Effectiveness of in vivo T-cell-depleted regimen containing porcine anti-lymphocyte globulin or rabbit anti-thymocyte globulin in preventing acute graft-versus-host disease after haploidentical haematopoietic stem cell transplantation.

To compare the clinical efficacy of porcine anti-lymphocyte globulin (p-ALG) and rabbit anti-thymocyte globulin (r-ATG) in the treatment of haematological malignancies using haploidentical haematopoietic stem cell transplantation (haplo-HSCT), this study was conducted. The incidences of neutrophil and platelet engraftment, respectively, were 100%, 93.6% and 94.4%; 100%, 93.6% and 90.3% in p-ALG 75 mg/kg (n = 57), p-ALG 90 mg/kg (n = 49), and r-ATG 7.5 mg/kg (n = 72). The median time to neutrophil engraftment and platelet engraftment were 11, 12 and 12 days (p = 0.032); 13, 14 and 13 days (p = 0.013), respectively. The incidence of grades II-IV acute graft-versus-host disease and cumulative incidence of chronic graft-versus-host disease were 16.7% versus 12.5% versus 13.3% (p = 0.817) and 14.7% versus 12.1% versus 19.5% in p-ALG 75 mg/kg, p-ALG 90 mg/kg and r-ATG groups. Notably, the cytomegalovirus infection rate in the p-ALG 75 mg/kg group was significantly lower than the other two groups. The cumulative incidence of 2-year relapse and 2-year overall survival rates were similar (p = 0.901, p = 0.497). The lower dose of p-ALG (75 mg/kg) had a similar efficacy and safety profile compared with r-ATG (7.5 mg/kg) in the setting of haplo-HSCT. Therefore, p-ALG (75 mg/kg) may be an appropriate alternative to r-ATG in the conditioning regimen of haplo-HSCT.

Targeting PRMT1 prevents acute and chronic graft-versus-host disease.

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.

The oncometabolite R-2-hydroxyglutarate dysregulates the differentiation of human mesenchymal stromal cells via inducing DNA hypermethylation.

BACKGROUND: Isocitrate dehydrogenase (IDH1/2) gene mutations are the most frequently observed mutations in cartilaginous tumors. The mutant IDH causes elevation in the levels of R-enantiomer of 2-hydroxylglutarate (R-2HG). Mesenchymal stromal cells (MSCs) are reasonable precursor cell candidates of cartilaginous tumors. This study aimed to investigate the effect of oncometabolite R-2HG on MSCs. METHODS: Human bone marrow MSCs treated with or without R-2HG at concentrations 0.1 to 1.5 mM were used for experiments. Cell Counting Kit-8 was used to detect the proliferation of MSCs. To determine the effects of R-2HG on MSC differentiation, cells were cultured in osteogenic, chondrogenic and adipogenic medium. Specific staining approaches were performed and differentiation-related genes were quantified. Furthermore, DNA methylation status was explored by Illumina array-based arrays. Real-time PCR was applied to examine the signaling component mRNAs involved in. RESULTS: R-2HG showed no influence on the proliferation of human MSCs. R-2HG blocked osteogenic differentiation, whereas promoted adipogenic differentiation of MSCs in a dose-dependent manner. R-2HG inhibited chondrogenic differentiation of MSCs, but increased the expression of genes related to chondrocyte hypertrophy in a lower concentration (1.0 mM). Moreover, R-2HG induced a pronounced DNA hypermethylation state of MSC. R-2HG also improved promotor methylation of lineage-specific genes during osteogenic and chondrogenic differentiation. In addition, R-2HG induced hypermethylation and decreased the mRNA levels of SHH, GLI1and GLI2, indicating Sonic Hedgehog (Shh) signaling inhibition. CONCLUSIONS: The oncometabolite R-2HG dysregulated the chondrogenic and osteogenic differentiation of MSCs possibly via induction of DNA hypermethylation, improving the role of R-2HG in cartilaginous tumor development.

Generation of hematopoietic cells from mouse pluripotent stem cells in a 3D culture system of self-assembling peptide hydrogel.

