Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

LINC00987 knockdown inhibits the progression of acute myeloid leukemia by suppressing IGF2BP2-mediated PA2G4 expression.

This study aimed to investigate the role and potential mechanisms of LINC00987 in acute myeloid leukemia (AML) progression. The expression of LINC00987 in bone marrow specimens of AML patients and cell lines was measured by quantitative reverse transcription PCR (RT-qPCR). Small interfering RNA targeting LINC00987 (si-LINC00987) was transfected into AML cell lines HL-60 and KG-1, and the proliferation, invasion and apoptosis were detected with Cell Counting Kit-8 (CCK-8), Transwell and flow cytometry, respectively. Moreover, the binding between LINC00987 and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was validated with an RNA pull-down assay. Co-immunoprecipitation assay was used to verify the binding between IGF2BP2 and proliferation-associated 2G4 (PA2G4). Then rescue experiments were performed to explore the effects of LINC00987/IGF2BP2/PA2G4 axis on HL-60 and KG-1 cell functions. Additionally, HL-60 cells transfected with si-LINC00987 were injected into mice, followed by the evaluation of xenograft tumor growth. LINC00987 was upregulated in AML patient specimens and cell lines. LINC00987 knockdown inhibited proliferation and invasion and promoted apoptosis in AML cells. LINC00987 could bind with IGF2BP2 and promote its expression, and IGF2BP2 overexpression reversed the effects of LINC00987 knockdown on the proliferation, invasion and apoptosis in AML cells. Besides, IGF2BP2 could bind with PA2G4. IGF2BP2 knockdown inhibited proliferation and invasion, and promoted apoptosis in AML cells, whereas PA2G4 overexpression reversed these effects. Additionally, the LINC00987 knockdown inhibited the xenograft tumor growth of AML in vivo. Knockdown of LINC00987 inhibits AML cell proliferation and invasion, and promotes apoptosis in vitro and reduces tumor growth in vivo by suppressing IGF2BP2-mediated PA2G4 expression.

The CD200/CD200R mechanism in mesenchymal stem cells' regulation of dendritic cells.

OBJECTIVE: To investigate the CD200/CD200R pathway mechanism in mesenchymal stem cells' (MSC) regulation of dendritic cells (DC) (MSc). METHODS: We collected marrow samples from 40 patients admitted to our hospital from January 2018 to December 2019. The bone marrow MSCs were cultivated, and the peripheral blood mononuclear cells (PBMC) and peripheral blood DC were isolated to establish an in vitro immune response model. The expressions of the CD200 molecule on the surface of MSC were measured. Anti-CD200 blocking antibodies were added to the culture system to observe the effect of the PBMC differentiation and the immature DC (imDC) to mature DC (mDC). Then the impact of the different positive rates of CD200 in the same MSC on imDC maturity was measured. RESULTS: After adding mitogen pHA, the IL-4, IL-10, and TNF-α secretions were increased (all P<0.05), and the OD value of the PBMC+pHA group was higher than it was in the PBMC group. After stimulated by pHA, the CD200 of the MSC group was higher than it was in the MSC+PBMC group (P<0.05). The MSC+PBMC group co-culture inhibited the development of imDC to mDC. Adding anti-CD200 antibodies to the MSC+PBMC co-culture system, MSC could still inhibit the differentiation of PBMC to imDC, and MSC had a significant inhibition effect on imDC to mDC maturation (P=0.006). The addition of MSC reduces the maturation markers on the surface of mDC (P<0.05). The addition of MSC inhibited the ability of mDC to stimulate PBMC (POD<0.05) and decreased the IL-12 (PIL-12<0.05) levels. The addition of the anti-CD200 antibody increased the proliferation ability of mDC to stimulate PBMC (POD<0.05), and it also increased the IL-12 levels in mDC (PIL-12<0.05). The expression of the DC mature immune phenotype in the CD200 high expression group was weak (PCD83, CD86<0.05). CONCLUSION: The mechanism by which MSC inhibits DC may be achieved through the CD200/CD200R pathway, and the CD200/CD200R pathway mainly acts on the process from imDC to mDC.

The CD200/CD200R expression level and its mechanism of action in hematological malignancy patients.

