Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial.

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Combined Strategies for Improving Aflatoxin B1 Degradation Ability and Yield of a Bacillus licheniformis CotA-Laccase.

Aflatoxin B1 (AFB1) contamination is a serious threat to nutritional safety and public health. The CotA-laccase from Bacillus licheniformis ANSB821 previously reported by our laboratory showed great potential to degrade AFB1 without redox mediators. However, the use of this CotA-laccase to remove AFB1 in animal feed is limited because of its low catalytic efficiency and low expression level. In order to make better use of this excellent enzyme to effectively degrade AFB1, twelve mutants of CotA-laccase were constructed by site-directed mutagenesis. Among these mutants, E186A and E186R showed the best degradation ability of AFB1, with degradation ratios of 82.2% and 91.8% within 12 h, which were 1.6- and 1.8-times higher than those of the wild-type CotA-laccase, respectively. The catalytic efficiencies (kcat/Km) of E186A and E186R were found to be 1.8- and 3.2-times higher, respectively, than those of the wild-type CotA-laccase. Then the expression vectors pPICZαA-N-E186A and pPICZαA-N-E186R with an optimized signal peptide were constructed and transformed into Pichia pastoris GS115. The optimized signal peptide improved the secretory expressions of E186A and E186R in P. pastoris GS115. Collectively, the current study provided ideal candidate CotA-laccase mutants for AFB1 detoxification in food and animal feed and a feasible protocol, which was desperately needed for the industrial production of CotA-laccases.

Induction of zinc finger protein RNF6 auto-ubiquitination for the treatment of myeloma and chronic myeloid leukemia.

The zinc finger ubiquitin ligase RNF6 has been proposed as a potential therapeutic target in several cancers, but understanding its molecular mechanism of degradation has been elusive. In the present study, we find that RNF6 is degraded via auto-ubiquitination in a manner dependent on its Really Interesting New Gene (RING) domain. We determine that when the RING domain is deleted (ΔRING) or the core cysteine residues in the zinc finger are mutated (C632S/C635S), the WT protein, but not the ΔRING or mutant RNF6 protein, undergoes polyubiquitination. We also identify USP7 as a deubiquitinase of RNF6 by tandem mass spectrometry. We show that USP7 interacts with RNF6 and abolishes its K48-linked polyubiquitination, thereby preventing its degradation. In contrast, we found a USP7-specific inhibitor promotes RNF6 polyubiquitination, degradation, and cell death. Furthermore, we demonstrate the anti-leukemic drug Nilotinib and anti-myeloma drug Panobinostat (LBH589) induce RNF6 K48-linked polyubiquitination and degradation in both multiple myeloma (MM) and leukemia cells. In agreement with our hypothesis on the mode of RNF6 degradation, we show these drugs promote RNF6 auto-ubiquitination in an in vitro ubiquitination system without other E3 ligases. Consistently, reexpression of RNF6 ablates drug-induced MM and leukemia cell apoptosis. Therefore, our results reveal that RNF6 is a RING E3 ligase that undergoes auto-ubiquitination, which could be abolished by USP7 and induced by anti-cancer drugs. We propose that chemical induction of RNF6 auto-ubiquitination and degradation could be a novel strategy for the treatment of hematological malignancies including MM and leukemia.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation.

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma.

Circular RNA circ-CCT3 promotes bortezomib resistance in multiple myeloma via modulating miR-223-3p/BRD4 axis.

Multiple myeloma is a frequent hematologic malignancy. Bortezomib is the first-line drug for multiple myeloma chemotherapy. The present study aimed to investigate the potential role and mechanism of circular RNA chaperonin containing TCP1 subunit 3 (circ-CCT3) in bortezomib resistance of multiple myeloma. The levels of circ-CCT3, microRNA-223-3p (miR-223-3p), and bromodomain-containing 4 (BRD4) were detected by quantitative real-time PCR or western blot. Cell Counting Kit-8 (CCK-8) method was used to measure the half-inhibitory concentration of bortezomib and cell viability. Cell cycle distribution, apoptosis, proliferation and migration were determined by flow cytometry, 5-ethynyl-2'-deoxyuridine, and wound healing assay. The levels of relevant proteins were checked via western blot. The binding association between miR-223-3p and circ-CCT3/BRD4 was validated via a dual-luciferase reporter assay. Circ-CCT3 and BRD4 were upregulated, while miR-223-3p was downregulated in bortezomib-resistant multiple myeloma patients and cells. Silencing of circ-CCT3 enhanced the sensitivity of bortezomib-resistant multiple myeloma cells to bortezomib. Circ-CCT3 knockdown weakened bortezomib resistance via modulating miR-223-3p. Moreover, miR-223-3p increased bortezomib sensitivity by inhibiting BRD4. Downregulation of circ-CCT3 attenuated bortezomib resistance of multiple myeloma via regulating miR-223-3p/BRD4 pathway, which provided a new potential target for multiple myeloma chemoresistance.