In vitro generation of hematopoietic stem cells from pluripotent stem cells (PSCs) can be regarded as novel therapeutic approaches for replacing bone marrow transplantation without immune rejection or graft versus host disease. To date, many different approaches have been evaluated in terms of directing PSCs toward different hematopoietic cell types, yet, low efficiency and no function restrict the further hematopoietic differentiation study, our research aims to develop a three dimension (3D) hematopoietic differentiation approach that serves as recapitulation of embryonic development in vitro to a degree of complexity not achievable in a two dimension culture system. We first found that mouse PSCs could be efficiently induced to hematopoietic differentiation with an expression of hematopoietic makers, such as c-kit, CD41, and CD45 within self-assembling peptide hydrogel. Colony-forming cells assay results suggested mouse PSCs (mPSCs) could be differentiated into multipotential progenitor cells and 3D induction system derived hematopoietic colonies owned potential of differentiating into lymphocyte cells. In addition, in vivo animal transplantation experiment showed that mPSCs (CD45.2) could be embedded into nonobese diabetic/severe combined immunodeficiency mice (CD45.1) with about 3% engraftment efficiency after 3 weeks transplantation. This study demonstrated that we developed the 3D induction approach that could efficiently promote the hematopoietic differentiation of mPSCs in vitro and obtained the multipotential progenitors that possessed the short-term engraftment potential.

PTPN21-CDSlong isoform inhibits the response of acute lymphoblastic leukemia cells to NK-mediated lysis via the KIR/HLA-I axis.

Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a member of the non-receptor tyrosine phosphatase family. We have found that PTPN21 is mutated in relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation. PTPN21 consists of three types of isoforms according to the length of the protein encoded. However, the roles of different isoforms in leukemic cells have not been elucidated. In the study, PTPN21 isoform constitution in five ALL cell lines were identified by transcriptome polymerase chain reaction combined with Sanger sequencing, and the relationship between PTPN21 isoforms and sensitivity to natural killer (NK) cells mediated killing in ALL cell lines were further assessed by knock-out of different isoforms of PTPN21 using CRISPR-Cas9 technique. Subsequently, we explored the functional mechanisms through RNA sequencing and confirmatory testing. The results showed that there was no significant change when all PTPN21 isoforms were knocked out in ALL cells, but the sensitivity of NALM6 cells with PTPN21-CDSlong knock-out (NALM6-PTPN21lk ) to NK-mediated killing was significantly increased. Whole transcriptome sequencing and further validation testing showed that human leukocyte antigen class I (HLA-I) molecules were significantly decreased, accompanied by a significantly downregulated expression of antigen presenting-related chaperones in NALM6-PTPN21lk cells. Our results uncovered a previously unknown mechanism that PTPN21-CDSlong and CDSshort isoforms may play opposite roles in NK-mediated killing in ALL cells, and showed that the endogenous PTPN21-CDSlong isoform inhibited ALL cells to NK cell-mediated lysis by regulating the KIR-HLA-I axis.

Novel deep intronic mutation in the coagulation factor XIII a chain gene leading to unexpected RNA splicing in a patient with factor XIII deficiency.

BACKGROUND: Coagulation factor XIII (FXIII) plays an essential role in maintaining hemostasis by crosslinking fibrin. Deficiency in FXIII affects clot stability and increases the risk of severe bleeding. Congenital FXIII deficiency is a rare disease. Recently, we identified a Chinese family with FXIII deficiency and investigated the pathogenesis of congenital FXIII deficiency, contributing non-coding pathogenic variants. METHODS: We performed common tests, coding sequencing by targeted next-generation sequencing (NGS), whole-genome sequencing and splice-sites prediction algorithms. The pathogenesis was investigated via minigene and nonsense-mediated mRNA decay (NMD) by experiments in vitro. RESULTS: The proband is homozygote for a novel deep intronic c.799-12G > A mutation in the F13A1 gene. Through direct sequencing of the minigenes mRNA, we found 10 bases of intron 6 insert in the mRNA of mutant minigenes mRNA. The relative expression of EGFP-F13A1 was higher by suppression of NMD in vitro. Furthermore, we found the proband with enhanced thrombin generation (TG). CONCLUSION: We reported a novel deep intronic c.799-12G > A mutation of F13A1 which produced a new acceptor site and frame shifting during translation introducing a premature termination codon. Our results support the premature termination codon triggered NMD. We need to pay attention to the position of potential alterable splicing sites while counselling and genetic test. The finding of enhanced TG indicated that we should be aware of the risk of thrombosis in patients with FXIII deficiency during replacement therapy.

Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation.

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.

