Bendamustine combined with pomalidomide and dexamethasone in relapsed multiple myeloma with extramedullary disease: a multicenter study / 中华血液学杂志

Objective: To evaluate the efficacy and safety of bendamustine combined with pomalidomide and dexamethasone (BPD regimen) in the treatment of relapsed multiple myeloma (MM) with extramedullary disease. Methods: This open, single-arm, multicenter prospective cohort study included 30 relapsed MM patients with extramedullary disease diagnosed in seven hospitals including Qingdao Municipal Hospital. The patients were treated with BPD regimen from February 2021 to November 2022. This study analyzed the efficacy and adverse reactions of the BPD regimen. Results: The median age of the 30 patients was 62 (47-72) years, of which 18 (60% ) had first-time recurrence. The overall response rate (ORR) of the 18 patients with first-time recurrence was 100%, of which three (16.7% ) achieved complete remission, 10 (55.5% ) achieved very good partial remission (VGPR), and five (27.8% ) achieved partial remission (PR). The ORR of 12 patients with recurrence after second-line or above treatment was 50%, including zero patients with ≥VGPR and six patients (50% ) with PR. Three cases (25% ) had stable disease, and three cases (25% ) had disease progression. The one-year progression free survival rate of all patients was 65.2% (95% CI 37.2% -83.1% ), and the 1-year overall survival rate was 90.0% (95% CI 76.2% -95.4% ). The common grade 3-4 hematology adverse reactions included two cases (6.7% ) of neutropenia and one case (3.3% ) of thrombocytopenia. The overall adverse reactions are controllable. Conclusions: The BPD regimen has good efficacy and tolerance in relapsed MM patients with extramedullary disease.

Research advance in multi-component pharmacokinetics of Chinese herbal extracts in recent five years / 中国中药杂志

The multi-component pharmacokinetic study of Chinese herbal extracts elaborates the in vivo processes,including absorption,distribution,metabolism,and excretion,of multiple bioactive components,which is of significance in revealing pharmacodynamic material basis of Chinese herbal medicine. In recent years,with the innovation in ideas,and development of techniques and methods on traditional Chinese medicine( TCM) research,the pharmacokinetic studies of Chinese herbal extracts were extensively performed,and notable progress has been made. This paper reviewed the advancement of multi-component pharmacokinetics of Chinese herbal extracts in recent five years from analysis technology of biological sample,the pharmacokinetic characteristics of Chinese herbal medicine with complex system,and the impacts of processing and pathological state on pharmacokinetics of Chinese herbal extracts,aiming to provide a reference for quality control,product development and rational medication of Chinese herbal extracts.

MiR-144 Inhibits the Malignant Biologic Behaviors of Multiple Myeloma Cells by Regulating Wnt4/β-Catenin Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of miR-144 to the biological behavior of multiple myeloma cells and its mechanism.@*METHODS@#RT-PCR was used to detect the expression of miR-144 in multiple myeloma cells and plasma of MM patients. MTT assay was used to detect the proliferation and cloning ability of myeloma cells transfected by miR-144. Flow cytometry was used to detect the cell cycle distribution of myeloma cells with over-expression of miR-144. Apoptosis of myeloma cells with over-expression of miR-144 was detected by TUNEL assay. Transwell cell invasion and migration assay was used to detect the invasion and migration ability of myeloma cells with overexpressing on miR-144.Western blot analysis was used to detect the protein expression levels of MMP-9 and MMP-2 in myeloma cells with over expression of miR-144, as well as the expression levels of proteins related to Wnt/β-catenin signaling pathway.@*RESULTS@#The expression level of miR-144 in MM cell lines and blood of MM patients was significantly lower than that in control group (P＜0.05). The proliferation, invasion and migration of myeloma cells with over-expression of miR-144 were significantly decreased (P＜0.05), and the apoptosis level was increased (P＜0.05). The expression levels of MMP-9, MMP-2, Wnt/β-catenin signaling pathway in myeloma cells with over-expression of miR-144 were significantly lower than those in control group (P＜0.05).@*CONCLUSION@#MiR-144 can inhibit the proliferation, migration and invasion of multiple myeloma cells and induce cell apoptosis. The specific mechanism may be related with the activity of inhibiting Wnt/β-catenin signaling pathway.