Hypoxia-induced secretion of IL-10 from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma.

In this study, we explored how the altered paracrine of adipose mesenchymal stem cells (ADSCs) contributed to the growth and cancer stem cell (CSC) properties of the Burkitt lymphoma cells. Condition mediums from normoxia or hypoxia cultured ADSC (CM-ADSC-N or CM-ADSC-H) were collected, and their effects on growth, colony formation, and apoptosis of Burkitt's lymphoma cells were investigated. Differentially expressed cytokines and inflammatory factors were compared between CM-ADSC-N and CM-ADSC-H. The involvement of differentially expressed IL-10 in growth and CSC properties of Burkitt lymphoma was investigated using both in vitro and in vivo models. Findings of this study showed that hypoxia increased IL-10 secretion from ADSCs, through which the growth and CSC properties of BL2 cells were enhanced. Intratumoral injection of CM-ADSC-H or IL-10 enhanced in vivo Burkitt lymphoma growth in nude mice model at least partly via the JAK2/STAT3 signaling pathway.

Clinical and laboratory features of seven patients with acute myeloid leukemia (AML)-M2/M3 and elevated myeloblasts and abnormal promyelocytes.

BACKGROUND: There is limited information on a special subtype of Acute myeloid leukemia (AML) characterized by >20% myeloblasts and >20% abnormal promyelocytes in bone marrow and peripheral blood. OBJECTIVE: The objective of the present investigation was to explore the clinical and laboratory features of seven patients with AML-M2/M3. METHOD: We retrospectively assessed cell morphology, cytochemistry, immunophenotype, cytogenetics, and clinical features of seven patients with this rare subtype of AML. RESULTS: All seven cases had thrombocytopenia, coagulation abnormalities, >20% myeloblasts and abnormal promyelocytes. The PML/RARα fusion gene was present in six patients and two patients presented a mixed PML/RARα and AML1/ETO genotype. Five cases achieved CR and two cases did not achieve remission and one case transform into AML-M2 after CR1. CONCLUSIONS: The clinical and laboratory features of seven patients with AML-M2/M3 are demonstrated in the present study, providing information on the FAB sub-classification.

Sphingosine kinase 1 counteracts chemosensitivity and immune evasion in diffuse large B cell lymphoma cells via the PI3K/AKT/PD-L1 axis.

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive neoplasm of lymphatic system that represent 38-58 % of non-Hodgkin lymphoma. Chemoresistance and immune escape constitute the major obstacles to the treatment of patients. Sphingosine kinase 1 (SphK1) is involved in multiple processes of cancer. Up to now, little research focuses on its function in DLBCL. In the current research, GEPIA and human Protein Atlas databases confirmed high expression of SphK1 in DLBCL tissues. Analogously, increased expression of SphK1 were determined in DLBCL tissues and cells. Intriguingly, knockdown of SphK1 suppressed DLBCL cell viability and increased chemosensitivity to doxorubicin by decreasing cell viability and increasing caspase-3 activity. Reversely, SphK1 elevation facilitated cancer cell resistance to doxorubicin. Furthermore, loss of SphK1 increased the productions of inflammatory cytokine IFN-γ and TNF-α, but reduced IL-10 levels in co-culture model of CD8 + T cells and DLBCL cells. Importantly, SphK1 knockdown enhanced T cell cytotoxicity to DLBCL cells, while its elevation restrained the ability of T cells to kill cancer cells. Concomitantly, targeting SphK1 enhanced the percentage of CD8 + T cells and attenuated co-culture-evoked CD8 + T cell apoptosis, indicating the important roles in T cell escape. Mechanically, SphK1 overexpression enhanced and its knockdown suppressed activation of the PI3K/AKT/PD-L1 pathway. After blockage of this pathway by its antagonist, the beneficial effects of SpHK1 on chemoresistance and immune escape were abrogated. In vivo, targeting SphK1 inhibited tumor growth and enhanced the anti-tumor efficacy of doxorubicin in DLBCL xenograft tumor, concomitant with the inhibition of the PI3K/AKT/PD-L1 signaling. Collectively, SphK1 knockdown counteracted chemoresistance and immune escape from T cell killing by inhibiting the PI3K/AKT/PD-L1 pathway. Therefore, targeting SphK1 may represent a promising therapeutic strategy for overcoming chemoresistance and immune escape in DLBCL.

