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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li Department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular Research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

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Bone marrow microRNA-34a is a good indicator for response to treatment in acute myeloid leukemia

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Oncology Research 2024年第3期32卷 577-584页

作者： MONA SA BDELLATEIF NAGLAA MHASSAN MAHMOUD MKAMEL YOMNA MEL-MELIGUI Department of cancer Biology Medical Biochemistry and Molecular BiologyNational Cancer InstituteCairo UniversityCairo11976Egypt Department of Cinical Pathology National Cancer InstituteCairo UniversityCairo11976Egypt

Background:microRNA 34a(miR 34a)had been reported to have a diagnostic role in acute myeloid leukemia(AML).However,its value in the bone marrow(BM)of AML patients,in addition to its role in response to therapy is still *** current study was designed to assess the diagnostic,prognostic,and predictive significance of miR 34a in the BM of AML ***:The miR.34a was assed in BM aspirate of 82 AML patients in relation to 12 normal control subjects using *** data were assessed for correlation with the relevant dinical critenia,response to therapy,disease-free survival(DFS),and overall survival(OS)***:miR.34a was significantly downregulated in AML patients[0.005(3.3×10^(-6)-1.32)],compared to the control subjects[0.108(3.2× 10^(-4)-1.64),p=0.021].*** relative quantification(RQ)of miR-34a was 0.106(range;0-32.12).The specifaity,sensitivity,and area under the curve(AUC)for the diagnosis of AML were(58.3%,69.5%,0.707,respectively,p=0.021).patients with upregulated miR-34a showed decreased platelets count<34.5 × 10^(9)/L,and achieved early complete remission(CR,p=0.031,p=0.044,respectively).Similarly,patients who were refractory to therapy showed decreased miR 34a levels in comparison to those who achieved CR[0.002(0-0.01)and 0.12(0-32.12),respectively,p=0.002].Therefore,miR 34a could significantly identify patients with CR with a specificity of 75%and sensitivity of 100%at a cut-off of 0.014(AUC=0.927,p=0.005).There was no considerable association between miR-34a expression and survival rates of the induded AML ***:miR-34a could be a beneficial diagnostic biomarker for AML *** addition,it serves as a good indicator for response to therapy,which could possibly identify patients who are refractory to treatment with 100%sensitivity and 75%specificity.

关键词： AML miR 34a microRNA Leukemia

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Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma: a real-world study

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cancer Biology & Medicine 2024年第9期21卷 799-812页

作者： Yuxiao Liu Xiaofan Guo Peijun Xu Yuning Song Jing Huang Xingyun Chen Wenbo Zhu Jihui Hao Song Gao Department of Pancreatic cancer Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer

Objective: Little progress has been made in recent years using first-line chemotherapy, including gemcitabine combined with nabpaclitaxel, FOLFIRINOX, and NALIRIFOX, for advanced pancreatic adenocarcinoma(APC). In addition, the optimal second-line chemotherapy regimen has not been determined. This study aimed to compare the effectiveness of different types of second-line chemotherapy for ***: Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis. The primary and secondary endpoints were overall survival(OS) and progression-free survival(PFS), ***: Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil-and gemcitabine-based chemotherapy as first-line treatment, respectively. Demographic and clinical features, except age and liver metastasis, were comparable between the two groups(P < 0.05). The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil-and gemcitabine-based combined regimen for first-line therapy, respectively(HR = 1.244, 95% CI = 1.090±1.419; P < 0.001). The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care, respectively(HR = 0.766, 95% CI = 0.677±0.867; P < 0.001). The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination ***: A 5-fluorouracil-or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

关键词： 5-fluorouracil Second-line chemotherapy advanced pancreatic adenocarcinoma gemcitabine real-world study

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The evolution of cancer genomic medicine in Japan and the role of the national cancer Center Japan

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cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan national cancer Center Research institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the national cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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Electroluminescence from pure resonant states in hBN-based vertical tunneling junctions

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Light(Science & Applications) 2024年第8期13卷 1557-1564页

作者： Magdalena Grzeszczyk Kristina Vaklinova Kenji Watanabe Takashi Taniguchi Konstantin SNovoselov Maciej Koperski institute for Functional Intelligent Materials National University of SingaporeSingapore 117544Singapore Research Center for Functional Materials National Institute for Materials ScienceTsukuba 305-0044Japan International Center for Materials Nanoarchitectonics National Institute for Materials ScienceTsukuba 305-0044Japan Department of Materials Science and Engineering National University of SingaporeSingapore 117575Singapore