ADAMTS13 Level in Prothrombotic Status and Its Related Factor Analysis / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To detect the plasma activity of von Willebrand factor-cleaving protease (ADAMTS13) in the patients with prothrombotic status, and explore the effect and significance of ADAMTS13 in the prothrombotic status. The correlation of ADAMTS13 with von Willebrand factor (vWF), thrombospondin 1 (TSP1), C-reactive protein etc, and blood pressure was simultaneously analyzed．</p><p><b>METHODS</b>The activity of ADAMTS13 in patient groups (atherosclerosis, diabetes, acute promyelocytic leukemia, cancer and sepsis, a total of 260 cases) and in control group 50 cases were evaluated by residue collagen binding assay（R-CBA）, the protein levels of TSP1 and vWF were measured by ELISA kits； the correlation of ADAMTS13 activity with CRP, creatinine, and blood pressure was analyzed with statistical soft ware.</p><p><b>RESULTS</b>The activity of plasma ADAMTS13 in patient group was significantly lower than that in normal control group(P<0.05). And the protein levels of TSP1 and vWF in the patients with prothrombotic status were higher than those in the normal controls(P<0.05). Analysis of the correlation showed that the ADAMTS13 activity correlated negatively with the levels of TSP1 protein, blood sugar, blood pressure, D-dimer, creatinine,and CRP levels (P<0.05), however, the ADAMTS13 activity did not significantly correlate with the levels of serum lipids, blood type, platelet number and hemoglobin level(P>0.05).</p><p><b>CONCLUSION</b>The plasma ADAMTS13 activity is decreased in the patients with prothrombotic status, suggesting that the decreased ADAMTS13 activity may participate in the occurrence of prothrombotic status, and the dectection of plasma ADAMTS13 activity may help the diagnosis of pro-thrombotic disease.</p>

Clinical Efficacy of Dendritic Cells and Cytokine-induced Killer Cells Combined with Chemotherapy for Treating Newly diagnosed Multiple Myeloma and their Effect on Function of CD4(+) CD25(+) T Cells in Peripheral Blood / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the efficacy of dendritic cells and cytokine-induced killer cells (DC-CIK) combined with chemotherapy for treating newly diagnosed patients with multiple myeloma (MM) and their effect on cellular immune functions of CD4(+) CD25(+) Treg cells in peripheral blood after adoptive immunotherapy.</p><p><b>METHODS</b>Fouty two patients with MM were randomly divided into two groups: chemotherapy group and combined therapy group; 20 patients in chemotherapy group were treated by chemotherapy only, 22 patients in combined therapy group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy, and the clinical outcomes of patients and the levels of CD4(+) CD25(+) Treg cells in peripheral blood between 2 groups were compared.</p><p><b>RESULTS</b>After treating for 3 weeks, the quality of life, clinical index and survival of patients in combined therapy group were better than those of patients in chemotherapy group (P < 0.05); the ratios of CD4(+) CD25(+)/CD4(+) and CD4(+) CD25(+) FoxP3(+)/CD4(+) CD25(+) of patients in combined therapy group were obviously lower than those of patients in chemotherapy group (P < 0.05).</p><p><b>CONCLUSION</b>The immunotherapy of DC-CIK can strengthen the activities of CD4(+) CD25(+) Treg cells, which combined with chemotherapy can be an effective and promising effects for treatment of patients with MM.</p>

Effect of Immunotherapy of Dendritic Cells and Cytokine-Induced Killer Cells Combined with Chemotherapy on Secreting Function of T Lymphocytes in Patients with Multiple Myeloma / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To evaluate the treatment value of adoptive immunotherapy (dendritic cells and cytokine-induced killer cells, DC-CIK) combined with chemotherapy on patients with multiple myeloma (MM) and its effect on secreting function of T lymphocytes in MM patients.</p><p><b>METHODS</b>A total of 36 patients with MM were randomly divided into two groups, among them 28 patients in chemotherapy group were treated by chemotherapy only, 28 patients in combined therapy group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy, and the clinical outcomes and the levels of IL-2, IFN-γ, IL-4, IL-10 secreted by T lymphocytes between two groups were compared.</p><p><b>RESULTS</b>After treatment, the quality of life, clinical index and survival in combined therapy group were better than those in chemotherapy group (P <0.05); the levels of IL-2 and IFN-γ in combined therapy group was higher than these in chemotherapy group (P <0.05), and the levels of IL-4 and IL-10 in combined therapy group were lower than those in chemotherapy group (P <0.05).</p><p><b>CONCLUSION</b>DC-CIK combined with chemotherapy can be an effective and promising treatment for patients with MM, and it maybe strengthen the anti-tumor action of bodies by regulating the balance between Th1 and Th2 reaction.</p>

