Enhancing multiple myeloma staging: a novel cell death risk model approach.

The prognostication of survival trajectories in multiple myeloma (MM) patients presents a substantial clinical challenge. Leveraging transcriptomic and clinical profiles from an expansive cohort of 2,088 MM patients, sourced from the Gene Expression Omnibus and The Cancer Genome Atlas repositories, we applied a sophisticated nested lasso regression technique to construct a prognostic model predicated on 28 gene pairings intrinsic to cell death pathways, thereby deriving a quantifiable risk stratification metric. Employing a threshold of 0.15, we dichotomized the MM samples into discrete high-risk and low-risk categories. Notably, the delineated high-risk cohort exhibited a statistically significant diminution in survival duration, a finding which consistently replicated across both training and external validation datasets. The prognostic acumen of our cell death signature was further corroborated by TIME ROC analyses, with the model demonstrating robust performance, evidenced by AUC metrics consistently surpassing the 0.6 benchmark across the evaluated arrays. Further analytical rigor was applied through multivariate COX regression analyses, which ratified the cell death risk model as an independent prognostic determinant. In an innovative stratagem, we amalgamated this risk stratification with the established International Staging System (ISS), culminating in the genesis of a novel, refined ISS categorization. This tripartite classification system was subjected to comparative analysis against extant prognostic models, whereupon it manifested superior predictive precision, as reflected by an elevated C-index. In summation, our endeavors have yielded a clinically viable gene pairing model predicated on cellular mortality, which, when synthesized with the ISS, engenders an augmented prognostic tool that exhibits pronounced predictive prowess in the context of multiple myeloma.

Colossal anisotropic absorption of spin currents induced by chirality.

The chiral induced spin selectivity (CISS) effect, in which the structural chirality of a material determines the preference for the transmission of electrons with one spin orientation over that of the other, is emerging as a design principle for creating next-generation spintronic devices. CISS implies that the spin preference of chiral structures persists upon injection of pure spin currents and can act as a spin analyzer without the need for a ferromagnet. Here, we report an anomalous spin current absorption in chiral metal oxides that manifests a colossal anisotropic nonlocal Gilbert damping with a maximum-to-minimum ratio of up to 1000%. A twofold symmetry of the damping is shown to result from differential spin transmission and backscattering that arise from chirality-induced spin splitting along the chiral axis. These studies reveal the rich interplay of chirality and spin dynamics and identify how chiral materials can be implemented to direct the transport of spin current.

The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

Impacts of pilot carbon emission trading policies on urban environmental pollution: Evidence from China.

The trading of carbon emissions is a crucial regulatory method to address environmental pollution issues. This study takes China's carbon emission trading pilot policy established in 2013 as a quasi-natural experiment and uses the DID model to empirically test the urban panel data from 2006 to 2019. The results show that the carbon emission trading pilot policy can effectively reduce urban environmental pollution, and this effect is more noticeable in mid-western cities, northern cities, cities with fewer resources, and large-scale cities. In addition, to address the urban environmental pollution problem through this policy, the government is encouraged to raise its environmental protection awareness and put more effort into the innovation of technology. In general, this study uses carbon emission trading policies from China to confirm that market-based incentive environmental regulation tools can effectively reduce environmental pollution in urban areas. These findings can provide more theoretical support and empirical evidence for the government to use mechanisms of the market to effectively solve pollution problems, improve ecological environment quality, and accelerate the realization of green economy.

PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

Digital finance and green innovation efficiency: empirical data from Chinese listed manufacturing companies.

