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Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. The use of alpha fetoprotein (AFP) alone was not an accurate biomarker for HCC despite its high specificity. Therefore, we assessed the possible role of serum biomarkers that have been mentioned briefly in previous studies on Egyptian patients ion top of HCV. However these studies included small number of patients and did not assess the different stages of hepatocarcinogenesis. In the current study we assessed 1) the expression levels of Golgi protein 37(GP73),Midkine (MDK) and Dickkopf-1(DKK-1) proteins separately and in combination at different stages of hepatocarcinogenesis. GP73, MDK and DKK-1 proteins were assessed in 238 individuals divided into 4 groups (HCC, chronic HCV, and chronic HCV with cirrhosis and healthy subjects as a control) Serum levels of GP73, MDK, and DKK-1 were assessed in all subjects by ELISA. Serum levels of the studied markers were significantly higher in HCC compared to other groups (p < 0.001). The ROC curve analysis for the studied markers showed 1) 88.5% sensitivity, 80.6% specificity, 69% PPV, 93.5% NPV and (AUC 0.91)for MDK; 2) 93.6%, 86.9%, 77.7%, 96.5% for DKK-1. 3) 91%, 85%, 74.7%, 95% (AUC 0.96) for GP73 and 4) 74.4%, 84.4%, 69.9%, 87.1% (AUC 0.81) for AFP. Serum levels of GP73, MDK, and DKK-1 are comparable to AFP as promising predictor biomarkers for HCC patients from Egypt. A two markers panel including Gp73 and DKK-1 showed the highest specificity and sensitivity among different markers combinations.

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro , and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

Purpose Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti‐programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long‐term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin‐binding growth factor involved in various biological processes, including cell proliferation and chemotherapeutic resistance, in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, only a few studies have evaluated its expression and function in SCLC. This study aimed to evaluate the MDK expression in human SCLC tissue and human SCLC cell lines, and to clarify its function in tumorigenesis. Methods MDK expression was analyzed in vitro and in vivo through ELISA, immunohistochemistry, and western blotting. Its effects on cell proliferation, as well as the effects of cisplatin, were evaluated using the MTT assay. Results MDK was pathologically expressed in human SCLC tumor tissues but not in normal lung tissues. Serum MDK concentrations in patients with SCLC reflected the SCLC tumor burden and were correlated with response to treatment. Moreover, MDK induced cell proliferation and attenuated the effects of cisplatin in SCLC cell lines. An MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Furthermore, MDK positively regulated the AKT pathway. Conclusion Our findings indicate that MDK promotes cell proliferation and chemotherapeutic resistance by activating the AKT pathway in SCLC cells. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC.

Objective The objective of this study is to investigate the correlation between the expression levels of midkine (MDK) in the serum of patients with hepatocellular carcinoma (HCC) and various clinical features, and to evaluate the diagnostic efficacy of MDK in HCC cases that are negative for alpha-fetoprotein (AFP). Methods Serum samples from 330 patients were collected from electronic cases and divided into three groups: HCC, benign liver disease, and healthy people. Serum MDK levels in all three groups were detected by ELISA. Correlation analysis was conducted to evaluate the relationship between serum MDK and liver function indexes and other traditional tumor markers in the HCC group. The receiver operating characteristic curve was used to analyze the diagnostic utility of MDK in HCC and AFP-negative HCC. In addition, univariate and multivariate analyses were performed to determine the correlation between MDK level and tumor metastasis, and clinicopathological features. Results MDK is significantly elevated in negative HCC (P = 0.001). The serum expression level of MDK in patients with HCC was found to be positively correlated with various indicators of liver injury (P < 0.05). Notably, elevated MDK expression was significantly associated with the China liver cancer staging system (CNLC) stage (P = 0.003) and complications (P = 0.000). Furthermore, the CNLC stage significantly impacted patient survival and metastasis (P = 0.016). Specifically, we propose that high levels of MDK expression are closely linked to poor tumor prognosis. Conclusion The risk of tumor metastasis and the likelihood of poor prognosis in patients with HCC are significantly elevated in those exhibiting high levels of MDK. MDK could serve as a novel serum diagnostic marker for patients who are negative for AFP.

