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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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Dietary lycopene mitigates nonalcoholic steatohepatitis by regulating Nrf2/PPARα-dependent ferroptosis

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Food Science and Human Wellness 2024年

作者： Xunyu Song Daotong Li Jun Sun Xiaoying Zhang Li-Shu Wang Fang Chen College of Food Science and Nutritional Engineering， National Engineering Research centre for Fruit and Vegetable Processing， Key Laboratory of Fruits and Vegetables Processing， Ministry of Agriculture Engineering Research centre for Fruits and Vegetables Processing， Ministry of Education， China Agricultural University Department of Hematology and Hematopoietic Cell Transplantation comprehensive cancer Center， City of Hope National Medical Center

The global burden of non-alcoholic steatohepatitis (NASH) is on the rise. Researchers recognize inhibiting ferroptosis， a form of cell death leading to iron-dependent oxidative damage， as a promising therapy for treating NASH. Lycopene， a natural antioxidant compound， exhibits various pharmacological properties. However， the anti-NASH efficacy of the dietary recommended concentration of lycopene and the role of lycopene in combating ferroptosis in NASH have remained unclear. Our study investigated lycopene’s impact on ferroptosis in various diet-induced mouse NASH models and corresponding cellular models， unveiling its anti-inflammatory and anti-fibrotic effects. Our findings demonstrated that lycopene notably reduced ferroptosis in MCD (methionine- and choline-deficient diet)-fed mice and a normal mouse hepatocyte cell line (NCTC1469) by restoring balanced ferrous iron levels， lipid reactive oxygen species， and normal mitochondrial morphology. These effects were linked to the regulation of ferroptosis markers GPX4 and PTGS2. Additionally， lycopene’s anti-ferroptosis action was validated in mice fed a high-fat， high-cholesterol diet and HepG2 cells treated with free fatty acid. Our transcriptomic analysis highlighted PPARα as a primary target of lycopene， crucial for activating the glutathione system because GW6471， a PPARα antagonist， blocked lycopene-induced GPX4 activation. Furthermore， Nrf2 played a crucial role in lycopene’s impact on iron metabolism-related proteins (FTH1 and TFR1). Notably， when inhibiting PPARα or Nrf2 in MCD-fed mice by GW6471 or ML385， lycopene’s protective effects against ferroptosis and NASH progression diminished. These findings underscore the crucial role of PPARα-mediated glutathione system activation and Nrf2-mediated iron metabolism modulation in lycopene's anti-ferroptosis effects.

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First-line penpulimab(an anti-PD1 antibody)and anlotinib(an angiogenesis inhibitor)with nab-paclitaxel/gemcitabine(PAAG)in metastatic pancreatic cancer:a prospective,multicentre,biomolecular exploratory,phase II trial

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2960-2969页

作者： Huizi Sha Fan Tong Jiayao Ni Yi Sun Yahui Zhu Liang Qi Xiaoqin Li Wei Li Yan Yang Qing Gu Xing Zhang Xiaoxuan Wang Chan Zhu Dongsheng Chen Baorui Liu Juan Du The comprehensive cancer Center Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing University&Clinical Cancer Institute of Nanjing UniversityNanjingChina The comprehensive cancer Center Nanjing Drum Tower HospitalClinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina Department of Oncology The Affiliated Hospital of Jiangsu UniversityZhenjiangChina Department of Oncology The First Affiliated Hospital of Soochow UniversitySuzhouChina Department of Oncology The Affiliated Jiangning Hospital of Nanjing Medical UniversityNanjingChina National Institute of Healthcare Data Science at Nanjing University NanjingChina State Key Laboratory of Neurology and Oncology Drug Development Jiangsu Simcere Diagnostics Co.Ltd.Nanjing Simcere Medical Laboratory Science Co.Ltd.NanjingChina

Metastatic pancreatic cancer(mPC)has a dismal ***,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and *** 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,*** 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer ***,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable *** conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for *** biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.

