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, Volume 51 Issue 2 Previous Issue    Next Issue
Risk factors of acute kidney injury during BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma
LYU Yuqi,ZHANG Mingming,WEI Guoqing,DING Shuyi,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 137-143.   https://doi.org/10.3724/zdxbyxb-2022-0035
Abstract( 175 )   HTML( 18 )     PDF(2325KB)( 42 )

Objective: To explore the risk factors of acute kidney injury (AKI) during B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma (MM). Methods: The clinical data of 99 patients with relapsed/refractory MM who received BCMA CAR-T cell therapy in the First Affiliated Hospital of Zhejiang University School of Medicine from July 2018 to December 2021 was retrospectively analyzed. Dynamic changes of renal function before and after chemotherapy preconditioning and after CAR-T cell infusion were observed. Logistic regression was used to analyze the independent risk factors associated with the occurrence of AKI. Results: Among 99 patients, the AKI occurred in 25 cases with an incidence rate of 25.3%, and the median time was 8.0 (5.5,11.0)?d. The AKI grade 1, 2 and 3 accounted for 8.0%, 12.0% and 36.0%, respectively. Logistic regression analysis showed that serum creatinine (SCr) after chemotherapy preconditioning (OR=1.020, P<0.001), and the grade of cytokine release syndrome (CRS) (OR=6.501, P<0.01) were independent risk factors for AKI during treatment. The area under the ROC curve (AUC) of SCr after chemotherapy preconditioning in predicting AKI was 0.800 (95%CI: 0.694–0.904, P<0.001); using 83.0?μmol/L as cut-off value, the sensitivity, specificity and Youden index of SCr were 72.0%, 80.8% and 0.528, respectively. The incidence of AKI in patients with grade 3–4 CRS was 39.1%, while that was 13.2% in patients with CRS<grade 3 (χ2=8.767, P<0.01).Conclusions: AKI mostly occurred within 15.0?d after CAR-T cell infusion, causing transient severe renal damage. Patients with abnormal renal function after chemotherapy preconditioning should be alert to the occurrence of AKI, and attention should be paid to the management of the CRS.

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy
ZHANG Qiqi,ZU Cheng,MENG Ye,LYU Yuqi,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 144-150.   https://doi.org/10.3724/zdxbyxb-2022-0038
Abstract( 71 )   HTML( 2 )     PDF(2208KB)( 17 )

Objective: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. Method: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. Results: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0)?d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3–4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3–4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine (OR=1.015, P<0.01) and severe CRS (OR=9.371, P<0.01) were independent risk factors of TLS.Conclusions: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse
HUANG Luo,ZHANG Mingming,WEI Guoqing,ZHAO Houli,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 151-159.   https://doi.org/10.3724/zdxbyxb-2022-0036
Abstract( 60 )   HTML( 3 )     PDF(8367KB)( 6 )

Objective: To evaluate the efficacy and safety of CD19 chimeric antigen receptor (CAR) T cell therapy for patients with B cell acute lymphoblastic leukemia (B-ALL) involving extramedullary relapse. Methods: Fifteen patients with B-ALL involving extramedullary relapse who received CD19 CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2016 to October 2021 were enrolled in this study. The overall survival and leukemia-free survival of patients were analyzed using Kaplan-Meier curves, and the response of extramedullary lesions in different locations following the CD19 CAR-T cell therapy was observed. Cytokine release syndrome (CRS), hematological toxicity, and immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T cell therapy were analyzed. Results: The median follow-up time was 7 (3–71)?months, and 11 cases (73.3%) achieved complete response, median duration of complete response was 6 (2–27)?months; 3 cases (20.0%) achieved partial response; 1 case (6.7%) got progressive disease. The overall response rate was 93.3% (14/15), and the overall survival rate was 80.0% (12/15) at the end of follow-up. The cumulative incidence of relapse was 40.0% (6/15) and relapse mortality rate was 20.0% (3/15). Until last follow-up date, 9 cases (60.0%) were still in disease-free survival. Among the 15 patients, 13 cases (86.7%) developed cytokine release syndrome (CRS) after cell infusion, including 7 cases with grade 1–2 CRS, 6 cases with grade 3 CRS; 1 case suffered from reversible ICANS; 15 cases (100.0%) developed B cell dysplasia; 12 cases (80.0%) developed severe hematologic adverse reactions; 2 cases (13.3%) had abnormal liver function; 1 case (6.7%) had abnormal renal function; 4 cases (26.7%) developed infection. The adverse reactions mentioned above were well controlled. Conclusion: CD19 CAR-T cell therapy shows explicit efficacy and controllable adverse reactions for B-ALL patients with extramedullary relapse.

Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma
ZU Cheng,WANG Kexin,ZHANG Qiqi,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 160-166.   https://doi.org/10.3724/zdxbyxb-2022-0039
Abstract( 73 )   HTML( 2 )     PDF(2558KB)( 12 )

Objective : To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma. Methods : Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed. Results : CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0–19)?d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3–4), and robust expansion of CAR-T cells in the peripheral blood (all P <0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P <0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P >0.05]. Conclusions: The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma
FU Shan,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 167-174.   https://doi.org/10.3724/zdxbyxb-2022-0049
Abstract( 47 )   HTML( 3 )     PDF(5075KB)( 17 )

Objective: To evaluate the long-term efficacy of chimeric antigen receptor (CAR) T cell therapy in treatment of relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL). Methods: Clinical data of 27 patients with relapsed/refractory B-NHL treated with CAR-T cell in Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2016 to June 2020 were analyzed. Patients were followed up to February 1, 2022. The overall survival rate, progression free survival (PFS) rate were evaluated by Kaplan-Meier analysis, and the adverse reactions were recorded. Results: The median follow-up time of 27 patients was 32? (1, 56) months. The total response rate was 85.2% (23/27), the complete response rate was 63.0% (17/27), and the partial response rate was 22.2% (6/27). The 3-year overall survival rate was (50.0±10.1)%, and the PFS rate was (44.4±9.6)%. After CAR-T cell therapy, the overall survival and PFS of patients in the complete response group were significantly better than those in the non-complete response group [overall survival rate: (66.9±12.7)% vs. (20.0±12.6)%, P=0.01; PFS rate: (64.7±11.6)% vs. (10.0±9.5)%, P<0.01]. There was no significant difference in overall survival rate and PFS rate between CD19 targeted and CD19/CD22 dual-targeted CAR-T cell therapy (bothP>0.05). Cytokine release syndrome developed in 92.6% (25/27) of patients, and 88.9% (24/27) of patients had grade Ⅲ–Ⅳ myelosuppression. Other adverse reactions include immune effector cell-associated neurotoxicity syndrome, hepatitis B virus activation, and lung or gastrointestinal infections. No long-term adverse reactions occurred.Conclusions: CAR-T cell therapy is effective for patients with relapsed/refractory B-NHL, and the adverse reactions are controllable. The patients who obtain complete response after CAR-T cell therapy or survive for one year after therapy may have better long-term survival.

Advances in CAR-T cell therapy for malignant solid tumors
LIU Jiao,TU Xiaoxuan,LIU Lulu,FANG Weijia
J Zhejiang Univ (Med Sci), 2022, 51(2): 175-184.   https://doi.org/10.3724/zdxbyxb-2022-0044
Abstract( 110 )   HTML( 3 )     PDF(2359KB)( 40 )

T cells modified by chimeric antigen receptor (CAR) have the advantage of major histocompatibility complex-independent recognition of tumor-associated antigens, so can achieve efficient response to tumor targets. Chimeric antigen receptor (CAR) T cell therapy has shown a good therapeutic effect in hematological malignancies; however, its efficacy is generally not satisfactory for solid tumors. The reasons include the lack of tumor specific antigen target on solid tumors, the uncertainty of homing ability of engineered T cells and the inhibitory immune microenvironment of tumors. In clinical trials, the targets of CAR-T cell therapy for solid tumors are mainly disialoganglioside (GD2), claudin-18 isoform 2 (CLDN18.2), mesenchymal, B7 homolog 3 (B7H3), glypican (GPC) 3 and epidermal growth factor receptor variant Ш (EGFRvШ)Ⅲ. Combination of CAR-T cells with oncolytic viruses, tyrosine kinase inhibitors, and programmed death ligand-1 monoclonal antibodies may increase its efficacy. The CAR-T cell therapy for solid tumors can be optimized through gene editing to enhance the activity of CAR-T cells, adding corresponding regulatory components to make the activation of CAR-T cells safer and more controllable, and enhancing the persistence of CAR-T cells. In this article, we review the latest advances of CAR-T cell therapy in solid tumors to provide new insights for clinical application.

Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy
YE Baixin,HU Yongxian,ZHANG Mingming,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 185-191.   https://doi.org/10.3724/zdxbyxb-2022-0047
Abstract( 109 )   HTML( 8 )     PDF(9471KB)( 25 )

Chimeric antigen receptor (CAR) T cell therapy has shown significant efficacy for hematological malignancies, however, it needs to be further optimized. Recently, the lipid nanoparticle (LNP)-mRNA delivery system as a nonviral gene transfer vector has gained rapid progress in CAR-T cell therapy. The claudin-6 (CLDN6) mRNA is delivered to antigen presenting cells (APCs) through LNP system, thereby enhancing the function of CLDN6 CAR-T cells for the clearance of solid tumor cells. For treatment of acute cardiac injury, the fibroblast activation protein (FAP) CAR mRNA can be delivered to T cells through LNP system for the in vivo production of FAP CAR-T cells, thereby blocking the process of myocardial fibrosis. The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques. This article reviews the research advance in LNP-mRNA in vivo delivery system and its application in CAR-T cell therapy.

Progress on CAR-T cell therapy for hematological malignancies
HU Kejia,HUANG Yue,HU Yongxian,HUANG He
J Zhejiang Univ (Med Sci), 2022, 51(2): 192-203.   https://doi.org/10.3724/zdxbyxb-2022-0055
Abstract( 80 )   HTML( 10 )     PDF(3826KB)( 13 )

Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for hematological malignancies, which have experienced the development of CD19 CAR-T cells for B lymphoblastic leukemia and lymphoma, B cell maturation antigen (BCMA) CAR-T cells for multiple myeloid, and more recently, the development of CD7 CAR-T cells for T cell malignancies. There are more obstacles for myeloid malignancies compared to other hematological malignancies in this field, thus concerning researches are in more diverse ways. In order to obtain more effective clinical CAR-T cells with lower side effects, scientists have developed multi-target CAR-T cells, universal CAR-T cells, as well as CAR-T cells, CAR-NK cells, CAR-iMac cells derived from induced pluripotent stem cells (iPSC) by genetic engineering. Chinese scientists have made significant contribution to the invention and manufacture of origin CAR-T cells and the establishment of an intact clinical research system. This review introduces the latest progress involving CAR-T cell therapy for hematological malignancies including B lymphoblastic malignancies, T lymphoblastic malignancies and myeloid malignancies, and also discuss the future developments including multi-target, universal and iPSC-derived CAR-related cell therapy.

Impairment of endometrial decidual reaction in early pregnant mice fed with high fat diet
CHEN Zixuan,LI Weike,CHEN Xuemei,LIU Xueqing,DING Yubin,LI Fangfang,HE Junlin,WANG Yingxiong,GAO Rufei
J Zhejiang Univ (Med Sci), 2022, 51(2): 204-214.   https://doi.org/10.3724/zdxbyxb-2021-0354
Abstract( 123 )   HTML( 21 )     PDF(7805KB)( 39 )

