Search

This study aims to dynamically mine the demands of hotel consumers. A total of 378,270 online reviews in the cities of Beijing, Chengdu, and Guangzhou in China were crawled using Python. Natural language processing (e.g., opinion mining and the BERT model) and an improved Kano model (containing One-dimensional, Attractive, Indifferent, and Must-be) were utilised to analyse online hotel reviews. The results indicate that the hotel attributes that consumers care about (e.g., Clean, Breakfast, and Front Desk) are dynamically fluctuating, and the attention and satisfaction of corresponding attributes will also change. This study classified consumer demand into eight types across cities and found that it changes over time. In addition, we also found that hotel attributes, satisfaction and attention, and consumer demands vary among different cities. Existing studies of capturing consumer demand are usually time-consuming and static, and the results are subjective. This study compared and analysed the consumer demands of hotels in different cities via a dynamic perspective, and used hybrid methods to improve the granularity of the analysis, expanding the general applicability of the Kano model. Hotel managers can refer to the results of this article to allocate resources for improvement and create competitive hotel services.

Abstract Aim Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. Methods An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo‐coupled mass spectrometry to identify HClnc1‐interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull‐down assay. Results HClnc1 levels were considerably greater in patients with advanced tumor‐node‐metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2‐STAT3 signaling. Conclusions HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

Abstract Background Sarcopenia is associated with various adverse outcomes in hemodialysis patients. However, current tools for assessing and diagnosing sarcopenia have limited applicability. In this study, we aimed to develop a simple and reliable nomogram to predict the risk of sarcopenia in hemodialysis patients that could assist physicians identify high-risk patients early. Methods A total of 615 patients undergoing hemodialysis at the First Affiliated Hospital College of Medicine Zhejiang University between March to June 2021 were included. They were randomly divided into either the development cohort (n = 369) or the validation cohort (n = 246). Multivariable logistic regression analysis was used to screen statistically significant variables for constructing the risk prediction nomogram for Sarcopenia. The line plots were drawn to evaluate the effectiveness of the nomogram in three aspects, namely differentiation, calibration, and clinical net benefit, and were further validated by the Bootstrap method. Results The study finally included five clinical factors to construct the nomogram, including age, C-reactive protein, serum phosphorus, body mass index, and mid-upper arm muscle circumference, and constructed a nomogram. The area under the ROC curve of the line chart model was 0.869, with a sensitivity and specificity of 77% sensitivity and 83%, the Youden index was 0.60, and the internal verification C-statistic was 0.783. Conclusions This study developed and validated a nomogram model to predict the risk of sarcopenia in hemodialysis patients, which can be used for early identification and timely intervention in high-risk groups.

Abstract Immunotherapy has gradually emerged as the most promising anticancer therapy. In addition to conventional anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, CAR-T therapy, etc., immunotherapy can also be induced by stimulating the maturation of immune cells or inhibiting negative immune cells, regulating the tumor immune microenvironment and cancer vaccines. Lipid nanovesicle drug delivery system includes liposomes, cell membrane vesicles, bacterial outer membrane vesicles, extracellular vesicles and hybrid vesicles. Lipid nanovesicles can be used as functional vesicles for cancer immunotherapy, and can also be used as drug carriers to deliver immunotherapy drugs to the tumor site for cancer immunotherapy. Here, we review recent advances in five kinds of lipid nanovesicles in cancer immunotherapy and assess the clinical application prospects of various lipid nanovesicles, hoping to provide valuable information for clinical translation in the future.

Based on the theories of moral identity, community engagement, emotional attachment, and brand loyalty, this study aims to explore oppositional loyalty’s driving factors and dimensional structure (the willingness to pay a price premium, oppositional referrals, schadenfreude, and trash-talking). Our samples comprised 533 members who contributed more than three posts monthly in Xiaomi’s mobile online communities. The structural equation modeling method was utilized to test direct effects, and hierarchical regression was adopted to verify the moderating relationship. The findings show that community engagement and brand attachment positively affect oppositional loyalty, and brand attachment partly mediates the influence of community engagement on oppositional loyalty. Furthermore, moral identity positively moderates the impacts of community engagement and brand attachment on oppositional referrals. On the contrary, moral identity negatively moderates the relationships between community engagement and trash-talking as well as between community engagement, brand attachment, and schadenfreude. Negative effects on competing brands are harmful to favored brands through the moderating effects of moral identity. Enterprises and online communities should discard the idea that more oppositional loyalty is ideal and correctly guide members’ positive and negative behaviors.

