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Biomolecules Jun 2024Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer...
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The mutation status prediction model exhibited high accuracy in distinguishing between -positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping.
Topics: Humans; ErbB Receptors; Lung Neoplasms; Early Detection of Cancer; Mutation; Cell-Free Nucleic Acids; Female; Male; Middle Aged; Aged; Proof of Concept Study; Biomarkers, Tumor; Liquid Biopsy; Whole Genome Sequencing; Transcription Initiation Site; Circulating Tumor DNA
PubMed: 38927119
DOI: 10.3390/biom14060716 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs,... (Review)
Review
Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs, proteasome inhibitors, anti-CD38 antibodies, CAR-T, and HSCT have significantly improved the prognosis of patients with MM, however new therapeutic tools need to be developed to improve the prognosis of patients with relapsed/refractory after conventional regimens treatment. Bispecific antibodies are a novel immunotherapeutic approach that generates immune synapses by binding to targets on malignant plasma cells and cytotoxic immune effector cells (T cells/natural killer cells), leading to T/NK cells activation and malignant plasma cell lysis. Several preclinical and phase I clinical studies have shown good efficacy, bringing new possibilities for patients with relapsed/refractory MM to improve their prognosis in the future in combination with the rest of the treatment options. This article summarizes the classification of bispecific antibodies developed in recent years, and the results of preclinical and clinical trials, which will provide some reference for treating MM.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Immunotherapy; Killer Cells, Natural; Prognosis; T-Lymphocytes
PubMed: 38926994
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.046 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple...
OBJECTIVE
To investigate the correlation between the stimulator of interferon genes ( ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma.
METHODS
A total of 102 patients who had undergone chemotherapy for multiple myeloma in our hospital from January 2016 to July 2022 were selected. Depending on the presence or absence of infection after chemotherapy, the enrolled patients were divided into infection group (53 cases) and non-infection group (49 cases). The infection sites and distribution characteristics of pathogenic bacteria of the infection group were analyzed. The genotype distribution of gene promoter rs587777609 was compared between the two groups, and the risk factors of infection after chemotherapy for multiple myeloma were analyzed.
RESULTS
For infection site, digestive system, respiratory system, urinary system, skin and mucous membranes accounted for 43.40%, 26.42%, 20.75%, and 9.43%, respectively. For pathogenic bacteria, Gram-negative bacteria, Gram-positive bacteria and fungi accounted for 57.14%, 26.98%, and 15.87%, respectively. The CC genotype frequency of gene rs587777609 locus in the infection group was lower than that in the non-infection group, while the TT genotype frequency was higher than that in the non-infection group ( < 0.05). The proportions of patients with diabetes, chronic obstructive pulmonary disease, renal insufficiency, serum albumin level< 35 g/L, ISS stage III, mechanical ventilation, and indwelling catheter in the infection group were higher than those in the non-infection group ( < 0.05). Multivariate logistic regression analysis showed that diabetes ( =1.992), serum albumin level< 35 g/L ( =2.782), ISS stage III ( =2.707), mechanical ventilation ( =3.031), and TT genotype ( =2.401) were risk factors of infection after chemotherapy for multiple myeloma ( < 0.05).
CONCLUSION
There is a correlation between promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma, and patients with TT genotype have a higher risk of infection.
Topics: Humans; Multiple Myeloma; Membrane Proteins; Promoter Regions, Genetic; Genotype; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Male; Infections; Female
PubMed: 38926990
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.042 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing...
OBJECTIVE
To investigate the role of levofloxacin combined with recombinant human granulocyte colony-stimulating factor (G-CSF) or only G-CSF supportive therapy in preventing infection in autologous hematopoietic stem cell transplantation(ASCT), and to analyze the length of hospital stay, hospitalization cost and post-transplant survival of the patients.
METHODS
A retrospective analysis was performed in the patients with hematological malignancies who accepted ASCT at our hospital from January 2012 to July 2022, the febrile neutropenia, the incidence of bacterial infection and the use rate of intravenous antibiotics in the levofloxacin+G-CSF group and only G-CSF support group during ASCT were observed. The length of hospital stay, total cost during hospitalization and survival after 90 days of transplantation between the two groups were compared.