Clinical Efficacy of DC and CIK Immunotherapy Combined with Chemotherapy and Its Impact on Treg Cells in Newly Diagnosed Multiple Myeloma / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the clinical efficacy and immune mechanism of immunotherapy of dendritic cells (DC) and cytokine-induced killer cell (CIK) combined with chemotherapy in patients with newly diagnosed multiple myeloma (MM).</p><p><b>METHODS</b>twenty-two newly diagnosed MM patients were chosen and divided into two groups, out of them,12 patients in single chemotherapy group were treated by chemotherapy only, 10 patients in combined group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy. Using flow cytometry, the CD4 Treg cells in the peripheral blood of 22 MM patients were detected before and after treatment. And the clinical outcomes between two groups were also compared.</p><p><b>RESULTS</b>After treatment the overall response rate(ORR) of patients in the single chemotherapy group was 50% (6/12), among them 2 cases were in complete remission (CR) (16.67%), 2 cases very good partial remission (VGPR) (16.67%), 2 cases were in partial remission (PR) (16.67%). However, the ORR of patients in immunotherapy combined with chemotherapy group was 70.% (7/10), including in 3 cases of CR (30%), 2 cases of VGPR (20%), 2 cases of PR (20%). Compared to healthy volunteers, the proportion of Treg cells in peripheral blood of two groups before treatment was significantly higher (P<0.05). In contrast, the proportion of Treg cells in the peripheral blood of above-mentioned 2 groups after treatment was reduced significantly (P<0.05). In addition, compared to chemotherapy group, the proportion of Treg cells in the combined group decreased significantly (P<0.05). The further analysis found that the proportion of Treg cells in the peripheral blood of the 2 groups was not significant changed (P>0.05) in the patients with ineffictive clinical treatment, but the proportion of Treg cells significantly decreased (P<0.05) in the patients with effective clinical treatment.</p><p><b>CONCLUSION</b>DC-CIK immunotherapy can synergize or enhance the effect of chemotherapeutics, alleviate the immune dysfunction in MM; and DC-CIK immunotherapy combined with chemotherapy can elevate the clinical efficacy in patients with newly diagnosed multiple myeloma.</p>

Imbalance of treg/th17 in bone marrow of patients with multiple myeloma / 中国实验血液学杂志

The purpose of this study was to detect the distribution of Treg and Th17 cells in bone marrow and to investigate the relationship of Treg/Th17 imbalance with the pathogenesis and progression of multiple myeloma (MM). The Bone marrow was collected from 37 MM patients and 12 healthy volunteers, the ratio of Treg and Th17 cells was detected by flow cytometry. The expression of Treg and Th17 cells simultaneously was examined in peripheral blood of 19 MM patients with same method. The results indicated that the frequency of Treg cells was higher in MM patients than that in control group (P < 0.05), there was a trend of increasing of Treg cell number in the ISS stage from I+II to III (P < 0.05). Furthermore, in the patients with MM, the Treg cell number in bone marrow was higher than that in peripheral blood (P < 0.05). Th17 cell rate was not statistically different between MM patients and control group (P > 0.05), and at different ISS stage (P > 0.05). Th17 cell number between bone marrow and peripheral blood was not significantly different (P > 0.05).The ratio of Treg/Th17 in patients with MM was higher than that in control group (P < 0.05), and increased gradually from ISS stage I+II to stage III (P < 0.05). It is concluded that the Treg/Th17 immune imbalance is presenced in bone marrow of patients with MM, this imbalance may promote the progression of MM.