Defect centers in wide-band-gap crystals have garnered interest for their potential in applications among optoelectronic and sensor ***,defects embedded in highly insulating crystals,like diamond,silicon carbide,or aluminum oxide,have been notoriously difficult to excite electrically due to their large internal *** address this challenge,we realized a new paradigm of exciting defects in vertical tunneling junctions based on carbon centers in hexagonal boron nitride(hBN).The rational design of the devices via van der Waals technology enabled us to raise and control optical processes related to defect-to-band and intradefect *** fundamental understanding of the tunneling events was based on the transfer of the electronic wave function amplitude between resonant defect states in hBN to the metallic state in graphene,which leads to dramatic changes in the characteristics of electrons due to different band structures of constituent *** our devices,the decay of electrons via tunneling pathways competed with radiative recombination,resulting in an unprecedented degree of tuneability of carrier dynamics due to the significant sensitivity of the characteristic tunneling times on the thickness and structure of the *** enabled us to achieve a high-efficiency electrical excitation of intradefect transitions,exceeding by several orders of magnitude the efficiency of optical excitation in the sub-band-gap *** work represents a significant advancement towards a universal and scalable platform for electrically driven devices utilizing defect centers in wide-band-gap crystals with properties modulated via activation of different tunneling mechanisms at a level of device engineering.

关键词： carbide tunneling defect

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Expression of cyclin-dependent kinase 9 is positively correlated with the autophagy level in colon cancer

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 314-330页

作者： Lei Zheng Jia Lu Da-Lu Kong Department of Colorectal cancer Surgery National Clinical Research Center for CancerKey Laboratory of Cancer Immunology and Biotherapy of TianjinTianjin Key Laboratory of Digestive CancerKey Laboratory of Cancer Prevention and Therapy of TianjinTianjin’s Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjin 300060China Department of Infection Management National Clinical Research Center for CancerKey Laboratory of Cancer Immunology and Biotherapy of TianjinTianjin Key Laboratory of Digestive CancerKey Laboratory of Cancer Prevention and Therapy of TianjinTianjin’s Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjin 300060China

BACKGROUND Cyclin-dependent kinase 9(CDK9)expression and autophagy in colorectal cancer(CRC)tissues has not been widely ***9,a key regulator of transcription,may influence the occurrence and progression of *** expression of auto-phagy-related genes BECN1 and drug resistance factor ABCG2 may also play a role in *** normal physiological conditions,autophagy can inhibit tumorigenesis,but once a tumor forms,autophagy may promote tumor ***,understanding the relationship between autophagy and cancer,partic-ularly how autophagy promotes tumor growth after its formation,is a key motivation for this *** To investigate the relationship between CDK9 expression and autophagy in CRC,assess differences in autophagy between left and right colon cancer,and analyze the associations of autophagy-related genes with clinical features and *** We collected tumor tissues and paracarcinoma tissues from colon cancer patients with liver metastasis to observe the level of autophagy in tissues with high levels of CDK9 and low levels of *** also collected primary tissue from left and right colon cancer patients with liver metastasis to compare the autophagy levels and the expression of BECN1 and ABCG2 in the tumor and paracarcinoma *** The incidence of autophagy and the expression of BECN1 and ABCG2 were different in left and right colon cancer,and autophagy might be involved in the occurrence of chemotherapy *** analysis of the rela-tionship between the expression of autophagy-related genes CDK9,ABCG2,and BECN1 and the clinical features and prognosis of colorectal cancer showed that the high expression of CDK9 indicated a poor prognosis in colorectal *** This study laid the foundation for further research on the combination of CDK9 inhibitors and autophagy inhibitors in the treatment of patients with CRC.

关键词： Autophagy Tumorigenesis Tumor tissue Paracarcinoma tissue Expression Left/right colon cancer

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Enhancing single-cell encapsulation in droplet microfluidics with fine-tunable on-chip sample enrichment

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Microsystems & Nanoengineering 2024年第1期10卷 149-160页

作者： Tao Tang Hao Zhao Shaofei Shen Like Yang Chwee Teck Lim Department of Biomedical Engineering National University of Singapore117583 SingaporeSingapore Integrative Sciences and Engineering Programme NUS Graduate SchoolNational University of Singapore119077 SingaporeSingapore Shanxi Key Lab for Modernization of TCVM College of Life ScienceShanxi Agricultural UniversityTaiguShanxi 030801China institute for Health Innovation&Technology National University of Singapore117599 SingaporeSingapore Mechanobiology institute National University of Singapore117411 SingaporeSingapore institute for Digital Molecular Analytics and Science Nanyang Technological University636921 SingaporeSingapore

