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Microbiome-liver crosstalk:A multihit therapeutic target for liver disease

World Journal of Gastroenterology 2023年第11期29卷 1651-1668页

作者： Jorum Kirundi Sheida Moghadamrad Camilla Urbaniak Department of Biomedical Research University of BernBern 3014Switzerland Department of Gastroenterology/Hepatology Laboratories for Translational ResearchEnte Ospedaliero CantonaleBellinzona and Faculty of Biomedical SciencesUniversitàdella Svizzera italianaLugano 6900Switzerland Biotechnology and Planetary Protection group NASA Jet Propulsion LaboratoryPasadenaCA 91011United States ZIN technologies Middleburg HeightsOH 44130United States

Liver disease has become a leading cause of death,particularly in the West,where it is attributed to more than two million deaths *** correlation between gut microbiota and liver disease is still not fully ***,it is well known that gut dysbiosis accompanied by a leaky gut causes an increase in lipopolysaccharides in circulation,which in turn evoke massive hepatic inflammation promoting liver *** dysbiosis also leads to poor bile acid metabolism and low short-chain fatty acids,all of which exacerbate the inflammatory response of liver *** microbial homeostasis is maintained through intricate processes that ensure that commensal microbes adapt to the low oxygen potential of the gut and that they rapidly occupy all the intestinal niches,thus outcompeting any potential pathogens for available *** crosstalk between the gut microbiota and its metabolites also guarantee an intact gut *** processes that protect against destabilization of gut microbes by potential entry of pathogenic bacteria are collectively called colonization resistance and are equally essential for liver *** this review,we shall investigate how the mechanisms of colonization resistance influence the liver in health and disease and the microbial-liver crosstalk potential as therapeutic target areas.

关键词： Microbiome Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Liver disease Microbiome-host crosstalk Gut homeostasis Microbial metabolites

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Use of zebrafish embryos as avatar of patients with pancreatic cancer:A new xenotransplantation model towards personalized medicine

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World Journal of Gastroenterology 2020年第21期26卷 2792-2809页

作者： Gregorio Di Franco Alice Usai Niccola Funel Matteo Palmeri Ida Elena Rosamaria Montesanti Matteo Bianchini Desirée Gianardi NiccolòFurbetta Simone Guadagni Enrico Vasile Alfredo Falcone Luca Emanuele Pollina Vittoria Raffa Luca Morelli General Surgery Unit Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisa 56124Italy Department of Biology University of PisaPisa 56127Italy Division of Surgical Pathology Department of Laboratory of MedicineHospital-University of PisaPisa 56124Italy Division of Medical Oncology Pisa University HospitalPisa 56124Italy Department of translational Research and New technologies in Medicine and Surgery University of PisaPisa 56124Italy EndoCAS(Center for Computer Assisted Surgery) University of PisaPisa 56124Italy

BACKGROUND The response to chemotherapy treatment of patients with pancreatic ductal adenocarcinoma(PDAC)is difficult to predict and the identification of patients who most likely will benefit from aggressive chemotherapy approaches is *** concept of personalized medicine has emerged in the last years with the objective to tailor the medical treatment to the individual characteristics of each patient,and particularly to the tumor biology of each *** need for invivo xenotransplantation models for cancer patients has increased exponentially,and for this reason zebrafish avatars have gained *** studies were conducted also with PDAC *** To develop a simple,not expensive,diffusible zebrafish embryo model as avatar for patients affected by *** Tumor tissue was taken from the surgical specimen by the *** its fragmentation into small pieces,they are stained with *** pieces of stained tissue were transplanted into the yolk of wt AB zebrafish embryos with a glass capillary *** were incubated at 35°C in E3 medium supplemented with 1%Pen/Strep in the presence or absence of drugs for the following days in respect of the treatment plan(Gemcitabine;Gemcitabine and Oxaliplatin;Gemcitabine and nab-Paclitaxel;5-Fluorouracil and Folinic acid and Oxaliplatin and Irinotecan).The response of zebrafish xenografts to the chemotherapy options has been analyzed by monitoring the fluorescent stained area at 2 h post injection(hpi),1 d and 2 d post injection(dpi).In each time point,the mean size of the stained area was measured by ImageJ and it was normalized with respect to the 1 dpi time point mean relative tumor area(RTA).We evaluated the effect of the chemotherapy exposition comparing the mean RTA of each treated subgroup and the control group and evaluating the percentage reduction of the mean RTA by comparing each treated subgroup with the control *** Between July 2018 and October 2019,a t

关键词： Pancreatic ductal adenocarcinoma Zebrafish embryos Personalized medicine Xenotransplantation Chemotherapy efficacy Avatar of oncological patients

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Simulating traumatic brain injury in vitro:developing high throughput models to test biomaterial based therapies

