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Journal of Molecular Cell Biology 2022年第6期14卷 47-56页

作者： Runqiang Chen Hui Xie Sahba Khorsandzadeh Madison Smith Namir Shaabani Qidong Hu Xiaoxuan Lyu Hua Wang Wan-lin Lim Haotian Sun Henry Ji Brian Cooley Russell Ross David M.Francis Sorrento therapeutics Inc.San DiegoCA 92121USA Sofusa a Division of Sorrento TherapeuticsAtlantaGA 30350USA

The exploration and identification of safe and effective vaccines for the SARS-CoV-2 pandemic have captured the world's attention and remains an ongoing issue due to concerns of balancing protection against emerging variants of concern while also generating long-lasting immunity. Here, we report the synthesis of a novel messenger ribonucleic acid encoding the spike protein in a lipid nanoparticle formulation (STI-7264) that generates robust humoral and cellular immunity following immunization of C57Bl6 mice. In an effort to improve immunity, a clinically focused lymphatic drug delivery device (MuVaxx) was engineered to modulate immune cells at the injection site (epidermis and dermis) and draining lymph node (LN) and tested to measure adaptive immunity. Using MuVaxx, immune responses were elicited and maintained at a 10-fold dose reduction compared to traditional intramuscular (IM) administration as measured by anti-spike antibodies, cytokine-producing CD8 T cells, neutralizing antibodies against the Washington (wild type) strain and South African (Beta) variants, and LN-resident spike-specific memory B cells. Remarkably, a 4-fold-elevated T cell response was observed in MuVaxx-administered vaccination compared to that of IM-administered vaccination. Thus, these data support further investigation into STI-7264 and lymphatic-mediated delivery using MuVaxx for SARS-CoV-2 and VoC vaccines.

关键词： COVID-19 lymph nodes lymphatics vaccines drug delivery

Dieulafoy's lesion:A case series study

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World Journal of Gastroenterology 2005年第23期11卷 3574-3577页

作者： RS Walmsley Yuk-Tong Lee Joseph JY Sung Department of Gastroenterology Department of Medicine and therapeutics

AIM: Dieulafoy's lesion (DL) accounts for 1-5.8% of cases of acute upper gastrointestinal bleeding (GIB). Its mortality is high, approaching 20%, despite recent advances in endoscopic therapy. We aimed to report our experience in the treatment of ***: A retrospective case study of all patients with DL between January 1993 and January 2003 was done. Characteristics, treatment methods, success rates and 30-d mortality of the patients were analyzed. RESULTS: Thirty-six patients were noted to have DL in the study period. Thirty-three records were available for assessment in which 35 DL were identified. The median age of the patients was 67 years with male to female ratio of 5.6:1. Significant comorbidities existed in 69% of the patients. Eighty-nine percent of the DL was found at first endoscopy, three DL at laparotomy. Significant coexistent endoscopic findings existed in 23%. Hemostasis was achieved in 88% by using adrenaline injection, or in combination with heater probe application at first endoscopy. Four cases had re-bleeding, all were successfully treated endoscopically. The 30-d mortality rate was 23%.CONCLUSION: Successful endoscopic hemostasis could be achieved in 100% of cases of DL. The overall mortality may still remain high, mainly due to the comorbidities and age of these patients.

关键词： Dieulafoy Gastrointestinal bleeding

Multifaceted roles of extracellular RNAs in different diseases

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Military Medical Research 2023年第3期10卷 359-368页

作者： Abdullah Muhammad Sohail Muhammad Babar Khawar Ali Afzal Ali Hassan Sara Shahzaman Ahmed Ali Molecular Medicine and Cancer therapeutics Lab Department of ZoologyFaculty of SciencesUniversity of Central PunjabLahorePakistan Applied Molecular Biology and Biomedicine Lab Department of ZoologyUniversity of NarowalNarowalPakistan

Extracellular RNAs(exRNAs) are novel circulating factors that can be used as biomarkers in various diseases. Their unique and diverse kinds, as well as their role as biomarkers, make them significant biomarkers. There has been immense work carried out since the discovery of exRNAs in circulation and other biological fluids to catalog and determine whether exRNAs may be utilized as indicators for health and illness. In this review, we aim to understand the current state of exRNAs in relation to various diseases and their potential as biomarkers. We will also review current issues and challenges faced in using exRNAs, with clinical and lab trials, that can be used as viable markers for different diseases.

