Association between Pre-operative Body Mass Index and Surgical Infection in Perihilar Cholangiocarcinoma Patients Treated with Curative Resection: A Multi-center Study.

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m2), normal BMI (18.5-24.9 kg/m2), and high BMI (≥25.0 kg/m2). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

The proliferation and differentiation of spermatogonial stem cells in the frist wave of spermatogenesis in rats with Trib3 gene knockout.

This study explores the effects of Trib3 gene knockout on adult male rat spermatogenesis. Using CRISPR/Cas9, we knocked out the Trib3 gene in Wistar rats. Results indicate altered expression of PLZF, ID4, and c-KIT in knockout rats, suggesting impaired spermatogonial stem cell proliferation and differentiation. Histological analysis reveals reduced seminiferous tubule area and decreased spermatocyte numbers. Mating experiments demonstrate reduced offspring rates after the second self-mating in knockout rats. SYCP3, a meiosis marker, shows elevated expression in knockout rat testes at 14 days postpartum, suggesting an impact on reproductive processes. ELISA results indicate decreased testosterone, FSH, and FGF9 levels in knockout rat testicular tissues. In conclusion, Trib3 gene deletion may impede spermatogonial self-renewal and promote differentiation through the FSH-FGF9- c-KIT interaction and p38MAPK pathway, affecting reproductive capacity. These findings contribute to understanding the molecular mechanisms regulating spermatogenesis.

Cytochrome P450 Enzyme Design by Constraining the Catalytic Pocket in a Diffusion Model.

Although cytochrome P450 enzymes are the most versatile biocatalysts in nature, there is insufficient comprehension of the molecular mechanism underlying their functional innovation process. Here, by combining ancestral sequence reconstruction, reverse mutation assay, and progressive forward accumulation, we identified 5 founder residues in the catalytic pocket of flavone 6-hydroxylase (F6H) and proposed a "3-point fixation" model to elucidate the functional innovation mechanisms of P450s in nature. According to this design principle of catalytic pocket, we further developed a de novo diffusion model (P450Diffusion) to generate artificial P450s. Ultimately, among the 17 non-natural P450s we generated, 10 designs exhibited significant F6H activity and 6 exhibited a 1.3- to 3.5-fold increase in catalytic capacity compared to the natural CYP706X1. This work not only explores the design principle of catalytic pockets of P450s, but also provides an insight into the artificial design of P450 enzymes with desired functions.

Transformation of antibiotics to non-toxic and non-bactericidal products by laccases ensure the safety of Stropharia rugosoannulata.

The substantial use of antibiotics contributes to the spread and evolution of antibiotic resistance, posing potential risks to food production systems, including mushroom production. In this study, the potential risk of antibiotics to Stropharia rugosoannulata, the third most productive straw-rotting mushroom in China, was assessed, and the underlying mechanisms were investigated. Tetracycline exposure at environmentally relevant concentrations (<500 µg/L) did not influence the growth of S. rugosoannulata mycelia, while high concentrations of tetracycline (>500 mg/L) slightly inhibited its growth. Biodegradation was identified as the main antibiotic removal mechanism in S. rugosoannulata, with a degradation rate reaching 98.31 % at 200 mg/L tetracycline. High antibiotic removal efficiency was observed with secreted proteins of S. rugosoannulata, showing removal efficiency in the order of tetracyclines > sulfadiazines > quinolones. Antibiotic degradation products lost the ability to inhibit the growth of Escherichia coli, and tetracycline degradation products could not confer a growth advantage to antibiotic-resistant strains. Two laccases, SrLAC1 and SrLAC9, responsible for antibiotic degradation were identified based on proteomic analysis. Eleven antibiotics from tetracyclines, sulfonamides, and quinolones families could be transformed by these two laccases with degradation rates of 95.54-99.95 %, 54.43-100 %, and 5.68-57.12 %, respectively. The biosafety of the antibiotic degradation products was evaluated using the Toxicity Estimation Software Tool (TEST), revealing a decreased toxicity or no toxic effect. None of the S. rugosoannulata fruiting bodies from seven provinces in China contained detectable antibiotic-resistance genes (ARGs). This study demonstrated that S. rugosoannulata can degrade antibiotics into non-toxic and non-bactericidal products that do not accelerate the spread of antibiotic resistance, ensuring the safety of S. rugosoannulata production.

PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression.

Depression is a serious global mental disorder. Numerous studies have found that depression may be closely related to decreased neurogenesis, neuroinflammation, neurotransmitter imbalance, and synaptic plasticity dysfunction. The pathogenesis of depression is complex and involves multiple signal transduction pathways and molecular changes. The PI3K/AKT pathway is an essential signaling pathways in neurons, which is widely expressed in emotion-related regions of the brain. Therefore, the PI3K/AKT pathway may play a moderating role in mood disorders. However, the role and mechanism of the PI3K/AKT signaling pathway in depression have not been fully described. This review systematically summarized the role of the PI3K/AKT signaling pathway in the pathogenesis of depression and discussed its potential in the treatment of depression. This will help in the treatment of depression and the development of antidepressants.

Zebra-Patterned Stretchable Helical Yarn for Triboelectric Self-Powered Multifunctional Sensing.

Smart textiles capable of both energy harvesting and multifunctional sensing are highly desirable for next-generation portable electronics. However, there are still challenges that need to be conquered, such as the innovation of an energy-harvesting model and the optimization of interface bonding between fibers and active materials. Herein, inspired by the spiral structure of natural vines, a highly stretchable triboelectric helical yarn (TEHY) was manufactured by twisting the carbon nanotube/polyurethane nanofiber (CNT/PU NF) Janus membrane. The TEHY had a zebra-stripe-like design that was composed of black interval conductive CNTs and white insulative PU NFs. Due to the different electron affinity, the zebra-patterned TEHY realized a self-frictional triboelectric effect because the numerous microscopic CNT/PU triboelectric interfaces generated an alternating current in the external conductive circuit without extra external friction layers. The helical geometry combined with the elastic PU matrix endowed TEHY with superelastic stretchability and outstanding output stability after 1000 cycles of the stretch-release test. By virtue of the robust mechanical and electrical stability, the TEHY can not only be used as a high-entropy mechanical energy harvester but also serve as a self-powered sensor to monitor the stretching or deforming stimuli and human physiological activities in real time. These merits manifested the versatile applications of TEHY in smart fabrics, wearable power supplies, and human-machine interactions.

Surgical management of a foramen magnum tumor via a far-lateral approach using an oblique straight incision: a case series report and technique note.

Objective: To review our single-institution experience in the surgical management of foramen magnum tumors via a far-lateral approach using an oblique straight incision. Methods: From October 2023 to January 2024, four cases of tumors in the foramen magnum area treated at the Capital Medical University-affiliated XuanWu hospital neurosurgery department were involved in this study. All cases were managed with a far-lateral approach using an oblique straight incision. We retrospectively reviewed the clinical and imaging data, as well as the surgical strategies employed. Results: Three cases of foramen magnum meningiomas and one case of glioma of the ventral medulla. All cases underwent a far-lateral approach using an oblique straight incision; all cases had a gross total resection, and the wounds healed well without cerebral fluid leakage or scalp hydrops. Except for one case of right foramen magnum meningioma, which had dysphagia and pneumothorax, the other cases were without any postoperative complications. Conclusion: A far-lateral approach using an oblique straight incision can preserve muscle integrity and minimize subcutaneous exposure, allowing for complete anatomical reduction of muscles. This craniectomy method is simple and replicable, making it worthy of further clinical practice.

Effect of Ciprofol on Left Ventricular Myocardial Strain and Myocardial Work in Children Undergoing Cardiac Surgery: A Single-center Double-blind Randomized Noninferiority Study.

