PHOSPHO1 Serves as a Key Metabolism-Related Biomarker in the Tumorigenesis of Diffuse Large B-cell Lymphoma.

OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Due to its genetic heterogeneity and abnormal metabolism, many DLBCL patients have a poor prognosis. This study investigated the key metabolism-related genes and potential mechanisms. METHODS: Differentially expressed genes, differentially expressed transcription factors (TFs), and differentially expressed metabolism-related genes (DEMRGs) of glucose and lipid metabolic processes were identified using the edgeR package. Key DEMRGs were screened by Lasso regression, and a prediction model was constructed. The cell type identification by estimating relative subsets of RNA transcripts algorithm was utilized to assess the fraction of immune cells, and Gene Set Enrichment Analysis was used to determine immune-related pathways. A regulatory network was constructed with significant co-expression interactions among TFs, DEMRGs, immune cells/pathways, and hallmark pathways. RESULTS: A total of 1551 DEMRGs were identified. A prognostic model with a high applicability (area under the curve=0.921) was constructed with 13 DEMRGs. Tumorigenesis of DLBCL was highly related to the neutrophil count. Four DEMRGs (PRXL2AB, CCN1, DECR2 and PHOSPHO1) with 32 TF-DEMRG, 36 DEMRG-pathway, 14 DEMRG-immune-cell, 9 DEMRG-immune-gene-set, and 67 DEMRG-protein-chip interactions were used to construct the regulatory network. CONCLUSION: We provided a prognostic prediction model based on 13 DEMRGs for DLBCL. We found that phosphatase, orphan 1 (PHOSPHO1) is positively regulated by regulatory factor X5 (RFX5) and mediates MYC proto-oncogene (MYC) targeting the V2 pathway and neutrophils.

[The efficacy and safety analysis of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma].

OBJECTIVE: To evaluate the efficacy and safety of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma (MM), who previously responded to bortezomib. METHODS: Retrospective analysis of 76 MM patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to August 2011, received bortezomib retreatment when they relapsed or progressed. RESULTS: The overall response rate (ORR) was 60.5%, among them 6.5% patients achieved CR, 5.8% patients achieved very good partial response (VGPR), 38.2% patients achieved PR. Then we further stratified all patients into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 84.6%, 73.1% and 43.2%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 7(1-39) and 5(1-14) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 16(2-64) and 8(1-28) months, respectively (P<0.05). Adverse events (AE) were identified in 88% patients during bortezomib retreatment, including neutropenia, diarrhea and thrombocytopenia, only 9.2%(7 patients) reached Ⅲ-Ⅳ grade of AE. Severe peripheral neuropathy occurred in only one patient. CONCLUSION: Bortezomib retreatment regimen is demonstrated a higher response rate in patients who achieved deeper response in initial treatment, with no more adverse events.

[Allogeneic peripheral blood stem cell transplantation from sibling donors for 10 patients with multiple myeloma].

OBJECTIVE: To evaluate the efficacy of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from sibling donors for treatment of multiple myeloma (MM). METHODS: Ten patients with MM received allo-PBSCT with conditioning consisting of fludarabine plus melphalan and cyclophosphamide mostly.CsA plus mycophenolate mofetil (MMF) and short-term MTX were applied to prevent graft versus host disease (GVHD) in 8 patients, FK506 plus short-term MTX in other 2 patients. RESULTS: All patients engrafted successfully, the median time for ANC > 0.5 × 10(9)/L was 16 (12 - 24) days, and for BPC > 20 × 10(9)/L 23 (16 - 102) days. Five patients developed acute GVHD, and only one III-IV aGVHD. Of 9 patients, 7 developed chronic GVHD. The transplant-related mortality (TRM) at 100 days was 10% (1/10), mainly from heart and renal failure and severe infection. The 1-year expected overall survival (OS), 1-year disease-free survival (DFS) and relapse rate were 67.5%, 55.56% and 11.11% respectively. Up to now, 6 patients were still alive, of them 1 patient have survived over 99 months after allo-PBSCT. CONCLUSION: Young MM patients having HLA-identical sibling donors well tolerated allo-PBSCT based on fludarabine to prolong their OS by reducing TRM, though further work is warranted.

[Clinical observation of prophylactic lactulose for prevention of oral morphine-induced constipation].