Affected by COVID-19, there is a growing trend toward healthy lifestyles and organic food consumption. The literature on organic foods focuses on the factors that influence buying behavior. A thriving organic business requires both sustained consumption and consumer contributions beyond the purchase—customer engagement behavior. The purpose of this study is to examine the factors that may drive member customers to engage with organic grocerants. This study surveyed 280 Chinese member customers of an organic grocerant to explore how to drive customer engagement behavior. Based on value co-creation theory and the customer engagement literature, this study proposed a “value acquisition–value co-creation” framework to explore the relationship between perceived value, brand trust, and customer engagement behavior. The results show that emotional and social value can directly and effectively motivate customer engagement behavior in organic grocerants. However, consumers’ perceived quality value and price value will not directly affect customer engagement behavior but instead indirectly affect it through brand trust. Furthermore, improving the perceived value of emotion, quality and price can strengthen brand trust in organic grocerants. The study confirms that brand trust is critical to organic grocerant and customer engagement. Our findings provide a new perspective for understanding the relationship between the value customers receive from organic food consumption and value co-creation through customer engagement behavior.

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10–100 nM concentration range (Fisher’s Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.

Offering organic food is a new trend in the hospitality industry seeking sustainable competitiveness. Premiums and information barriers impede continued growth in organic consumption. This study aims to explore the role of comparative advertising (CA) in organic food communication. Three empirical studies were used to verify the effect of CA vs. non-comparative advertising (NCA) on consumers’ willingness to pay a premium (WTPP) for organic food, examining how benefit appeals (health vs. environmental) and consumers’ organic skepticism affects CA. The results indicate that matching CA and health appeals increase consumers’ WTPP, while environmental appeals have no significant differences between the CA and NCA groups (Study 1). Information persuasiveness mediates the interaction between CA and benefit appeal on WTPP (Study 2). CA increases WTPP among consumers with high organic skepticism, while the interaction between CA and health appeal is only effective for low skepticism consumers (Study 3). The findings unravel and explain the mechanics of how CA works in organic products, which can help restaurants, retailers and tourist destinations advertise organic food to increase consumers’ WTPP.

Background. Regulatory T cell (Treg)/T helper (Th) 17 skewing is important in the development of acute respiratory distress syndrome (ARDS). Immunomodulatory effects of mesenchymal stem cell- (MSC-) secreted transforming growth factor- (TGF-) β1 on CD4+ T cells are environment-sensitive and lack discussion in hypoxic and inflammatory conditions. Methods. Mouse splenic CD4+ T cells were precoated with anti-CD3 (5 μg/ml) and anti-CD28 (2 μg/ml) overnight. RAW264.7 cells were added as antigen-presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0, 10, 100, and 1000 ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100 ng/ml) and hypoxia conditions (5% O2) as stimuli, MSCs were set as direct coculture or indirect coculture by transwell system. Anti-TGF-β1 neutralization antibody was added to explore the role of TGF-β1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+ T cells was performed by transfection, and then, cells were added to the MSC-CD4+ T cell coculture system in hypoxic- and LPS-stimulated condition. After 48 hours, cells or supernatants were collected for detection of frequency of Treg and Th17 subsets, CD4+ T cell apoptosis and proliferation capacity assay by flow cytometry, secretion of INF-γ, IL-17A, IL-21, TGF-β1, and IL-10 by ELISA, and levels of miR-155, Rorc, Foxp3, and Ptpn2 mRNA expression of CD4+ T cells by RT-PCR. Results. MSCs could restore skewed Treg/Th17 induced by LPS and hypoxia compared to groups without MSCs with increased secretion of TGF-β1, IL-10, and IL-17A (P

Corporate social responsibility (CSR) in the food industry has received increasing attention in recent years. Many scholars have paid attention to case studies and other empirical analyses in this field, but there is no systematic or scientific literature review. The purpose of this study is to quantitatively evaluate the knowledge structure, research hotspots, and development history in CSR in the food industry. After searching, screening, and commenting, 498 articles were left for citation analysis, co-citation analysis, and co-word analysis. The main findings of the research are as follows: (1) The overall development status of the research in the field. The analysis of the three fields that constitute the knowledge structure. (2) Research in this field has become a hot spot, but the research is rather scattered, and the scholars and experts do not have a special research core. (3) The keywords’ cluster results in 9 clustering tags, which are further grouped into 7 groups. The research of the scholars focuses on the food supply chain, consumer perception, and social media communication. (4) The research topics in this field focus on environmental responsibility, nutrition and health, and food safety. The research results show that future research should be more in-depth and reflect the new characteristics of the Internet, digitalization, and big data.

