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Abstract Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; P

Abstract The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif −1116 TTAAAA−1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif −1116 TTAAAA−1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif −1116TTAAAA−1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM.

Abstract The effects of a second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen after graft failure in patients with severe aplastic anemia remain unclear. Eight severe aplastic anemia patients with graft failure with a median age of 12.5 (range, 3–22) years were retrospectively reviewed. At the second transplantation, they received a median mononuclear cell number of 15.7 (range, 11.2–20.9) × 108/kg or a median CD34+ cell number of 6.2 (range, 2.5–17.5) × 106/kg. They were all successfully engrafted, with a median time of 12.5 (range, 11–16) days for neutrophils and 24 (range, 14–50) days for platelets. Three patients developed skin acute graft-versus-host disease Grades I–II, and another 3 developed limited chronic graft-versus-host disease. All patients successfully recovered after treatment with methylprednisolone (0.5–1 mg/kg/day) and tacrolimus. One patient each died of respiratory failure caused by multidrug-resistant Klebsiella pneumoniae at 8 months and invasive fungal disease at 23 months after transplantation. Six patients survived with a 5-year estimated overall survival of 75% and a median follow-up time of 61 (range, 8–129) months. A second haploidentical bone marrow transplantation with an antithymocyte antibody-containing conditioning regimen was feasible for saving severe aplastic anemia patients with graft failure.

Abstract Multiple myeloma (MM) is a distinguished hematologic malignancy, with existing studies elucidating its interaction with neutrophil extracellular traps (NETs), which may potentially facilitate tumor growth. However, systematic investigations into the role of NETs in MM remain limited. Utilizing the single-cell dataset GSE223060, we discerned active NET cell subgroups, namely neutrophils, monocytes, and macrophages. A transcriptional trajectory was subsequently constructed to comprehend the progression of MM. Following this, an analysis of cellular communication in MM was conducted with a particular emphasis on neutrophils, revealing an augmentation in interactions albeit with diminished strength, alongside abnormal communication links between neutrophils and NK cells within MM samples. Through the intersection of differentially expressed genes (DEGs) between NET active/inactive cells and MM versus healthy samples, a total of 316 genes were identified. This led to the development of a 13-gene risk model for prognostic prediction based on overall survival, utilizing transcriptomics dataset GSE136337. The high-risk group manifested altered immune infiltration and heightened sensitivity to chemotherapy. A constructed nomogram for predicting survival probabilities demonstrated encouraging AUCs for 1, 3, and 5-year survival predictions. Collectively, our findings unveil a novel NET-related prognostic signature for MM, thereby providing a potential avenue for therapeutic exploration.

Summary: The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

Abstract Background Currently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation. Methods We searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI). Results This meta-analysis included 10 studies involving a total of 243 patients. The pooled complete response and complete response with incomplete blood count recovery rate of Venetoclax combined with HMAs for post-transplantation relapse in AML/MDS was 32% (95% CI, 26-39%, I2 = 0%), with an overall response rate of 48% (95% CI, 39-56%, I2 = 37%). The 6-month survival rate was 42% (95% CI, 29-55%, I2 = 62%) and the 1-year survival rate was 23% (95% CI, 11-38%, I2 = 78%). Conclusion This study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.

ObjectiveWe sought to evaluate the use of quantitative Dixon (Q-Dixon) and intravoxel incoherent motion diffusion imaging (IVIM) for the differential diagnosis of aplastic anemia (AA) and acute myeloid leukemia (AML).MethodsBetween August 2021 and October 2023, we enrolled 68 diagnosed patients, including 36 patients with AA and 32 patients with AML, as well as 26 normal controls. All patients underwent 3-Tesla magnetic resonance imaging, which included IVIM and T2*-corrected Q-Dixon imaging at the L2–4 level. The iliac crest biopsy’s pathology was used as the diagnostic criterion. The interobserver measurement repeatability was evaluated using the intraclass correlation coefficient (ICC). One-way analysis of variance, Spearman analysis, and receiver operating characteristic curve analysis were used.ResultsThe fat fraction (FF) and perfusion fraction (f) values were statistically significantly different between the three groups (p < 0.001 and p = 0.007). The FF and f values in the AA group were higher than those in the AML group. The true apparent diffusion coefficient (D) value was substantially negatively correlated to the FF and R2* values (r = −0.601, p < 0.001; r = −0.336, p = 0.002). The f value was positively correlated with both FF and pseudo-apparent diffusion coefficient (D*) values (r = 0.376, p < 0.001; r = 0.263, p = 0.017) and negatively correlated with the D value (r = −0.320, p = 0.003). The FF and f values were negatively correlated with the degree of myelodysplasia (r = −0.597, p < 0.001; r = −0.454, p = 0.004), and the D value was positively correlated with the degree of myelodysplasia (r = 0.395, p = 0.001). For the differential diagnosis of AA and AML, the Q-Dixon model’s sensitivity (93.75%) and specificity (84%) confirmed that it outperformed the IVIM model.ConclusionQ-Dixon parameters have the potential to be used as new biomarkers to differentiate AA from AML.

