Combination therapy with venetoclax and azacitidine for the treatment of myelodysplastic syndromes with DDX41 mutations.

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 (DDX41) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. Venetoclax and azacitidine are safe and effective in high-risk MDS/AML. In this study, we evaluated the efficacy of venetoclax and azacitidine combination therapy in eight consecutive MDS patients with DDX41 mutations at our centre from March 2021 to November 2023. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Validation and comparison of 5th edition World Health Organization classification (WHO 2022) and International Consensus Classification proposals for MDS-SFB31.

The criteria of myelodysplastic syndromes (MDS) with mutated SFB31 (MDS-SFB31) proposed by the 5th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) need validation. We analysed 125 consecutive MDS cases with SFB31 mutation or ring sideroblasts (RS) ≥15% without excess blasts. We found that SFB31-negative MDS with RS had significantly different clinical features and worse prognosis. According to WHO 2022, the detection of ≥15% RS may substitute for SF3B1 mutation and our analyses support this proposal for similar prognosis of two groups after excluding high-risk genetic features referred by WHO 2022. Patients with variant allele frequency (VAF) <10% SFB31 tend to have briefer survival, supporting the VAF 10% threshold of ICC. Patients with multilineage dysplasia (MLD) had significantly shorter OS than those with single lineage dysplasia. MLD is still a powerful morphological marker of worse outcome in WHO 2022 and ICC-defined MDS-SF3B1.

Nano-selenium enhances melon resistance to Podosphaera xanthii by enhancing the antioxidant capacity and promoting alterations in the polyamine, phenylpropanoid and hormone signaling pathways.

Powdery mildew is one of the main problematic diseases in melon production, requiring the use of chemical pesticides with disease-resistant cultivars for control. However, the often rapid acquisition of fungicidal resistance by mildew pathogens makes this practice unsustainable. The identification of crop treatments that can enhance resistance to powdery mildew resistance is therefore important to reduce melon crop attrition. This study indicates that the application of Nano-Se can reduce the powdery mildew disease index by 21-45%. The Nano-Se treatment reduced reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation, with increases in glutathione (GSH), proline and 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH). Increases were also observed in the activities and transcriptional levels of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and peroxidase (POD). Assays with four different cultivars of melon with differing levels of mildew resistance demonstrated that relative to the control, the Nano-Se treatment resulted in larger responses to mildew infection, including increases in the levels of putrescine (PUT; 43-112%) and spermine (SPM; 36-118%), indoleacetic acid (IAA; 43-172%) and salicylic acid (SA; 24-73%), the activities of phenylalanine ammonium lyase (PAL), trans-cinnamate 4-hydroxylase (C4H) and 4-coumarate: Co A ligase (4CL) of the phenylpropanoid pathway (22-38%, 24-126% and 19-64%, respectively). Key genes in the polyamine and phenylpropanoid pathway were also upregulated. These results indicate that the foliar application of Nano-Se improved melon defenses against powdery mildew infection, with a significant reduction in mildew disease development.

Case of cryptic TNIP1::PDGFRB rearrangement presenting with myelodysplastic syndrome achieved hematologic and cytogenetic remission with low-dose imatinib plus decitabine therapy.

For a long time, FIP1L1::PDGFRA fusion seems to be the only cryptic rearrangement of myeloid/lymphoid neoplasm with tyrosine kinase gene fusions. Recently, with the wide application of RNA sequencing, more cryptic rearrangements of other TK genes have been identified, especially the PDGFRB. Here we report a case of myelodysplastic syndrome with severe thrombocytopenia. Conventional karyotype analysis revealed a t (5;19) (q33; p13.2) but no PDGFRB rearrangement was detected by the PDGFRB break-apart probe. The TNIP1::PDGFRB fusion was eventually found by RNA sequencing, leading us to treat with low-dose imatinib plus decitabine, and the patient achieved hematologic improvement and cytogenetic remission.

Integrated non-targeted and targeted metabolomics analysis reveals the mechanism of inhibiting lignification and optimizing the quality of pea sprouts by combined application of nano-selenium and lentinans.