关键词： CA724 prospective centre

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Combined hepatocellular cholangiocarcinoma: A clinicopathological update

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World Journal of Hepatology 2024年第5期16卷 766-775页

作者： Mukul Vij Fadl H Veerankutty Ashwin Rammohan Mohamed Rela Department of Pathology Institute of Liver Disease and TransplantationChennai 600044India comprehensive Liver Care Institute VPS LakeshoreCochin 682040India Institute of Liver Disease and Transplantation Dr.Rela Institute and Medical CentreChennai 600044India

Combined hepatocellular-cholangiocarcinoma(cHCC-CCA)is a rare primary liver cancer associated with an appalling *** diagnosis and manage-ment of this entity have been challenging to physicians,radiologists,surgeons,pathologists,and oncologists *** diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin,a progenitor cell marker,have been explored *** a better understanding of biology and the clinical course of cHCC-CCA,newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare *** this review,we give an account of the recent developments in the pathology,diagnostic approach,and management of cHCC-CCA.

关键词： Combined hepatocellular-cholangiocarcinoma Immunotherapy Nestin Hepatocellular carcinoma Cholangiocarcinoma Liver cancer Biomarker Immune checkpoint inhibitors Pathology Genomic landscape

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Long-term follow-up of intravesical abobotulinumtoxinA (Dysport®) injections in women with idiopathic detrusor overactivity

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Asian Journal of Urology 2024年第1期11卷 93-98页

作者： Mohammad Sajjad Rahnama'i Amin Bagheri Elham Jahantabi Hanieh Salehi-Pourmehr Hadi Mostafaei Brigitte Schurch Aida Javan Balegh Marand Sakineh Hajebrahimi Department of Urology St.Elisabeth-Tweesteden Hospital Tilburgthe Netherlands Research Center for Evidence-based Medicine Iranian EBM Centre:A Joanna Briggs Institute(JBI)Center of ExcellenceTabriz University of Medical SciencesTabrizIran Urology Department Faculty of MedicineTabriz University of Medical SciencesTabrizIran Department of Urology Comprehensive Cancer CenterMedical University of ViennaViennaAustria Service de Neuroréhabilitation CHUVLausanneSwitzerland Society of Urological Research and Education(SURE) Heerlenthe Netherlands

Objective:Only a few numbers of studies have been published on the use of abobotulinumtoxinA(Dysport®)in idiopathic detrusor overactivity(IDO).This study reported the long-term follow-up of women with IDO who were treated with intravesical Dysport®***:Two hundred and thirty-six patients with IDO who had failed first-line conservative and antimuscarinic therapy received 500-900 units of Dysport®between April 2014 and July *** patients were followed up for 5 years after their initial injection and interviewed on the ***:A total of 236 women with IDO aged from 18 years to 84 years(mean±standard deviation:49.6±15.9 years)were included in our *** median follow-up time for patients was 36.5(range:10-70)months,and the median recovery time after injection was 18.5(range:0-70)months.A total of 83(35.2%)patients stated that they had subjective improvement of their symptoms whereas 84(35.6%)patients did not report any improvement in *** initial International Consultation on Incontinence Questionnaire Overactive Bladder mean score was 6.9(standard deviation 3.4).There was a positive association between the median recovery time and the components of the International Consultation on Incontinence Questionnaire Overactive Bladder ***:In a sub-population of overactive bladder patients with IDO who have failed first-line therapy,a single intravesical Dysport®injection can resolve patient symptoms completely or reduce the symptoms to an acceptable level that can be controlled with antimuscarinics or re-injection on demands.

