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.

Multicenter Prospective Study of Different Induction Regimens of Azacytidine in Treatment of Elderly Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and safety of different induction regimens of same total dosage of azacitidine (Aza), including standard dose (standard dose group) and low-dose long-term (adjusted dose group), in the treatment of elderly acute myeloid leukemia (AML).@*METHODS@#A total of 103 elderly patients with AML (non-acute promyelocytic leukemia) from January 2020 to June 2021 were enrolled. Aza was administered at the standard dose of 75 mg/(m2·d) for 7 days in the standard dose group (50 cases), while at 100 mg/d for 7-12 days in the adjusted dose group (53 cases). The administration days in adjusted dose group was calculated based on the total standard dose of the patient's single course of treatment. The efficacy and safety between standard dose group and adjusted dose group were compared. Subgroup analysis were performed in the two groups for Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy for efficacy and safety.@*RESULTS@#There were no significant differences in overall response rate (ORR), incidence of adverse reaction, and 1-year overall survival (OS) rate between standard dose group and adjusted dose group (P >0.05). The ORR of combination was higher than that of Aza alone (P < 0.05), while there was no significant difference in ORR between Aza combined with BCL-2 inhibitor and Aza combined with low-dose chemotherapy (P >0.05). The combination of BCL-2 inhibitor did not increase the incidence of adverse reactions compared wtih Aza alone. There was a higher risk of myelosuppression and pulmonary infection with a combination of low-dose chemotherapy than with a combination of BCL-2 inhibitor and Aza alone (P <0.05). No significant difference was observed in 1-year OS between Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy (P >0.05).@*CONCLUSIONS@#Both two induction regimens can be used in elderly AML patients who cannot tolerate intensive chemotherapy with similar overall effectiveness and safety. Aza combined with low-dose chemotherapy may result in increased ORR and an increased incidence of serious adverse reactions, and may not result in longer survival compared with Aza alone. Aza combined with BCL-2 inhibitor not only has similar effect in complete remission, objective response rate, and OS compared with Aza combined with low-dose chemotherapy, but also has higher safety.

Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa

Background@#Chronic exposure to elevated levels of saturated fatty acids results in pancreatic β-cell senescence. However, targets and effective agents for preventing stearic acid-induced β-cell senescence are still lacking. Although melatonin administration can protect β-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse β-cells and elucidated the possible role of microRNAs in this process. @*Methods@#β-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated β-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked β-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs. @*Results@#Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR- 8114 expression in both mouse islets and β-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced β-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5pand miR-8114-transfected β-cells. @*Conclusion@#These data demonstrate that melatonin protects against stearic acid-induced β-cell senescence by inhibiting miR-146a- 5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced β-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.

Proventive and Therapentic Effects of Endothelial Progenitor Cells on Monocrotaline-Induced Hepatic Vein Occlusion Disease / 中国实验血液学杂志

OBJECTIVE@#To investigate the preventive and therapeutic effects of endothelial progenitor cells on monocrotaline-induced hepatic vein occlusion disease in mice.@*METHODS@#C57BL/6 mice were randomly divided into 3 groups: saline group (n=15), monocrotaline group (n=15), and endothelial progenitor cell infusion group (n=15). Liver function (TBIL, ALT, AST), liver index, and serum levels of TNF-α and IL-6 were measured on the 8 day after intragastric administration. Hepatic sinusoidal endothelial cells, hepatic central venous endothelial cells and hepatocytes were observed by both HE and immunohistochemical staining. Hepatic fibrosis was observed by Masson's trichrome staining.@*RESULTS@#By the light microscopy, the liver of the monocrotaline group showed moderate to the severe injuries of hepatic sinusoidal and central venous endothelial cells, and hepatic venous congestion. Masson staining showed moderate to severe hepatic fibrosis of central vein and hepatic sinus. In the endothelial progenitor cell group, hepatic sinusoidal and central venous endothelial cell injuries, and the fibrosis of central hepatic vein and hepatic sinus were mild to moderate. Hepatic venous congestion was reduced in comparison with that in the mice of the monocrotaline group. Compared with the endothelial progenitor cell group, the liver index was higher, the liver function was more abnormal, and the serum expression levels of TNF-α and IL-6 were higher in the monocrotaline group.@*CONCLUSION@#The monocrotaline-induced damage of hepatic sinusoidal and central venous endothelial cells is an linitiating factor for hepatic vein occlusive disease. Infusion of endothelial progenitor cells can play a role in preventing and treating hepatic vein occlusion.