OBJECTIVE: The current work was designed to compare the effects of ciprofol and propofol on left ventricular systolic function and myocardial work by noninvasive speckle-tracking echocardiography in children undergoing surgical repair of atrial septal or ventricular septal defects. DESIGN: A single-center double-blind randomized noninferiority study was conducted. SETTING: The research occurred at a tertiary care center affiliated with Shanghai Jiao Tong University, China. PARTICIPANTS: One hundred and twelve children aged 1 month to 16 years undergoing atrial septal or ventricular septal defect surgery with cardiopulmonary bypass were included. INTERVENTIONS: One hundred and twelve children were allocated randomly to receive ciprofol (n = 67) or propofol (n = 45) in a 1.5:1 ratio. Ciprofol or propofol were intravenously infused at loading doses of 0.4 mg/kg or 2.0 mg/kg, respectively, over 30 seconds, depending on the physical condition of each patient. When the bispectral index was maintained between 45 and 55 after induction, transthoracic echocardiography, including apical two-chamber, three-chamber, and four-chamber views, were collected bedside. MEASUREMENTS AND MAIN RESULTS: Of the 112 patients enrolled, 104 completed the study. Global longitudinal strain in the ciprofol and propofol groups after anesthesia was -17.3% (95% confidence interval [CI] -18.0% to -16.6%) and -17.8% (95% CI -18.7 to -17.0%) in the full analysis set and -17.5% (95% CI -18.2% to -16.9%) and -17.8% (95% CI -18.7% to -17.0%) in the per-protocol set, respectively. The noninferiority margin was set at 2% and confirmed with a lower limit of two-sided 95% CI for the intergroup difference of 1.58% in the full analysis set and 1.34% in the per-protocol set. There were no significant differences between the groups in left ventricular systolic and diastolic function and myocardial work indices. Postoperative vasoactive-inotropic score, NT-proBNP, duration of mechanical ventilation, and the length of stay in the cardiac intensive care unit and hospital were also comparable between the two groups (all p > 0.05). CONCLUSIONS: Ciprofol did not show different effects on myocardial function and postoperative outcomes from propofol. Further, on the sensitive cardiac systole marker global longitudinal strain, ciprofol demonstrated noninferiority to propofol. Ciprofol might be an alternative solution for cardiac anesthesia in children with congestive heart disease with mild lesion.

Generation and Characterization of Induced Pluripotent Stem Cells Carrying An ASXL1 Mutation.

Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for ASXL1-mutated diseases are mainly based on the complete deletion of Asxl1 or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous ASXL1 mutation. The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without ASXL1 mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that ASXL1 mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant ASXL1 was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying ASXL1 mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.

Sirolimus-eluting iron bioresorbable scaffold versus cobalt-chromium everolimus-eluting stents in patients with coronary artery disease: Rationale and design of the IRONMAN-II trial.

BACKGROUND: The previous first-in-human study established the preliminary safety and effectiveness of the novel thin-strut iron bioresorbable scaffold (IBS). The current study aims to directly compare the imaging and physiological efficacy, and clinical outcomes of IBS with contemporary metallic drug-eluting stents (DES). METHODS: A total of 518 patients were randomly allocated to treatment with IBS (257 patients) or metallic DES (261 patients) from 36 centers in China. The study is powered to test noninferiority of the IBS compared with the metallic everolimus-eluting stent in terms of the primary endpoint of in-segment late lumen loss at 2 years, and major secondary endpoints including 2-year quantitative flow ratio and cross-sectional mean flow area measured by optical coherence tomography (OCT) (limited to the OCT subgroup, 25 patients in each group). CONCLUSION: This will be the first powered randomized trial investigating the safety and efficacy of the novel thin-strut IBS compared to a contemporary metallic DES. The findings will provide valuable evidence for future research of this kind and the application of metallic bioresorbable scaffolds.