关键词： AbobotulinumtoxinA Dysport Intravesical ldiopathic Detrusor overactivity

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Comparison and Verification of Coherent Doppler Wind Lidar and Radiosonde Data in the Beijing Urban Area

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Advances in Atmospheric Sciences 2024年第11期41卷 2203-2214页

作者： Zexu LUO Xiaoquan SONG Jiaping YIN Zhichao BU Yubao CHEN Yongtao YU Zhenlu ZHANG College of Marine Technology Faculty of Information Science and EngineeringOcean University of ChinaQingdao 266100China Laboratory for Regional Oceanography and Numerical Modeling Laoshan LaboratoryQingdao 266237China Qingdao Leice Transient Technology Co.LTD Qingdao 266100China CMA Meteorological Observation centre Beijing 100081China Beijing Municipal Meteorological Observation Center Beijing 102600China Qingdao Meteorological comprehensive Support Center Qingdao 266003China

As a new type of wind field detection equipment, coherent Doppler wind lidar(CDWL) still needs more relevant observation experiments to compare and verify whether it can achieve the accuracy and precision of traditional observation equipment in urban areas. In this experiment, a self-developed CDWL provided four months of observations in the southern Beijing area. After the data acquisition time and height match, the wind profile data obtained based on a Doppler beam swinging(DBS) five-beam inversion algorithm were compared with radiosonde data released from the same location. The standard deviation(SD) of wind speed is 0.8 m s^(–1), and the coefficient of determination R~2 is 0.95. The SD of the wind direction is 17.7° with an R~2 of 0.96. Below the height of the roughness sublayer(about 400 m), the error in wind speed and wind direction is significantly greater than the error above the height of the boundary layer(about 1500 m). For the case of wind speeds less than 4 m s^(–1), the error of wind direction is more significant and is affected by the distribution of surrounding buildings. Averaging at different height levels using suitable time windows can effectively reduce the effects of turbulence and thus reduce the error caused by the different measurement methods of the two devices.

关键词： coherent Doppler wind lidar radiosonde wind measurement urban boundary layer

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IgG4 Coronary Arteritis Presenting as a Cardiac Pseudo-Tumour

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Case Reports in Clinical Medicine 2024年第9期13卷 345-352页

作者： Elaine Mo-Chee Chau Catherine Yuet-Hung Wong Raymond Hin-Suen Liang Cardiology centre Hong Kong Sanatorium & Hospital Hong Kong SAR China Nuclear Medicine Department Hong Kong Sanatorium & Hospital Hong Kong SAR China comprehensive Oncology centre Hong Kong Sanatorium & Hospital Hong Kong SAR China

We report on an unusual case presenting with a cardiac pseudo-tumour on echocardiogram, which corresponded to a large soft tissue mural thickening around the mid-right coronary artery. There were similar but not as thick mural lesions around other parts of the coronary arteries. The so-called “pigs-in-a-blanket” sign on computed tomography (CT) scan was pathognomonic of IgG4 coronary arteritis. The IgG4 level was grossly elevated at more than 10 times the upper limit of normal. Positron emission tomography (PET)-CT scans with 18F-fluoro-deoxy-glucose (FDG) and 68Ga-Fibroblast Activation Protein Inhibitor (FAPI) were performed to assess the extent of organ involvement of the IgG4-related disease. The patient was treated with 8 injections of rituximab with good serological response. However, the coronary arteritis findings on CT scan remained unchanged.

关键词： IgG4-Related Disease Coronary Arteritis Cardiac Pseudo-Tumour “Pigs-in-a-Blanket” Sign

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The PI3K/Akt/m TOR pathway in ovarian cancer: therapeutic opportunities and challenges

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Chinese Journal of cancer 2015年第1期34卷 4-16页

作者： Bianca Cheaib Aurélie Auguste Alexandra Leary Gynecological Unit Department of MedicineGustave Roussy Comprehensive Cancer Centre Gynecological Tumor Team Translational Research Laboratory U981 Gustave Roussy Comprehensive Cancer Centre