Idarubicin-Intensified Hematopoietic Cell Transplantation Improves Relapse and Survival of High-Risk Acute Leukemia Patients with Minimal Residual Disease.

The optimal conditioning regimen of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients with minimal residual disease (MRD) remains controversial. We studied the results in 98 high-risk acute leukemia patients transplanted with idarubicin (IDA)-intensified conditioning regimens between 2012 January and 2017 January. Among these patients, 31 (31.6%) had more than 5% marrow blasts at time of transplantation and 67 patients were in morphologic remission: MRD negative status at time of conditioning was achieved in 39 patients (39.8%), whereas 28 (28.6%) remained carriers of any other positive MRD level in the bone marrow. Three-year relapse estimates of patients with MRD-positive remission was 22.0%, which was remarkably lower than patients with active disease (45.4%, P = .027) but approximate to that of patients in MRD-negative remission (15.5%, P = .522). There were no significant differences in terms of 3-year estimated overall survival (OS) and disease-free survival (DFS) between MRD-positive remission and MRD-negative remission groups (71.4% versus 79.1% [P = .562] and 67.9% versus 76.9% [P = .634], respectively). Moreover, the estimated rates of 3-year OS and DFS of patients in MRD-positive remission were significantly better than those in patients with active disease (71.4% versus 41.9% [P = .033] and 67.9% versus 38.7% [P = .037], respectively). These data indicate that IDA-intensified conditioning allo-HSCT could overcome the negative prognostic impact of MRD.

Time-series transcriptome provides insights into the gene regulation network involved in the volatile terpenoid metabolism during the flower development of lavender.

BACKGROUND: Essential oils (EOs) of Lavandula angustifolia, mainly consist of monoterpenoids and sesquiterpenoids, are of great commercial value. The multi-flower spiciform thyrse of lavender not only determines the output of EOs but also reflects an environmental adaption strategy. With the flower development and blossom in turn, the fluctuation of the volatile terpenoids displayed a regular change at each axis. However, the molecular mechanism underlying the regulation of volatile terpenoids during the process of flowering is poorly understood in lavender. Here, we combine metabolite and RNA-Seq analyses of flowers of five developmental stages at first- and second-axis (FFDSFSA) and initial flower bud (FB0) to discover the active terpenoid biosynthesis as well as flowering-related genes. RESULTS: A total of 56 mono- and sesquiterpenoids were identified in the EOs of L. angustifolia 'JX-2'. FB0' EO consists of 55 compounds and the two highest compounds, ß-trans-ocimene (20.57%) and (+)-R-limonene (17.00%), can get rid of 74.71 and 78.41% aphids in Y-tube olfactometer experiments, respectively. With sequential and successive blossoms, temporally regulated volatiles were linked to pollinator attraction in field and olfaction bioassays. In three characteristic compounds of FFDSFSA' EOs, linalyl acetate (72.73%) and lavandulyl acetate (72.09%) attracted more bees than linalool (45.35%). Many transcripts related to flowering time and volatile terpenoid metabolism expressed differently during the flower development. Similar metabolic and transcriptomic profiles were observed when florets from the two axes were maintained at the same maturity grade. Besides both compounds and differentially expressed genes were rich in FB0, most volatile compounds were significantly correlated with FB0-specific gene module. Most key regulators related to flowering and terpenoid metabolism were interconnected in the subnetwork of FB0-specific module, suggesting the cross-talk between the two biological processes to some degree. CONCLUSIONS: Characteristic compounds and gene expression profile of FB0 exhibit ecological value in pest control. The precise control of each-axis flowering and regular emissions at transcriptional and metabolic level are important to pollinators attraction for lavender. Our study sheds new light on lavender maximizes its fitness from "gene-volatile terpenoid-insect" three layers.

Haploinsufficiency of NR3C1 drives glucocorticoid resistance in adult acute lymphoblastic leukemia cells by down-regulating the mitochondrial apoptosis axis, and is sensitive to Bcl-2 blockage.

