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Background: Hepatocellular carcinoma (HCC) posed significant health problems and deaths. There are various challenges in the management of HCC, including the late detection or diagnosis. The ongoing diagnostic method in HCC also hinders the detection on the early stages of the disease, thus biomarkers need to be explored further for HCC detection. Serum alpha fetoprotein (AFP) and Midkine (MDK) are two proteins which might be the biomarker of choice in the detection of HCC. This meta-analysis aims to analyze the accuracy of Midkine and AFP in the detection of HCC. Methods: The systematic review and meta-analysis was conducted by adhering to the Preferred Reporting System for Systematic Review and Meta-Analysis (PRISMA) guidelines. We conduct literature screening and selection followed by quality assessment from various databases such as PubMed, MEDLINE, SpringerLink, ProQuest, EBSCOhost, Cochrane, and EMBASE. The included studies were then extracted and analyzed cumulatively using MedCalc and MetaDTA with forest plot and ROC curve as outcome. Results: 12 studies were included in this study. The AFP biomarker yields sensitivity value of 62.5% (97.5% CI 0.442 - 0.778) and specificity value of 95% (97.5% CI 0.842 - 0.986), while the Midkine biomarker denotes sensitivity value of 91.6% (97.5% CI 0.83 - 0.961) and specificity value of 82.2% (97.5% CI 0.83 - 0.96). Conclusions: Both AFP and MDK are proven to be a good diagnostic tool or biomarker in the detection of HCC. The use of both in combination should provide high quality diagnostic marker for HCC suspected patients. Further studies on this should be conducted. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background/Aim: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. Materials and Methods: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. Results: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. Conclusion: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC. [ABSTRACT FROM AUTHOR]

Midkine (MDK) is a protein that contributes to both physiological and pathological processes. Several studies provide insight into the different roles of MDK in development, tissue repair, neural plasticity, and health and disease processes. This research further examined how MDK contributed to conditions, including neurological diseases, inflammation, and ischaemia. Furthermore, MDK overexpression has been reported in many kinds of cancer and MDK is recognized as a malignancy marker. MDK stimulates pro-tumor activity by regulating a number of signaling pathways, which increase cancer cell proliferation, survival, metastasis, and treatment resistance. However, studies have shown that MDK also functions as a molecule that regulates drug resistance. Several cancer therapy techniques have been suggested to modify MDK function, including antibody-based therapies, oligonucleotides, oncolytic viruses, and small compounds. Further research and experimentation will be required to establish the therapeutic relevance and efficacy of these treatments. This review focuses on the role of MDK in cancer biology, as well as its multiple different roles in health and disease processes. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Clinical Hepatology / Linchuang Gandanbing Zazhi is the property of Journal of Clinical Hepatology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Thyroid hormone deficiency, with a variety of causes and symptoms, is known as hypothyroidism. Morbidity and mortality are increased by untreated hypothyroidism. Midkine is highly expressed during embryogenesis and governs cell proliferation, angiogenesis, anti-apoptotic actions, survival, and migration, though it is commonly low in maturity. Studies demonstrate that MK expression is highly elevated in thyroid cancers and connected to pathological and clinical characteristics, This study evaluates the relationship of MK with thyroid hormone levels in newly diagnosed hypothyroidism and subclinical hypothyroidism compared with healthy. a case-control study was conducted For the period from November 2022 to January 2023. The 120 participants in the current study, who were Baghdad residents between the ages of)20-65(, were divided into three groups: 30 patients were newly diagnosed with hypothyroidism, and 30 patients had subclinical hypothyroidism. In contrast with 60 healthy subjects (control group). Measurements of S.TSH, Total S.T3, and Total S.T4 parameters. were measured on all groups and the results were compared between them by system automatically and (midkine) by ELISA and whole Electrolytes (Na, k, cl) were measured using a Manual spectrophotometer (colorimetric). The Results The midkine levels were measured and compared between the control group with the newly diagnosed hypothyroidism group, and the subclinical hypothyroidism group. There was a difference, but this difference did not reach statistical significance, there was a trend towards higher midkine levels in the NDH group compared to the SCH groups and control (p=0.07). while Statistical analysis indicated a significant difference in the midkine levels were measured and compared between the control group and the newly diagnosed hypothyroidism group (p<0.04). As for Age, weight, height and BMI However, these results were not statistically significant. (The probability value was greater than 0.05). The control group had a mean sodium level of 145.32 ±6.90, the NDH group had a mean sodium level of 144.43 ±6.30, and the SCH group had a mean sodium level of 143.83 ±7.97. Statistical analysis did not show a significant difference in sodium levels among the groups p=0.62. while observing Statistical analysis revealed a significant difference in potassium levels among the groups (p<0.001). A pairwise comparison showed that the control group had higher potassium levels compared to both the NDH and SCH groups (p<0.001). As for chloride, it was noted Statistical analysis indicated a significant difference in chloride levels among the groups (p=0.01). The pairwise comparison revealed that the SCH group had significantly lower chloride levels compared to both the control and NDH groups (p<0.05). [ABSTRACT FROM AUTHOR]

Background: Midkine plays a significant role in the pathophysiology of malignant and other diseases since it is involved in a number of physiological processes, including development, reproduction, and repair. Different types of cells express this protein. Thus, in healthy conditions, significant MDK expression is observed in lymphocytes, the epidermis, and the bronchial epithelium. The sample obtained during fine needle aspiration can help in the diagnosis of or rule out disorders like cancer. Blood is the most practical and least likely bodily fluid to pollute while diagnosing illnesses. Finding successful prognostic markers in patients with well-defined thyroid cancer was the goal of the current investigation. Methods: Midkine level was measured in serum samples by using Elisa technique for 80 patients (40 patient was diagnosed with papillary thyroid carcinoma and another 40 with benign thyroid goiter), Age (25-55) from Iraqis people. Results: The current study revealed highly significant difference the median serum level of medkine in the TC patients was much higher than that of BTT patients with a highly significant difference The sensitivity and specificity of the test at cut off value of medkine=129 pg/ml were 90% for both. While FNA result, the sensitivity and specificity of FNAC was 80.77% and 89.66% respectively. Conclusions: The thyroid cancer group's serum MDK result was noticeably higher than that of the healthy control groups. proposed that the midkine might serve as a biochemical marker for thyroid cancer early identification and diagnosis. [ABSTRACT FROM AUTHOR]

Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations in critical illness and sepsis and to verify its value as a prognostic biomarker. Thus, we analyzed the Mdk serum concentrations of 192 critically ill patients on admission to the medical intensive care unit (ICU). While the serum levels of Mdk at admission were similar in septic and nonseptic critical illness (362 vs. 337 ng/L, p = 0.727), we found several interesting correlations of Mdk to laboratory and clinical markers associated with ischemia or hypoxia, e.g., to renal failure and hepatic injury. Mdk serum concentrations at admission did not differ between various causes of sepsis or other critical illness. Most noticeable, we observed upregulated Mdk serum concentrations at admission in patients surviving in the long-term, which was only seen in nonseptic critical illness but not in sepsis. Our study suggests a relevant role of Mdk in critically ill patients in general and highlights the possible protective features of Mdk in critical illness. [ABSTRACT FROM AUTHOR]