Airway smooth muscle cell (ASMC) dysfunction drives airway remodeling in asthma, yet the molecular mediators remain incompletely defined. Midkine, a pleiotropic growth factor, has emerged as a potential regulator of inflammatory and proliferative responses. This study investigated midkine expression and function in platelet‐derived growth factor‐BB (PDGF‐BB)‐stimulated ASMCs. Serum midkine levels were quantified in asthmatic children and healthy controls. Primary human ASMCs were stimulated with PDGF‐BB and subjected to midkine knockdown using siRNA. Proliferation, migration, extracellular matrix (ECM) deposition, inflammatory cytokine production, glycolytic activity, and PI3K/Akt signaling were assessed using MTT, Transwell, RT‐qPCR, ELISA, western blotting, and metabolic assays. Serum midkine levels were significantly elevated in patients with asthma. PDGF‐BB stimulation increased midkine expression and ASMC proliferation, which were markedly suppressed by midkine silencing. Knockdown attenuated PDGF‐BB‐induced PI3K/Akt phosphorylation, reduced ASMC migration, and decreased collagen I and fibronectin expression levels. Midkine silencing also diminished TNF‐α, IL‐1β, and IL‐6 production and lowered glucose consumption, lactate release, ATP generation, and the expression of PKM2 and LDHA. These findings indicate that midkine promotes ASMC proliferation, migration, inflammation, extracellular matrix deposition, and glycolysis via the PI3K/Akt signaling pathway, thereby contributing to airway remodeling in asthma.

To explore the relationship between serum levels of midkine and omentin-1 and the severity of sepsis in patients, and their prognostic value. A retrospective analysis was conducted on the clinical data of 180 sepsis patients. According to the severity of the patient's condition, they were separated into sepsis group (  = 76), severe sepsis group (  = 59), and sepsis shock group (  = 45). Based on the survival within 28 days of admission, they were grouped into survivors group (  = 128) and nonsurvivors group (  = 52). The serum Midkine level and APACHE II score in the sepsis shock group were higher than those in the severe sepsis group and sepsis group, while the Omentin-1 level was lower than that in the severe sepsis group and sepsis group (  < 0.05). The serum Midkine level and APACHE II score in the severe sepsis group were higher than those in the sepsis group, while the Omentin-1 level was lower than that in the sepsis group (  < 0.05). The Midkine and APACHE II score in the nonsurvivors group was higher than those in the survivors group, while the Omentin-1 score was lower than that in the survivors group (  < 0.05). Midkine and APACHE II score were independent risk factors for the prognosis of sepsis patients, while Omentin-1 was a protective factor for the prognosis of sepsis patients (  < 0.05). The AUC of the combined prediction of serum Midkine and Ommentin-1 for the prognosis of sepsis patients was 0.880, with a sensitivity of 90.38% and a specificity of 72.66%. The combined prediction of serum Midkine and Ommentin-1 was better than that of individual prediction of Midkine and Ommentin-1. Serum Midkine is highly expressed and Omentin-1 is lowly expressed in sepsis patients, and the combination of the two has a high predictive power for the prognosis of sepsis patients.

Elevated blood glucose levels may serve as an early indicator of underlying pancreatic cancer. Discriminating between pancreatic cancer‐associated new‐onset diabetes (PCAND) and new‐onset type 2 diabetes mellitus (T2DM) holds promise for enabling an earlier diagnosis of pancreatic cancer. Nevertheless, the absence of effective biomarkers for distinguishing PCAND from the more prevalent new‐onset T2DM persists, primarily because of the elusive pathogenesis of PCAND. In this study, the intricate intercellular communication is comprehensively elucidated through single‐cell RNA sequencing. The findings identified Midkine (MDK) as a potential mediator of the interaction between tumor and beta cells. MDK, which originated from pancreatic ductal adenocarcinoma cells, exerted deleterious effects on paraneoplastic beta cells by binding to the SDC4 receptor on the beta cell surface and subsequently downregulating the Ras signaling pathway, thereby impairing insulin production and secretion. Notably, the plasma levels of MDK are higher in patients with PCAND than in those with T2DM. In conclusion, MDK has emerged as a pivotal driver of PCAND pathogenesis and may function as a blood‐based biomarker for discriminating between PCAND and T2DM in populations with new‐onset diabetes, thereby facilitating the advancement of early detection strategies for pancreatic cancer. Midkine (MDK) is a mediator of the interaction between pancreatic cancer and beta cells. MDK, which originated from pancreatic ductal adenocarcinoma cells, exerted deleterious effects on paraneoplastic beta cells by binding to the SDC4 receptor on the beta cell surface and subsequently downregulating the Ras signaling pathway, thereby impairing insulin production and secretion.

