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Purpose: The pain threshold index (PTI), a novel index of nociception based on spontaneous EEG wavelet analysis, has been reported to provide reliable accuracy for predicting postoperative pain and hemodynamic reactivity. The present study is aimed to investigate whether PTI-guided analgesia reduces the pain intensity and rate of remedial analgesia in the post-anesthesia care unit (PACU). Methods: A total of 122 females undergoing elective gynecologic surgeries had been randomized to receive either PTI-guided analgesia (PTI group) or standard clinical care (control group). Remifentanil administration in the PTI group was guided by PTI to maintain the value between 40 and 65, while that in the control group was guided by hemodynamic changes. The primary outcome was remedial analgesia rate in the PACU. The postoperative pain scores, intraoperative remifentanil requirements, opioid-related adverse events and perioperative serum stress hormone concentrations between the two groups were also compared. Findings: It was found that 23 of 58 patients (40%) in the control group and 8 of 58 patients (14%) in the PTI group needed remedial analgesia. The relative risk of receiving remedial analgesia was 2.88 (95% CI, 1.40–5.89, P = 0.002) in the control group. Sufentanil consumption in the PACU (μg) was lower in the PTI group (P = 0.002) than in the control group. Remifentanil and propofol consumption, opioid-related adverse events between these two groups were comparable. Implications: PTI-guided analgesia during gynaecologic operations resulted in 25.87% less remedial analgesia. However, studies with different PTI thresholds and larger, more diverse populations should be conducted to further demonstrate the clinical effectiveness of PTI.

Objective: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy. Materials and methods: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015. Results: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in nonprimary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended. Conclusions: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: We have previously reported a cardioprotective effect with Xin-Ji-Er-Kang (XJEK) treatment in mice with myocardial infarction (MI)-induced heart failure, but no report about its potential functions in myocardial ischemia-reperfusion (MIR) injury. Here we studied the therapeutic effects of XJEK on MIR injury and investigated the mechanisms involved.Experimental Approach: MIR model of Balb/c mice induced by left anterior descending coronary artery ligation for half an hour, followed by reperfusion, was utilized to study the potential therapeutic effects of XJEK on MIR-induced cardiac injury. Ultra-performance liquid chromatography tandem Orbitrap mass spectrometry platform was used for studying serum lipid metabolic signatures.Key Results: MIR caused cardiac dysfunctions, cardiac injury, myocardial fibrosis, and increased inflammation, and all the observed abnormalities caused by MIR were largely corrected by XJEK treatment. Mechanistically, XJEK exerts its cardioprotective effect in the context of MIR injury by suppressing MIR-induced inflammation and dysregulation of serum lipid metabolism.Conclusion and Implications: We have demonstrated for the first time that XJEK protects heart from MIR injury by restoring dysregulated lipidomics. Our data provide new evidence to support a therapeutic effect for XIEK on MIR-induced cardiac injury, and pave the way for exploring the therapeutic potential of XJEK in large animal study and early clinical trial.

In this letter, a two-element wide-band patch antenna array with low cross-polarization is presented. The patch is excited by a magnetic-coupled loop. The two elements are placed symmetrically about the center of the array. Compared to the conventional feeding structure, the proposed feeding structure has the advantages of simple structure and much lower cross polarization. Parametric studies show the usefulness of the proposed feeding structure. Prototypes for the element and array have been fabricated and tested. The antenna array can achieve an impedance of 29.1% for VSWR < 2 and a stable gain around 11.2 dBi. Unidirectional radiation patterns with low cross polarization less than -18 dB within the 3-dB beamwidths are obtained. The height of antenna is about 0.12λ (where λ is the free-space wavelength referring to the center frequency of the working band). Moreover, the proposed antenna is dc grounded, which is suitable for outdoor base station applications. [ABSTRACT FROM AUTHOR]

Copper is a trace element necessary for the normal functioning of organisms, but excessive copper contents may be toxic to the heart. The goal of this study was to investigate the role of excessive copper accumulation in mitochondrial damage and cell apoptosis inhibition. In vivo, the heart copper concentration and cardiac troponin I (c-TnI) and N-terminal forebrain natriuretic peptide (NT-pro-BNP) levels increased in the copper-laden model group compared to those of the control group. Histopathological and ultrastructural observations revealed that the myocardial collagen volume fraction (CVF), perivascular collagen area (PVCA) and cardiomyocyte cross-sectional area (CSA) were markedly elevated in the copper-laden model group compared with the control group. Furthermore, transmission electron microscopy (TEM) showed that the mitochondrial double-layer membrane was incomplete in the copper-laden model groups. Furthermore, cytochrome C (Cyt-C) expression was downregulated in mitochondria but upregulated in the cytoplasm in response to copper accumulation. In addition, Bcl-2 expression decreased, while Bax and cleaved caspase-3 levels increased. These results indicate that copper accumulation in cardiomyocyte mitochondria induces mitochondrial injury, and Cyt-C exposure and induces apoptosis, further resulting in heart damage.