Copyright of Jinekoloji-Obstetrik & Neonatoloji Tip Dergisi is the property of T.C. Saglik Bakanligi Ankara Sehir Hastanesi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes themodes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that poses a significant challenge to medical professionals due to its increasing incidence and prevalence coupled with the limited understanding of its underlying molecular mechanisms. In this study, we employed a novel approach by integrating five expression datasets from bulk tissue with single-cell datasets; they underwent pseudotime trajectory analysis, switch gene selection, and cell communication analysis. Utilizing the prognostic information derived from the GSE47460 dataset, we identified 22 differentially expressed switch genes that were correlated with clinical indicators as important genes. Among these genes, we found that the midkine (MDK) gene has the potential to serve as a marker of Idiopathic pulmonary fibrosis because its cellular communicating genes are differentially expressed in the epithelial cells. We then utilized midkine and its cellular communication)related genes to calculate the midkine score. Machine learning models were further constructed through midkine and related genes to predict Idiopathic pulmonary fibrosis disease through the bulk gene expression datasets. The midkine score demonstrated a correlation with clinical indexes, and the machine learning model achieved an AUC of 0.94 and 0.86 in the Idiopathic pulmonary fibrosis classification task based on lung tissue samples and peripheral blood mononuclear cell samples, respectively. Our findings offer valuable insights into the pathogenesis of Idiopathic pulmonary fibrosis, providing new therapeutic directions and target genes for further investigation. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a leading cause of long‐term disability in young adults and induces complex neuropathological processes. Cellular autonomous and intercellular changes during the subacute phase contribute substantially to the neuropathology of TBI. However, the underlying mechanisms remain elusive. In this study, we explored the dysregulated cellular signaling during the subacute phase of TBI. Methods: Single‐cell RNA‐sequencing data (GSE160763) of TBI were analyzed to explore the cell–cell communication in the subacute phase of TBI. Upregulated neurotrophic factor signaling was validated in a mouse model of TBI. Primary cell cultures and cell lines were used as in vitro models to examine the potential mechanisms affecting signaling. Results: Single‐cell RNA‐sequencing analysis revealed that microglia and astrocytes were the most affected cells during the subacute phase of TBI. Cell–cell communication analysis demonstrated that signaling mediated by the non‐canonical neurotrophic factors midkine (MDK), pleiotrophin (PTN), and prosaposin (PSAP) in the microglia/astrocytes was upregulated in the subacute phase of TBI. Time‐course profiling showed that MDK, PTN, and PSAP expression was primarily upregulated in the subacute phase of TBI, and astrocytes were the major source of MDK and PTN after TBI. In vitro studies revealed that the expression of MDK, PTN, and PSAP in astrocytes was enhanced by activated microglia. Moreover, MDK and PTN promoted the proliferation of neural progenitors derived from human‐induced pluripotent stem cells (iPSCs) and neurite growth in iPSC‐derived neurons, whereas PSAP exclusively stimulated neurite growth. Conclusion: The non‐canonical neurotrophic factors MDK, PTN, and PSAP were upregulated in the subacute phase of TBI and played a crucial role in neuroregeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: One of the questions that experts are trying to answer about COVID-19 is whether it will have a positive or negative effect on cancer. It is important to consider the added risk of COVID-19 symptoms when making decisions about cancer treatments. To gain a deeper understanding of this, we discussed the relationship between COVID-19 and nasopharyngeal carcinoma (NPC), a type of cancer that, like COVID-19, initially causes inflammation in the nasopharynx. Specifically, we looked at the biomolecular variety and underlying intercellular ligand–receptor mechanisms through midkine (MK) signaling. We were astounded to discover how complex MK's role is in the inflammatory response of these diseases, as it impacts the infiltration of immune cells into the inflamed microenvironment. This includes the abundance and interaction of immune cells, which can affect cancer progression and COVID-19 severity. As a result, exploring new cancer therapies that target MK gives hope of personalizing treatments for better outcomes. Clinical evidence suggests that the severe respiratory illness coronavirus disease 2019 (COVID-19) is often associated with a cytokine storm that results in dysregulated immune responses. Prolonged COVID-19 positivity is thought to disproportionately affect cancer patients. With COVID-19 disrupting the delivery of cancer care, it is crucial to gain momentum and awareness of the mechanistic intersection between these two diseases. This review discusses the role of the cytokine midkine (MK) as an immunomodulator in patients with COVID-19 and nasopharyngeal carcinoma (NPC), both of which affect the nasal cavity. We conducted a review and analysis of immunocellular similarities and differences based on clinical studies, research articles, and published transcriptomic datasets. We specifically focused on ligand–receptor pairs that could be used to infer intercellular communication, as well as the current medications used for each disease, including NPC patients who have contracted COVID-19. Based on our findings, we recommend close monitoring of the MK axis to maintain the desirable effects of therapeutic regimens in fighting both NPC and COVID-19 infections. [ABSTRACT FROM AUTHOR]

Background: There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD). Methods: CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels. Results: Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts. Conclusions: Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients. [ABSTRACT FROM AUTHOR]

The exact pathogenesis of Hidradenitis suppurativa (HS) has not been known yet. Midkine (MK) is a heparin-binding protein that has crucial roles in many processes such as cell proliferation, cell survival, cell migration, anti-apoptotic activity, and also inflammation and angiogenesis. No data exists in the literature on the evaluation of MK in patients with HS. The present study aimed to determine the serum levels of MK and metabolic parameters in patients with HS and to compare them with healthy subjects. Forty-five patients with HS and 45 healthy controls were included. The severity of the disease was assessed with Hurley staging system in the patient group. Levels of MK, C-reactive protein (CRP), lipids, and fasting glucose were measured with the enzyme-linked immunosorbent assay (ELISA) method. MK levels were significantly higher in the patient group (p < 0.05). Moreover, smoking habit, total cholesterol, triglyceride (TG), low-density lipoprotein (LDL) and CRP were significantly higher in the patient group (for all p < 0.05). Correlation analyses revealed that MK value was correlated positively with waist circumference, TG, total cholesterol level and diastolic blood pressure (for all p < 0.05), while negatively correlated with high-density lipoprotein (HDL) level (p = 0.046, r = − 0.219). There was no difference in the MK levels according to the severity of the disease among patients. This is the first preliminary study showing that these patients with HS have higher serum MK levels, which may also be related to autoinflammation, angiogenesis, atherosclerosis and metabolic syndrome risk. [ABSTRACT FROM AUTHOR]

Midkine plays a critical role in angiogenesis by regulating the vascular endothelial growth factor (VEGF) signalling pathway, which is known to be associated with psoriasis pathogenesis. However, research on midkine‐psoriasis relationship remains limited. The objective of this study was to detect midkine expression in psoriasis and investigate its potential role in the disease. Midkine expression was measured using immunohistochemistry and ELISA. Effects of midkine on HaCaT cell proliferation, VEGF‐A production and signalling pathways were assessed using CCK8, RT‐PCR and WB. Scratch and in vitro tube formation tests were used to evaluate the effects of HaCaT‐cell‐activated midkine on the migration and tube formation of human dermal microvascular endothelial cells. Murine psoriasiform models were injected with midkine recombinant protein and midkine monoclonal antibody to investigate skin lesions, tissue sections and dermal microvessel density. Levels of midkine significantly increased in both lesions and serum of patients with psoriasis. Serum expression of midkine decreased after treatment and a positive correlation was found between midkine and disease severity. Midkine promoted HaCaT cell proliferation and VEGF‐A production. The Notch2/HES1/JAK2‐STAT5A pathway expression increased after midkine treatment of HaCaT cells. The supernatant of HaCaT cells treated with midkine promoted HMEC‐1 migration and angiogenesis in vitro. Recombinant midkine protein exacerbated psoriasiform lesions with increased expressions of VEGF‐A and microvessel density, while midkine monoclonal antibody alleviated psoriasis lesions. Midkine may have a significant impact on psoriasis angiogenesis by regulating VEGF‐A expression through the Notch2/HES1/JAK2‐STAT5A pathway, highlighting a potential therapeutic target for psoriasis treatment. [ABSTRACT FROM AUTHOR]

