Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

Comparable long-term outcomes between upfront haploidentical and identical sibling donor transplant in aplastic anemia: a national registry-based study.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.

Labilibacter sediminis sp. nov., isolated from marine sediment.

A Gram-stain-negative, rod-shaped and facultatively anaerobic strain, designated CG51T, was isolated from marine sediment collected from a coastal area in Weihai, PR China. Strain CG51T grew at 4-37 °C (optimum, 28-30 °C), with 1.0-6.0 % (w/v) NaCl (2.0-3.0 %) and at pH 6.0-8.5 (pH 7.0-7.5). The predominant fatty acids were iso-C15 : 0, anteiso-C15 : 0 and iso-C14 : 0. Major polar lipids included an unidentified lipid and a phospholipid. The respiratory quinone was MK-7 and the genomic DNA G+C content was 35.9 mol%. The results of phylogenetic analysis based on 16S rRNA gene sequences placed strain CG51T in the genus Labilibacter with the close relatives being Labilibacter marinus Y11T and Labilibacter aurantiacus HQYD1T, exhibiting 96.5 and 96.3 % 16S rRNA pairwise similarity, values which are clearly below the 98.7 % threshold value recommended for species demarcation. Based on the phylogenetic, physiological, chemotaxonomic and genetic data, strain CG51T represents a novel species within the genus Labilibacter, for which the name Labilibacter sediminis sp. nov. is proposed. The type strain is CG51T (=MCCC 1K03739T=JCM 33138T).

Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy.

In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG-(1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng·kg(-1)·min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.

[The value of narrow-band imaging with magnifying endoscopy in diagnosis of early gastric cancer: a meta-analysis].

OBJECTIVE: To assess the diagnostic value of narrow-band imaging with magnifying endoscopy (NBI-ME) for early gastric cancer (EGC). METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library for literature of NBI-ME in diagnosis of EGC, and then performed meta-analysis. RESULTS: A total of 12 articles involving 2 278 samples from 2 048 patients were included. The overall sensitivity of NBI-ME for diagnosis of EGC was 0.84 [95% CI: 0.80~0.87], specificity was 0.96 (95% CI: 0.95~0.97),and area under the symmetric receiver operator characteristic curve (AUC) was 0.9592. The AUC value of the NBI-ME plus conventional white light endoscopy (C-WLE) subgroup (0.9706) was higher than that of NBI-ME alone (0.8162). The incremental yield of NBI-ME plus C-WLE over C-WLE was significant (IY = 9.4%, P = 0.011), while NBI-ME alone over C-WLE was not significant (IY = 0.8%, P = 0.498). CONCLUSIONS: The results show that NBI-ME plus C-WLE is an effective and preferable method for diagnosis of EGC; however, NBI-ME alone is not superior to C-WLE.

Characteristics of acute myeloid leukemia with myelodysplasia-related changes: A retrospective analysis in a cohort of Chinese patients.

We retrospectively analyzed 449 patients with AML under the WHO classification of AML 2008 and probed implications of this classification in diagnosis and treatment of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) among them. The clinical presentations, biological features, treatments, and prognosis of patients diagnosed with AML-MRC were analyzed and compared with those of AML not otherwise specified (AML-NOS). In all patients, 115 (25.6%) were diagnosed as AML-MRC including 64 males and 51 females with median onset age of 48 years (range from 17 to 78). Their complete remission (CR) rate was 60.9% and relapse rate was 57.1%. The observed median overall survival (OS) and disease-free survival (DFS) were 10 and 5 months, respectively, which was significantly shorter than those of AML-NOS patients (P < 0.05). The prognosis of AML-MRC patients with myelodysplastic syndrome (MDS)-related cytogenetics sole was similar to those with history of MDS or myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Patients with MDS-related cytogenetic abnormalities and/or history of MDS or MDS/MPN predisposed significantly shortened CR, OS, and DFS than AML-MRC patients with only multilineage dysplasia (MLD) and AML-NOS patients (P < 0.05). Multivariate analysis showed that age, cytogenetics, and history of MDS or MDS/MPN were independent prognostic factors. Patient diagnosed as AML-MRC presented distinctive clinical and biological features. Presence of MLD does not change the prognosis.

Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells.

