Clustering pattern and evolution characteristic of microRNAs in grass carp (Ctenopharyngodon idella).

BACKGROUND: A considerable fraction of microRNAs (miRNAs) are highly conserved, and certain miRNAs correspond to genomic clusters. The clustering of miRNAs can be advantageous, possibly by allowing coordinated expression. However, little is known about the evolutionary forces responsible for the loss and acquisition of miRNA and miRNA clusters. RESULTS: The results demonstrated that several novel miRNAs arose throughout grass carp evolution. Duplication and de novo production were critical strategies for miRNA cluster formation. Duplicates accounted for a smaller fraction of the expansion in the grass carp miRNA than de novo creation. Clustered miRNAs are more conserved and change slower, whereas unique miRNAs usually have high evolution rates and low expression levels. The expression level of miRNA expression in clusters is strongly correlated. CONCLUSIONS: This study examines the genomic distribution, evolutionary background, and expression regulation of grass carp miRNAs. Our findings provide novel insights into the genesis and development of miRNA clusters in teleost.

LncRNA-adm2 targets adm2 via cid-miR-n3 and negatively regulates the inflammatory response in grass carp (Ctenopharyngodon idella).

Long non-coding RNAs (lncRNAs), which impact gene expression following pathogen infections, have garnered significant attention in recent years. Recent discoveries have revealed that lncRNAs play a crucial role in fish immune responses to pathogen infections. We investigated the influence of lncRNA-adm2 on the antibacterial immune response generated by Aeromonas hydrophila in grass carp (Ctenopharyngodon idella) through the adsorption of cid-miR-n3. Furthermore, we found that cid-miR-n3 interacts with lncRNA-adm2 and targets the 3' UTR of adm2. The upregulation of lncRNA-adm2 expression led to the suppression of pro-inflammatory cytokines (il-1ß and il-6) in CIK cells, while anti-inflammatory cytokines (il-10) increased. Our research provides evidence that lncRNAs are involved in the antibacterial immune response of fish, expanding our understanding of the function of lncRNAs in teleosts.

Identification of multifunctionality of grass carp (Ctenopharyngodon idella) TBK1 during bacterial infection.

TBK1 is an atypical IκB kinase family member with a set of functions. It is involved in congenital immunization and autophagy in mammals. In this study, we reported that grass carp TBK1 gene expression could be upregulated by bacterial infection. Overexpression of TBK1 could decrease the number of adhesive bacteria in CIK cells. TBK1 could promote cellular migration, proliferation, vitality, and anti-apoptosis ability. Furthermore, the expression of TBK1 could activate the NF-κB signaling pathway by inducing inflammatory cytokines. In addition, we found that the grass carp TBK1 could cause the autophagy level of CIK cells within the decreasing level of p62 protein. Our finding indicated that TBK1 participated in grass carp innate immune progress and autophagy. This study provides evidence of the positive regulation of TBK1 in teleost innate immunity with its multiple functions. It thus may provide important information about the defense and immune mechanisms used by teleost against pathogens.

miR-23a regulates the disease resistance of grass carp (Ctenopharyngodon idella) by targeting autophagy-related genes, ATG3 and ATG12.

miRNAs play a key role in the autophagy process. In recent years, the emerging role of autophagy in regulating immune response has attracted increasing attention. Since then, specific miRNAs have also been found to play an immune function indirectly by modulating autophagy as well. This study proved that miR-23a could downregulate grass carp autophagy simultaneously by targeting ATG3 and ATG12. Besides, both ATG3 and ATG12 mRNA levels were increased in kidney and intestine after being infected by Aeromonas hydrophila; yet almost at the same time, miR-23a was decreased. Besides, we illustrated that grass carp miR-23a could affect antimicrobial capacity, proliferation, migration, and antiapoptotic abilities of CIK cells. These results indicate that miR-23a was related to grass carp autophagy and plays an important role in antimicrobial immunity through targeting ATG3 and ATG12, which provides important information on autophagy-related miRNAs about the defense and immune mechanisms against pathogens in teleost.

