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Effects of Histotripsy on local Tumor Progression in an in vivo Orthotopic Rodent liver Tumor Model

Biomedical Engineering Frontiers 2020年第1期1卷 50-63页

作者： Tejaswi Worlikar Mishal Mendiratta-lala Eli Vlaisavljevich Ryan Hubbard Jiaqi Shi timothy l.hall Clifford S.Cho Fred T.lee Joan Greve Zhen Xu Department of Biomedical Engineering University of MichiganAnn ArborMichigan 48109USA Division of Abdominal Radiology University of MichiganAnn ArborMichigan 48109USA Department of Biomedical Engineering and Mechanics Virginia Polytechnic Institute and State UniversityBlacksburgVirginia 24061USA Department of Pathology University of MichiganAnn ArborMichigan 48109USA Department of Surgery University of MichiganAnn ArborMichigan 48109USA Department of Surgery VA Ann Arbor Healthcare SystemAnn ArborMichigan 48105USA Department of Radiology University of WisconsinMadisonWisconsin 53705USA

Objective and Impact *** is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an in vivo orthotopic,immunocompetent rat hepatocellular carcinoma(HCC)*** is the first noninvasive,nonionizing,nonthermal,mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter ***,histotripsy has demonstrated in vivo ablation of noncancerous liver ***.N1-S1 HCC tumors were generated in the livers of immunocompetent rats(n=6,control;n=15,treatment).Real-time ultrasound-guided histotripsy was applied to ablate either 100%tumor volume+up to 2 mm margin(n=9,complete treatment)or 50-75%tumor volume(n=6,partial treatment)by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF(pulse repetition frequency)with p−≥30 MPa using a custom 1 MHz *** were monitored weekly using MRI(magnetic resonance imaging)for 3 months or until tumors reached~25 *** revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15(93.3%)treated *** showedl,fibrous tissue at the treatment site at 3 *** with increased tumor burden(3/6 control and 1 partial treatment)were euthanized early by 2-4 *** 3 other controls,histology revealed fibrous tissue at original tumor site at 3 *** was no evidence of histotripsy-induced off-target tissue *** and partial histotripsy ablation resulted in effective tumor removal for 14/15 rats,with no evidence of local tumor progression or recurrence.

关键词： repetition debris cavitation

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Tale of mitochondria and mitochondria-associated ER membrane in patient-derived neuronal models of Wolfram syndrome

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Neural Regeneration Research 2025年第9期20卷 2587-2588页

作者： laetitia Aubry timothy Barrett Sovan Sarkar I-STEM CECSCorbeil-EssonnesFrance UniversitéParis-Saclay Universitéd’EvryINSERMI-STEMUMR861Corbeil-EssonnesFrance Institute of Cancer and Genomic Sciences Institute of Biomedical ResearchCollege of Medical and Dental SciencesUniversity of BirminghamEdgbastonBirminghamUK Department of Endocrinology Birmingham Women’s and Children’s HospitalSteelhouse LaneBirminghamUK

Mitochondria and mitochondria-associated endoplasmic reticulum membrane in neurodegenerative diseases:Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells,and thus are often referred to as the"powerhouse"of the ***,this organelle is also involved in a pleth,ora of different cellular functions such as calcium(Ca^(2+))homeostasis,apoptosis,oxidative stress,and several metabolic pathways including oxidative phosphorylation,tricarboxylic acid cycle,andβ-oxidation of fatty acids.

关键词： oxidative cycle carboxylic

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Colorectal cancer and dysplasia in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第17期14卷 2662-2669页

作者： timothy l Zisman David T Rubin Clinical Research Fellow in Gastro-enterology the University of Chicago Medical Center The University of Chicago Medical Center

Both ulcerative colitis and Crohn’s disease carry an increased risk of developing colorectal cancer. Established risk factors for cancer among patients with inflammatory bowel disease (IBD) include the younger age at diagnosis, greater extent and duration of disease, increased severity of inflammation, family history of colorectal cancer and coexisting primary sclerosing cholangitis. Recent evidence suggests that current medical therapies and surgical techniques for inflammatory bowel disease may be reducing the incidence of this complication. Nonetheless heightened vigilance and a careful, comprehensive approach to prevent or minimize the complications of invasive cancer are warranted in this unique cohort of patients. Current guidelines for the prevention and early detection of cancer in this high risk population are grounded in the concept of an inflammation-dysplasia- carcinoma sequence. A thorough understanding of the definition and natural history of dysplasia in IBD, as well as the challenges associated with detection and interpretation of dysplasia are fundamental to developing an effective strategy for surveillance and prevention, and understanding the limitations of the current approach to prevention. This article reviews the current consensus guidelines for screening and surveillance of cancer in IBD, as well as presenting the evidence and rationale for chemoprevention of cancer and a discussion of emerging technologies for the detection of dysplasia.