OBJECTIVE: To evaluate the effects of different doses of lactulose on preventing oral morphine-induced constipation. METHODS: From January 2011 to May 2012, a total of 112 patients received oral lactulose solution to prevent morphine-induced constipation at our hospital and their clinical data were retrospectively analyzed. The doses of morphine were adjusted according to the pain scores and lactulose was taken simultaneously. There were 52 males and 60 females. They were randomized into Group 30 ml/d (n = 40), Group 60 ml/d (n = 43) and Group 90 ml/d (n = 29). The incidences of constipation and adverse reactions were obtained at 1 week after the start of medicine. The measurement data were analyzed with analysis of variance. And the enumeration data were analyzed with χ(2), Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The incidence of constipation was 67.5% (27/40) in Group 30 ml/d, 46.5% (20/43) in Group 60 ml/d, and 37.9% (11/29) in Group 90 ml/d. And there were statistical differences (P = 0.036). The incidence of constipation in Group 30 ml was significantly higher than Group 90 ml/d (P = 0.015). No statistical difference existed in the incidence of constipation between Groups 30 ml/d and 60 ml/d (P = 0.054) or Groups 60 ml/d and 90 ml/d (P = 0.471). The incidence of vomiting was 34.5% (10/29) in Group 90 ml/d and it was significantly higher than 10.0% (4/40) in Group 30 ml/d (P = 0.013) and 9.3% (4/43) in Group 60 ml/d (P = 0.009). No statistical difference existed in the incidence of vomiting between Groups 30 ml/d and 60 ml/d (P = 0.915). The incidence of diarrhea was 17.2% (5/29) in Group 90 ml/d and it was significantly higher than 0 (0/40) in Group 30 ml/d (P = 0.007). No statistical difference existed in the incidence of diarrhea between Groups 30 ml/d and 60 ml/d (4.7% (2/43), P = 0.170) or Groups 60 ml/d and 90 ml/d (P = 0.072). CONCLUSION: The correct dosage of lactulose for the prevention of oral morphine-induced constipation is 60 ml/d.

Clinical effects of autologous stem cell transplantation as consolidation treatment in 70 multiple myeloma patients: a case-controlled study.

BACKGROUND: Autologous stem cell transplantation (ASCT) is a part of the standard induction therapy of multiple myeloma (MM). This case-controlled clinical trial aimed to further evaluate the therapeutic effects of ASCT as a consolidation therapy for MM and discuss factors influencing the prognosis. METHODS: Clinical data of 70 patients diagnosed as MM who received ASCT as a consolidation therapy in our hospital between October 1998 and August 2010 were analyzed retrospectively (ASCT group). Other 70 MM patients receiving routine chemotherapy without ASCT (non-ASCT group) during the same period were used as controls. Differences in the degree and duration of remission, progression-free survival (PFS) and overall survival (OS) were compared to explore factors that may influence the prognosis. RESULTS: The median follow-up period was 38 months (range 1 - 128 months). The complete response (CR) rate of ASCT group increased from 27.1% (19/70) before ASCT to 51.4% (36/70) after ASCT. The median PFS of ASCT group was significantly higher than non-ASCT group (45 months vs. 25 months, P < 0.001). The median OS of ASCT group was also significantly higher (55 months vs. 30 months, P = 0.016). Single-factor analysis showed that International Staging System (ISS) stage, very good partial response (VGPR) or better outcome were significantly correlated with PFS and OS (P < 0.001). Multi-factor analysis showed that whether or not VGPR or better outcome was achieved were independent factors influencing the disease prognosis. CONCLUSION: Used as a consolidation therapy, ASCT can achieve better responses and higher OS and PFS of MM patients.

Transcriptional regulation of survivin by c-Myc in BCR/ABL-transformed cells: implications in anti-leukaemic strategy.