Amid the flourishing digital economy, digital finance overcomes the constraints of the conventional financial model and largely improves the supply efficiency and use of funds. This provides new opportunities for manufacturing corporations to improve their green innovation efficiency. Employing Chinese Shenzhen and Shanghai A-share listed manufacturing corporations between 2011 and 2021, this paper conducts an empirical analysis to study the effect of digital finance on corporate green innovation efficiency. Discoveries suggest that digital finance significantly improves manufacturing corporations' green innovation efficiency. After a few robustness tests, the results are still accurate. According to a mechanism analysis, digital finance increases the effectiveness of green innovation in manufacturing corporations by removing financing constraints. According to the heterogeneity analysis, the impact of digital finance on manufacturing corporations exhibits distinctive financial and geographical regional heterogeneity, particularly accentuated in Zhejiang Province and the central and western regions. This paper can provide a valuable reference for digital finance in supporting manufacturing corporations in green innovation ventures and improving the level of green innovation in the context of digitalization.

Health-related quality of life trajectories up to 15 years after curative treatment for esophageal cancer: a prospective cohort study.

BACKGROUND: The differentiation of specific, long-term health-related quality of life (HRQL) trajectories among esophageal cancer survivors remains unclear. The authors aimed to identify potentially distinctly different HRQL-trajectories and uncover the underlying factors of such trajectories in patients having undergone surgery (esophagectomy) for esophageal cancer. MATERIALS AND METHODS: This nationwide, prospective, and longitudinal cohort study included 420 patients who underwent curative treatment for esophageal cancer, including esophageal cancer surgery, in Sweden from 2001to 2005. The main outcome was HRQL summary score trajectories, measured by the well-validated EORTC QLQ-C30 questionnaire at 6 months, 3, 5, 10, and 15 years after esophagectomy, and analyzed using growth mixture models. Potentially underlying factors for these trajectories (age, sex, education, proxy baseline HRQL, comorbidity, tumor histology, chemo(radio)therapy, pathological tumor stage, and postoperative complications) were analyzed using weighted logistic regression providing odds ratios (OR) with 95% CI. RESULTS: Four distinct HRQL summary score trajectories were identified: Persistently good, improving, deteriorating, and persistently poor. The odds of belonging to a persistently poor trajectory were decreased by longer education (>12 years versus <9 years: OR 0.18, 95% CI: 0.05-0.66) and adenocarcinoma histology (adenocarcinoma versus squamous cell carcinoma: OR 0.37, 95% CI: 0.16-0.85), and increased by more advanced pathological tumor stage (III-IV versus 0-I: OR 2.82, 95% CI: 1.08-7.41) and postoperative complications (OR 2.94, 95% CI: 1.36-6.36). CONCLUSION: Distinct trajectories with persistently poor or deteriorating HRQL were identified after curative treatment for esophageal cancer. Education, tumor histology, pathological tumor stage, and postoperative complications might influence HRQL trajectories. The results may contribute to a more tailored follow-up with timely and targeted interventions. Future research remains to confirm these findings.

Cancer-related fatigue trajectories up to 5 years after curative treatment for oesophageal cancer.

BACKGROUND: Whether cancer-related fatigue develops differently after curative-intended oesophageal cancer treatment and the related modifiable factors are unclear. METHODS: This population-based and longitudinal cohort included 409 oesophageal cancer patients who underwent curative oesophagectomy in 2013-2020 in Sweden. The main outcome was cancer-related fatigue trajectories with measurements at 1, 1.5, 2, 2.5, 3, 4 and 5 years postoperatively by validated EORTC QLQ-FA12 questionnaire, and analysed using growth mixture models. Weighted logistic regressions provided odds ratios (OR) with 95% confidence intervals (95% CI) for underlying sociodemographic, clinical, and patient-reported outcome factors in relation to the identified trajectories. RESULTS: Two distinct overall cancer-related fatigue trajectories were identified: low level of persistent fatigue and high level of increasing fatigue, with 64% and 36% of patients, respectively. The odds of having high level of fatigue trajectory were increased by Charlson comorbidity index (≥ 2 versus 0: OR = 2.52, 95% CI 1.07-5.94), pathological tumour Stage (III-IV versus 0-I: OR = 2.52, 95% CI 1.33-4.77), anxiety (OR = 7.58, 95% CI 2.20-26.17), depression (OR = 15.90, 95% CI 4.44-56.93) and pain (continuous score: OR = 1.02, 95% CI 1.01-1.04). CONCLUSIONS: Long-term trajectories with high level of increasing cancer-related fatigue and the associated modifiable factors were identified after oesophageal cancer treatment. The results may facilitate early identification and targeted intervention for such high-risk patients.

