Browsing by Author "Wu, Tong"

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    Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome
    (BioOne, 2022) Patterson, Andrea M.; Vemula, Sasidhar; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Wu, Tong; Sellamuthu, Rajendran; Feng, Hailin; Katz, Barry P.; DesRosiers, Colleen M.; Pelus, Louis M.; Cox, George N.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of Medicine
    The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly.
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    Design for Additive Manufacturing of Conformal Cooling Channels Using Thermal-Fluid Topology Optimization and Application in Injection Molds
    (ASME, 2018-08) Wu, Tong; Tovar, Andres; Mechanical Engineering, School of Engineering and Technology
    Additive manufacturing allows the fabrication parts and tools of high complexity. This capability challenges traditional guidelines in the design of conformal cooling systems in heat exchangers, injection molds, and other parts and tools. Innovative design methods, such as network-based approaches, lattice structures, and structural topology optimization have been used to generate complex and highly efficient cooling systems; however, methods that incorporate coupled thermal and fluid analysis remain scarce. This paper introduces a coupled thermal-fluid topology optimization algorithm for the design of conformal cooling channels. With this method, the channel position problem is replaced to a material distribution problem. The material distribution directly depends on the effect of flow resistance, heat conduction, as well as forced and natural convection. The problem is formulated based on a coupling of Navier-Stokes equations and convection-diffusion equation. The problem is solved by gradient-based optimization after analytical sensitivity derived using the adjoint method. The algorithm leads a two -dimensional conceptual design having optimal heat transfer and balanced flow. The conceptual design is converted to three-dimensional channels and mapped to a morphological surface conformal to the injected part. The method is applied to design an optimal conformal cooling for a real three dimensional injection mold. The feasibility of the final designs is verified through simulations. The final designs can be exported as both three-dimensional graphic and surface mesh CAD format, bringing the manufacture department the convenience to run the tool path for final fitting.
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    Design for Crashworthiness of Categorical Multimaterial Structures Using Cluster Analysis and Bayesian Optimization
    (ASME, 2019-12) Liu, Kai; Wu, Tong; Detwiler, Duane; Panchal, Jitesh; Tovar, Andres; Mechanical and Energy Engineering, School of Engineering and Technology
    This work introduces a cluster-based structural optimization (CBSO) method for the design of categorical multimaterial structures subjected to crushing, dynamic loading. The proposed method consists of three steps: conceptual design generation, design clustering, and Bayesian optimization. In the first step, a conceptual design is generated using the hybrid cellular automaton (HCA) algorithm. In the second step, threshold-based cluster analysis yields a lower-dimensional design. Here, a cluster validity index for structural optimization is introduced in order to qualitatively evaluate the clustered design. In the third step, the optimal design is obtained through Bayesian optimization, minimizing a constrained expected improvement function. This function allows to impose soft constraints by properly redefining the expected improvement based on the maximum constraint violation. The Bayesian optimization algorithm implemented in this work has the ability to search over (i) a real design space for sizing optimization, (ii) a categorical design space for material selection, or (iii) a mixed design space for concurrent sizing optimization and material selection. With the proposed method, materials are optimally selected based on multiple attributes and multiple objectives without the need for material ranking. The effectiveness of this approach is demonstrated with the design for crashworthiness of multimaterial plates and thin-walled structures.
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    Design Optimization of Injection Molds with Conformal Cooling for Additive Manufacturing
    (Office of the Vice Chancellor for Research, 2015-04-17) Wu, Tong; Jahan, Suchana A.; Kumaar, Praveen; Tovar, Andres; El-Mounayri, Hazim; Zhang, Yi; Zhang, Jing; Acheson, Doug; Nalim, M. Razi
    Abstract This is a framework for optimizing additive manufacturing of plastic injection molds. The proposed system consists of three modules, namely process and material modeling, multi-scale topology optimization, and experimental testing, calibration and validation. Advanced numerical simulation is implemented for a typical die with conformal cooling channels to predict cycle time, part quality and tooling life. A thermo-mechanical topology optimization algorithm is being developed to minimize the die weight and enhance its thermal performance. The technique is implemented for simple shapes for validation before it is applied to dies with conformal cooling in future work. A method for designing a die with porous material which can be produced in additive manufacturing is developed. Also a comprehensive set of systemic design rules are developed and to be integrated with CAD modeling to automate the process of obtaining viable plastic injection dies with conformal cooling channels. Finally, material modeling using simulation as well as design of experiments is underway for obtaining the material properties and their variations.