LncRNA-ANAPC2 and lncRNA-NEFM positively regulates the inflammatory response via the miR-451/npr2/ hdac8 axis in grass carp.

In grass carp (Ctenopharyngodon idella), septicemia is a systemic inflammatory response to bacterial infection and could be leaded to lethality. MiR-451 involved in septicemia progression has been reported. However, the underlying mechanism of miR-451 in septicemia induced inflammatory response remains to be revealed. In the present study, miR-451 was highly expressed in Aeromonas hydrophila induced CIK cells, opposite to lncRNA-ANAPC2 and lncRNA-NEFM expression. Furthermore, we found that miR-451 interacted with lncRNA-ANAPC2 and lncRNA-NEFM, also targeted the 3' UTR of npr2 and hdac8. In CIK cells, the inhibition of npr2 and hdac8 were down-regulated by lncRNA-ANAPC2 and lncRNA-NEFM knockdown, while downstream proinflammatory factors were inhibited. In a word, this study indicates that lncRNA-ANAPC2 and lncRNA-NEFM regulation the LPS-induced progression of inflammatory response by modulating miR-451/npr2/hdac8 axis.

Up-regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia.

The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event-free survival (EFS) than the low expressers among the chemotherapy-only group (all P < .001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo-HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo-HSCT had longer EFS and OS than those who received chemotherapy alone (all P < .01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN-AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo-HSCT.

Clinical and Biological Implications of Mutational Spectrum in Acute Myeloid Leukemia of FAB Subtypes M0 and M1.

BACKGROUND/AIMS: Acute myeloid leukemia (AML) of French-American-British (FAB) subtypes M0 and M1 are both poorly differentiated AML, but their mutational spectrum and molecular characteristics remain unknown. This study aimed to explore the mutational spectrum and prognostic factors of AML-M0 and M1. METHODS: Sixty-five AML patients derived from The Cancer Genome Atlas (TCGA) database were enrolled in this study. Whole-genome sequencing was performed to depict the mutational spectrum of each patient. Clinical characteristics at diagnosis, including peripheral blood (PB) white blood cell counts (WBC), blast percentages in PB and bone marrow (BM), FAB subtypes and the frequencies of known recurrent genetic mutations were described. Survival was estimated using the Kaplan-Meier methods and log-rank test. Univariate and multivariate Cox proportional hazard models were constructed for event-free survival (EFS) and overall survival (OS), using a limited backward elimination procedure. RESULTS: Forty-six patients had more than five recurrent genetic mutations. FLT3 had the highest mutation frequency (n=20, 31%), followed by NPM1 (n=18, 28%), DNMT3A (n=16, 25%), IDH1 (n=14, 22%), IDH2 (n=12, 18%), RUNX1 (n=11, 17%) and TET2 (n=7, 11%). Univariate analysis showed that age ≥60 years and TP53 mutations had adverse effect on EFS (P=0.015, P=0.036, respectively) and OS (P=0.003, P=0.004, respectively), WBC count ≥50×109/L and FLT3-ITD negatively affected EFS (P=0.003, P=0.034, respectively), whereas NPM1 mutations had favorable effect on OS (P=0.035) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) on EFS and OS (all P< 0.001). Multivariate analysis suggested that allo-HSCT and NPM1 mutations were independent favorable prognostic factors for EFS and OS (all P< 0.05), WBC count ≥50×109/L was an independent risk factor for EFS (P=0.002) and TP53 mutations for OS (P=0.043). CONCLUSIONS: Our study provided new insights into the mutational spectrum and molecular signatures of AML-M0 and M1. We proposed that FLT3-ITD, NPM1 and TP53 be identified as markers for risk stratification of AML-M0 and M1. Patients with AML-M0 and M1 would likely benefit from allo-HSCT.

A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia.

MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 downregulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex. In this study, we demonstrate that miR-9-1 expression increases significantly after the treatment of RUNX1-RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1 by binding to RUNX1-binding sites in the promoter region of miR-9-1 and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR-9-1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1-RUNX1T1 are all regulated by miR-9-1, the silencing of miR-9-1 enhances the oncogenic activity of these genes. Besides, overexpression of miR-9-1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1, contributing to leukemogenesis in RUNX1-RUNX1T1 (+) AML cell lines.

High expression of CPNE3 predicts adverse prognosis in acute myeloid leukemia.

CPNE3, a member of a Ca2+ -dependent phospholipid-binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3low ), high CPNE3 expression (CPNE3high ) was associated with adverse overall survival (OS, P < 0.001) and event-free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome-wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome-wide gene/microRNA expression and related cell signaling pathways.

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions.

BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329). CONCLUSIONS: Our results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT.

[Efficacy of R±BEACOP regimen in patients with poor-prognosis lymphoma].

OBJECTIVE: To analyze the efficacy of cyclophosphamideplus, epirubicin, vincristine, prednisone plus etoposide and/or bleomycin, with or without rituximab (R±BEACOP) regimen in patient with poor-prognosis lymphoma.
 METHODS: A total of 89 patients, who had poor-prognosis lymphoma and received at least 1 cycle of R±BEACOP regimen during 2002 to 2012, were enrolled and analyzed by a retrospective study.
 RESULTS: The rate of complete response was 62.9% (56 patients). The efficacy of Hodgkin lymphoma (HL) and T/NK NHL was better than that of other types of lymphoma. There was no significant difference in efficacy among the patients with different age, stage or international prognosis index (IPI) (all P>0.05).
 CONCLUSION: R±BEACOP regimen is effective in some patients with poor prognosis, especially in HL patients. Thus, multicenter prospective study regarding the R±BEACOP regimen needs to be done to further test its efficacy.

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.

Advances and challenges in MXene-based electrocatalysts: unlocking the potential for sustainable energy conversion.

MXenes, a novel class of two-dimensional materials, have garnered significant attention for their promising electrocatalytic properties in various energy conversion applications such as water splitting, fuel cells, metal-air batteries, and nitrogen reduction reactions. Their excellent electrical conductivity, high specific surface area, and versatile surface chemistry enable exceptional catalytic performance. This review highlights recent advancements in the design and application strategies of MXenes as electrocatalysts, focusing on key reactions including hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and nitrogen reduction reaction (NRR). We discuss the tunability of MXenes' layered structures and surface properties through surface modification, MXene lattice substitution, defect and morphology engineering, and heterostructure construction. Despite the considerable progress, MXenes face challenges such as restacking during catalysis, stability issues, and difficulties in large-scale production. Addressing these challenges through innovative engineering approaches and advancing industrial synthesis techniques is crucial for the broader application of MXene-based materials. Our review underscores the potential of MXenes in transforming electrocatalytic processes and highlights future research directions to optimize their catalytic efficiency and stability.

Real-World Analysis of Barriers to Timely Administration of Chimeric Antigen Receptor T Cell (CAR T) Therapy in Diffuse Large B-cell Lymphoma.

