Meng Lv

Allogeneic hematopoietic stem cell transplantation in China: where we are and where to go

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and sometimes the only curative therapy for patients with certain hematological diseases. Allo-HSCT has been practiced in China for approximately 30 years, and great improvements have been made within the past decade, particularly in fields such as the haploidentical HSCT system, strategies to overcome relapse and GVHD, and modified HSCT for elderly patients. This review will describe the current situation and provide a prospective of these unique aspects of Allo-HSCT in China.

Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G-CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation

We investigated the effects of granulocyte colony‐stimulating factor (G‐CSF) on monocytic (M), promyelocytic (P), and granulocytic (G) myeloid‐derived suppressor cells (MDSCs) both in bone marrow and peripheral blood of 20 healthy donors and the association of MDSCs subgroups with acute and chronic graft‐versus‐host disease (aGvHD/cGvHD) in 62 patients who underwent haplo‐identical allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Patients who received a higher absolute counts of M‐MDSCs or P‐MDSCs exhibited lower incidence of grade II–IV aGvHD (P = 0.001; P = 0.031) and extensive cGvHD (P = 0.011; P = 0.021). In the multivariate analysis, absolute counts of MDSCs in allografts emerged as independent factors that reduced the occurrence of grade II–IV aGvHD (M‐MDSCs: HR = 0.087, 95% CI = 0.020–0.381, P = 0.001; P‐MDSCs: HR = 0.357, 95% CI = 0.139–0.922, P = 0.033) and extensive cGvHD (M‐MDSCs: HR = 0.196, 95% CI = 0.043–0.894, P = 0.035; P‐MDSCs: HR = 0.257, 95% CI = 0.070–0.942, P = 0.04). Delayed M‐MDSC reconstitution was associated with aGvHD onset. The 3‐year cumulative incidence of transplant related mortality and relapse, 3‐year probability of disease‐free survival, and overall survival did not differ significantly between these subgroups. Our results suggested that G‐CSF‐induced immune tolerance may be mediated by M/P‐MDSCs in allo‐HSCT. Am. J. Hematol. 90:E9–E16, 2015.

Gender difference in association of cognition with BDNF in chronic schizophrenia

While numerous studies have reported that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia, very few studies have explored its association with cognitive impairment or gender differences in schizophrenia which we explored. We compared gender differences in 248 chronic schizophrenic patients (male/female=185/63) to 188 healthy controls (male/female=98/90) on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF. Schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Our results showed that schizophrenic patients performed worse than normals on most of the cognitive tasks, and male patients had significantly lower immediate memory and delayed memory scores than female patients. BDNF levels were significantly lower in patients than controls, and male patients had significantly lower BDNF levels than female patients. For the patients, BDNF was positively associated with immediate memory and the RBANS total score. Furthermore, these associations were only observed in female not male patients. Among healthy controls, no gender difference was observed in cognitive domains and BDNF levels, or in the association between BDNF and cognition. Our results suggest gender differences in cognitive impairments, BDNF levels and their association in chronic patients with schizophrenia. However, the findings should be regarded as preliminary due to the cross-sectional design and our chronic patients, which need replication in a first-episode and drug naïve patients using a longitudinal study.

Decreased serum TNF-alpha levels in chronic schizophrenia patients on long-term antipsychotics: correlation with psychopathology and cognition

ObjectiveA substantial body of evidence implicates TNF-alpha (TNFα) and TNFα-related signaling pathways in the pathophysiology of schizophrenia. The current study examined the relationship between TNFα serum levels and both psychopathological as well as cognitive symptoms in schizophrenia.Materials and methodsSerum TNFα levels were assessed in 89 patients diagnosed with schizophrenia and compared to 43 healthy control subjects matched for age and gender. Schizophrenic symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS), and serum TNFα levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA).ResultsTNFα levels were significantly lower in patients with chronic schizophrenia relative to healthy control subjects (p < 0.01). Correlation analysis revealed a significant negative correlation between the TNFα levels and the PANSS total score (p < 0.01). Additionally, TNFα levels were significantly negatively correlated with scores on general psychopathology (p < 0.01), positive (p < 0.05) and cognitive subscales (p < 0.05). Stepwise multiple regression analysis identified TNFα levels as a significant predictor of scores on the general psychopathology subscale of the PANSS.ConclusionThe significant relations observed in the current study between TNFα and the PANSS and its subscales suggest that immune disturbance may be involved in the psychopathology and cognitive deficits of schizophrenia.

Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelins important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis.

