Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Fe-TiO2-x/TiO2 S-scheme homojunction for efficient photocatalytic CO2 reduction.

CO2-to-high value-added chemicals via a photocatalytic route is of interest but strangled by the low efficiency. Herein, a novel Fe-TiO2-x/TiO2 S-scheme homojunction was designed and constructed by using a facile surface modification approach whereby oxygen vacancy (OV) and Fe introducing on the TiO2 nanorod surface. The as-synthesized Fe-TiO2-x/TiO2 S-scheme homojunction exhibits positive properties on promoting photocatalytic CO2 reduction: i) the nanorod structure provides numerous active sites and a radical charge transfer path; ii) the doped Fe and OV not only synergistically enhance light utilization but also promote CO2 adsorption; iii) the Fe-TiO2-x/TiO2 S-scheme homojunction benefits photoexcited charge separation and retains stronger redox capacity. Thanks to those good characters, the Fe-TiO2-x/TiO2 homojunction exhibits superior CO2 reduction performances with optimized CO/CH4 generation rates of 122/22 µmol g-1h-1 which exceed those of pure TiO2 by more than 9.4/7.3 folds and most currently reported catalytic systems. This manuscript develops a facile and universal approach to synthesize well-defined homojunction and may inspire the construction of other more high-efficiency photocatalysts toward CO2 reduction and beyond.

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.

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.

La2O3 Nanoparticles Can Cause Cracking of Tomato Fruit through Genetic Reconstruction.

La2O3 nanoparticles (NPs) have shown great potential in agriculture, but cracking of plant sensitive tissue could occur during application, resulting in a poor appearance, facilitating entry for insects and fungi, and increasing economic losses. Herein, exocarp cracking mechanisms of tomato (Solanum lycopersicum L.) fruit in response to La2O3 NPs were investigated. Tomato plants were exposed to La2O3 NPs (0-40 mg/L, 90 days) by a split-root system under greenhouse condition. La2O3 NPs with high concentrations (25 and 40 mg/L) increased the obvious cracking of the fruit exocarp by 20.0 and 22.7%, respectively. After exposure to 25 mg/L La2O3 NPs, decreased thickness of the cuticle and cell wall and lower wax crystallization patterns of tomato fruit exocarp were observed. Biomechanical properties (e.g., firmness and stiffness) of fruit exocarp were decreased by 34.7 and 25.9%, respectively. RNA-sequencing revealed that the thinner cuticle was caused by the downregulation of cuticle biosynthesis related genes; pectin remodeling, including the reduction in homogalacturonan (e.g., LOC101264880) and rhamnose (e.g., LOC101248505), was responsible for the thinner cell wall. Additionally, genes related to water and abscisic acid homeostasis were significantly upregulated, causing the increases of water and soluble solid content of fruit and elevated fruit inner pressure. Therefore, the thinner fruit cuticle and cell wall combined with the higher inner pressure caused fruit cracking. This study improves our understanding of nanomaterials on important agricultural crops, including the structural reconstruction of fruit exocarp contributing to NPs-induced cracking at the molecular level.

Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins.

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.

Synthesis of 3-aminoquinolines from α-imino rhodium carbenes and 2-aminobenzaldehydes.

A facile and efficient synthetic method for 3-aminoquinolines has been reported. The straightforward process starts from easily available triazoles and 2-aminobenzaldehydes. Low catalyst loading and good functional group compatibility are the other two merits of this transformation. Easy decoration of the 3-aminoquinoline motifs enabled the convenient synthesis of bioactive molecules, demonstrating the potential of this protocol in organic synthesis.

Catalyst-Free Synthesis of Polycyclic Spiroindolines by Cascade Reaction of 3-(2-Isocyanoethyl)indoles with 1-Sulfonyl-1,2,3-triazoles.

A catalyst-free cascade reaction of 3-(2-isocyanoethyl)indoles and 1-sulfonyl-1,2,3-triazoles was realized. This dearomative spirocyclization provided an efficient protocol to synthesize a series of polycyclic indolines bearing spiro-α-carboline in moderate to high yields in one step under thermal reaction conditions.

Synthesis of Piperidin-4-one Derivatives via α-Imino Rhodium Carbene-Initiated 1,2-Aryl/Alkyl Migration and Annulation.

