Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

Targeted disruption of the BCR-ABL fusion gene by Cas9/dual-sgRNA inhibits proliferation and induces apoptosis in chronic myeloid leukemia cells.

The BCR-ABL fusion gene, formed by the fusion of the breakpoint cluster region protein ( BCR) and the Abl Oncogene 1, Receptor Tyrosine Kinase ( ABL) genes, encodes the BCR-ABL oncoprotein, which plays a crucial role in leukemogenesis. Current therapies have limited efficacy in patients with chronic myeloid leukemia (CML) because of drug resistance or disease relapse. Identification of novel strategies to treat CML is essential. This study aims to explore the efficiency of novel CRISPR-associated protein 9 (Cas9)/dual-single guide RNA (sgRNA)-mediated disruption of the BCR-ABL fusion gene by targeting BCR and cABL introns. A co-expression vector for Cas9 green fluorescent protein (GFP)/dual-BA-sgRNA targeting BCR and cABL introns is constructed to produce lentivirus to affect BCR-ABL expression in CML cells. The effects of dual-sgRNA virus-mediated disruption of BCR-ABL are analyzed via the use of a genomic sequence and at the protein expression level. Cell proliferation, cell clonogenic ability, and cell apoptosis are assessed after dual sgRNA virus infection, and phosphorylated BCR-ABL and its downstream signaling molecules are detected. These effects are further confirmed in a CML mouse model via tail vein injection of Cas9-GFP/dual-BA-sgRNA virus-infected cells and in primary cells isolated from patients with CML. Cas9-GFP/dual-BA-sgRNA efficiently disrupts BCR-ABL at the genomic sequence and gene expression levels in leukemia cells, leading to blockade of the BCR-ABL tyrosine kinase signaling pathway and disruption of its downstream molecules, followed by cell proliferation inhibition and cell apoptosis induction. This method prolongs the lifespan of CML model mice. Furthermore, the effect is confirmed in primary cells derived from patients with CML.

Genetic characteristics predict response to venetoclax plus hypomethylating agents in relapsed or refractory acute myeloid leukemia.

BACKGROUND: The heterogeneity of relapsed or refractory (R/R) acute myeloid leukemia (AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are considered important predictors for response to treatment in adults with AML. However, the association of genetic characteristics with outcomes receiving VEN-based therapy is incompletely understood in R/R AML. OBJECTIVE: To evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potential genetic predictors of response in R/R AML. METHODS: A total of 150 R/R AML patients treated with VEN combined with HMA were enrolled in this retrospective study. Outcomes of the response and overall survival (OS) were analyzed. The predictors of response and OS were analyzed by logistic regression or Cox proportional hazards model. RESULTS: With a median of two (range, 1-4) cycles of therapy, the overall response rate was 56.2%, including 22.0% complete remission (CR), 21.3% CR with incomplete hematologic recovery, 2.0% morphologic leukemia-free state, and 10.7% partial remission, in which 25 patients achieved measurable residual disease (MRD)-negative response. With a median follow-up of 11.2 [95% confidence interval (CI), 7.2-14.8] months, 1- and 2-year OS were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively. Adverse cytogenetics and European Leukemia Net (ELN) risk predicted inferior response to VEN-based therapy. Mutations in IDH1/2, NPM1, ASXL1, and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response. CONCLUSION: VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.

Hypomethylating agents plus modified priming regimens compared with venetoclax-based regimens based on molecular characteristics for newly diagnosed patients with acute myeloid leukemia: a multi-center cohort study.

Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.

Sedation efficacy of different dose of remimazolam with sufentanil for nerve block in young and elderly patients: a randomized, controlled study.

