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CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma

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Genomics, Proteomics & Bioinformatics 2020年第1期18卷 26-40页

作者： Ziyi Li Binbin Wang Shengqing Gu Peng Jiang Avinash Sahu Chen-Hao Chen Tong Han Sailing Shi Xiaoqing Wang Nicole Traugh Hailing Liu Yin Liu Qiu Wu myles brown Tengfei Xiao Genevieve M.Boland X.Shirley Liu Clinical Translational Research Center Shanghai Pulmonary HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical SchoolBostonMA 02215USA Department of Data Sciences Dana-Farber Cancer InstituteHarvard T.H.Chan School of Public HealthBostonMA 02115USA Department of Clinical Laboratory Shanghai Pulmonary HospitalTongji University School of MedicineShanghai 200433China Center for Functional Cancer Epigenetics Dana-Farber Cancer InstituteBostonMA 02115USA Center for Cancer Research Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Department of Surgery Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA

BRAF is a serine/threonine kinase that harbors activating mutations in^7%of human malignancies and^60%of *** initial clinical responses to BRAF inhibitors,patients frequently develop drug *** identify candidate therapeutic targets for BRAF inhibitor resistant melanoma,we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF *** investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas,we integrate expression,ATAC-seq,and CRISPR screen *** identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6,which together enable resistance to BRAF inhibitors in melanoma *** findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720,providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.

关键词： Drug resistance CRISPR screen Melanoma BRAF inhibitor Gene regulation

Characterizing objective and self-report habitual physical activity and sedentary time in outpatients with an acquired brain injury

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Sports Medicine and Health Science 2024年第4期6卷 338-343页

作者： Liam P.Pellerine Katerina Miller Ryan J.Frayne myles W.O'Brien Division of Kinesiology School of Health and Human PerformanceFaculty of HealthDalhousie UniversityHalifaxNova ScotiaCanada Acquired Brain Injury NeuroCommons Nova Scotia Health AuthorityHalifaxNova ScotiaCanada School of Physiotherapy(Faculty of Health)&Department of Medicine(Faculty of Medicine) Dalhousie UniversityHalifaxNova ScotiaCanada Geriatric Medicine Research Dalhousie University&Nova Scotia HealthHalifaxNova ScotiaCanada Centre de Formation Medicale Du Nouveau-Brunswick New Brunswick&Department of MedicineUniversite de SherbrookeSherbrookeQuebecCanada

Outpatients with an acquired brain injury(ABI)experience physical,mental,and social *** can be classified into two subgroups based on mechanism of injury:mild traumatic brain injury(mTBI;e.g.,concussion)and other ABI(e.g.,stroke,brain aneurysm,encephalitis).Our understanding of habitual activity levels within ABI populations is limited because they are often collected using self-report *** purpose of this study was to,1)describe the habitual activity levels of outpatients with ABI using objective and self-report monitoring,and 2)compare the activity levels of outpatients with mTBI *** *** outpatients with other ABI(mean±standard deviation:[58±13]years,9 females)and 12 outpatients with mTBI([48±11]years,9 females)wore a thigh-worn activPAL 24 h/day(h/day)for *** with ABI averaged(6.0±2.3)h/day of upright time,(10.6±2.2)h/day of sedentary time,(5.6±2.7)h/day in prolonged sedentary bouts>1 h,(5960±3037)steps/day,and(11±13)minutes/day(min/day)of moderate-vigorous physical activity(MVPA).There were no differences between activPAL-derived upright,sedentary,prolonged sedentary time,and physical activity between the mTBI and other ABI groups(all,p>0.31).Outpatients with ABI overestimated their MVPA levels(t138 min/week)and underestimated sedentary time(-4.3 h/day)compared to self-report(all,p<0.001).Despite self-reporting high activity levels,outpatients with ABI objectively exhibit highly inactive and sedentary *** habitual movement behaviours of our sample did not differ by mechanism of injury(i.e.,mTBI versus other ABI).Targeting reductions in objectively measured sedentary time are needed to progressively improve the habitual movement behaviours of outpatients with ABI.

