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Approach to loss of response to advanced therapies in inflammatory bowel disease

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World Journal of Gastroenterology 2024年第22期30卷 2902-2919页

作者： Nikil Vootukuru Abhinav Vasudevan department of Gastroenterology and Hepatology Eastern HealthVictoriaBox Hill 3128Australia eastern Health clinical school Monash UniversityVictoriaBox Hill 3128Australia

BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel *** now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many ***,issues of primary non-response(PNR)and secondary loss of response(SLOR)to non-tumour necrosis factor inhibitor(TNFi)therapies remains a common *** issues include the choice of optimization of therapy,identifying when dose optimization will recapture response,establishing optimal dose for escalation and when to switch *** To explores the issues of PNR and SLOR to non-TNFi *** This review explores the current evidence and literature to elucidate management options in cases of PNR/*** will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring(TDM).RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin(IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture *** Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of *** The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

关键词： Inflammatory bowel disease Ulcerative colitis Crohn Biologics Interleukin-12 and interleukin-23 inhibitors Alpha-beta7-integrin inhibitors Janus kinase inhibitors Sphingosine-1-phosphate receptor modulators

Macrocyclic trichothecenes from Myrothecium verrucaria PA 57 and their cytotoxic activity

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Chinese Journal of Natural Medicines 2024年第9期22卷 854-863页

作者： MO Jisong TAN Yufen AI Wenjing LI Yunyun YUAN Yiyun JIANG Yueping XU Kangping TAN Guishan WANG Wenxuan LI Jing LIU Shao department of Pharmacy National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangsha 410008China Xiangya school of Pharmaceutical Sciences Central South UniversityChangsha 410008China

Four novel macrocyclic trichothecenes,termed mytoxins D-G(1-4),along with four known analogs(5-8),were isolated from the ethyl acetate extract of fermented rice inoculated with the fungus Myrothecium verrucaria *** compound features a tricyclic 12,13-epoxytrichothec-9-ene(EPT)***,mytoxin G(4)represents the first instance of a macrocyclic trichothecene incorporating a glucosyl unit within the trichothecene *** structures of the newly identified compounds were elucidated through comprehensive spectroscopic analysis combined with quantum chemical *** isolated compounds demonstrated cytotoxic activity against the CAL27 and HCT116 cell lines,which are models for human oral squamous cell carcinoma and colorectal cancer,***,mytoxin D(1)and mytoxin F(3)exhibited pronounced cytotoxic effects against both cancer cell lines,with IC_(50)values ranging from 3 to 6 nmol·L^(-1).Moreover,compounds 1 and 3 were found to induce apoptosis in HCT116 cells by activating caspase-3.

关键词： Macrocyclic trichothecenes Myrothecium verrucaria Cytotoxicity Secondary metabolite Soil fungi

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Nano-Bacillus Calmette-Guérin immunotherapies for improved bladder cancer treatment

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 557-567页

作者： Sheng ZENG Shaoqiang XING Yifei ZHANG Haifeng WANG Qian LIU department of Urology Tianjin First Central HospitalTianjin 300192China department of Urology First Central Clinical CollegeTianjin Medical UniversityTianjin 300192China

Cancer immunotherapy has rapidly become the fourth mainstream treatment alternative after surgery,radiotherapy,and chemotherapy,with some promising *** aims to kill tumor cells by mobilizing or stimulating cytotoxic immune ***,the clinical applications of tumor immunotherapies are limited owing to a lack of adequate delivery pathways and high ***,nanomaterials and genetic engineering have shown great potential in overcoming these limitations by protecting the delivery of antigens,activating targeted T cells,modulating the immunosuppressive tumor microenvironment,and improving the treatment *** Calmette-Gué;rin(BCG)is a live attenuated Mycobacterium bovis vaccine used to prevent tuberculosis,which was first reported to have antitumor activity in *** therapy can activate the immune system by inducing various cytokines and chemokines,and its specific immune and inflammatory responses exert antitumor *** was first used during the 1970s as an intravesical treatment agent for bladder cancer,which effectively improved immune antitumor activity and prevented tumor *** recently,nano-BCG and genetically engineered BCG have been proposed as treatment alternatives for bladder cancer due to their ability to induce stronger and more stable immune *** this study,we outline the development of nano-BCG and genetically engineered BCG for bladder cancer immunotherapy and review their potential and associated challenges.