RESULTS
A total of 102 cases were included in this study, including 57 cases of multiple myeloma, 36 cases of acute leukaemia, 7 cases of lymphoma, 3 cases of myelodysplastic syndrome, 1 case of light chain amyloidosis, and 1 case of POEMS syndrome. 47 patients received levofloxacin+ G-CSF antibacterial prophylaxis, and 55 patients received G-CSF supportive therapy. In the levofloxacin+ G-CSF group, 40 cases (85.11%) developed febrile neutropenia, and 13 cases (27.66%) were confirmed as bacterial infection. In the G-CSF group, 44 cases (80.00%) developed febrile neutropenia, and 16 cases (29.09%) were bacterial infection. There was no statistically significant difference in the incidence of febrile neutropenia and bacterial infection between the two groups (χ=0.46, =0.50; χ=0.03, =0.87). The use rate of intravenous antibiotics in the levofloxacin+ G-CSF group was 85.11% (40/47), which was not statistically different from 85.45% (47/55) in the G-CSF group (χ=0.04, =0.84). The detection rates of levofloxacin-resistant bacteria in the levofloxacin+ G-CSF group and G-CSF group were 8.57% (3/35) and 21.43% (6/28), respectively, with no statistical difference (χ=0.65, >0.05). The median length and median cost of hospitalization in the levofloxacin+ G-CSF group and G-CSF group were 25 d 22 d and 78 216.24 yuan 80 724.38 yuan, with no statistically significant differences ( =3.00, =0.09; =0.94, =0.09). Within 90 days after transplantation, two cases (4.26%) died in the levofloxacin+ G-CSF group and one case (1.82%) died in the G-CSF group, with no statistically significant difference between the two groups (χ=0.53, =0.47).
CONCLUSION
Application of levofloxacin+ G-CSF showed no significant benefit compared to G-CSF support for the prevention of bacterial infections during ASCT.
Topics: Humans; Levofloxacin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Transplantation, Autologous; Bacterial Infections; Anti-Bacterial Agents; Male
PubMed: 38926987
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.039 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma...
OBJECTIVE
To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma (MM).
METHODS
The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively, and the patients were divided into two groups: normal PT and APTT group and prolonged PT or APTT group. The differences in sex, age, classification, staging, bleeding events, laboratory indicators [including hemoglobin (Hb), platelet count (PLT), serum calcium, serum albumin (ALB), lactate dehydrogenase (LDH), serum creatinine and β-microglobulin], and cytogenetic characteristics between the two groups of patients were compared. The effect of prolonged PT or APTT on survival of patients with MM was analyzed.
RESULTS
Compared with patients in normal PT and APTT group, patients in prolonged PT or APTT group were more likely to experience bleeding events (=5.087, =0.024), with lower ALB levels (=4.962, =0.026) and PLT levels (=4.309, =0.038), and higher serum calcium levels (=5.056, =0.025). The positive rates of del17p, del13q and 1q21+ in prolonged PT or APTT group were higher than those in normal PT and APTT group, but the difference was not statistically significant ( >0.05). K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival (PFS) ( =0.032) and overall survival (OS) ( =0.032). Multivariate Cox analysis showed that prolonged PT or APTT (=2.116, 95% :1.025-4.372, =0.043) and age ≥65 years (=2.403, 95% : 1.195-4.836, =0.014) were independent risk factor for OS in newly diagnosed MM patients. However, prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients (=1.162, 95% : 0.666-2.026, =0.597).
CONCLUSION
Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators, shorter PFS and OS. Prolonged PT or APTT is an independent risk factor for OS in MM patients.
Topics: Humans; Multiple Myeloma; Partial Thromboplastin Time; Prognosis; Retrospective Studies; Prothrombin Time; Male; Female; Middle Aged
PubMed: 38926971
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.023 -
[Bone Metabolism of Multiple Myeloma Bone Disease Patients with Different Blood Separation Results].Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD)...
OBJECTIVE
To investigate the clinical significance of bone metabolic indexes for disease assessment and curative effect monitoring in multiple myeloma (MM) bone disease (MBD) patients with different blood separation results.
