[Clinical Characteristics and Prognosis of Acute Myeloid Leukemia Patients with GATA2 Gene Mutation].

OBJECTIVE: To investigate the clinical characteristics, coexisting gene mutations and prognosis of acute myeloid leukemia (AML) patients with GATA2 gene mutation. METHODS: The clinical data of 370 newly diagnosed AML patients treated in our hospital from January 2008 to January 2021 was analyzed retrospectively, the next-generation sequencing technology was used to detect the mutated genes in those patients. The clinical characteristics of AML patients with GATA2 mutations, the co-mutated genes of GATA2 mutations, and the effect of GATA2 mutation on prognosis were analyzed. RESULTS: A total of 23 patients (6.2%) with GATA2 mutation was detected in 370 AML patients. Compared with GATA2 non-mutation group, patients in GATA2 mutation group were mostly normal karyotypes (P =0.037) and in low-risk cytogenetic stratification (P =0.028). The incidence of CEBPAdm and NRAS in GATA2 mutation group was significantly higher than that in GATA2 non-mutation group (P =0.010, P =0.009). There were no statistically significant differences between the two groups in terms of sex, age, white blood cell count (WBC), platelet count, hemoglobin, bone marrow (BM) blast, induction chemotherapy regimen and CR rate (P >0.05). Among the 23 patients with GATA2 mutation, the most common co-mutated genes were CEBPAdm, NRAS (both 39.1%), NPM1, FLT3, TET2, WT1 (all 17.4%), ASXL1 and IDH1 (both 13.0%). Survival analysis showed that there was no statistical difference in 5-year overall survival (OS) and leukemia-free survival (LFS) rates between patients with and without GATA2 mutations in whole cohort (n=370) (P =0.306, P =0.308). Among 306 patients without CEBPAdm, the 5-year OS and LFS rates in GATA2 mutation group showed an increasing trend compared with GATA2 non-mutation group, but the difference was not statistically significant (P =0.092, P =0.056). Among 64 patients with CEBPAdm, there was no statistically significant difference in 5-year OS rate between the GATA2 mutation group and the GATA2 non-mutation group (P =0.104), but the 5-year LFS rate of the GATA2 mutation group was significantly decreased (P =0.047). Among the 23 patients with GATA2 mutation, 16 cases received the "3+7" induction regimen, of which 12 cases received allogeneic hematopoietic stem cell transplantation (allo-HSCT); 7 cases received the "DCAG" induction regimen, of which 3 cases received allo-HSCT. The CR rate was not statistically different between the "3+7" regimen group and the "DCAG" regimen group (P =1.000). The 5-year OS rate and LFS rate in the transplantation group were significantly higher than the chemotherapy group (P =0.021, P =0.020). CONCLUSION: GATA2 mutation is more common in AML patients with normal karyotype and low-risk cytogenetic stratification, and it is significantly associated with CEBPAdm and NRAS co-mutations. The prognostic significance of GATA2 is influenced by CEBPAdm. The choice of "3+7" or "DCAG" induction regimen in patients with GATA2 mutation does not affect their CR rate, while the choice of allo-HSCT can significantly improved the prognosis compared with chemotherapy only.

Upfront allogeneic hematopoietic stem cell transplantation for adult T-cell acute lymphoblastic leukemia/lymphoma in first complete remission: a single-center study.