BACKGROUND: Lignification causes a detrimental impact on the quality of edible sprouts. However, the mechanism of inhibition of lignification of edible sprouts by nano-selenium and lentinans remains unclear. RESULTS: To reveal the mechanism of lignification regulation of sprouts by nano-selenium and lentinans, this study investigated the changes in antioxidant indicators, phytohormones, polyphenols, and metabolites in the lignin biosynthesis in pea sprouts following sprays of nano-selenium or/and lentinans twice. There was an overall increase in the aforementioned indices following treatment. In particular, the combined application of 5 mg L-1 nano-selenium and 20 mg L-1 lentinans was more effective than their individual applications in enhancing peroxidase, catalase, DPPH free-radical scavenging rate, luteolin, and sinapic acid, as well as inhibiting malondialdehyde generation and lignin accumulation. Combined with the results from correlation analysis, nano-selenium and lentinans may inhibit lignification by enhancing antioxidant systems, inducing phytohormone-mediated signaling, and enriching precursor metabolites (caffeyl alcohol, sinapyl alcohol, 4-coumaryl alcohol). In terms of the results of non-targeted metabolomics, the combined application of 5 mg L-1 nano-selenium and 20 mg L-1 lentinans mainly affected biosynthesis of plant secondary metabolites, biosynthesis of phenylpropanoids, phenylpropanoid biosynthesis, arginine and proline metabolism, and linoleic acid metabolism pathways, which supported and complemented results from targeted screenings. CONCLUSION: Overall, the combined sprays of nano-selenium and lentinans showed synergistic effects in delaying lignification and optimizing the quality of pea sprouts. This study provides a novel and practicable technology for delaying lignification in the cultivation of edible sprouts. © 2023 Society of Chemical Industry.

Impact of the International Consensus Classification of myelodysplastic syndromes.

The impact of the 2022 International Consensus Classification (ICC) of myelodysplastic syndromes (MDS) needs study. We analysed data from 989 MDS subjects classified using the 2016 World Health Organization (WHO) criteria to determine the impact of the new proposal. Our analyses suggested the ICC criteria of MDS-SF3B1 identifies a more homogenous disease entity than the WHO 2016 criteria of myelodysplastic syndromes with ring sideroblasts (MDS-RS). MDS, not otherwise specified with single lineage dysplasia (MDS, NOS-SLD) patients had a better prognosis than MDS, NOS with multilineage dysplasia (MDS, NOS-MLD) patients. MDS with mutated TP53 and MDS/acute myeloid leukaemia with mutated TP53 patients had the briefest survivals. These data support the ICC of MDS, which allows more accurate diagnoses and risk stratification.

IPSS-M has greater survival predictive accuracy compared with IPSS-R in persons ≥ 60 years with myelodysplastic syndromes.

There are considerable new data on mutation topography in persons with myelodysplastic syndromes (MDS). These data have been used to update conventional risk models such as the Revised International Prognostic Scoring System (IPSS-R). Whether the molecular IPSS (IPSS-M) which includes these data improves survival prediction accuracy is untested. To answer this question, we compared survival prediction accuracies of the IPSS-R and IPSS-M in 852 consecutive subjects with de novo MDS. Concordance statistics (C-statistics) of the IPSS-R and IPSS-M in the entire cohort were similar, 0.67 (95% Confidence Interval [CI] 0.64, 0.71) and 0.68 (0.64, 0.71). Average numbers of mutations and of IPSS-M related mutations were greater in persons ≥ 60 years (2.0 [Interquartile Range [IQR], 1, 3] vs. 1.6 [0, 2], P = 0.003; 1.6 [0, 2] vs. 1.3 [0, 2], P = 0.006). Subjects ≥ 60 years had a higher incidence of mutations in RUNX1, TP53, TET2, SRSF2, DNMT3A, STAG2, EZH2 and DDX41. In contrast, mutations in U2AF1 were more common in persons < 60 years. Next we tested survival prediction accuracy based on age < or ≥ 60 years. C-statistics of the IPSS-R and IPSS-M in subjects ≥ 60 years were 0.66 (0.61, 0.71) and 0.69 (0.64, 0.73) whereas in subjects < 60 years they were 0.67 (0.61, 0.72) and 0.65 (0.59, 0.71). These data indicate an advantage for the IPSS-M over the IPSS-R in subjects ≥ 60 years but not in those < 60 years probably because of a great frequency of mutations correlated with survival in those ≥ 60 years.

Correlation of Body Mass Index with Clinicopathologic Parameters in Patients with Idiopathic Membranous Nephropathy.