Customer participation in brand environmental responsibility is necessary for enterprises and consumers to co-create value. However, it is not yet clear why some corporate social responsibility (CSR) communications are more effective in attracting higher customer participation in a digitally transparent environment. Based on signal theory and social identity theory, this study examines the impact of the interactive effect of CSR strategy (proactive vs. reactive) and transparency signals (high vs. low) on customer trust (perceived integrity and perceived competence), customer–brand identification, and participation intention in brand environmental responsibility. We conduct a 2 × 2 study with 140 respondents. The findings reveal a significant interaction effect of CSR strategy and transparency signals on perceived integrity, perceived competence, and participation intention in brand environmental responsibility. Mediation analysis reveals that the impact of CSR strategy on participation intention is serially mediated via perceived trust and customer–brand identification and varies across different transparency levels.

Background: Multiple organ injury and dysfunction often occurs in acute critical illness and adversely affects survival. However, in patients who survive, organ function usually recovers without permanent damage. It is, therefore, likely that there are reversible mechanisms, but this is poorly understood in the pathogenesis of multiple organ dysfunction syndrome (MODS). Aims: Based on our knowledge of extracellular histones and pneumolysin, as endogenous and exogenous pore-forming toxins, respectively, here we clarify if the extent of cell membrane disruption and recovery is important in MODS. Methods: This is a combination of retrospective clinical studies of a cohort of 98 patients from an intensive care unit (ICU) in a tertiary hospital, with interventional animal models and laboratory investigation. Results: In patients without septic shock and/or disseminate intravascular coagulation (DIC), circulating histones also strongly correlated with sequential organ failure assessment (SOFA) scores, suggesting their pore-forming property might play an important role. In vivo, histones or pneumolysin infusion similarly caused significant elevation of cell damage markers and multiple organ injury. In trauma and sepsis models, circulating histones strongly correlated with these markers, and anti-histone reagents significantly reduced their release. Comparison of pneumolysin deletion and its parental strain-induced sepsis mouse model showed that pneumolysin was not essential for sepsis development, but enhanced multiple organ damage and reduced survival time. In vitro, histones and pneumolysin treatment disrupt cell membrane integrity, resulting in changes in whole-cell currents and elevated intracellular Ca2+ to lead to Ca2+ overload. Cell-specific damage markers, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and cardiac troponin I (cTnI), were released from damaged cells. Once toxins were removed, cell membrane damage could be rapidly repaired and cellular function recovered. Conclusion: This work has confirmed the importance of pore-forming toxins in the development of MODS and proposed a potential mechanism to explain the reversibility of MODS. This may form the foundation for the development of effective therapies.

Corporate social irresponsibility (CSI) seriously damages the rights and interests of stakeholders, particularly consumers. This study analyzes the consumer response to food performance irresponsibility and food corporate ethics irresponsibility by moral emotions. A situational simulation experiment was conducted with the following results: (1) Food performance irresponsibility has the greatest impact on consumer boycotts, while corporate ethics irresponsibility more often leads to consumers’ negative word of mouth (NWOM). (2) Moral emotions play a strong mediating role between CSI and consumers’ NWOM and boycott behavior. (3) Gender significantly moderates the propagation path from moral emotions to NWOM, and female consumers react more strongly to food performance irresponsibility. In conclusion, the paper offers empirical evidence of the effect food corporate social irresponsibility has on consumers’ different responses. Furthermore, it can help food enterprises to identify different CSI types and develop corresponding governance strategies.