BACKGROUND: Real-world data on outcomes of upfront allogeneic hematopoietic stem cell transplantation (allo-HCT) for adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patients in first complete remission (CR1) is still lacking. METHODS: A single center retrospective study was conducted from 94 consecutive patients received their first allo-HCT between 2010 and 2021, which include 76 patients received upfront allo-HCT and 18 patients received allo-HCT in non-upfront settings. RESULTS: There were no significant differences in most variables. In the upfront allo-HCT group, 52 (68%) patients achieved CR1 with one cycle of induction regimen. 24 (32%) patients achieved CR1 with more than one cycle. In the non-upfront group, there were 14 patients with active disease and 4 patients in second CR before transplant. The majority of patients received antithymocyte globulin-based graft-versus-host disease prophylaxis. Median follow-up time was 51 months for both groups. 5-year overall survival (OS) was 54% in the upfront allo-HCT group. While, in the non-upfront group, 5-year OS were 19% (P = 0.013). 5-year progression free survival in the upfront group was higher than that in the non-upfront group (50% versus 20%, P = 0.02). 5-year cumulative incidence relapse rate was significantly higher in non-upfront group (64% vs. 32%, P = 0.006). While, there was no difference in the 5-year non-relapse mortality (NRM) rate (19% versus 16%, P = 0.56). The most common cause of death was disease progression. In multivariable analysis, non-upfront allo-HCT (hazard ratios (HR) 2.14, P = 0.03) and HCT-CI (≥ 2) (HR 6.07, P = 0.002) were identified to be associated with worse OS. Non-upfront allo-HCT and HCT-CI (≥ 2) were also found to be independent risk factors for higher relapse rate. While, haploidentical-HCT was found to be associated with increased NRM. CONCLUSIONS: Our study indicated that allo-HCT remains an important curative treatment for adult patients with T-ALL, especially when it was performed in the upfront setting.

Pentachlorophenol exposure induced neurotoxicity by disrupting citrulline metabolism in larvae and adult zebrafish.

Pentachlorophenol (PCP) is a ubiquitous environmental toxicant with various adverse effects. Although its neurotoxicity has been reported, the underlying mechanism and subsequent detoxification remain unclear. In this study, embryos and adult zebrafish were exposed to PCP to determine its potential neurotoxic mechanism and protective indicators. The survival rate, heart rate, mobility time, active status and moving distance were significantly decreased in larvae after 30 µg/L PCP exposure. Likewise, the mobile time, latency to the first movement, velocity and moving distance of adult zebrafish were significantly reduced by PCP exposure. Untargeted metabolomics analysis of larvae revealed that arginine and proline metabolism was the primary pathway affected by PCP exposure, reflected by increased proline and decreased citrulline (CIT) contents, which were confirmed by quantitative data. PCP exposure suppressed the conversion from arginine to CIT in larvae by downregulating the expression of nos1 and nos2a. Ornithine content was increased in the brains and intestines of adult zebrafish after PCP exposure, which inhibited ornithine catabolism to CIT by downregulating otc, resulting in reduced CIT. Intriguingly, CIT supplementation significantly restored the neurobehavioral defects induced by PCP in larvae and adult zebrafish. CIT supplementation upregulated the expression of ef1α and tuba1 in larvae and inhibited the downregulation of ef1α in the brains of adult zebrafish. Taken together, these results indicated that CIT supplementation could protect against PCP-induced neurotoxicity by upregulating the expression of genes involved in neuronal development and function.

Identification and Development of a 4-Gene Ferroptosis Signature Predicting Overall Survival for Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is a well-differentiated disease, which makes the diagnosis and therapeutic strategy a difficult problem. While ferroptosis, as an iron-dependent form of regulated cell death, it plays an important role in causing several types of cancer. This study is aimed at exploring the prognostic value of ferroptosis-related genes in DLBCL. Methods: In our study, mRNA expression and matching clinical data of DLBCL patients were derived from Gene Expression Omnibus (GEO) database. First, multivariate cox regression model and nomogram which can predict the DLBCL patients' prognosis were built and validated. The multigene signature was constructed and optimized by the least absolute shrinkage and selection operator (LASSO) cox regression model. Also, ferroptosis-related subtypes were developed by consistent cluster. Last but not least, we explored the association between categories of infiltrating immune cells and model genes' expression. Results: Our results showed that 27 gene expressions were correlated with overall survival (OS) in the univariate cox regression analysis. A 4-gene signature was constructed through these genes to stratify patients into high-low risk groups using risk score derived from model (model 1:gene expression model). The OS of patients in the high-risk group was shorter than that of patients in the low-risk group in the TNM stage and clinically distinct subtypes (activated B cell [ABC], germinal center B cell [GCB]) (P < .001). Furthermore, it was shown that the risk score was an independent factor in clinical cox regression model for OS (model 2:clinical model) (HR>1, P < .010). Besides, in consistent cluster analysis, ferroptosis prognosis status was different among 3 subtypes. Moreover, the correlation analysis between 4-gene with immune cells showed dendritic cells may be significantly associated with DLBCL. Conclusion: This research constructed an innovative ferroptosis-related gene signature for prognostic estimation of DLBCL patients. Solutions targeting ferroptosis could be an important therapeutic intervention for DLBCL.

