FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Clinical Distribution and Drug Susceptibility Characterization of Invasive Candida Isolates in a Tertiary Hospital of Xinjiang Province.

Objective: This study aims to investigate the clinical distribution characteristics and drug susceptibility profiles of invasive Candida isolates in a tertiary hospital in Urumqi. Methods: The examination was conducted on samples obtained from patients who were clinically diagnosed with invasive candidiasis in this hospital. A total of 109 strains of Candida strains were identified through the use of internal transcribed spacer (ITS) sequencing and fungal cultivation methods.The clinical distribution of the strains was analyzed. Antifungal drug susceptibility tests were performed using the Sensititre YO10 fungal drug susceptibility plate based on the micro-broth dilution method. Results: Candida albicans had the highest percentage (51.38%) among 109 Candida isolates, followed by C. glabrata (18.35%) and C. tropicalis (15.60%). The isolates were predominantly found in the respiratory department (41.28%), intensive care unit (ICU) (31.19%), and infection department (9.17%).The results of drug susceptibility tests indicated that amphotericin B, 5-fluorocytosine, and echinocandins exhibited good in vitro antifungal activity, with a susceptibility rate of over 96%. However, the azoles demonstrated low antifungal activity, especially posaconazole and voriconazole, which had high resistance rates of 64.71% for C. tropicalis and 70% for C. glabrata, respectively. Conclusion: In our hospital, Candida albicans was identified as the primary causal agent of invasive candidiasis. In terms of in vitro antifungal activity, echinocandins, amphotericin B, and 5-fluorocytosine demonstrated efficacy against invasive Candida infections. However, it was important to note that C. glabrata and C. tropicalis exhibited low susceptibility to azoles.

Visualizing the fibre texture of satin spar using laboratory 2D X-ray diffraction.

The suitability of point focus X-ray beam and area detector techniques for the determination of the uniaxial symmetry axis (fibre texture) of the natural mineral satin spar is demonstrated. Among the various diffraction techniques used in this report, including powder diffraction, 2D pole figures, rocking curves looped on φ and 2D X-ray diffraction, a single simple symmetric 2D scan collecting the reciprocal plane perpendicular to the apparent fibre axis provided sufficient information to determine the crystallographic orientation of the fibre axis. A geometrical explanation of the 'wing' feature formed by diffraction spots from the fibre-textured satin spar in 2D scans is provided. The technique of wide-range reciprocal space mapping restores the 'wing' featured diffraction spots on the 2D detector back to reciprocal space layers, revealing the nature of the fibre-textured samples.

Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors.

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.

SAGL: A self-attention-based graph learning framework for predicting survival of colorectal cancer patients.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The accurate survival prediction for CRC patients plays a significant role in the formulation of treatment strategies. Recently, machine learning and deep learning approaches have been increasingly applied in cancer survival prediction. However, most existing methods inadequately represent and leverage the dependencies among features and fail to sufficiently mine and utilize the comorbidity patterns of CRC. To address these issues, we propose a self-attention-based graph learning (SAGL) framework to improve the postoperative cancer-specific survival prediction for CRC patients. METHODS: We present a novel method for constructing dependency graph (DG) to reflect two types of dependencies including comorbidity-comorbidity dependencies and the dependencies between features related to patient characteristics and cancer treatments. This graph is subsequently refined by a disease comorbidity network, which offers a holistic view of comorbidity patterns of CRC. A DG-guided self-attention mechanism is proposed to unearth novel dependencies beyond what DG offers, thus augmenting CRC survival prediction. Finally, each patient will be represented, and these representations will be used for survival prediction. RESULTS: The experimental results show that SAGL outperforms state-of-the-art methods on a real-world dataset, with the receiver operating characteristic curve for 3- and 5-year survival prediction achieving 0.849±0.002 and 0.895±0.005, respectively. In addition, the comparison results with different graph neural network-based variants demonstrate the advantages of our DG-guided self-attention graph learning framework. CONCLUSIONS: Our study reveals that the potential of the DG-guided self-attention in optimizing feature graph learning which can improve the performance of CRC survival prediction.

Evaluation of water resources security in Anhui Province based on GA-BP model.

Water resources security is an important cornerstone of regional sustainable development, but the current evaluation system of water resources security is not scientific, and the measurement of safety level has not been optimized by combining algorithms. In this paper, indicators are selected according to the actual situation in Anhui Province. Firstly, correlation analysis (CA) and principal component analysis (PCA) are used to reduce the dimensionality of indicators, and then, the scientific evaluation is carried out based on genetic algorithm optimized back propagation neural network (GA-BP). This paper improves the generalization ability of the evaluation model and overcomes the shortcomings of the traditional model, which is slow in convergence and easy to fall into local optimality. The results showed that the water resources security level showed an obvious improvement trend from 2006 to 2020 and stabilized at a relatively safe level from 2014 to 2020. The subsystem of water resources environmental security is the least secure, followed by the subsystem of social and economic security, and the security of water resources regulation and response is basically stable at a relatively safe level. The conclusion of this study can provide decision-making basis for the relevant research of government, society, and scientific community.