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Neural Regeneration Research 2023年第2期18卷 289-292页

作者： Raja Haseeb Basit Jessica Wiseman Farhana Chowdhury Divya Maitreyi Chari Bradford Royal infirmary BradfordWest YorkshireUK Sheffield Institute for translational Neuroscience University of SheffieldSheffieldUK Labcorp Drug Development HarrogateUK Neural Tissue Engineering Keele group School of MedicineKeele UniversityStaffordshireUK

Traumatic brain injuries are serious clinical incidents associated with some of the poorest outcomes in neurological *** with the limited regenerative capacity of the brain,this has significant implications for patients,carers,and healthcare systems,and the requirement for life-long care in some *** treatment currently focuses on limiting the initial neural damage with longterm care/support from multidisciplinary *** targeting neuroprotection and neural regeneration are not currently available but are the focus of intensive ***-based interventions are gaining popularity for a range of applications including biomolecule and drug delive ry,and to function as cellular *** investigations into the development of such novel therapeutics for traumatic brain injury will be critically underpinned by the availability of appropriate high thro ughput,facile,ethically viable,and pathomimetic biological model *** represents a significant challenge for researchers given the pathological complexity of traumatic brain ***,there is a concerted post-injury response mounted by multiple neural cell types which includes microglial activation and astroglial scarring with the expression of a range of growth inhibito ry molecules and cytokines in the lesion ***,we review common models used for the study of traumatic brain injury(ranging from live animal models to in vitro systems),focusing on penetrating traumatic brain injury *** discuss their relative advantages and drawbacks for the developmental testing of biomaterial-based therapies.

关键词： astroglial scar biomaterial cortical culture in vitro model microglial infiltration multicellular model penetrating injury scaffold traumatic brain injury

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Unusual switchable peroxidase-mimicking nanozyme for the determination of proteolytic biomarker

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Nano Research 2019年第3期12卷 509-516页

作者： Claire McVey Natasha Logan Nguyen T. K. Thanh Christopher Elliott Cuong Cao Institute for Global Food Security School of Biological Sciences Queens University Belfast 18-30 Malone Road Belfast BT9 5BN UK Biophysics group Department of Physics and Astronomy University College London London WC1E 6BT UK UCL healthcare Biomagnetic and Nanomaterials Laboratories 21 Albemarle Street London W1S 4BS UK Material and Advanced technologies for healthcare Queens University Belfast 18-30 Malone Road Belfast BT9 5BN UK

Detection of enzyme biomarkers originating from either bio-fluids or contaminating microorganisms is of utmost importance in clinical diagnostics and food safety. Herein, we present a simple, low-cost and easy-to-use sensing approach based on the switchable peroxidase-mimicking activity of plasmonic gold nanoparticles (AuNPs) that can catalyse for the oxidation of 3,3’,5’5-tetramethylbenzidine (TMB) for the determination of protease enzyme. The AuNP surface is modified with casein, showing dual functionalities. The first function of the coating molecule is to suppress the intrinsic peroxidase-mimicking activity of AuNPs by up to 77.1%, due to surface shielding effects. Secondly, casein also functions as recognition sites for the enzyme biomarker. In the presence of protease, the enzyme binds to and catalyses the degradation of the coating layer on the AuNP surface, resulting in the recovery of peroxidase-mimicking activity. This is shown visually in the development of a blue colored product (oxidised TMB) or spectroscopically as an increase in absorbance at 370 and 650 nm. This mechanism allows for the detection of protease at 44 ng·mL^-1 in 90 min. The nanosensor circumvents issues associated with current methods of detection in terms of ease of use, compatibility with point-of-care testing, low-cost production and short analysis time. The sensing approach has also been applied for the detection of protease spiked in ultra-heat treated (UHT) milk and synthetic human urine samples at a limit of detection of 490 and 176 ng·mL^-1, respectively, showing great potential in clinical diagnostics, food safety and quality control.

关键词： gold nano particles peroxidase-mimicking nanozyme enzyme detection biomarkers

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Atom-economic macrocyclic amphiphile based on guanidinium-functionalized selenacrown ether acting as redox-responsive nanozyme

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Chinese Chemical Letters 2023年第4期34卷 266-270页

作者： Bo Li Qiangqiang Xu Xin Shen Tiezheng Pan Jie Shang Yan Ge Zhenhui Qi Sino-German Joint Research Lab for Space Biomaterials and translational Technology Synergetic Innovation Center of Biological Optoelectronics and Healthcare Engineering(BOHE)Shaanxi Provincial Synergistic Innovation Center for Flexible Electronics&Health Sciences(FEHS)School of Life SciencesNorthwestern Polytechnical UniversityXi’an 710072China

Control of self-assembly is significant to the preparation of supramolecular materials, but the control of hydration, responsiveness, dimension, catalysis of macrocyclic amphiphiles in an atom-economic manner is still a great challenge. The herein presented 527 Da low-molecular-weight macrocyclic amphiphile was fabricated by utilizing the selenium-containing crown ether as a hydrophobic motif together with guanidinium group as the hydrophilic moiety. The resulting benzo[21]crown-7 based macrocyclic amphiphile readily forms a redox-responsive solid nanoparticles in water, which can further interconnect into wrinkled pattern on-surface, as well as exhibits as a nanozyme for catalyzing disulfid bond formation. The present work highlights the great potential of guanidinium-and selenium-containing crown ethers for the control of functional assemblies.