OBJECTIVE: To explore the CD200/CD200R expression level in the peripheral blood mononuclear cells (PBMC) of hematological malignancy patients and to analyze its mechanism of action. METHODS: Thirty hematological malignancy patients who were hospitalized in our hospital from June 2019 to December 2019 were recruited as the study cohort and placed in the disease group, and 30 healthy people were also recruited for the study and placed in the healthy control group. The CD200/CD200R expression level in the two groups' peripheral blood was measured using real-time fluorescent quantitative PCR, and enzyme-linked immunosorbent assays were used to measure the interleukin 17 (IL-17), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) expression levels in the two groups' peripheral blood. We monitored the effects of the effective treatment on the CD200/CD200R level in the hematological malignancy patients. RESULTS: Compared with the healthy group, the CD200 and CD200R mRNA expression level in the PBMC of the disease group was down-regulated, but the IL-17, TNF-α and IFN-γ expression levels in the peripheral blood plasma were up-regulated, and the differences were statistically significant (P < 0.001). The CD200 and CD200R levels showed a negative correlation with the IL-17, TNF-α, and IFN-γ expression levels in the hematological malignancy patients (P < 0.001). The CD200/CD200R expression level was significantly increased in the PBMC of the effectively treated hematological malignancy patients compared with their pre-treatment expression level, and the difference was statistically significant (P < 0.001). CONCLUSION: CD200/CD200R exhibits a low expression level in hematological malignancy patients, reducing the inhibitory effect on the inflammatory factor expressions, enhancing the inflammatory factors, and mediating the occurrence and development of hematological malignancies.

The improved anticancer effects of Bortezomib-loaded hollow mesoporous silica nanospheres on lymphoma development.

As the first clinical proteasome inhibitor, Bortezomib (BTZ) has been reported to improve the outcome of lymphoma. However, due to the unstable property, low bioavailability, and hydrophobic properties of BTZ, it is needed to develop effective drug delivery systems to deliver BTZ into targeted cells or organs. Here we developed a bortezomib (BTZ)-loaded HMSNs (BTZ@HMSNs) system, which can sustain the release of BTZ in targeted tissues. In vitro assays showed that BTZ@HMSNs limited cell proliferation and augmented apoptosis of lymphoma SNK-1 cells. Moreover, BTZ@HMSNs significantly diminished migration and invasion of SNK-1 cells as compared with BTZ. In contrast to the upregulation of SHP-1, BTZ@HMSNs decreased the mRNA levels of c-Kit, NF-κB, and JAK1, which elicit oncogenic role in lymphoma development. Importantly, lymphoma mice model showed that BTZ@HMSNs significantly activated p53 signaling and reduced tumor volume and weight compared with free BTZ. Our data thus demonstrate that BTZ@HMSNs manifests improved tumor-suppressing effect in vitro and in vivo compared to free BTZ. We believe that HMSNs is a promising strategy for delivering therapeutic agents for cancer treatment.

Apatinib enhances the anti-tumor effect of cisplatin on gastric cancer by inhibiting HMGA2 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effect of apatinib (APA) combined with cisplatin (DDP) on the proliferation, invasion and migration capacity of gastric carcinoma (GC) cells and its molecular mechanism. Methods: Cancer and para-cancerous tissue samples resected from 50 GC patients, who were surgically treated in Wuwei People's Hospital from January 2016 to June 2019, were collected for this study; in addition, GC cell lines MGC803 and SGC7901 were also collected. qPCR was used to detect the HMGA2 expression in tissues and mRNA expressions of molecules related to cell proliferation, migration and invasion in GC cell lines. MGC803 and SGC7901 cells were transfected with pcHMGA2 by liposome transfection technology. After treatment with DDP and APA at different concentrations, the cells were divided into NC, pcHMGA2, pcHMGA2+DDP and pcHMGA2+DDP+APA groups. Protein expression of HMGA2 in GC cells was detected by Western blotting, and proliferation, migration and invasion of the cells were detected by MTT and Transwell assay, respectively. Results: The mRNA expression of HMGA2 in GC tissues was higher than that in para-cancerous tissues (P<0.05), and the survival rate of GC patients in the high expression group was significantly reduced (P<0.01). DDP significantly inhibited the proliferation, invasion and migration of MGC803 and SGC7901 cells (all P<0.01); the proliferation, invasion and migration of MGC803 and SGC7901 cells in DDP+APA group significantly decreased (all P<0.01) as compared with DDP group; APA significantly enhanced the inhibitory effect of DDP on HMGA2 expression in GC cells (P<0.01); APA enhanced the anticancer activity of DDP against GC by down-regulating HMGA2 expression. Conclusion: APA promotes the anticancer activity of DDP against GC, and its molecular mechanism is the promotion of the inhibitory effect of DDP on HMGA2 expression.