METHODS
A total of 134 newly diagnosed MM patients treated in Cangzhou Hospital of Integrated TCM-WM-Hebei were enrolled and divided into control group [119 cases, serum, colloid and red blood cell (RBC) from top to bottom of sample] and abnormal group (15 cases, serum, mixed layer of RBC and serum, colloid and RBC from top to bottom of sample) according to the results of blood separation. According to the imaging findings, MBD was classified into grade 0-4, grade 0-2 was mild, and grade 3-4 was severe. The MBD grade of patients in the two groups was analyzed. The curative effect of MBD patients after chemotherapy and the changes of blood separation results and bone metabolic indexes before and after treatment were evaluated. The correlation between β-microglobulin (MG) and bone metabolic indexes was analyzed by Pearson correlation analysis.
RESULTS
In the control group, there were 69 cases of grade 0-2 and 50 cases of grade 3-4, while in the abnormal group, there were 5 cases of grade 0-2 and 10 cases of grade 3-4, the difference was statistically significant ( < 0.05). The serum β-MG, β-CTX levels in abnormal group were both significantly higher than those in control group, while the levels of P1NP and osteocalcin (OC) were significantly lower (all < 0.001). In the control group, there were 95 patients with ≥ partial response (PR) and the blood separation results were not changed, while 24 patients with
0.05). Compared with before treatment, the levels of β-CTX and β-MG in the control group with unchanged blood separation results were significantly decreased (both < 0.001), while the levels of P1NP and OC were significantly increased ( < 0.01, < 0.001), and the level of each index in the patients transformed to abnormal blood separation result after treatment did not significantly change ( >0.05); the levels of β-CTX and β-MG in the abnormal group transformed to normal blood separation result were significantly decreased (both < 0.01), while the levels of P1NP and OC were significantly increased ( < 0.001, < 0.01), and the level of each index in patients with unchanged blood separation results did not significantly change (P>0.05). Pearson correlation analysis showed that serum β-MG was positively correlated with β-CTX ( =0.709, < 0.001), and negatively correlated with P1NP and OC ( =-0.410, =-0.412, both < 0.001). CONCLUSION
MBD patients with abnormal blood separation results have higher bone disease grade and poor prognosis, which is closely related to the significant increase of bone resorption index β-CTX level and decrease of bone formation index P1NP and OC levels, leading to more serious bone metabolic homeostasis disorder. The results of blood separation combined with the changes of bone metabolic indexes can be used as one of the comprehensive predictors of disease condition, efficacy monitoring and prognosis evaluation of MBD patients.
Topics: Humans; Multiple Myeloma; Bone and Bones; Bone Diseases; beta 2-Microglobulin; Collagen Type I; Osteocalcin; Male; Middle Aged
PubMed: 38926970
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.022 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the value of serum free light chain (sFLC) and serum calcium ion in the diagnosis and prognosis of multiple myeloma (MM).
OBJECTIVE
To investigate the value of serum free light chain (sFLC) and serum calcium ion in the diagnosis and prognosis of multiple myeloma (MM).
METHODS
Forty patients with MM treated in Henan Provincial People's Hospital from January 2018 to January 2022 were selected as the observation group, and 40 healthy volunteers were selected as the control group. The differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc between the two groups were compared. Meanwhile, the differences of sFLC-κ、sFLC-λ、sFLC-κ/λ, serum calcium ions, etc in different international staging systems (ISS), chemotherapy efficacy and prognosis patients were analyzed.