PURPOSE: Anxiety and pain commonly occur during nerve block, we aimed to investigate the sedation efficacy of different doses of remimazolam with sufentanil in young and elderly patients. METHODS: In this randomized trial, patients aged 18-85 years who underwent nerve block was enrolled. All patients received sufentanil 0.08 µg/kg for analgesia. Young patients (age < 65 years) were randomized into the control group (Group C, 0.9% saline), medium-dose remimazolam (Group M, 0.06 mg/kg) and high-dose remimazolam group (Group H, 0.08 mg/kg). Elderly patients (age ≥ 65 years) were randomized into the Group C, low-dose remimazolam group (Group L, 0.04 mg/kg) and Group M. Primary outcome was the success rate of procedure sedation. Respiratory depression and hypoxia were the interested safety outcomes. RESULTS: Ninety young and 114 elderly patients were enrolled, respectively. In comparison with Groups C and M, young patients in Group H had the highest success rate of procedure sedation (80.0 vs. 73.3 vs. 43.3%, P = 0.006). Elderly patients in Groups M and L had similar success rates of procedure sedation, which were significantly higher than that in Group C (78.9 vs. 78.9 vs. 50.0%, P = 0.007). In elderly patients, the incidence of respiratory depression and hypoxia tended to be higher in Group M than those in Groups L and C (both P < 0.001). CONCLUSION: Remimazolam 0.08 mg/kg provided the best sedation efficacy in young patients while remimazolam 0.04 mg/kg with the trend of less respiratory adverse events was more optimal for elderly patients. TRIAL REGISTRATION: http://www.chictr.org.cn/showproj.aspx?proj=122016 .

A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia.

BACKGROUND: Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. METHODS: To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). RESULTS: Twenty-six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n = 3), grade 3 or 4 acute graft-vs-host disease (n = 2), and grade 3 skin rash (n = 1). No treatment-related deaths occurred during the therapy of refractory CNSL. CONCLUSIONS: Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. LAY SUMMARY: Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.

Effect of sorafenib maintenance on Epstein-Barr virus and cytomegalovirus infections in patients with FLT3-ITD AML undergoing allogeneic hematopoietic stem cell transplantation: a secondary analysis of a randomized clinical trial.

BACKGROUND: Use of kinase inhibitors such as dasatinib and imatinib might increase the risk of opportunistic infections, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. However, the effect of sorafenib on EBV and CMV infections remains unclear. The aim of this study was to investigate the effect of sorafenib maintenance post-transplantation on the incidence and mortality of EBV and CMV infections in patients with FLT3-ITD acute myeloid leukemia. METHODS: This was a follow-up of our randomized controlled trial undertaken at seven hospitals in China. The primary endpoint was EBV and CMV infections within 3 years post-transplantation. Secondary endpoints included the cumulative incidences of relapse, non-relapse mortality (NRM), overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) at 3 years. RESULTS: Two hundred two patients were assigned to sorafenib maintenance (n=100) or non-maintenance (control, n=102). Median extended follow-up post-transplantation was 36.8 (range, 2.5-67.1) months. The 3-year cumulative incidences of EBV-DNAemia and EBV-associated diseases were 24.0% (95% CI: 16.1-32.8%) and 5.0% (1.8-10.6%) in the sorafenib group, and 24.5% (16.6-33.2%) and 5.9% (2.4-11.6%) in the control group (P=0.937; P=0.771). The 3-year cumulative incidences of CMV-DNAemia and CMV-associated diseases were 56.0% (45.6-65.1%) and 8.0% (3.7-14.4%) in the sorafenib group, and 52.9% (42.7-62.1%) and 8.8% (4.3-15.3%) in the control group (P=0.997; P=0.826). The 3-year cumulative mortality of EBV- and CMV-associated diseases was 0.0% (0.0-0.0%) and 2.0% (0.4-6.4%) in the sorafenib group, and 1.0% (0.1-4.8%) and 2.0% (0.4-6.3%) in the control group (P=0.322, P=0.980). The 3-year cumulative incidences of relapse, NRM, OS, LFS, and GRFS were 13.0%, 11.1%, 79.0%, 75.9%, and 65.8% in the sorafenib group and 34.8%, 12.7%, 61.4%, 52.5%, and 46.6% in the control group, respectively (P<0.001, P=0.656, P=0.005, P<0.001, P=0.003). The reconstitution of T lymphocyte subsets, B lymphocytes, and natural killer cells was similar between the two groups (all P>0.05). CONCLUSIONS: Sorafenib maintenance post-transplantation does not increase the incidence and mortality of EBV and CMV infections, demonstrating a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02474290 . Registered on June 14, 2015.

Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial.

BACKGROUND: Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. METHODS: This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. RESULTS: A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. CONCLUSIONS: In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications.

Effectively Converting Cane Molasses into 2,3-Butanediol Using Clostridiumljungdahlii by an Integrated Fermentation and Membrane Separation Process.