Studies on chemical constituents and activities of lignans and terpenes from stem of Moringa oleifera / 中草药

Objective: To study lignans and terpenes of Moringa oleifera Lam. Methods: The compounds were isolated and purified by various column chromatographic techniques and High Performance Liquid Chromatography (HPLC). The structures of the compounds were identified through the combined analysis of physicochemical properties and spectroscopic evidence. The antineoplastic activity, α-glucosidase and acetylcholinesterase inhibitory activity of compounds were evaluated by MTT method, PNPG method and Ellman colorimetric method, respectively. Results: Twelve compounds were isolated from M. oleifera by various chromatographic methods and were identified as lariciresinol (1), 3-(α,4-dihydroxy-3-methoxybenzyl)-4-(4-hydroxy-3- methoxybenzyl) tetrahydrofuran (2), (7S,8R)-dihydrodehydrodiconiferyl alcohol (3), macadiol (4), diethyl pinoresinol (5), pinoresinol (6), evofolin B (7), erythro-guaiacylglycerol-β-O-4’-dihydroconiferyl alcohol (8), tricyclohumuladiol (9), 9α-hydroxy-2β-methoxyclovane (10), 3β-hydroxy-oleana-11,13 (18)-dien-28-oic acid (11), oleanolic acid (12). Compounds 12 showed antineoplastic activity. Compound 1 and 2 exhibited α-glucosidase inhibitory activity. Conclusion: Compounds 1-11 are separated from Moringa Adans for the first time. This plant has the potential of developing functional product for their antineoplastic and α-glucosidase inhibitory activity.

Effects of Ursolic Acid on Cholesterol Metabolism in Hepatic Cells / 医药导报

Objective To explore the effects and mechanism of ursolic acid ( UA) on cholesterol metabolism in human hepatocellular carcinoma HepG2 and mouse hepatocyte AML-12. Methods HepG2 and AML-12 cells were treated with different concentrations of UA (0,10,20,40 μmol·L-1)for 24 h, then the mRNA and protein expression of cholesterol 7alpha-hydroxylase (CYP7A1) and intracellular cholesterol level was detected by RT-PCR、Western blotting and enzymatic method, respectively. Results Compared with 0 μmol·L-1 UA, 20 μmol·L-1 and 40 μmol·L-1 UA significantly increased the expressions of CYP7A1 mRNA and protein(P<0. 05), and decreased intracellular cholesterol level in HepG2 and AML-12 cells (P<0. 05). Conclusion A certain concentration of UA can reduce the level of cholesterol in HepG2 and AML-12 cells. CYP7A1 may be involved in the regulation process.

Research Progress on role of Abnormal Tryptophan Metabolism in Immune Thrombocytopenia / 中国实验血液学杂志

Immune thrombocytopenia (ITP) is a common acquired autoimmune hematological disorders. Platelet autoantibodies lead to the decrease of platelet production and (or) increase of its destruction. The latest researches showed that the abnormal tryptophan metabolism mediated by indoleamine-2, 3-dioxygenase(IDO) is related with the pathogenesis of ITP. The patients with ITP show less expression of IDO, reduction of Treg cells and increase of autoreactive T cells and autoantibodies. CTLA-4-Ig can improve the expression of IDO in the patients with ITP, which also can inhibit the proliferation and activation of self-reactive T cells. Thus, clarifying the abnormal tryptophan metabolism mediated by IDO may provide a new idea for improving the understand of the pathogenesis and treatment of ITP. This review focuses on reasearch progress of the tryptophan metabolism mediated by IDO and ITP.

