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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin Xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun Yuzhu Hu Yuanyuan Zhang Zhiyong Qian Xiang Gao Zhirong Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

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Exploring plant adaptation strategies to phosphorus limitation induced by nitrogen addition:foliar phosphorus allocation and root functional traits analysis in two dominant subalpine tree species

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Journal of Plant Ecology 2024年第4期17卷 154-166页

作者： Yan Su Yongfeng Tang Yi Hu Meiyu Liu Xuyang Lu Baoli Duan Institute of Mountain Hazards and Environment Chinese Academy of SciencesChengdu 610041China sichuan Ecological Environment Construction Engineering Supervision Co. Ltd.Chengdu 610084China

Plants adapt to the limitation of soil phosphorus(P)induced by nitrogen(N)deposition through a complex interaction of various root and leaf functional *** this study,a pot experiment was conducted to explore the effects of different levels of N addition(control,low N[LN]:25 kg N ha^(-1) yr^(-1),high N[HN]:50 kg N ha^(-1) yr^(-1))on tree growth,leaf nutrient content,foliar P fractions and root characteristics of two dominant tree species,the pioneer species Salix rehderiana Schneid and the climax species Abies fabri(Mast.)Craib,in a subalpine forest in southwestern *** results demonstrated that LN addition had a minimal impact on leaf N and P ***,HN addition significantly decreased the leaf P content in both *** rehderiana exhibited more pronounced increases in specific root length and specific root area under P deficiency triggered by HN addition when compared with *** contrast,*** showed weaker morphological responses to N addition but had a higher proportion of foliar P to metabolic P,as well as higher root exudates rate and root phosphatase activity in response to HN *** fabri employs a synergistic approach by allocating a greater amount of leaf P to metabolite P and extracting P from the soil through P-mobilizing exudates and root phosphatase activity,while *** exhibits higher flexibility in modifying its root morphology in response to P limitation induced by HN *** study provides insights into subalpine tree species adaptation to N-induced P limitation,emphasizing its significance for guiding forest management and conservation in the context of global climate change.

关键词： N deposition root functional traits root morphology root exudation P-scavenging strategy

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Different effects of 24 dietary intakes on gastroesophageal reflux disease: A mendelian randomization

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World Journal of Clinical Cases 2024年第14期12卷 2370-2381页

作者： Yu-Xin Liu Wen-Tao Yang Yang Li Department of Oncology Hospital of Chengdu University of Traditional Chinese MedicineChengdu 610072Sichuan ProvinceChina Department of Cardiovascular Chengdu Integrated TCM&Western Medicine HospitalChengdu 610041Sichuan ProvinceChina Department of Nuclear Medicine Hospital of Chengdu University of Traditional Chinese MedicineChengdu 610072Sichuan ProvinceChina

BACKGROUND In observational studies,dietary intakes are associated with gastroesophageal re-flux disease(GERD).AIM To conduct a two-sample mendelian randomization(MR)analysis to determine whether those associations are *** To explore the relationship between dietary intake and the risk of GERD,we extracted appropriate single nucleotide polymorphisms from genome-wide asso-ciation study data on 24 dietary *** methods were adopted for data analysis:Inverse variance weighting,weighted median methods,and MR-Egger's *** odds ratio(OR)and 95%confidence interval(CI)were used to eva-luate the causal association between dietary intake and *** Our univariate Mendelian randomization(UVMR)results showed significant evidence that pork intake(OR,2.83;95%CI:1.76-4.55;P=1.84×10–5),beer intake(OR,2.70,95%CI:2.00-3.64;P=6.54×10–11),non-oily fish intake(OR,2.41;95%CI:1.49-3.91;P=3.59×10–4)have a protective effect on *** addition,dried fruit intake(OR,0.37;95%CI:0.27-0.50;6.27×10–11),red wine intake(OR,0.34;95%CI:0.25-0.47;P=1.90×10-11),cheese intake(OR,0.46;95%CI:0.39-0.55;P=3.73×10-19),bread intake(OR,0.72;95%CI:0.56-0.92;P=0.0009)and cereal intake(OR,0.45;95%CI:0.36-0.57;P=2.07×10-11)were negatively associated with the risk of *** was a suggestive asso-ciation for genetically predicted coffee intake(OR per one SD increase,1.22,95%CI:1.03-1.44;P=0.019).Multi-variate Mendelian randomization further confirmed that dried fruit intake,red wine intake,cheese intake,and cereal intake directly affected *** contrast,the impact of pork intake,beer intake,non-oily fish intake,and bread intake on GERD was partly driven by the common risk factors for ***,after adjusting for all four elements,there was no longer a suggestive association between coffee intake and *** This study provides MR evidence to support the causal relationship between a broad range of dietary intake and GERD,providing new insights for the treatment and p