Objective: To investigate the effect of obesity induced by high fat diet on decidual reaction of endometrium in mice, and the effect of high fat treatment on decidual reaction of endometrial stromal cells. Methods: Twelve 4-week-old healthy C57BL/6J female mice were randomly divided into high fat diet group and control group with 6 mice in each group. They were fed with high fat diet (22?kJ/g) or normal diet (16?kJ/g) for 12 weeks, respectively. The body weight of mice was measured every week. After feeding for 12 weeks, the body length and width of mice were measured, and the levels of fasting serum triglyceride and total cholesterol were determined. Then the mice were mated with healthy C57BL/6J male mice, and the uterine tissues were collected on the seventh day of pregnancy. The decidual cells and collagen fibers in mouse endometrium was observed by HE staining and Masson staining respectively. The expression of decidual reaction related proteins in mouse endometrium were detected by immunohistochemistry and Western blotting. Mouse endometrial stromal cells (mESCs) were isolated and treated with the oleic acid and palmitic acid in vitro , and the decidual reaction was induced with estradiol and progesterone. The accumulation of lipid droplets in mESCs was observed by oil red O and Bodipy staining. The cytoskeleton of mESCs was observed by phalloidin staining. The levels of decidual reaction related genes and proteins were detected by real-time fluorescence quantitative PCR and Western blotting. Results: After feeding for 12 weeks, the body weight of mice in the high fat group was significantly higher than that in the control group ( P <0.01), and there was no significant difference in body length between two groups ( P >0.05), but the body width of mice in the high fat group was significantly larger than that in the control group ( P <0.01), and the levels of serum triglyceride and total cholesterol were significantly higher than those in the control group (Both P <0.05). The number of embryo implantation in the high fat group was significantly less than that in the control group ( P <0.01). The differentiation of mESCs to decidual cells in high fat group was slow and abnormal. The expression levels of decidual reaction markers bone morphogenetic protein (BMP)2 and homeobox A10 (HOXA10) were lower than those in the control group, and there was significant difference in the expression level of HOXA10 ( P <0.01). The results of oil red O and Bodipy staining in mESCs showed that after high fat treatment, the accumulation of lipid droplets increased significantly, phalloidin staining showed abnormal cytoskeleton morphology. The expression levels of decidual reaction related genes dtprp , HOXA10 and proteins BMP2, HOXA10 and cyclooxygenase (COX)2 were significantly lower than those in the control group ( P <0.05). Conclusion: Obesity induced by high fat diet and high fat treatment can impair the decidual reaction of endometrium and endometrial stromal cells in mice.

Effect of circPUM1 on radioresistance of cervical cancer cells through targeting miR-144-3p
HU Bin,YUAN Jinjin
J Zhejiang Univ (Med Sci), 2022, 51(2): 215-224.   https://doi.org/10.3724/zdxbyxb-2022-0021
Abstract( 107 )   HTML( 13 )     PDF(14655KB)( 208 )

Objective: To investigate the effect of circular RNA pumilio RNA binding family member (circPUM) 1 on radioresistance of cervical cancer cells and its mechanism. Methods: Cancer tissue and corresponding paricancerous tissue samples were collected from 47 patients with cervical cancer who underwent surgical treatment in the Second Affiliated Hospital of Zhengzhou University from August 2019 to February 2020. The expression levels of circPUM1 and miR-144-3p in cervical cancer tissues and paricancerous tissues were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The Pearson method was used to analyze the correlation between circPUM1 and miR-144-3p expression in cervical cancer tissues. circPUM1 lentiviral short hairpin RNA (sh-circPUM1) and its negative control (sh-NC), miR-144-3p oligonucleotide mimic (miR-144-3p mimic) and its negative control (miR-NC), sh-circPUM1 and miR-144-3p inhibitor (anti-miR), and sh-circPUM1 and anti-miR negative control (anti-miR-NC) were transfected into human cervical carcinoma SiHa cells, respectively, and the cells were irradiated with 0 and 4?Gy irradiation doses. Cell proliferation, colony formation, apoptosis, migration and invasion were detected by cell counting kit (CCK-8 method), plate colony formation assay, flow cytometry and Transwell assay, respectively. The protein expression of cleaved-caspase3 was detected by Western blotting. The targeting relationship between circPUM1 and miR-144-3p was analyzed with Starbase platform. Results: Compared with adjacent tissue, the expression of circPUM1 in cervical cancer tissue was significantly increased (P<0.05), while the expression of miR-144-3p was decreased (P<0.05). The circPUM1 was negatively correlated with miR-144-3p (r=–0.9282, P<0.01). After transfection with sh-circPUM1 or miR-144-3p mimic, the inhibition rate of cell proliferation, the rate of apoptosis and the expression level of cleaved-caspase3 protein increased (allP<0.05), while the number of colonies formed, migrated and invaded cells decreased (allP<0.05). CircPUM1 could targeted to miR-144-3p. After co-transfection of sh-circPUM1 and anti-miR, the inhibition rate of cell proliferation, the rate of apoptosis and the expression level of cleaved-caspase3 protein significantly decreased (allP<0.05), while the number of colonies formed, migrated and invaded cells increased (allP<0.05).Conclusion: Silencing circPUM1 may inhibit the proliferation, colony formation, migration, invasion and induce apoptosis of cervical cancer cells through targeting and regulating the expression of miR-144-3p.