Rewritable printing of ionic liquid nanofilm utilizing focused ion beam induced film wetting.

Manipulating liquid flow over open solid substrate at nanoscale is important for printing, sensing, and energy devices. The predominant methods of liquid maneuvering usually involve complicated surface fabrications, while recent attempts employing external stimuli face difficulties in attaining nanoscale flow control. Here we report a largely unexplored ion beam induced film wetting (IBFW) technology for open surface nanofluidics. Local electrostatic forces, which are generated by the unique charging effect of Helium focused ion beam (HFIB), induce precursor film of ionic liquid and the disjoining pressure propels and stabilizes the nanofilm with desired patterns. The IBFW technique eliminates the complicated surface fabrication procedures to achieve nanoscale flow in a controllable and rewritable manner. By combining with electrochemical deposition, various solid materials with desired patterns can be produced.

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry.

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Genome-Wide Association Studies on Chinese Wheat Cultivars Reveal a Novel Fusarium Crown Rot Resistance Quantitative Trait Locus on Chromosome 3BL.

Fusarium crown rot (FCR), primarily caused by Fusarium pseudograminearum, has emerged as a new threat to wheat production and quality in North China. Genetic enhancement of wheat resistance to FCR remains the most effective approach for disease control. In this study, we phenotyped 435 Chinese wheat cultivars through FCR inoculation at the seedling stage in a greenhouse. Our findings revealed that only approximately 10.8% of the wheat germplasms displayed moderate or high resistance to FCR. A genome-wide association study (GWAS) using high-density 660K SNP led to the discovery of a novel quantitative trait locus on the long arm of chromosome 3B, designated as Qfcr.hebau-3BL. A total of 12 significantly associated SNPs were closely clustered within a 1.05 Mb physical interval. SNP-based molecular markers were developed to facilitate the practical application of Qfcr.hebau-3BL. Among the five candidate FCR resistance genes within the Qfcr.hebau-3BL, we focused on TraesCS3B02G307700, which encodes a protein kinase, due to its expression pattern. Functional validation revealed two transcripts, TaSTK1.1 and TaSTK1.2, with opposing roles in plant resistance to fungal disease. These findings provide insights into the genetic basis of FCR resistance in wheat and offer valuable resources for breeding resistant varieties.

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism.

Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice.

Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.

Stepwise degradable PGA-SF core-shell electrospinning scaffold with superior tenacity in wetting regime for promoting bone regeneration.

Regenerating bone in the oral and maxillofacial region is clinically challenging due to the complicated osteogenic environment and the limitation of existing bone graft materials. Constructing bone graft materials with controlled degradation and stable mechanical properties in a physiological environment is of utmost importance. In this study, we used silk fibroin (SF) and polyglycolic acid (PGA) to fabricate a coaxial PGA-SF fibrous scaffold (PGA-SF-FS) to meet demands for bone grafts. The SF shell exerted excellent osteogenic activity while protecting PGA from rapid degradation and the PGA core equipped scaffold with excellent tenacity. The experiments related to biocompatibility and osteogenesis (e.g., cell attachment, proliferation, differentiation, and mineralization) demonstrated the superior ability of PGA-SF-FS to improve cell growth and osteogenic differentiation. Furthermore, in vivo testing using Sprague-Dawley rat cranial defect model showed that PGA-SF-FS accelerates bone regeneration as the implantation time increases, and its stepwise degradation helps to match the remodeling kinetics of the host bone tissue. Besides, immunohistochemical staining of CD31 and Col-1 confirmed the ability of PGA-SF-FS to enhance revascularization and osteogenesis response. Our results suggest that PGA-SF-FS fully utilizing the advantages of both components, exhibites stepwise degradation and superior tenacity in wetting regime, making it a promising candidate in the treatment of bone defects.

Application of three-dimensional technology in video-assisted thoracoscopic surgery sublobectomy.