Boldness of personality is an important theme in animal behavior and has significant ecological and evolutionary consequences. Studies on boldness in crustaceans typically focus on their behavior, while relatively few studies have focused on the formation and maintenance of and change in boldness, such as energy metabolism and neurotransmission. In this study, we measured the boldness of swimming crabs (Portunus trituberculatus) and analyzed the relationship between boldness and oxygen consumption rate, energy concentration, and the relative expression of energy-metabolism-related and 5-HT genes in mRNA. The results showed that boldness remained stable across repeated tests but changed under dangerous conditions. Swimming crabs could be divided into bold and shy individuals. Bold individuals consumed oxygen at a significantly higher rate than shy individuals. Lactate and glucose concentrations in hemolymph were significantly lower in bold individuals than in shy individuals, and mRNA relative expression of Na+/K+-ATPase and 5-HT genes was significantly higher in bold than in shy individuals. Preliminary results indicate that energy metabolism and neurotransmitters may underlie the formation and maintenance of personality characteristics of swimming crabs. Swimming crabs also exhibit behavioral flexibility in order to cope with risks. This may be an adaptation to their complex environments.

Abstract Objective To evaluate the incidence, clinical laboratory characteristics, and gene mutation spectrum of Ph‐negative MPN patients with atypical variants of JAK2, MPL, or CALR. Methods We collected a total of 359 Ph‐negative MPN patients with classical mutations in driver genes JAK2, MPL, or CALR, and divided them into two groups based on whether they had additional atypical variants of driver genes JAK2, MPL, or CALR: 304 patients without atypical variants of driver genes and 55 patients with atypical variants of driver genes. We analyzed the relevant characteristics of these patients. Results This study included 359 patients with Ph‐negative MPNs with JAK2, MPL, or CALR classical mutations and found that 55 (15%) patients had atypical variants of JAK2, MPL, or CALR. Among them, 28 cases (51%) were male, and 27 (49%) were female, with a median age of 64 years (range, 21–83). The age of ET patients with atypical variants was higher than that of ET patients without atypical variants [70 (28–80) vs. 61 (19–82), p = 0.03]. The incidence of classical MPL mutations in ET patients with atypical variants was higher than in ET patients without atypical variants [13.3% (2/15) vs. 0% (0/95), p = 0.02]. The number of gene mutations in patients with atypical variants of driver genes PV, ET, and Overt‐PMF is more than in patients without atypical variants of PV, ET, and Overt‐PMF [PV: 3 (2–6) vs. 2 (1–7), p

Summary: Pseudouridylation plays a regulatory role in various physiological and pathological processes. A prime example is the mitochondrial myopathy, lactic acidosis, and sideroblastic anemia syndrome (MLASA), characterized by defective pseudouridylation resulting from genetic mutations in pseudouridine synthase 1 (PUS1). However, the roles and mechanisms of pseudouridylation in normal erythropoiesis and MLASA-related anemia remain elusive. We established a mouse model carrying a point mutation (R110W) in the enzymatic domain of PUS1, mimicking the common mutation in human MLASA. Pus1-mutant mice exhibited anemia at 4 weeks old. Impaired mitochondrial oxidative phosphorylation was also observed in mutant erythroblasts. Mechanistically, mutant erythroblasts showed defective pseudouridylation of targeted tRNAs, altered tRNA profiles, decreased translation efficiency of ribosomal protein genes, and reduced globin synthesis, culminating in ineffective erythropoiesis. Our study thus provided direct evidence that pseudouridylation participates in erythropoiesis in vivo. We demonstrated the critical role of pseudouridylation in regulating tRNA homeostasis, cytoplasmic translation, and erythropoiesis.

Summary: Energy metabolism in the context of erythropoiesis and related diseases remains largely unexplored. Here, we developed a primary cell model by differentiating hematopoietic stem progenitor cells toward the erythroid lineage and suppressing the mitochondrial oxidative phosphorylation (OXPHOS) pathway. OXPHOS suppression led to differentiation failure of erythroid progenitors and defects in ribosome biogenesis. Ran GTPase-activating protein 1 (RanGAP1) was identified as a target of mitochondrial OXPHOS for ribosomal defects during erythropoiesis. Overexpression of RanGAP1 largely alleviated erythroid defects resulting from OXPHOS suppression. Coenzyme Q10, an activator of OXPHOS, largely rescued erythroid defects and increased RanGAP1 expression. Patients with Diamond-Blackfan anemia (DBA) exhibited OXPHOS suppression and a concomitant suppression of ribosome biogenesis. RNA-seq analysis implied that the substantial mutation (approximately 10%) in OXPHOS genes accounts for OXPHOS suppression in these patients. Conclusively, OXPHOS disruption and the associated disruptive mitochondrial energy metabolism are linked to the pathogenesis of DBA.

