Acute myeloid leukemia (AML) with t(16;21)(p11;q22)/FUS::ERG is a rare AML subtype associated with poor prognosis. However, its clinical and molecular features remain poorly defined. We determined the clinicopathological, genomic, and transcriptomic characteristics and outcomes of patients with AML harboring FUS::ERG at our center. Thirty-six AML patients harboring FUS::ERG were identified, with an incidence rate of 0.3%. These patients were characterized by high lactate dehydrogenase levels (median: 838.5 U/L), elevated bone marrow blast counts (median: 71.5%), and a CD56-positive immunophenotype (94.3%). Notably, we found that RTK-RAS GTPase (RAS) pathway genes, including NRAS (33%) and PTPN11 (24%), were frequently mutated in this subtype. Transcriptome analysis revealed enrichment of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt), mitogen-activated protein kinase (MAPK), and RAS signaling pathways and upregulation of BCL2, the target of venetoclax, in FUS::ERG AML compared to RUNX1::RUNX1T1 AML, a more common AML subtype with good prognosis. The median event-free survival in patients with FUS::ERG AML was 11.9 (95% confidence interval [CI]: 9.0-not available [NA]) months and the median overall survival was 18.2 (95% CI: 12.4-NA) months. Allogeneic hematopoietic stem cell transplantation failed to improve outcomes. Overall, the high incidence of RTK-RAS pathway mutations and high expression of BCL2 may indicate promising therapeutic targets in this high-risk AML subset.
Introduction: For acute myeloid leukemia (AML), prognosis is particularly poor in patients harboring FMS-like tyrosine kinase 3 (FLT3) gene mutations, though routine screening for these mutations at diagnosis has been shown to be insufficient. The understanding of the impact of FLT3 mutations on treatment decisions is limited. Methods: In this retrospective, observational study, we investigated the key epidemiological characteristics, treatment patterns and responses among adult patients with newly diagnosed (ND) AML in China, who initiated treatment from January 1, 2015, to December 31, 2019, or progressed to relapsed/refractory (R/R) AML by December 31, 2020. Results: Of the 853 ND AML patients included, 63.4% were screened for FLT3 status, and 20.1% tested positive (FLT3MUT) at initial diagnosis. Of 289 patients who progressed to R/R AML during the study period, 24.9% were screened at the diagnosis of R/R AML, and 19.4% tested positive; 20.5% of screened patients changed FLT3 status at first diagnosis of R/R AML. Initial treatment regimens or treatment responses did not seem to differ in patients with ND AML by FLT3 mutation status. In patients with R/R AML, there was an apparent difference in second-line treatment choices by FLT3 mutation status; however, the number of FLT3-mutated patients were limited to demonstrate any meaningful distinction. FLT3-mutated R/R AML was associated with shorter relapse time. Conclusion: Study findings showed that there was a lack of routine testing for FLT3 mutations at first diagnosis of R/R AML, and initial treatment decisions did not differ by FLT3 mutation status. Given the clinical burden of FLT3MUT, likelihood of FLT3 status changes, and emerging FLT3 inhibitors, further routine FLT3 screening is needed to optimize treatment of R/R AML.
Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.
MultiCal is an affordable, high-precision measuring device designed for the on-site calibration of industrial robots. Its design features a long measuring rod with a spherical tip that is attached to the robot. By restricting the rod's tip to multiple fixed points under different rod orientations, the relative positions of these points are accurately measured beforehand. A common issue with MultiCal is the gravitational deformation of the long measuring rod, which introduces measurement errors into the system. This problem becomes especially serious when calibrating large robots, as the length of the measuring rod needs to be increased to enable the robot to move in a sufficient space. To address this issue, we propose two improvements in this paper. Firstly, we suggest the use of a new design of the measuring rod that is lightweight yet has high rigidity. Secondly, we propose a deformation compensation algorithm. Experimental results have shown that the new measuring rod improves calibration accuracy from 20% to 39%, while using the deformation compensation algorithm, the accuracy increases from 6% to 16%. In the best configuration, the calibration accuracy is similar to that of a measuring arm with a laser scanner, producing an average positioning error of 0.274 mm and a maximum positioning error of 0.838 mm. The improved design is cost-affordable, robust, and has sufficient accuracy, making MultiCal a more reliable tool for industrial robot calibration.