The phosphatidylinositol 3 kinase(PI3K) pathway is frequently altered in cancer, including ovarian cancer(OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin(m TOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective m TOR complex-1(m TORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual m TORC1/m TORC2, Akt, and PI3 K inhibitors. Although it is likely that inhibition of the PI3K/Akt/m TOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha(PIK3CA) and/or phosphatase and tensin homolog(PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3 K signaling network, PI3 K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3 K pathway in OC and provide an up-to-date review of clinical trials of novel PI3 K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

关键词： mTOR 信号通路卵巢癌磷脂酰肌醇3激酶 AKT 激素疗法治疗临床试验

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Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats

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Neural Regeneration Research 2024年第4期19卷 900-907页

作者： Haoshuai Tang Junjin Li Hongda Wang Jie Ren Han Ding Jun Shang Min Wang Zhijian Wei Shiqing Feng Department of Othopaedics Tianjin Medical University General Hospital International Science and Technology Cooperation Base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General Hospital Tianjin Key Laboratory of Lung cancer Metastasis and Tumor Microenvironment Tianjin Lung Cancer InstituteTianjin Medical University General Hospital Department of Othopaedics Qilu Hospital of Shandong UniversityShandong University Centre for OthopedicsAdvanced Medical Research InstituteShandong University Orthopedic Research Center of Shandong University&Advanced Medical Research Institute Cheeloo College of MedicineShandong University

Complete transverse injury of peripheral nerves is challenging to *** secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue *** previous studies,a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal *** three-dimensional(3D)composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly(lactic-co-glycolic acid)***,whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains *** this study,we tested a comprehensive strategy for repairing long-gap(10 mm)peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived *** effectiveness was evaluated by sciatic functional index,sciatic nerve compound muscle action potential recording,recovery of muscle mass,measuring the cross-sectional area of the muscle fiber,Masson trichrome staining,and transmission electron microscopy of the regenerated nerve in *** results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function,similar to autograft *** CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes,which may have contributed to the observed increase in axon regeneration and distal nerve ***,the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury.

关键词： axon growth collagen exosome human umbilical cord mesenchymal stem cells hyaluronic acid muscular atrophy nerve guidance conduits peripheral nerve regeneration

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Comprehending drivers of land use land cover change from 1999 to 2021 in the Pithoragarh District,Kumaon Himalaya,Uttarakhand,India

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Journal of Mountain Science 2024年第7期21卷 2394-2407页

作者： Mahika PHARTIYAL Sanjeev SHARMA centre for the Study of Regional Development Jawaharlal Nehru UniversityNew Delhi 110067India

The Himalayan region has been experiencing stark impacts of climate change,demographic and livelihood pattern *** analysis of land use and land cover(LULC)change provides insights into the shifts in spatial and temporal patterns of *** changes are the combined effects of anthropogenic and natural/climatic *** present study attempts to monitor and comprehend the main drivers behind LULC changes(1999-2021)in the Himalayan region of Pithoragarh district,*** district is a border district,remotely located in the north-east region of Uttarakhand,*** study draws upon primary and secondary data sources.A total of 400 household surveys and five group discussions from 38 villages were conducted randomly to understand the climate perception of the local community and the drivers of *** imagery,CRU(Climatic Research Unit)climate data and climate perception data from the field have been used to comprehensively comprehend,analyze,and discuss the trends and reasons for LULC *** and remote sensing techniques were used to construct LULC *** multifaceted approach ensures comprehensive and corroborated *** classes were identified and formed viz-cultivation,barren,settlement,snow,and *** show that vegetation and builtup have increased whereas cultivation,barren land,and snow cover have *** study further aims to elucidate the causes behind LULC changes in the spatially heterogeneous region,distinguishing between those attributed to human activities,climate shifts,and the interconnected impacts of *** study provides a comprehensive picture of the study area and delivers a targeted understanding of local drivers and their potential remedies by offering a foundation for formulating sustainable adaptation policies in the region.

关键词： Himalayan region Land use/land cover change Anthropogenic factors Climate change Socioecological system

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