Background: Due to the widespread use of imaging techniques, the detection rate of early-stage lung cancer has increased. Video-assisted thoracoscopic surgery (VATS) sublobectomy has emerged as a prominent alternative to lobectomy, offering advantages like reduced resection range, better preservation of lung function, and enhanced postoperative quality of life. However, sublobectomy is more intricate than lobectomy, necessitating a higher level of surgical proficiency and anatomical understanding. Methods: Three electronic databases were searched to capture relevant studies from January 2016 to March 2023, which related to the application of three-dimensional(3D) technology in VATS sublobectomy. Results: Currently, clinical departments such as orthopedics, hepatobiliary surgery, and urology have started using 3D technology. This technology is expected to be widely used in thoracic surgery in future. Now 3D technology assists in preoperative planning, intraoperative navigation and doctor-patient communication. Conclusion: 3D technologies, instrumental in locating pulmonary nodules and identifying variations in target lung segmental vessels and bronchi, play pivotal roles in VATS sublobectomy, especially in preoperative planning, intraoperative navigation, and doctor-patient communication. The limitations of 3D technology in clinical application are analyzed, and the future direction of existing 3D technology development is prospected.

Quantitative Anatomic Analysis and Clinical Application of Lumbar Spinous Process Split Laminotomy.

AIM: To investigate the feasibility and safety of lumbar spinous process split laminotomy by quantitative anatomic analysis. MATERIAL AND METHODS: Nine fresh adult human cadaveric specimens (including 45 lumbar segments) were divided into 3 groups randomly. The simulated operations and anatomic measurements were performed to evaluate the visibility angle and surgical corridor at different retraction widths (8 mm, 10 mm, and 12 mm). By measuring the width causing bony fracture in 45 lumbar segments, the safety margin of retraction width was determined. The findings of lumbar spinous process split laminotomy in one typical case were presented. RESULTS: At 8 mm retraction width, there was not enough surgical corridor for the operation procedures. At 10 mm and 12 mm retraction width, all operation procedures could be conducted smoothly. The 12 mm group presented a larger surgical corridor and shorter operative time compared with the 10 mm group. The imaging examination confirmed no bony fracture and articular capsule impairment. The visibility angle and exposure extent increased in proportion to the retraction width. The retraction width that resulted in the bony fracture ranged from 12.34 mm to 16.82 mm, with an average of (14.56 ± 1.73) mm. The positions of fracture were in the pedicle of the vertebral arch (68.9%), the lamina (26.7%), and the vertebral body (4.4%). CONCLUSION: The retraction width of 10 mm-12 mm is safe and effective. The micromanipulations such as tumor resection, nervous exploration, dural suture, etc. can be conducted smoothly via the surgical corridor. In addition, the retraction width of 12.34~16.82 mm could serve as a safety margin for surgical planning. Our findings may provide a quantitative reference for clinical application of lumbar spinous process split laminotomy.

Hypoxic environment promotes angiogenesis and bone bridge formation by activating Notch/RBPJ signaling pathway in HUVECs.

After epiphyseal fracture, the epiphyseal plate is prone to ischemia and hypoxia, leading to the formation of bone bridge and deformity. However, the exact mechanism controlling the bone bridge formation remains unclear. Notch/RBPJ signaling axis has been indicated to regulate angiogenesis and osteogenic differentiation. Our study aims to investigate the mechanism of bone bridge formation after epiphyseal plate injury, and to provide a theoretical basis for new therapeutic approaches to prevent the bone bridge formation. The expression of DLL4 and RBPJ was significantly up-regulated in HUVECs after ischemia and hypoxia treatment. Notch/RBPJ pathway positively regulated the osteogenic differentiation of BMSCs. HUVECs can induce osteogenic differentiation of BMSCs under ischemia and hypoxia. Notch/RBPJ pathway is involved in the regulation of the trans-epiphyseal bridge formation. Notch/RBPJ in HUVECs is associated with osteogenic differentiation of BMSCs and may participate in the regulation of the bone bridge formation across the epiphyseal plate.

Galleria mellonella in vitro model for chromoblastomycosis shows large differences in virulence between isolates.

BACKGROUND: Chromoblastomycosis is the World Health Organization (WHO)-recognized fungal implantation disease that eventually leads to severe mutilation. Cladophialophora carrionii (C. carrionii) is one of the agents. However, the pathogenesis of C. carrionii is not fully investigated yet. METHODS: We investigated the pathogenic potential of the fungus in a Galleria mellonella (G. mellonella) larvae infection model. Six strains of C. carrionii, and three of its environmental relative C. yegresii were tested. The G. mellonella model was also applied to determine antifungal efficacy of amphotericin B, itraconazole, voriconazole, posaconazole, and terbinafine. RESULTS: All strains were able to infect the larvae, but virulence potentials were strain-specific and showed no correlation with clinical background of the respective isolate. Survival of larvae also varied with infection dose, and with growth speed and melanization of the fungus. Posaconazole and voriconazole exhibited best activity against Cladophialophora, followed by itraconazole and terbinafine, while limited efficacy was seen for amphotericin B. CONCLUSION: Infection behavior deviates significantly between strains. In vitro antifungal susceptibility of tested strains only partly explained the limited treatment efficacy in vivo.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.