关键词： Dietary Gastroesophageal reflux disease Mendelian randomization Disease management Randomized controlled trial

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A folic acid-decorated nanoparticles loaded JQ1 for oral squamous cell carcinoma therapy

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Chinese Chemical Letters 2024年第3期35卷 332-336页

作者： Dequan Zeng Zhongkai Ma Xin Zan Ting Luo Xiang Wang Xiang Gao Xianghui Fu School of Health Management Xihua UniversityChengdu 610039China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China College of StomatologySichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Breast Disease Center Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality *** poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC *** that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these ***,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor *** then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type *** conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.

关键词： Folic acid Nanoparticles JQ1 Oral squamous cell carcinoma Macrophages

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Microbiome-friendly PS/PVP electrospun fibrous membrane with antibiofilm properties for dental engineering

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Regenerative Biomaterials 2024年第4期3卷 27-37页

作者： Jiamin Chen Jia Guo Xueyun Lu Derong Yin Cuisong Zhou Yuqing Li Xuedong Zhou State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesDepartment of Operative Dentistry and EndodonticsWest China Hospital of StomatologySichuan UniversityChengduSichuan610041China Stomatological Hospital affiliated Suzhou Vocational Health College Department of Operative Dentistry and EndodonticsSuzhou215000China College of Chemistry Sichuan UniversityChengduSichuan610064China

Dental caries is one of the most prevalent and biofilm-associated oral diseases in *** mutans,with a high ability to form biofilms by adhering to hard surfaces,has been established as an important etiological agent for dental ***,it is crucial to find a way to prevent the formation of cariogenic ***,we report an electrospun fibrous membrane that could inhibit the adhesion and biofilm formation of ***,the polystyrene(PS)/polyvinyl pyrrolidone(PVP)electrospun fibrous membrane altered the 3D biofilm architecture and decreased water-insoluble extracellular polysaccharide ***,the anti-adhesion mechanism which laid in Coulomb repulsion between the negatively charged PS/PVP electrospun fibrous membrane and *** was detected by zeta ***,metagenomics sequencing analysis and CCK-8 assay indicated that PS/PVP electrospun fibrous membrane was microbiome-friendly and displayed no influence on the cell viability of human gingival epithelial cells and human oral ***,an in vitro simulation experiment demonstrated that PS/PVP electrospun fibrous membrane could decrease colony-forming unit counts of *** effectively,and PS/PVP electrospun fibrous membrane carrying calcium fluoride displayed better anti-adhesion ability than that of PS/PVP electrospun fibrous membrane ***,this research showed that the PS/PVP electrospun fibrous membrane has potential applications in controlling and preventing dental caries.

关键词： Streptococcus mutans PS/PVP electrospun fibrous membrane biofilm(s) anti-adhesion Coulomb repulsion

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Lung microbiome:new insights into the pathogenesis of respiratory diseases

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Signal Transduction and Targeted Therapy 2024年第2期9卷 652-678页

作者： Ruomeng Li Jing Li Xikun Zhou Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial *** microbiome of healthy lungs is mainly derived from the upper respiratory tract(URT)microbiome but also has its own characteristic *** selection mechanisms in the lung,including clearance by coughing,pulmonary macrophages,the oscillation of respiratory cilia,and bacterial inhibition by alveolar surfactant,keep the microbiome transient and mobile,which is different from the microbiome in other *** pulmonary bacteriome has been intensively studied recently,but relatively little research has focused on the mycobiome and *** up-to-date review retrospectively summarizes the lung microbiome’s history,composition,and *** focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune *** importantly,we focus on multiple respiratory diseases,including asthma,chronic obstructive pulmonary disease(COPD),fibrosis,bronchiectasis,and *** impact of the lung microbiome on coronavirus disease 2019(COVID-19)and lung cancer has also been comprehensively ***,by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field,we propose an outlook of the direction of lung microbiome research.