Identification and validation of 5-methylcytosine-associated genes in diffuse large B-cell lymphoma.

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

Immune modulation of gut microbiota and its metabolites in chronic hepatitis B.

The gut microbiota is a diverse ecosystem consisting of 100 trillion microbiomes. The interaction between the host's gut and distal organs profoundly impacts various functions such as metabolism, immunity, neurology, and nutrition within the human body. The liver, as the primary immune organ, plays a crucial role in maintaining immune homeostasis by receiving a significant influx of gut-derived components and toxins. Perturbations in gut microbiota homeostasis have been linked to a range of liver diseases. The advancements in sequencing technologies, such as 16S rRNA and metagenomics, have opened up new avenues for comprehending the intricate physiological interplay between the liver and the intestine. Metabolites produced by the gut microbiota function as signaling molecules and substrates, influencing both pathological and physiological processes. Establishing a comprehensive host-bacterium-metabolism axis holds tremendous potential for investigating the mechanisms underlying liver diseases. In this review, we have provided a summary of the detrimental effects of the gut-liver axis in chronic liver diseases, primarily focusing on hepatitis B virus-related chronic liver diseases. Moreover, we have explored the potential mechanisms through which the gut microbiota and its derivatives interact with liver immunity, with implications for future clinical therapies.

The Aurora kinase inhibitor AT9283 inhibits Burkitt lymphoma growth by regulating Warburg effect.

Objective: To investigate the effect of the kinase inhibitor AT9283 on Burkitt lymphoma (BL) cells and elucidate the underlying mechanisms. Methods: The effect of AT9283 on the proliferation of BL cell lines was tested using the MTT assay. Apoptosis and cell cycle were measured by flow cytometry. The proteins associated with the cell cycle, apoptosis, and the Warburg effect were detected using Western blotting. Alterations in glycolytic metabolism in terms of glucose intake and lactate concentrations were determined by glucose and lactate assays. Results: The current study utilized the GEPIA, the Human Protein Atlas (HAP) database and immunohistochemistry to conduct analyses, which revealed a high expression of Aurora kinases and Warburg effect-related proteins in malignant B-cell lymphoma tissues. AT9283 significantly inhibited the cell proliferation of BL cells and induced G2/M arrest. Additionally, AT9283 induced apoptosis in BL cells and reversed the Warburg effect by increasing glucose uptake and reducing lactate production. Moreover, the protein expression of hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A was significantly suppressed by AT9283, possibly through the inhibition of c-Myc and HIF-1α protein expression. Conclusion: The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL.

Anisotropic Nonlocal Damping in Ferromagnet/α-GeTe Bilayers Enabled by Splitting Energy Bands.

The understanding and manipulation of anisotropic Gilbert damping is crucial for both fundamental research and versatile engineering and optimization. Although several works on anisotropic damping have been reported, no direct relationship between the band structure and anisotropic damping was established. Here, we observed an anisotropic damping in Fe/GeTe manipulated by the symmetric band structures of GeTe via angle-resolved photoemission spectroscopy. Moreover, the anisotropic damping can be modified by the symmetry of band structures. Our Letter provides insightful understandings of the anisotropic Gilbert damping in ferromagnets interfaced with Rashba semiconductors and suggests the possibility of manipulating the Gilbert damping by band engineering.

Dynamic Simulation of Nitrifying Microbial Communities for Establishing Acidic Partial Nitritation in Suspended Activated Sludge.