Up-front autologous hematopoietic stem cell transplantation after first complete remission improved prognosis of advanced extra-nodal NKT cell lymphoma: A multicenter real-world study in China.

OBJECTIVES: The advanced extra-nodal NK/T-cell lymphoma (ENKTL) is highly aggressive and lacks effective treatment with a poor prognosis. This study aimed to investigate the effectiveness and safety of autologous hematopoietic stem cell transplantation (ASCT) in CR1. METHODS: Forty of 121 patients with advanced ENKTL from four Chinese hospitals between January 2006 to December 2021 who achieved first complete remission (CR1) and received at least 4 cycles chemotherapy, were enrolled for analysis. Twenty patients received ASCT as up-front consolidation therapy (Group A), and 20 patients only received chemotherapy (Group B). Clinical features, treatment and follow-up information were collected. RESULTS: With a median follow-up of 27 months (range, 4-188 months), the 2-year overall survival (OS) in Group A, 61% (95% CI 37%-85%), was better than that in Group B, 26% (95% CI 2%-50%), p = .018. The 2-year progression-free survival (PFS) was 56% (95% CI 32%-80%) in Group A, 26% (95% CI 2%-50%) in Group B, p = .026. III-IV grade hematological toxicity was the most common adverse event. No treatment-related deaths were observed in both groups. CONCLUSION: Up-front ASCT could improve survival of advanced ENKTL patients in first complete remission, but need be confirmed by a prospective clinical trial.

Impact of Autologous Stem Cell Transplantation on Primary Central Nervous System Lymphoma in First-Line and Relapse Settings: A Retrospective Study in China.

BACKGROUND Myeloablative chemotherapy supported by autologous stem cell transplantation (ASCT) is an option for primary central nervous system lymphoma (PCNSL) in both the relapse setting and as postremission consolidation, but the level of evidence in this field is still low. MATERIAL AND METHODS We retrospectively analyzed 47 HIV-negative PCNSL patients from 2010 to 2021. To assess the outcomes in patients undergoing ASCT. RESULTS Of the 47 patients, the median age was 51 (range, 21-77) years, and 28 (59.6%) were male. After induction, 33 (70.2%) patients achieved complete remission, and 6 (12.8%) patients achieved partial remission. At a median follow-up of 21.4 months (95% CI 8.86-33.95), the median progression-free survival (PFS) was 23.3 months (95% CI 14.87-31.73), and the 4-year PFS rate was 14.6%. The median overall survival (OS) time was 62.4 months (95% CI 41.93-82.87), and the 4-year OS rate was 71.5%. Among 20 patients who received ASCT (10 consolidation, 10 salvage), the 4-year PFS and 4-year OS rates were 57.3% and 71.2%, respectively. In the multivariate analysis, ASCT therapy (hazard ratio [HR] 0.16, P=0.016) and early remission (HR 0.12, p=0.003) were found to be independent prognostic factors for a longer PFS. Two treatment-related deaths occurred in patients with multiple relapses before ASCT. Pancytopenia and diarrhea were the most common adverse events. CONCLUSIONS ASCT offers potential long-term PFS with good tolerability for patients with PCNSL. Our retrospective cohort adds to the currently available literature and identifies disease status after induction as a significant factor affecting survival.

Elemicin exposure induced aberrant lipid metabolism via modulation of gut microbiota in mice.