Abstract Background Individuals diagnosed with Fanconi anemia (FA), an uncommon disorder characterized by chromosomal instability affecting the FA signaling pathway, exhibit heightened vulnerability to the onset of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Methods Herein, we employed diverse bioinformatics and statistical analyses to investigate the potential associations between the expression/mutation patterns of FA pathway genes and MDS/AML. Results The study included 4295 samples, comprising 3235 AML and 1024 MDS from our and nine other online cohorts. We investigated the distinct proportion of race, age, French-American-British, and gender factors. Compared to the FA wild-type group, we observed a decrease in the expression of FNACD2, FANCI, and RAD51C in the FA mutation group. The FA mutation group exhibited a more favorable clinical overall survival prognosis. We developed a random forest classifier and a decision tree based on FA gene expression for cytogenetic risk assessment. Furthermore, we created an FA-related Nomogram to predict survival rates in AML patients. Conclusions This investigation facilitates a deeper understanding of the functional links between FA and MDS/AML.

Abstract Objective The clinical characteristics and survival of patients with myeloproliferative neoplasms (MPNs) with secondary cancer were analyzed to explore the possible risk factors for secondary cancer in MPN patients. Methods The clinical characteristics of 1060 Chinese patients with MPN were retrospectively analyzed. The Kaplan–Meier method was used to analyze the survival. The Cox multivariate regression model was used to analyze the risk factors for developing secondary cancer in patients with MPNs. Results The 1060 patients with MPN had a median follow‐up of 10 years (range 1–50) and a median age of 55 years (range 21–86), and 497 (45.2%) were male. The proportion of PV, ET, and PMF was 52.2%, 33.5%, and 14.3%, respectively. About 28.1% (298/1060) of 1060 MPN patients died. The median survival times of the PV, ET, and PMF groups were 20, 24, and 12 years, respectively (p

Abstract Background Fanconi anemia (FA) is a rare disease of bone marrow failure. FA patients are prone to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the molecular clonal evolution of the progression from FA to MDS/AML remains elusive. Methods Herein, we performed a comprehensive genomic analysis using an FA patient (P1001) sample that transformed to MDS and subsequently AML, together with other three FA patient samples at the MDS stage. Results Our finding showed the existence of polyclonal pattern in these cases at MDS stage. The clonal evolution analysis of FA case (P1001) showed the mutations of UBASH3A, SF3B1, RUNX1 and ASXL1 gradually appeared at the later stage of MDS, while the IDH2 alteration become the dominant clone at the leukemia stage. Moreover, single-cell sequencing analyses further demonstrated a polyclonal pattern was present at either MDS or AML stages, whereas IDH2 mutated cell clones appeared only at the leukemia stage. Conclusions We thus propose a clonal evolution model from FA to MDS and AML for this patient. The results of our study on the clonal evolution and mutated genes of the progression of FA to AML are conducive to understanding the progression of the disease that still perplexes us.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with dismal prognosis. Identification of better biomarkers remained a priority to improve established stratification and guide therapeutic decisions. Therefore, we extracted the RNA sequence data and clinical characteristics of AML from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to identify the key factors for prognosis. We found UNC93B1 was highly expressed in AML patients and significantly linked to poor clinical features (p < 0.05). We further validated the high expression of UNC93B1 in another independent AML cohort from GEO datasets (p < 0.001) and performed quantitative PCR of patient samples to confirm the overexpression of UNC93B1 in AML (p < 0.005). Moreover, we discovered high level of UNC93B1 was an independent prognostic factor for poorer outcome both in univariate analysis and multivariate regression (p < 0.001). Then we built a nomogram model based on UNC93B1 expression, age, FAB subtype and cytogenetic risk, the concordance index of which for predicting overall survival was 0.729 (p < 0.001). Time-dependent ROC analysis for predicting survival outcome at different time points by UNC93B1 showed the cumulative 2-year survival rate was 43.7%, and 5-year survival rate was 21.9%. The differentially expressed genes (DEGs) between two groups divided by UNC93B1 expression level were enriched in innate immune signaling and metabolic process pathway. Protein–protein interaction (PPI) network indicated four hub genes (S100A9, CCR1, MRC1 and CD1C) interacted with UNC93B1, three of which were also significantly linked to inferior outcome. Furthermore, we discovered high UNC93B1 tended to be infiltrated by innate immune cells, including Macrophages, Dendritic cells, Neutrophils, Eosinophils, and NK CD56dim cells. We also found UNC93B1 had a significantly positive correlation with CD14, CD68 and almost all Toll-like receptors. Finally, we revealed negatively correlated expression of UNC93B1 and BCL2 in AML and conjectured that high-UNC93B1 monocytic AML is more resistant to venetoclax. And we found high MCL-1 expression compensated for BCL-2 loss, thus, we proposed MCL-1 inhibitor might overcome the resistance of venetoclax in AML. Altogether, our findings demonstrated the utility of UNC93B1 as a powerful poor prognostic predictor and alternative therapeutic target.

