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Phase II study of novel orally PI3Kα/δinhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2193-2201页

作者： Huaqing Wang Jifeng Feng Yanyan Liu Zhengzi Qian Da Gao Xuehong Ran Hui Zhou Lihong Liu Binghua Wang Meiyun Fang Hebing Zhou Zhenqian Huang Shi Tao Zhuowen Chen Liping Su Hang Su Yu Yang Xiaobao Xie Huijing Wu Ping Sun Guoyu Hu Aibin Liang Zhiming Li Department of Oncology Tianjin Union Medical Center of Nankai UniversityTianjin 300121PR China The Institute of Translational medicine Tianjin Union Medical Center of Nankai UniversityTianjin 300121PR China Department of Medical Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing 210009PR China Department of Medical Oncology Henan Cancer HospitalThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhou 450003PR China Department of Medical Oncology Tianjin Medical University Cancer Institute and HospitalTianjin 300060PR China Department of Hematology The Affiliated Hospital of Inner Mongolia Medical College010050 HohhotPR China Department of Hematology Weifang People’s HospitalThe First Affiliated Hospital of Weifang Medical University261000 WeifangPR China Department of Lymphoma&Hematology Hunan Cancer HospitalThe Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University410013 ChangshaPR China Department of Hematology The Fourth Hospital of Hebei Medical University and Hebei Tumor Hospital050011 ShijiazhuangPR China Department of Lymphoma Weihai Central Hospital264400 WeihaiPR China Department of Hematology and Rheumatology The Affiliated Zhongshan Hospital of Dalian University116001 DalianPR China Department of Hematology Beijing Luhe Hospital101199 BeijingPR China Department of Hematology The First Affiliated Hospital of Guangzhou Medical University510120 GuangzhouPR China Department of Hematology The First Affiliated Hospital of Hainan Medical College570102 HaikouPR China Department of Hematology The First People’s Hospital of Foshan528000 FoshanPR China Department of Hematology Shanxi Cancer Hospital030013 TaiyuanPR China Department of Lymphoma Senior Department of HematologyThe Fifth Medical Center of Chinese PLA General Hospital100039 BeijingPR China Department of Lymphoma and Head and Neck Cancer Fujian Cancer Hospital350014 FuzhouPR China Department of Hematology The First People’s Hospit

This registration study assessed clinical outcomes of TQ-B3525,the dual phosphatidylinositol-3-kinase(PI3K)α/δinhibitor,in relapsed and/or refractory follicular lymphoma(R/R FL).This phase II study(ClinicalTrials.gov NCT04324879.Registered March 27,2020)comprised run-in stage and stage 2.R/R FL patients after≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression.Primary endpoint was independent review committee(IRC)-assessed objective response rate(ORR).Based on results(ORR,88.0%;duration of response[DOR],11.8 months;progression-free survival[PFS],12.0 months)in 25 patients at run-in stage,second stage study was initiated and included 82 patients for efficacy/safety analysis.Patients received prior-line(median,3)therapies,with 56.1%refractory to previous last therapies;73.2%experienced POD24 at baseline.At stage 2,ORR was 86.6%(71/82;95%CI,77.3-93.1%),with 28(34.2%)complete responses.Disease control rate was 95.1%due to 7(8.5%)stable diseases.Median time to response was 1.8 months.Among 71 responders,median DOR was not reached;18-month DOR rate was 51.6%.with median follow-up of 13.3 months,median PFS was 18.5(95%CI,10.2-not estimable)months.Median overall survival(OS)was not reached by cutoff date;24-month OS rate was estimated as 86.1%.Response rates and survival data were consistent across all subgroups.Grade 3 or higher treatment-related adverse events were observed in 63(76.8%)cases,with neutropenia(22.0%),hyperglycemia(19.5%),and diarrhea(13.4%)being common.TQ-B3525 showed favorable efficacy and safety for R/R FL patients after≥2 lines prior therapies.