关键词： respiratory diseases Lung

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Development of pharmacological immunoregulatory anticancer therapeutics:current mechanistic studies and clinical opportunities

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2477-2526页

作者： Nanhao Yin Xintong Li Xuanwei Zhang Shaolong Xue Yu Cao Gabriele Niedermann You Lu Jianxin Xue Division of Thoracic Tumor Multimodality Treatment Cancer Center&State Key Laboratory of Biotherapyand The National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China Department of Gynecology and Obstetrics West China Second University HospitalSichuan UniversityNo.20Section 3South Renmin RoadChengdu 610041 SichuanPR China Department of Emergency Medicine Laboratory of Emergency MedicineWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China Institute of Disaster Medicine&Institute of Emergency Medicine Sichuan UniversityNo.17Gaopeng AvenueChengdu 610041 SichuanPR China Department of Radiation Oncology Medical Center—University of FreiburgFaculty of MedicineUniversity of FreiburgGerman Cancer Consortium(DKTK)Partner Site DKTK-FreiburgRobert-Koch-Strasse 379106 FreiburgGermany Laboratory of Clinical Cell Therapy West China HospitalSichuan UniversityNo.2222Xinchuan RoadChengdu 610041 SichuanPR China

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still *** to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable ***,comprehending the larger picture is *** this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint *** with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T *** by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical ***-generation agents also include immune epigenetic drugs and cytokine-based *** therapies,cancer vaccines,and oncolytic viruses are not covered in this *** comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

关键词： clinical immuno landscape

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Refining the targeted population and achieving better for colorectal cancer screening

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World Journal of Gastroenterology 2024年第25期30卷 3140-3142页

作者： Nuo-Ya Zhou Yi-Xiu Lin Liu-Xiang Chen Lian-Song Ye Bing Hu Department of Gastroenterology and Hepatology/Medical Engineering Integration Laboratory of Digestive Endoscopy West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina

This editorial comments on the article entitled“Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?”by Agatsuma et al,who conducted a retrospective study aiming at clarifying the stage at colorectal cancer(CRC)diagnosis based on different diagnostic *** share our opinion about CRC screening *** current situation suggests the need for a more specific and targeted population for CRC screening.

关键词： Colorectal cancer Screening Early diagnosis Technology Cost-effectiveness

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Chemical derivatization strategies for enhancing the HPLC analytical performance of natural active triterpenoids

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Journal of Pharmaceutical Analysis 2024年第3期14卷 295-307页

作者： Xiao-Feng Huang Ying Xue Li Yong Tian-Tian Wang Pei Luo Lin-Sen Qing chengdu Institute of Biology Chinese Academy of SciencesChengdu610041China State Key Laboratory for Quality Research in Chinese Medicines Macao University of Science and TechnologyMacaoChina sichuan Center for Disease Control and Prevention Chengdu610041China University of Chinese Academy of Sciences Beijing100049China

Triterpenoids widely exist in nature,displaying a variety of pharmacological *** triterpenoids in different matrices,especially in biological samples holds great ***-performance liquid chromatography(HPLC)has become the predominant method for triterpenoids analysis due to its exceptional analytical ***,due to the structural similarities among botanical samples,achieving effective separation of each triterpenoid proves challenging,necessitating significant improvements in analytical ***,triterpenoids are characterized by a lack of ultraviolet(UV)absorption groups and chromophores,along with low ionization efficiency in mass ***,routine HPLC analysis suffers from poor *** derivatization emerges as an indispensable technique in HPLC analysis to enhance its *** the structural characteristics of triterpenoids,various derivatization reagents such as acid chlorides,rhodamines,isocyanates,sulfonic esters,and amines have been employed for the derivatization analysis of *** review comprehensively summarized the research progress made in derivatization strategies for HPLC detection of ***,the limitations and challenges encountered in previous studies are discussed,and future research directions are proposed to develop more effective derivatization methods.

关键词： Triterpenoid HPLC Derivatization Quantification

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Development of small molecule drugs targeting immune checkpoints

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Cancer Biology & Medicine 2024年第5期21卷 382-399页

作者： Luoyi Chen Xinchen Zhao Xiaowei Liu Yujie Ouyang Chuan Xu Ying Shi Department of Oncology Sichuan Academy of Medical SciencesSichuan Provincial People’s HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610054China Institute for Breast Health Medicine State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Acupuncture and Massage College Chengdu University of Traditional Chinese MedicineChengdu 611137China

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune *** of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely ***,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule *** structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical *** way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic *** ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle *** this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

关键词： Immune checkpoints small molecule drugs programmed death protein 1 CD47 signal-regulatory proteinα

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