ABSTRACTObjectives: The meta-analysis sought to evaluate the efficacy and safety of a combination of venetoclax (Ven) and azacitidine (AZA) in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Methods We searched PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, and Web of Science for eligible studies from inception to June 2022. We used the Cochrane Risk of Bias 2.0 (RoB 2.0) and Methodological Index for Non-Randomized Studies (MINORS) to evaluate the quality of the included literature. The inverse variance method was used to calculate the pooled proportion and 95% confidence interval (CI).Results The meta-analysis included nineteen studies with a total of 1615 patients. The pooled overall CR/CRi (complete response (CR)/complete response with incomplete blood count recovery (CRi)) rate for AML and MDS was 57.9% (95% CI 49.5-65.9%, I2 = 83%). Subgroup analyses showed that the rate of pooled CR/CRi was 67.5% (95% CI 61.1-73.3%, I2 = 54%) for the new-diagnosed (ND) AML group, 30% (95% CI 20-44.1%, I2 = 66%) for relapsed/refractory (R/R) AML, and 67.6% (95% CI 52.6-79.8%, I2 = 65%) for MDS, respectively. One randomized controlled trial (RCT) showed that CR/CRi was 64.7% in ND-AML patients. A total of 9 studies reported adverse events, with neutropenia being the most common of grade 3–4 adverse events, with a rate of 53.7% (95% CI 61.1-73.3%, I2 = 54%).Conclusion The present meta-analysis demonstrated that the Ven + AZA regimen is efficacious for the treatment of AML and MDS, with it being more effective for ND-AML than R/R AML. The most common adverse effects of this regimen are grade 3–4 neutropenia and neutropenia with fever.

Abstract Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a refractory and recurrent subtype of B-cell ALL enriched with kinase-activating rearrangements. Incomplete understanding of the heterogeneity within the tumor cells presents a major challenge for the diagnosis and therapy of Ph-like ALL. Here, we exhibited a comprehensive cell atlas of one Ph-like ALL patient with a novel TPR-PDGFRB fusion gene at diagnosis and relapse by using single-cell RNA sequencing (scRNA-seq). Twelve heterogeneous B-cell clusters, four with strong MKI67 expression indicating highly proliferating B cells, were identified. A relapse-enriched B-cell subset associated with poor prognosis was discovered, implicating the transcriptomic evolution during disease progression. Integrative single-cell analysis was performed on Ph-like ALL and Ph+ ALL patients, and revealed Ph-like specific B-cell subpopulations and shared malignant B cells characterized by the ectopic expression of the inhibitory receptor CLEC2D. Collectively, scRNA-seq of Ph-like ALL with a novel TPR-PDGFRB fusion gene provides valuable insights into the underlying heterogeneity associated with disease progression and offers useful information for the development of immunotherapeutic techniques in the future.