关键词： Selenium Guanidinium Macrocycle amphiphile Crown ether Molecular assembly Winkled surface Nanozyme

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Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease

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Biomedical Engineering Frontiers 2021年第1期2卷 44-54页

作者： Alicia Megia-Fernandez Adam Marshall Ahsan R.Akram Bethany Mills Sunay V.Chankeshwara Emma Scholefield Amy Miele Bruce C.McGorum Chesney Michaels Nathan Knighton Tom Vercauteren Francois Lacombe Veronique Dentan Annya M.Bruce Joanne Mair Robert Hitchcock Nik Hirani Chris Haslett Mark Bradley Kevin Dhaliwal EaStCHEM The University of Edinburgh School of ChemistryJoseph Black BuildingWest Mains RoadEdinburghUK EH93FJ translational healthcare technologies group Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of Edinburgh47 Little France CrescentEdinburgh BioQuarterEdinburghUK EH164TJ The Roslin Institute and Royal(Dick)School of Veterinary Studies University of EdinburghEaster BushMidlothianUK EH259RG Department of Biomedical Engineering University of Utah36 S Wasatch DrSalt Lake CityUT 84112USA School of Biomedical Engineering&Imaging Sciences King’s College LondonLondonUK SE17EH Mauna Kea technologies 9Rue d’EnghienParisFrance 75010

Objective and Impact *** is a need to develop platforms delineating inflammatory biology of the distal human *** describe a platform technology approach to detect in situ enzyme activity and observe drug inhibition in the distal human lung using a combination of matrix metalloproteinase(MMP)optical reporters,fibered confocal fluorescence microscopy(FCFM),and a bespoke delivery *** development of new therapeutic agents is hindered by the lack of in vivo in situ experimental methodologies that can rapidly evaluate the biological activity or drug-target engagement in *** optimised a novel highly quenched optical molecular reporter of enzyme activity(FIB One)and developed a translational pathway for in-human *** demonstrate the specificity for matrix metalloproteases(MMPs)2,9,and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical ***,in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease,we demonstrate,through FCFM,the MMP activity in the alveolar space measured through FIB One fluorescence increase(with pharmacological inhibition).*** translational in situ approach enables a new methodology to demonstrate active drug target effects of the distal lung and consequently may inform therapeutic drug development pathways.

关键词： Lung lung specificity

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Tissue microarray-chip featuring computerized immunophenotypical characterization more accurately subtypes ampullary adenocarcinoma than routine histology

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World Journal of Gastroenterology 2020年第43期26卷 6822-6836页

作者： Matteo Palmeri Niccola Funel Gregorio Di Franco Niccolo Furbetta Desiree Gianardi Simone Guadagni Matteo Bianchini Luca E Pollina Claudio Ricci Marco Del Chiaro Giulio Di Candio Luca Morelli General Surgery Unit Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisa 56124Italy Division of Surgical Pathology University-Hospital of PisaPisa 56124Italy Department of Surgical MedicalMolecular Pathology and Critical AreaUniversity of PisaPisa 56124Italy Department of Surgery University of ColoradoDenverCO 80045United States

BACKGROUND Ampullary adenocarcinomas(AACs)are heterogeneous tumors currently classified into three important sub-classes(SC):Intestinal(INT),Pancreato-Biliary(PB)and Mixed-Type(MT).The different subgroups have similar clinical presentation and are treated by pancreatoduodenectomy with curative ***,they respond differently to chemotherapy and have different prognostic *** SC are often difficult to identify with conventional histology *** clinical outcome of all three remains unclear,particularly for *** To identify two main subtypes of AACs,using an immunohistochemical(IHC)score based on CDX2,CK7 and *** Tissue samples from 21 patients who had undergone resection of AAC were classified by HE histology and IHC expression of CDX2,CK7 and CK *** IHC score was obtained for each marker by counting the number of positive cells(0=no stained cells;150%)and their intensity(1=weak;2=moderate and 3=strong).A global score(GS)was then obtained by summation of the IHC scores of each *** MT tumors were grouped either with the INT or PB group based on the predominant immuno-molecular phenotype,obtaining only two AACs *** overall survival in INT and PB patients was obtained by Kaplan-Meier *** Histological parameters defined the AACs subtypes as follows:15%INT,45%PB and 40%*** IHC expression and the GS,75%and 25%of MT samples were assigned to either the INT or the PB *** mean value of the GS was 9.5(range 4-16).All INT samples had a GS above the average,distinct from the PB samples which had a GS score significantly below the average(P=0.0011).The INT samples were identified by high expression of CDX2 and CK20,whereas PB samples exhibited high expression of CK7 and no expression of CK20(P=0.0008).The INT group had a statistically significant higher overall survival than in the PB group(85.7 mo vs 20.3 mo,HR:8.39;95%CI:1.38 to 18.90;P=0.0152).CONCLUSION The combination of histopathological a

