Comprehensive analysis of single-cell RNA and bulk RNA sequencing based on M2 tumor-associated macrophage and angiogenesis-related genes to assess prognosis and therapeutic response in lung adenocarcinoma.

M2 tumor-associated macrophage (M2 TAM), a crucial component of the tumor microenvironment, has a significant impact on tumor invasion and metastasis in the form of angiogenesis for lung adenocarcinoma (LUAD). In this study, both single-cell RNA and bulk RNA sequencing data were analyzed to identify 12 M2 TAM and angiogenesis-related genes (OLR1, CTSL, HLA-DPB1, NUPR1, ALOX5, DOCK4, CSF2RB, PTPN6, TNFSF12, HNRNPA2B1, NCL, and BIRC2). These genes were used to construct a prognostic signature, which was subsequently validated using an external cohort. Moreover, the immune profile analysis indicated that the low-risk group exhibited a distinct immune cell infiltration and relatively active status. Importantly, the prognostic signature was closely associated with PD-1, CTLA4, tumor mutation burden, and anti-cancer drug sensitivity. In summary, this study proposes a new prognostic signature for patients with LUAD based on M2 TAM and angiogenesis-related genes. The signature forecasts the prognosis of LUAD by an independent manner, reveals the potential molecular mechanisms involved in tumor immune-related functions, and offers appropriate clinical strategies for the treatment of patients with LUAD.

Artificial intelligence tools utilized in nursing education: Incidence and associated factors.

BACKGROUND: Artificial intelligence technology is among the most significant advancements that provide students with effective learning opportunities in this digital era. Therefore, the National League for Nursing states that it is necessary to reframe the nursing education process. OBJECTIVE: This study aimed to determine the factors that affect the usefulness and sustainability of artificial intelligence tools used in nursing education. DESIGN: A descriptive cross-sectional study was conducted among. Three models, including the Technological Acceptance Model (TAM), the Information System Success Model (ISSM), and the Online Learning Self-Efficacy (OLSE), were used. PARTICIPANT: All of fourth- year undergraduate nursing students who were enrolled in nursing department regularly (N = 420), and who respond (n = 204). SETTING: In the nursing department of the health professions faculty at AL-Quds University, in Palestine. RESULTS: Among the 204 students who responded, 9.80 % employed simulation, 5.40 % utilized virtual reality, 19.10 % used Chat GPT, 42.20 % used mobile applications, and 23.50 % utilized PowerPoint AI as part of their learning process. The mean and standard deviation (SD) were computed for key parameters related to the information system success model (AI) (ISSM) (M = 4.52, SD = 1.17). Technology Acceptance Model (TAM) (M = 4.61, SD = 1.16). Online Learning Self-Efficacy (OLSE) (M = 4.55, SD = 1.28). CONCLUSION: There is a need to adapt teaching strategies and integrate AI tools as useful learning tools, which have become essential for students to complete their learning activities through enhancing knowledge of the multimodal technological factors that should be taken into consideration while creating AI tools across several domains for universities and developers.

Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.

Tumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive, likely contributing to mixed outcomes in clinical trials. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD-1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Our analyses of reciprocal tumor-TAM interactions revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A with known contribution to immunosuppression, tumor proliferation, invasion and TAM recruitment. Spatially resolved transcriptomics further elucidated the architectural organization of highlighted communications. Furthermore, we demonstrated significant upregulation of ANXA1, FN1, NRP1, and TNFRSF12A genes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors indicating that the interactive network of malignant states with TAMs does not drastically change upon recurrence. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.

Acceptance of e-learning and associated factors among postgraduate medical and health science students at first generation universities in Amhara region, 2023: using modified technology acceptance model.