Plasma extracellular vesicles proteomics in meningioma patients.

Tumor derived Extracellular vesicles (EVs) in circulating system may contain tumor-specific markers, and EV detection in body fluids could become an important tool for early tumor diagnosis, prognosis assessment. Meningiomas are the most common benign intracranial tumors, few studies have revealed specific protein markers for meningiomas from patients' body fluids. In this study, using proximity labeling technology and non-tumor patient plasma as a control, we detected protein levels of EVs in plasma samples from meningioma patients before and after surgery. Through bioinformatics analysis, we discovered that the levels of EV count and protein count in meningioma patients were significantly higher than those in healthy controls, and were significantly decreased postoperatively. Among EV proteins in meningioma patients, the levels of MUC1, SIGLEC11, E-Cadherin, KIT, and TASCTD2 were found not only significantly elevated than those in healthy controls, but also significantly decreased after tumor resection. Moreover, using publicly available GEO databases, we verified that the mRNA level of MUC1, SIGLEC11, and CDH1 in meningiomas were significantly higher in comparison with normal dura mater tissues. Additionally, by analyzing human meningioma specimens collected in this study, we validated the protein levels of MUC1 and SIGLEC11 were significantly increased in WHO grade 2 meningiomas and were positively correlated with tumor proliferation levels. This study indicates that meningiomas secret EV proteins into circulating system, which may serve as specific markers for diagnosis, malignancy predicting and tumor recurrent assessment.

Whole-exome sequencing screening for candidate genes and variants associated with primary sporadic keratoconus in Chinese patients.

The pathogenesis of keratoconus (KC) is complex, and genetic factors play an important role. The purpose of this study was to screen and analyse candidate genes and variants in Chinese patients with primary sporadic KC. Whole-exome sequencing (WES) was performed to identify candidate genes and variants in 105 unrelated Chinese patients with primary sporadic KC. Through a series of screening processes, 54 candidate variants in 26 KC candidate genes were identified in 53 KC patients (53/105, 50.5%). These 54 candidate variants included 10 previously identified variants in 9 KC candidate genes and 44 novel variants in 20 KC candidate genes. The previously identified variants occurred in 25.7% (27/105) of patients. Of these, 4 variants (COL6A5, c.5014T > G; CAST, c.1814G > A; ZNF469, c.946G > A; and MPDZ, c.3836A > G) were identified for the first time in Chinese KC patients. The novel variants occurred in 33.3% (35/105) of patients. Of the 26 screened KC candidate genes, 11 KC candidate genes (CAT, COL12A1, FLG, HKDC1, HSPG2, PLOD1, ITGA2, TFAP2B, USH2A, WNT10A, and COL6A5) were found to be potentially pathogenic in Chinese KC patients for the first time. Gene Ontology (GO) biological process (BP) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the 26 KC candidate genes using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The results showed that the KC candidate genes were significantly enriched in biological processes such as collagen fibril organization and extracellular matrix (ECM) organization and in ECM-receptor interaction and protein digestion and absorption pathways. The results further expand the spectrum of KC candidate variants and provide a basis for further KC gene studies.

16S rRNA gene sequencing reveals altered gut microbiota in young adults with schizophrenia and prominent negative symptoms.

BACKGROUND: Gut dysbiosis has been established as a characteristic of schizophrenia (SCH). However, the signatures regarding SCH patients with prominent negative symptoms (SCH-N) in young adults have been poorly elucidated. METHODS: Stool samples were obtained from 30 young adults with SCH-N, 32 SCH patients with prominent positive symptoms (SCH-P) along with 36 healthy controls (HCs). Microbial diversity and composition were analyzed by 16S rRNA gene sequencing. Meanwhile, psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). RESULTS: There is a significant difference in ß-diversity but not α-diversity indexes among the three groups. Moreover, we found a higher abundance of Fusobacteria and Proteobacteria phyla and a lower abundance of Firmicutes phyla in SCH-N when compared with HC. Besides, we identified a diagnostic potential panel comprising six genera (Coprococcus, Monoglobus, Prevotellaceae_NK3B31_group, Escherichia-Shigella, Dorea, and Butyricicoccus) that can distinguish SCH-N from HC (area under the curve = 0.939). However, the difference in microbial composition between the SCH-N and SCH-P is much less than that between SCH-N and the HC, and SCH-N and SCH-P cannot be effectively distinguished by gut microbiota. CONCLUSION: The composition of gut microbiota was changed in the patients with SCH-N, which may help in further understanding of pathogenesis in young adults with SCH-N.