关键词： Extracellular RNAs(exRNAs) Extracellular vehicles(EVs) Cancer Biomarkers Exosomes

Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia

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Cancer Drug Resistance 2023年第3期6卷 567-589页

作者： Priyanka Sharma Gautam Borthakur Department of Leukemia Section of Molecular Hematology and TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

关键词： OXPHOS DHODH leukemia stem cells mesenchymal stromal cells IDH

Loss of hepatic VMP1 trapped VLDL in the bilayer of endoplasmic reticulum membrane

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Liver Research 2023年第2期7卷 161-163页

作者： Hong-Min Ni Benjamin Ding Allen Chen Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA

Non-alcoholic fatty liver disease(NAFLD)is a highly prevalent form of liver disease associated with obesity,diabetes,and other metabolic diseases.1 NAFLD is characterized by hepatocyte lipid *** untreated,this disease can progress to nonalcoholic steatohepatitis(NASH),typified by increased hepatocyte death,hepatocyte ballooning,inflammation,and fibrosis.2,3 The molecular basis of NAFLD/NASH development and progression is still poorly understood;thus,no effective treatments currently exist to combat this burgeoning health problem.

关键词： Autophagy Lipid droplet Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH)

Microarchitectural mimicking of stroma-induced vasculature compression in pancreatic tumors using a 3D engineered model

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Bioactive Materials 2023年第4期22卷 18-33页

作者： Marcel Alexander Heinrich Irene Uboldi Praneeth Reddy Kuninty Marc J.K.Ankone Joop van Baarlen Yu Shrike Zhang Kartik Jain Jai Prakash Department of Advanced Organ Bioengineering and therapeutics Engineered Therapeutics SectionTechnical Medical CentreUniversity of Twente7500AEEnschedethe Netherlands Laboratorium Pathologie Oost-Nederland(LabPON) 7550 AMHengelothe Netherlands Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical School65 Landsdowne StCambridgeMA02139USA Department of Thermal and Fluid Engineering Biofluid Dynamics SectionUniversity of Twente7500 AE Enschedethe Netherlands

Fibrotic tumors,such as pancreatic ductal adenocarcinoma(PDAC),are characterized for high desmoplastic reaction,which results in high intra-tumoral solid stress leading to the compression of blood *** microarchitectural alterations cause loss of blood flow and poor intra-tumoral delivery of ***,there is a lack of relevant in vitro models capable of replicating these mechanical characteristics and to test anti-desmoplastic ***,a multi-layered vascularized 3D PDAC model consisting of primary human pancreatic stellate cells(PSCs)embedded in collagen/fibrinogen(Col/Fib),mimicking tumor tissue within adjunct healthy tissue,is presented to study the fibrosis-induced compression of vasculature in *** is demonstrated how the mechanical and biological stimulation induce PSC activation,extracellular matrix production and eventually vessel *** clinical relevance is confirmed by correlating with patient transcriptomic ***,the effects of gradual vessel compression on the fluid dynamics occurring within the channel is evaluated in ***,it is demonstrated how cancer-associated fibroblast(CAF)-modulatory therapeutics can inhibit the cell-mediated compression of blood vessels in PDAC in vitro,in silico and in *** is envisioned that this 3D model is used to improve the understanding of mechanical characteristics in tumors and for evaluating novel anti-desmoplastic therapeutics.

关键词： Pancreatic ductal adenocarcinoma Cancer-associated fibroblasts Collagen Fibrinogen Computational flow dynamics 3D in vitro model

Concordance between bio-impedance analysis and clinical score in fluid-status assessment of maintenance haemodialysis patients: A single centre experience

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World Journal of Nephrology 2022年第4期11卷 127-138页

作者： Kamiti Muchiri Joshua K Kayima Elijah N Ogola Seth McLigeyo Sally W Ndung’u Samuel K Kabinga Clinical Medicine and therapeutics University of NairobiNairobi+254Kenya Department of Clinical Medicine and therapeutics University of NairobiNairobi+254Kenya Department of Public Health University of NairobiNairobi+254Kenya East African Kidney Institute University of NairobiNairobi+254Kenya