Robotics , Calibration , Algorithms
Isodesmic reactions represent mild alternatives to other chemical transformations that require harsh oxidizing agents or highly reactive intermediates. However, enantioselective isodesmic C-H functionalization is unknown and enantioselective direct iodination of inert C-H bond is very rare. Rapid synthesis of chiral aromatic iodides is of significant importance for synthetic chemistry. Herein, we report an unprecedented highly enantioselective isodesmic C-H functionalization to access chiral iodinated phenylacetic Weinreb amides via desymmetrization and kinetic resolution with PdII catalysis. Importantly, further transformations of the enantioenriched products are readily available at the iodinated or the Weinreb amide position, paving the way of related studies for synthetic and medicinal chemists.
In this work, a series of CuCo2O4-x (x = N, A and C) catalysts were synthesized using different metal salt precursors by urea hydrothermal method for catalytic soot combustion. The effect of CuCo2O4-x catalysts on soot conversion and CO2 selectivity in both loose and tight contact mode was investigated. The CuCo2O4-N catalyst exhibited outstanding catalytic activity with the characteristic temperatures (T10, T50 and T90) of 451 °C, 520 °C and 558 °C, respectively, while the CO2 selectivity reached 98.8% during the reaction. With the addition of NO, the soot combustion was further accelerated over all catalysts. Compared with the loose contact mode, the soot conversion was improved in the tight contact mode. The CuCo2O4-N catalysts showed better textural properties compared to the CuCo2O4-A and CuCo2O4-C, such as higher specific surface areas and pore volumes. The XRD results confirmed that the formation of a CuCo2O4 crystal phase in all catalysts. However, the CuO crystal phase only presented in CuCo2O4-N and CuCo2O4-A. The relative contents of Cu2+, Co3+ and Oads on the surface of CuCo2O4-x (x = N, A and C) catalysts were analyzed by XPS. The CuCo2O4-N catalyst displayed the highest relative content of Cu2+, Co3+ and Oads. The activity of catalytic soot combustion showed a good correlation with the order of the relative contents of Cu2+, Co3+ and Oads. Additionally, the CuCo2O4-N catalyst exhibited lower reduction temperature compared to the CuCo2O4-A and CuCo2O4-C. The cycle tests clarified that the copper-cobalt spinel catalyst obtained good stability. In addition, based on the Mars-van Krevelen mechanism, the process of catalytic soot combustion was described combined with the electron transfer process and the role of oxygen species over CuCo2O4 spinel catalysts.
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Salvage Therapy , Humans , Retrospective Studies , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Remission Induction
The classic electrophilic bromination leads to ortho- and para-bromination of anilines due to their electron-rich properties. Herein we report the development of an unprecedented Pd-catalyzed meta-C-H bromination of aniline derivatives using commercially available N-bromophthalimide (NBP), which overcomes the competing ortho/para-selectivity of electrophilic bromination of anilines. The addition of acid additives is crucial for the success of this reaction. A broad range of substrates with various substitution patterns can be tolerated in this reaction. Moreover, benzoic acid derivatives bearing complex substitution patterns are also viable with this mild bromination reaction, and meta-C-H chlorination is also feasible under similar reaction conditions. The ease of the directing group removal and subsequent diverse transformations of the brominated products demonstrate the application potential of this method and promise new opportunities for drug discovery.