A total synthesis approach of CS-E oligosaccharides was established and a series of derivatives were synthesized. These oligosaccharides were evaluated for a glycosaminoglycan (GAG)-binding protein interaction against cytokines, midkine, and pleiotrophin, by surface-plasmon resonance (SPR) assay. The binding epitopes of oligosaccharides to midkine were mapped using a saturation transfer difference (STD) NMR technique. The groups on the reducing end contributed to binding affinity, and should not be ignored in biological assays. These findings contribute to the structure and activity relationship research and a foundation of understanding that will underpin potential future optimization of this class of oligosaccharides as pharmaceutical agents. [ABSTRACT FROM AUTHOR]

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug resistance in cancer. MDK, a secretory cytokine found in blood, can be exploited as a potent biomarker for the non-invasive detection of drug resistance expressed in various cancers and, thereby, can be targeted. We summarize the current information on the involvement of MDK in drug resistance, and transcriptional regulators of its expression and highlight its potential as a cancer therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: To date, alpha-feto protein (AFP) remains the most widely used serum biomarker for hepatocellular carcinoma (HCC) diagnosis and prognosis. However, its role has become controversial as close to 30% of early stage HCC patients are AFP negative. Different studies on the diagnostic performance of novel AFP-negative HCC biomarkers have shown inconsistent results of sensitivity, specificity, and area under the receiver operating curve (AUROC). Here, we conducted a systematic review and meta-analysis to resolve this inconsistency. Methods: Relevant studies were systematically searched from PubMed, Embase, Cochrane library, Scopus, and the China National Knowledge Infrastructure (chkd-cnki) databases up to the 20th October 2022. The Newcastle–Ottawa Scale was used to assess the methodological quality of included studies. Sensitivity, specificity, and area under the curve were pooled using the random effect model. Results: Five studies, with a total of 286 patients, were included. Serum Midkine was assessed using enzyme-linked immunosorbent assay (ELISA) in all the studies, at diagnostic thresholds varying from 0.387 to 5.1 ng/ml. The summary estimates for serum Midkine were 76% (95% CI 70–81%) sensitivity, 85% (95% CI 82–87%) specificity, and 91% area under the receiver operating characteristic curve (AUC), while the pooled diagnostic odds ratio (DOR) was 27.64 (95% CI 4.95–154.17). Conclusion: Based on these findings, serum Midkine is a very promising diagnostic biomarker for AFP-negative HCC and should be validated further in large cohort studies. [ABSTRACT FROM AUTHOR]

Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. PTN and MY10, an RPTPβ/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPβ/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPβ/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPβ/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain. [ABSTRACT FROM AUTHOR]

Background: In-depth knowledge of the cellular and molecular composition of dental pulp (DP) and the crosstalk between DP cells that drive tissue homeostasis are not well understood. To address these questions, we performed a comparative analysis of publicly available single-cell transcriptomes of healthy adult human DP to 5 other reference tissues: peripheral blood mononuclear cells, bone marrow, adipose tissue, lung, and skin. Results: Our analysis revealed that DP resident cells have a unique gene expression profile when compared to the reference tissues, and that DP fibroblasts are the main cell type contributing to this expression profile. Genes coding for pleiotrophin (PTN) and midkine (MDK), homologous heparin-binding growth-factors, possessed the highest differential expression levels in DP fibroblasts. In addition, we identified extensive crosstalk between DP fibroblasts and several other DP resident cells, including Schwann cells, mesenchymal stem cells and odontoblasts, mediated by PTN and MDK. Conclusions: DP fibroblasts emerge as unappreciated players in DP homeostasis, mainly through their crosstalk with glial cells. These findings suggest that fibroblast-derived growth factors possess major regulatory functions and thus have a potential role as dental therapeutic targets. [ABSTRACT FROM AUTHOR]

Objectives: The tumor microenvironment (TME) play important roles in progression of endometrial carcinoma (EC). We aimed to assess the cell populations in TME of EC. Methods: We downloaded datasets of single-cell RNA-seq (scRNA-seq) and spatial transcriptome (ST) for EC from GEO, and downloaded RNA-Seq (FPKM) and clinical data of TCGA-UCEC project from TCGA. The datasets were analyzed using R software. Results: We obtained 5 datasets of scRNA-seq, 1 of ST and 569 samples of RNA-seq. Totally, 0.2 billion transcripts and 33,408 genes were detected in 33,162 cells from scRNA-seq. The cells were classified into 9 clusters, and EC cells were originated from epithelial cells and ciliated cells. Gene set variation analysis (GSVA) indicated that the pathways enriched in the subclusters of epithelial cells and endothelial cells were significantly different, indicating great heterogeneity in EC. Cell-cell communication analyses showed that EC cells emitted the strongest signals, and endothelial cells received more signals than other cells. Further analysis found that subclusters of 1 and 2 of epithelial cells were showed a more malignant phenotype, which may confer malignant phenotype to subcluster of 0 of endothelial cells through MK pathway by MDL-NCL signal. We also analyzed communications between spatial neighbors with ST data and confirmed the findings on MDL-NCL in cell-cell communication. TCGA and GEO analyses indicated that the expression levels of NCL was inversely correlated with ImmuneScore. Conclusion: Our study revealed EC cells can confer malignant phenotype to endothelial cells by MDK-NCL signal, and NCL is associated with suppressed immune activity. EC cells may shape TME by inhibiting immune cells and "educating" stromal cells via MDK-NCL signal. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Which substances and signal transduction pathways are potentially active downstream to the effect of FSH and LH in the regulation of human oocyte maturation in vivo ? SUMMARY ANSWER The regulation of human oocyte maturation appears to be a multifactorial process in which several different signal transduction pathways are active. WHAT IS KNOWN ALREADY Many studies in animal species have provided insight into the mechanisms that govern the final maturation of oocytes. Currently, these studies have identified several different mechanisms downstream to the effects of FSH and LH. Some of the identified mechanisms include the regulation of cAMP/cGMP levels in oocytes involving C-type natriuretic peptide (CNP), effects of epidermal growth factor (EGF)-related peptides such as amphiregulin (AREG) and/or epiregulin (EREG), effect of TGF-β family members including growth differentiation factor 9 (GDF9) and morphogenetic protein 15 (BMP15), activins/inhibins, follicular fluid meiosis activating sterol (FF-MAS), the growth factor midkine (MDK), and several others. However, to what extent these pathways and mechanisms are active in humans in vivo is unknown. STUDY DESIGN, SIZE, DURATION This prospective cohort study included 50 women undergoing fertility treatment in a standard antagonist protocol at a university hospital affiliated fertility clinic in 2016–2018. PARTICIPANTS/MATERIALS, SETTING, METHODS We evaluated the substances and signalling pathways potentially affecting human oocyte maturation in follicular fluid (FF) and granulosa cells (GCs) collected at five time points during the final maturation of follicles. Using ELISA measurement and proteomic profiling of FF and whole genome gene expression in GC, the following substances and their signal transduction pathways were collectively evaluated: CNP, the EGF family, inhibin-A, inhibin-B, activins, FF-MAS, MDK, GDF9, and BMP15. MAIN RESULTS AND THE ROLE OF CHANCE All the evaluated substances and signal transduction pathways are potentially active in the regulation of human oocyte maturation in vivo except for GDF9/BMP15 signalling. In particular, AREG, inhibins, and MDK were significantly upregulated during the first 12–17 h after initiating the final maturation of follicles and were measured at significantly higher concentrations than previously reported. Additionally, the genes regulating FF-MAS synthesis and metabolism were significantly controlled in favour of accumulation during the first 12–17 h. In contrast, concentrations of CNP were low and did not change during the process of final maturation of follicles, and concentrations of GDF9 and BMP15 were much lower than reported in small antral follicles, suggesting a less pronounced influence from these substances. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION Although GC and cumulus cells have many similar features, it is a limitation of the current study that information for the corresponding cumulus cells is not available. However, we seldom recovered a cumulus–oocyte complex during the follicle aspiration from 0 to 32 h. WIDER IMPLICATIONS OF THE FINDINGS Delineating the mechanisms governing the regulation of human oocyte maturation in vivo advances the possibility of developing a platform for IVM that, as for most other mammalian species, results in healthy offspring with good efficacy. Mimicking the intrafollicular conditions during oocyte maturation in vivo in small culture droplets during IVM may enhance oocyte nuclear and cytoplasmic maturation. The primary outlook for such a method is, in the context of fertility preservation, to augment the chances of achieving biological children after a cancer treatment by subjecting oocytes from small antral follicles to IVM. Provided that aspiration of oocytes from small antral follicles in vivo can be developed with good efficacy, IVM may be applied to infertile patients on a larger scale and can provide a cheap alternative to conventional IVF treatment with ovarian stimulation. Successful IVM has the potential to change current established techniques for infertility treatment. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the University Hospital of Copenhagen, Rigshospitalet, the Independent Research Fund Denmark (grant number 0134-00448), and the Interregional EU-sponsored ReproUnion network. There are no conflicts of interest to be declared. [ABSTRACT FROM AUTHOR]