A NADPH-Dependent Aldo/Keto Reductase Is Responsible for Detoxifying 3-Keto-Deoxynivalenol to 3-epi-Deoxynivalenol in Pelagibacterium halotolerans ANSP101.

Deoxynivalenol (DON), primarily generated by Fusarium species, often exists in agricultural products. It can be transformed to 3-epi-deoxynivalenol (3-epi-DON), with a relatively low toxicity, via two steps. DDH in Pelagibacterium halotolerans ANSP101 was proved to convert DON to 3-keto-deoxynivalenol (3-keto-DON). In the present research, AKR4, a NADPH-dependent aldo/keto reductase from P. halotolerans ANSP101, was identified to be capable of converting 3-keto-DON into 3-epi-DON. Our results demonstrated that AKR4 is clearly a NADPH-dependent enzyme, for its utilization of NADPH is higher than that of NADH. AKR4 functions at a range of pH 5-10 and temperatures of 20-60 °C. AKR4 is able to degrade 89% of 3-keto-DON in 90 min at pH 7 and 50 °C with NADPH as the cofactor. The discovery of AKR4, serving as an enzyme involved in the final step in DON degradation, might provide an option for the final detoxification of DON in food and feed.

g-C3N4 nanosheet supported NiCo2O4 nanoparticles for boosting degradation of tetracycline under visible light and ultrasonic irradiation.

The doping of semiconductor materials through some facile and appropriate methods holds significant promise in enhancing the catalytic performance of catalysts. Herein, NiCo2O4/g-C3N4 composite catalysts were synthesized via a high-energy ball milling method. The microstructure and physicochemical characterization of the as-prepared composites confirmed the successful loading of NiCo2O4 nanoparticles onto the g-C3N4 nanosheets. The NiCo2O4/g-C3N4 composites showed excellent catalytic effect under visible light/ultrasonic irradiation, and the efficiency of tetracycline hydrochloride (TCH) degradation reached 90% within 15 min. The optical properties of g-C3N4 nanosheets were improved by doping, and the diffusion of active materials and carrier migration rate were improved by ultrasonic assistance. Possible catalytic mechanisms and potential pathways of the NiCo2O4/g-C3N4 composites for the degradation of TCH triggered by visible light/ultrasonic irradiation were proposed. This study provides a new strategy for energy-assisted photocatalytic degradation of organic pollutants.

Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis.

Induction of pyroptosis is proposed as a promising strategy for the treatment of hematological malignancies, but little is known. In the present study, we find clioquinol (CLQ), an anti-parasitic drug, induces striking myeloma and leukemia cell pyroptosis on a drug screen. RNA sequencing reveals that the interferon-inducible genes IFIT1 and IFIT3 are markedly upregulated and are essential for CLQ-induced GSDME activation and cell pyroptosis. Specifically, IFIT1 and IFIT3 form a complex with BAX and N-GSDME therefore directing N-GSDME translocalization to mitochondria and increasing mitochondrial membrane permeabilization and triggering pyroptosis. Furthermore, venetoclax, an activator of BAX and an inhibitor of Bcl-2, displays strikingly synergistic effects with CLQ against leukemia and myeloma via pyroptosis. This study thus reveals a novel mechanism for mitochondrial GSDME in pyroptosis and it also illustrates that induction of IFIT1/T3 and inhibition of Bcl-2 orchestrate the treatment of leukemia and myeloma via pyroptosis.

Theta-burst transcranial magnetic stimulation attenuates chronic ischemic demyelination and vascular cognitive impairment in mice.