Clinical features of multifocal papillary thyroid carcinoma and risk factors of cervical metastatic lymph nodes
NI Yaqiong,WANG Tao,WANG Xingyue,TIAN Youxin,WEI Wentao,LIU Qinjiang
J Zhejiang Univ (Med Sci), 2022, 51(2): 225-232.   https://doi.org/10.3724/zdxbyxb-2021-0389
Abstract( 131 )   HTML( 8 )     PDF(2273KB)( 18 )

Objective: To analyze the clinical features of multifocal papillary thyroid carcinoma (PTC) and the risk factors of cervical metastatic lymph nodes. Methods: A total of 1524 patients with papillary thyroid carcinoma admitted in Gansu Provincial Cancer Hospital from January 2020 to August 2021 were enrolled, including 492 cases of multifocal PTC and 1032 cases of unifocal PTC. The clinicopathologic features of multifocal PTC and unifocal PTC were analyzed by comparing their differences in gender, ethnicity, age, body mass index, accompanying diabetes mellitus, accompanying hypertension, preoperative thyroid stimulating hormone and thyroglobulin levels, location of lesions, maximum diameter of lesions, sum of lesion diameters, central metastatic lymph nodes, lateral cervical metastatic lymph nodes, presence of Hashimoto’s thyroiditis, and thyroid capsule invasion. Patients were also assessed according to the presence or absence of central metastatic lymph nodes and lateral cervical metastatic lymph nodes to understand clinicopathological parameter differences, and multivariate logistic regression analysis was used to explore the risk factors. Results: Compared with unifocal PTC group, multifocal PTC group had significantly higher proportion of patients aged over 55?years, accompanying hypertension, central metastatic lymph nodes or cervical metastatic lymph nodes, Hashimoto’s thyroiditis and capsule invasion (all P<0.05); 55.1% of patients with multifocal PTC had lesions distributed bilaterally, and the maximum diameter and diameter sum of the lesions were greater than those in unifocal PTC group (allP<0.01). Multivariate logistic regression analysis showed that male, maximum diameter of lesion more than 7?mm, capsular invasion were independent risk factors for central metastatic lymph nodes (allP<0.05); while male, maximum diameter of lesion more than 7?mm, preoperative thyroglobulin more than 55?ng/mL, and central metastatic lymph nodes were risk factors for lateral cervical metastatic lymph nodes in patients with multifocal PTC (allP<0.05).Conclusion: Patients with multifocal PTC have significantly higher central and lateral cervical metastatic lymph nodes, particularly for male patients with a maximum diameter of lesion more than 7?mm, invasion of capsule, and preoperative thyroglobulin more than 55?ng/mL.