关键词： Cancer Dysplasia Inflammatory Bowel Disease Ulcerative Colitis Crohn's Disease Chemoprevention

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Interaction of obesity and inflammatory bowel disease

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World Journal of Gastroenterology 2016年第35期22卷 7868-7881页

作者： Jason W Harper timothy l Zisman Department of Gastroenterology Swedish Medical CenterWA 98195United States Inflammatory Bowel Disease Program Division of GastroenterologyUniversity of Washington Medical CenterSeattleWA98195 United States

Inflammatory bowel disease(IBD) is a chronic inflammatory condition of unknown etiology that is thought to result from a combination of genetic, immunologic and environmental factors. The incidence of IBD has been increasing in recent decades, especially in developing and developed nations, and this is hypothesized to be in part related to the change in dietary and lifestyle factors associated with modernization. The prevalence of obesity has risen in parallel with the rise in IBD, suggesting a possible shared environmental link between these two conditions. Studies have shown that obesity impacts disease development and response to therapy in patients with IBD and other autoimmune conditions. The observation that adipose tissue produces pro-inflammatory adipokines provides a potential mechanism for the observed epidemiologic links between obesity and IBD, and this has developed into an active area of investigative inquiry. Additionally, emerging evidence highlights a role for the intestinal microbiota in the development of both obesity and IBD, representing another potential mechanistic connection between the two conditions. In this review we discuss the epidemiology of obesity and IBD, possible pathophysiologic links, and the clinical impact of obesity on IBD disease course and implications for management.

关键词： Inflammatory bowel disease Crohn’s disease Ulcerative colitis Obesity Body mass index

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Impact of frailty on approach to colonic resection: laparoscopy vs open surgery

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World Journal of Gastroenterology 2016年第43期22卷 9544-9553页

作者： Catalina Mosquera Konstantinos Spaniolas timothy l Fitzgerald Department of General Surgery Division of Surgical Oncology East Carolina University Brody School of Medicine Division of Bariatric and Minimally Invasive Surgery East Carolina University Brody School of Medicine

AIM To understand the influence of frailty on postoperative outcomes for laparoscopic and open colectomy. METHODS Data were obtained from the National Surgical Quality Improvement Program(2005-2012) for patients undergoing colon resection [open colectomy(OC) and laparoscopic colectomy(lC)]. Patients were classified as non-frail(0 points), low frailty(1 point), moderate frailty(2 points), and severe frailty(≥ 3) using the Modified Frailty Index. 30-d mortality and complications were used as the primary end point and analyzed for the overall population. Complications were grouped into major and minor. Subset analysis was performed for patients undergoing colectomy(total colectomy, partial colectomy and sigmoid colectomy) and separately for patients undergoing rectal surgery(abdominoperineal resection, low anterior resection, and proctocolectomy). We analyzed the data using SAS Platform JMP Pro version 10.0.0(SAS Institute Inc., Cary, NC, United States). RESUlTS A total of 94811 patients were identified; the majority underwent OC(58.7%), were white(76.9%), andnon-frail(44.8%). The median age was 61.3 years. Prolonged length of stay(lOS) occurred in 4.7%, and 30-d mortality was 2.28%. Patients undergoing OC were older(61.89 ± 15.31 vs 60.55 ± 14.93) and had a higher ASA score(48.3% ASA3 vs 57.7% ASA2 in the lC group)(P l(42.5% OC vs 48% lC, P lications, prolonged lOS, and mortality were significantly more common in patients undergoing OC(P lications compared to lC for all frailty scores(non-frail: OR = 4.7, and OR = 4.67; mildly frail: OR = 2.51, and OR = 2.47; moderately frail: OR = 2.94, and OR = 2.02, severely frail: OR = 2.37, and OR = 2.34, P lute mortality with increasing frailty(non-frail 0.68% OC, mildly frail 1.39%, moderately frail 3.44%, and severely frail 5.83%, P lUSION lC is associated with improved outcomes. A

关键词： Frailty Outcome Mortality Morbidity Colectomy

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IFNγsignaling integrity in colorectal cancer immunity and immunotherapy

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Cellular & Molecular Immunology 2022年第1期19卷 23-32页

作者： Wan Du timothy l.Frankel Michael Green Weiping Zou Department of Surgery University of Michigan School of MedicineAnn ArborMIUSA Center of Excellence for Cancer Immunology and Immunotherapy Rogel Cancer CenterUniversity of Michigan School of MedicineAnn ArborMIUSA Department of Radiation Oncology University of Michigan School of MedicineAnn ArborMIUSA Veterans Affairs Ann Arbor Healthcare System University of Michigan School of MedicineAnn ArborMIUSA Graduate Programs in Immunology University of Michigan School of MedicineAnn ArborMIUSA Tumor Biology University of Michigan School of MedicineAnn ArborMIUSA Department of Pathology University of Michigan School of MedicineAnn ArborMIUSA

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor *** this review,we summarize recent advances in the epigenetic,genetic,and functional integrity of the IFNγsignaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ***,we discuss how to target IFNγsignaling to inform novel clinical trials to treat patients with colorectal cancer.