Objective: To investigate the association between body mass index (BMI) and clinicopathologic parameters in patients with idiopathic membranous nephropathy (IMN). Methods: This study was retrospective and included patients with biopsy-proven IMN from 2018 to 2021 in Hebei General Hospital. Patients were categorized into two groups based on BMI. Clinical and histopathologic data were analyzed at the time of renal biopsy. Pathological data included immunofluorescence staining, glomerulosclerosis (GS, 0-2), mesangial cell proliferation (MCP, 0-1), tubular atrophy (TA, 0-1), interstitial fibrosis (IF, 0-1), vascular wall thickness (VWT, 0-1) and a combination score (GMTIV) graded from 0 to 5. Results: Our study revealed that the obese group had a higher prevalence of hypertension and diabetes than the overweight/normal weight group (P=0.001, P=0.002). Systolic blood pressure (P=0.005), diastolic blood pressure (P<0.001), haemoglobin (P=0.006), triglycerides (P<0.001), serum uric acid (P=0.05), 24 h urine proteinuria concentration (UP) (P=0.012), MCP (P=0.042), IF (P=0.033), and GMITV (P=0.033) score were higher in obese group compared to the other group, while the high-density lipoprotein-cholesterol (P=0.034) and immunoglobulin A deposition score (P=0.005) were lower. Factors significantly associated with UP were the ratio of lymphocyte count to white blood cell count, serum pre-albumin, immunoglobulin G, microscopic hematuria, anti-phospholipase A2 receptor (anti-PLA2R), C3 deposit on multivariable analysis (adjusted R 2=0.343). Binary logistic regression analysis illustrated that MCP was correlated to BMI (OR=2.528, P=0.036). Ordinal logistic regression analysis demonstrated that GMTIV was associated with BMI (OR=1.114, P=0.010) and C3 deposit (OR=1.655, P=0.001). Conclusion: High BMI was associated with MCP and GMTIV score in IMN patients. Obesity may play an essential role in mesangial lesions of IMN. This study emphasized the relation between BMI and histological parameters under the universal usage of anti-PLA2R antibodies for diagnosis and prognosis in IMN.

Myelodysplastic syndromes are multiclonal diseases derived from hematopoietic stem and progenitor cells.

Myelodysplastic syndromes (MDS) are generally considered as a group of clonal diseases derived from hematopoietic stem cells, but a number of studies have suggested that they are derived from myeloid progenitor cells. We aimed to identify the cell of origin in MDS by single-cell analyses. Targeted single-cell RNA sequencing, covering six frequently mutated genes (U2AF1, SF3B1, TET2, ASXL1, TP53, and DNMT3A) in MDS, was developed and performed on individual cells isolated from the CD34+ and six lineage populations in the bone marrow of healthy donors (HDs) and patients with MDS. The detected mutations were used as clonal markers to define clones. By dissecting the distribution of clones in six lineages, the clonal origin was determined. We identified three mutations both in HDs and patients with MDS, termed clonal hematopoiesis (CH) mutations. We also identified fifteen mutations only detected in patients with MDS, termed MDS mutations. Clonal analysis showed that CH clones marked by CH mutations and MDS clones marked by MDS mutations were derived from hematopoietic stem cells as well as various hematopoietic progenitor cells. Most patients with MDS showed the chimeric state with CH clones and MDS clones. Clone size analysis suggested that CH mutations may not contribute to clonal expansion of MDS. In conclusion, MDS comprise multiple clones derived from hematopoietic stem and progenitor cells.

Landscape of immunoglobulin heavy chain gene repertoire and its clinical relevance to LPL/WM.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous disease in which the role of immunoglobulin heavy-chain genes (IGHs) remains unknown. To determine the clinical relevance of the IGH repertoire in patients with LPL/WM, we performed immunoglobulin gene rearrangement and complementarity determining region 3 (CDR3) analysis. The IGH variable gene (IGHV) repertoire was remarkably biased in LPL/WM. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7, and IGHV3-74 accounted for one-half of the cohort's repertoire. Most cases (97.1%) were found to carry mutated IGHV genes, based on a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating there was specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor the 6q deletion (P < .001) and an abnormal karyotype (P = .004). The IGHV hypermutation rate in patients with the MYD88 L265P mutation was significantly higher than that of wild-type patients (P = .050). IGHV3-23 and IGHV3-74 segments were more frequently detected in patients with MYD88-mutated LPL/WM (P = .050), whereas IGHV3-7 presented more frequently in MYD88 wild-type patients (P = .042). Patients with IGHV4, especially IGHV4-34, had higher levels of lactate dehydrogenase, and IGHV4 was a predictive marker of shorter progression-free survival. These results showed for the first time that the IGHV repertoire has clinical relevance in LPL/WM.

The clinical characteristics and prognosis in adult Ph negative acute lymphoblastic leukemia with TP53 aberrations.