To compare maternal serum midkine (MK) level in pregnant women with idiopathic fetal growth restriction (FGR) and healthy. In addition, we assessed the value of maternal serum MK level in predicting neonatal intensive care unit (NICU) admission. A total of 144 pregnant women were included, 72 with idiopathic FGR and 72 healthy in this study. The control group was matched for the mother's age, parity, gestational age, and pre-pregnancy body mass index (BMI) with the idiopathic FGR group at the time of recruitment into the study and sample collection. Serum MK level is higher in the idiopathic FGR than the control group (0.24 ng/mL (0.19–0.32) vs. 0.18 ng/mL (0.14–0.23), p<0.001). In addition, we compared the maternal serum MK level of those with and without NICU admission in the FGR group (0.25 ng/mL (0.19–0.37) vs. 0.21 ng/mL (0.18–0.28), p=0.014). We performed ROC curve analysis to serum MK level predicting NICU admission in the FGR group (AUC: 0.668, %95 CI [0.550, 0.785], p=0.014). A sensitivity of 63% and a specificity of 62% for the serum MK level were achieved with a cut-off value of 0.22 for NICU admission. To the best of our knowledge, this study is the first to compare maternal serum MK level in pregnant women with idiopathic FGR and healthy. We showed that maternal serum MK level was significantly elevated in pregnant women with FGR than healthy. [ABSTRACT FROM AUTHOR]

Introduction: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a limited survival time. In this study, we aimed to examine expression levels of genes selected from relevant literature and to utilize in silico methods to determine genes whose expression could reflect the prognosis of patients with MPM by ex-vivo validation experiments. Material and methods: The study group consisted of 54 MPM patients treated with chemotherapy. Expression of 6 genes - midkine (MDK), syndecan-1 (SDC1), hyaluronan synthase-2 (HAS2), sestrin-1 (SESN1), laminin subunit alpha-4 (LAMA4), and fibulin-3 (FBLN3) - was examined by qPCR in tumor tissues. Sestrin-1 and LAMA4 were identified using an in house R-based script: Unsupervised Survival Analysis Tool. Midkine, SDC1, HAS2, and FBLN3 were selected from current literature. We used two housekeeping genes, i.e. glucose-6-phosphate dehydrogenase and TATA-box binding protein, as controls. Results: Of the patients, 43 (79.6%) had epithelioid mesothelioma. The median survival for all patients was 10 (±1.2 SE) months (95% CI: 7.7-12.3). In multivariate analyses, MDK (p = 0.007), HAS2 (p = 0.008) and SESN1 (p = 0.014) expression levels were related to survival time in the whole group. In epithelioid type MPM patients, MDK (p = 0.014), FBLN3 (p = 0.029), HAS2 (p = 0.014) and SESN1 (p = 0.045) expression was related to survival time in multivariate analyses. Conclusions: High HAS2 and SESN1 expressions and low MDK are potential biomarkers of good prognosis in MPM. High HAS2 and SESN1 expression and low MDK and FBLN3 can also be utilized as biomarkers of good prognosis for epithelioid MPM. Those results should be further investigated in sera, plasma, and pleural effusions. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aim of the study was to longitudinally investigate the serum levels of mesothelin, sestrin1, hyaluronan synthase 2 (HAS2), midkine, and high mobility group box 1 (HMGB1) before and after chemotherapy and at the time of relapse in malignant pleural mesothelioma (MPM) patients treated with chemotherapy and to compare the changes in biomarker levels with radiological treatment outcome. METHODS: A total of 64 MPM patients treated with chemotherapy were enrolled in the study and longitudinally followed for changes in biomarker levels in response to treatment. Biomarkers levels were measured in serum using a human ELISA kit. Relative and absolute changes in biomarker levels were compared with the best radiological overall response at each time point. RESULTS: Median survival was 20.0 ± 2.4 (15.3–24.7) months in patients with partial and complete response, 17.0 ± 1.0 (15.0–19.0) months in patients with stable disease, and 9.0 ± 1.0 (7.0–11.0) months in patients with progressive disease. A significant decrease in serum levels of mesothelin, midkine, and HMGB1 was observed in patients with radiologically partial and complete responses to chemotherapy (p < 0.001, p = 0.016, and p = 0.039, respectively). In these patients, mesothelin levels decreased by 15%, midkine levels by 7%, and HMGB1 levels by 15%. In addition, HMGB1 serum levels were found to significantly increase by 15% in patients with radiologically progressive responses to chemotherapy compared to pretreatment serum levels (p = 0.035). In patients with partial and complete response to chemotherapy, mesothelin levels increased by 15%, midkine by 12%, and sestrin1 by 8% when the disease recurred (p = 0.004, p = 0.004 and p = 0.044, respectively). CONCLUSION: Biomarkers may be useful in the longitudinal monitoring of response to treatment in MPM. However, the results of our study should be validated in larger groups with sufficient case numbers from multicenter institutions. [ABSTRACT FROM AUTHOR]