IntroductionPost-operative delirium (POD) is a serious complication which occurs after surgery, especially in the elderly undergoing abdominal surgery. Increasing evidence has revealed an association between the gut microbiota and psychological disorders involving the “brain-gut” axis. However, the association between the pathogenesis of POD after abdominal surgery in aging and composition of the gut microbiota remains unclear.MethodsForty patients (≥65 years old) who underwent abdominal surgery were included in the study. Twenty patients had POD, whereas 20 patients did not. POD was diagnosed and assessed using the confusion assessment method (CAM) during the postoperative period. Total DNA fractions were extracted from all fecal samples of patients. 16S rRNA sequencing was performed to determine the composition of the gut microbiota. The quality of the samples was determined by calculating the α- and β-diversities.ResultsThe α- and β-diversities indicated that the samples were eligible for detection and comparison. We observed multiple differentially abundant bacteria in patients with and without POD. Generally, Proteobacteria, Enterbacteriaceae, Escherichia shigella, Klebsiella, Ruminococcus, Roseburia, Blautia, Holdemanella, Anaerostipes, Burkholderiaceae, Peptococcus, Lactobacillus, and Dorea were abundant in the POD cohort, whereas Streptococcus equinus and Blautia hominis were abundant in the control cohort. The results of receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of Escherichia shigella was 0.75. Phenotype prediction showed that the gut microbiota may influence POD by altering the tolerance to oxidative stress.ConclusionThere were significant associations between the pathogenesis of POD and composition of the gut microbiota. Escherichia shigella are promising diagnostic bacterial species for predicting POD onset after abdominal surgery in elderly people.Clinical Trial Registrationhttp://www.chictr.org.cn/index.aspx, Chinese Clinical Trial Registry ChiCTR200030131.

Abundant evidence indicates that propofol profoundly affects memory processes, although its specific effects on memory retrieval have not been clarified. A recent study has indicated that hippocampal glycogen synthase kinase-3β (GSK-3β) activity affects memory. Constitutively active GSK-3β is required for memory retrieval, and propofol has been shown to inhibit GSK-3β. Thus, the present study examined whether propofol affects memory retrieval, and, if so, whether that effect is mediated through altered GSK-3β activity. Adult Sprague-Dawley rats were trained on a Morris water maze task (eight acquisition trials in one session) and subjected under the influence of a subhypnotic dose of propofol to a 24-hour probe trial memory retrieval test. The results showed that rats receiving pretest propofol (25 mg/kg) spent significantly less time in the target quadrant but showed no change in locomotor activity compared with those in the control group. Memory retrieval was accompanied by reduced phosphorylation of the serine-9 residue of GSK-3β in the hippocampus, whereas phosphorylation of the tyrosine-216 residue was unaffected. However, propofol blocked this retrieval-associated serine-9 phosphorylation. These findings suggest that subhypnotic propofol administration impairs memory retrieval and that the amnestic effects of propofol may be mediated by attenuated GSK-3β signaling in the hippocampus.

A diode-side-pumped, high-energy, high-beam-quality, pulsed solid-state Nd3+:Y3Al5O12 (Nd:YAG) laser with a thermoelectric cooler (TEC) is investigated in this study. The pump laser was a pulsed laser diode array with maximum peak power of 15 kW. A 350 mJ laser pulse was obtained with a wavelength of 1064 nm, a pulse duration of 10 ns, a total electrical-to-optical efficiency of 7.5%, a relative stability of output energy of 5%, and a beam quality of M2 < 4.