关键词： Accelerometry Stroke Brain aneurysm Encephalitis Mild traumatic brain injury Rehabilitation

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis

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Cellular & Molecular Immunology 2024年第1期21卷 33-46页

作者： Anja Meyer Stephanie R.Zack Wes Nijim Adel Burgos Vishwa Patel Brian Zanotti Michael V.Volin M.Asif Amin myles J.Lewis Costantino Pitzalis Shiva Arami Joseph A.Karam Nadera J.Sweiss Shiva Shahrara Jesse brown VA Medical Center ChicagoILUSA Department of Medicine Division of RheumatologyThe University of Illinois at ChicagoChicagoILUSA Department of Microbiology and Immunology Midwestern UniversityDowners GroveILUSA Division of Rheumatology and Clinical Autoimmunity Center of Excellence University of MichiganAnn ArborMIUSA Centre for Experimental Medicine and Rheumatology William Harvey Research InstituteBarts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUnited Kingdom Centre for Experimental Medicine&Rheumatology William Harvey Research InstituteQueen Mary University of London and Barts NIHR BRC&NHS TrustLondonUK Department of Biomedical Sciences Humanitas Universityand Humanitas Research HospitalMilanItaly Department of Orthopedic Surgery the University of Illinois at ChicagoChicagoILUSA

A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR ***,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR *** Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative ***,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP *** enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 *** found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA *** to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient ***,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by *** conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

关键词： Syntenin-1 Syndecan-1 RA FLS RA explants immunometabolism

Cytotoxicity, Toxicity and Anticancer Activity of Manuka Honey, Saudi’s Honey and Peganum harmala Plant against Cancer Cells

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Journal of Biosciences and Medicines 2024年第2期12卷 311-325页

作者： Naif M. Alhawiti Elber-Lewis myles Anaif M. Alhewaitey Yousef M. Almutairi Fadhah M. Alhawiti CAHFS University of California Davis Davis USA Department of Biological Science Tennessee State University Nashville Tennessee USA Department of Chemistry University of Tabuk Tabuk Saudi Arabia Ministry of Health East Jeddah General Hospital Jeddah Saudi Arabia

Cancer occurs when the body’s cells grow beyond the usual control. Normal body cells multiply in a controlled manner and undergo apoptosis when the body no longer needs them. Different types of cancers exist, and the common ones include breast, cervical, prostate, lung, colon, and skin cancers. Several factors have been associated with cancers, and these factors include poor dieting, exposure to harmful chemicals and radiation, weak immune system, and genetics. Cancer presents an enormous health threat in the modern world and thus the need to identify an effective treatment. The conventional treatments used in the management of cancer include chemotherapy and physiotherapy. These forms of cancer treatments usually have enormous side effects on the subjects. In this respect, an alternative form of treatment would be effective in managing cancer patients. A substantial number of natural products have been observed to be effective in the management of cancer. These natural products include plants and other natural substances such as honey. This study focuses on the efficiency of natural products in the treatment of cancer. Also, the anticancer effects of Peganum harmala, Manuka honey, and Saudi honey will be analyzed. Bee honey and Peganum harmala have been traditionally used in the treatment of cancer. The extracts from Peganum harmala plant have also been shown to exhibit divers’ antitumor effects similar to the mode of action of a vast number of anticancer agents. These established hypotheses thus give the rationale for this study. In this experiment, extracts were obtained from Peganum harmala leaves and exposed to cervical, lung, and prostate cancer cells. Similarly, solutions of Manuka honey and Saudi honey were exposed to the cervical, lung, and prostate cancer cells. The experiment duration was 24 hours, which obtained results were recorded and analyzed. Peganum harmala extracts inhibit cancer cell growth at different and achievable concentrations. Manuka honey

关键词： Peganum harmala Manuka Honey Saudi Honey Anticancer Apoptosis Natural Products

Antibacteria Activity of Peganum harmala and Haloxylon salicornicum Leaves Extracts

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Advances in Microbiology 2024年第2期14卷 122-136页

作者： Naif M. Alhawiti Agnes K. Nthenge Waeel H. Alramadhan William Boadi Abdulrahman F. Alqahtani Elber-Lewis myles CAHFS University of California Davis USA Department of Agricultural and Environmental Sciences College of Agriculture Tennessee State University Nashville USA Department of Biological Science Tennessee State University Nashville USA Department of Chemistry Tennessee State University Nashville USA Saudi Food and Drug Authority Riyadh Saudi Arabia