BCR/ABL can cause chronic myelogenous leukaemia (CML) in part by altering the transcription of specific genes with growth- and/or survival-promoting functions. Recently, BCR/ABL has been shown to activate survivin, an important regulator of cell growth and survival, but the precise molecular mechanisms behind its expression and consequences thereof in CML cells remain unclear. Here, we reported that BCR/ABL promotes survivin expression and its cytoplasmic accumulation. The increase of survivin was largely controlled at the transcriptional level through a mechanism mediated by JAK2/PI3K signal pathways that activated c-Myc, leading to transactivation of survivin promoter. Dynamic down-regulation of survivin was a key event involved in imatinib-induced cell death while forced expression of survivin partially counteracted imatinib's effect on cell survival. Additionally, shRNA-mediated silencing of survivin or c-Myc eradicated colony formation of K562 cells in semi-solid culture system, implying an essential role for this transcriptional network in BCR/ABL-mediated cell transformation and survival. Finally, interruption of c-Myc activity by 10058-F4 exerted an anti-leukaemia effect with a synergistic interaction with imatinib and overcame the anti-apoptosis rescued by IL-3 supplement. In conclusion, we have identified JAK2/PI3K-mediated and c-Myc-dependent transactivation of survivin as a novel pathway in the transcriptional network orchestrated by BCR/ABL. These results suggest that the interference with this circuitry might be a potential utility for CML treatment.

[Clinical analysis of 438 patients with essential thrombocythemia].

OBJECTIVE: To analyse the clinical feature and natural course of essential thrombocythemia (ET). METHODS: A retrospective analysis was conducted in ET patients treated in our hospital during May 1980 to December 2006. RESULTS: Four hundred and thirty eight patients (201 males and 237 females with a median age of 48 years) were diagnosed. Hemorrhage occurred in 101 cases (23.1%), thrombosis in 86 cases (19.6%), and both hemorrhage and thrombosis in 13 cases (3.0%). Splenomegaly occurred in 150 cases and hepatomegaly occurred in 60 cases. One hundred and forty-nine cases (34%) had no symptoms at diagnosis and 145 cases (33.1%) confirmed by routine blood tests due to other diseases. The median platelet count at diagnosis was 1000 x 10(9)/L [(533 -3740) x 10(9)/L]. Bone marrow biopsy was performed in 255 cases which showed mainly increase of enlarged mature megakaryocytes with hyper-lobulated nuclei and local proliferation of reticular fiber was revealed in 51 cases. JAK2V617F mutation was detected in 90(78.9%) of 114 patients studied. Karyotype analysis was performed in 180 cases and 6 (3.3%) had clonal chromosomal aberrations. Two hundred and sixty-one patients were followed up over 12 months with a median of 60 months (range from 12 to 300 months). Seventeen cases (6.5%) evolved into marrow fibrosis (MF) and one case into polycythemia vera (PV). One case evolved into PV 6 years and then MF 20 years after diagnosis of ET. Three cases developed acute monocyte leukemia (M5), myelodysplastic syndrome (MDS) and multiple myeloma (MM), respectively. CONCLUSIONS: ET is a chronic myeloproliferative disorder characterized predominantly by thrombocytosis and hemorrhage. The percentage of asymptomatic cases is high. The prognoses for most cases were good with a few cases may evolve into MF.

Enhancement of neovascularization with mobilized blood cells transplantaion: supply of angioblasts and angiogenic cytokines.

We have recently provided evidence that transplantation of G-CSF mobilized peripheral blood mononuclear cells (M-PBMNCs) improves limb ischemia in diabetic patients. This method represents a simple, safe, effective, and novel therapeutic approach for diabetic ischemia. Here we investigated the mechanisms by which mobilized blood cells transplantation improves limb ischemia. Unilateral hindlimb ischemia was surgically induced in streptozotocin-induced diabetic nude mice, and they were intramuscularly injected 10(6) M-PBMNCs, or human umbilical vein endothelial cells (HUVECs), PBS controls. We compared their blood-flow restoration via laser Doppler perfusion image (LDPI), angiogenesis via histological determination of capillary density. Physiological and histological assessment revealed an acceleration of ischemia recovery and increase in capillary density with less apoptosis in M-PBMNCs group, compared with those in HUVECs and PBS groups. In vivo noninvasive imaging and immunofluorescence revealed the survival, migration, proliferation, differentiation, and incorporation of M-PBMNCs into foci of vessel networks. More angioblasts were from blood cells after mobilization, and they also produced a number of antiapoptotic and proagniogenic factors that promoted angiogenesis in vivo. M-PBMNCs and its conditioned medium augmented the vessel formation in matrigel plugs in vivo. Thus, transplantation of M-PBMNCs achieved therapeutic neovascularization via supply of abundant angioblasts and angiogenic factors.