OBJECTIVE: To test the hypothesis that chronic infusion of angiotensin-(1-7) [Ang-(1-7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1-7) may stabilize mature plaque by targeting macrophages. APPROACH AND RESULTS: In vivo, the effects of Ang-(1-7) on atherogenesis and plaque stability were observed in ApoE(-/-) mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1-7) on vascular smooth muscle cells' proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1-7) dose-dependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells' proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1-7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1-7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques. CONCLUSIONS: Ang-(1-7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE(-/-) mice, thus providing a novel and promising approach to the treatment of atherosclerosis.

Simvastatin increases Prolyl-4-Hydroxylase α1 expression in atherosclerotic plaque and ox-LDL-stimulated human aortic smooth muscle cells via p38 MAPK and ERK1/2 signaling.

Prolyl-4-Hydroxylase α1 (P4Hα1) is essential for collagen synthesis but the effect of statin on P4Hα1 is unknown. We hypothesize that simvastatin may increase the expression of P4Hα1 in atherosclerotic plaques and ox-LDL-stimulated human aortic smooth muscle cells (HASMCs). In HASMCs, ox-LDL suppressed P4Hα1 expression significantly with peak value occurring at 50 ug/ml treated for 8h. Ox-LDL also inhibited the expression of type I and III collagen and increased the phosphorylation level of p38 MAPK and ERK1/2, but blockade or silencing of p38 and ERK1/2 inhibited the suppressive effect of ox-LDL on P4Hα1. Then HASMCs were stimulated with or without ox-LDL (50 ug/ml) for 8h after simvastatin pretreatment for 1h. Simvastatin significantly attenuated the suppressive effect of ox-LDL on P4Hα1 and collagen production by inhibiting ox-LDL uptake and the activation of p38 MAPK and ERK1/2. In apolipoprotein E-deficient mice, simvastatin and the inhibitors of p38 and ERK1/2 significantly increased the stability of the carotid plaques. We also found that simvastatin significantly increased the expression of P4Hα1 and collagen possibly due to decreased ox-LDL content and phosphorylation of p38 and ERK1/2 in plaques. Thus, simvastatin increases P4Hα1 and collagen expression in ox-LDL-stimulated HASMCs and atherosclerotic plaques via p38 MAPK and ERK1/2, thereby exerting a plaque stabilizing effect.

Allogeneic peripheral blood stem cell transplantation is a promising and safe choice for the treatment of refractory/relapsed acute myelogenous leukemia, even with a higher leukemia burden.

The prognosis of patients with refractory/relapsed acute myelogenous leukemia (rAML) is poor. Recent studies have shown that more transplant centers are choosing allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for recipients, even with a higher leukemia burden. The purpose of the present study is to evaluate the outcome of rAML patients undergoing allo-PBSCT and to determine whether the disease status can predict the post-transplantation survival. The outcome of 58 patients (median age, 34 years; range, 14 to 52) with rAML who underwent allo-PBSCT in our institution from January 2000 until September 2011 was retrospectively studied. Thirty-three patients had complete remission (CR) before PBSCT, whereas 25 patients had no remission. Donors were matched related (31 patients) and unrelated (27 patients). Reduced-intensity conditioning was used for 18 patients with rAML, and myeloablative conditioning was used for others. Sixty-six consecutive non-rAML patients (median age, 33 years; range, 15 to 51) who received an allo-PBSCT at the same period were used as a control. Full donor-type engraftment was achieved in all patients. After a median follow-up of 61 months, the 5-year overall survival of rAML patients was 54.21% ± 7.06%, which was lower than non-rAML patients (71.82% ± 6.4%, P = .0386). However, the 5-year event-free survival for rAML and non-rAML patients had no statistical significance (53.54% ± 6.87% versus 62.07% ± 6.78%, P = .2626). The 5-year overall survival between rAML patients who had CR and no remission before PBSCT was 56.06% ± 9.2% and 51.85% ± 10.83%, respectively (P = .6408). These data demonstrate that allo-PBSCT is a promising and safe choice for the treatment of rAML, and the results were partially due to the rapid tapering of immunosuppressants in the early stage after PBSCT and prophylactic donor lymphocyte infusion. Meanwhile, the patients who did not achieve CR before PBSCT could also benefit from allo-PBSCT.