关键词： lymphoma assessed initiated

Cardiac-Adaptive Conductive Hydrogel Patch Enabling Construction of Mechanical–Electrical Anisotropic Microenvironment for Heart Repair

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Research 2024年第1期2023卷 489-507页

作者： Xiaoping Song Jifeng Zhang Si Shen Dan Liu Jie Zhang Wenming Yin Genlan Ye Leyu Wang Liu Cai Honghao Hou Xiaozhong Qiu Central Laboratory The Fifth Affiliated HospitalSouthern Medical UniversityGuangzhouGuangdong 510910China Department of Anatomy Neuroscience Laboratory for Cognitive and Developmental DisordersMedical College of Jinan UniversityGuangzhou 510630China Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering School of Basic Medical ScienceBiomaterials Research CenterSchool of Biomedical EngineeringSouthern Medical UniversityGuangzhouGuangdong 510515China

The biomimetic construction of a microstructural–mechanical–electrical anisotropic microenvironment adaptive to the native cardiac tissue is essential to repair myocardial infarction(MI).Inspired by the 3D anisotropic characteristic of the natural fish swim bladder(FSB),a novel flexible,anisotropic,and conductive hydrogel was developed for tissue-specific adaptation to the anisotropic structural,conductive,and mechanical features of the native cardiac extracellular matrix.The results revealed that the originally stiff,homogeneous FSB film was tailored to a highly flexible anisotropic hydrogel,enabling its potential as a functional engineered cardiac patch(ECP).In vitro and in vivo experiments demonstrated the enhanced electrophysiological activity,maturation,elongation,and orientation of cardiomyocytes(CMs),and marked MI repair performance with reduced CM apoptosis and myocardial fibrosis,thereby promoting cell retention,myogenesis,and vascularization,as well as improving electrical integration.Our findings offer a potential strategy for functional ECP and provides a novel strategy to bionically simulate the complex cardiac repair environment.

关键词： bladder thereby patch

CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain

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neuroscience Bulletin 2023年第6期39卷 947-961页

作者： Ting Xu Zhen-Yu Li Meng Liu Su-Bo Zhang Huan-Huan Ding Jia-Yan Wu Su-Yan Lin Jun Liu Jia-You Wei Xue-Qin Zhang Wen-Jun Xin neuroscience program of zhongshan school of medicine and the fifth affiliated hospital Sun Yat-sen UniversityGuangzhou510080China Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-sen UniversityGuangzhou510120China Department of Anesthesia and Pain medicine Guangzhou First People’s HospitalGuangzhou510000China Department of Physiology Xuzhou Medical UniversityXuzhou221004China Department of Neurology The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou510000China Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong Provincial Key Laboratory of Biomedical Imagingand Department of Interventional MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityZhuhai519000China The affiliated Brain hospital(Guangzhou Huiai hospital)and school of Health Management Guangzhou Medical UniversityGuangzhou510182China Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Guangzhou510000China

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms.The circRNAs are mainly enriched in the central nervous system.However,their function in various physiological and pathological conditions have yet to be determined.Here,we identified circFhit,an exon-intron circRNA expressed in GABAergic neurons,which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain.Moreover,we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R^(+) neurons by promoting the expression of its parental gene Fhit in cis.Mechanistically,circFhit was directly bound to the intronic region of Fhit,and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron.In summary,we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R^(+) neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

关键词： Chronic pain Neuropathic pain CircRNA Inhibitory transmission Epigenetic regulation

Lack of evolutionary convergence in multiple primary lung cancer suggests insufficient specificity of personalized therapy

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Journal of Genetics and Genomics 2023年第5期50卷 330-340页

作者： Hua Cheng Ziyan Guo Xiaoyu Zhang Xiao-Jin Wang Zizhang Li Wen-Wen Huo Hong-Cheng Zhong Xiao-Jian Li Xiang-Wen Wu Wen-Hao Li Zhuo-Wen Chen Tian-Chi Wu Xiang-Feng Gan Bei-Long Zhong Vassily ALyubetsky Leonid Yu Rusin Junnan Yang Qiyi Zhao Qing-Dong Cao Jian-Rong Yang Department of Thoracic Surgery The Fifth Affiliated HospitalSun Yat-Sen UniversityZhuhaiGuangdong 519000China Department of Genetics and Biomedical Informatics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouGuangdong 510080China program in Cancer Research Zhongshan School of MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080China Kharkevich Institute for Information Transmission Problems Russian Academy Sciences Moscow 127051Russia Department of Mathematical Logic and Theory of Algorithms Faculty of Mechanics and MathematicsLomonosov Moscow State UniversityMoscow 119991Russia Department of Infectious Diseases Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510630China Guangdong Provincial Key Laboratory of Liver Disease Research the Third affiliated hospital Sun Yat-sen UniversityGuangzhouGuangdong 510630China Key Laboratory of Tropical Disease Control Ministry of EducationSun Yat-sen UniversityGuangzhouGuangdong 510080China

Multiple primary lung cancer(MPLC)is an increasingly prevalent subtype of lung cancer.According to recent genomic studies,the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence.We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found.Using our own and other relevant public data,evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk,indicating evolutionary contingency rather than adaptive convergence.Additionally,tumors from the same MPLC patient are as genetically diverse as those from different patients,while within-tumor genetic heterogeneity is significantly lower.Furthermore,the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor,but not with samples from other tumors or other patients.Overall,there is no evidence of adaptive convergence during the evolution of MPLC.Most importantly,the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient.To fully exploit the strategic value of precision medicine,targeted therapies should be designed and delivered on a per-lesion basis.