Background: The incidence of liver cancer is increased worldwide with 75%–85% diagnosed as hepatocellular carcinoma (HCC). Current practice has low sensitivity limitations to diagnose the early stages of HCC, thus urging the need for a biomarker with higher sensitivity to detect HCC, specifically in the early stage. This study aimed to determine the association between midkine levels and progressiveness of hepatocellular carcinoma (HCC), according to tumor size, Barcelona Clinic Liver Cancer (BCLC), and presence of portal venous thrombosis. Methods: This cross-sectional study involved 100 patients in Adam Malik General Hospital diagnosed with HCC, collected with a consecutive sampling method, whose diagnoses were confirmed by findings of hypervascular on arterial phase imaging and portal vein or delayed phase washout triple-phase CT Scan. Samples are later categorized according to Barcelona Clinic Liver Cancer (BCLC) stages, tumor size, and presence of portal venous thrombosis. Blood samples were drawn to measure serum midkine using ELISA. Kruskal-Wallis and Mann-Whitney U tests were conducted to determine the difference of midkine levels based on tumor size, BCLC staging, and presence of portal venous thrombosis. Results: Serum midkine level shows a significant difference over tumor size (p=0.014), no significant difference found compared to BCLC stages and presence of portal venous thrombosis. Conclusion: Serum midkine levels are associated with the tumor size of HCC, thus helping physicians determine treatment plans. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of cancer-associated fibroblast (CAF)-derived midkine (MK) in cisplatin (DDP) resistance. The primary cultures of CAFs and non-cancer fibroblasts (NFs) were isolated and purified. The DDP-resistant gastric cancer (GC) cells were cultured with CAF-conditioned medium. QRT-PCR and Elisa assays were employed to determine MK expression. The expression of ST7-AS1 was measured by qRT-PCR. The impact of CAFs, MK, and ST7-AS1 silencing on DDP resistance was determined by MTT and Annexin V/PI staining assay. Expression of EMT markers and PI3K/AKT was determined by Western blot and qRT-PCR. The role of MK in DDP resistance was confirmed in a xenograft model. Incubation with CAF-conditioned medium increased the IC50 to DDP. Also, incubation with CAF-conditioned medium increased cell viability, reduced cell apoptosis, and promoted EMT in DDP-resistant GC cells, which were all blocked with MK neutralization antibody treatment. MK increased the DDP resistance and upregulated the expression of ST7-AS1 in DDP-resistant GC cells. Additionally, ST7-AS1 knockdown increased the sensitivity to DDP by inhibiting EMT. Moreover, ST7-AS1 knockdown significantly decreased the phosphorylation of PI3K and AKT, and suppressed EMT, which were restored by MK addition. Finally, MK promoted tumor growth and DDP resistance in a mice model bearing the SGC-7901/DDP xenografts. CAF-derived MK promotes EMT-mediated DDP resistance via upregulation of ST7-AS1 and activation of PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

NF-κB signaling is a key regulator of inflammation and atherosclerosis. NF-κB cooperates with bromodomain-containing protein 4 (BRD4), a transcriptional and epigenetic regulator, in endothelial inflammation. This study aimed to investigate whether BRD4 inhibition would prevent the proinflammatory response towards TNF-α in endothelial cells. We used TNF-α treatment of human umbilical cord-derived vascular endothelial cells to create an in vitro inflammatory model system. Two small molecule inhibitors of BRD4—namely, RVX208 (Apabetalone), which is in clinical trials for the treatment of atherosclerosis, and JQ1—were used to analyze the effect of BRD4 inhibition on endothelial inflammation and barrier integrity. BRD4 inhibition reduced the expression of proinflammatory markers such as SELE, VCAM-I, and IL6 in endothelial cells and prevented TNF-α-induced endothelial tight junction hyperpermeability. Endothelial inflammation was associated with increased expression of the heparin-binding growth factor midkine. BRD4 inhibition reduced midkine expression and normalized endothelial permeability upon TNF-α treatment. In conclusion, we identified that TNF-α increased midkine expression and compromised tight junction integrity in endothelial cells, which was preventable by pharmacological BRD4 inhibition. [ABSTRACT FROM AUTHOR]

Recent studies identified Midkine (MDK) as playing a key role in immune regulation. In this study, we aimed to discover the clinical significance and translational relevance in prostate cancer (PCa). We retrospectively analyzed 759 PCa patients who underwent radical prostatectomy from Huashan Hospital, Fudan University (training cohort, n = 369) and Chinese Prostate Cancer Consortium (validation cohort, n = 390). A total of 325 PCa patients from The Cancer Genome Atlas (TCGA) database (external cohort) were analyzed for exploration. Immune landscape and antitumor immunity were assessed through immunohistochemistry and flow cytometry. Patient‐derived explant culture system was applied for evaluating the targeting potential of MDK. We found that intratumoral MDK expression correlated with PCa progression, which indicated an unfavorable biochemical recurrence (BCR)‐free survival for postoperative PCa patients. Addition of MDK expression to the postoperative risk assessment tool CAPRA‐S could improve its prognostic value. Tumors with MDK abundance characterized the tumor‐infiltrating CD8+ T cells with less cytotoxicity production and increased immune checkpoint expression, which were accompanied by enriched immunosuppressive contexture. Moreover, MDK inhibition could reactivate CD8+ T cell antitumor immunity. MDK mRNA expression negatively correlated with androgen receptor activity signature and positively associated with radiotherapy‐related signature. In conclusion, intratumoral MDK expression could serve as an independent prognosticator for BCR in postoperative PCa patients. MDK expression impaired the antitumor function of CD8+ T cells through orchestrating an immunoevasive microenvironment, which could be reversed by MDK inhibition. Moreover, tumors with MDK enrichment possessed potential sensitivity to postoperative radiotherapy while resistance to adjuvant hormonal therapy of PCa. MDK could be considered as a potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