Valuable piperidin-4-one derivatives were synthesized in excellent yields via an α-imino carbene-initiated cascade reaction involving 1,2-aryl/alkyl migration and annulation. The excellent selectivity of alkyl migration was attributed to the neighboring group participation of 2-bromoethyl. Features such as high efficiency, excellent migrating selectivity, broad substrate scope, and convenient one-pot procedure qualified this protocol as an effective tool for piperidine derivative synthesis. The product could be transformed to a bioactive molecule easily. The migration-annulation reaction of α-imino carbene provided a powerful strategy for heterocycle construction.

Durable and rechargeable antimicrobial cotton driven by enhanced UV stability and real-time detection of biocidal factors.

In this study, graphene oxide/N-halamine nanocomposite was synthesized through Pickering miniemulsion polymerization, which was then coated on cotton surface. The modified cotton exhibited excellent superhydrophobicity, which could effectively prevent microbial infestation and reduce the probability of hydrolysis of active chlorine, with virtually no active chlorine released in water after 72 h. Deposition of reduced graphene oxide nanosheets endowed cotton with ultraviolet-blocking properties, attributing to enhanced UV adsorption and long UV paths. Moreover, encapsulation of polymeric N-halamine resulted in improved UV stability, thus extending the life of N-halamine-based agents. After 24 h of irradiation, 85 % of original biocidal component (active chlorine content) was retained, and approximately 97 % of initial chlorine could be regenerated. Modified cotton has been proven to be an effective oxidizing material against organic pollutants and a potential antimicrobial substance. Inoculated bacteria were completely killed after 1 and 10 min of contact time, respectively. An innovative and simple scheme for determination of active chlorine content was also devised, and real-time inspection of bactericidal activity could be achieved to assure antimicrobial sustainability. Moreover, this method could be utilized to evaluate hazard classification of microbial contamination in different locations, thus broadening the application scope of N-halamine-based cotton fabrics.

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.

Efficacy and safety of combination therapies vs monotherapy of hypomethylating agents in accelerated or blast phase of Philadelphia negative myeloproliferative neoplasms: a systematic review and meta-analysis.

BACKGROUND: There is a lack of evidence regarding whether combination therapy of hypomethylating agents (HMAs) has better outcomes than HMA monotherapy in patients with Philadelphia chromosome-negative accelerated or blast phase myeloproliferative neoplasms (MPN-AP/BP). MATERIALS AND METHODS: Pubmed, Embase, Web of Science and Cochrane library databases were searched for studies from inception of each database until 31 December 2021. Data extraction and synthesis were conducted following the PRISMA reporting guideline. RESULTS: It was found that HMAs plus venetoclax therapy yielded a higher CR/CRi rate than HMAs alone [36% vs 19%, p = .0204] and a higher CR rate than HMAs plus ruxolitinib [22% vs 8%, p = .0313]. HMAs plus ruxolitinib combination showed a higher ORR than HMA monotherapy [45% vs 30%, p = .0395], but there was no improvement in CR/CRi. The one-year and two-year OS rate for patients treated with HMAs plus venetoclx/ruxolitinib demonstrated a trend towards prolonged survival than HMAs alone [HMAs plus venetoclax: 24% vs 11%, p = .1295 and 12% vs 3%, p = .2357; HMAs plus ruxolitinib: 25% vs 11%, p = .0774 and 33% vs 3%, p = .051]. CONCLUSION: It was confirmed that HMA in combination with venetoclax is an effective and well-tolerated option in MPN-AP/BP patients in pre- as well as post-haematopoietic stem cell transplantation settings. HMA plus ruxolitinib therapy was revealed to be effective in patients with MPN-AP.Key MessagesCombination therapy with HMAs and venetoclax/ruxolitinib was associated with improved outcomes than HMAs alone in MPN-AP/BP patients.Further large-scale randomized controlled trials are needed to confirm regarding to the optimal treatment for this patient population.

Clinical and molecular characteristics of forty Chinese children with essential thrombocythemia: A single-center, retrospective analysis.

Due to the infrequency of essential thrombocythemia (ET) in children, little is known about its pathophysiological mechanism. To learn about the clinical and molecular features of Chinese children with ET, we retrospectively analysed 40 children with ET in a single center from 2015-2021. More than half of the children (51.3%, 20/39) were asymptomatic at diagnosis. Nearly half of the children (48.7%, 19/39) had microvascular symptoms, including headache, dizziness, stomachache, and paresthesia. Only two cases experienced vascular events. The proportion of children with typical "driver gene mutations" (i.e., JAK2 p.V617F, CALR exon 9, or MPL exon 10 mutation) was low (12.5%, 5/40). The equivalent ratio of children carried atypical driver gene mutations; however, 30 (75%) patients did not harbour driver gene mutations. Children carrying JAK2 p.V617F had lower platelet count (938 × 109 /L vs. 1654 × 109 /L, p = 0.031) compared to those without driver gene mutations. Cases harbouring typical driver mutations had higher median WBC counts than those without driver gene mutations (15.14 × 109 /L vs. 8.01 × 109 /L, p = 0.015). Compared to those without driver gene mutations, cases carrying typical and atypical driver gene mutations were both younger (median ages were 12, 6, and 7 years old, respectively; p = 0.023). The most prevalent non-driver gene mutations and those mutations with prognostic significance in adult counterparts were less common in children with ET compared to adults with ET.