Fault-slip rock burst is one type of the tectonic rock burst during mining. A detailed understanding of the precursory information of fault-slip rock burst and implementation of monitoring and early warning systems, as well as pressure relief measures, are essential to safety production in deep mines. This paper first establishes a mechanical model of stick-slip instability in fault-slip rock bursts and then reveals the failure characteristics of the instability. Then, change rule of mining-induced stress and microseismic signals before the occurrence of fault-slip rock burst are proposed, and multiparameter integrated early warning methods including mining-induced stress and energy are established. Finally, pressure relief methods targeting large-diameter boreholes and coal seam infusion are presented in accordance with the occurrence mechanism of fault-slip rock burst. The research results have been successfully applied in working faces 2310 of the Suncun Coal Mine, and the safety of the mine has been enhanced. These research results improve the theory of fault-slip rock burst mechanisms and provide the basis for prediction and forecasting, as well as pressure relief, of fault-slip rock bursts.

Oxadiazon (ODZ) is extensively utilized in agricultural fields for weed control owing to its strong effectiveness. However, excessive loading of ODZ in water bodies and agricultural soils can lead to various environmental concerns. Therefore, it is crucial to understand the ODZ metabolic process and associated mechanisms in crops to assess the likelihood of ODZ contamination in the environment. This study aimed to assess the effects of ODZ on the growth and toxicological responses of rice (Oryza sativa). The growth of rice tissues was notably compromised with the increase in ODZ concentrations. RNA sequencing in combination with liquid chromatography–quadrupole-time-of-flight–high-resolution mass spectrometry/mass spectrometry (LC–Q-TOF–HRMS/MS) analysis allowed for the identification of numerous transcriptional components associated with ODZ metabolism. Four libraries comprising rice roots and shoots exposed to ODZ were RNA-sequenced in triplicate. The application of environmentally realistic ODZ concentrations upregulated the expression of 844 genes in shoots and 1476 genes in roots. Gene enrichment analysis revealed the presence of multiple enzymes involved in ODZ metabolism and detoxification. These enzymes play a critical role in mitigating environmental stress and facilitating xenobiotic metabolism. Notably, among differentially expressed genes, several key enzymes were identified, including cytochrome P450s, protein kinases, aminotransferases, and ATP-binding cassette transporters involved in the metabolic process. Using LC–Q-TOF–HRMS/MS, 3 metabolites and 13 conjugates were identified in multiple metabolic pathways involving oxidation, hydrolysis, glycosylation, acetylation, and methylation. This study successfully established a potential link between the specific metabolic products of ODZ and increased activities of their corresponding enzymes. Moreover, this study considerably elucidates the detailed pathways and mechanisms involved in ODZ metabolism. The study findings provide valuable insights into the development of genotypes for reducing ODZ residues in paddy fields and minimizing their accumulation in rice crops.

RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML- RUNX1 mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML- RUNX1 mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1 mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P ＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P =0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P =0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1 mut was not an independent prognostic factor for OS (HR=1.352, P =0.068) or EFS (HR=1.129, P =0.513). When patients were stratified according to induction regimen, RUNX1 mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1 mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1 mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1 , which merits a larger prospective cohort to illustrate. • RUNX1 mutations were rarely isolated genetic abnormities. • Prognostic value of RUNX1 mutation in AML was influenced by the treatment type. • RUNX1 mutation was not an independent prognostic factor for survival. [ABSTRACT FROM AUTHOR]

Relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) are frequently aggressive and associated with unfavorable prognoses. Pan-targeted Chimeric Antigen Receptor (CAR) T-cell therapy have shown promising results in clinical trials. In recent years, CD7 CAR T-cell and CD5 CAR T-cell demonstrate effectiveness in treating r/r T-ALL/LBL patients with bone marrow infiltration. However, nearly half of r/r T-ALL/T-LBL patients are accompanied by extramedullary disease (EMD), where comprehensive data on the efficacy and safety of CAR T-cell therapy remain limited. Additionally, CD7 CAR T-cell and CD5 CAR T-cell therapy can cause severe immunodeficiency and hematologic toxicity, complicating with difficult immune reconstitution. This review provides an in-depth analysis of the safety profile and adverse events associated with CAR T-cell therapy in r/r T-ALL/LBL, with a a particular emphasis on its impact in patients with EMD., Competing Interests: Declarations. Ethical approval: Not applicable. Competing interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk myelodysplastic syndrome (HR MDS) patients. However, the management of patients with relapsed disease post allo-HSCT remains a challenge with few standard treatments. Chidamide, a new selective histone deacetylase, has shown synergistic anti-leukemia effect combined with azacitidine in acute myeloid leukemia patients. Herein, we reported a 50-year-old HR MDS patient who experienced molecular relapse post allo-HSCT and was successfully salvaged by preemptive treatment of chidamide combined with azacitidine (CHI-AZA). This patient maintained a deep remission lasting over 2 years by regular maintenance treatment of CHI-AZA, without sever treatment-related adverse events or increased risk of graft versus host disease. This case report demonstrated that double epigenetic regimen of CHI-AZA was effective and tolerable. Formally evaluating this regimen in HR MDS patients post allo-HSCT may be meaningful., Competing Interests: Declarations. Ethics approval: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University. The patient has provided written informed consent for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group ( p  = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 ( p  = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 ( p  = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 ( p  = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 ( p  = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare no conflict of interest.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a similar gene expression profile to Philadelphia chromosome-positive (Ph+) ALL, but is highly heterogeneous in terms of genomic alterations. Approximately 10-20% of patients with Ph-like ALL harbor ABL class (e.g. ABL1, ABL2, PDGFRB, and CSF1R) rearrangements. Additional genes that form fusion genes with ABL class genes are still being researched. These aberrations result from rearrangements including chromosome translocations or deletions and may be targets of tyrosine kinase inhibitors (TKIs). However, due to the heterogeneity and rarity of each fusion gene in clinical practice, there is limited data on the efficacy of tyrosine kinase inhibitors. Here, we report three cases of Ph-like B-ALL with ABL1 rearrangements treated with the dasatinib backbone for the CNTRL::ABL1, LSM14A::ABL1, and FOXP1::ABL1 fusion genes. All three patients achieved rapid and profound remission with no significant adverse events. Our findings suggest that dasatinib is a potent TKI for the treatment of ABL1-rearranged Ph-like ALL and can be used as a first-line treatment option for such patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

T cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is an aggressive malignancy of progenitor T cells. Despite significant improvements in survival of T-ALL/LBL over the past decades, treatment of relapsed and refractory T-ALL (R/R T-ALL/LBL) remains extremely challenging. The prognosis of R/R T-ALL/LBL patients who are intolerant to intensive chemotherapy remains poor. Therefore, innovative approaches are needed to further improve the survival of R/R T-ALL/LBL patients. With the widespread use of next-generation sequencing in T-ALL/LBL, a range of new therapeutic targets such as NOTCH1 inhibitors, JAK-STAT inhibitors, and tyrosine kinase inhibitors have been identified. These findings led to pre-clinical studies and clinical trials of molecular targeted therapy in T-ALL/LBL. Furthermore, immunotherapies such as CD7 CAR T cell therapy and CD5 CAR T cell therapy have shown profound response rate in R/R T-ALL/LBL. Here, we review the progress of targeted therapies and immunotherapies for T-ALL/LBL, and look at the future directions and challenges for the further use of these therapies in T-ALL/LBL., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Despite approval of B-cell lymphoma (BCL)-2 inhibitor venetoclax for certain hematologic malignancies, its broader clinical benefit is curtailed by resistance. Our study aimed to determine if treatment with novel anticancer agents targeting BCL-2 and mouse double minute 2 (MDM2) could overcome venetoclax resistance in preclinical models., Experimental Design: Venetoclax-sensitive and venetoclax-resistant acute myeloid leukemia (AML) and acute lymphoblastic leukemia cells and xenograft models were used to evaluate antitumor effects and underlying mechanisms associated with combined BCL-2 inhibitor lisaftoclax (APG-2575) and MDM2 inhibitor alrizomadlin (APG-115)., Results: The combination exhibited synergistic antiproliferative and apoptogenic activities in TP53 wild-type AML cell lines in vitro. This synergy was further exemplified by deep antitumor responses and prolonged survival in AML cell line-derived and patient-derived xenograft models. Interestingly, the combination treatment resensitized (to apoptosis) venetoclax-resistant cellular and mouse models established via chronic drug exposure or genetically engineered with clinically relevant BCL-2 gene mutations. Synergistic effects in reducing cellular viability and proliferation were also demonstrated in primary samples of patients with venetoclax-resistant AML treated with lisaftoclax and alrizomadlin ex vivo. Mechanistically, alrizomadlin likely primes cancer cells to BCL-2 inhibition-induced cellular apoptosis by downregulating expression of antiapoptotic proteins myeloid cell leukemia-1 and BCL-extra-large and upregulating pro-death BCL-2-associated X protein., Conclusions: Lisaftoclax in combination with alrizomadlin overcomes venetoclax resistance mediated by various mechanisms, including BCL-2 mutations. In addition, we posit further, putative molecular mechanisms. Our data rationalize clinical development of this treatment combination in patients with diseases that are insensitive or resistant to venetoclax., (©2022 American Association for Cancer Research.)