Firstly, 2,3-butanediol (2,3-BDO) is a chemical platform used in several applications. However, the pathogenic nature of its producers and the expensive feedstocks used limit its scale production. In this study, cane molasses was used for 2,3-BDO production by a nonpathogenic Clostridium ljungdahlii. It was found that cane molasses alone, without the addition of other ingredients, was favorable for use as the culture medium for 2,3-BDO production. Compared with the control (i.e., the modified DSMZ 879 medium), the differential genes are mainly involved in the pathways of carbohydrate metabolism, membrane transport, and amino acid metabolism in the case of the cane molasses alone. However, when cane molasses alone was used, cell growth was significantly inhibited by KCl in cane molasses. Similarly, a high concentration of sugars (i.e., above 35 g/L) can inhibit cell growth and 2,3-BDO production. More seriously, 2,3-BDO production was inhibited by itself. As a result, cane molasses alone with an initial 35 g/L total sugars was suitable for 2,3-BDO production in batch culture. Finally, an integrated fermentation and membrane separation process was developed to maintain high 2,3-BDO productivity of 0.46 g·L-1·h-1. Meanwhile, the varied fouling mechanism indicated that the fermentation properties changed significantly, especially for the cell properties. Therefore, the integrated fermentation and membrane separation process was favorable for 2,3-BDO production by C. ljungdahlii using cane molasses.

Fermentative Production of Fructo-Oligosaccharides Using Aureobasidium pullulans: Effect of Dissolved Oxygen Concentration and Fermentation Mode.

Fructo-oligosaccharides (FOS) are prebiotics with numerous health benefits. So far, the dissolved oxygen (DO) concentration control strategy for fermentative production of FOS is still unknown. In order to improve FOS production, the effects of DO concentration and fermentation mode on FOS using Aureobasidium pullulans were investigated in this study. The greatest FOS production (123.2 ± 6.2 g/L), with a yield of 61.6% ± 3.0% (g FOS/g sucrose), was obtained in batch culture under high DO concentration. Furthermore, repeated-batch culture revealed that enzyme production and FOS production were not closely associated with cell growth. By keeping the DO concentration above 5% in the repeated-batch culture, a maximum FOS concentration of 548.3 ± 37.4 g/L and yield of 68.6% ± 2.6% (g FOS/g sucrose) were obtained, which were 3.45% and 11.4% times higher than those obtained in the batch culture without DO control, respectively. Additionally, the ratios of 1-fructofuranosyl nystose (GF4) and 1,1,1,1-kestohexose (GF5) were 33.8% and 23.2%, respectively, in the product of repeated-batch culture, but these compounds were not detected in batch culture. Thus, it can be concluded that the DO concentration affects not only the yield of FOS but also the composition of FOS with different degrees of polymerization, which is the key factor in the fermentative production of FOS with a high polymerization degree.

Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial.

BACKGROUND: Findings of retrospective studies suggest that sorafenib maintenance post-transplantation might reduce relapse in patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. We investigated the efficacy and tolerability of sorafenib maintenance post-transplantation in this population. METHODS: We did an open-label, randomised phase 3 trial at seven hospitals in China. Eligible patients (aged 18-60 years) had FLT3-ITD acute myeloid leukaemia, were undergoing allogeneic haematopoietic stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days post-transplantation. Patients were randomly assigned (1:1) to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days post-transplantation. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 1-year cumulative incidence of relapse in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02474290; the trial is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were enrolled and randomly assigned to sorafenib maintenance (n=100) or control (n=102). Median follow-up post-transplantation was 21·3 months (IQR 15·0-37·0). The 1-year cumulative incidence of relapse was 7·0% (95% CI 3·1-13·1) in the sorafenib group and 24·5% (16·6-33·2) in the control group (hazard ratio 0·25, 95% CI 0·11-0·57; p=0·0010). Within 210 days post-transplantation, the most common grade 3 and 4 adverse events were infections (25 [25%] of 100 patients in the sorafenib group vs 24 [24%] of 102 in the control group), acute graft-versus-host-disease (GVHD; 23 [23%] of 100 vs 21 [21%] of 102), chronic GVHD (18 [18%] of 99 vs 17 [17%] of 99), and haematological toxicity (15 [15%] of 100 vs seven [7%] of 102). There were no treatment-related deaths. INTERPRETATION: Sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. This strategy could be a suitable therapeutic option for patients with FLT3-ITD acute myeloid leukaemia. FUNDING: None.