关键词： Bladder cancer Bacillus Calmette-Gué rin vaccine Nanocarrier Genetic engineering Immunotherapy

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 844-856页

作者： Yu-Liang Zhang Zi-Rong Liu Zhi Liu Yi Bai Hao Chi Da-Peng Chen Ya-Min Zhang Zi-Lin Cui First central clinical College Tianjin Medical UniversityTianjin 300070China department of Hepatobiliary Surgery Tianjin First Central HospitalSchool of MedicineNankai UniversityTianjin 300192China

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common types of cancers worldwide,ranking fifth among men and seventh among women,resulting in more than 7 million deaths *** the development of medical tech-nology,the 5-year survival rate of HCC patients can be increased to 70%.How-ever,HCC patients are often at increased risk of cardiovascular disease(CVD)death due to exposure to potentially cardiotoxic treatments compared with non-HCC ***,CVD and cancer have become major disease burdens ***,further research is needed to lessen the risk of CVD death in HCC patient *** This study was conducted on the basis of the Surveillance,Epidemiology,and End Results database and included HCC patients with a diagnosis period from 2010 to *** independent risk factors were identified using the Fine-Gray model.A nomograph was constructed to predict the CVM in HCC *** nomograph performance was measured using Harrell’s concordance index(C-index),calibration curve,receiver operating characteristic(ROC)curve,and area under the ROC curve(AUC)***,the net benefit was estimated via decision curve analysis(DCA).RESULTS The study included 21545 HCC patients,of whom 619 died of ***(5 cm:2.090(1.543-2.830),P<0.001],surgery(no)[0.376(0.297-0.476),P<0.001],and chemotherapy(none/unknown)[0.578(0.472-0.709),P<0.001]were independent risk factors for CVD death in HCC *** discrimination and calibration of the nomograph were *** C-index values for the training and validation sets were 0.736 and 0.665,*** AUC values of the ROC curves at 2,4,and 6 years were 0.702,0.725,0.740 in the training set and 0.697,0.710,0.744 in the validation set,*** calibration curves showed that the

关键词： Hepatocellular carcinoma Cardiovascular disease deaths Fine-Gray model Risk factor Nomograph Predict

Pannexins in the musculoskeletal system:new targets for development and disease progression

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Bone Research 2024年第2期12卷 255-269页

作者： Yan Luo Shengyuan Zheng Wenfeng Xiao Hang Zhang Yusheng Li department of Orthopedics Xiangya HospitalCentral South UniversityChangshaHunan 410008China National clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China department of clinical Medicine Xiangya Medicine SchoolCentral South UniversityChangshaHunan 410008China Shenzhen Institute of Advanced Technology Chinese Academy of SciencesShenzhen 518055China

During cell differentiation,growth,and development,cells can respond to extracellular stimuli through communication ***(Panx)family and connexin(Cx)family are two important types of channel-forming *** family contains three members(Panx1-3)and is expressed widely in bone,cartilage and *** there is no sequence homology between Panx family and Cx family,they exhibit similar configurations and *** to Cxs,the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed ***,we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis,chondrogenesis,and muscle *** also focus on the comparison between Cx and *** a new key target,Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.

关键词： skeletal diseases system

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Identification of a novel MYO1D variant associated with laterality defects,congenital heart diseases,and sperm defects in humans

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Frontiers of Medicine 2024年第3期18卷 558-564页

作者： Zhuangzhuang Yuan Xin Zhu Xiaohui Xie Chenyu Wang Heng Gu Junlin Yang Liangliang Fan Rong Xiang Yifeng Yang Zhiping Tan department of Cardiovascular Surgery The Second Xiangya Hospital of Central South UniversityChangsha410011China clinical Center for Gene Diagnosis and Therapy The Second Xiangya Hospital of Central South UniversityChangsha410011China department of Cell Biology School of Life SciencesCentral South UniversityChangsha410013China department of Gynecology and Obstetrics Xiangya Hospital of Central South UniversityChangsha410008China