BACKGROUND: Electronic learning is the process of remote teaching and learning through the use of electronic media. There is a dearth of research on the factors influencing e-learning acceptance in Ethiopia using the modified technology acceptance model (TAM). Previous research appears to have overlooked the mediating impact of factors on e-learning acceptability Therefore, the present study aimed to assess the acceptance of e-learning and its associated factors among postgraduate medical and health science students by applying TAM at first-generation universities in the Amhara region. METHODS: This institutional-based cross-sectional study was conducted from March 15 to April 20, 2023, at Amhara First Generation University, Ethiopia. A total of 659 students participated in the study. A self-administered questionnaire in the Amharic language was used to collect the data. SEM analysis was employed to test the proposed model and the relationships among factors using SPSS version 25 and AMOS version 26. RESULTS: The proportion of postgraduate students who agreed to use e-learning was 60.7%, 95% CI (56.9-64.4). SEM analysis revealed that perceived ease of use (ß = 0.210, p < 0.001), attitude (ß = 0.377, p < 0.001) and perceived usefulness (ß = 0.330, p < 0.001) had positive direct relationships with acceptance of e-learning. Perceived usefulness (ß = 0.131, p < 0.001), and perceived ease of use (ß = 0.029, p < 0.01) significantly mediate the relationship between self-efficacy, and acceptance of e-learning. Accessibility had a positive indirect effect on acceptance of e-learning through perceived ease of use (ß = 0.040, p < 0.01). Facilitating condition had a positive indirect on acceptance of e-learning through perceived ease of use (ß = 0.070, p < 0.01), and perceived usefulness (ß = 0.084, p < 0.001). CONCLUSION AND RECOMMENDATION: Overall, the proportion of postgraduate students who accepted e-learning is promising. Perceived ease of use perceived usefulness, and attitude had positive direct effects on the acceptance of e-learning. Facilitating conditions and self-efficacy had positive indirect effects on the acceptance of e-learning. Thus, implementers need to prioritize enhancing the provision of devices, students' skills, and knowledge of e-learning by providing continuous support to improve students' acceptance of the use of e-learning.

Enhancing Healthcare Management: Assessing User Acceptance and Usability of the 'SmartCG' Mobile Application.

In Thailand, increasing caregiving needs for senior citizens, particularly in low-income homes, may elevate the caregiver (CG) burden. This study assesses the user acceptance and usability of the 'SmartCG' mobile application in enhancing healthcare management. The app offers health evaluations, home visits, knowledge management, screening forms, and care plans. Using the Technology Acceptance Model, 402 caregivers from Mahasarakham province evaluated the app's usability on a 5-point Likert scale. Results showed a significant increase in acceptance scores after using SmartCG (11.49 ± 1.54 to 13.19 ± 2.74, p < 0.001). Users reported high satisfaction with its ease of use (mean = 4.10 ± 0.61) and found the knowledge-based menu (mean = 4.07 ± 0.63) and visiting/map menus (mean = 4.05 ± 0.63) user-friendly. This study provides empirical evidence that the SmartCG app effectively enhances healthcare management, emphasizing the importance of user-friendly interfaces in healthcare technology.

Molecular epidemiology of bovine theileriosis and genetic diversity of Theileria annulata in three governorates of Egypt.

Bovine theileriosis is a protozoan disease caused by the intracellular parasite (Theileria spp.) transmitted by ticks and it is considered one of the most significant parasitic diseases, potentially endangering Egyptian cattle herd industry. The present study was conducted for a molecular survey of bovine theileriosis and its associated risk factors (season variations, geographical locations, breeds, age, sex, tick infestation, and acaricide applications) in three Egyptian governorates, Beni-Suef, Al-Faiyum, and Al-Minya for a year extended from December 2021 to November 2022, in addition, genetic diversity of Theileria isolates. A total of 961 cattle were examined for Theileria infection clinically, microscopically, and by Polymerase Chain Reaction (PCR) using 18S rRNA gene for piroplasms DNA detection, Theileria genus-specific primers of the small subunit of rRNA gene, and Theileria annulata specific primers of the Tams-1 gene. The prevalence rate of bovine theileriosis was 9.26%, and 11.86% using Giemsa-stained blood smear and PCR, respectively. All positive samples screened by Theileria genus-specific primers were positive for T. annulata when screened by the specific primers. Based on molecular screening, season, cattle breeds and acaricide applications were considered risk factors for T. annulata infection, while locality, age, sex and tick infestation had insignificant effects with the occurrence of the disease. A potential novel T. annulata haplotype based on the Tam-1 gene was identified with accession numbers OR364144 and OR915851. Therefore, T. annulata was the only Theileria species found and played a significant problem in the cattle population. This study could be the basis for future studies on unexplored regions and different animal species for well-structured prevention and control measures.

Hallmarks of pancreatic cancer: spotlight on TAM receptors.

Pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent type of pancreatic cancer and ranks among the most aggressive tumours, with a 5-year survival rate of less than 11%. Projections indicate that by 2030, it will become the second leading cause of cancer-related deaths. PDAC presents distinctive hallmarks contributing to its dismal prognosis: (i) late diagnosis, (ii) heterogenous and complex mutational landscape, (iii) high metastatic potential, (iv) dense fibrotic stroma, (v) immunosuppressive microenvironment, and (vi) high resistance to therapy. Mounting evidence has shown a role for TAM (Tyro3, AXL, MerTK) family of tyrosine kinase receptors in PDAC initiation and progression. This review aims to describe the impact of TAM receptors on the defining hallmarks of PDAC and discuss potential future directions using these proteins as novel biomarkers for early diagnosis and targets for precision therapy in PDAC, an urgent unmet clinical need.

Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry.

Low-oxygen conditions (hypoxia) have been associated primarily with cell-cycle arrest in dividing cells. Macrophages are typically quiescent in G0 but can proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in macrophages. Cell cycle progression is largely limited to G0-G1/S phase transition with little progression to G2/M. This cell cycle transitioning is triggered by an HIF2α-directed transcriptional program. The response is accompanied by increased expression of cell-cycle-associated proteins, including CDK1, which is known to phosphorylate SAMHD1 at T592 and thereby regulate antiviral activity. Prolyl hydroxylase (PHD) inhibitors are able to recapitulate HIF2α-dependent cell cycle entry in macrophages. Finally, tumor-associated macrophages (TAMs) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at the single-cell level. These findings have implications for inflammation and tumor progression/metastasis where low-oxygen environments are common.

An Approach to Potentially Increasing Adoption of an Artificial Intelligence-Enabled Electronic Medical Record Encounter in Canadian Primary Care: Protocol for a User-Centered Design.

BACKGROUND: Primary care physicians are at the forefront of the clinical process that can lead to diagnosis, referral, and treatment. With electronic medical records (EMRs) being introduced and, over time, gaining acceptance by primary care users, they have now become a standard part of care. EMRs have the potential to be further optimized with the introduction of artificial intelligence (AI). There has yet to be a widespread exploration of the use of AI in primary health care and how clinicians envision AI use to encourage further uptake. OBJECTIVE: The primary objective of this research is to understand if the user-centered design approach, rooted in contextual design, can lead to an increased likelihood of adoption of an AI-enabled encounter module embedded in a primary care EMR. In this study, we use human factor models and the technology acceptance model to understand the results. METHODS: To accomplish this, a partnership has been established with an industry partner, TELUS Health, to use their EMR, the collaborative health record. The overall intention is to understand how to improve the user experience by using user-centered design to inform how AI should be embedded in an EMR encounter. Given this intention, a user-centered approach will be used to accomplish it. The approach of user-centered design requires qualitative interviewing to gain a clear understanding of users' approaches, intentions, and other key insights to inform the design process. A total of 5 phases have been designed for this study. RESULTS: As of March 2024, a total of 14 primary care clinician participants have been recruited and interviewed. First-cycle coding of all qualitative data results is being conducted to inform redesign considerations. CONCLUSIONS: Some limitations need to be acknowledged related to the approach of this study. There is a lack of market maturity of AI-enabled EMR encounters in primary care, requiring research to take place through scenario-based interviews. However, this participant group will still help inform design considerations for this tool. This study is targeted for completion in the late fall of 2024. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54365.

Combining cashew gum with cyclophosphamide in murine melanoma model: A strategy for the reduction of side effects.

The understanding of cancer immunity and antitumor factors generated by natural polysaccharides is not yet fully comprehended. Polysaccharides, like cashew gum (CG), can exhibit immunomodulatory action and may assist in the antitumor process and side effects relieve. This study aimed to determine the antitumor effect of CG alone or in combination with cyclophosphamide (CTX), and its interactions with immune cells, in a murine melanoma model, using the B16-F10 cell line. Tumor growth inhibition, hematological, histopathological, ELISA, flow cytometry, immunofluorescence, and qRT-PCR analyses were performed to elucidate the antitumor potential, involvement of immune cells, and potential toxic effects. CG showed significant tumor growth inhibition, reaching up to 42.9 % alone and 51.4 % in combination with CTX, with mild toxicity to organs. CG enhanced leukocyte count, even in the presence of CTX. Furthermore, CG influenced the activation of tumor-associated macrophages (TAM), characterized by an increase in Il4, as well as a reduction in Ifng, Il1b, Tgfb, and Il6 gene expression. Nevertheless, these effects did not compromise the antitumor activity of CG. In summary, the combination of CG with CTX is a promising approach for leukopenia, one of the most important side effects of cancer treatment and deserves further investigation.

Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.

The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.

Potential protumor function of CD74 in clear cell renal cell carcinoma.

CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC.

Therapists' perspective on acceptance of robot-assisted physical rehabilitation in a middle-income country: a study from Vietnam.