Lowering hepatic venous pressure agent carvedilol versus variceal banding ligation for clinical outcomes of cirrhotic portal hypertension.

OBJECTIVE: Carvedilol is nonselective beta-blocker with a mild anti-alpha-1-adrenergic effect. Several studies proposed improved hemodynamic effects of carvedilol compared with propanolol. Our study was to perform a systematic review and meta-analysis of randomized control trials comparing carvedilol with variceal banding ligation (VBL). METHODS: Studies were searched on online databases MEDLINE, EMBASE(Ovid), the Cochrane Library, Chinese Wanfang Database, and China National Knowledge Infrastructure between January 2000 and May 2018. Incidence of bleeding and mortality were main outcome measures. Subgroup analysis and sensitivity analysis were conducted to ensure the robustness of pooled estimates. RESULTS: Ten randomized control trials including 1,269 cirrhotic patients were chosen. Compared with VBL, carvedilol showed similar preventive efficacy of risk ratios (RRs) in variceal bleeding, and bleeding-related mortality over different follow-up periods from 6 months to 24 months. Also, significant differences between carvedilol and VBL in overall mortality and other causes of mortality were failed to be found. Carvedilol achieved a lower incidence of portal hypertension gastropathy in both 6 months (RR=0.49, 95% CI: 0.38-0.64, P<0.00001) and 12 months (RR=0.35, 95% CI: 0.26-0.47, P<0.00001). Two trials compared combination of carvedilol and VBL with VBL alone; however, the results failed to find an improved preventive efficacy of bleeding (RR=0.71, 95% CI: 0.15-3.30, P=0.67). CONCLUSION: Carvedilol is equivalent to invasive VBL for variceal bleeding prevention. It can be well tolerated and may be of benefit to portal hypertension gastropathy. However, available data during 24 months follow-up did not support a potential advantage of carvedilol for prognosis as a lowering hepatic venous pressure agent.

[Randomized controlled trials of needle knife therapy combined with rotation traction manipulation for the treatment of cervical spondylotic radiculopathy].

OBJECTIVE: To compare the therapeutic effects between needle knife therapy combined with rotation traction manipulation and rotation traction manipulation for the treatment of cervical spondylotic radiculopathy. METHODS: From November 2013 to June 2015, 80 patients with cervical spondylotic radiculopathy meeting the inclusion criteria were divided into two groups randomly:the control group in which 39 patients were treated with rotation traction manipulation, and the treatment group in which 41 patients were treated with needle knife combined with rotation traction manipulation. The patients in the control group were treated once dayly for 2 weeks, which was 1 course. The patients in the treatment group were treated with needle knife firstly once a week for 2 weeks, which was 1 course;then were treated with the same methods as the patients in the control group. The symptoms, signs score and the therapeutic effects of the two groups before and after treatment were observed. RESULTS: After treatment, symptoms and signs scores declined in both groups(P<0.05). The results of the treatment group were better than effects in the control group(P<0.05). In the treatment group, 19 patients got an excellent result, 16 good, 5 fair and 1 bad;while in the control group, 10 patients got an excellent result, 10 good, 16 fair and 3 bad;the results of the treatment group were better than the results of the control group(P<0.01). CONCLUSIONS: Needle knife combined with rotation traction manipulation is an effective method for the treatment of cervical spondylotic radiculopathy, which is better than using manipulation method simply. Needle knife therapy has follow advantages:improving local blood circulation, reducing local content of pain substance, increasing production of substances resisting pain, opening channels and collaterals, and make body reaching new static and dynamic balance on the new foundation.

Multiple myeloma with intracranial extension and bilateral renal infiltration: A case report and review of the literature.