关键词： Multiple primary lung cancer Cancer evolution Convergent evolution

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2280-2291页

作者： Bowen Wang Li Wang Sijie Gu Yankun Yu Huaxing Huang Kunlun Mo He Xu Fanzhu Zeng Yichen Xiao Lulu Peng Chunqiao Liu Nan Cao Yizhi Liu Jin Yuan Hong Ouyang State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510623China program of Stem Cells and Regenerative medicine Fifth Affiliated HospitalZhongshan School of MedicineSun Yat-Sen UniversityGuangdong 510080China

Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the elderly.However,an effective therapy for this disease is lacking.Here,we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate(SI)-induced oxidative cell death and prolonged their healthy survival.D609 effectively attenuated excessive reactive oxygen species(ROS)and prevented severe mitochondrial loss due to oxidative stress in the RPE cells.Surprisingly,the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein.The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model.These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609,which may ultimately have clinical applications for the treatment of AMD.

关键词： D609 degeneration protective

Endophilin isoforms have distinct characteristics in interactions with N-type Ca^(2+) channels and dynamin I

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neuroscience Bulletin 2012年第5期28卷 483-492页

作者： Qi Tian Ji-Feng Zhang Jinjin Fan Zhihong Song Yuan Chen Center for Neurobiology Zhongshan School of Medicine Department of Nephrology The First Affiliated Hospital Department of Biochemistry Zhongshan School of Medicine Sun-Yat Sen University Guangzhou 510080 China

Objective Formation of the endophilin II-Ca 2＋ channel complex is Ca 2＋ -dependent in clathrin-mediated endocytosis. However, little is known about whether the other two endophilin isoforms have the same features. The present study aimed to investigate the characteristics of the interactions of all three isoforms with Ca 2＋ channels and dynamin I. Methods N-type Ca 2＋ channel C-terminal fragments （NCFs） synthesized with a 3 H-leucine-labeled kit, were incubated with endophilin-GST fusion proteins, followed by pull-down assay. Results were counted on a scintillation counter. In addition, the different endophilin isoforms were each co-transfected with dynamin I into 293T cells, followed by flow cytometry and co-immunoprecipitation assay. Immunostaining was performed and an image analysis program was used to evaluate the overlap coefficient of cells expressing endophilin and dynamin I. Results All three isoforms interacted with NCF. Endophilins I and II demonstrated clear Ca 2＋ -dependent interactions with NCF, whereas endophilin III did not. Co-immunoprecipitation showed that, compared to endophilin I/II, the interaction between endophilin III and dynamin I was significantly increased. Similar results were obtained from flow cytometry. Furthermore, endophilin III had a higher overlap coefficient with dynamin I in co-transfected 293T cells. Conclusion Endophilin isoforms have distinct characteristics in interactions with NCF and dynamin I. Endophilin III binding to NCF is Ca 2＋ -independent, implying that it plays a different role in clathrin-mediated endocytosis.

关键词： endophilin Ca2＋ dynamin I endocytosis proline-rich domain SH3 domain

Specificity of mRNA Folding and Its Association with Evolutionarily Adaptive mRNA Secondary Structures

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Genomics, Proteomics & Bioinformatics 2021年第6期19卷 882-900页

作者： Gongwang Yu Hanbing Zhu Xiaoshu Chen Jian-Rong Yang program in Cancer Research Zhongshan School of MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Medical Informatics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China zhongshan school of medicine Sun Yat-sen UniversityGuangzhou 510080China Department of Genetics and Cell Biology Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China RNA Biomedical Institute Sun Yat-Sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