The implementation of chimeric antigen receptor T (CAR T) therapy in the real-world setting is hindered by logistical and financial barriers, impacting timely access to this life-saving treatment. Clinical trials have reported the time from leukapheresis to CAR T cell infusion (vein-to-vein time) but not the time from CAR T referral to infusion (decision-to-vein time). Herein, we report the barriers to CAR T therapy in a real-world setting. We evaluated the factors influencing the decision-to-vein time and explored the association with clinical outcomes in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who received CAR T therapy. We conducted a retrospective study of adult patients with relapsed/refractory DLBCL who underwent consultation for CAR T cell therapy at Levine Cancer Institute and Wake Forest Comprehensive Cancer Center and collected information regarding demographic data, referral type, insurance type, CAR T product, and survival outcomes. The effects of variables on decision-to-vein time were analyzed by Fisher's exact test for categorial variables and Wilcoxon rank-sum test for continuous variables. Survival analyses were performed using Kaplan-Meier and Cox Proportional Hazard models. The study included 142 patients who were referred for CAR T of which 99 patients received CAR T. Median decision-to-vein time was 62 days compared to median vein-to-vein time of 32 days. Patients with private insurance took longer to obtain financial clearance compared to patients with government insurance (median 25 versus 9 days, P < .001). Of those with private insurance (n = 63), 35% needed a single-case agreement (SCA) which led to significant delay in receiving financial clearance (median 50.5 versus 19 days, P < .001) and increased decision-to-vein time (median 75 versus 55 days, P < .001) compared to those who did not need SCA. Decision-to-vein time was significantly different among various products, clinical trial being the shortest (median 47 days, n = 9) and non-conforming products being the longest (median 94.5 days, n = 6) (P< .001). Axi-cel had the shortest median decision-to-vein time at 61 days compared to 81 days with tisa-cel and 85 days with liso-cel. Although delays in receiving CAR T therapy did not impact survival, the median overall survival for patients who were referred for CAR T therapy but did not receive it, was significantly lower than those who received CAR T cell therapy (9.0 versus 21.0 months, P < .001). Decision-to-vein time is a major cause of delay in receiving CAR T therapy. SCAs lead to significant increase in decision-to-vein time leading to delays in CAR T therapy in a real-world setting. Patients who were referred for CAR T but are not able to receive it, have inferior survival compared to CAR T recipients. Our findings underscore the significance of addressing administrative hurdles, such as SCAs and insurance approvals, for timely access to CAR T therapy for patients with DLBCL.

Immunopathogenic mechanisms and modulatory approaches to graft-versus-host disease prevention in acute myeloid leukaemia.

Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only potential cure for intermediate to high-risk acute myeloid leukaemia (AML). The therapeutic effect of HSCT is largely dependent on the powerful donor-derived immune response against recipient leukaemia cells, known as graft-versus-leukaemia effect (GvL). However, the donor-derived immune system can also cause acute or chronic damage to normal recipient organs and tissues, in a process known as graft-versus-host disease (GvHD). GvHD is a leading cause of non-relapse mortality in HSCT recipients. There are many similarities and cross talk between the immune pathways of GvL and GvHD. Studies have demonstrated that both processes require the presence of mismatched alloantigens between the donor and recipient, and activation of immune responses centered around donor T-cells, which can be further modulated by various recipient or donor factors. Dissecting GvL from GvHD to achieve more effective GvHD prevention and enhanced GvL has been the holy grail of HSCT research. In this review, we focused on the key factors that contribute to the immune responses of GvL and GvHD, the effect on GvL with different GvHD prophylactic strategies, and the potential impact of various AML relapse prevention therapy or treatments on GvHD.

MiR-217 targets TBK1 to modulate inflammatory response in grass carp following infection with Aeromonas hydrophila.

The current study demonstrated that miR-217 modulates inflammation in grass carp (Ctenopharyngodon Idella) infected with Aeromonas hydrophila. Bacterial infection in grass carp causes high levels septicemia, which arises with systemic inflammatory responses. As a result leading to the development of hyperinflammatory state which causes septic shocks and lethality. Based on the current data, TBK1 was confirmed to be the target gene of miR-217 after a successful gene expression profiling or luciferase experiment and miR-217 expression in CIK cells. Furthermore, TargetscanFish6.2 predicted TBK1 as the target gene of miR-217. Quantitative real-time PCR was performed to measure miR-217 expression levels for six immune-related genes and miR-217 regulation in grass carp after A. hydrophila infection in CIK cells. In grass carp CIK cells, the expression of TBK1 mRNA was up-regulated under poly (I: C) stimulation. The transcriptional analysis of the immune-related genes demonstrated that the expression levels of tumor necrosis factor-α (TNF-α), interferon (ifn), interleukin 6 (il-6), interleukin 8 (il-8), and interleukin 12 (il-12) were altered after a successful transfection into the CIK cells, proposing that miRNA regulates immune responses in grass carp. These results provided a theoretical basis and contribute to further studies on the pathogenesis and host defensive system during A. hydrophila infection.