A novel Ag-loaded 4 Å zeolite as an efficient catalyst for epoxidation of styrene.

In this study, a novel Ag-loaded 4 Å zeolite was synthesized through the combined action of strong ultrasound and a high-voltage electrostatic field (the Z-Ag-UE) and its catalytic activity was evaluated in the epoxidation of styrene. The prepared catalysts were characterized using XRD, SEM, XPS, BET, TG, ICP-OES. The results showed that the silver evenly dispersed inside the octahedral 4 Å zeolite structure rather than being attached to the surface of the material like in the impregnation method, and this Ag-loaded 4 Å zeolite had a high surface area, uniform particle size distribution, and excellent high temperature thermal stability. The catalytic performance of the Ag-loaded 4 Å zeolite was investigated by varying the reaction conditions such as the amount of catalyst, temperature, and reaction time. Under optimized conditions, the Ag-loaded 4 Å zeolite showed high selectivity and conversion for the epoxidation of styrene, achieving a conversion rate of up to 98% and a selectivity of 94%. In particular, the catalyst had excellent recyclability and was reused more than fifteen times with the catalytic performance remaining unchanged. This method of loading metal prepared under external field conditions provides a new method and idea for future research in related fields.

Blocking SLC7A11 attenuates the proliferation of esophageal squamous cell carcinoma cells.

The role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of ß-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

Nitrogen, sulfur co-coordinated iron single-atom catalysts with the optimized electronic structure for highly efficient oxygen reduction in Zn-air battery and fuel cell.

Atomically dispersed iron-nitrogen-carbon (FesbndNsbndC) materials have been considered ideal catalysts for the oxygen reduction. Unfortunately, designing and adjusting the electronic structure of single-atom Fe sites to boost the kinetics and activity still faces grand challenges. In this work, the coordination environment engineering is developed to synthesize the FeSA/NSC catalyst with the tailored N, S co-coordinated Fe atomic site (Fe-N3S site). The structural characterizations and theoretical calculations demonstrate that the incorporation of sulfur can optimize the charge distribution of Fe atoms to weaken the adsorption of OH* and facilitate the desorption of OH*, thus leading to enhanced kinetics process and intrinsic activity. As a result, the S-modified FeSA/NSC exhibits outstanding catalytic activity with the half-wave potentials (E1/2) of 0.915 V and 0.797 V, as well as good stability, in alkaline and acidic electrolytes, respectively. Impressively, the excellent performance of FeSA/NSC is further confirmed in Zn-air batteries (ZABs) and fuel cells, with high peak power densities (146 mW cm-2 and 0.259 W cm-2).

Quantified difference of the collapsed cone convolution (CCC) and Monte Carlo (MC) algorithms based on DVH and gamma analysis for cervical cancer radiation therapy.