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    Design Optimization of Plastic Injection Tooling for Additive Manufacturing
    (Elsevier, 2017) Wu, Tong; Jahan, Suchana A.; Zhang, Yi; Zhang, Jing; El-Mounayri, Hazim; Tovar, Andres; Mechanical Engineering, School of Engineering and Technology
    This work presents a systematic and practical finite element based design optimization approach for the injection tooling adaptive to additive manufacturing (AM) technology using stereo-lithography (SLA) and powder bed fusion (PBF). First a thermomechanical optimization of conformal cooling is implemented to obtain the optimal parameters associated with conformal cooling design. Then, a multiscale thermomechanical topology optimization is implemented to obtain a lightweight lattice injection tooling without compromising the thermal and mechanical performance. The design approach is implemented to optimize a real design mold and the final optimal design is prototyped in SLA and the manufacturability in PBF has been discussed.
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    Development and Validation of a Nomogram for Forecasting Survival of Alcohol Related Hepatocellular Carcinoma Patients
    (Frontiers Media, 2022-11-11) Yan, Tao; Huang, Chenyang; Lei, Jin; Guo, Qian; Su, Guodong; Wu, Tong; Jin, Xueyuan; Peng, Caiyun; Cheng, Jiamin; Zhang, Linzhi; Liu, Zherui; Kin, Terence; Ying, Fan; Liangpunsakul, Suthat; Li, Yinyin; Lu, Yinying; Medicine, School of Medicine
    Background: With the increasing incidence and prevalence of alcoholic liver disease, alcohol-related hepatocellular carcinoma has become a serious public health problem worthy of attention in China. However, there is currently no prognostic prediction model for alcohol-related hepatocellular carcinoma. Methods: The retrospective analysis research of alcohol related hepatocellular carcinoma patients was conducted from January 2010 to December 2014. Independent prognostic factors of alcohol related hepatocellular carcinoma were identified by Lasso regression and multivariate COX proportional model analysis, and the nomogram model was constructed. The reliability and accuracy of the model were assessed using the concordance index(C-Index), receiver operating characteristic (ROC) curve and calibration curve. Evaluate the clinical benefit and application value of the model through clinical decision curve analysis (DCA). The prognosis was assessed by the Kaplan-Meier (KM) survival curve. Results: In sum, 383 patients were included in our study. Patients were stochastically assigned to training cohort (n=271) and validation cohort (n=112) according to 7:3 ratio. The predictors included in the nomogram were splenectomy, platelet count (PLT), creatinine (CRE), Prealbumin (PA), mean erythrocyte hemoglobin concentration (MCHC), red blood cell distribution width (RDW) and TNM. Our nomogram demonstrated excellent discriminatory power (C-index) and good calibration at 1-year, 3-year and 5- year overall survival (OS). Compared to TNM and Child-Pugh model, the nomogram had better discriminative ability and higher accuracy. DCA showed high clinical benefit and application value of the model. Conclusion: The nomogram model we established can precisely forcasting the prognosis of alcohol related hepatocellular carcinoma patients, which would be helpful for the early warning of alcohol related hepatocellular carcinoma and predict prognosis in patients with alcoholic hepatocellular carcinoma.
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    The ETS family transcription factors Etv5 and PU.1 function in parallel to promote Th9 cell development
    (American Association of Immunologists, 2016-09-15) Koh, Byunghee; Hufford, Matthew M; Pham, Duy; Olson, Matthew R.; Wu, Tong; Jabeen, Rukhsana; Sun, Xin; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    The IL-9-secreting Th9 subset of CD4 T helper cells develop in response to an environment containing IL-4 and TGFβ, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report we demonstrate that the ETS transcription factor ETV5 promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct affects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.