Assessment of the effects of Radix bupleuri and vinegar-baked Radix bupleuri on cytochrome 450 activity by a six-drug cocktail approach / 中国天然药物

AIM@#To assess the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity of rats.@*METHODS@#Six probe drugs (caffeine, midazolam, dextromethorphan, tolbutamide, omeprazole, chlorzoxazone) were simultaneously given to rats after different dosing of Radix Bupleuri or vinegar-baked Radix Bupleuri for seven days. The plasma concentrations of the six probes were measured by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS/MS) and their corresponding pharmacokinetic parameters were calculated.@*RESULTS@#The AUC and T1/2 of midazolam, dextromethorphan and chlorzoxazone decreased significantly (P 0.05) from that of controlled rats, however, treatment of Radix Bupleuri decreased tolbutamide T1/2. The pharmacokinetics of caffeine in all Radix Bupleuri or vinegar-baked Radix Bupleuri-treated rats showed no statistically significant difference (P > 0.05) from that of controlled rats.@*CONCLUSION@#The Radix Bupleuri and vinegar-baked Radix Bupleuri have different effects on the CYP2C9 and CYP2C19. Radix Bupleuri and vinegar-baked Radix Bupleuri have strong induction effects on the CYP2E1, CYP2D6 and CYP3A4, however, have no impact on CYP1A2. The reason of different therapeutic effects of Radix Bupleuri and vinegar-baked Radix Bupleuri extract may be the different effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on the CYP2C9 and CYP2C19.

In vitro effects of mesenchymal stem cells on secreting function of T lymphocytes and CD4⁺CD25⁺ T cells from patients with immune thrombocytopenia / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze in vitro the effect of mesenchymal stem cells (MSCs) on secreting cytokines by T lymphocytes and ratio of CD4⁺CD25⁺ T cells from patients with immune thrombocytopenia (ITP).</p><p><b>METHODS</b>Human bone marrow-derived MSCs were isolated by Ficoll Hypaque and cultured for proliferating to passage cells. Allogeneic T lymphocytes of health adults and ITP patients were isolated from peripheral blood by Ficoll Hypaque and nylon cotton column, and the ratio of CD4⁺CD25⁺ T cells was detected by flow cytometry. Then the different amounts of 1 × 10⁴, 5 × 10⁴, 2 × 10⁵ MSCs per well treated with mitomycin as stromal feeder layers were co-cultured with above-mentioned T lymphocytes, 5 days after cocultivation, the ratio of CD4⁺CD25⁺ T cells was detected by flow cytometry and the levels of IL-2, IFN-γ, IL-4, IL-10 were measured by enzyme- linked immune sorbent assay (ELISA).</p><p><b>RESULTS</b>After co-cultured with 2 × 10⁵ MSCs for 5 days, the ratio of CD4⁺CD25⁺ T cells and CD4⁺CD25⁺/CD4⁺ were significantly higher than of separate T lymphocytes in ITP patients [(4.56 ± 0.70)% vs (2.24 ± 0.81)%, (9.91 ± 1.18)% vs (4.08 ± 1.17)%, respectively] (P<0.05). To compare with separate T lymphocytes in ITP patients, the cytokine concentrations of IL-2 and IFN-γ from the culture supernatants significantly reduced from (280.47 ± 17.33) pg/ml to (97.21 ± 12.07) pg/ml and from (129.33 ± 16.34) pg/ml to (72.75 ± 7.81) pg/ml, respectively. In contrast, the cytokine concentrations of IL-4 and IL-10 increased from (16.34 ± 2.60) pg/ml to (37.98 ± 4.05) pg/ml and from (54.78 ± 5.62) pg/ml to (113.77 ± 5.68) pg/ml, respectively.</p><p><b>CONCLUSION</b>MSCs significantly inhibited the cytokine levels of IL-2 and IFN-γ secreted by Th1 cells and promoted the releases of IL-4 and IL-10 by Th2 cells in ITP , thereby regulating the balance between Th1 and Th2 reaction, as well as up-regulating the expression of CD4⁺CD25⁺ T cells in vitro,then induced the immunologic tolerance of ITP.</p>

