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

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(*** *** 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 *** 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 *** received prior-line(median,3)therapies,with 56.1%refractory to previous last therapies;73.2%experienced POD24 at *** stage 2,ORR was 86.6%(71/82;95%CI,77.3-93.1%),with 28(34.2%)complete *** control rate was 95.1%due to 7(8.5%)stable *** time to response was 1.8 *** 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)*** 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 *** 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 ***-B3525 showed favorable efficacy and safety for R/R FL patients after≥2 lines prior therapies.

关键词： lymphoma assessed initiated

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Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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Genes & Diseases 2024年第5期11卷 140-162页

作者： Xudong Li Wei Li Yanli Zhang Linping Xu Yongping Song department of hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China department of hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China

The advent of tyrosine kinase inhibitors(TKI)targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia(CML),greatly prolonged the life of CML patients,and improved their ***,TKI resistance is still a major problem with CML patients,reducing the efficacy of treatment and their quality of *** resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent ***,the main clinical strategy addressing TKI resistance is to switch to newly developed ***,data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance ***,finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system(UPS)has emerged as a *** UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological *** recent years,the study of UPS in hematological malignant tumors has resulted in effective treatments,such as bortezomib in the treatment of multiple myeloma and mantle cell *** CML,the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL,interfering with CML-related signaling pathways,and negatively or positively affecting leukemia stem *** of these molecules may help overcome TKI resistance and treat *** this review,the mechanism of TKI resistance is briefly described,the components of UPS are introduced,existing studies on UPS participating in TKI resistance are listed,and UPS as the therapeutic target and strategies are discussed.

关键词： Chronic myeloid leukemia Deubiquitinases E3 ligase PROTAC TKI resistance Ubiquitin-proteasome system

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Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss

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Research 2024年第1期2023卷 637-649页

作者： Hyun-Kyung So Hyebeen Kim Jinwoo Lee Chang-Lim You Chae-Eun Yun Hyeon-Ju Jeong Eun-Ju Jin Yunju Jo Dongryeol Ryu Gyu-Un Bae Jong-Sun Kang department of Molecular cell biology Sungkyunkwan University School of MedicineSuwonKorea Single cell Network Research Center Sungkyunkwan University School of MedicineSuwonKorea Research Institute of Aging-Related Diseases AniMusCureInc.SuwonKorea Drug Information Research Institute Muscle Physiome Research CenterCollege of PharmacySookmyung Women’s UniversitySeoulKorea

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative ***,the molecular mechanisms underlying neuromuscular dysfunction are currently *** studies have proposed important roles of Protein arginine methyltransferase 1(Prmt1)in muscle stem cell function and muscle *** the current study,we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1(mnKO)using *** exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and ***1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve *** transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation,cell death,oxidative stress,and ***,mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor ***,Prmt1 inhibition in motor neurons elicited mitochondrial *** findings demonstrate that Prmt1 ablation in motor neurons causes agerelated motor neuron degeneration attributing to muscle ***,Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.

关键词： degeneration impaired prevention

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BFP1:One of 700 Arabidopsis F-box proteins mediates degradation of JA oxidases to promote plant immunity

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Molecular Plant 2024年第3期17卷 375-376页

作者： Claus Wasternack Bettina Hause department of Molecular Signal Processing Leibniz Institute of Plant Biochemistry7 Weinberg 306120 Halle(Saale)Germany department of cell and Metabolic biology Leibniz Institute of Plant Biochemistry06120 Halle(Saale)Germany

A switch off in jasmonate(JA)signaling by hydroxylation upon wounding was described in 2008(Miersch et al.,2008).This initiated the cloning of CYP450 enzymes involved in hydroxylation and carboxylation of JA and its amino acid conjugate JA-le,the most active form of JA compounds(reviewed by Wasternack and Feussner[2018]and Heitz et al.[2019]).Due to the central role of JA and JA-lle in plant stress responses and development(Wasternack and Hause,2013),catabolism of JA and its derivatives is an essential component in the sustainment of homeostasis of active JA compounds(Howe et al.,2018;Heitz et al.,2019).Catabolism of JA and JAIle takes place by JA-induced oxygenases(JOXs),also named JA-oxidases(JAOs),and by hydroxylation(CYP94B3/B1)followed by carboxylation(CYP94C1),respectively(Heitz et al.,2019).Another reaction performed by IAR3/ILL6 results in the deconjugation of JA-lle and 12-OH-JA-le to JA and 12-OH-JA,respectively(Heitz et al.,2019;Wasternack and Feussner,2018).