New tricks for an old slug: descending serotonergic system in pain / 生理学报

A large body of research including animal and human studies has confirmed the crucial role of the serotonin (5-HT) system in the regulation of nociception and chronic pain-related behaviors. In recent years, the functional status of the 5-HT system in descending inhibition and facilitation of spinal nociceptive processing has been reevaluated by novel genetic manipulation techniques and selective agents for 5-HT receptor subtypes. Although these studies shed more light on several aspects of descending 5-HT and spinal 5-HT receptors functioning in descending modulation in pain perception, the current knowledge about the specific role of descending 5-HT system in the induction and maintenance of persistent pain remains fragmentary. In this paper, we review the available data from recent studies of the inhibitory or facilitatory influence from descending 5-HT-spinal 5-HT receptor system in acute and persistent pain, attempt to dissect the involvement of this signaling pathway in neural circuits of maintenance of persistent pain and discuss some issues that need to be considered for further pain research.

Survey on the transmission of HIV drug resistance in Kunming, Yunnan province in 2010 / 中华流行病学杂志

Objective To study the HIV drug resistance (HIVDR) transmission in Kunming city of Yunnan province in 2010.Methods Referring to the guidelines for HIV drug resistance threshold survey (HIVDR-TS) set by WHO,62 plasma samples of recently reported HIV-infected individuals who were older than 25 years of age,were collected from January to August 2010.Genotyping of pol genetic mutations associated with HIVDR with reverse transcriptional PCR was performed and the prevalence of HIV-1 drug resistance transmission was evaluated.Results Of the 62 plasma samples,54 were successfully sequenced and genotyped on pol sequence.Based on the pol sequences,HIV subtypes including CRF08_BC ( 53.2％ ),CRF07_BC ( 25.5％ ),CRF01_AE ( 19.1％ )and C (2.1％) were identified.According to the time of sampling,the first 47 sequenced samples were used for drug resistance prevalence analysis.A protease inhibitor (PI) relative mutation was found in one sample.Based on the WHO standard,the prevalence of transmitted HIV-1 drug resistance was ＜5％.Conclusion HIV-1 drug resistant strains transmission was still catalogued as low prevalence level in Kunming.To prevent the increase of HIVDR prevalence,normative treatment and scientific management to AIDS patients seemed to be quite important.

Role of dendritic cells and their Toll-like receptor 4 in the pathogenesis of idiopathic thrombocytopenic purpura / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the surface antigen of the dendritic cells (DC) and their Toll-like receptor 4 (TLR4) expression in patients with idiopathic thrombocytopenic purpura (ITP), and to explore their role in ITP pathogenesis.</p><p><b>METHODS</b>The peripheral blood mononuclear cells isolated from complete remission patients (CR), non-complete remission patients (n-CR) and normal controls were stimulated by rhGM-CSF and rhIL-4. The surface antigen of the DC was analyzed by flow cytometry. The level of IL-12p70 in the supernatant was detected by enzyme linked immunosorbent assay. The expression of TLR4 mRNA of DC was detected by real time PCR.</p><p><b>RESULTS</b>In the 21 CR ITP patients, the expression of both CD80 and CD86 in DC was significantly increased compared with that in normal controls \[(51.60 ± 13.47)% vs (36.03 ± 15.43)%, (61.50 ± 15.93)% vs (40.28 ± 11.49)%, respectively\] (P < 0.01). The expression of CD80 and CD86 in n-CR group was also significantly increased \[(53.29 ± 19.49)% and (62.91 ± 18.43)%, respectively\] (P < 0.01). After HD-DXM treatment, both CD80 and CD86 in CR patients were decreased (P < 0.01). There was no difference between the DXM treatment patients and the normal controls. In n-CR group, there was no difference in CD80 and CD86 expression before and after DXM therapy \[(52.30 ± 20.98% and (49.79 ± 20.28)%, respectively\] (P > 0.05). CD80 was still higher than normal (P < 0.05), while CD86 was not changed. The level of IL-12p70 in CR ITP patients before treatment was significantly higher \[(67.52 ± 14.43) pg/ml\] than that of the controls \[(39.78 ± 10.03) pg/ml\](P < 0.01), and after treatment, was significantly decreased to (43.90 ± 8.49) pg/ml, being no difference from that in control. In n-CR group, IL-12p70 was lower after treatment \[(48.45 ± 9.68) pg/ml\] than that before treatment \[(65.35 ± 12.52) pg/ml\] (P < 0.01), but still higher than that in control (P < 0.05). The TLR4 mRNA level in DCs of CR ITP patients before treatment were significantly higher 0.69 ± 0.17 than that of controls (0.31 ± 0.09) (P < 0.01) and after treatment, was reduced to 0.35 ± 0.11, being no difference from that in control. In n-CR group, TLR4 mRNA was decreased from 0.65 ± 0.09 to 0.52 ± 0.21 after treatment (P < 0.01), but still higher than normal (P < 0.01).</p><p><b>CONCLUSION</b>DC may play an important role in ITP by their Toll-like receptor and cytokine secretion.</p>