Effect of Astragalus polysaccharide on pancreatic cell mass in type 1 diabetic mice / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effect of Astragalus polysaccharide (APS) on pancreatic beta cell mass in type 1 diabetic mice.</p><p><b>METHOD</b>Diabetic mice induced by multiple low dose streptozotocin (MLD-STZ) were administered either APS (100, 200, 400 mg x kg(-1) body weight) or saline intraperitoneally daily, and sacrificed after 15 or 30 days of treatment. Streptavidin-peroxidase immunohistochemical method with counterstain was performed to determine the effect of APS on insulitis. Indirect double immunofluorescence for Insulin/Ki67 (counterstained by Hoechst33258) and Insulin/Cleaved caspase-3 was used to evaluate pancreatic cell (besides beta cell) proliferation, beta cell neogenesis, beta cell apoptosis and beta cell mass. Semi-quantitative RT-PCR was utilized to characterize pancreatic regenerating protein 1 mRNA levels, and ELISA method was performed to measure the levels of cytokine IFN-gamma and IL-4 secreted by splenocytes.</p><p><b>RESULT</b>Attenuated insulitis, upregulated beta cell mass, increased number of neogenetic pancreas islets, decreased number of apoptosis beta cells and downregulation of Th1/Th2 cytokine ratio were significantly time-and dose-dependent on APS treatment, when compared to saline controls. However, no significant differences of the number of pancreatic proliferative cells or replicative cells and pancreatic regenerating protein 1 mRNA levels were demonstrated between APS (APS100, APS200 and APS400) and saline vehicle group on day 15 and 30 with APS treatment.</p><p><b>CONCLUSION</b>APS can upregulate pancreatic beta cell mass in type 1 diabetic mice, strongly associated with improved autoimmunity.</p>

Expression of adrenomedullin and its receptor mRNA in the tissues of normal adrenal medulla and pheochromocytoma / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the expression of human adrenomedullin (ADM) and its receptor-receptor activity modifying protein 2/calcitonin receptor-like receptor (RAMP2/CRLR) mRNA in the tissues of normal adrenal medulla and pheochromocytoma.</p><p><b>METHODS</b>Total RNA was extracted from normal adrenal medulla and pheochromocytomas. The expression of ADM and RAMP2/CRLR mRNA were studied by reverse transcription-polymerase chain reaction. The ratios of ADM/GAPDH, RAMP2/ GAPDH, CRLR/GAPDH were used to evaluate the expression levels of ADM, RAMP2 and CRLR mRNA.</p><p><b>RESULTS</b>Expressions of ADM and its receptor- RAMP2/CRLR mRNA were detected in normal adrenal medulla and pheochromocytoma tissues. ADM/GAPDH were 0.48+/-0.09 and 0.75+/-0.24, RAMP2/ GAPDH 0.79+/-0.12 and 1.29+/-0.30, CRLR/GAPDH 0.40+/-0.08 and 0.87+/-0.22 in normal adrenal medulla and pheochromocytomas, respectively (P < 0.05).</p><p><b>CONCLUSION</b>ADM exerts a possible autocrine or paracrine effect in the adrenal. ADM may be involved in the pathogenesis of pheochromocytoma.</p>

Expression of urotensin II and G-protein coupled receptor 14 mRNA in human pheochromocytoma tissues / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the expression of urotensin II (U II) and G-protein coupled receptor 14 (GPR14) mRNA in human pheochromocytoma tissues.</p><p><b>METHODS</b>Total RNA from normal adrenal and pheochromocytoma tissues was extracted. The reverse transcription-polymerase chain reaction method was used to evaluate the levels of U II and GPR14 mRNA expression in human pheochromocytoma tissues.</p><p><b>RESULTS</b>There was no significant difference of U II and GPR14 mRNA expression between normal adrenal cortex and medulla. The expression of U II and GPR14 mRNA in pheochromocytoma was significantly lower than that in normal adrenal cortex and medulla (P < 0.05). The expression of GPR14 mRNA in adrenal pheochromocytomas was significantly lower than that of extra-adrenal pheochromocytomas (P < 0.05).</p><p><b>CONCLUSION</b>U II and GPR14 may play a role in the pathogenesis and hypertension regulating of pheochromocytoma.</p>

A vasoactive peptide: urotensin II / 中国医学科学院学报

Urotensin II (U II ) is currently the most potent vasoconstrictor. G-protein coupled receptor 14 ( GPR-14) is its specific receptor. This review mainly discribes the structure and distribution of U II and GPR14, the activities that U II and GPR14 stimulates proliferation of vascular smooth muscle cells and vasoconstriction, as well as its mechanism.