RESULTS
The levels of sFLC-κ[(98.39±21.19) (12.01±4.45) mg/L], sFLC-λ[(210.20±45.54) (14.10±5.11) mg/L] and proportions of hypocalcemia (65% 0) in the observation group were significantly higher than those in the control group ( < 0.05), while sFLC-κ/ λ ratio[(0.44±0.10) (0.87±0.12)] and serum calcium ions [(1.98±0.46) (2.42±0.40)mmol/L] were significantly lower than those in the control group ( < 0.05). The sFLC-κ, sFLC-λ, the proportion of hypocalcemia and the course of hypocalcemia in ISS stage III patients in the observation group were significantly higher than those in stage I and II patients ( < 0.05), while sFLC-κ/λ ratio, and serum calcium ions were significantly lower than those in stage I and II patients ( < 0.05). The levels of sFLC-κ [(107.76±21.22) (94.67±20.11)mg/L], sFLC- λ[(245.54±41.12) (205.54±50.22)mg/L] of patients with hypocalcemia in the observation group was significantly higher than those without hypocalcemia ( < 0.05), while the sFLC-κ/λ ratio was significantly lower than those without hypocalcemia [(0.42±0.04) (0.47±0.06); < 0.05]. The levels of sFLC-κ [(107.29±20.14) ( 91.11±18.92)mg/L], sFLC-λ[(247.98±42.26) (179.29±39.32)mg/L] in patients with ineffective chemotherapy were significantly higher than those in patients with effective chemotherapy ( < 0.05), while the sFLC-κ/λ ratio was significantly lower than those in patients with effective chemotherapy [(0.43±0.10) (0.50±0.09); < 0.05)]. The area under the ROC curve for sFLC-κ, sFLC-λ, sFLC-κ/λ predicting ineffective chemotherapy was 0.803, 0.793 and 0.699 respectively, < 0.05. There was no significant difference in sFLC-κ, sFLC-λ, sFLC-κ/λ ratio, serum calcium ion, hypocalcemia ratio and hypocalcemia course between survival and death patients ( >0.05).
CONCLUSION
sFLC and serum calcium are related to ISS stage of MM patients. sFLC level has a certain value to predict the curative effect of chemotherapy in MM patients. However, the prognostic values of sFLC and serum calcium are not yet confirmed for MM patients.
Topics: Humans; Multiple Myeloma; Calcium; Prognosis; Immunoglobulin kappa-Chains; Immunoglobulin Light Chains; Hypocalcemia; Case-Control Studies; Female; Immunoglobulin lambda-Chains; Male; Middle Aged
PubMed: 38926969
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.021 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the relative expression level and clinical significance of in serum of patients with multiple myeloma (MM).
OBJECTIVE
To investigate the relative expression level and clinical significance of in serum of patients with multiple myeloma (MM).
METHODS
The expression of in serum of 108 MM patients and five MM cell lines including RPMI 8226, NCI-H929, U266, OPM2 and CAG were detected by real-time fluorescence quantitative PCR. The diagnostic value of in MM was evaluated by receiver operating characteristic (ROC) curve analysis. The correlation of with patients' characteristics was analyzed.
RESULTS
Compared with control groups, the expression of was up-regulated in serum of MM patients and MM cell lines (all < 0.05). ROC curve analysis showed that the optimal cut-off value of was 262.4, the area under curve (AUC) was 0.924(95% : 0.884-0.964), and sensitivity and specificity was 83.3% and 91.7%, respectively, which indicated that had good evaluation value in MM patients. Compared with low- expression group, patients in high- expression group had higher levels of βmicroglobulin (β-MG) and Cystatin C (Cys-C) but lower albumin (ALB) (all < 0.05). Compared with MM patients with International Staging System (ISS) stage I, the expression level of was significantly higher in patients with stage II and III (both < 0.05).
CONCLUSION
is helpful to distinguish MM patients from healthy adults, which is correlated with the prognostic indicators such as β-MG, ALB, and ISS stage.
Topics: Humans; Multiple Myeloma; RNA, Long Noncoding; Cell Line, Tumor; beta 2-Microglobulin; ROC Curve; Clinical Relevance
PubMed: 38926968
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.020 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the role of serum adenosine deaminase (ADA) combined with globulin (GLB), creatinine (CREA), β-microglobulin (β-MG) and hemoglobin (HGB) in the initial...
OBJECTIVE
To investigate the role of serum adenosine deaminase (ADA) combined with globulin (GLB), creatinine (CREA), β-microglobulin (β-MG) and hemoglobin (HGB) in the initial screening of multiple myeloma (MM), in order to reduce missed diagnosis and misdiagnosis of MM.