C-H functionalization via functional group metathesis is extremely rare. A protocol of remote site-selective C-H iodination of 2-aryl benzoic acid derivatives via formal C(sp2)-H/C(sp2)-I metathesis using readily available 1-iodo-4-methoxy-2-nitrobenzene as the mild iodinating reagent was reported herein. A range of 2-aryl benzoic acid derivatives including 2-(naphthalen-1-yl)benzoic acids and [1,1'-binaphthalene]-2-carboxylic acids were iodinated under mild conditions to give valuable iodinated products in a site- and chemo-selective fashion.
Benzoic Acid , Halogenation , Benzoates , Catalysis , Iodides
BACKGROUND: Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). For years, RARA, RARB and RARG rearrangement were found in resembling APL continually. The confirmed partner genes of RARG rearrangement included CPSF6, NUP98, NPM1, PML, and HNRNPC. These patients were a group of resembling APL with rare molecular genetic abnormality and unfavorable prognosis. They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy. CASE PRESENTATION: We reported a 25-year-old female patient with a novel fusion gene RARG-HNRNPM (RARG chr12:53606869: -; HNRNPM chr19: 8527413: + based on GRCh37/hg19 Assembly) through RNA-seq as resembling APL. The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse. DISCUSSION AND CONCLUSIONS: RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.
Arsenicals , Leukemia, Promyelocytic, Acute , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/therapeutic use , Chromosome Aberrations , Female , Gene Fusion , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Humans , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Oxides , Tretinoin/therapeutic use
The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p < 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.
CCAAT-Enhancer-Binding Protein-alpha , Leukemia, Myeloid, Acute , CCAAT-Enhancer-Binding Protein-alpha/genetics , CCAAT-Enhancer-Binding Proteins/genetics , Cytarabine/therapeutic use , Homoharringtonine , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Neoplasm Recurrence, Local , Prognosis , Receptors, Colony-Stimulating Factor , Retrospective Studies
The use of a native directing group to promote C-H activation is highly desirable. Herein, we report a method of native carboxyl-assisted, Pd(II)-catalyzed ortho-C-H acetoxylation of both hydrocinnamic and phenylacetic acids that can be found in many biologically active molecules as the key moieties. Based on the broad scope and the application potential showcased with drug molecules, it is anticipated that this C-H acetoxylation reaction will find attractive applicability in future synthetic endeavors.
Palladium , Phenylacetates , Catalysis
Acute leukemias of ambiguous lineage, not otherwise specified (ALAL-NOS) is a rare type of acute leukemia. Management of relapse/refractory (R/R) patients is still challenging.traditional chemotherapy treatment is not effective. In this paper, we reported 6 R/R patients diagnosed as ALAL-NOS in our hospital, who were treated with venetoclax based treatment (venetoclax combining with azacitidine or chemotherapy). All 6 patients achieved CR. Five of the six patients received allo-HSCT, four patients were still alive in CR until the follow-up day. Our data provide preliminary evidence and show that venetoclax based regimens are effective and safety in patients with R/R ALAL-NOS.
Intra-operative target pose estimation is fundamental in minimally invasive surgery (MIS) to guiding surgical robots. This task can be fulfilled by the 2-D/3-D rigid registration, which aligns the anatomical structures between intra-operative 2-D fluoroscopy and the pre-operative 3-D computed tomography (CT) with annotated target information. Although this technique has been researched for decades, it is still challenging to achieve accuracy, robustness and efficiency simultaneously. In this paper, a novel orthogonal-view 2-D/3-D rigid registration framework is proposed which combines the dense reconstruction based on deep learning and the GPU-accelerated 3-D/3-D rigid registration. First, we employ the X2CT-GAN to reconstruct a target CT from two orthogonal fluoroscopy images. After that, the generated target CT and pre-operative CT are input into the 3-D/3-D rigid registration part, which potentially needs a few iterations to converge the global optima. For further efficiency improvement, we make the 3-D/3-D registration algorithm parallel and apply a GPU to accelerate this part. For evaluation, a novel tool is employed to preprocess the public head CT dataset CQ500 and a CT-DRR dataset is presented as the benchmark. The proposed method achieves 1.65 ± 1.41 mm in mean target registration error(mTRE), 20% in the gross failure rate(GFR) and 1.8 s in running time. Our method outperforms the state-of-the-art methods in most test cases. It is promising to apply the proposed method in localization and nano manipulation of micro surgical robot for highly precise MIS.