Acute kidney injury (AKI) after major trauma is associated with increased mortality. The aim of this study was to assess if measurement of blood biomarkers in combination with clinical characteristics could be used to develop a tool to assist clinicians in identifying which orthopaedic trauma patients are at risk of AKI. This is a prospective study of 237 orthopaedic trauma patients who were consecutively scheduled for open reduction and internal fixation of their fracture between May 2012 and August 2013. Clinical characteristics were recorded, and 28 biomarkers were analysed in patient blood samples. Post operatively a combination of H-FABP, sTNFR1 and MK had the highest predictive ability to identify patients at risk of developing AKI (AUROC 0.885). Three clinical characteristics; age, dementia and hypertension were identified in the orthopaedic trauma patients as potential risks for the development of AKI. Combining biomarker data with clinical characteristics allowed us to develop a proactive AKI clinical tool, which grouped patients into four risk categories that were associated with a clinical management regime that impacted patient care, management, length of hospital stay, and efficient use of hospital resources.

Background There are no studies investigating the role of midkine (MK) in vascular calcification (VC) or vascular disease associated with chronic kidney disease (CKD). This study assessed serum MK level and investigated its relationship with carotid atherosclerosis and coronary artery calcification (CAC) in non-dialysis CKD. Methods The study comprised 80 controls and 185 adult patients with CKD at stages 3–5 who were free of cardiovascular diseases. Acute renal failure, chronic hemodialysis, severe liver disease, inflammatory states, anticoagulation therapy and cancer were excluded. The patients were classified based on presence of CAC score into severe and mild to moderate CAC groups. They were also divided into atherosclerotic and non-atherosclerotic groups based on carotid atherosclerosis. CBC, kidney function tests, lipid profile, intact parathyroid hormone (iPTH), and phosphorus were assessed. Serum levels of MK, tumor necrosis factor- α (TNF- α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were quantitatively tested using ELISA. Cardiac CT scan was done to calculate CAC score. Carotid ultrasonography was used to evaluate carotid intima media thickness (CIMT) and identify plaques. Results All CKD categories, including CKD-3, CKD-4, and CKD-5, showed higher rates of carotid plaques ( p  = 0.007, p  < 0.001, and p  < 0.001, respectively), higher levels of MK ( p  < 0.001 for each), and higher CAC scores ( p  < 0.001 for each) as CKD worsened. Compared to mild to moderate CAC patients, severe CAC patients showed increased CIMT ( p  < 0.001) and raised serum levels of MK ( p  < 0.001), TNF-α ( p  = 0.001), IL-6 ( p  = 0.002), hs-CRP ( p  = 0.003), iPTH ( p  = 0.02), phosphorus ( p  < 0.001), total cholesterol (TC), and low density lipoprotein-cholesterol (LDL-C). Multivariate linear regression revealed that CAC was reliably predicted by MK ( p  = 0.008) and serum creatinine ( p  = 0.001). Carotid atherosclerotic patients had higher serum levels of MK, TNF-α, IL-6, hs-CRP, iPTH, phosphorus, TC, total triglycerides and LDL-C ( p  < 0.001 for each). Multivariate logistic regression showed that serum MK ( p  = 0.001), serum creatinine ( p  = 0.005), age ( p  < 0.001), iPTH ( p  = 0.007), and IL-6 ( p  = 0.024) were significant predictors of carotid atherosclerosis. Conclusions As CKD worsened, MK levels, carotid atherosclerosis and CAC increased. Serum MK was a reliable biomarker for asymptomatic carotid atherosclerosis and CAC in non-dialysis CKD, allowing prompt early diagnosis to avert cardiovascular morbidity and death in the future. Trial registration The trial number was 1138 and its registration was approved by the hospital’s Research Ethics Committee in 4/2024.

In a previous study, we have reported an increased plasma midkine (MK) and pleiotrophin (PTN) concentrations in patients with systemic lupus erythematosus (SLE) and the increase in MK and PTN associated with inflammatory cytokines interleukin (IL)-17 level and some clinical manifestations, suggesting the underlying association of MK and PTN with SLE. This study was conducted to investigate the association between common single-nucleotide polymorphisms (SNPs) in the and gene and SLE susceptibility. A total of 989 subjects (496 SLE patients and 493 healthy controls) were included and genotyped for three SNPs and seven SNPs in using improved multiple ligase detection reaction (iMLDR). Results have demonstrated no significant differences for genotype and allele frequencies in all 10 SNPs between SLE patients and healthy controls. Case-only analysis in SLE revealed that, in gene, the genotype frequency of AA/AG (rs35324223) was significantly lower in patients with photosensitivity than those without; the allele frequency of A/G (rs20542) was significantly higher in patients without serositis. In gene, the A/G allele frequency (rs322236), C/T allele frequency, and TT/CT genotype frequency (rs6970141) showed significantly increased results in patients with immunological disorder compared to those without. Furthermore, no significant differences in plasma MK and PTN concentrations with its SNPs genotypes were found. and SNPs showed no associations with SLE genetic susceptibility, but it may be associated with the course of this disease; further studies are needed to focus on the mechanism of and genes in the pathogenesis of SLE.