Elemicin (Ele) is a constituent of natural alkenylbenzene present in many foods and herbs. Ele exposure could induce hepatomegaly and hepatosteatosis. However, the role of gut microbiota in Ele-induced hepatotoxicity remains unclear. Here, the mice were treated with 200 mg/kg/day of Ele for 4 weeks with or without depletion of gut microbiota by antibiotics cocktail treatment. The mice treated with Ele showed enlargement of liver and slight hepatosteatosis, accompanied by higher levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG). Ele could also shift the structure of fecal microbiota and increase the richness. Functional prediction of the microbiota revealed the enrichment of non-alcoholic fatty liver disease pathway upon Ele exposure. Compared with control group, Patescibacteria and Epsilonbacteraeota were significantly enriched at the phylum level upon Ele treatment. A total of 20 genera were significant with respect specifically to Ele exposure, including decreased Alistipes and elevated Ruminiclostridium_9 and Gordonibacter. Among them, 13 retained significant associations with ALT and TG by Spearman correlation test, 4 were correlated with AST. Further MaAsLin analysis revealed that ALT was associated with 4 differentially abundant genera, such as Alistipes and Ruminiclostridium_9 and Gordonibacter. In addition, only Alistipes was significantly correlated with serum TG. Intriguingly, depletion of the microbiota significantly attenuated hepatosteatosis, restore increased ALT, AST and TG and inhibit the expression of genes involved in de novo lipogenesis and adipocyte differentiation, such as Fasn, ADIPOQ and leptin. Collectively, depletion of gut microbiota protected against Ele induced aberrant lipid metabolism in mice.

The impact of intestinal microbiota in antithymocyte globulin-based myeloablative allogeneic hematopoietic cell transplantation.

BACKGROUND: The correlation between intestinal microbiota and clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HCT) has been reported in platforms with T-cell depletion or postcyclophosphamide-based graft-vs-host disease (GVHD) prophylaxis regimens. It is still unclear whether it is the same in platforms of antithymocyte globulin (ATG)-based myeloablative allo-HCT. METHODS: A total of 603 fecal specimens from 100 consecutive patients receiving allo-HCT were collected between December 2018 and July 2020. Fetal samples were profiled with next-generation sequencing of bacterial 16S ribosomal RNA (rRNA) genes. RESULTS: The diversity decreased to the lowest level at approximately day 12 after allo-HCT and then increased over time. According to the diversity of 314 samples that were collected from 86 patients during the engraftment period, patients were grouped into the low- and high-diversity groups. Two-year overall survival in the high-diversity group was significantly longer than that in the low-diversity group (83.7% vs 60.6%, P = .026). Further analysis revealed that worse outcomes for patients with low diversity were associated with increased risk of worse outcomes for patients with low diversity (adjusted hazard ratio, 4.95; P = .046). Its association with relapse and GVHD was not found. Compositional analysis of fecal microbiota revealed that the abundance of bacteroides decreased greatly during allo-HCT, whereas that of Enterococcus, Klebsiella, and Escherichia was found to be increased. CONCLUSIONS: This study indicates that gut dysbiosis in platforms of ATG-based myeloablative allo-HCT featured loss of bacterial diversity. The diversity of the intestinal flora at the engraftment period was an independent predictor of longer survival. LAY SUMMARY: The correlation between intestinal microbiota and clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HCT) is reported in platforms with T-cell depletion or postcyclophosphamide-based graft-vs-host disease (GVHD) prophylaxis regimens. It is still unclear whether it is the same pattern in platforms of antithymocyte globulin (ATG)-based T-cell repletion myeloablative allo-HCT. Our study indicated that gut dysbiosis in platforms of ATG-based myeloablative allo-HCT also features loss of bacterial diversity. The diversity of the intestinal flora at the engraftment period is an independent predictor of longer survival.

Eltrombopag in the treatment of patients with persistent thrombocytopenia after haploidentical peripheral blood stem cell transplantation: a single-center experience.

Persistent thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of bleeding and poor survival. The exact pathogenesis underlying PT remains unclear, and its management is difficult. Here we conducted a retrospective study to evaluate the efficacy and safety of eltrombopag (EPAG) in 34 patients with PT after allo-HSCT. Seven patients suffered from prolonged isolated thrombocytopenia (PIT), and 27 had secondary failure of platelet recovery (SFPR). For most patients, the initial dose was 25 mg or 50 mg daily, then adjusted to the maximum dose of 50-100 mg per day according to the response of platelet recovery and toleration of patients. The cumulative incidence (CI) of platelet recovery to at least 20 × 109/L and 50 × 109/L without transfusion support for at least 7 days was 72.1% and 60.7%, respectively. Nineteen (86.4%) of 22 responders were able to taper off the medication; furthermore, the platelet counts remained stable 1 month after withdrawal of EPAG. Although two patients discontinued EPAG during treatment due to headache and nausea, no patients developed grade 3 or 4 toxicities. Hypoplasia of bone marrow and decreased megakaryocytes (MKs) were found to be risk factors for overall response (OR) and complete response (CR) in multivariate analysis, respectively. Overall, our results indicated that EPAG can be used in the treatment of PT and that continuous exposure to EPAG may not be necessary.

Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis.

Dietary interventions, including dietary ingredients, nutrients and probiotics, exert anti-inflammatory effects in ulcerative colitis (UC). Our previous study showed that Akkermansia muciniphila (Akk), a promising probiotic, could protect against colitis via the regulation of the immune response. However, whether it can restore aberrant tryptophan (Trp) metabolism during colitis remains unclear. In this study, untargeted serum metabolomics of patients with UC and colitis mice showed that Trp metabolism was activated, which was confirmed by quantification of Trp metabolites from a validation cohort and animal study. Integrative analysis of faecal metagenomes and serum metabolomes revealed significant associations between Akk and three Trp metabolites. Live Akk, pasteurised Akk and Amuc_1100 failed to restore the reduction in Trp metabolites involved in the serotonin pathway in colitis mice. However, live Akk, pasteurised Akk and Amuc_1100 increased kynurenine (Kyn) but decreased 2-picolinic acid (PIC) levels and the PIC/Kyn ratio without regulating any of the genes involved in Trp metabolism, suggesting that they could suppress the Kyn pathway (KP) independent of colon tissue. In addition, they could significantly restore the enrichment of Trp metabolism mediated by faecal microbiota. Specifically, live Akk, pasteurised Akk and Amuc_1100 could significantly offset the reduction in indoleacetic acid (IAA) levels. Pasteurised Akk significantly elevated the serum levels of indole acrylic acid (IA). In addition, live Akk, pasteurised Akk and Amuc_1100 could upregulate aryl hydrocarbon receptor (AhR) targeted genes, including CYP1A1, IL-10 and IL-22, suggesting that Akk could activate AhR signaling by regulating Trp metabolism, thereby attenuating colonic inflammation.

A multicenter retrospective study on the real-world outcomes of autologous vs. allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphoma in China.

BACKGROUND: There were few studies on real-world data about autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic HSCT (allo-HSCT) in peripheral T-cell lymphoma (PTCL). This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China. METHODS: From July 2007 to June 2017, a total of 128 patients who received auto-HSCT (n  = 72) or allo-HSCT (n  = 56) at eight medical centers across China were included in this study. We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups. RESULTS: Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease (95% vs. 82%, P = 0.027), bone marrow involvement (42% vs. 15%, P = 0.001), chemotherapy-resistant disease (41% vs. 8%, P = 0.001), and progression disease (32% vs. 4%, P < 0.001) at transplantation than those receiving auto-HSCT. With a median follow-up of 30 (2-143) months, 3-year overall survival (OS) and progression-free survival (PFS) in the auto-HSCT group were 70%(48/63) and 59%(42/63), respectively. Three-year OS and PFS for allo-HSCT recipients were 46%(27/54) and 44%(29/54), respectively. There was no difference in relapse rate (34%[17/63] in auto-HSCT vs. 29%[15/54] in allo-HSCT, P = 0.840). Three-year non-relapse mortality rate in auto-HSCT recipients was 6%(4/63) compared with 27%(14/54) for allo-HSCT recipients (P = 0.004). Subanalyses showed that patients with lower prognostic index scores for PTCL (PIT) who received auto-HSCT in an upfront setting had a better outcome than patients with higher PIT scores (3-year OS: 85% vs. 40%, P = 0.003). Patients with complete remission (CR) undergoing auto-HSCT had better survival (3-year OS: 88% vs. 48% in allo-HSCT, P = 0.008). For patients beyond CR, the outcome of patients who received allo-HSCT was similar to that in the atuo-HSCT group (3-year OS: 51% vs. 46%, P = 0.300). CONCLUSIONS: Our study provided real-world data about auto-HSCT and allo-HSCT in China. Auto-HSCT seemed to be associated with better survival for patients in good condition (lower PIT score and/or better disease control). For patients possessing unfavorable characteristics, the survival of patients receiving allo-HSCT group was similar to that in the auto-HSCT group.