Abstract Background Acute lymphoblastic leukemia (ALL) is a type of heterogeneous hematopoietic malignancy that accounts for approximately 20% of adult ALL. Although ALL complete remission (CR) rate has increased to 85–90% after induction chemotherapy, 40–50% of patients eventually relapsed. Therefore, it is necessary to improve the outcomes of ALL via accurate diagnosis and individualized treatments, which benefits in part from molecular biomarkers. Here, we identified a new fusion gene, Acyl-CoA Thioesterase 7–Nephrocystin 4 (ACOT7–NPHP4), in a 34-year-old patient with ALL. The fusion gene contributed to chemoresistance to doxorubicin and acted as a new molecular marker. Case presentation A 34-year-old male patient was diagnosed with ALL (common B cell) based on clinical manifestations and laboratory results. Although the patient received two cycles of the hyper-CVAD-L regimen as chemotherapy, the induction treatment failed. Because of the refusal of further treatments, the patient died of rapid progression of ALL one month later. Finally, a new fusion transcript, ACOT7–NPHP4, was detected in the patient’s lymphoblastic leukemia cells via RNA sequencing. Conclusion This is the first report of a patient with ALL carrying an ACOT7–NPHP4 fusion gene. These findings may help understand the impact of ACOT7–NPHP4 in clinical molecular monitoring and drug resistance to doxorubicin; furthermore, its leukemogenesis will be essential to explore in future.

BackgroundRefractory/relapsed acute myeloid leukemia (R/R AML) has unsatisfactory outcomes even after allogeneic hematopoietic stem cell transplantation. Long-term survival is mainly influenced by complete remission (CR) rates after induction therapies.ObjectivesTo investigate CR/CR with incomplete hematologic recovery (CRi) rates and adverse events with a new induction therapy (bortezomib, homoharringtonine, and cytarabine [BHA]) for patients with R/R AML.MethodsWe enrolled 21 patients with R/R AML (median age, 42 [range, 30–62] years), who received BHA for remission induction (bortezomib, 1.3 mg/m2/day on days 1 and 4; homoharringtonine, 4 mg/m2/day for 5 days, and cytarabine, 1.5 g/m2/day for 5 days). CR and adverse events were assessed.ResultsAfter one course of BHA, the CR/CRi and partial remission rates were 38.1% and 14.3%, respectively, with an overall response rate (ORR) of 52.4% in 21 patients. 9 of 21 patients harbored FLT3-ITD or FLT3-TKD mutations, and achieved either CR/CRi or ORR of 66.7% (P=0.03) by comparison with that in R/R AML without FLT3 mutation. After induction therapy, consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation led to a one-year overall survival of 27.8% in all patients. One-year relapse-free survival was 50% in 8 patients who had achieved CR/CRi after one course of BHA. During induction, non-hematologic adverse events (grade 3/4) commonly were infection (90.5%), hypokalemia (14.4%), hypocalcemia (14.3%), and mucositis (9.5%). In patients achieving CR, the median time to neutrophil count >0.5×109/L and time to platelet count >20×109/L were 15 (13–17) days and 13 (13–18) days, respectively.ConclusionBHA chemotherapy regimen was safe and tolerable to serve as an induction therapy for R/R AML, particularly with FLT3 mutation. The higher CR/CRi rate will give a clue to determine a potentialeffectiveness of BHA for AML patients carrying FLT3 mutation in a further investigation.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2000029841.

Abstract Background Rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients. Methods DNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling. Results We identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32). Conclusions The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.

Abstract Background With the progression of next‐generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. Recent findings A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine‐rich quadruplex DNA (G4‐DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome‐wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune‐deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1, thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over‐expression was directed toward G4‐unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre‐malignant cellular compartments. Conclusions Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

Abstract Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Genomic loss of mismatched human leukocyte antigen (HLA loss) is one of the most vital immune escape mechanisms of leukemic cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the methods currently used for HLA loss analysis have some shortcomings. Limited literature has been published, especially in lymphoid malignancies. This study aims to evaluate the incidences, risk factors of HLA loss, and clinical outcomes of HLA loss patients. In all, 160 patients undergoing partially mismatched related donor (MMRD) transplantation from 18 centers in China were selected for HLA loss analysis with the next-generation sequencing (NGS)-based method, which was validated by HLA-KMR. Variables of the prognostic risk factors for HLA loss or HLA loss–related relapse were identified with the logistic regression or the Fine and Gray regression model. An HLA loss detection system, HLA-CLN [HLA chimerism for loss of heterozygosity (LOH) analysis by NGS], was successfully developed. Forty (25.0%) patients with HLA loss were reported, including 27 with myeloid and 13 with lymphoid malignancies. Surprisingly, 6 of those 40 patients did not relapse. The 2-year cumulative incidences of HLA loss (22.7% vs 22.0%, P = 0.731) and HLA loss–related relapse (18.4% vs 20.0%, P = 0.616) were similar between patients with myeloid and lymphoid malignancies. The number of HLA mismatches (5/10 vs