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    The Exploration of an Effective Medical Countermeasure Enhancing Survival and Hematopoietic Recovery and Preventing Immune Insufficiency in Lethally-Irradiated Mice
    (2020-08) Wu, Tong; Orschell, Christie M.; Basile, David P.; Unthank, Joseph L.; Haneline, Laura S.; Pelus, Louis M.; MacVittie, Thomas J.
    There is an urgent demand for effective medical countermeasures (MCM) in the event of high-dose radiation exposure ranging from nuclear plant disasters to potential nuclear warfare. Victims of lethal-dose radiation exposure face multi-organ injuries including the hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE) years after irradiation. Defective lymphocyte reconstitution and its subsequent immune insufficiency are some of the most serious consequences of H-ARS and DEARE. In order to investigate potential MCMs to protect or mitigate these radiation injuries, the prolonged tissue-specific immunosuppression at all levels of lymphocyte development in established murine H-ARS and DEARE models was defined, along with unique sex-related and age-related changes present in some tissues but not others. The “double hits” of irradiation and age-related stress on lymphopoiesis led to significant myeloid skew and long-term immune involution. Different kinds and different combinations of hematopoietic growth factors, some in combination with angiotensin converting enzyme inhibitor, were administered to lethally irradiated mice. These radiomitigators were found to significantly increase survival and enhance hematopoiesis in H-ARS, but they did little to alleviate the severity of DEARE including immune insufficiency. 16,16 dimethyl-prostaglandin E2 (dmPGE2), a long-acting formulation of PGE2 with similar biological effects as PGE2, was found to enhance survival and hematopoiesis in lethal-irradiated mice when used as radiomitigator or radioprotectant. The optimum time window for administration of radioprotectant and radiomitigator dmPGE2 was defined, which is -3hr to -15min prior to irradiation and +6hr to +30hr post irradiation. Significant survival efficacy of radioprotectant dmPGE2 was also demonstrated in pediatric and geriatric mice. Using specific PGE2 receptor (EP) agonists, the EP4 receptor was defined as the PGE2 receptor potentially responsible for dmPGE2 radioprotection. Radioprotectant dmPGE2 was also found to prevent radiation-induced thymic involution and to ameliorate the long-term immune suppression in radiation survivors in the DEARE phase via promoting hematopoietic stem cell differentiation towards to the lymphoid lineage. This is the first report of an effective MCM for H-ARS which also targets long-term thymic involution and lymphoid lineage reconstitution.
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    A Framework for Optimizing the Design of Injection Molds with Conformal Cooling for Additive Manufacturing
    (2015-01-01) Wu, Tong; Jahan, Suchana A.; Kumaar, Praveen; Tovar, Andres; El-Mounayri, Hazim; Zhang, Yi; Zhang, Jing; Acheson, Doug; Brand, Kim; Nalim, M. Razi
    This work presents a framework for optimizing additive manufacturing of plastic injection molds. The proposed system consists of three modules, namely process and material modeling, multi-scale topology optimization, and experimental testing, calibration and validation. Advanced numerical simulation is implemented for a typical die with conformal cooling channels to predict cycle time, part quality and tooling life. A multi-scale thermo-mechanical topology optimization algorithm is being developed to minimize the die weight and enhance its thermal performance. The technique is implemented for simple shapes for validation before it is applied to dies with conformal cooling in future work. Finally, material modeling using simulation as well as design of experiments is underway for obtaining the material properties and their variations.
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    Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome
    (BioOne, 2023) Wu, Tong; Pelus, Louis M.; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Feng, Hailin; Liu, Liqiong; Li, Hongge; Ortiz, Miguel; Chittajallu, Supriya; Luo, Qianyi; Bhatwadekar, Ashay D.; Meyer, Timothy B.; Zhang, Xin; Zhou, Daohong; Fischer, Kathryn D.; McKinzie, David L.; Miller, Steven J.; Orschell, Christie M.; Medicine, School of Medicine
    Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.