Donor Th17 cells and IL-21 may contribute to the development of chronic graft-versus-host disease after allogeneic transplantation

The roles of Th17 cells and IL‐21 in the pathogenesis of chronic graft‐versus‐host disease (cGVHD) in patients who undergo allogeneic transplantation are still unknown. Here, we examined this question by monitoring eight patients with new‐onset cGVHD for the presence of Th17 cells, Th1 cells, and IL‐21. Allografts from an additional 41 patients were also analyzed for Th17 and Th1 cells. Out of these 41 patients, the last 32 enrolled patients were further analyzed for Th17 cells, Th1 cells, and plasma IL‐21 levels at day 30 post‐transplantation regarding cGVHD. Th17 cells and IL‐21 plasma levels were significantly increased at cGVHD onset and drastically decreased after complete remission. Patients who received a higher number of Th17 cells in their allograft had a higher incidence of cGVHD compared with patients who received a lower number of Th17 cells. Meanwhile, positive plasma IL‐21 levels at day 30 post‐transplantation predicted cGVHD occurrence. These results suggest that Th17 cells and IL‐21 may contribute to the development of cGVHD.

Smoking and BDNF Val66Met polymorphism in male schizophrenia: a case-control study.

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smokers response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.

Early lymphocyte recovery predicts superior overall survival after unmanipulated haploidentical blood and marrow transplant for myelodysplastic syndrome and acute myeloid leukemia evolving from myelodysplastic syndrome

Abstract We investigated whether early lymphocyte recovery, after unmanipulated, haploidentical, blood and marrow transplant (HBMT), affected clinical outcomes in 78 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia evolving from MDS. Lymphocyte recovery was based on the absolute lymphocyte count on day 30 (ALC-30). Patients with high ALC-30 (≥ 300 cells/μL) had lower relapse rates (13.8% vs. 35.5%, p = 0.049) and lower incidence of bacterial infections (3.4% vs. 25.8%, p = 0.015) than those with low ALC-30 values. Multivariate analysis showed that a high ALC-30 was associated with improved overall survival (OS, hazard ratio [HR]: 0.099, 95% confidence interval [CI]: 0.029–0.337; p < 0.0001), improved leukemia-free survival (HR: 0.245, 95% CI: 0.112–0.539; p < 0.0001), lower relapse rate (HR: 0.096, 95% CI: 0.011–0.827; p = 0.033) and lower transplant-related mortality (TRM, HR: 0.073, 95% CI: 0.016–0.324; p = 0.001). Combinations of three mismatches in the human leukocyte antigen loci were associated with a higher TRM (HR: 5.026, 95% CI: 1.392–18.173; p = 0.014). Our results suggest that the ALC-30 can predict a favorable OS after unmanipulated HBMT.

Arsenic trioxide induces apoptosis in B-cell chronic lymphocytic leukemic cells through down-regulation of survivin via the p53-dependent signaling pathway

Arsenic trioxide (As2O3) can induce apoptosis in many tumors. However, the associated mechanisms are not clearly understood. We found that As2O3 significantly inhibited the proliferation of WSU-CLL cells and induced apoptosis in dose- and time-dependent manners. WSU-CLL cells treated with 2μM As2O3 showed survivin down-regulation and p53 up-regulation. Survivin siRNA combined with As2O3 further inhibited the proliferation of WSU-CLL cells. p53 inhibition by siRNA prevented the down-regulation of survivin by As2O3 and prevented the As2O3-induced cytotoxicity of WSU-CLL cells. These results suggest that As2O3 may be of therapeutic value for chronic lymphocytic leukemia.

Ginkgo biloba and vitamin E ameliorate haloperidol-induced vacuous chewingmovement and brain-derived neurotrophic factor expression in a rat tardive dyskinesia model.

Neurodegeneration may be involved in the development of tardive dyskinesia (TD), and low levels of brain-derived neurotrophic factor (BDNF) may play a role. Ginkgo biloba (EGb761), a potent antioxidant, may have neuroprotective effects. We hypothesized that there would be decreased BDNF expression in TD, but that treatment with EGb761 would increase BDNF expression and reduce TD manifestations in a rat model. Forty rats were treated with haloperidol (2mg/kg/day via intraperitoneal injections) for 5weeks. EGb761 (50mg/kg/day) and vitamin E (20mg/kg/day) were then administered by oral gavage for another 5weeks, and we compared the effects of treatment with EGb761 or vitamin E on haloperidol-induced vacuous chewing movements (VCMs) and BDNF expression in four brain regions: prefrontal cortex (PFC), striatum (ST), substantia nigra (SNR), and globus pallidus (GP). Our results showed that haloperidol administration led to a progressive increase in VCMs, but both EGb761 and vitamin E significantly decreased VCMs. Haloperidol also decreased BDNF expression in all four brain regions, but both EGb761 and vitamin E administration significantly increased BDNF expression. Our results showed that both EGb761 and VE treatments exerted similar positive effects in a rat model of TD and increased BDNF expression levels in the four tested brain regions, suggesting that both EGb761 and vitamin E improve TD symptoms, possibly by enhancing BDNF in the brain and/or via their free radical-scavenging actions.