PURPOSE: Dasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood-brain barrier in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). METHODS: Plasma and cerebrospinal fluid (CSF) samples collected from Ph+ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay. FINDINGS: Orally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF. IMPLICATIONS: Based on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. ClinicalTrials.gov identifier: NCT02523976.
Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Blood-Brain Barrier , Chromatography, Liquid , Dasatinib , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors , Tandem Mass Spectrometry
Although pediatric-like treatment regimen has remarkably improved the survival rates of adults with acute lymphoblastic leukemia (ALL), the outcome of some adult patients is still poor owing to adverse genetic features. These molecular abnormalities, especially gene deletions, may be considered for the prognosis assessment for adult patients with ALL. In this study, using multiplex ligation-dependent probe amplification (MLPA) method, gene deletions were analyzed in from 211 adult B-ALL patients treated in our center. The data showed that 68.2% (144/211) adult B-ALL patients carried gene deletions, and the frequency is much higher in Ph+B-ALL patients. IKZF1 gene deletion is the most common gene deletion in adult B-ALL, followed by CDKN2A/B deletion. In Ph-B-ALL patients, the overall survival of patients with gene deletions is inferior to that of patients without any gene deletions. More obviously, patients with IKZF1 or CDKN2A/B deletion had a worse prognosis, whereas, allogeneic hematopoietic stem cell transplantation could improve OS in patients with IKZF1 deletion, but not in patients with CDKN2A/B deletion. Moreover, the outcome of Ph-B-ALL patients with double deletion of IKZF1and CDKN2A/B may be much worse than that of patients with IKZF1 or CDKN2A/B alone. Minimal residual disease (MRD) was also analyzed together with gene deletions and demonstrated that gene deletions have a negative impact on survival only in MRD positive Ph-B-ALL patients. In conclusion, gene deletions are closely related with the prognosis of adult Ph-B-ALL patients.
In this work, an integrated system combining non-thermal plasma (NTP) and FeMn catalysts was developed for ethylene oxide (EO) oxidation. The effect of Fe/Mn molar ratio on the oxidation rate of EO and energy yield of the plasma-catalytic process has been investigated as a function of specific energy density (SED). Compared with the case of using plasma alone, the combination of plasma and FeMn catalysts greatly enhanced the reaction performance by the factor of 25.2% to 97.6%. The maximum oxidation rate of 98.8% was achieved when Fe1Mn1 catalyst was placed in the dielectric barrier discharge (DBD) reactor at the SED of 656.1 J·L-1. The highest energy yield of 2.82 g·kWh-1 was obtained at the SED of 323.2 J·L-1 over the Fe1Mn1 catalyst. The interactions between Fe and Mn species resulted in larger specific surface area of the catalyst. Moreover, the reducibility of the catalysts was improved, while more surface adsorbed oxygen (Oads) was detected on the catalyst surfaces. Moreover, the redox cycles between Fe and Mn species facilitated consumption and supplementation of reactive oxygen species, which contributed to the plasma-catalytic oxidation reactions. The major reaction products of plasma-induced EO oxidation over the FeMn catalysts, including CH3COOH, CH3CHO, CH4, C2H6 and C2H4, were observed using the FT-IR analyzer and GC-MS instrument. The reaction mechanisms of EO oxidation were discussed in terms of both gas-phase reaction and catalyst surface reaction. The redox cycles between Fe and Mn species facilitated the plasma reaction and accelerated the deep oxidation of by-products.
Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1. The objectives of our study were to quantitatively compare the predictive value of MRD reduction and absolute copies and assess the influence of other prognostic factors on MRD. A total of 224 consecutive patients with RUNX1-RUNX1T1 aged ≤55 years were included in the MRD study. Patients received different induction regimens including conventional- or intermediate-dose cytarabine plus low-dose daunorubicin and omacetaxine mepesuccinate or daunorubicin at 60 mg/m2/day on days 1-3. As continuous variables, both MRD reduction and absolute MRD level were significantly associated with cumulative incidence of relapse (CIR; hazard ratio [HR]â¯=â¯1.610, 95% confidence interval [CI]: 1.370-1.890, p < 0.001, and HRâ¯=â¯1.170, 95% CI: 1.120-1.230, p < 0.001, respectively). For the CIR, the area under the curves (AUCs) of MRD reduction and absolute MRD level after the first consolidation chemotherapy were 0.629 and 0.629, respectively. Intermediate-dose cytarabine induction (HRâ¯=â¯0.494; pâ¯=â¯0.039 for CIR, HR, 0.451; pâ¯=â¯0.014 for RFS, and HR, 0.262; pâ¯=â¯0.006 for OS) remained significantly associated with outcomes after adjusting for MRD reduction after the first consolidation therapy (HRâ¯=â¯1.456, p < 0.001, for CIR; HRâ¯=â¯1.467, pâ¯=â¯0.001, for relapse-free survival; and HRâ¯=â¯1.468, pâ¯=â¯0.014, for overall survival) in multivariate analyses. In conclusion, the prognostic significance of MRD after the first consolidation therapy was influenced by the induction regimen in acute myeloid leukemia with RUNX1-RUNX1T1.
Core Binding Factor Alpha 2 Subunit/genetics , Leukemia, Myeloid, Acute/diagnosis , Neoplasm, Residual/diagnosis , RUNX1 Translocation Partner 1 Protein/genetics , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/therapeutic use , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Neoplasm, Residual/drug therapy , Neoplasm, Residual/genetics , Oncogene Proteins, Fusion/genetics , Prognosis , Young Adult
Sesarmops sinensis is a dominant omnivorous crab species, which plays an important ecological function in salt marsh ecosystems. To better understand its immune system and immune related genes under pathogen infection, the transcriptome was analyzed by comparing the data of S. sinensis hepatopancreas stimulated by PBS and PGN. A set of assembly and annotation identified 39,039 unigenes with an average length of 1105 bp, obtaining 1300 differentially expressed genes (DEGs) in all, which included 466 remarkably up-regulated unigenes and 834 remarkably down-regulated unigenes. In addition, based on mensurable real time-polymerase chain reaction and high-throughput sequencing, several immune responsive genes were found to be markedly up-regulated under PGN stimulation. In conclusion, in addition to enriching the existing transcriptome data of S. sinensis, this study also clarified the immune response of S. sinensis to PGN stimulation, which will help us to further understand the crustacean's immune system.
Brachyura , Hepatopancreas , Animals , Brachyura/genetics , Ecosystem , Gene Expression Profiling , Peptidoglycan/genetics , Transcriptome
Mitochondrial genomes (mitogenomes) are important for understanding molecular evolution and phylogenetic relationships. The complete mitogenome of Perisesarma bidens was determined, which is 15,641 bp in length. The A + T content of P. bidens mitogenome was 74.81%. The AT skew was slightly negative (-0.021). The 22 tRNAs ranged from 65 to 73 bp and were highly A + T biased. All tRNA genes had typical cloverleaf structures, except for the trnS1 gene, which lacked a dihydrouridine (DHU) arm. The gene order within the P. bidens mitogenome was identical to the pancrustacean ground pattern, except for the translocation of the trnH. Additionally, the gene order of trnI-trnQ-trnM in pancrustacean ground pattern became trnQ-trnI-trnM in P. bidens. Phylogenetic analyses supported the inclusion of P. bidens in Sesarmidae and the promotion of Sesarminae to Sesarmidae. The results will help us to better understand the status and evolutionary history of Grapsoidea crabs.