Sorafenib Therapy Is Associated with Improved Outcomes for FMS-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation.

The optimal therapy for patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. In this study we retrospectively evaluated the efficacy of sorafenib combined with other therapeutic strategies as salvage therapy for these patients. Eighty-three AML patients with FLT3-ITD relapsing after allo-HSCT were enrolled in this study. Fifty-three patients received salvage therapy containing sorafenib and 30 patients did not. Salvage therapy containing sorafenib was superior to that without sorafenib with respect to complete remission rates, overall survival (OS), and progression-free survival (PFS) (66.0% versus 30.0%, 46.8% versus 20.0%, and 44.9% versus 16.7%, respectively; P = .002, P = .003, and P = .001). Further subgroup analysis revealed that the OS and PFS of patients who received sorafenib combined with chemotherapy followed by donor lymphocyte infusion (DLI) were superior to those receiving other therapeutic regimens, including sorafenib combined with chemotherapy, chemotherapy followed by DLI, and monochemotherapy (P = .003, P < .001). Multivariate analysis revealed that salvage therapy including sorafenib was the only protective factor for longer OS (P = .035; hazard ratio [HR], .526); salvage therapy including sorafenib and DLI were the protective factors for longer PFS (P = .011, HR, .423; P = .019, HR, .508). Our data suggest that sorafenib therapy is associated with improved outcomes for FLT3-ITD AML relapsing after allo-HSCT, and whether sorafenib combined with chemotherapy followed by DLI reveals an optimal efficacy merits further study.

Effect of sorafenib on the outcomes of patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The objective of this study was to evaluate the effect of sorafenib on the outcomes of patients with acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 144 patients with FLT3-ITD AML undergoing allo-HSCT between January 2012 and December 2015 were enrolled in this study. Depending on whether they were receiving sorafenib before transplantation or sorafenib maintenance after transplantation, patients were divided into 4 groups: patients receiving sorafenib before transplantation (group A; n = 36), patients receiving sorafenib after transplantation (group B; n = 32), patients receiving sorafenib both before and after transplantation (group C; n = 26), and patients receiving sorafenib neither before nor after transplantation (group D; n = 50). Outcomes were compared among these groups. RESULTS: The 3-year relapse rates were 22.2%, 18.8%, 15.8%, and 46.1% for groups A, B, C, and D, respectively (P = .006). The 3-year overall survival (OS) rates were 74.9%, 78.1%, 84.6%, and 50.9%, respectively (P = .023), and the 3-year leukemia-free survival (LFS) rates were 69.4%, 78.1%, 80.4%, and 34.8%, respectively (P < .001). The relapse rate was higher and the LFS was shorter in group D versus groups A, B, and C. The OS in group D was shorter than the OS in group C but was similar to the OS in groups A and B. A multivariate analysis revealed that sorafenib before transplantation, sorafenib maintenance after transplantation, and their combined application were protective factors for a lower relapse rate (hazard ratios [HRs], 0.436 [P = .048], 0.431 [P = .046], and 0.173 [P = .002], respectively) and longer LFS (HRs, 0.322 [P = .010], 0.343 [P = .014], and 0.187 [P = .001], respectively). CONCLUSIONS: Sorafenib before transplantation, sorafenib maintenance after transplantation, and their combined application all could improve the outcomes for patients with FLT3-ITD AML. Further study is needed to determine whether the use of sorafenib both before and after transplantation might be ideal. Cancer 2018;124:1954-63. © 2018 American Cancer Society.

The long-term outcomes and safety of severe aplastic anemia treated with porcine antilymphocyte globulin plus cyclosporine, with or without thrombopoietin receptor agonists: a double-center retrospective study.