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL., (© 2022 Wiley Periodicals LLC.)

The complete remission (CR) rate and overall survival (OS) of relapsed/refractory (R/R) B-cell acute lymphoblastic leukaemia (B-ALL) are not satisfactory. The available salvage regimens include standard chemotherapy, inotuzumab ozogamicin, blinatumomab and cluster of differentiation (CD)19 chimeric antigen receptor T cells (CAR T), and the NCCN guidelines recommend all of these therapies with no preference. Dual CD19/CD22 CAR T-cells have emerged as new treatments and have shown some efficacy, with high CR rates and preventing CD19-negative relapse. However, direct comparisons of the CR rate and long-term survival among the different salvage therapies are lacking. Databases including PubMed, Embase, Web of Science and Cochrane were searched from inception to January 31, 2022, for relevant studies. The outcomes of interest were complete remission/complete remission with incomplete haematologic recovery (CR/CRi) rates and 1-year overall survival (OS) rates. Odds ratios (ORs) were generated for binary outcomes, and the mean difference (MD) was generated for consecutive outcomes by network meta-analysis. CD19 CAR T-cells demonstrated a significantly better effect in improving the CR/CRi rate than blinatumomab (OR = 8.32, 95% CI: 1.18 to 58.44) and chemotherapy (OR = 16.4, 95% CI: 2.76 to 97.45). In terms of OS, CD19 CAR T-cells and dual CD19/CD22 CAR T-cells both had a higher 1-year OS rate than blinatumomab, inotuzumab ozogamicin and chemotherapy. There was no significant difference between CD19 CAR T-cells and dual CD19/CD22 CAR T-cells in terms of 1-year OS and CR/CRi rates. CD19 CAR T-cells are effective in inducing CR, and CD19 CAR T-cells and dual CD19/CD22 CAR T-cells show benefits for overall survival. More high-quality randomized controlled trials and longer follow-ups are needed to confirm and update the results of this analysis in the future., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare the clinical efficacy and safety of hypomenthylating agents (HMA) combined with Venetoclax (VEN) and half dose priming regimen (CAG-like) in the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy., Methods: The clinical data of 43 newly diagnosed elderly patients with AML who were not suitable for intensive chemotherapy in our hospital from April 2019 to October 2020 were retrospectively analyzed. Among them, 16 cases received HMA-VEN regimen and 27 cases received HMA-CAG-like regimen. The remission rate, early mortality and survival were compared between the two groups. And, the patients were grouped according to HCT-CI score. The effects of two different regimens in different groups on the efficacy and survival of patients were compared, and the prognosis of patients was further analyzed., Results: After one course of treatment, the total remission rate of HMA-VEN group and HMA-CAG-like group was 81.3% (13/16) and 51.9% (14/27), respectively, and the difference between the two groups was statistically significant (χ2=4.650, P =0.045). The median overall survival (OS) time of HMA-VEN group had not yet reached, while that of HMA-CAG-like group was 11.2 months, and the HMA-VEN group had a longer OS ( P =0.055). There was no tumor lysis syndrome occurred in both groups. The main adverse reactions were digestive tract reaction, bone marrow suppression and infection. The amount of agranulocytosis infection, pulmonary infection and platelet infusion in HMA-VEN group were significantly lower than those in HMA-CAG-like group ( P <0.05), while the time of agranulocytosis and amount of erythrocyte infusion were similar ( P >0.05). In HMA-Ven group 1 case died early, while in HMA-CAG-like group 8 cases died early due to pulmonary infection, respiratory failure, cerebral hemorrhage, and alveolar hemorrhage, the mortality in HMA-CAG-like group was significantly higher than that in HMA-VEN group ( P =0.043). Among 43 patients, there was a significant difference in OS between HCT score 0-2 group and ≥3 group ( P =0.033). In HMA-CAG-like group, patients with HCT score ≥3 had a worse prognosis ( P =0.01), while in HMA-VEN group patients showed no statistically significant difference in prognosis ( P =0.681). In HCT score 0-2 group, 9 cases receiving HMA-VEN regimen and 22 cases receiving HMA-CAG-like regimen showed no statistical difference in OS ( P =0.281). In HCT score ≥3 group, 7 cases receiving HMA-VEN regimen had a longer OS than 5 cases receiving HMA-CAG-like regimen ( P =0.015)., Conclusion: Venetoclax combined with HMA can achieve higher response rate, lower early mortality, and longer OS, especially in those with more comorbidities and poor tolerability.