METHODS
A retrospective analysis was performed on 62 newly diagnosed multiple myeloma (NDMM) patients who were admitted to the Department of Hematology of the First Affiliated Hospital of Chengdu Medical College from April 2018 to December 2021, and 33 patients with benign hematologic diseases and 30 healthy subjects were selected as the control group. The expression of ADA in pan-cancer was analyzed using TCGA and GTEx databases. The general data and laboratory indicators of the subjects were collected, and the differences of ADA activity and other laboratory indicators in each group were compared. The relationship between serum ADA activity and clinical data of NDMM patients was analyzed. The changes of ADA activity before and after chemotherapy in NDMM patients and the differences of ADA activity in NDMM patients with different DS and ISS stages were compared. Multivariate logistic regression was used to analyze the risk factors of NDMM. The receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of ADA and other laboratory indicators in MM. Bioinformatics method was used to analyze the co-expression networks and enrichment pathways of ADA.
RESULTS
ADA level was significantly upregulated in tissues of 14 types of cancer in TCGA database, and ADA was highly expressed in 11 types of cancer in TCGA combined with GTEx databases. The serum levels of ADA, GLB, uric acid (UA), cystatin C (CysC) and β-MG in the NDMM group were significantly higher than those in benign hematologic disease group and healthy control group ( < 0.05), while the levels of ALB and the value of albumin to globulin ratio (A∶G) in the NDMM group were significantly lower than those in the other two groups ( < 0.001). There were significant differences in DS stage ( =0.036), ISS stage ( =0.019) and the levels of CREA ( =0.036), UA ( =0.034), β-MG ( =0.019) in NDMM patients with different ADA activity levels. After primary chemotherapy, ADA activity and β-MG concentration were decreased in NDMM patients ( < 0.01). The comparison results of patients in different stages showed that ADA activity of patients in DS stage I+II was significantly lower than that of patients in DS stage III ( <0.05), and ADA activity of patiens in ISS stage I+II was significantly lower than that of patients in ISS stage III ( < 0.01). Multivariate logistic regression analysis showed that increased GLB, increased ADA activity, increased CREA, increased β-MG and decreased HGB were independent risk factors for NDMM. The area under the curve (AUC) of ADA in the diagnosis of MM was 0.847, and the AUC of ADA combined with GLB, CREA, β-MG and HGB in the diagnosis of MM was 0.940. The results of co-expression network and enrichment pathway analysis showed that ADA bounded to 20 proteins and it was significantly associated with the metabolic pathways of purine, pyrimidine, nicotinate and nicotinamide.
CONCLUSION
The detection of ADA activity in serum is of positive significance for the auxiliary diagnosis, therapeutic evaluation and monitoring the progress of NDMM patients. ADA combined with GLB, CREA, β-MG and HGB can improve the detection rate of MM, and reduce missed diagnosis and misdiagnosis to a certain extent.
Topics: Humans; Adenosine Deaminase; Multiple Myeloma; beta 2-Microglobulin; Retrospective Studies; Creatinine; Hemoglobins; Male; Female; Clinical Relevance
PubMed: 38926967
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.019 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0...
OBJECTIVE
To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0 score.
METHODS
Clinical data were collected from 16 patients with mSMART3.0 score high-risk relapsed refractory MM treated at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from May 2020 to May 2023, all of whom received daltezumab-based regimen (regimen drugs including dexamethasone, isazomib, bortezomib, lenalidomide). The efficacy and safety of the treatment were retrospectively analyzed.
RESULTS
The median age of 16 patients was 63.5 (47-70) years old, including 10 cases of IgG type, 2 cases of IgA type, and 4 cases of light chain type. The curative efficacy was judged in all 16 patients, with an overall response rate of 93.75% (15/16), including 4 cases of strict complete remission (sCR), 1 case of complete remission (CR), 2 case of very good partial remission (VGPR), partial remission (PR) in 5 cases, and minor remission (MR) in 3 cases. The median follow-up time was 11(2-30) months, and the median progression-free survival and median overall survival were not achieved in 16 patients at the median follow-up period. The hematologic adverse effects of the treatment regimen using daratumumab-based were mainly neutropenia, and the non-hematologic adverse effects were mainly infusion-related adverse reactions and infections.
CONCLUSION
Daratumumab-based regimen for the treatment of relapsed refractory MM patients with high risk of mSMART3.0 score has better efficacy and safety.
Topics: Humans; Multiple Myeloma; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Male; Retrospective Studies; Female; Antibodies, Monoclonal; Dexamethasone; Treatment Outcome; Antibodies, Monoclonal, Humanized; Lenalidomide; Bortezomib
PubMed: 38926966
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.018