关键词： conjugate initiated media

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Chromatin condensation but not DNA integrity of pig sperm is greater in the sperm-rich fraction

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Journal of Animal Science and Biotechnology 2024年第1期15卷 171-181页

作者： Estel Viñolas-Vergés Jordi Ribas-Maynou Isabel Barranco Camila Peres Rubio Sergi Bonet Jordi Roca Marc Yeste Unit of cell biology Department of BiologyFaculty of SciencesUniversity of GironaGironaSpain Biotechnology of Animal and Human Reproduction(TechnoSperm) Institute of Food and Agricultural TechnologyUniversity of GironaGironaSpain department of Medicine and Animal Surgery Faculty of Veterinary ScienceUniversity of MurciaMurciaSpain Catalan Institution for Research and Advanced Studies(ICREA) S08010 BarcelonaSpain

Background Protamination and condensation of sperm chromatin as well as DNA integrity play an essential role during fertilization and embryo *** some mammals,like pigs,ejaculates are emitted in three separate fractions:pre-sperm,sperm-rich(SRF)and post sperm-rich(PSRF).These fractions are known to vary in volume,sperm concentration and quality,as well as in the origin and composition of seminal plasma(SP),with differences being also observed within the SRF ***,whether disparities in the DNA integrity and chromatin condensation and pro-tamination of their sperm exist has not been *** This study determined chromatin protamination(Chromomycin A3 test,CMA_(3)),condensation(Dibromobi-mane test,DBB),and DNA integrity(Comet assay)in the pig sperm contained in the first 10 m L of the SRF(SRF-P1),the remaining portion of the sperm-rich fraction(SRF-P2),and the post sperm-rich fraction(PSRF).While chromatin protamination was found to be similar between the different ejaculate fractions(P>0.05),chromatin condensation was seen to be greater in SRF-P1 and SRF-P2 than in the PSRF(P=0.018 and P=0.004,respectively).Regarding DNA integrity,no differences between fractions were observed(P>0.05).As the SRF-P1 has the highest sperm concentra-tion and ejaculate fractions are known to differ in antioxidant composition,the oxidative stress index(OSi)in SP,calcu-lated as total oxidant activity divided by total antioxidant capacity,was tested and confirmed to be higher in the SRF-P1 than in SRF-P2 and PSRF(0.42±0.06 vs.0.23±0.09 and 0.08±0.00,respectively;P<0.01);this index,in addition,was observed to be correlated to the sperm concentration of each fraction(Rs=0.973;P<0.001).Conclusion While sperm DNA integrity was not found to differ between ejaculate fractions,SRF-P1 and SRF-P2 were observed to exhibit greater chromatin condensation than the *** could be related to the OSi of each fraction.

关键词： Chromatin Condensation DNA integrity Ejaculate fractions Pig Protamination Sperm

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SENP3 Promotes Mantle cell Lymphoma Development through Regulating Wnt10a Expression

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Current Medical Science 2024年第1期44卷 134-143页

作者： Yan-ni MA Yun-ding ZOU Zhi-long LIU Gui-xian WU Yuan-ze ZHOU Cheng-xin LUO Xiang-tao HUANG Ming-ling XIE Shuang-nian XU Xi LI department of hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China department of hematology the Third Affiliated Hospital(Daping Hospital)Third Military Medical University(Army Medical University)Chongqing 400042China

Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 *** of SENP3 has been proven to be involved in the development of various ***,its role in mantle cell lymphoma(MCL),a highly aggressive lymphoma,remains *** study was aimed to elucidate the effect of SENP3 in *** The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR,Western blotting or *** cells with stable SENP3 knockdown were constructed using short hairpin *** proliferation was assessed by CCK-8 assay,and cell apoptosis was determined by flow *** sequencing(mRNA-seq)was used to investigate the underlying mechanism of SENP3 knockdown on MCL development.A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in *** SENP3 was upregulated in MCL patient samples and *** of SENP3 in MCL cells inhibited cell proliferation and promoted cell ***,the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 ***,the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse *** SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

关键词： mantle cell lymphoma SENP3 cell proliferation apoptosis

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Degradation and resynthesis of chlorophyll during increased oxidative stress and prolonged darkness differ between annual and perennial flax(Linum L.)