Single-cell encapsulation in droplet microfluidics is commonly hindered by the tradeoff between cell suspension density and on-chip focusing *** this study,we introduce a novel droplet microfluidic chip to overcome this *** chip comprises a double spiral focusing unit,a flow resistance-based sample enrichment module with fine-tunable outlets,and a crossflow droplet generation *** a low-density cell/bead suspension(2×10^(6) objects/mL),cells/beads are focused into a near-equidistant linear arrangement within the double spiral *** excess water phase is diverted while cells/beads remain focused and sequentially encapsulated in individual *** performance was assessed through numerical simulations and experiments at three flow rates(40,60,80μL/min),demonstrating successful focusing at 40 and 80μL/min for beads and cells,*** addition,both simulation and experimental results revealed that the flow resistance at the sample enrichment module is adjustable by punching different outlets,allowing over 50%of the aqueous phase to be ***8n-based droplet detection algorithms realized the counting of cells/beads in droplets,statistically demonstrating single-cell and bead encapsulation rates of 72.2%and 79.2%,*** the results indicate that this on-chip sample enrichment approach can be further developed and employed as a critical component in single-cell encapsulation in water-in-oil droplets.

关键词： beads outlet sample

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Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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Oncology Research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical Oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

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Protein-nucleic acid hybrid nanostructures for molecular diagnostic applications

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Nano Research 2024年第10期17卷 9003-9014页

作者： Noah R.Sundah Yuxuan Seah Auginia Natalia Xiaoyan Chen Panida Cen Yu Liu Huilin Shao institute for Health Innovation and Technology National University of SingaporeSingapore 117599Singapore Department of Biomedical Engineering College of Design and EngineeringNational University of SingaporeSingapore 117583Singapore Integrative Sciences and Engineering Programme NUS Graduate SchoolNational University of SingaporeSingapore 119077Singapore institute of Molecular and Cell Biology Agency for ScienceTechnology and ResearchSingapore 138673Singapore Department of Surgery Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore

Molecular diagnostic technologies empower new clinical opportunities in precision ***,existing approaches face limitations with respect to performance,operation and *** molecules including proteins and nucleic acids are being increasingly adopted as tools in the development of new molecular diagnostic *** particular,leveraging their complementary properties—the functional diversity of proteins and the precision programmability of nucleic acids—a wide range of protein–nucleic acid hybrid nanostructures have been *** hybrid structures take diverse forms,ranging from one-dimensional to three-dimensional hybrids,as static assemblies to dynamic machines,and possess myriad functions to recognize target biomarkers,encode vast information and execute catalytic *** by recent advances in this area of molecular nanotechnology,we review the state-of-art design and application of various types of protein–nucleic acid hybrid nanostructures for molecular diagnostics,and present an outlook on the challenges and opportunities for emerging pre-clinical and clinical applications,highlighting the promise for earlier detection,more refined diagnosis and highly tailored treatment decision that ultimately lead to improved patient outcomes.

关键词： molecular nanotechnology DNA-protein hybrid molecular diagnostics precision medicine

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High mechanical strength Si anode synthesis with interlayer bonded expanded graphite structure for lithium-ion batteries

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Journal of Energy Chemistry 2024年第6期93卷 253-263,I0007页

作者： Wenhui Lai Jong Hak Lee Lu Shi Yuqing Liu Yanhui Pu Yong Kang Ong Carlos Limpo Ting Xiong Yifan Rao Chorng Haur Sow Barbaros Ozyilmaz Department of Material Science&Engineering National University of SingaporeSingapore 117575Singapore Center for Advanced 2D Materials National University of SingaporeSingapore 117546Singapore Department of Physics National University of SingaporeSingapore 117551Singapore institute forFunctional Intelligent Materials National University of SingaporeSingapore 117544Singapore

Despite advancements in silicon-based anodes for high-capacity lithium-ion batteries,their widespread commercial adoption is still hindered by significant volume expansion during cycling,especially at high active mass loadings crucial for practical *** root of these challenges lies in the mechanical instability of the material,which subsequently leads to the structural failure of the ***,we present a novel synthesis of a composite combining expanded graphite and silicon *** composite features a unique interlayer-bonded graphite structure,achieved through the application of a modified spark plasma sintering ***,this innovative structure not only facilitates efficient ion and electron transport but also provides exceptional mechanical strength(Vickers hardness:up to658 MPa,Young's modulus:11.6 GPa).This strength effectively accommodates silicon expansion,resulting in an impressive areal capacity of 2.9 mA h cm^(-2)(736 mA h g^(-1)) and a steady cycle life(93% after 100cycles).Such outsta nding performance is paired with features appropriate for large-scale industrial production of silicon batteries,such as active mass loading of at least 3.9 mg cm^(-2),a high-tap density electrode material of 1.68 g cm^(-3)(secondary clusters:1.12 g cm^(-3)),and a production yield of up to 1 kg per day.

关键词： Lithium-ion battery Silicon anode Spark plasma sintering Interlayer bonding Mechanical strength Tap density

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