Copyright of Adicciones is the property of Sociedad Cientifica Espanola de Estudios sobre el Alcohol and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: In end-stage renal disease, a high cardiovascular risk profile and endothelial damage prevails. The heparin-binding growth factor midkine stimulates neo-angiogenesis in ischemic diseases, coordinates neutrophil influx, and raises blood pressure through stimulated angiotensin synthesis. Methods: We determined changes of midkine serum levels during hemodialysis sessions under the assumption that endothelial cell-derived midkine is released. Periprocedural differences (∆midkine) were calculated and correlated with cardiovacular biomarkers and fluid status (clinical assessment, V. cava collapse, comet tail phenomenon), cardiovascular morbidities, mortality rates. Blood was collected before and after dialysis from hemodialysis patients (n = 171; diabetes: n = 70; hypervolemia: n = 83; both: n = 32). Results: Baseline midkine levels were ~ fourfold elevated compared to healthy controls (n = 100). Further, on average a tenfold rise was detected during dialysis, the extent of which was partially related to non-fractionated heparin application (r2 = 0.17). Inter-individual differences were highly reproducible. Hypervolemic patients responded with a less than average rise in midkine levels during dialysis (p < 0.02), this difference became more obvious with co-existing diabetes (p < 0.001 for long dialysis-free interval) and was confirmed in an independently enrolled dialysis cohort (n = 88). In Kaplan Meier survival curves, low delta midkine levels correlated with cardiovascular/overall mortality rates, similar to elevated uPAR levels, whereas other markers (NTproANP, galectin, tenascin-C) were less predictive. Following intervention with successful fluid removal in hypervolemic dialysis patients to optimize fluid homeostasis, midkine values increased (p < 0.002), which was not observed in patients that failed to decrease weight. Conclusion: Thus, for dialysis patients inadequate periprocedural midkine upregulation is linked with hypervolemia and associates with cardiovascular events. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: This study aims to estimate the concentrations of MK, hs-CRP, TnI, AST, ALT and ALP in serum for MI in comparison to wholesome controls, in an effort to check the quantity of this impact at the pathological condition, in addition to understanding the position of MK in MI sufferers and its relationship to liver function tests and may be used as biochemical markers to decide the severity of MI in sufferers. Methods: The studying include the investigation of midkine (MK), High-sensitivity C-reactive protein (hs-CRP), Troponin I (TnI), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in myocardial infarction (MI) patients. The study includes (84) samples: 34 of myocardial infarction patients (19 male and 15 female) and 50 sample of apparently healthy as control group (25 male and 25 female). Samples were collected during the period from Jan. 2021 to July 2021 from in-patients of Cardiac Surgery Center admitted at Ibn Sina Teaching Hospital and Mosul General Hospital, Mosul, Iraq with matching age ranged between 26-86 years. The clinical diagnosis in each case is made according to a cardiovascular specialist. Results: The results showed that there was a significant increase in MK, TnI, GOT, GPT and ALP for all studied groups (males and females) of MI patients compared with control groups, and there was no any a significant in hs-CRP. Beside of, showed significant positive correlation between MK with BMI, hs-CRP, TnI, AST, ALT and ALP in control and patients group. Whereas there were no any correlation between MK with age, in patients and control under study. Conclusion: The study indicated that the MK increased in patients with myocardial infarction, and it's increased in males more than female patients, and that may act as a good markers for diagnosis of myocardial infarction disease. [ABSTRACT FROM AUTHOR]

Introduction: Currently there are no biomarkers that are predictive of when patients with type-2 diabetes (T2D) will progress to more serious kidney disease i.e., diabetic nephropathy (DN). Biomarkers that could identify patients at risk of progression would allow earlier, more aggressive treatment intervention and management, reducing patient morbidity and mortality. Materials and Methods: Study participants (N=88; control n=26; T2D n=32; DN n=30) were recruited from the renal unit at Antrim Area Hospital, Antrim, UK; Whiteabbey Hospital Diabetic Clinic, Newtownabbey, UK; Ulster University (UU), Belfast, UK; and the University of the Third Age (U3A), Belfast, UK; between 2019 and 2020. Venous blood and urine were collected with a detailed clinical history for each study participant. Results: In total, 13/25 (52.0%) biomarkers measured in urine and 25/34 (73.5%) biomarkers measured in serum were identified as significantly different between control, T2D and DN participants. DN patients, were older, smoked more, had higher systolic blood pressure and higher serum creatinine levels and lower eGFR function. Serum biomarkers significantly inversely correlated with eGFR. Conclusion: This pilot-study identified several serum biomarkers that could be used to predict progression of T2D to more serious kidney disease: namely, midkine, sTNFR1 and 2, H-FABP and Cystatin C. Our results warrant confirmation in a longitudinal study using a larger patient cohort. [ABSTRACT FROM AUTHOR]

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR -mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs. [Display omitted] • Macrophages in CSF of LMs displayed heterogeneity and immunosuppressive properties • Lipid-associated macrophages are linked to osimertinib resistance and LM development • Macrophages are regulated by MDK and may be a prognostic biomarker for LMs • CD47-SIRPA signaling by tumor cells and macrophages facilitates drug resistance Li et al. identify heightened immunosuppressive macrophages within LMs. Lipid-associated macrophages in CSF are associated with osimertinib resistance and LM development. Midkine from malignant epithelial cells potentially regulates LMs and macrophage polarization. CD47-SIRPA interactions between tumor cells and macrophages facilitate immune escape, suggesting potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Midkine (MK) is a soluble cytokine, and its serum levels strongly correspond to protein expression levels in tumors. The present study aimed to clarify the clinicopathological and prognostic significance of serum MK (s-MK) in patients with hepatocellular carcinoma (HCC). Serum samples were obtained before surgery from 123 patients with HCC who had undergone surgery between January 2012 and December 2020. The receiver operating characteristic curve revealed that the best cut-off value for s-MK in differentiating HCC from healthy cases was 426 pg/ml. The clinicopathological variables and overall survival of patients were compared between the s-MK-positive group and s-MK-negative group. The sensitivity, specificity and accuracy of s-MK were 82.1, 97.4 and 88.0%, respectively. An s-MK-positive status was significantly associated with the number of tumors (≥2). The positivity rate of s-MK was significantly higher compared with that of α-fetoprotein and protein-induced by vitamin K absence-II. In total, only 28% of the patients were positive for s-MK. The s-MK-positive group showed significantly worse overall survival compared with the s-MK-negative group. Moreover, multivariate analysis revealed that an s-MK-positive status was independently associated with poor prognosis. s-MK was useful in detecting early HCC. The findings of this study indicated that the s-MK-positive status is associated with the number of tumors and can act as an independent prognostic risk factor. [ABSTRACT FROM AUTHOR]

Simple Summary: Most patients with glioblastoma, the most frequent primary brain tumor in adults, develop resistance to standard first-line treatment combining temozolomide and radiotherapy. Signaling through the hepatocyte growth factor receptor (c-MET) and the midkine (ALK ligand) promotes gliomagenesis and glioma stem cell maintenance, contributing to the resistance of glioma cells to anticancer therapies. This trial reports for the first time that the addition of crizotinib, an ALK, ROS1, and c-MET inhibitor, to standard RT and TMZ is safe and resulted in a promising efficacy for newly diagnosed patients with glioblastoma. Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33–76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7–13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1–31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study. [ABSTRACT FROM AUTHOR]