[Single Center Analysis of Bloodstream Infection Clinical Characteristics and Prognosis in Patients with Hematological Malignancies in the Tropics].

OBJECTIVE: To analyze the characteristics, prognosis and risk factors of bloodstream infection in patients with hematological malignancies in the tropics, so as to provide evidence for the prevention and treatment of bloodstream infection. METHODS: The clinical features, blood culture results and prognosis of patients with bloodstream infection in patients with hematological malignancies admitted to Hainan Hospital of PLA General Hospital were retrospectively studied. RESULTS: The most common primary infection site of the 81 patients with hematological malignancies was lung (46.91%), followed by PICC (11.11%). The detection rate of Gram-positive bacteria and Gram-negative bacteria in the blood culture was 60.98% and 30.02%, respectively. Coagulase-negative staphylococci was the most common Gram-positive bacteria resulting in bloodstream infection in our study. Of the Gram-negatives, Klebsiella pneumoniae (34.38%) was predominant, followed by Escherichia coli (18.75%) and Pseudomonas aeruginosa (18.75%). Gram-positive bacteria was highly sensitive (100%) to vancomycin, linezolid and tigecycline. Study showed that Gram-negative bacteria had low sensitive to quinolones, in particular, the resistance rate of Escherichia coli to quinolones was as high as 83.33%. In terms of overall survival (OS), the 30-days OS of patients with Gram-negative and Gram-positive septicemia was 77.42% and 92.00%, respectively. There was no statistically significant difference between the two groups. Multivariate analysis revealed that septic shock (P=0.001, RR=269.27) was an independent risk factor for 30-day mortality, and remission status (P=0.027, RR=0.114) was an independent predictor of a favourable outcome of bloodstream infection in patients with hematological malignancies. CONCLUSION: Gram-positive bacteria are the main pathogens causing bloodstream infections in patients with hematological malignancies in the tropics. Improving the care of PICC is an important measure to reduce the incidence of bloodstream infection in patients with hematological malignancies in the tropics. A correct treatment relieving disease and effective prevention and treatment of septic shock can reduce mortality of patients with bloodstream infection in patients with hematological malignancies in the tropics.

[Clinical Significance of Serum Immunoglobulin Level after Peri- pheral Blood Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies].

OBJECTIVE: To investigate the clinical significance of post-transplantation serum immunoglobulin level in the outcome of patients with hemalologic malignancies treated by haploidentical peripheral hematopoietic stem cell transplanta-tion(Haplo-HSCT). METHODS: The clinical data of 157 patients treated by haplo-HSCT were analyzed retrospectively. The overall survival rate (OS), graft versus host disease (GVHD) incidence, infection incidence, serum immunoglobulin level, the relationship of immunoglobulin levels with OS and transplant complications were analyzed. RESULTS: The 2-year OS rate was 59.2%(95%CI:51.6%-66.9%), 2-year relapse mortality was 11.5%(95%CI: 6.4%-16.6%), and non-relapse mortality was 29.3%(95%CI:21.7%-36.9%). The cumulative incidence of III-IV aGVHD was 16.6%(95%CI:10.8%-22.9%); the cumulative incidence of extensive cGVHD was 21.7%(95%CI:15.3%-28.6%); the cumulative incidence of severe bacterial infection within 1 year was 59.2%(95%CI:51.6%-66.2%); the cumulative incidence of invasive fungal infection was 47.1%(95%CI:38.9%-54.8%). The occurrence of extensive cGVHD after haplo-HSCT related with the gender match of donor-recipient and bacterial infection. The levels of IgG in patients with 0-II aGVHD and patients with III-IV aGVHD for 1 month after haplo-HSCT were (6.96±2.47) and (4.27±2.42) g/L （P=0.003）, IgG levels at 3 months afte haplo-HSCT were (8.71±4.47) and (6.65±2.95) g/L (P=0.038); IgG levels at 1 month after haplo-HSCT showed predictive value for III-IV aGVHD susceptibility(P=0.003); for patients with IgG<4 g/L at any time after haplo-HSCT, the incidence of extensive cGVHD was significantly increased (35.5% vs 18.3%) (P=0.037), the incidence of fungal infection within 1 year after haplo-HSCT was significantly increased(71.0% vs 41.3%) (P=0.003), and the 2-year survival rate was reduced significantly (P=0.035). CONCLUSION: Haplo-HSCT is effective for the treatment of hematologic malignancies. Patients with lower IgG at 1 month after haplo-HSCT are more likely to develop III-IV aGVHD, and IgG levels at 1 month after haplo-HSCT can predict its susceptibility to a certain extent. Patients with severe hypoimmunoglobulinemia (IgG<4 g/L) after haplo-HSCT are more likely to develop extensive cGVHD, fungal infection and show worse survival prognosis.