Vascular cognitive impairment and dementia (VCID) is mainly caused by chronic cerebral hypoperfusion and subsequent white matter lesions. Noninvasive transcranial magnetic stimulation has been utilized in treating various neurological disorders. However, the function of theta-burst transcranial magnetic stimulation on VCID remains to be defined. We utilized 4-week bilateral carotid artery stenosis model of male mice to mimic VCID. Intermittent theta-burst stimulation (iTBS) or consecutive theta-burst stimulation (cTBS) was administered for 14 consecutive days. Through luxol fast blue staining, electron microscopy and immunofluorescence, we found that iTBS, not cTBS, significantly improved demyelination, axonal damage and ß-amyloid deposition, without affecting cerebral blood flow in VCID mice. At cellular levels, iTBS rescued the loss of mature oligodendrocytes, promoted precursor cell differentiation, and inhibited pro-inflammatory activation of astrocytes and microglia. Notably, iTBS attenuated cognitive deterioration in both short-term retention and long-term spatial memory of VCID mice as indicated by serial neurobehavioral tests. To explore the molecular involvement of iTBS, mRNA sequencing was carried out. By real-time PCR and combined RNA fluorescence in situ hybridization with immunofluorescence, iTBS was confirmed to increase Rxrg expression specifically in mature oligodendrocytes. Collectively, iTBS could ameliorate vascular cognitive dysfunction, probably via mitigating white matter lesions and neuroinflammation in the corpus callosum. Rxrg signaling in mature oligodendrocytes, which was increased by iTBS, might be a potential target for VCID treatment.

Phase II study of novel orally PI3Kα/δ inhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma.

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.

Circulating lipocalin-2 as a novel biomarker for early neurological deterioration and unfavorable prognosis after acute ischemic stroke.

INTRODUCTION: Lipocalin-2 (LCN2) is an acute-phase protein that could mediate neuroinflammation after brain injury. We aimed to evaluate if LCN2 level was associated with early neurological deterioration (END) in acute ischemic stroke patients, thus hindering clinical recovery. METHODS: We conducted a prospective study of acute ischemic stroke patients between June 2021 and February 2022. Serum LCN2 concentration was measured after admission using an enzyme-linked immunosorbent assay. Outcomes included END and 90-day poor functional outcome (modified Rankin Scale 3-6). The National Institutes of Health Stroke Scale increment ≥4 points within 72 h after admission was defined as END. RESULTS: A total of 253 acute ischemic stroke patients (mean age, 65.2 ± 13.4 years; 64.0% male) were recruited. In the multivariate adjustment, increased serum LCN2 levels (per 1-SD increase of LCN2) were associated with a higher risk of END (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.20-2.25; p = .002) and 90-day poor outcome (OR, 1.73; 95% CI, 1.22-2.45; p = .002). Restricted cubic splines found a linear relationship between LCN2 level and 90-day unfavorable outcome (END, p = .001 for linearity; 90-day poor outcome, p = .013 for linearity). Subgroup analysis further confirmed the significant association of LCN2 with clinical outcomes. CONCLUSIONS: This study demonstrated that higher circulating LCN2 level was associated with an increased risk of early clinical worsening and 90-day unfavorable outcomes in ischemic stroke patients.

Association between Citrullinated Histone H3 and White Matter Lesions Burden in Patients with Ischemic Stroke.

INTRODUCTION: Neutrophil extracellular traps play a role in the pathophysiology of stroke and are associated with severity and mortality. We aimed to investigate whether the citrullinated histone H3 (CitH3), a biomarker for neutrophil extracellular traps formation, is associated with the white matter lesion (WML) burden in ischemic stroke patients. METHODS: Between September 2021 and April 2022, 322 patients were enrolled in this prospective observational cohort study. Serum CitH3 levels were measured after admission using an enzyme-linked immunosorbent assay. WMLs severity was graded according to the Fazekas scale and conceptually defined as mild (total Fazekas score 0-2) and severe (total Fazekas score 3-6). We used multivariable regression models to determine the relationship between CitH3 concentrations and the severity of WMLs burden. RESULTS: One-hundred and forty-eight (46.0%) patients were diagnosed with severe WMLs burden after admission. Increased CitH3 levels (first quartile vs. fourth quartile of H3Cit, odds ratio, 3.311, 95% confidence interval, 1.336-8.027; p = 0.011) were independently associated with a greater WML burden in the fully adjusted multivariable model. Similar results were found when the H3Cit was analyzed as a continuous variable. Furthermore, the multiple-adjusted spline regression model showed a linear association between H3Cit levels and severe WMLs (P = 0.001 for linearity). CONCLUSIONS: In the present study, increased CitH3 levels were positively associated with extensive WMLs in ischemic stroke patients, indicating a role of neutrophil extracellular traps formation in the pathogenesis of WMLs.

USP7 promotes non-small-cell lung cancer cell glycolysis and survival by stabilizing and activating c-Abl.