BACKGROUND: Porcine antilymphocyte globulin (p-ALG) combined with cyclosporine (CsA) has been commonly used for severe aplastic anemia (SAA) patients, but few studies on the combination of p-ALG and thrombopoietin receptor agonist (TPO-RA). RESEARCH DESIGN AND METHODS: We retrospectively analyzed the data of 85 people with diagnosed SAA who underwent p-ALG plus CsA, with or without TPO-RA from 2014 to 2023. RESULTS: The overall response rates were 55.3% and 65.9% at 3 and 6 months, and the TPO-RA group were 66.7% and 72.3% at 3 and 6 months, without TPO-RA group were 27.8% and 55.6%. In multivariate analysis, baseline platelet count of > 10 × 109/L was a simple predictor of favorable response at 6 months (p = 0.015). The median follow-up time for all patients was 39 months (range 0.4 ~ 104), the 5-year overall survival (OS) rate was 90.6% [95% CI = 82.1-95.2%], and the failure-free survival (FFS) rate was 68.9% [95% CI = 56.6-78.4%]. Having hematologic responses in 6 months was an independent positive predictor for FFS (p = 0.000). Twelve patients (14.1%) suffered from serum sickness, and 9.5% of patients had mild hepatic impairment. CONCLUSIONS: p-ALG along with CsA is an effective choice for patients with SAA. p-ALG combined with TPO-RA may contribute to the early restoration of hematopoiesis.

A novel pectate lyase with high specific activity from Bacillus sp. B58-2: Gene cloning, heterologous expression and use in ramie degumming.

Pectinase plays a crucial role in ramie degumming. A gene encoding a putative pectate lyase from Bacillus sp. strain B58-2 was cloned and heterologously expressed in Escherichia coli. The amplified gene BvelPL1 encoded a mature protein of 400 amino acids. BvelPL1 shared the highest amino acid sequence identity (78.75%) with the enzymatically characterized pectate lyase Pel from Bacillus subtilis strain RCK (GenBank: AFH66771.1). The purified recombinant enzyme rBvelPL1-Ec exhibited a maximum specific activity of 2433.26 U/mg at pH 8.5 and 50 °C towards polygalacturonic acid. This specific activity was higher than that of most reported pectate lyases. Remarkably, the enzymatic activity of rBvelPL1-Ec increased by 23.28 times in the presence of 0.4 mM calcium ion. The effect of calcium ion on promoting the enzymatic activity of rBvelPL1-Ec was greater than that for all reported pectate lyases. After degumming with rBvelPL1-Ec, a weight loss of 21.27 ± 1.17% of circled ramie fibers was obtained, and the surfaces of the ramie fibers became smoother. Moreover, a weight loss of 30.47 ± 0.46% was obtained through enzymatic treated and subsequent NaOH treated circled ramie fibers. The excellent performance in degumming suggests that rBvelPL1-Ec may serve as a promising biocatalyst in the textile industry.

Clinical and genetic characteristics predict outcomes of acute myeloid leukemia patients with FLT3 mutations receiving venetoclax-based therapy.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3mut ) and FLT3 wild-type (FLT3wt ) patients and identify the predictors of efficacy in FLT3mut patients. METHODS: A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3mut and FLT3wt patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. RESULTS: With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3mut group had a comparable composite complete remission (CRc) rate with the FLT3wt group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3mut group exhibited a lower CRc rate than the FLT3wt group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3mut and FLT3wt groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3mut patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3mut patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). CONCLUSIONS: FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.

[The biological functions of lysine methyltransferase PR-SET7].

PR-SET7 (also named SET8 or KMT5a) is a sole lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20me1) in higher eukaryotes. The abundance of PR-SET7 is dynamically mediated by the distinct E3 ubiquitin ligases in different cell cycle phases. PR-SET7 is closely related to the regulation of cell proliferation, and the H4K20me1 catalyzed by PR-SET7 has been implicated in regulating the diverse biological processes, including DNA replication, chromosome condensation and the activation of DNA replication checkpoints. Loss of PR-SET7 results in mas-sive DNA damage, cell cycle arrest and induction of apoptosis. In addition, PR-SET7 involves in regulating the transcrip-tion of several genes, such as ERa, Wnt and p53. PR-SET7 is also essential for individual development and participates in the formation of genomic imprinting. Moreover, PR-SET7 has been reported to promote tumorigenesis and metastasis, sug-gesting that PR-SET7 may be a potential target for cancer treatment. In this review, we focus on analyzing the structure of PR-SET7 and factors influencing histone modification on regulation of PR-SET7, and discuss the mechanisms by which PR-SET7 modulates cell-cycle progression, gene transcription, individual development and tumorigenesis.