OBJECTIVE: To quantify the difference between the (collapsed cone convolution) CCC algorithm and the (Monte Carlo) MC algorithm and remind that the planners should pay attention to some possible uncertainties of the two algorithms when employing the two algorithms. METHODS: Thirty patients' cervical cancer VMAT plans were designed with a Pinnacle TPS (Philips) and divided equally into two groups: the simple group (SG, target volume was only the PTV) and the complex group (CG, target volume included the PTV and PGTV). The plans from the Pinnacle TPS were transferred to the Monaco TPS (Elekta). The plans' parameters all remained unchanged, and the dose was recalculated. Gamma passing rates (GPRs) obtained from dose distribution from Pinnacle TPS compared with that from Monaco TPS with SNC software based on three triaxial planes (transverse, sagittal and coronal). GPRs and DVH were used to quantify the difference between the CCC algorithm in pinnacle TPS and the MC algorithm in Monaco TPS. RESULTS: Among the statistical dose indexes in DVHs from the Pinnacle and Monaco TPSs, there were 7(7/15) dose indexes difference with statistically significant differences in the SG, and 10(10/18) dose indexes difference with statistically significant differences in the CG. With 3%/3 mm criterion, the most (5/6) GPRs were greater than 95% from the SG and CG. But with 2%/2 mm criterion, the most (5/6) GPRs were less than 90% from the two groups. In addition, we found that GPRs were also related to the selected triaxial planes and the complexity of the plan (GPRs varied with the SG and CG). CONCLUSIONS: Obvious difference between the CCC and MC algorithms from Pinnacle and Monaco TPS. DVH maybe better than 2D gamma analysis on quantifying difference of the CCC and MC algorithms. Some attention should be paid to the uncertainty of the TPS algorithm, especially when the indicator on the DVH is at the critical point of the threshold value, because the algorithm used may overestimate or underestimate the DVH indicator.

TIF1ß activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia.

TIF1ß/KAP1/TRIM28, a chromatin modulator, both represses and activates the transcription of genes in normal and malignant cells. Analyses of datasets on leukemia patients revealed that the expression level of TIF1ß was increased in patients with chronic myeloid leukemia at the blast crisis and acute myeloid leukemia. We generated a BCR::ABL1 conditional knock-in (KI) mouse model, which developed aggressive myeloid leukemia, and demonstrated that the deletion of the Tif1ß gene inhibited the progression of myeloid leukemia and showed longer survival than that in BCR::ABL1 KI mice, suggesting that Tif1ß drove the progression of BCR::ABL1-induced leukemia. In addition, the deletion of Tif1ß sensitized BCR::ABL1 KI leukemic cells to dasatinib. The deletion of Tif1ß decreased the expression levels of TIF1ß-target genes and chromatin accessibility peaks enriched with the Fosl1-binding motif in BCR::ABL1 KI stem cells. TIF1ß directly bound to the promoters of proliferation genes, such as FOSL1, in human BCR::ABL1 cells, in which TIF1ß and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCR::ABL1 KI cells, Tif1ß and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCR::ABL1 KI stem cells and drove the progression of myeloid leukemia.

Targeting BIRC5 as a therapeutic approach to overcome ASXL1-associated decitabine resistance.

Hypomethylating agents (HMAs) are widely employed in the treatment of myeloid malignancies. However, unresponsive or resistant to HMAs occurs in approximately 50 % of patients. ASXL1, one of the most commonly mutated genes across the full spectrum of myeloid malignancies, has been reported to predict a lower overall response rate to HMAs, suggesting an essential need to develop effective therapeutic strategies for the patients with HMA failure. Here, we investigated the impact of ASXL1 on cellular responsiveness to decitabine treatment. ASXL1 deficiency increased resistance to decitabine treatment in AML cell lines and mouse bone marrow cells. Transcriptome sequencing revealed significant alterations in genes regulating cell cycle, apoptosis, and histone modification in ASXL1 deficient cells that resistant to decitabine. BIRC5 was identified as a potential target for overcoming decitabine resistance in ASXL1 deficient cells. Furthermore, our experimental evidence demonstrated that the small-molecule inhibitor of BIRC5 (YM-155) synergistically sensitized ASXL1 deficient cells to decitabine treatment. This study sheds light on the molecular mechanisms underlying the ASXL1-associated HMA resistance and proposes a promising therapeutic strategy for improving treatment outcomes in affected individuals.