Robot-assisted physical rehabilitation offers promising benefits for patients, yet its adoption among therapists remains a complex challenge. This study investigates the acceptance of robot-assisted physical rehabilitation technology among therapists in Vietnam, a middle-income country with a growing demand for rehabilitation services. Drawing on the Technology Acceptance Model 2 (TAM2) and the Theory of Planned Behaviour (TPB), an online survey and semi-structured interviews were conducted to explore therapists' attitudes and intentions towards using this technology. The results show that Vietnamese therapists recognised its potential benefits and expressed a willingness to use it. Although having similar acceptance patterns compared to developed regions, they demonstrated significantly higher levels of agreement across acceptance constructs. This may be attributed to factors such as the novelty effect, cultural perceptions of robots, and the high workload of therapists in Vietnam. Gender and location were found to influence two acceptance constructs-subjective norms and image, respectively-highlighting the need for tailored strategies in technology implementation. The study underscores the importance of considering socio-cultural factors in the adoption of technology and provides insights for enhancing the acceptance and effectiveness of robot-assisted physical rehabilitation in Vietnam. This contributes to the global understanding of therapist acceptance of technology in this field.

While robot-assisted physical rehabilitation offers promising benefits, there is limited understanding of therapist acceptance on a global scale, highlighting the need for more research in this area.This study in a middle-income country, Vietnam, reveals a generally positive view among therapists, but specific issues such as the novelty effect, cultural perceptions of robots, and high therapist workload impact acceptance levels, indicating the need for tailored strategies.Strategies for implementing robot-assisted physical rehabilitation should include addressing training needs, providing technological support, and considering sociocultural factors to enhance acceptance and effectiveness.

Description, life cycle, and development of the myxozoan Myxobolus rasmusseni n. sp. in fathead minnows, Pimephales promelas: A possible emerging pathogen in southern Alberta, Canada.

Morphological, gene sequence, host tissue tropism, and life cycle characteristics were utilized to describe the myxozoan, Myxobolus rasmusseni n. sp. from fathead minnow, Pimephales promelas, collected from reservoirs in southern Alberta. Results from serial histological sections of whole heads showed that myxospores were contained within irregular-shaped and sized coelozoic capsules (=plasmodia). Clusters of membrane-bound, myxospore-filled plasmodia filled the head cavities of juvenile fathead minnows, leading to the development of large, white, disfiguring lesions in mid to late summer. Bilateral exopthalmia (pop-eye disease) was a common outcome of M. rasmusseni n. sp. development. BLASTn search of a 1974 bp sequence of the 18S rDNA gene isolated from myxospores indicated that M. rasmusseni n. sp. was distinct from other coelozoic and histozoic Myxobolus spp. cataloged in GenBank. 18S rDNA gene sequences from triactinomyxon spores released from the oligochaete Tubifex were 100% identical to sequences from myxospores collected from syntopic fathead minnows. Results from a longitudinal survey of the 2020 cohort of fathead minnows showed that young-of-the-year are exposed at 1-5 mo and that 60-90% of these had developed myxospore-filled lesions approximately one year later. Data regarding potential sources and timing of M. rasmusseni n. sp. emergence in fathead minnow populations are needed.

Unveiling Spatiotemporal Diffusion of Hot Carriers Influenced by Spatial Nonuniform Hot Phonon Bottleneck Effect in Monolayer MoS2.

The exceptional semiconducting properties of two-dimensional (2D) transition metal dichalcogenides (TMDs) have made them highly promising for the development of future electronic and optoelectronic devices. Extensive studies of TMDs are partly associated with their ability to generate 2D-confined hot carriers above the conduction band edges, enabling potential applications that rely on such transient excited states. In this work, room-temperature spatiotemporal hot carrier dynamics in monolayer MoS2 is studied by transient absorption microscopy (TAM), featuring an initial ultrafast expansion followed by a rapid negative diffusion, and ultimately a slow long-term expansion of the band edge C-excitons. We provide direct experimental evidence to identify the abnormal negative diffusion process as a spatial contraction of the hot carriers resulting from spatial variation in the hot phonon bottleneck effect due to the Gaussian intensity distribution of the pump laser beam.

Could Gas6/TAM Axis Provide Valuable Insights into the Pathogenesis of Systemic Sclerosis?

Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular injury, extracellular matrix deposition, autoimmunity, inflammation, and fibrosis. The clinical complexity and high heterogeneity of the disease make the discovery of potential therapeutic targets difficult. However, the recent progress in the comprehension of its pathogenesis is encouraging. Growth Arrest-Specific 6 (Gas6) and Tyro3, Axl, and MerTK (TAM) receptors are involved in multiple biological processes, including modulation of the immune response, phagocytosis, apoptosis, fibrosis, inflammation, cancer development, and autoimmune disorders. In the present manuscript, we review the current evidence regarding SSc pathogenesis and the role of the Gas6/TAM system in several human diseases, suggesting its likely contribution in SSc and highlighting areas where further research is necessary to fully comprehend the role of TAM receptors in this condition. Indeed, understanding the involvement of TAM receptors in SSc, which is currently unknown, could provide valuable insights for novel potential therapeutic targets.

Exploring Chinese Secondary School Students' Acceptance of Live Video-Streamed Teaching Platforms in EFL Class: An Application of the Technology Acceptance Model.

Live video-streamed teaching platforms are widely used in language teaching. However, how students perceive these platforms has scarcely been investigated. By adopting the Technology Acceptance Model (TAM), this study investigated Chinese secondary school students' perceptions of the platforms (i.e., Tencent meeting, Tencent classroom and Dingtalk) being adopted in English as a foreign language (EFL) class. Gender and age differences were also investigated. Data were collected from 602 students; the results showed the following: (1) The acceptance level of all the participants was high for the five variables in TAM, i.e., perceived ease of use (PEU), perceived usefulness (PU), attitude (ATT), computer self-efficacy (CSE) and behavioral intention to use (BI), but with significant individual differences. There existed no gender differences, while age differences existed between junior high school students and those from senior high school. (2) The five variables were correlated with each other significantly. In addition, CSE, PEU, PU and ATT can predict BI in parallel. (3) The relationship between CSE and BI was mediated by PEU, PU and ATT. Also, PU had the strongest mediating effect, with PEU and ATT exerting slightly lower effects. The theoretical and practical implications are discussed at the end.

MERTK Inhibition as a Targeted Novel Cancer Therapy.

In this issue honoring the contributions of Greg Lemke, the Earp and Graham lab teams discuss several threads in the discovery, action, signaling, and translational/clinical potential of MERTK, originally called c-mer, a member of the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases. The 30-year history of the TAM RTK family began slowly as all three members were orphan RTKs without known ligands and/or functions when discovered by three distinct alternate molecular cloning strategies in the pre-genome sequencing era. The pace of understanding their physiologic and pathophysiologic roles has accelerated over the last decade. The activation of ligands bridging externalized phosphatidylserine (PtdSer) has placed these RTKs in a myriad of processes including neurodevelopment, cancer, and autoimmunity. The field is ripe for further advancement and this article hopefully sets the stage for further understanding and therapeutic intervention. Our review will focus on progress made through the collaborations of the Earp and Graham labs over the past 30 years.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

High M2-TAM Infiltration and STAT3/NF-κB Signaling Pathway as a Predictive Factor for Tumor Progression and Death in Cervical Cancer.

INTRODUCTION: The tumor microenvironment (TME) plays a crucial role in the progression, invasion, and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the CC TME, but studies on their correlation with CC progression are still controversial. This study aimed to investigate the relationship between TAM infiltration, the STAT3/NF-κB signaling pathway, and Overall Survival (OS) in CC patients. METHODS: In a retrospective study, 691 CC patients who had received a definitive histopathologic diagnosis of CC scored by the FIGO staging system and not undergone preoperative treatment were selected from a database. The effect of TAM infiltration on tumor progression biomarkers using Tissue Microarray (TMA) and immunohistochemistry was evaluated. Furthermore, the impact of the expression of these biomarkers and clinical-pathological parameters on recurrence-free (RF) and OS using Kaplan-Meier and multivariable Cox regression methods was also analyzed. RESULTS: High stromal CD163 + 204 + TAMs density and via STAT3 and NF-κB pathways was relevant to the expression of E-cadherin, Vimentin, MMP9, VEGFα, Bcl-2, Ki-67, CD25, MIF, FOXP3, and IL-17 (all p < 0.0001). In addition, elevated TNM staging IV had a strong association correlation with STAT3 and NF-κB pathways (p < 0.0001), CD25 (p < 0.001), VEGFα (p < 0.001), MIF (p < 0.0001), and Ki-67 (p < 0.0001). On the other hand, overall and recurrence survival was shown to be strongly influenced by the expression of SNAIL (HR = 1.52), E-cadherin (HR = 1.78), and Ki-67 (HR = 1.44). CONCLUSION: M2-TAM and via STAT3/NF-κB pathways had a strong effect on CC tumor progression which reverberated in the severity of clinicopathological findings, becoming an important factor of poor prognosis.