The atherosclerotic vascular disease is a cardiovascular continuum in which the main role is attributed to atherosclerosis, from its appearance to its associated complications. The increasing prevalence of cardiovascular risk factors, population ageing, and burden on both the economy and the healthcare system have led to the development of new diagnostic and therapeutic strategies in the field. The better understanding or discovery of new pathophysiological mechanisms and molecules modulating various signaling pathways involved in atherosclerosis have led to the development of potential new biomarkers, with key role in early, subclinical diagnosis. The evolution of technological processes in medicine has shifted the attention of researchers from the profiling of classical risk factors to the identification of new biomarkers such as midregional pro-adrenomedullin, midkine, stromelysin-2, pentraxin 3, inflammasomes, or endothelial cell-derived extracellular vesicles. These molecules are seen as future therapeutic targets associated with decreased morbidity and mortality through early diagnosis of atherosclerotic lesions and future research directions. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most common malignancy in females and is the second leading cause of cancer-related death among women worldwide. Midkine (MDK) is a heparin-binding growth factor that is abnormally expressed at high levels in various human malignancies. We aimed to uncover the biological function and molecular mechanism of MDK in BC cells. Methods and results: MDA-MB-231-shMDK and T47D-shMDK BC cells were established. The in vitro biological functions of MDK were demonstrated by CCK-8 assays, Transwell assays and Western blotting, whereas qPCR pathway arrays were implemented to explore the mechanism of MDK in BC cells. Functionally, we verified that silencing MDK significantly suppressed BC cell proliferation and migration by inhibiting the activation of the nuclear factor kappa B (NF-κB) pathway and the nuclear distribution of NF-κB. Meanwhile, Ingenuity Pathway Analysis (IPA) and a qPCR pathway array revealed that silencing MDK decreased the expression of NR3C1, a potential downstream target of the NF-κB pathway. We also confirmed that treatment with an NF-κB inhibitor suppressed NR3C1 expression in BC cells. Finally, we demonstrated that silencing NR3C1 repressed BC cell proliferation and migration. Conclusions: Our findings highlight a novel mechanism by which MDK influences BC progression via regulation of the NF-κB-NR3C1 pathway. [ABSTRACT FROM AUTHOR]

Copyright of Gynecological Endocrinology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cell-penetrating peptides (CPPs) have been regarded as potential drug carriers for cancer therapy. However, most well-studied CPPs fail to deliver exogenous drugs efficiently and selectively. In this study, a tumour-targeted CPP with high efficiency derived from heparin-binding domain (HBD) of Midkine (named HMD) was discovered. HMD exhibited higher delivery efficiency than classic CPPs (TAT and R9) and manifested selectivity in tumour cells. Normally, the positive charge is the key factor for the transmembrane activity of CPPs such as TAT and R9. Here, the length of α-helix inside CPP was found also important for in the recognition of heparan sulphate proteoglycans (HSPGs). Subsequently, the introduction of HMD enhanced the inhibitory effect of Momordica antiviral protein of 30 kDa (MAP30) on tumour cells, resulting in a 6.07-fold and 5.42-fold increase in HeLa cells and MGC80-3 cells respectively without enhanced cytotoxicity in normal cells. These results show that HMD possesses high efficiency and good tumour specificity and can be utilised as a promising agent for the tumour-targeted delivery of drug. This study is also a supplement to the existing theories about the biological activities of the α-helix in CPPs. [ABSTRACT FROM AUTHOR]

Background: Activation of the insulin-like growth factor 1 receptor (IGF-1R)-mediated Janus kinase (JAK)1/2-Stat3 pathway contributes to hepatocarcinogenesis. Specifically, a previous study showed that IGF-1R inhibition downregulated Midkine expression in hepatocellular carcinoma (HCC). Aims: The present study investigated the role of IGF-1R-JAK1/2-Stat3 and Midkine signaling in HCC, in addition to the molecular link between the IGF-1R-Stat3 pathway and Midkine. Methods: The expression levels of IGF-1R, Stat3, and Midkine were measured using reverse transcription-quantitative PCR, following which the association of IGF-1R with Stat3 and Midkine expression was evaluated in HCC. The molecular link between the IGF-1R-Stat3 pathway and Midkine was then investigated in vitro before the effect of IGF-1R-Stat3 and Midkine signaling on HCC growth and invasion was studied in vitro and in vivo. Results: IGF-1R, Stat3, and Midkine mRNA overexpressions were all found in HCC, where the levels of Stat3 and Midkine mRNA correlated positively with those of IGF-1R. In addition, Midkine mRNA level also correlated positively with Stat3 mRNA expression in HCC tissues. IGF-1R promoted Stat3 activation, which in turn led to the upregulation of Midkine expression in Huh7 cells. Similarly, Midkine also promoted Stat3 activation through potentiating JAK1/2 phosphorylation. Persistent activation of this Stat3-Midkine-Stat3 positive feedback signal loop promoted HCC growth and invasion, the inhibition of which resulted in significant antitumor activities both in vitro and in vivo. Conclusions: Constitutive activation of the IGF-1R-mediated Stat3-Midkine-Stat3 positive feedback loop is present in HCC, the inhibition of which can serve as a potential therapeutic intervention strategy for HCC. [ABSTRACT FROM AUTHOR]

Background Early diagnosis and treatment are the keys for effective treatment of patients with hepatocellular carcinoma (HCC). The use of serological markers in patients at the highest risk of developing HCC may thus decrease HCC mortality and reduce medical costs. Midkine (MK) has an essential role in activities related to carcinogenesis such as proliferation, anti-apoptosis, transformation, migration, and angiogenesis, in many types of tumors, including HCC. Aim To evaluate serum levels of MK as a diagnostic biomarker for early detection of HCC in relation to conventional markers, such as alpha-fetoprotein (AFP). Patients and methods This study was conducted on 90 individuals who attended the Hepatogastroenterology and Infectious Diseases Department, Al-Zahraa University Hospital, Al Azhar University. The patients were divided into three groups: group I comprised 30 patients with HCC on top of hepatitis C virus and group II comprised 30 patients with cirrhotic liver post-hepatitis C virus. Control group The control group comprised 30 healthy adult participants. Results Highly statistically significant increase in serum MK in groups I and II in comparison to the control group and statistically significant increase in group I in comparison to group II. Serum MK can be used to discriminate between groups I and II at a cutoff level of more than 97.7, with 80% sensitivity, 90% specificity, 88.9% positive predictive value and 81.8% negative predictive value and area under curve=0.94. Also, it used to discriminate between groups I and III at a cutoff level of more than 76.5, with 100% sensitivity, specificity, positive predictive value, and negative predictive value with area under the curve=1.0. Conclusion MK is more accurate than AFP in diagnosing HCC, especially in detecting early stage HCC and AFPnegative HCC. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Long‐range communication between tumor cells and the lymphatic vasculature defines competency for metastasis in different cancer types, particularly in melanoma. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole‐body analyses of tumor progression. Here, we exploit immunocompetent and immunodeficient mouse models for live imaging of Vegfr3‐driven neolymphangiogenesis, as a versatile platform for drug screening in vivo. Spatiotemporal analyses of autochthonous melanomas and patient‐derived xenografts identified double‐stranded RNA mimics (dsRNA nanoplexes) as potent inhibitors of neolymphangiogenesis, metastasis, and post‐surgical disease relapse. Mechanistically, dsRNA nanoplexes were found to exert a rapid dual action in tumor cells and in their associated lymphatic vasculature, involving the transcriptional repression of the lymphatic drivers Midkine and Vegfr3, respectively. This suppressive function was mediated by a cell‐autonomous type I interferon signaling and was not shared by FDA‐approved antimelanoma treatments. These results reveal an alternative strategy for targeting the tumor cell‐lymphatic crosstalk and underscore the power of Vegfr3‐lymphoreporters for pharmacological testing in otherwise aggressive cancers. SYNOPSIS: This study reports the "Lymphoreporter‐MetAlert" mice as a platform for non‐invasive imaging and screening for antimetastatic agents. The focus is on melanoma, but these animals can be used for other tumor types and other pathologies that involve an aberrant activation of the lymphatic vasculature. MetAlert mice allow for in vivo analyses of drug response in patient‐derived xenografts (PDX) and genetically modified melanoma models (GEMM).Inhibitors of BRAF or immune checkpoints result in a limited anti‐lymphangiogenic and antitumoral activity in MetAlert (as in the clinic).dsRNA nanoplexes (BO‐110) were identified to blunt neo‐lymphangiogenesis after just one systemic administration.BO‐110 blocked neolymphangiogenesis at two levels: in melanoma cells via repression of Midkine (MDK) and in lymphatic cells via VEGFR3.Imaging metastatic relapse after surgical excision set the proof of principle for BO‐110 in adjuvant treatment. [ABSTRACT FROM AUTHOR]