关键词： IFNGR Interferon MHC Palmitoylation T cell EZH2 ARID1A PD-1 PD-l1 Apoptosis Ferroptosis Colorectal cancer Immunity

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Coordination chemistry of surface-associated ligands for solid-liquid adsorption of rare-earth elements

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Journal of Rare Earths 2023年第1期41卷 1-18页

作者： Jessica l.Hovey timothy M.Dittrich Matthew J.Allen Department of Chemistry Wayne State University5101 Cass AvenueDetroitMI48202USA Department of Civil and Environmental Engineering 5050 Anthony Wayne DriveWayne State UniversityDetroitMIl48202USA

General guidelines for the design of ligands for the enrichment of rare-earth elements by solid-liquid adsorption are described using coordination *** properties of ligands include selectivity of metal ions based on adjustment of donor atom polarizability,denticity,and the pKarange of the binding *** selectivity of solid-phase materials for the enrichment of rare-earth ions by the ligand design guidelines is outlined,with special consideration of additional variable factors including steric hindrance,saturated binding sites,variability in speciation caused by the identity of counterions and ionic strength,and size-exclusivity in ligands stemming from differences in bite angle,preo rganization of ligands,or intraligand *** review analyzes some principles of selectivity of rare-earth elements with ligands organized by donor type from examples collected from reports published between 2009 and 2021.

关键词： Chelating ligand Coordination chemistry Solid-phase material Rare-earth element Separation Solid-liquid extraction

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Comparison of visual acuity outcomes between ranibizumab and bevacizumab treatment in neovascular age-related macular degeneration

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International Journal of Ophthalmology(English edition) 2011年第1期4卷 85-88页

作者： Ian J Constable Ian l McAllister timothy Isaacs lions Eye Institute Centre for Ophthalmology and Visual ScienceUniversity of Western AustraliaPerthWestern AustraliaAustralia

AIM: To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD). METHODS: We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA. RESUlTS: There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patient from losing letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained 15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857). CONClUSION: There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.

关键词： age-related macular degeneration anti-VEGF bevacizumab ranibizumab choroidal neovascularization

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An apple rootstock overexpressing a peach CBF gene alters growth and flowering in the scion but does not impact cold hardiness or dormancy

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Horticulture Research 2016年第1期3卷 287-295页

作者： timothy S Artlip Michael E Wisniewski Rajeev Arora John l Norelli USDA-ARS Appalachian Fruit Research StationKearneysvilleWVUSA Department of Horticulture Iowa State UniversityAmesIAUSA

The C-repeat binding factor(CBF)transcription factor is involved in responses to low temperature and water deficit in many plant *** of CBF genes leads to enhanced freezing tolerance and growth inhibition in many *** overexpression of a peach CBF(PpCBF1)gene in a transgenic line of own-rooted apple(Malus×domestica)M.26 rootstock(T166)trees was previously reported to have additional effects on the onset of dormancy and time of spring *** the current study,the commercial apple cultivar‘Royal Gala’(RG)was grafted onto either non-transgenic M.26 rootstocks(RG/M.26)or transgenic M.26(T166)rootstocks(RG/T166)and field grown for 3 *** PpCBF1 transcript was detected in the phloem or cambium of RG scions grafted on T166 rootstocks indicating that no graft transmission of transgene mRNA had *** contrast to own-rooted T166 trees,no impact of PpCBF1 overexpression in T166 rootstocks was observed on the onset of dormancy,budbreak or non-acclimated leaf-cold hardiness in RG/T166 ***,however,as measured by stem caliper,current-year shoot extension and overall height,was reduced in RG/T166 trees compared with RG/M.26 *** flowering was evident in both RG/T166 and RG/M.26 trees in the second season,the number of trees in flower,the number of shoots bearing flowers,and the number of flower clusters per shoot was significantly higher in RG/M.26 trees than RG/T166 trees in both the second and third year after *** levels of RGl(DEllA)gene expression were observed in RG/T166 trees and T166 trees,which may play a role in the reduced growth observed in these tree types.A model is presented indicating how CBF overexpression in a rootstock might influence juvenility and flower abundance in a grafted scion.

关键词： impact CBF grafted

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Burnett Order Stress and Spatially-Dependent Boundary Conditions for the lattice Boltzmann Method

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Communications in Computational Physics 2020年第1期27卷 167-197页

作者： timothy Reis School of Computing and Mathematical Sciences University of GreenwichLondon SE109LSUK

Stress boundary conditions for the lattice Boltzmann equation that are consistent to Burnett order are proposed and imposed using a moment-based *** accuracy of the method with complicated spatially-dependent boundary conditions for stress and velocity is investigated using the regularized lid-driven cavity *** complete set of boundary conditions,which involve gradients evaluated at the boundaries,are implemented locally.A recently-derived collision operator with modified equilibria and velocity-dependent collision rates to reduce the defect in Galilean invariance is also *** results are in excellent agreement with existing benchmark data and exhibit second-order *** lattice Boltzmann stress field is studied and shown to depart significantly from the Newtonian viscous stress when the ratio of Mach to Reynolds numbers is not negligibly small.

关键词： lattice Boltzmann method moment based boundary conditions Burnett stress reg-ularized cavity

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