BACKGROUND The burden of chronic kidney disease(CKD)is rising rapidly *** overload(FO),an independent predictor of mortality in CKD,should be accurately assessed to guide estimation of the volume of fluid to be removed during haemodialysis(HD).Clinical score(CS)and bio-impedance analysis(BIA)have been utilized in assessment of FO and BIA has demonstrated reproducibility and accuracy in determination of fluid status in patients on *** is need to determine the performance of locally-developed CSs in fluid status assessment when evaluated against *** To assess the hydration status of patients on maintenance HD using BIA and a CS,as well as to evaluate the performance of that CS against BIA in fluid status *** This was a single-centre,hospital-based cross-sectional study which recruited adult patients with CKD who were on maintenance HD at Kenyatta National *** patients were aged 18 years and above and had been on maintenance HD for at least 3 *** with pacemakers,metallic implants,or bilateral limbs amputations were *** on the patients’clinical history,physical examination,and chest radiograph findings were *** was performed on each of the study participants using the Quantum®II bio-impedance analyser manufactured by RJL Systems together with the BC 4®*** evaluating the performance of the CS,BIA was considered as the gold standard test.A 2-by-2 table of the participants’fluid status at each of the CS values obtained compared to their paired BIA results was constructed(either++,+-,--or-+for FO using the CS and BIA,respectively).The results from this 2-by-2 table were used to compute the sensitivity and specificity of the CS at the various reference points and subsequently plot a receiver operating characteristic(ROC)curve that was used to determine the best cut-off *** above and below the best CS cut-off point as determined by the ROC were classified as being positive and negative for FO

关键词： Bio-impedance analysis Clinical score Chronic kidney disease Maintenance haemodialysis Fluid overload Concordance

Early-onset colorectal cancer:Current insights and future directions

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World Journal of Gastrointestinal Oncology 2022年第1期14卷 230-241页

作者： Claudia Wing-Kwan Wu Rashid N Lui Division of Gastroenterology and Hepatology Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongChina Department of Clinical Oncology The Chinese University of Hong KongHong KongChina

Early-onset colorectal cancer(EOCRC)has seen an alarming rise worldwide over the past two *** reason for this global trend is poorly *** appears to have its own unique clinical and molecular features when compared with late-onset colorectal *** patients appear to have more distal or rectal disease,a more advanced stage of disease at presentation,and more unfavorable histological *** risk factors for EOCRC is the first step in mitigating the rising burden of this *** we summarize several noteworthy biological factors and environmental exposures that are postulated to be responsible *** can hopefully translate in clinical practice to the development of better risk stratification tool for identifying highrisk individuals for early colorectal cancer screening,and identifying areas needed for further research to curb this rising trend.

关键词： Early-onset colorectal cancer Young-onset colorectal cancer Risk factors Environmental exposures Microbiome Genetics

Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

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Cancer Biology & Medicine 2015年第4期12卷 316-327页

作者： Alex Matter Experimental therapeutics Center & D3 A*STAR

This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

关键词： Drug discovery drug development translational R&D targeted anti-cancer agents

Utilizing zebrafish and okadaic acid to study Alzheimer's disease

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Neural Regeneration Research 2018年第9期13卷 1538-1541页

作者： Daniel Koehler Frederick E.Williams Department of Pharmacology and Experimental therapeutics University of Toledo

Despite the many years of extensive research using rodent models to study Alzheimer＇s disease （AD）, no cure or disease halting drug exists. An increasing number of people are suffering from the disease and a therapeutic intervention is needed. Therefore, it is necessary to have complementary models to aid in the drug discovery. The zebrafish animal model is emerging as a valuable model for the investigation of AD and neurodegenerative drug discovery. The main genes involved in human AD have homologous counter- parts in zebrafish and have conserved function. The basic brain structure of the zebrafish is also conserved when compared to the mammalian brain. Recently an AD model was established by administering okadaic acid to zebrafish. It was used to test the efficacy of a novel drug, lanthionine ketimine-5-ethyl ester, and to elucidate its mechanism of action. This demonstrated the ability of the okadaic acid-induced AD zebrafish model to be implemented in the drug discovery process for therapeutics against AD.

关键词： Alzheimer's disease Zebrafish okadaic acid protein phosphatase 2A learning and memory lanthionine ketimine-5-ethyl ester