Study of a humanized anti-platelet GP VI single chain Fv phage antibody / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the anti-platelet GPVI single chain Fv phage antibody which can inhibit the aggregation function of platelet by using phage antibody library technology.</p><p><b>METHODS</b>ITP patients with anti-platelet GPVI autoantibody that could inhibit the aggregation function of platelet were screened by MAIPA assay and platelet aggregation test. The gene fragments of heavy chain and light chain variable region (VH and VL) of immunoglobulin were amplified by RT-PCR from peripheral blood lymphocytes mRNA of the screened patients. The VH and and VL fragments were linked through a DNA linker encoding the peptide (Gly4Ser)3 to construct single chain Fv (ScFv) gene. The ScFv gene was digested with SfiI/NotI restriction enzymes and cloned into the pHEN2 phage display vector, then electrically transformed to E. coli TG1. The TG1 containing ScFv-pHEN2 was rescued by helper phage M13K07 to produce ScFv phage antibody. The anti-platelet GPVI phage ScFv antibody was enriched and purified. The effect of the phage antibody on platelet aggregation function was studied.</p><p><b>RESULTS</b>Of 806 chronic ITP patients, 11 (1.36%) were positive for anti-platelet GPVI autoantibody and 2 (0.24%) patients'plasma significantly inhibited the collagen induced platelet aggregation. The length of VH and VL fragments was about 380 to 400 bp, and were successfully formed ScFv fragments of about 800 bp by DNA linker. After cloning ScFv to phagemid vector pHEN2 and transforming ScFv-pHEN2 to TG1, 4.1x10(7) clones were obtained. After M13K07 rescue, 2.62x10(10) cfu/ml ScFv phage antibodies were produced. The purified anti-platelet GPVI ScFv phage antibody inhibited the collagen induced platelet aggregation.</p><p><b>CONCLUSION</b>Anti-platelet GPVI ScFv phage antibody produced by phage antibody library technology can inhibit the aggregation function of platelet.</p>

The immunoreactivity of IgG and its fragments from ITP patients and their effects on platelet aggregation function / 中华血液学杂志

<p><b>OBJECTIVE</b>To prepare ITP plasma IgG and its F(ab')2 fragments and investigate their immunoreactivity to platelet GPIIb/IIIa and/or GPIb/IX and their effects on platelet aggregation function.</p><p><b>METHODS</b>The ITP patients having inhibitory autoantibody to the platelet aggregation were selected by modified MAIPA and platelet aggregation test with turbidimetry. Plasma IgG and its F(ab')2 fragments were prepared by streptococcal protein A affinity column and pepsin digestion. The immunoreactivity and the effects on platelet aggregation function of the whole antibody and its fragments were detected by modified MAIPA and platelet aggregation test, respectively.</p><p><b>RESULTS</b>(1) Anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies were detected in 34 of 68 (53.6%) ITP patients' plasmas and that from 5 patients significantly inhibited the platelet aggregation induced by ADP or ristocetin. (2) By using protein A column combined with protease digestion, pure IgG and its F(ab')2 fragments were successfully obtained. (3) The purified IgG and its F(ab')2 fragments retained the ability to bind to their respective glycoproteins and inhibited the platelet aggregation function, whereas the IgG depleted plasma lost the ability of binding to the platelet GPs.</p><p><b>CONCLUSIONS</b>F(ab')2 fragment of the IgG antibody is a functional fragment, which not only has the binding ability to the platelet GPs but also inhibits the platelet aggregation function in a dose-dependent manner.</p>