Chronic graft-versus-host disease is characterized by high levels and distinctive tissue-of-origin patterns of cell-free DNA.

Chronic graft-versus-host disease (cGvHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT). Effective early detection may improve the outcome of cGvHD. The potential utility of circulating cell-free DNA (cfDNA), a sensitive marker for tissue injury, in HSCT and cGvHD remains to be established. Here, cfDNA of prospectively collected plasma samples from HSCT recipients (including both cGvHD and non-cGvHD) and healthy control (HC) subjects were evaluated. Deconvolution methods utilizing tissue-specific DNA methylation signatures were used to determine cfDNA tissue-of-origin. cfDNA levels were significantly higher in HSCT recipients than HC and significantly higher in cGvHD than non-cGvHD. cGvHD was characterized by a high level of cfDNA from innate immune cells, heart, and liver. Non-hematologic tissue-derived cfDNA was significantly higher in cGvHD than non-cGvHD. cfDNA temporal dynamics and tissue-of-origin composition have distinctive features in patients with cGvHD, supporting further exploration of the utility of cfDNA in the study of cGvHD.

Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience.

BACKGROUND: Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine-total body irradiation (TBI) with fludarabine among patients with hematologic diseases. PATIENTS AND METHODS: This retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years. RESULTS: The donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P = .06, and 5-year OS rate 53% vs 39%, P = .13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P = .003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P = .001) in both groups. A high disease risk index was possibly associated with inferior OS (P = .07) in both groups. CONCLUSIONS: The FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.

Post-hematopoietic stem cell transplantation immune-mediated anemia: a literature review and novel therapeutics.

Anemia after allogeneic hematopoietic stem cell transplantation (HSCT) can be immune or non-immune mediated. Auto- or alloimmunity resulting from blood group incompatibility remains an important cause in post-HSCT immune-mediated anemia. ABO incompatibility is commonly encountered in HSCT and may lead to serious clinical complications, including acute hemolysis, pure red cell aplasia, and passenger lymphocyte syndrome. It remains controversial whether ABO incompatibility may affect HSCT outcomes, such as relapse, nonrelapse mortality, graft-versus-host disease, and survival. Non-ABO incompatibility is less frequently encountered but can have similar complications to ABO incompatibility, causing adverse clinical outcomes. It is crucial to identify the driving etiology of post-HSCT anemia in order to prevent and treat this condition. This requires a comprehensive understanding of the mechanism of anemia in blood group-incompatible HSCT and the temporal association between HSCT and anemia. In this review, we summarize the literature on post-HSCT immune-mediated anemia with a focus on ABO and non-ABO blood group incompatibility, describe the underlying mechanism of anemia, and outline preventive and treatment approaches.

The ISHLT chronic lung allograft dysfunction consensus criteria are applicable to pulmonary chronic graft-versus-host disease.

Pulmonary chronic graft-versus-host disease (PcGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 National Institutes of Health cGVHD consensus criteria (NIH criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGVHD and compared the performance of this criteria with the NIH criteria to identify patients with high-risk PcGVHD. We reviewed consecutive patients in a cGVHD natural history protocol (#NCT00092235) and adapted the 2019 CLAD criteria (the adapted criteria) to define PcGVHD as post-HCT forced expiratory volume at 1 second < 80% predicted value, with 4 phenotypes: obstructive, restrictive, mixed obstructive/restrictive, and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the adapted criteria, including obstruction (n = 12, 3.4%), restriction (n = 67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%), and undefined (n = 40, 11.4%). In these patients, less than half (n = 78) met the NIH criteria for BOS (NIH+); the rest (n = 88) did not (NIH-). The NIH- subjects showed increased risk of death compared with those without PcGVHD (hazard ratio = 1.88, 95% confidence interval = 1.20-2.95; P = .006) that was similar to NIH+ subjects (P = .678). Our study demonstrated the potential of the adapted criteria in identifying patients with high-risk PcGVHD that have been missed by the NIH criteria. The adapted criteria could become a valuable tool to better phenotype and study lung disease in cGVHD.