The establishment of left–right asymmetry is a fundamental process in animal *** with this process leads to a range of disorders collectively known as laterality defects,which manifest as abnormal arrangements of visceral *** patients with laterality defects,congenital heart diseases(CHD)are *** multiple model organisms,extant research has established that myosin-Id(MYO1D)deficiency causes laterality *** study investigated over a hundred cases and identified a novel biallelic variant of MYO1D(NM_015194:c.1531G>A;p.D511N)in a consanguineous family with complex CHD and laterality *** examination of the proband revealed asthenoteratozoospermia and shortened ***,the effects of the D511N variant and another known MYO1D variant(NM_015194:c.2293C>T;p.P765S)were *** assessment showed that both enhance the interaction withβ-actin and ***,this study revealed the genetic heterogeneity of this rare disease and found that MYO1D variants are correlated with laterality defects and CHD in ***,this research established a connection between sperm defects and MYO1D *** offers guidance for exploring infertility and reproductive health *** findings provide a critical basis for advancing personalized medicine and genetic counseling.

关键词： MYO1D laterality defect congenital heart disease sperm defect β-actin SPAG6

Glymphatic system:a gateway for neuroinflammation

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Neural Regeneration Research 2024年第12期19卷 2661-2672页

作者： Kailu Zou Qingwei Deng Hong Zhang Changsheng Huang department of Anesthesiology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Xiangya school of Medicine Central South UniversityChangshaHunan ProvinceChina National clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the *** evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic *** diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous *** review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system *** addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and *** research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.

关键词： aquaporin-4 central nervous system disease cerebrospinal fluid chronic neuroinflammation glymphatic dysfunction neurodegeneration peripheral nerve injury perivascular space systemic disease vicious cycle

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Enantioselective iridium-catalyzed allylic substitution with a Reformatsky reagent: direct construction of β-stereogenic homoallylic esters

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Science China Chemistry 2024年第11期67卷 3791-3797页

作者： Debasis Pal Kirana D.Veeranna Yuk Fai Wong P.Andrew Evans department of Chemistry Queen's University Xiangya school of Pharmaceutical Sciences Central South University

The Reformatsky reagent derived from ethyl bromoacetate circumvents the challenge associated with the direct regio-and enantioselective iridium-catalyzed allylic alkylation with an unstabilized aliphatic ester enolate. Notably, this work represents the first example of using a Reformatsky reagent in a metal-allyl reaction, which permits the direct construction of enantioenriched β-stereogenic homoallylic esters without preactivation of the pronucleophile or post-reaction modification of the product(e.g., thermal decarboxylation of a 1,3-dicarbonyl). Moreover, the process allows the coupling of a broad range of sterically and electronically diverse electrophiles bearing aryl, heteroaryl and alkenyl derivatives, including the significantly more challenging alkyl-substituted allylic carbonates. The versatility of the ester product is exemplified by a series of functional group manipulations and the development of a concise and efficient enantioselective total synthesis of the natural product,(+)-descurainolide A. Finally, mechanistic studies indicate that the zinc enolate behaves as a soft nucleophile that undergoes outer-sphere alkylation.

关键词： allylic substitution asymmetric catalysis mechanistic studies natural product synthesis Reformatsky reagent

Immunologic tumor microenvironment modulators for turning cold tumors hot

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Cancer Communications 2024年第5期44卷 521-553页

作者： Gholam-Reza Khosravi Samaneh Mostafavi Sanaz Bastan Narges Ebrahimi Roya Safari Gharibvand Nahid Eskandari department of Medical immunology School of MedicineIsfahan University of Medical SciencesIsfahanIran department of immunology Faculty of Medical SciencesTarbiat Modares UniversityTehranIran department of immunology School of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment(TME).Hot tumors,characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors(ICIs),stand in stark contrast to cold tumors,which lack immune infiltration and remain resistant to *** overcome immune evasion mechanisms employed by tumor cells,novel immunologic modulators have emerged,particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1).These agents disrupt inhibitory signals and reactivate the immune system,transforming cold tumors into hot ones and promoting effective antitumor ***,challenges persist,including primary resistance to immunotherapy,autoimmune side effects,and tumor response *** these challenges requires innovative strategies,deeper mechanistic insights,and a combination of immune interventions to enhance the effectiveness of *** the landscape of cancer medicine,where immune cold tumors represent a formidable hurdle,understanding the TME and harnessing its potential to reprogram the immune response is *** review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies,offering hope for patients with immune-resistant tumors.

关键词： cold tumor hot tumor immunologic modulator immunotherapy therapeutic strategy tumor microenvironment