Abstract Background Inactivation of the tumor suppressor p53 is critical for pathogenesis of glioma, in particular glioblastoma multiforme (GBM). MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. Hitherto, it is unclear whether the stability of the p53/MDM2 complex is affected by lncRNAs, in particular circular RNAs that are usually abundant and conserved, and frequently implicated in different oncogenic processes. Methods RIP-seq and RIP-qPCR assays were performed to determine the most enriched lncRNAs (including circular RNAs) bound by p53, followed by bioinformatic assays to estimate the relevance of their expression with p53 signaling and gliomagenesis. Subsequently, the clinical significance of CDR1as was evaluated in the largest cohort of Chinese glioma patients from CGGA (n = 325), and its expression in human glioma tissues was further evaluated by RNA FISH and RT-qPCR, respectively. Assays combining RNA FISH with protein immunofluorescence were performed to determine co-localization of CDR1as and p53, followed by CHIRP assays to confirm RNA-protein interaction. Immunoblot assays were carried out to evaluate protein expression, p53/MDM2 interaction and p53 ubiquitination in cells in which CDR1as expression was manipulated. After AGO2 or Dicer was knocked-down to inhibit miRNA biogenesis, effects of CDR1as on p53 expression, stability and activity were determined by immunoblot, RT-qPCR and luciferase reporter assays. Meanwhile, impacts of CDR1as on DNA damage were evaluated by flow cytometric assays and immunohistochemistry. Tumorigenicity assays were performed to determine the effects of CDR1as on colony formation, cell proliferation, the cell cycle and apoptosis (in vitro), and on tumor volume/weight and survival of nude mice xenografted with GBM cells (in vivo). Results CDR1as is found to bind to p53 protein. CDR1as expression decreases with increasing glioma grade and it is a reliable independent predictor of overall survival in glioma, particularly in GBM. Through a mechanism independent of acting as a miRNA sponge, CDR1as stabilizes p53 protein by preventing it from ubiquitination. CDR1as directly interacts with the p53 DBD domain that is essential for MDM2 binding, thus disrupting the p53/MDM2 complex formation. Induced upon DNA damage, CDR1as may preserve p53 function and protect cells from DNA damage. Significantly, CDR1as inhibits tumor growth in vitro and in vivo, but has little impact in cells where p53 is absent or mutated. Conclusions Rather than acting as a miRNA sponge, CDR1as functions as a tumor suppressor through binding directly to p53 at its DBD region to restrict MDM2 interaction. Thus, CDR1as binding disrupts the p53/MDM2 complex to prevent p53 from ubiquitination and degradation. CDR1as may also sense DNA damage signals and form a protective complex with p53 to preserve p53 function. Therefore, CDR1as depletion may play a potent role in promoting tumorigenesis through down-regulating p53 expression in glioma. Our results broaden further our understanding of the roles and mechanism of action of circular RNAs in general and CDR1as in particular, and can potentially open up novel therapeutic avenues for effective glioma treatment.

Dasatinib treatment is approved as first-line therapy for chronic myeloid leukemia. However, pulmonary hypertension (PH) is a highly morbid and often fatal side-effect of dasatinib, characterized by progressive pulmonary vascular remodeling. Melatonin exerts strong antioxidant capacity against the progression of cardiovascular system diseases. The present work aimed to investigate the effect of melatonin on dasatinib-aggravated hypoxic PH and explore its possible mechanisms. Dasatinib-aggravated rat experimental model of hypoxic PH was established by utilizing dasatinib under hypoxia. The results indicated that melatonin could attenuate dasatinib-aggravated pulmonary pressure and vascular remodeling in rats under hypoxia. Additionally, melatonin attenuated the activity of XO, the content of MDA, the expression of NOX4, and elevated the activity of CAT, GPx, and SOD, the expression of SOD2, which were caused by dasatinib under hypoxia. In vitro, dasatinib led to decreased LDH activity and production of NO in human pulmonary microvascular endothelial cells (HPMECs), moreover increased generation of ROS, and expression of NOX4 both in HPMECs and primary rat pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. Dasatinib up-regulated the expression of cleaved caspase-3 and the ratio of apoptotic cells in HPMECs, and also elevated the percentage of S phase and the expression of Cyclin D1 in primary PASMCs under hypoxia. Melatonin ameliorated dasatinib-aggravated oxidative damage and apoptosis in HPMECs, meanwhile reduced oxidative stress level, proliferation, and repressed the stability of HIF1-α protein in PASMCs under hypoxia. In conclusion, melatonin significantly attenuates dasatinib-aggravated hypoxic PH by inhibiting pulmonary vascular remodeling in rats. The possible mechanisms involved protecting endothelial cells and inhibiting abnormal proliferation of smooth muscle cells. Our findings may suggest that melatonin has potential clinical value as a therapeutic approach to alleviate dasatinib-aggravated hypoxic PH.