Acidic partial nitritation (PN) is a promising technology to achieve low-cost and energy-efficient shortcut nitrogen removal from wastewater. However, a comprehensive understanding of the acidic PN under dynamic changes of pH in a sequencing batch reactor (SBR) is still lacking. In this study, we successfully established acidic PN (NO2- accumulation ratio >80%) under dynamic pH variation from 7.0 to 4.5 in a lab-scale SBR. By accumulating in situ free nitrous acid (FNA) generation based on the dynamic pH change, acidic PN maintained stability even at a low NH4+ concentration of 100 mg N L-1. The microbial community analysis revealed that two ammonium-oxidizing bacteria (AOB) genera, Nitrosospira and Nitrosomonas, successfully coexisted and cooperated during acidic PN. None of the species of nitrite-oxidizing bacteria (NOB) showed adaptation to intermittent inhibition of in situ FNA even under high DO conditions (>4.0 mg O2 L-1). Furthermore, we innovatively incorporated the classic nitrification model with the growth and decay of different nitrifying bacterial species and their inhibition by pH, FNA, and free ammonia (FA) to predict the nitrifying microbial communities shifting for establishing acidic PN. The extended model was calibrated by using short-term batch experiments and was validated by using long-term dynamic data of the nitrifying microbial community during SBR operation. The validated model was further used to identify feasible influent conditions for the SBR PN process, including influent HCO3- concentration, NH4+ concentration and molar ratio (HCO3/NH4+). Outcomes from this study support the optimal design of acidic PN-based short-cut nitrogen removal processes for future application.

Diagnostic role of transient elastography in patients with autoimmune liver diseases: A systematic review and meta-analysis.

BACKGROUND: Noninvasive methods have been developed to detect fibrosis in many liver diseases due to the limits of liver biopsy. However, previous studies have focused primarily on chronic viral hepatitis and nonalcoholic fatty liver disease. The diagnostic value of transient elastography for autoimmune liver diseases (AILDs) is worth studying. AIM: To compare the diagnostic accuracy of imaging techniques with serum biomarkers of fibrosis in AILD. METHODS: The PubMed, Cochrane Library and EMBASE databases were searched. Studies evaluating the efficacy of noninvasive methods in the diagnosis of AILDs [autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)] were included. The summary area under the receiver operating characteristic curve (AUROC), diagnostic odds ratio, sensitivity and specificity were used to assess the accuracy of these noninvasive methods for staging fibrosis. RESULTS: A total of 60 articles were included in this study, and the number of patients with AIH, PBC and PSC was 1594, 3126 and 501, respectively. The summary AUROC of transient elastography in the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in patients with AIH were 0.84, 0.88 and 0.90, respectively, while those in patients with PBC were 0.93, 0.93 and 0.91, respectively. The AUROC of cirrhosis for patients with PSC was 0.95. However, other noninvasive indices (aspartate aminotransferase to platelet ratio index, aspartate aminotransferase/alanine aminotransferase ratio, fibrosis-4 index) had corresponding AUROCs less than 0.80. CONCLUSION: Transient elastography exerts better diagnostic accuracy in AILD patients, especially in PBC patients. The appropriate cutoff values for staging advanced fibrosis and cirrhosis ranged from 9.6 to 10.7 and 14.4 to 16.9 KPa for PBC patients.

Immune infiltration and drug specificity analysis of different subtypes based on functional status in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Surface coupling in Bi2Se3 ultrathin films by screened Coulomb interaction.

Single-particle band theory has been very successful in describing the band structure of topological insulators. However, with decreasing thickness of topological insulator thin films, single-particle band theory is insufficient to explain their band structures and transport properties due to the existence of top and bottom surface-state coupling. Here, we reconstruct this coupling with an equivalently screened Coulomb interaction in Bi2Se3 ultrathin films. The thickness-dependent position of the Dirac point and the magnitude of the mass gap are discussed in terms of the Hartree approximation and the self-consistent gap equation. We find that for thicknesses below 6 quintuple layers, the magnitude of the mass gap is in good agreement with the experimental results. Our work provides a more accurate means of describing and predicting the behaviour of quasi-particles in ultrathin topological insulator films and stacked topological systems.