Learning-based robotic grasping: A review.

As personalization technology increasingly orchestrates individualized shopping or marketing experiences in industries such as logistics, fast-moving consumer goods, and food delivery, these sectors require flexible solutions that can automate object grasping for unknown or unseen objects without much modification or downtime. Most solutions in the market are based on traditional object recognition and are, therefore, not suitable for grasping unknown objects with varying shapes and textures. Adequate learning policies enable robotic grasping to accommodate high-mix and low-volume manufacturing scenarios. In this paper, we review the recent development of learning-based robotic grasping techniques from a corpus of over 150 papers. In addition to addressing the current achievements from researchers all over the world, we also point out the gaps and challenges faced in AI-enabled grasping, which hinder robotization in the aforementioned industries. In addition to 3D object segmentation and learning-based grasping benchmarks, we have also performed a comprehensive market survey regarding tactile sensors and robot skin. Furthermore, we reviewed the latest literature on how sensor feedback can be trained by a learning model to provide valid inputs for grasping stability. Finally, learning-based soft gripping is evaluated as soft grippers can accommodate objects of various sizes and shapes and can even handle fragile objects. In general, robotic grasping can achieve higher flexibility and adaptability, when equipped with learning algorithms.

L-Cys-Assisted Conversion of H2/CO2 to Biochemicals Using Clostridium ljungdahlii.

Carbon fixation and conversion based on Clostridium ljungdahlii have great potential for the sustainable production of biochemicals (i.e., 2,3-butanediol, acetic acid, and ethanol). Here, the effects of reducing agents on the production of biochemicals from H2/CO2 using C. ljungdahlii were studied. It was found that the element S and reducing power could significantly affect the production of biochemicals, and cysteine (Cys) was better than sodium sulfide for the production of biochemicals, especially for the production of 2,3-butanediol. Moreover, comparing to the control (i.e., without the addition of Cys), the gene expression profiles indicated that the fdh and adhE1 were significantly upregulated with the addition of Cys, which involved in pathways of the CO2 fixation and ethanol production. Therefore, the irreplaceability of Cys on the production of biochemicals was both caused by its utilization as a reducing agent and its effect on the metabolic pathway. Finally, compared to the control, the production of 2,3-butanediol was increased by 2.17 times under the addition of 1.7 g/L Cys.

Gene cloning, expression, and characterization of two endo-xylanases from Bacillus velezensis and Streptomyces rochei, and their application in xylooligosaccharide production.

Endo-xylanase hydrolyzing xylan in cellulosic residues releasing xylobiose as the major product at neutral pH are desirable in the substitute sweeteners industry. In this study, two endo-xylanases were obtained from Streptomyces rochei and Bacillus velezensis. SrocXyn10 showed the highest identity of 77.22%, with a reported endo-xylanase. The optimum reaction temperature and pH of rSrocXyn10-Ec were pH 7.0 and 60°C, with remarkable stability at 45°C or pHs ranging from 4.5 to 11.0. rBvelXyn11-Ec was most active at pH 6.0 and 50°C, and was stable at 35°C or pH 3.5 to 10.5. Both rSrocXyn10-Ec and rBvelXyn11-Ec showed specific enzyme activities on wheat arabinoxylan (685.83 ± 13.82 and 2809.89 ± 21.26 U/mg, respectively), with no enzyme activity on non-xylan substrates. The Vmax of rSrocXyn10-Ec and rBvelXyn11-Ec were 467.86 U mg-1 and 3067.68 U mg-1, respectively. The determined Km values of rSrocXyn10-Ec and rBvelXyn11-Ec were 3.08 g L-1 and 1.45 g L-1, respectively. The predominant product of the hydrolysis of alkaline extracts from bagasse, corncob, and bamboo by rSrocXyn10-Ec and rBvelXyn11-Ec were xylooligosaccharides. Interestingly, the xylobiose content in hydrolysates by rSrocXyn10-Ec was approximately 80%, which is higher than most reported endo-xylanases. rSrocXyn10-Ec and rBvelXyn11-Ec could be excellent candidates to produce xylooligosaccharides at neutral/near-neutral pHs. rSrocXyn10-Ec also has potential value in the production of xylobiose as a substitute sweetener.