Abstract Acute myeloid leukemia (AML) is a deadly cancer characterized by an expanded self-renewal capacity that is associated with the accumulation of immature myeloid cells. Emerging evidence shows that methyl-CpG-binding domain protein 2 (MBD2), a DNA methylation reader, often participates in the transcriptional silencing of hypermethylated genes in cancer cells. Nevertheless, the role of MBD2 in AML remains unclear. Herein, by using an MLL-AF9 murine model and a human AML cell line, we observed that loss of MBD2 could delay the initiation and progression of leukemia. MBD2 depletion significantly reduced the leukemia burden by decreasing the proportion of leukemic stem cells (LSCs) and inhibiting leukemia cell proliferation in serial transplantation experiments, thereby allowing leukemic blasts to transition to a more mature state reflecting normal myelopoiesis. Both gene expression analyses and bioinformatic studies revealed that MBD2 negatively modulated genes related to myeloid differentiation, and was necessary to sustain the MLL-AF9 oncogene-induced gene program. We further demonstrated that MBD2 could promote LSC cell cycle progression through epigenetic regulation of CDKN1C transcription probably by binding to its promoter region. Taken together, our data suggest that MBD2 promotes AML development and could be a therapeutic target for myeloid malignancies.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The protein tyrosine phosphatase SHP2 is a central node regulating RAS/mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) signaling pathway which plays a crucial role in the pathogenesis and proteasome inhibitor (PI) resistance of MM. Several preclinical studies have demonstrated that SHP2 inhibitors exerted antitumor activity in cancer-harboring diverse mutations in the RAS pathway, offering the potential for targeting myeloma. In this study, we showed that pharmacological inhibition of SHP2 activity using SHP099 and RMC-4550 efficiently inhibited the proliferation of MM cells by inducing apoptosis and cell cycle arrest. As per the mechanism, SHP2 inhibitors activated the level of cleaved caspase3, BAK, and P21 and downregulated ERK phosphorylation in MM cells. Moreover, the blockade of SHP2 exhibited anti-myeloma effect in vivo in a mouse xenograft model. In addition, SHP2 inhibitors synergized the antineoplastic effect of bortezomib in bortezomib-sensitive MM cells and showed identical efficacy in targeting bortezomib-resistant MM cells. Overall, our findings suggest that SHP2-specific inhibitors trigger anti-myeloma activity in vitro and in vivo by regulating the ERK pathway and enhancing cytotoxicity of bortezomib, providing therapeutic benefits for both bortezomib naïve and resistant MM.

Rapamycin, also known as sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), is a regulatory kinase responsible for multiple signal transduction pathways. Although rapamycin has been widely used in treating various hematologic diseases, the effects of rapamycin are still not fully understood. Here we found that both oral and intraperitoneal administration of rapamycin led to the expansion of myeloid lineage, while intraperitoneal administration of rapamycin impaired granulocyte differentiation in mice. Rapamycin induced bone marrow mesenchymal stem cells to produce more G-CSF in vitro and in vivo, and promoted the myeloid cells expansion. Our results thus demonstrated that intraperitoneal administration of rapamycin might promote the expansion of myeloid lineage while impair myeloid cell differentiation in vivo.