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Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This nonrandomized interventional pragmatic clinical trial had a particular aim. It explored whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD − CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD − CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD − CR patients who received allo-HSCT and those who did not. However, event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups. This was with either high (≥5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < .05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD <5% and without poor prognostic markers (P > .05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers.

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BackgroundTuberculosis (TB) is the notifiable infectious disease with the second highest incidence in the Qinghai province, a province with poor primary health care infrastructure. Understanding the spatial distribution of TB and related environmental factors is necessary for developing effective strategies to control and further eliminate TB.MethodsOur TB incidence data and meteorological data were extracted from the China Information System of Disease Control and Prevention and statistical yearbooks, respectively. We calculated the global and local Moran’s I by using spatial autocorrelation analysis to detect the spatial clustering of TB incidence each year. A spatial panel data model was applied to examine the associations of meteorological factors with TB incidence after adjustment of spatial individual effects and spatial autocorrelation.ResultsThe Local Moran’s I method detected 11 counties with a significantly high-high spatial clustering (average annual incidence: 294/100 000) and 17 counties with a significantly low-low spatial clustering (average annual incidence: 68/100 000) of TB annual incidence within the examined five-year period; the global Moran’s I values ranged from 0.40 to 0.58 (all P-values < 0.05). The TB incidence was positively associated with the temperature, precipitation, and wind speed (all P-values < 0.05), which were confirmed by the spatial panel data model. Each 10 °C, 2 cm, and 1 m/s increase in temperature, precipitation, and wind speed associated with 9 % and 3 % decrements and a 7 % increment in the TB incidence, respectively.ConclusionsHigh TB incidence areas were mainly concentrated in south-western Qinghai, while low TB incidence areas clustered in eastern and north-western Qinghai. Areas with low temperature and precipitation and with strong wind speeds tended to have higher TB incidences.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0139-4) contains supplementary material, which is available to authorized users.

Background Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. Methods The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. Results Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. Conclusion Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

BackgroundMyeloid-derived suppressor cells (MDSCs) is a heterogeneous population of immature myeloid cells, inhibiting both the innate and adaptive immunity. Recent studies validated that MDSCs caused immune suppression and promoted cancer progression through various mechanisms. However, the prognostic value of MDSCs in cancer remains controversial.MethodsHere, we performed this meta-analysis to evaluate the prognostic value of MDSCs in various types of cancer. The electric databases, such as Pubmed, Embase and Web of Science, were searched for relevant publications. Hazards ratios (HRs) with the corresponding 95% confidence intervals (95%CIs) were calculated to evaluate the prognostic role of MDSCs in cancer.ResultsA total of 16 studies with 1864 patients were enrolled in our meta-analysis. Elevated MDSCs frequency was shown to be associated with shorter overall survival (OS) (HR = 2.46, 95%CI: 1.87–3.23), and poor disease-free survival / recurrence-free survival (DFS / RFS) (HR = 3.26, 95%CI: 2.10–5.04) after treatment. Furthermore, similar results were also observed in the stratified subgroup analysis, which included the analysis by region, sample size, cancer type, NOS scores, subtype and cut-off value of MDSCs.ConclusionHigh MDSCs might be related to poor clinical outcomes of patients with cancer, that is, MDSCs might be a potential prognostic biomarker in cancer.

BackgroundProtein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown.MethodsThirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis.ResultsA total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1–71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61–14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73±6.92 U/dl and 75.17±4.84 U/dl, respectively.ConclusionsThis is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis.

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