关键词： Ampullary adenocarcinoma Histo-molecular phenotype Prognostic CK7 CK20 CDX2

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Surgical decompression in acute spinal cord injury： A review of clinical evidence, animal model studies, and potential future directions of investigation

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Frontiers in Biology 2014年第2期9卷 127-136页

作者： Yiping LI Chandler L. WALKER Yi Ping ZHANG Christopher B. SHIELDS Xiao-Ming XU Spinal Cord and Brain Injury Research group Stark Neurosciences Research Institute Department of Neurological Surgery and Goodmanand Campbell Brain and Spine Indiana University School of Medicine Indianapolis IN 46202 USA Norton Neuroscience Institute Norton Healthcare Louisville KY 40202 USA

The goal for treatment in acute spinal cord injury （SCI） is to reduce the extent of secondary damage and facilitate neurologic regeneration and functional recovery. Although multiple studies have investigated potential new therapies for the treatment of acute SCI, outcomes and management protocols aimed at ameliorating neurologic injury in patients remain ineffective. More recent clinical and basic science research have shown surgical interventions to be a potentially valuable modality for treatment; however, the role and timing of surgical decompression, in addition to the optimal surgical intervention, remain one of the most controversial topics pertaining to surgical treatment of acute SCI. As an increasing number of potential treatment modalities emerge, animal models are pivotal for investigating its clinical application and translation into human trials. This review critically appraises the available literature for both clinical and basic science studies to highlight the extent of investigation that has occurred, specific therapies considered, and potential areas for future research.

关键词： acute spinal cord injury surgical decompression durotomy animal models

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Comments on National guidelines for diagnosis and treatment of breast cancer 2022 in China (English version)

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Chinese Journal of Cancer Research 2022年第5期34卷 451-452页

作者： Xinguang Wang Zhaoqing Fan Key Laboratory of Carcinogenesis and translational Research(Ministry of Education/Beijing) Breast CenterPeking University Cancer Hospital&InstituteBeijing 100142China

China is facing growing number of cancer cases and deaths,as well as growing crude incidence and mortality of *** cancer is the most common cancer type in females in China and the incidence rate for breast cancer in Chinese females has increased during the last two ***, breast cancer prognosis in China is poorer than that in developed countries. Population aging may at least partially explain the transition of cancer profiles we have seen in recent years. Breast cancer screening technologies and public healthcare strategies targeting the high-risk population are being developed to reduce the cancer burden in China.

关键词： breast diagnosis Breast

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Construction of a novel predictive model with seven metabolism-related genes for hepatocellular carcinoma by machine learning

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Genes & Diseases 2023年第5期10卷 1806-1808页

作者： Lisha Mou Lin Liu Yumiao Qiu Yingying Liang Zuhui Pu Imaging Department Shenzhen Institute of Translational MedicineHealth Science CenterThe First Affiliated Hospital of Shenzhen UniversityShenzhen Second People's HospitalShenzhenGuangdong 518035China

Single-cell RNA sequencing (scRNA-seq) and machine learning technologies, developed rapidly in recent years, offer an unparalleled opportunity to study the mechanism of tumorigenesis. Changes in metabolism-related genes (MRGs) result in hepatocellular carcinoma (HCC) progression, and MRGs have the potential to be used as a clinical prognostic indicator. In this study, a machine learning model was built using LASSO regression to find prognostic genes and create a new MRG risk signature of HCC patients. The patients were divided into the MRG high- and low-risk groups based on their risk scores. Significant overall survival advantages were observed in the MRG low-risk group. In addition, risk score and cancer status were used to establish a nomogram with high accuracy. The calibration curves and decision curves further demonstrated the satisfactory agreement between the predicted and observed values in the probability of overall survival. Subsequently, we discovered the different characteristics of the MRG high- and low-risk group patients based on tumor mutation burden, gene set enrichment, and immune infiltration. Our study identifies a novel MRG signature for risk-stratification and accurate identification of HCC patients with poor subtypes, which could precisely predict the prognosis of HCC and may guide personalized treatment for HCC patients.

关键词： metabolism hepatocellular signature

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