In this work, we reported a young man complaining of asthenia and intermittent fever for 10 days, and an ultrasound showed an undefined lesion on his liver. Facing the patient's situation with severe agranulocytosis, anemia, and thrombocytopenia, we passed through a tough diagnostic process for choosing an appropriate treatment for him with an ambiguous result of pathological biopsy. The undefined liver lesion was successfully solved by withdrawing the androgen for observation, without lobectomy. The lesion gradually diminished over 2 years of follow-up.

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer with a mortality rate of approximately 3–6/100,000 and is the third leading cause of cancer-related death worldwide. Although several small-molecule drugs have been developed for the treatment of HCC, the choice of an agent for patients who require systemic chemotherapy at an advanced stage is still limited. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway commonly dysregulated in HCC, which makes it a promising target for anti-HCC therapies. Homoharringtonine (HHT) is an FDA-approved anti-leukemia drug with proven strong anti-tumor activity in solid tumors. In this study, we found that HHT could significantly inhibit HCC cell growth by suppressing cell proliferation and colony formation. Moreover, HHT repressed cell invasion and migration remarkably. Additionally, HHT induced cell cycle arrest at S phase and promoted apoptosis. Most importantly, we showed that HHT-induced apoptosis was a consequence of the Hippo pathway activation. Consistently, the MST1/2 inhibitor, XMU-MP-1, could restore cell viability and reverse HHT-induced cell apoptosis. Furthermore, in vivo results confirmed the tumor inhibitory effect of HHT. Taken together, our findings suggest that HHT is a potential alternative therapeutic agent for the treatment of HCC.

High exposure to advanced glycation end-products (AGEs) may induce cardiotoxicity. However, the effects and mechanisms remain to be further clarified. CYP4A plays an important role in the pathophysiological process of myocardial abnormalities by modulating oxidative stress and apoptosis (OS/Apop) signaling pathway. The present work aimed to investigate whether CYP4A mediates AGEs-induced myocardial injury. AGEs solution was administered intragastrically to C57BL/6 mice for 60 days, while the specific inhibitor of CYP4A, HET0016, was given from the 47th day via intraperitoneal injection for 2 weeks. Levels of OS/Apop in heart tissue were measured. The effects on the cell viability and apoptosis were detected in primary rat cardiomyocytes. To further investigate the mechanism, H9c2 cells were treated with HET0016 or small interfering RNAs (siRNAs) against CYP4a mRNA before incubation with AGEs. Exposure to AGEs led to significantly increased expression of CYP4A and levels of OS/Apop in heart and H9c2 cells both in vivo and in vitro. The OS/Apop pathway was activated with increased expression of NOX2, p-JNK, and cleaved caspase-3 (c-caspase-3) and decreased expression of p-Akt and Bcl-xL both in vivo and in vitro. Specific CYP4A suppression by HET0016 or siRNA exerted significant protective effects by attenuating AGEs-induced OS/Apop pathways in vitro. Our results demonstrate that specific inhibition of CYP4A might be a potential therapeutic option for myocardial injury induced by AGEs.