BACKGROUND: Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for developing innovative treatment strategies. Glucocorticoids (GCs) such dexamethasone and prednisolone are the backbone of combination chemotherapy regimens for treating all lymphoid tumors. However, the biological mechanisms of primary GC resistance in ALL is not completely understood. We previously performed a longitudinal whole-exome sequencing analysis on diagnosis/relapse pairs from adult patients with ALL. Our data revealed that relapse-specific truncation mutations in the NR3C1 gene, encoding the GC receptor, are frequently detected. METHODS: In the current study, we used discovery-based strategies including RNA sequencing (RNA-seq) and CRISPR/Cas9, followed by confirmatory testing, in human ALL cell lines, bone marrow blast samples from ALL patients and xenograft models, to elucidate the mechanisms responsible for resistance. RESULTS: Our results revealed a positive correlation between endogenous expression of NR3C1 in ALL cells and sensitivity to GCs and clinical outcomes. We further confirmed that ectopic expression of NR3C1 in ALL cells could reverse GC resistance, while deletion of NR3C1 confers resistance to GCs in ALL cell lines and xenograft models. RNA-seq analysis revealed a remarkable abundance of gene signatures involved in pathways in cancer, DNA replication, mismatch repair, P53 signalling, cell cycle, and apoptosis regulated by NR3C1. Significantly increased expression of pro-apoptotic genes including BCL2L11/Bim, BMF, BAD, BAX and BOK, and decreased transcription of anti-apoptotic genes including BCL2, BCL2L1 and BAG2 were observed in GC-resistant ALL cells following ectopic expression of NR3C1. Finally, we explored that GC resistance in ALL cells with haploinsufficiency of NR3C1 can be treated with Bcl-2 blockage. CONCLUSIONS: Our findings suggest that the status of NR3C1 gene mutations and basal expression levels of NR3C1 in ALL cells are associated with sensitivity to GCs and clinical treatment outcomes. Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders.

Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial.

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 non-randomized 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.

Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis.

BACKGROUND: Myeloid-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. METHODS: Here, 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. RESULTS: A 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. CONCLUSION: High MDSCs might be related to poor clinical outcomes of patients with cancer, that is, MDSCs might be a potential prognostic biomarker in cancer.

Common genetic risk factors for venous thrombosis in the Chinese population.

Venous thrombosis is a major medical disorder caused by both genetic and environmental factors. Little is known about the genetic background of venous thrombosis in the Chinese population. A total of 1,304 individuals diagnosed with a first venous thrombosis and 1,334 age- and sex-matched healthy participants were enrolled in this study. Resequencing of THBD (encoding thrombomodulin) in 60 individuals with venous thrombosis and 60 controls and a functional assay showed that a common variant, c.-151G>T (rs16984852), in the 5' UTR significantly reduced the gene expression and could cause a predisposition to venous thrombosis. Therefore, this variant was genotyped in a case-control study, and results indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. The THBD c.-151G>T variant was further investigated in a family analysis involving 176 first-degree relatives from 38 index families. First-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. In addition, five rare mutations that might be deleterious were also identified in thrombophilic individuals by sequencing. This study is the largest genetic investigation of venous thrombosis in the Chinese population. Further study on genetics of thrombosis should focus on resequencing of THBD and other hemostasis genes in different populations.

Improvement and transcriptome analysis of root architecture by overexpression of Fraxinus pennsylvanica DREB2A transcription factor in Robinia pseudoacacia L. 'Idaho'.

Transcription factors play a key role to enable plants to cope with abiotic stresses. DREB2 regulates the expression of several stress-inducible genes and constitutes major hubs in the water stress signalling webs. We cloned and characterized a novel gene encoding the FpDREB2A transcription factor from Fraxinus pennsylvanica, and a yeast activity assay confirmed its DRE binding and transcription activation. Overexpression of FpDREB2A in R. pseudoacacia showed enhanced resistance to drought stress. The transgenic plant survival rate was significantly higher than that of WT in soil drying and re-watering treatments. Transgenic lines showed a dramatic change in root architecture, and horizontal and vertical roots were found in transgenic plants compared to WT. The vertical roots penetrated in the field soil to more than 60 cm deep, while horizontal roots expanded within the top 20-30 cm of the soil. A physiological test demonstrated that chlorophyll contents were more gradually reduced and that soluble sugars and proline levels elevated more sharply but malondialdehyde level stayed the same (P < 0.05). Plant hormone levels of abscisic acid and IAA were higher than that of WT, while gibberellins and zeatin riboside were found to be lower. The root transcriptomes were sequenced and annotated into 2011 differential expression genes (DEGs). The DEGs were categorized in 149 pathways and were found to be involved in plant hormone signalling, transcription factors, stimulus responses, phenylalanine, carbohydrate and other metabolic pathways. The modified pathways in plant hormone signalling are thought to be the main cause of greater horizontal and vertical root development, in particular.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

PURPOSE: Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS: Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS: In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION: This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Bispecific Antibodies for Multiple Myeloma: Recent Advancements and Strategies for Increasing Their Efficacy.