BACKGROUND: Abelson tyrosine kinase (c-Abl) is frequently mutated and highly expressed, and promotes non-small-cell lung cancer (NSCLC) survival, metastasis and tumorigenesis. c-Abl could also be modified through ubiquitination, but the underlying mechanism is not well understood. METHODS: Mass spectrometry assays were performed to search c-Abl deubiquitination enzymes. The molecular mechanism was determined using Co-IP assays, pull-down assays, Western blotting upon gene knockdown or overexpression. Cell lines and animal models were used to investigate the role of c-Abl and USP7 in NSCLC. EdU staining assay and Transwell assay were performed to evaluate the proliferation and migration ability of NSCLC cells, respectively. RESULTS: Ubiquitin-specific protease 7 (USP7) is found to upregulate c-Abl via the deubiquitinase screen. USP7 interacts with c-Abl and decreases its K48-linked polyubiquitination, thereby increasing the stability of c-Abl. In addition to the wild-type one, c-Abl mutants can also be deubiquitinated and stabilized by USP7. Moreover, USP7 promotes c-Abl accumulation in cytoplasm by increasing its binding to 14-3-3α/ß and activates the oncogenic c-Abl signalling pathway. Furthermore, the USP7/c-Abl axis promotes NSCLC cell glycolysis by direct phosphorylating and stabilizing hexokinase-2 (HK2). Knockdown of USP7 or c-Abl suppresses NSCLC cell glycolysis and reduces lactate production. Further studies revealed that overexpression of USP7 facilitates NSCLC cell growth and metastasis as well as xenograft growth in nude mice, while these activities are suppressed with USP7 or c-Abl being knocked down. CONCLUSIONS: USP7 is a deubiquitinase of c-Abl and upregulates its oncogenic activity. USP7 promotes NSCLC cell metabolism by activating c-Abl and HK2. Targeting the USP7/c-Abl/HK2 axis might be a potential strategy to the precision therapy of NSCLC.

Evaluation of physician guideline adherence and areas for improvement in managing patients with chronic myeloid leukemia: a cross-sectional survey.

The experience of a physician at a clinical center is among the critical factors in managing chronic myeloid leukemia (CML) during its treatment with tyrosine kinase inhibitors (TKIs). The authors conducted a cross-sectional questionnaire to investigate barriers to physician use of published evidence-based guidelines in CML management in a real-world setting. Among the participating physicians (N = 407), 99.8% of physicians reported that CML guidelines were useful; however, only 62.9% of physicians reported that they follow guidelines in real-time. Although 90.7% of physicians prefer second-generation TKIs as the first-line treatment, imatinib (88.2%) remains the most widely administered TKI in the first-line setting. Only 50.6% of physicians switched the treatment when patients failed to achieve early molecular response (at 3 months), whereas 70.3% of physicians switched the treatment when patients' response to TKI was inadequate at 6 months and/or 12 months. Moreover, only 43.5% of physicians considered treatment-free remission (TFR) as one of the top 3 goals for their patients. The major concern to obtain TFR was patients' adherence. This study demonstrated that CML management was generally in line with the current guidelines, but some of the details at the point of care are needed to be improved in CML.

Immediate early response 3 gene promotes aggressive progression and autophagy of AML by negatively regulating AKT/mTOR.

BACKGROUND: Immediate early response 3 (IER3) plays a vital role in many tumors. This study aims to explore the function and mechanism of IER3 in Acute myeloid leukemia (AML). METHODS: The expression of IER3 in AML was performed by bioinformatics analysis. CCK-8 proliferation assay, flow cytometry cycle assay, clone formation assay, and tumorigenic ability were used to investigate the effect of IER3 on AML cells. Unbiased label-free quantitative proteomics and label-free quantitative phosphoproteomics analysis were performed. The regulatory relationship between SATB1(Special AT-rich sequence binding protein 1) and IER3 was investigated by Real time-PCR, Western blot, Chromatin immunoprecipitation (CHIP), and PCR. RESULTS: The result indicated that the prognosis of the high IER3 expression group was significantly worse than that of the low expression group. CCK-8 assay showed that IER3 enhanced the proliferation ability. Cell cycle analysis showed IER3 could promote HL60 cells to enter the S phase of DNA synthesis from the quiescent phase. IER3 could stimulate HEL cells to enter mitosis. Clone-formation experiments suggested that IER3 enhanced clonogenic ability.IER3 promoted the tumorigenesis of AML. Further experimental investigation revealed that IER3 promoted autophagy and induced the occurrence and development of AML by negatively regulating the phosphorylation activation of AKT/mTOR pathway. SATB1 was found to bind to the promoter region of IER3 gene and negatively regulate its transcription. CONCLUSION: IER3 could promote the development of AML and induce autophagy of AML cells by negatively regulating the phosphorylation and activation of AKT/mTOR. By the way, SATB1 may negatively target regulates IER3 transcription.