The secondary structure is a fundamental feature of both non-coding RNAs(ncRNAs)and messenger RNAs(mRNAs).However,our understanding of the secondary structures of mRNAs,especially those of the coding regions,remains elusive,likely due to translation and the lack of RNA-binding proteins that sustain the consensus structure like those binding to ncRNAs.Indeed,mRNAs have recently been found to adopt diverse alternative structures,but the overall functional significance remains untested.We hereby approach this problem by estimating the folding specificity,i.e.,the probability that a fragment of an mRNA folds back to the same partner once refolded.We show that the folding specificity of mRNAs is lower than that of ncRNAs and exhibits moderate evolutionary conservation.Notably,we find that specific rather than alternative folding is likely evolutionarily adaptive since specific folding is frequently associated with functionally important genes or sites within a gene.Additional analysis in combination with ribosome density suggests the ability to modulate ribosome movement as one potential functional advantage provided by specific folding.Our findings reveal a novel facet of the RNA structurome with important functional and evolutionary implications and indicate a potential method for distinguishing the mRNA secondary structures maintained by natural selection from molecular noise.

关键词： Evolutionary genomics RNA secondary structure RNA folding specificity RNA alternative folding Ribosome density

The evolution of sex chromosome dosage compensation in animals

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Journal of Genetics and Genomics 2020年第11期47卷 681-693页

作者： Jiabi Chen Menghan Wang Xionglei He Jian-Rong Yang Xiaoshu Chen Department of Biology and Medical Genetics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina State Key Laboratory of Biocontrol College of Life SciencesSun Yat-sen UniversityGuangzhouChina Department of Biomedical Informatics Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina RNA Biomedical Institute Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina program in Cancer Research Zhongshan School of MedicineThe Fifth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

The evolution of heteromorphic sex chromosomes shall lead to gene expression dosage problems,as in at least one of the sexes,the sex-linked gene dose has been reduced by half.It has been proposed that the transcriptional output of the whole X or Z chromosome should be doubled for complete dosage compensation in heterogametic sex.However,owing to the variability of the existing methods to determine the transcriptional differences between sex chromosomes and autosomes(S:A ratios)in different studies,we collected more than 500 public RNA-Seq data set from multiple tissues and species in major clades and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species.We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes.We found that in mammals and birds,the S:A ratio is approximately 0.5,whereas in insects,fishes,and flatworms,the S:A ratio is approximately 1.0.Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the X/Z chromosome is significantly correlated with the S:A ratio.In addition,the degree of degeneration of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage compensation mechanism.Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that dosage sensitivity states of sex chromosomes are a major factor underlying different evolutionary strategies of dosage compensation.

关键词： Dosage compensation Sex chromosome Genomic evolution

Immunopotentiator Thymosin Alpha-1 Promotes Neurogenesis and Cognition in the Developing Mouse via a Systemic Th1 Bias

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neuroscience Bulletin 2017年第6期33卷 675-684页

作者： Ge Wang Fen He Yunlong Xu Yuwei Zhang Xiao Wang Chunhua Zhou Yihong Huang Juntao Zou Department of Anatomy and Neurobiology Zhongshan School of Medicine Sun Yat-Sen University Department of Radiation Oncology First Affiliated HospitalGuangzhou Medical University South China Research Center for Acupuncture and Moxibustion Medical College of Acu-Moxi and RehabilitationGuangzhou University of Chinese Medicine Department of Anatomy Wannan Medical College Department of Neurology The Fifth Affiliated Hospital of Southern Medical University

In early life, the immune system plays an essential role in brain development. In our study, the immunopotentiator thymosin alpha-1（Ta1） was peripherally administered to neonatal mice to explore whether the peripheral immunopotentiator affects neurodevelopment and cognition, and to further investigate the relevant mechanism. Compared with the control group, the Ta1 mice displayed better cognitive abilities in early life. The numbers of 5-bromodeoxyuridine（Brd U）＋, nestin＋,T-box transcription factor 2（Tbr2）＋, Brd U＋/doublecortin（DCX）＋, Brd U＋/ionized calcium-binding adaptor molecule 1（Iba1）＋, and Brd U＋/neuronal nuclei（Neu N）＋ cells in the hippocampus were increased in the Ta1 group,accompanied by increased interleukin-4（IL-4）, interferon-gamma, brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor-1 as well as decreased IL-6 and tumor necrosis factor-a. Furthermore, the Ta1-group showed a Th1-polarized immune response, and the neurotrophic factors were positively associated with the Th1/Th2 ratio. More importantly, administration of Ta1 blocked lipopolysaccharide-induced impairment of hippocampal neurogenesis in early life. These findings suggest that peripheral Ta1 contributes to neurogenesis and cognition probably through a systemic Th1 bias, as well as neuroprotection against LPS infection by Ta1.

关键词： Microglia Th1/Th2 bias IGF-1 Brain-derived neurotrophic factor Nerve growth factor