The use of antibiotics in humans and animals has been marked as a significant step in health due to their effectiveness in controlling and treating bacterial infections. The misuse and overuse of antibiotics have been identified as risk factors for bacterial resistance since microorganisms adapt and develop mechanisms to defend against antibiotics. According to the Centers for Disease Protection and Control (CDC), around 23,000 individuals die every year in the United States due to antibiotic resistance complications. As a result, a demand for alternative treatments has been a goal for scientists as the microbes adapt to selective pressure. The aim of this study is to test the antibacterial activity of leaf extracts of Peganum harmala and Haloxylon salicornicum on both Gram-positive and Gram-negative bacteria on various mediums. The results of the study showed that both P. harmala and H. salicornicum inhibited the bacterial growth in two different media. The results were also compared with different common antibiotics used in both human’s and animal’s fields and showed a promising outcome as alternative antibiotics.

关键词： Peganum harmala Haloxylon salicornicum Antibiotics Resistance Medicinal Plants Gram-Positive Gram-Negative

Blockchain-based Peer-to-Peer Energy Trading Method

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CSEE Journal of Power and Energy Systems 2022年第5期8卷 1318-1326页

作者： myles J.Thompson Hongjian Sun Jing Jiang Department of Engineering Durham UniversityDurhamUK Department of Mathematics Physics and Electrical EngineeringNorthumbria UniversityNewcastle upon TyneUK

For grid-connected neighbors within communities,blockchain-enabled peer-to-peer energy trading proves to be a coherent approach to trade energy from locally produced and distributed renewable energy *** matching among peers enables enhanced energy efficiency during energy transactions,thereby improving the power quality and preferentially increasing user *** proposed algorithm builds upon work to develop a system of scoring an energy *** employs a McAfee-priced double auction mechanism and assigns the scores based on the preference of factors like price,locality,and the type of energy generation,in addition to the quantity of energy being *** transactions are pre-evaluated by the said algorithm to determine the optimal transactional *** a result,the transaction that is finally executed is the one holding the highest cumulative *** proposed algorithm is simulated over a range of scenarios and tends to boost the user welfare percentile by an average of 75%.From an economic perspective,the algorithm may be implemented in small to large settlements while remaining *** reducing power loss,this energy trading algorithm empowers consumers to save around 25%on their energy costs and offers prosumers a 50%increase in revenue.

关键词： Peer-to-peer energy trading smart grid blockchain matching algorithm renewable energy source

When the bowel meets the bladder: Optimal management of colorectal pathology with urological involvement

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World Journal of Gastrointestinal Surgery 2020年第5期12卷 208-225页

作者： Conor Keady Daniel Hechtl myles Joyce Department of Colorectal Surgery Galway University HospitalGalway H91 YR71Ireland

Fistulae between the gastrointestinal and urinary systems are rare but becoming increasingly more common in current surgical *** are a heterogeneous group of pathological entities that are uncommon complications of both benign and malignant *** the incidence of complicated diverticular disease and colorectal malignancy increases,so too does the extent of fistulous connections between the gastrointestinal and urinary *** complex problems will be more common as a factor of an aging population with increased life *** disease is the most commonly encountered aetiology,accounting for up to 80%of cases,followed by colorectal malignancy in up to 20%.A high index of suspicion is required in order to make the diagnosis,with ever improving imaging techniques playing an important role in the diagnostic *** strategies vary,with most surgeons now advocating for a single-stage approach to enterovesical fistulae,particularly in the elective *** bladder management techniques are also ***,open techniques were the standard;however,increased experience and advances in surgical technology have contributed to refined and improved laparoscopic ***,due to the relative rarity of these entities,no randomised studies have been performed to ascertain the most appropriate management *** fistulae have dramatically increased in incidence with advances in the non-operative management of prostate *** radiotherapy being a major contributing factor in the development of these complex fistulae,optimum surgical approach and exposure has changed accordingly to optimise their *** management in the form of diversion therapy is effective in temporising the situation and allowing for the diversion of faecal contents if there is associated soiling,macerated tissues or associated *** may plan for definitive surgical intervention