Multiple myeloma (MM) is a rare hematological malignancy, characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM is usually confined to the bone marrow, however, it may occasionally infiltrate other tissues, which is known as extramedullary plasmacytoma (EMP). The majority of EMPs involve the head and neck region, although different anatomical sites, including the gastrointestinal tract, central nervous system, thyroid gland and breast may also be affected. The simultaneous presentation of EMP in the kidney and head is rare, presenting diagnostic challenges due to its unusual location and non-specific or absent symptoms. To the best of our knowledge, no case of extramedullary plasmacytoma presenting with simultaneous renal and intracranial infiltration has been reported in the literature thus far. However, the present study reports a case of primary renal and intracranial extramedullary plasmacytoma in a 76-year-old male patient. The patient presented with a swelling over the right side of the forehead, which had slowly increased in size prior to hospital admission. The swelling was associated with dizziness and weakness, without bone pain. Contrast magnetic resonance imaging suggested an osteolytic skull lesion with intracranial extension. Abdominal enhanced computed tomography scanning revealed a large tumor mass extending around and into the kidneys. Immunohistochemical examination of the renal tumor biopsy, and blood and serum samples, as well as immunoelectrophoresis of serum proteins, resulted in a diagnosis of EMP being proposed. Therefore, the patient was administered with two cycles of cyclophosphamide and thalidomide in combination with dexamethasone. Follow-up imaging performed 4 months later revealed almost complete disappearance of the intracranial tumor mass and renal infiltration. The current study also presented a review of the literature. This study revealed that EMPs may co-exist with MM or present as the main symptom of MM. The diagnosis of an EMP is complex and requires radiological, hematological, biochemical and histological investigation. At present, no guidelines for EMP treatment have been established and thus, treatment options include surgery, chemotherapy and radiotherapy, either alone or in combination. We hypothesize that combined treatment may provide the best patient outcome.

Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis.

Multiple myeloma is a type of malignancy, which affects the plasma cells of the bone marrow. Recent studies have found that malignant plasma cells may express urokinase plasminogen activator (uPA) and uPA receptor (uPAR), and that initiation of proteolytic events by this system contributes to the process of invasion and destruction of the bone marrow. Studies have also suggested that the level of the soluble form of uPAR (suPAR) may act as a marker for prognosis in patients with multiple myeloma, and that there is an association between uPAR/suPAR expression, and clinical characteristics, efficacy of treatment in disease control and patient survival. In order to investigate this, the present study used flow cytometry to detect the monoclonal antibodies associated with multiple myeloma, specifically, uPAR (CD87), CD56 and CD38. Patients with multiple myeloma were divided into the following groups: The effective groups (remission and stable disease) and the ineffective group (progressive disease). suPAR expression in the effective groups was 257.6±32.47 pg/ml and 331.0±99.80 pg/ml respectively, which was not significantly different from that of the normal control group (P>0.05). By contrast, the suPAR level in the invalid group was 562.2±291.0 pg/ml, which was significantly different from the levels in the normal control group (P<0.01) and the effective groups (P<0.05). suPAR levels were positively correlated with disease stage (P<0.01), renal function (P<0.05), C-reactive protein (P<0.005), ß2-microglobulin (P<0.001), extramedullary involvement (P<0.001), chromosome 13 deletion (P<0.01) and survival >2 years (P<0.01). They were was negatively correlated with hemoglobin concentration. No correlation was observed between uPAR expression and suPAR levels. The present study also indicated that the stage of disease and suPAR expression were independent factors, which predicted survival of <2 years. In conclusion, high suPAR expression appears to predict disease progression, a shortened survival period and early extramedullary infiltration.

[Role of CD47 in hematologic malignancies].

CD47 is a ubiquitously expressed transmembrane glycoprotein on surface of many cells. Through its interaction with integrin, signal regulatory protein alpha (SIRPα) and thrombin sensitive protein-1 (TSP-1), it plays important roles in various immunological processes including inflammatory response, immune response and tumor immunity. Recently, it has been found that CD47 interacts with SIRPα expressed on phagocytic cells, which transfers a negative signal when being activated. By the mechanisms described above, CD47-SIRPα signal complex is involved in the pathogenesis of hematological diseases and might provide some informations for the therapy of patients. This review focuses on the structure and immunoregulatory functions of CD47, the mechanism of CD47 in tumor therapy, the CD47 and hematologic malignancies including acute leukemia, B-cell lymphoma and multiple myeloma, as well as CD47 and hematopoietic stem cell transplantation.