Objective: We sought to evaluate the use of quantitative Dixon (Q-Dixon) and intravoxel incoherent motion diffusion imaging (IVIM) for the differential diagnosis of aplastic anemia (AA) and acute myeloid leukemia (AML). Methods: Between August 2021 and October 2023, we enrolled 68 diagnosed patients, including 36 patients with AA and 32 patients with AML, as well as 26 normal controls. All patients underwent 3-Tesla magnetic resonance imaging, which included IVIM and T2*-corrected Q-Dixon imaging at the L2-4 level. The iliac crest biopsy's pathology was used as the diagnostic criterion. The interobserver measurement repeatability was evaluated using the intraclass correlation coefficient (ICC). One-way analysis of variance, Spearman analysis, and receiver operating characteristic curve analysis were used. Results: The fat fraction (FF) and perfusion fraction (f) values were statistically significantly different between the three groups (p < 0.001 and p = 0.007). The FF and f values in the AA group were higher than those in the AML group. The true apparent diffusion coefficient (D) value was substantially negatively correlated to the FF and R2* values (r = -0.601, p < 0.001; r = -0.336, p = 0.002). The f value was positively correlated with both FF and pseudo-apparent diffusion coefficient (D*) values (r = 0.376, p < 0.001; r = 0.263, p = 0.017) and negatively correlated with the D value (r = -0.320, p = 0.003). The FF and f values were negatively correlated with the degree of myelodysplasia (r = -0.597, p < 0.001; r = -0.454, p = 0.004), and the D value was positively correlated with the degree of myelodysplasia (r = 0.395, p = 0.001). For the differential diagnosis of AA and AML, the Q-Dixon model's sensitivity (93.75%) and specificity (84%) confirmed that it outperformed the IVIM model. Conclusion: Q-Dixon parameters have the potential to be used as new biomarkers to differentiate AA from AML. [ABSTRACT FROM AUTHOR]

Using angle-resolved X-ray photoelectron spectroscopy, sum-frequency generation vibrational spectroscopy, contact angle measurements, and molecular dynamics simulations, we verify that the glass transition temperature (Tg) of polymer glass is lower near the free surface. However, the experimental Tg-gradients showed a linear variation with depth (z) from the free surface, while the simulated equilibrium Tg-gradients exhibited a double exponential z-dependence. In typical simulations, Tg is determined based on the relaxation time of the system reaching a prescribed threshold value at equilibrium. Conversely, the experiments determined Tg by observing the unfreezing of molecular mobility during heating from a kinetically arrested, nonequilibrium glassy state. To investigate the impact of nonequilibrium effects on the Tg-gradient, we reduced the thermal annealing time in simulations, allowing the system to fall out of equilibrium. We observe a decrease in the relaxation time and the emergence of a modified z-dependence consistent with a linear Tg-gradient near the free surface. We further validate the impact of nonequilibrium effects by studying the dependence of the Tg on the heating/cooling rate for polymer films of varying thickness (h). Our experimental results reveal significant variations in the Tg-heating/cooling rate dependence with h below the bulk Tg, which are also observed in simulation when the simulated system is not equilibrated. We explain our findings by the reduction in mass density within the inner region of the system under nonequilibrium conditions, as observed in simulation, and recent research indicating a decrease in the local Tg of a polymer when placed next to a softer material. [ABSTRACT FROM AUTHOR]

