lipid-based conversion assay, rigid loop PrP converted to a PK resistant, aggregated isoform at lower concentrations than wild-type PrP. Using both proteins as substrates in real time quaking-induced conversion, rigid loop PrP adopted a misfolded isoform more readily than wild type PrP. Taken together, these findings may help explain the high transmission rates observed for CWD within cervids. 相似文献