The treatment options for multiple myeloma (MM) have undergone significant transformation with the advent of immunotherapy. Novel therapies that focus on tumor antigens now drive advances in MM research. Bispecific antibodies (bsAbs) leverage revolutionary advances in bioengineering techniques and embody the second generation of antibody-based tumor therapy. Recent studies on bsAbs in relapsed/refractory MM cases have revealed remarkable efficacy and acceptable safety profiles. The approval of elranatamab and teclistamab represents the next step in the development of bsAbs for the treatment of MM. This review article addresses the antigen targeting, efficacy, safety, and strategies in the application of bsAbs against treatment-resistant MM, with a focus on clinical trials and real-world data.

Correction: EGFP-EGF1-Conjugated PLGA Nanoparticles for Targeted Delivery of siRNA into Injured Brain Microvascular Endothelial Cells for Efficient RNA Interference.

[This corrects the article DOI: 10.1371/journal.pone.0060860.].

Associations of blood pressure in the third trimester and risk of venous thromboembolism postpartum.

Studies on the associations of blood pressure (BP) and the risk of venous thromboembolism (VTE) had been performed neither among pregnant women nor in Chinese population. This study included participants of pregnant women from a retrospective multicenter cohort, between May 2020 and April 2023. Systolic BP (SBP) and diastolic BP (DBP) of the participants were measured in the third trimester. The incidences of VTE (including deep venous thrombosis and/or pulmonary embolism) at 42 days postpartum were followed. With regards to SBP, pregnant women in the Q1 (≤114 mmHg), Q2 (115-122 mmHg), and Q4 group (≥131 mmHg) had increased risk of VTE than those in Q3 group (123-130 mmHg), with ORs 4.48 [1.69, 11.85], 3.52 [1.30, 9.59], and 3.17 [1.12, 8.99], respectively. Compared with pregnant women with the Q4 of DBP (≥85 mmHg), women of Q1 (≤71 mmHg) were found to have elevated risk of VTE (OR 2.73 [1.25, 5.96]). A one standard deviation decrease of DBP (9 mmHg) was related with 37% elevated risk of VTE (OR 1.37 [1.05, 1.79]). This study demonstrated a U-shaped association of SBP in the third trimester and VTE postpartum and inverse association of DBP in the third trimester and VTE postpartum.

Molecular basis of protein S deficiency in China.

Protein S (ProS) is a physiological inhibitor of coagulation with an important function in the down-regulation of thrombin generation. ProS deficiency is a major risk factor for venous thrombosis. This study enrolled 40 ProS-deficient probands to investigate the molecular basis of hereditary ProS deficiency in Chinese patients. A mutation analysis was performed by resequencing the PROS1 gene. Large deletions were identified by multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 20 different mutations, including 15 novel mutations, were identified in 21 of the 40 index probands. Small mutations were detected in 18 (45.0%) probands, and large deletions were found in 3 (7.5%) probands, leaving 19 (47.5%) patients without causative variants. To evaluate the functional consequences of 2 novel missense variants, ex vivo thrombin-generation assays, bioinformatics tools, and in vitro expression studies were employed. The p.Asn365Lys ProS variant was found to have moderately impaired secretion and reduced activated protein C cofactor activity. In contrast, the p.Pro410His mutant appeared to have severely impaired secretion but full anticoagulant activity. This study is the largest investigation of ProS deficiency in China and the first investigation of the influence of Type I ProS missense mutations on the global level of coagulation function. The p.K196E mutation, which is common in the neighboring Japanese population, was not found in our Chinese population, and null mutations were common in our Chinese population but not common in Japan. Further genetic analysis is warranted to understand the causes of ProS deficiency in patients without a genetic explanation.

Corrigendum: Pre-transplant CRP-albumin ratio as a biomarker in patients receiving haploidentical allogeneic hematopoietic transplantation: developing a novel DRCI-based nomogram.

[This corrects the article DOI: 10.3389/fimmu.2023.1128982.].