Purpose Arthroscopic Bankart repair combined with remplissage and autologous scapular spine bone grafting have been described as a treatment for off‐track Hill–Sachs lesions with subcritical glenoid bone defects in the anterior shoulder instability. However, whether these two techniques can achieve satisfactory postoperative outcomes is unclear, and there are few comparative studies between them. Therefore, this study compared the postoperative efficacy of the two techniques for off‐track Hill–Sachs lesions with subcritical glenoid bone loss. Method Between June 2017 and December 2020, 62 patients with shoulder instability due to Off‐Track Hill–Sachs lesions with subcritical glenoid bone loss underwent surgical treatment and were included in this regression study. Thirty‐two patients underwent arthroscopic Bankart repair combined with remplissage (B + R group), and 30 patients underwent additional autologous scapular glenoid bone grafting (additional bone grafting group). The general information of the patients was recorded. The patient's activity before and after surgery was recorded. The DASH score and Constant–Murley (CM) score were used to assess the patient's functional status; the Rowe score was used to evaluate the patient's shoulder stability. The shoulder function and stability before and after surgery were analyzed and compared between the two groups. Results The final DASH scores of the B + R group and the additional bone grafting group were significantly lower than those before surgery, with a statistically significant difference (9.76 ± 4.32 vs. 27.89 ± 6.63, 8.50 ± 3.32 vs. 28.0 ± 4.27, p = 0.000); the final CM scores of the two groups were significantly higher than those before surgery (88.71 ± 3.74 vs. 73.68 ± 3.74, 87.16 ± 2.29 vs. 71.37 ± 2.68, p = 0.000). There was no statistical difference in the final DASH score and final CM score between the two groups (p > 0.05). In terms of postoperative stability, the final Rowe scores of the two groups were significantly higher than those before surgery, with a statistically significant difference (89.06 ± 9.19 vs. 41.71 ± 4.13; 93.16 ± 4.99 vs. 42.33 ± 2.53, p = 0.000). Compared with the control group, the additional bone graft group achieved higher final Rowe scores (93.16 ± 4.99 vs. 89.06 ± 9.19, p = 0.032). Conclusion For patients with anterior shoulder instability due to off‐track Hill–Sachs lesions with subcritical glenoid bone loss, although Bankart and remplissage can achieve satisfactory clinical results, additional autogenous scapular spine bone grafting can provide better stability of the shoulder, especially for patients with high sports demands.

Objectives: The objective of this study was to investigate the resistance mechanisms of a multidrug-resistant Salmonella Kentucky ST198 FJ-2064 isolated from a patient in China. Methods: The antimicrobial susceptibility of FJ-2064 was determined by the standard disc dilution and broth microdilution methods. The complete genome of FJ-2064 was sequenced using PacBio and Illumina MiSeq platforms. Polymerase chain reaction (PCR) and S1-PFGE were utilized to confirm the mutation sites and the genomic plasmids, respectively. Results: Isolate FJ-2064 belongs to sequence type ST198 and harboured no visible large plasmids, but was concurrent resistant to 22 detected antimicrobial agents including cefotaxime, ciprofloxacin, and azithromycin. The complete genome sequence identified 20 acquired antibiotic resistance genes (ARGs) and five chromosomal mutations in the gyrA and parC genes of the quinolone resistance determining regions (QRDRs) in FJ-2064. In addition, PCR sequencing confirmed that most of the ARGs were clustered on one multidrug-resistant region and a variant of SGI1-K. In particular, the bla-TEM-1 and bla-CTX−M-55, qnrS1, mph(A) genes, which confer resistance to cephalosporins, quinolones, and macrolides respectively, were all located on the multidrug-resistant region. Conclusions: We have demonstrated one multidrug-resistant region and a variant of SGI1-K in a Salmonella Kentucky ST198 that is co-resistant to cefotaxime, ciprofloxacin, and azithromycin.

To explore the variances between single-reinforced and hybrid-reinforced Al–Mg–Si alloys with TiC and B4C, 10 wt.%-(TiC + B4C)/6061Al, 10 wt.%-B4C/6061Al, 10 wt.%-TiC/6061Al and 6061Al were prepared via wet mixing for 8 h followed by vacuum hot-press sintering at 580 °C and 30 MPa for 2 h. Microstructure evolution, mechanical properties, and wear behavior were investigated in this study. The results show that unlike single reinforcement of TiC, single reinforcement of B4C and hybrid reinforcement of TiC and B4C altered the distribution of Si and facilitated the in-situ formation of SiC. Both single reinforcement and hybrid reinforcement resulted in mixed fracture characteristics of ductile fracture and cleavage fracture, while hybrid reinforcement of TiC and B4C demonstrated superior strength and plasticity matching. At equivalent particle mass fractions, single reinforcement of TiC was more conducive to inducing recrystallization during sintering, followed by single reinforcement of B4C, and hybrid reinforcement of TiC and B4C had the least effect. At equivalent particle mass fractions, single reinforcement of B4C had the most significant effect on improving the wear resistance, followed by hybrid reinforcement of TiC and B4C, and single reinforcement of TiC had the least effect. All particle addition methods demonstrated a mixed wear mechanism involving abrasive wear, adhesive wear, and spalling wear. This study provides valuable insights into the development of aluminum matrix composites.