关键词： Colovesical fistula Enterovesical fistula Rectourinary fistula Intestinal fistula Diverticular fistula Diverticular disease Laparoscopic surgery Colorectal cancer

Subtotal colectomy in ulcerative colitis—long term considerations for the rectal stump

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World Journal of Gastrointestinal Surgery 2021年第2期13卷 198-209页

作者： Orla Hennessy Laurence Egan myles Joyce Department of Colorectal Surgery Galway University HospitalGalway H91RR2NIreland Department of Gastroenterology Galway University HospitalGalway H91RR2NIreland

BACKGROUND The initial operation of choice in many patients presenting as an emergency with ulcerative colitis is a subtotal colectomy with end ileostomy.A percentage of patients do not proceed to completion proctectomy with ileal pouch anal *** To review the existing literature in relation to the significant long-term complications associated with the rectal stump,to provide an overview of options for the surgical management of remnant rectum and anal canal and to form a consolidated guideline on endoscopic screening recommendations in this *** A systematic review was carried out in accordance with PRISMA guidelines for papers containing recommendations for endoscopy surveillance in rectal remnants in ulcerative colitis.A secondary narrative review was carried out exploring the medical and surgical management options for the retained *** For rectal stump surveillance guidelines,20%recommended an interval of 6 mo to a year,50%recommended yearly surveillance 10%recommended 2 yearly surveillance and the remaining 30%recommended risk stratification of patients and different screening intervals based on *** studies agreed surveillance should be carried out via endoscopy and *** vigilance is needed in endoscopy in these *** review revealed a number of options for surgical management of the remnant *** The retained rectal stump needs to be surveyed endoscopically according to risk *** care must be taken to avoid rectal perforation and pelvic sepsis at time of *** completion proctectomy is indicated the authors favour removal of the anal canal using an intersphincteric dissection technique.

关键词： Stump Ulcerative colitis Surveillance Endoscopy Rectal Screening

Recent Advancements on Three‑Dimensional Electrospun Nanofiber Scaffolds for Tissue Engineering

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Advanced Fiber Materials 2022年第5期4卷 959-986页

作者： Yujie Chen Xutao Dong Muhammad Shafiq Gregory myles Norbert Radacsi Xiumei Mo Shanghai Engineering Research Center of Nano‑Biomaterials and Regenerative Medicine State Key Laboratory for Modification of Chemical Fibers and Polymer MaterialsCollege of ChemistryChemical Engineering and BiotechnologyDonghua UniversitySongjiangShanghai 201600China School of Engineering Institute for Materials and ProcessesThe University of EdinburghKing’s BuildingsEdinburgh EH93FBUnited Kingdom

Electrospinning is widely accepted as a technique for the fabrication of nanofibrous three-dimensional(3D)scaffolds which mimic extracellular matrix(ECM)microenvironment for tissue engineering(TE).Unlike normal densely-packed two-dimensional(2D)nanofibrous membranes,3D electrospun nanofiber scaffolds are dedicated to more precise spatial control,endowing the scaffolds with a sufficient porosity and 3D environment similar to the in vivo settings as well as optimizing the properties,including injectability,compressibility,and ***,the 3D morphology regulates cellular interaction and mediates growth,migration,and differentiation of cell for matrix *** variation among scaffold structures,functions and applications depends on the selection of electrospinning materials and methods as well as on the post-processing of electrospun *** review summarizes the recent new forms for building electrospun 3D nanofiber scaffolds for TE applications.A variety of approaches aimed at the fabrication of 3D electrospun scaffolds,such as multilay-ering electrospinning,sacrificial agent electrospinning,wet electrospinning,ultrasound-enhanced electrospinning as well as post-processing techniques,including gas foaming,ultrasonication,short fiber assembly,3D printing,electrospraying,and so on are discussed,along with their advantages,limitations and ***,the current challenges and prospects of 3D electrospun scaffolds are rationally discussed,providing an insight into developing the vibrant fields of biomedicine.

关键词： Electrospun Nanofibers Three-dimensional Tissue engineering Regenerative medicine Scaffold Polymer