Nano-drug delivery system for the treatment of acute myelogenous leukemia
ZHANG Shaoqi,SUN Jie
J Zhejiang Univ (Med Sci), 2022, 51(2): 233-240.   https://doi.org/10.3724/zdxbyxb-2022-0084
Abstract( 148 )   HTML( 27 )     PDF(2097KB)( 26 )

Administration of therapeutic drugs has been the core strategy for acute myelogenous leukemia (AML), but it is generally limited by its low bioavailability, toxic side effects and intravenous administration. The nano-drug delivery system significantly improves the anti-AML activity through targeted optimization of the drug delivery system. Organic nanocarriers include polymers, liposomes, nanoemulsion, nanomicelle and proteins, which have the advantages of high loading capacity, biocompatibility and functionalization. Inorganic nanocarriers include gold nanoparticles, silicon nanoparticles, iron nanoparticles and other inorganic nanoparticles, which exhibit diverse physical and chemical properties, and have a wide range of biomedical applications including drug carriers. Both organic and inorganic nanocarriers exhibit the potential to alter the pharmacokinetics and pharmacodynamics of drugs. This article reviews the recent progress of nanocarriers as drug delivery system in clinical applications of AML treatment.

Current status of cancer starvation therapy
LI Jianyi,TONG Dandan,LIN Junsheng
J Zhejiang Univ (Med Sci), 2022, 51(2): 241-250.   https://doi.org/10.3724/zdxbyxb-2021-0297
Abstract( 161 )   HTML( 25 )     PDF(4419KB)( 47 )

Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive cancer cells of nutritional supply. There are several approaches to“starve” cancer cells: to intervene tumor angiogenesis by targeted inhibition of angiogenic factors or their receptors and integrins; to block the blood supply of cancer cells by embolizing or compressing blood vessels; to intervene metabolic process of cancer cells by inhibition of the signal pathways of mitochondrial serine-glycine-one earbon metabolism, glycolysis and amino acid metabolism; cancer starvation therapy can be employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-autophagy therapy or other therapies to achieve synergistic effects. This article reviews the research progress of cancer starvation therapy in recent years and discusses the existing problems.

Methyltransferase SET domain family and its relationship with cardiovascular development and diseases
XING Jingci,JIE Wei
J Zhejiang Univ (Med Sci), 2022, 51(2): 251-260.   https://doi.org/10.3724/zdxbyxb-2021-0192
Abstract( 115 )   HTML( 7 )     PDF(2160KB)( 21 )

Abnormal epigenetic modification is closely related to the occurrence and development of cardiovascular diseases. The SET domain (SETD) family is an important epigenetic modifying enzyme containing SETD. They mainly affect gene expression by methylating H3K4, H3K9, H3K36 and H4K20. Additionally, the SETD family catalyzes the methylation of non-histone proteins, thereby affects the signal transduction of signal transduction and activator of transcription (STAT) 1, Wnt/β-catenin, hypoxia-inducible factor (HIF)-1α and Hippo/YAP pathways. The SETD family has the following regulatory effects on cardiovascular development and diseases: regulating coronary artery formation and cardiac development; protecting cardiac tissue from ischemia reperfusion injury; regulating inflammation, oxidative stress and apoptosis in cardiovascular complications of diabetes; participating in the formation of pulmonary hypertension; regulating thrombosis, cardiac hypertrophy and arrhythmia. This article summarizes the basic structures, expression regulation mechanisms and the role of existing SETD family members in cardiovascular development and diseases, in order to provide a basis for understanding the molecular mechanism of cardiovascular disease and exploring the therapeutic targets.

Necroptosis in pathogenesis of osteoarthritis and its therapeutic implications
LIU Zhichao,QIAN Zhouyang,WANG Yingnan,WANG Huiming
J Zhejiang Univ (Med Sci), 2022, 51(2): 261-265.   https://doi.org/10.3724/zdxbyxb-2021-0402
Abstract( 109 )   HTML( 13 )     PDF(2583KB)( 14 )

Osteoarthritis is a progressive degenerative joint disease induced by many causes, for which there is no radical cure currently. Necroptosis is a newly reported programmed cell death, and its related factors are also inseparable from the progress of osteoarthritis. For examples, damage-associated?molecular?pattern promotes the release of various inflammatory factors, so as to recruit macrophages and promote local inflammation of the joint; inhibition of receptor-interacting protein kinase can reduce the death of cell and the expression of inflammatory factors, so as to reduce cartilage damage. Therefore, in-depth study of the regulatory mechanism of necroptosis in osteoarthritis will help to further reveal the pathogenesis of osteoarthritis, so as to provide potential targets for the treatment of osteoarthritis.

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