Very few reports elucidate the prognosis of patients with TP53 aberrations using both measurable residual disease (MRD) and the status of having undergone allogeneic hematopoietic stem cell transplantation (allo-SCT). In this study, aberrations of TP53 were analyzed using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) in patients with Philadelphia chromosome-negative (Ph-) ALL enrolled in a prospective single-arm clinical trial at our leukemia center. We analyzed the survival of the patients grouped according to the MRD level at the third month and whether or not received allo-SCT. We found that allo-SCT could improve the OS in patients with TP53 aberrations; Patients having negative MRD at the third month still showed worse 3-year OS and 3-year DFS without undergoing allo-SCT, which is different from previous studies, moreover, the prognostic significance of TP53 deletions was as important as TP53 mutations, the importance of screening both TP53 deletions and mutations in adult Ph- ALL at diagnosis should be emphasized.

ASXL2 mutated myelodysplastic syndrome in a novel germline G6b variant.

The 2016 revised World Health Organization classification identified myeloid neoplasms with germline predisposition as a new diagnostic category. Germline loss-of-function mutations in G6b (G6b-B, C6orf25 or MPIG6B) are associated with congenital macro-thrombocytopenia with focal myelofibrosis, a rare autosomal recessive disease. It is unclear whether germline G6b variants increase the risk of developing a myeloid neoplasm. Here we describe an adult with Myelodysplastic syndromes and a homozygous germline G6b mutation who achieved hematopoietic reconstitution by hematopoietic stem cell transplantation. As far as we know, this is the first report of adult Myelodysplastic syndromes with germline G6b homozygous variant in the literatures.

A Phenogenetic Axis that Modulates Clinical Manifestation and Predicts Treatment Outcome in Primary Myeloid Neoplasms.

Although the concept of "myeloid neoplasm continuum" has long been proposed, few comparative genomics studies directly tested this hypothesis. Here we report a multi-modal data analysis of 730 consecutive newly diagnosed patients with primary myeloid neoplasm, along with 462 lymphoid neoplasm cases serving as the outgroup. Our study identified a "Pan-Myeloid Axis" along which patients, genes, and phenotypic features were all aligned in sequential order. Utilizing relational information of gene mutations along the Pan-Myeloid Axis improved prognostic accuracy for complete remission and overall survival in adult patients of de novo acute myeloid leukemia and for complete remission in adult patients of myelodysplastic syndromes with excess blasts. We submit that better understanding of the myeloid neoplasm continuum might shed light on how treatment should be tailored to individual diseases. Significance: The current criteria for disease diagnosis treat myeloid neoplasms as a group of distinct, separate diseases. This work provides genomics evidence for a "myeloid neoplasm continuum" and suggests that boundaries between myeloid neoplastic diseases are much more blurred than previously thought.

Hydrogen-Rich Water Ameliorates Autistic-Like Behavioral Abnormalities in Valproic Acid-Treated Adolescent Mice Offspring.

Due to its anti-inflammatory and anti-oxidative effects, recent research has demonstrated that molecular hydrogen can serve as a new medical approach for depression, anxiety and traumatic brain injury. However, its potential effects on neurodevelopmental diseases, such as autism are still elusive. The present study aims to investigate the potential effects of hydrogen-rich water (HRW) administration on valproic acid (VPA)-induced autistic-like behavioral deficits, and the associated underlying mechanism in adolescent mice offspring. Pregnant ICR mice were randomly divided into five groups (n = 6). One group was injected with saline (NAV group) and provided hydrogen-free water. The other four groups were injected with VPA (600 mg/kg, intraperitoneally, i.p.) on pregnant day (PND) 12.5. One group was provided with hydrogen-free water (VEH group) and the other three groups were provided HRW at different segments, postnatal day 1 (PND 1) to PND 21 (PHV group), PND 13 to PND 21 (PVS group) or from PND 13 to postnatal day 42 (PVL group). Behavioral tests, including open field, novelty suppressed feeding (NSF), hot plate, social interaction (SI) and contextual fear memory tests were conducted between postnatal day 35-42. We found that HRW administration significantly reversed the autistic-like behaviors induced by maternal VPA exposure in the adolescent offspring of both male and female adolescent offspring. Furthermore, HRW administration significantly reversed the alternation of serum levels of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), but without any effects on the BDNF levels in maternal VPA-exposed mice offspring. These data suggest the need for additional research on HRW as a potential preventive strategy for autism and related disorders. Lay Summary: Maternal VPA injection induces autistic-like behavioral deficits in adolescent mice offspring. HRW administration ameliorates autistic-like behavioral deficits. HRW administration reverses the alternation of serum levels of IL-6 and TNF-α induced by VPA.

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes.

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AFS34 subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1S34 subjects had more frequently platelet levels of <50 × 109 /L (P = .043) and U2AF1Q157 /U2AF1R156 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.