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Oil Crop Science 2024年第2期9卷 121-130页

作者： Kenyon J. Nisbett Abida Alokozai Su Hyun Elizabeth Ko G. Adam Mott Jason C.L. Browna department of Biological Sciences University of Toronto ScarboroughTorontoONCanada department of cell&Systems biology University of TorontoTorontoONCanada Centre for the Analysis of Genome Evolution&Function University of TorontoTorontoONCanada

Among plants,there is considerable variation in lifespan:annuals live less than one year,whereas perennials live for several years,with the longest-living perennial having survived 43,600 *** proposed by the Disposable Soma Theory,this lifespan variation among plants likely reflects differential investment of limited energy and nutrient resources,with perennials investing more energy and nutrients into biomolecular maintenance compared to annuals in order to ensure persistence over multiple *** differential investment may be particularly important during periods of exogenous stress,which are known to accelerate biomolecular *** present study evaluated this hypothesis using annual and perennial flax(Linum L.)subjected to two exogenous stressors—increased oxidative stress(i.e.,foliar H2O2spraying)and complete prolonged *** chlorophyll has been shown to exhibit degradation in response to changes in environmental conditions,we utilized changes in chlorophyll levels during and after periods of exogenous stress to evaluate our *** predicted that i)perennials would exhibit a slower rate of chlorophyll degradation during exposure to exogenous stressors compared to annuals,and ii)perennials would exhibit a faster rate of chlorophyll resynthesis following such exposure compared to *** levels before,during,and after exposure to both exogenous stressors were measured in two separate trails,once using image colour analysis and once using *** chlorophyll degradation rates in response to oxidative stress did not differ between annuals and perennials,contrary to our predictions,chlorophyll resynthesis rates following such exposure were significantly higher in perennials,as *** plants were subjected to complete prolonged darkness,chlorophyll degradation rates were significantly lower in perennials than annuals,as predicted;however,when plants were subsequently reintroduced to natural photoperiod,ch

关键词： Ageing Life history Maximum lifespan Oxidative stress Somatic maintenance

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Monomorphic epitheliotropic intestinal T-cell lymphoma with bone marrow involved: A case report

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World Journal of Clinical Cases 2024年第4期12卷 814-819页

作者： Fen-Juan Zhang Wen-Juan Fang Cang-Jian Zhang department of hematology Lishui Municipal Central HospitalLishui 323000Zhejiang ProvinceChina

BACKGROUND Monomorphic epithelial intestinal T-cell lymphoma(MEITL)is a rare type of peripheral T-cell *** clinical manifestations are diarrhea,abdominal pain,perforation and an abdominal *** SUMMARY We present a 52-year-old female patient who was diagnosed with *** disease progression was observed after multiline ***,the patient died of a severe *** MEITL is a rare intestinal primary T-cell lymphoma with aggressive behavior,a high risk of severe life-threatening complications,and a poor prognosis.

关键词： Monomorphic epithelial intestinal T-cell lymphoma Autologous stem cell transplantation Chemotherapeutics Case report

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Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu Yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting Niu department of hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)*** targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in ***,novel targets for enhancing CAR-T cell therapy in MM remain *** receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for *** further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome *** the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and *** in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor *** results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering

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Morphometric Study of the Mastoid Process and its Role in Sex Differentiation:A Nigerian Computed Tomography Study

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Journal of Forensic Science and Medicine 2024年第1期10卷 1-10页

作者： Beryl Shitandi Ominde John NIgabari Joyce Ekeme Ikubor department of Human Anatomy and cell biology Delta State UniversityAbrakaNigeria department of Mathematics Delta State UniversityAbrakaNigeria department of Radiology Delta State University Teaching HospitalOgharaNigeria

Background:The mastoid process can be utilized in forensic identification due to its resistance to alterations and population variations in its *** study investigated the role of mastoid parameters in the determination of sex in a Nigerian *** and Objectives:The aim of this study was to determine the gender differences in measurements of the mastoid ***,the study aimed at assessing the percentage accuracy of using the mastoid variables in sex *** and Methods:This cross-sectional study used computed tomographic images of the brain,stored in the radiology unit of a referral hospital in Delta State,*** was granted by the hospital’s Ethics *** measurements of the mastoid process were taken on images of 310 patients(170 males and 140 females)aged 20-80 *** were summarized using means and standard ***,side,and age group comparisons were assessed using the independent t-test,paired t-test,and analysis of variance,*** association between variables was probed using Pearson’s correlation *** discriminant function analysis was used to determine the accuracy of correct sex *** probability value was set at<***:All the measurements were larger in males than in females(P<0.05).All except the conventional height,oblique sagittal diameter,and mediolateral inclination angle showed significant differences between age groups(P<0.05).The true height and oblique coronal diameter showed a significant positive correlation with age(0

关键词： Forensic mastoid process measurements sex determination

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