Advances in the studies of platelet glycoprotein VI (GPVI): review / 中国实验血液学杂志

Platelet glycoprotein VI (GPVI) is a major receptor for collagen on the platelet surface. It mediates the initial platelet contact with collagen, generates intracellular signals, increases the affinity of integrin receptor, and causes platelet aggregation and thrombosis. Suppression of GPVI function can significantly inhibit collagen-induced platelet adhesion, aggregation and thrombosis, so GPVI has become a novel target for antiplatelet therapy. Within the last few years, major advances have been made in understanding platelet-collagen interactions. In this paper, the advances of study on GPVI, including composition of GPVI, functions of GPVI, factors related with functions of GPVI, GPVI and clinic were summarized.

Increased subthalamic neuronal activity after dorsal raphe nucleus lesion by 5,7-dihydroxytryptamine in the rat / 生理学报

In vivo extracellular recordings were made in the subthalamic nucleus (STN) of intact control rats and rats with 5,7-dihydroxytryptamine (5,7-DHT) -produced lesion of dorsal raphe nucleus (DRN). The results showed that the firing rate of STN neurons in control rats and DRN-lesioned rats were (6.93+/-6.55) Hz and (11.27+/-9.31) Hz, respectively, and the firing rate of DRN-lesioned rats significantly increased when compared to the control rats (P<0.01). In control rats, 13% of STN neurons discharged regularly, 46% irregularly and 41% in bursts. In DRN-lesioned rats, 9% of STN neurons discharged regularly, 14% irregularly and 77% in bursts, the percentage of STN neurons firing in bursts was obviously higher than that of the control rats (P<0.01). In addition, the mean interspike interval coefficient of variation of STN neurons in control rats and DRN-lesioned rats were (0.05+/-0.04) and (0.11+/-0.09), respectively. The mean interspike interval coefficient of variation of DRN-lesioned rats was significantly higher than that of the control rats (P<0.001). These results show that the firing rate and the bursting pattern rate of neurons in STN of DRN-lesioned rats increase significantly, suggesting that DRN inhibits the neuronal activity of the subthalamic neurons in the intact rat.

Advances in the studies of humanized anti-platelet antibody--review / 中国实验血液学杂志

Platelet plays an important role in bleeding and thrombotic diseases. Humanized anti-platelet antibodies have great clinical effects in treatment of ITP and preventing thrombosis. The important role of platelet in bleeding and thrombotic diseases, the present status of development on study of humanized anti-platelet antibody and its application in treatment of bleeding and thrombotic diseases were summarized in this review.

Changes of discharge rate and pattern of 5-hydroxytrypamine neurons of dorsal raphe nucleus in a rat model of Parkinson's disease / 生理学报

In the present study, changes of the neuronal activity of 5-hydroxytrypamine (5-HT) neurons of dorsal raphe nucleus(DRN) in a rat model of Parkinson's disease (PD) were investigated with glass microelectrode recording. The results showed that the discharge rates of 5-HT neurons in control and PD rats were (1.61+/-0.56) Hz and (2.61+/-1.97) Hz, respectively. The discharge rate of PD rats was significantly increased when compared to that of the control rats. In control rats, 79% of 5-HT neurons discharged regularly and 21% in bursts. In PD rats, however, 36% of 5-HT neurons discharged regularly, 16% irregularly and 47% in bursts. The percentage of 5-HT neurons discharging in bursts was obviously higher than that of the control rats (P<0.05). The data suggest that the discharge rate and bursting pattern of 5-HT neurons in DRN are increased in a rat model of Parkinson's disease.