Matrix Metallopeptidase 14: A Candidate Prognostic Biomarker for Diffuse Large B-Cell Lymphoma.

BACKGROUND: Matrix metallopeptidase 14 (MMP14) is an important gene in the regulation of T-cell function. However, the correlation between MMP14 expression, prognosis, and immune cell infiltration in diffuse large B-cell lymphoma (DLBCL) remains unclear. METHODS: We investigated the influence of MMP14 on clinical prognosis using data obtained from three Gene Expression Omnibus (GEO) database sets (GSE98588, GSE10846, and GSE4475). The expression of MMP14 was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA). The correlation between MMP14 and immune cell infiltration was investigated using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) tools. In addition, the correlation between MMP14 expression and immune gene markers was analyzed by TIMER and GEPIA. RESULTS: MMP14 expression positively correlated with favorable progression-free survival (PFS; GSE98588, P = 0.02) and overall survival (OS; GSE98588, P = 0.003; GSE10846, P = 5.517e-05; and GSE4475, P = 9.85e-04). Moreover, MMP14 expression was higher in DLBCL tumors than in normal tissues. Regarding clinical characteristics, high MMP14 expression was found to be correlated with race. MMP14 expression was also correlated with immune cell infiltration and had a remarkable correlation with various immune marker sets. It was found that M0 macrophages were the immune cells most related to survival, decreasing with the increase in Ann Arbor clinical stage. The results especially showed that MMP14 was a prognostic biomarker and related to the macrophages M0. CONCLUSION: The results suggest that MMP14 is a novel prognostic molecular marker for DLBCL and is related to the immune cell infiltration, especially related to the macrophages M0. Our study provides insights for understanding the potential roles of MMP14 in tumor immunology and its suitability as a prognosis biomarker in DLBCL.

Integrative Analysis of Long Noncoding RNAs in Patients with Graft-versus-Host Disease.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a major cause of late non-recurrence mortality despite remarkable improvements in the field of allogeneic hematopoietic stem cell transplantation. Although recent studies have found that B-cell receptor (BCR)-activated B cells contribute to pathogenesis in cGVHD, the specific molecular mechanisms of B cells in this process remain unclear. METHODS: In our study, human long noncoding RNA (lncRNA) microarrays and bioinformatic analysis were performed to identify different expressions of lncRNAs in peripheral blood B cells from cGVHD patients compared with healthy ones. The differential expression of lncRNA was confirmed in additional samples by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The microarray analysis revealed that 106 of 198 differentially expressed lncRNAs were upregulated and 92 were downregulated in cGVHD patients compared with healthy controls. Intergenic lncRNAs accounted for the majority of differentially expressed lncRNAs. A KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that the differentially expressed mRNAs, which were coexpressed with lncRNA, between the cGVHD group and the healthy group were significantly enriched in the BCR signaling pathway. Further analysis of the BCR signaling pathway and its coexpression network identified three lncRNAs with the strongest correlation with BCR signaling and cGVHD, as well as a series of protein-coding genes and transcription factors associated with them. The three candidate lncRNAs were further validated in another group of cGVHD patients by qRT-PCR. CONCLUSIONS: This is the first study on the correlation between lncRNA and cGVHD using lncRNA microarray analysis. Our study provides novel enlightenment in exploring the molecular pathogenesis of cGVHD.