HDAC inhibitor chidamide overcomes drug resistance in chronic myeloid leukemia with the T315i mutation through the Akt-autophagy pathway.

Currently, therapy for Chronic Myeloid Leukemia (CML) patients with the T315I mutation is a major challenge in clinical practice due to its high degree of resistance to first- and second-generation Tyrosine Kinase Inhibitors (TKIs). Chidamide, a Histone Deacetylase Inhibitor (HDACi) drug, is currently used to treat peripheral T-cell lymphoma. In this study, we investigated the anti-leukemia effects of chidamide on the CML cell lines Ba/F3 P210 and Ba/F3 T315I and primary tumor cells from CML patients with the T315I mutation. The underlying mechanism was investigated, and we found that chidamide could inhibit Ba/F3 T315I cells at G0/G1 phase. Signaling pathway analysis showed that chidamide induced H3 acetylation, downregulated pAKT expression and upregulated pSTAT5 expression in Ba/F3 T315I cells. Additionally, we found that the antitumor effect of chidamide could be exerted by regulating the crosstalk between apoptosis and autophagy. When chidamide was used in combination with imatinib or nilotinib, the antitumor effects were enhanced compared with chidamide alone in Ba/F3 T315I and Ba/F3 P210 cells. Therefore, we conclude that chidamide may overcome T315I mutation-related drug resistance in CML patients and works efficiently if used in combination with TKIs.

An ESIPT-Based Fluorescent Probe for Aqueous Cu+ Detection through Strip, Nanofiber and Living Cells.

Constructed on the benzothiazole-oxanthracene structure, a fluorescent probe RBg for Cu+ was designed under the ESIPT mechanism and synthesized by incorporating amide bonds as the connecting group and glyoxal as the identifying group. Optical properties revealed a good sensitivity and a good linear relationship of the probe RBg with Cu+ in the concentration range of [Cu+] = 0-5.0 µmol L-1. Ion competition and fluorescence-pH/time stability experiments offered further possibilities for dynamic Cu+ detection in an aqueous environment. HRMS analysis revealed a possible 1:1 combination of RBg and Cu+. In addition, colorimetric Cu+ detection and lysosome-targeted properties of the probe RBg were analyzed through RBg-doped PVDF nanofiber/test strips and RBg-Mito/Lyso trackers that were co-stained in living HeLa cells, enabling the probe's future applications as real-time detection methods for dynamic Cu+ tracking in the lysosomes and Cu+ detection under diversified conditions.

BP­1­102 exerts antitumor effects on T­cell acute lymphoblastic leukemia cells by suppressing the JAK2/STAT3/c­Myc signaling pathway.

Drug resistance and relapse of T-cell acute lymphoblastic leukemia (T-ALL) remain significant concerns for physicians; hence, the development and screening of effective targeted drugs remain important. Considering that STAT3 is emerging as a potential therapeutic target for T-ALL, T-ALL cell lines (MOLT-4 and CUTLL1) were treated with BP-1-102, a small-molecule inhibitor that blocks STAT3 phosphorylation. Cell Counting Kit-8 assay and colony formation assay results showed that BP-1-102 inhibited T-ALL cell proliferation and colony formation. Flow cytometry and morphological results demonstrated that BP-1-102 dramatically induced apoptosis and caused cell cycle arrest at the G0/G1 phase in T-ALL cell lines. Western blotting results indicated that BP-1-102 suppressed the JAK2/STAT3/c-Myc pathway activity in T-ALL cell lines. In conclusion, BP-1-102 suppressed the JAK2/STAT3/c-Myc signaling pathway in T-ALL cells and exerted various antitumor effects, representing a promising targeted antitumor inhibitor.