Background: Increased perioperative pro-inflammatory biomarkers, renal hypoperfusion and ischemia reperfusion injury (IRI) heighten cardiac surgery acute kidney injury (CS-AKI) risk. Increased urinary anti-inflammatory cytokines attenuate risk. We evaluated whether blood and urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation, hypoperfusion and IRI are increased in CS-AKI patients. Methods: Preoperative and 24-h postoperative blood and urinary pro-inflammatory and anti-inflammatory cytokines, blood VEGF and H-FABP (hypoperfusion biomarkers), and MK, a biomarker for IRI, were measured in 401 cardiac surgery patients. Pre- and postoperative concentrations of biomarkers and selected ratios thereof, were compared between non-CS-AKI and CS-AKI patients. Results: Compared with non-CS-AKI, blood pro-inflammatory (pre- and post-op TNFα, IP-10, IL-12p40, MIP-1α, NGAL; pre-op IL-6; post-op IL-8, MK) and anti-inflammatory (pre- and post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers together with urinary pro-inflammatory (pre- and post-op uIL-12p40; post-op uIP-10, uNGAL) and anti-inflammatory (pre- and post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers, were significantly higher in CS-AKI patients. Urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation (blood and urine), hypoperfusion (blood H-FABP and VEGF) and IRI (blood MK) were decreased in CS-AKI. In contrast, blood anti-inflammatory biomarkers expressed as similar ratios with blood biomarkers were increased in CS-AKI. Conclusions: The urinary anti-inflammatory response may protect against the injurious effects of perioperative inflammation, hypoperfusion and IRI. These finding may have clinical utility in bioprediction and earlier diagnosis of CS-AKI and informing future therapeutic strategies for CS-AKI patients. [ABSTRACT FROM AUTHOR]

Background: Increased perioperative pro-inflammatory biomarkers, renal hypoperfusion and ischemia reperfusion injury (IRI) heighten cardiac surgery acute kidney injury (CS-AKI) risk. Increased urinary anti-inflammatory cytokines attenuate risk. We evaluated whether blood and urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation, hypoperfusion and IRI are increased in CS-AKI patients.Methods: Preoperative and 24-h postoperative blood and urinary pro-inflammatory and anti-inflammatory cytokines, blood VEGF and H-FABP (hypoperfusion biomarkers), and MK, a biomarker for IRI, were measured in 401 cardiac surgery patients. Pre- and postoperative concentrations of biomarkers and selected ratios thereof, were compared between non-CS-AKI and CS-AKI patients.Results: Compared with non-CS-AKI, blood pro-inflammatory (pre- and post-op TNFα, IP-10, IL-12p40, MIP-1α, NGAL; pre-op IL-6; post-op IL-8, MK) and anti-inflammatory (pre- and post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers together with urinary pro-inflammatory (pre- and post-op uIL-12p40; post-op uIP-10, uNGAL) and anti-inflammatory (pre- and post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers, were significantly higher in CS-AKI patients. Urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation (blood and urine), hypoperfusion (blood H-FABP and VEGF) and IRI (blood MK) were decreased in CS-AKI. In contrast, blood anti-inflammatory biomarkers expressed as similar ratios with blood biomarkers were increased in CS-AKI.Conclusions: The urinary anti-inflammatory response may protect against the injurious effects of perioperative inflammation, hypoperfusion and IRI. These finding may have clinical utility in bioprediction and earlier diagnosis of CS-AKI and informing future therapeutic strategies for CS-AKI patients. [ABSTRACT FROM AUTHOR]

Background: Fine-needle aspiration cytology (FNAC) is a basic diagnostic tool for thyroid nodules. However, 15–30% of nodules are cytologically indeterminate. Midkine (MK), a pleiotropic growth factor, is often upregulated in patients with cancers. This study aimed to evaluate the role of MK and its ratios in fine-needle aspirates (FNA) for predicting thyroid malignancy. Methods: This retrospective study included patients with thyroid nodules who underwent preoperative FNA and/or thyroidectomy between April 2017 and September 2017. MK levels in FNA washout were measured by enzyme-linked immunosorbent assay, and thyroglobulin (TG) and free thyroxine (FT4) levels in FNA washout were measured by chemiluminescent immunometric assays. Results: A total of 217 patients with 242 nodules were included in this study. The concentrations of TG, FT4, MK/TG, MK/FT4, and FT4/MK were significantly different between papillary thyroid carcinomas and benign thyroid nodules. Both MK/TG and MK/FT4 ratios were positively correlated with maximum tumor diameter, extrathyroidal extension, and T and N stages. The area under the curve for MK/TG was 0.719 with a cutoff value of 55.57 ng/mg, while the area under the curve for MK/FT4 was 0.677 with a cutoff value of 0.11 μg/pmol. FNAC in combination with MK/FT4 had a higher sensitivity (95% vs. 91%) and accuracy (96% vs. 92%) than FNAC alone for cytologically indeterminate specimens, those of unknown significance, or those suspected of malignancy. Conclusions: MK/FT4 and MK/TG may have diagnostic utility for evaluation of papillary thyroid carcinomas, particularly for cytologically indeterminate thyroid nodules. [ABSTRACT FROM AUTHOR]

Background: Our previous bioinformatics-based study found that midkine (MDK) was associated with poor prognosis of glioblastoma (GBM). However, the mechanism of MDK in GBM remains elusive. Methods: A public GBM-related dataset and GBM tissues from our center were used validate the aberrant expression of MDK in GBM at the RNA and protein levels. The relationship between MDK expression and survival of GBM patients was also explored through survival analysis. Subsequently, we identified MDK-related GBM-specific genes using differential expression analysis. Functional enrichment analyses were performed to reveal their potential biological functions. CCK-8, 5-ethynyl-2′-deoxyuridine, and Matrigel-transwell assays were performed in GBM cell lines in which MDK was knocked out or overexpressed in order assess the effects of MDK on proliferation, migration, and invasion of GBM cells. Western blotting was performed to detect candidate proteins. Results: Our study showed MDK is a promising diagnostic and prognostic biomarker for GBM because it is highly expressed in the disease and it is associated with poor prognosis. MDK is involved in various cancer-related pathways, such as PI3K-Akt signaling, the cell cycle, and VEGF signaling. A comprehensive transcriptional regulatory network was constructed to show the potential pathways through which MDK may be involved in GBM. In vitro, Overexpression of MDK augmented proliferation, migration, and invasion of GBM cell lines, whereas suppression of MDK led to the opposite effects. Furthermore, our study confirmed that MDK promotes the progression of GBM by activating the PI3K-Akt signaling pathway. Conclusions: Our present study proposes that MDK promotes GBM by activating the PI3K-Akt signaling pathway, and it describes a potential regulatory network involved. [ABSTRACT FROM AUTHOR]