[Clinical Characteristics and Prognosis of U2AF1 Mutation in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the incidence, clinical features of U2AF1 gene mutation in patients with acute myeloid leukemia(AML) and its effect of prognosis. METHODS: A total of 161 patients with AML were enrolled. The second-generation sequencing method was used to detect U2AF1 gene mutation, and the relationship between U2AF1 mutation and clinical features, prognosis was analyzed. RESULTS: The mutation rate of U2AF1 gene in 161 AML patients was 3.73%. The counts of peripheral blood leukocytes and platelets in the U2AF1 gene mutation group were lower than those in the wild type group. The complete response rate of U2AF1 gene mutation group was 66.67%, while that in wild type group was 55.48%, which shows no significant difference between the two groups (P=0.70). The median EFS of wild type group and the mutant group was not reached and reached to 133 days, respectively (P=0.03), while the medium OS in two groups was not reached and reached to 210 days (P=0.01). CONCLUSION: The AML patients with U2AF1 mutation positive have a poor prognosis as compared with the wild type group, which may be a poor prognostic factor for acute myeloid leukemia.

Emerging role of long non-coding RNAs in normal and malignant hematopoiesis.

Long noncoding RNAs (lncRNAs) have recently been discovered and are increasingly recognized as vital components of modern molecular biology. Accumulating evidence shows that lncRNAs have emerged as important mediators in diverse biological processes such as cell differentiation, pluripotency, and tumorigenesis, while the function of lncRNAs in the field of normal and malignant hematopoiesis remains to be further elucidated. Here, we widely reviewed recent advances and summarize the characteristics and basic mechanisms of lncRNAs and keep abreast of developments of lncRNAs within the field of normal and malignant hematopoiesis. Based on gene regulatory networks at different levels of lncRNAs participation, lncRNAs have been shown to regulate gene expression from epigenetics, transcription and post transcription. The expression of lncRNAs is highly cell-specific and critical for the development and activation of hematopoiesis. Moreover, we also summarized the role of lncRNAs involved in hematological malignancies in recent years. LncRNAs have been found to play an emerging role in normal and malignant hematopoiesis, which may provide novel ideas for the diagnosis and therapeutic targets of hematological diseases in the foreseeable future.

Unmanipulated haploidentical peripheral blood stem cell transplantation for patients with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission.

Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (p = .274). The 3-year probability of disease-free survival (DFS) and overall survival (OS) for the standard-risk versus high-risk groups were 84.6% versus 50% (p = .0063) and 92.3% versus 61.1% (p = .046), respectively. Univariate analysis showed that a diagnosis of high risk with fusion/mutation genes were associated with worse outcomes, which was confirmed by multivariate analysis (p = .016). In summary, haplo-PBSCT may be a promising alternative for patients with Ph-negative ALL in CR1, although the fusion/mutation genes in high-risk patients may relatively impair the long-term efficacy compared with standard-risk patients.

S1PR5 regulates NK cell responses in preventing graft-versus-host disease while preserving graft-versus-tumour activity in a murine allogeneic haematopoietic stem cell transplantation model.

Graft-versus-host disease (GVHD) remains a major complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT) leading to high transplant-related mortality. Natural killer (NK) cells have been found to mitigate GVHD without attenuating the graft-versus-tumour (GVT) activity in the murine model of haematopoietic stem cell transplantation. Sphingosine-1-phosphate receptor 5 (S1PR5) is a very important chemokine receptor on NK cells that governs NK cell distribution in vivo and trafficking at lesion sites. Our preliminary studies showed that the incidence of GVHD was negatively correlated with S1PR5 expression in the NK cells of patients after allo-HSCT. In the present study, we found that S1PR5 deficiency in murine NK cells blocked the migration of NK cells from the bone marrow to the GVHD target organs and attenuated the inhibitory effects on the alloreactive T cells, especially CD3+ CD8+ T cells, which may be the reason why the loss of S1PR5 in NK cells could aggravate GVHD in recipient mice. Furthermore, we also demonstrated that the absence of S1PR5 expression in NK cells did not interfere with the antitumour effects of NK cells and T cells in vivo. Taken together, our data indicate that S1PR5 plays an essential role in balancing GVHD and GVT activity.