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.

ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis-mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.

Apart from the central role of the activated JAK/STAT signaling pathway, ASXL1 mutations are the most recurrent additional mutations in myeloproliferative neoplasms and occur much more commonly in myelofibrosis than in essential thrombocythemia and polycythemia vera. However, the mechanism of the association with ASXL1 mutations and bone marrow fibrosis remains unknown. Here, integrating our own data from patients with myeloproliferative neoplasms and a hematopoietic-specific Asxl1 deletion/Jak2V617F mouse model, we show that ASXL1 mutations are associated with advanced myeloproliferative neoplasm phenotypes and onset of myelofibrosis. ASXL1 mutations induce skewed monocyte/macrophage and neoplastic monocyte-derived fibrocyte differentiation, consequently they enhance inflammation and bone marrow fibrosis. Consistently, the loss of ASXL1 and JAK2V617F mutations in hematopoietic stem and progenitor cells leads to enhanced activation of polycomb group target genes, such as EGR1. The upregulation of EGR1, in turn, accounts for increased hematopoietic stem and progenitor cell commitment to the monocyte/macrophage lineage. Moreover, EGR1 induces the activation of TNFA and thereby further drives the differentiation of monocytes to fibrocytes. Accordingly, combined treatment with a TNFR antagonist and ruxolitinib significantly reduces fibrocyte production in vitro. Altogether, these findings demonstrate that ASXL1 mutations accelerate fibrocyte production and inflammation in myeloproliferative neoplasms via the EGR1-TNFA axis, explaining the cellular and molecular basis for bone marrow fibrosis and the proof-ofconcept for anti-fibrosis treatment.

Comparison of the revised 4th (2016) and 5th (2022) editions of the World Health Organization classification of myelodysplastic neoplasms.

We used data from 852 consecutive subjects with myelodysplastic neoplasms (MDS) diagnosed according to the 2016 (revised 4th) World Health Organization (WHO) criteria to evaluate the 2022 (5th) edition WHO classification of MDS. 30 subjects previously classified as MDS with an NPM1 mutation were re-classified as acute myeloid leukaemia (AML). 9 subjects previously classified as MDS-U were re-classified to clonal cytopenia of undetermined significance (CCUS). The remaining 813 subjects were diagnosed as: MDS-5q (N = 11 [1%]), MDS-SF3B1 (N = 70 [9%]), MDS-biTP53 (N = 53 [7%]), MDS-LB (N = 293 [36%]), MDS-h (N = 80 [10%]), MDS-IB1 (N = 161 [20%]), MDS-IB2 (N = 103 [13%]) and MDS-f (N = 42 [5%]) and MDS-biTP53 (N = 53 [7%]). 34 of these subjects came from the 53 (64%) MDS-biTP53 previously diagnosed as MDS-EB. Median survival of subjects classified as MDS using the WHO 2022 criteria was 45 months (95% Confidence Interval [CI], 34, 56 months). Subjects re-classified as MDS-biTP53 and MDS-f had significantly briefer median survivals compared with other MDS sub-types (10 months, [8, 12 months] and 15 months [8, 23 months]). In conclusion, our analyses support the refinements made in the WHO 2022 proposal.

Synthesis of dihydropyrroles from in situ-generated zwitterions via Rh2(adc)4/TBAI dual catalysis.

Triggered by formation of α-imino carbene, the regioselective synthesis of dihydropyrroles was achieved via a cascade 1,3-sulfinate migration/annulation. The sulfinate group was converted into sulfone during the group migration, and a stable anion bearing two electron-withdrawing groups was thus formed. The addition of a catalytic amount of iodide is believed to assist the cleavage of the C-O bond, and the formation of a more stable carbocation. Thermodynamic product dihydropyrroles were produced efficiently rather than kinetic product cyclopropanes. This dual catalysis system would afford chemists a new strategy to control the annulation selectivity of zwitterions bearing multiple reactive sites and may be employed in flexible and divergent synthesis of different ring systems.