CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.

Resistance to glucocorticoids (GC), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-offunction experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

ALDH5A1 acts as a tumour promoter and has a prognostic impact in papillary thyroid carcinoma.

Thyroid cancer is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for 80%-90% of thyroid cancers. Accumulating studies reported that mitochondria plays an important role in the regulation of cell proliferation. ALDH5A1, may function as an oncogene or tumour suppressor in various human cancers, and the role of ALDH5A1 in PTC is still unclear. The aim of this study was to investigate the clinical significance of ALDH5A1 expression and its functions in PTC. In this present study, we studied ALDH5A1 expression on primary papillary thyroid carcinoma (PTC) in The Cancer Genome Atlas (TCGA) database. Results showed that the levels of ALDH5A1 were found positively correlated with tumour stage, metastasis, lymph node stage, and higher levels of ALDH5A1 demonstrated poor disease-free survival (DFS). Immunohistochemistry (IHC) revealed that significantly higher expression of ALDH5A1 was found in PTC tissues. On the other hand, knockdown of ALDH5A1 significantly inhibited PTC cell proliferation, migration and invasion detection found the migration and invasion of cells also were hindered when ALDH5A1 level was reduced. The knockdown of ALDH5A1 inhibited the expression of Vimentin and promoted the expression of E-cadherin. In brief, knockdown of ALDH5A1may act as a novel molecular target for the prevention and treatment of PTC. SIGNIFICANCE OF THE STUDY: The present study focused on the role and the potential mechanism of ALDH5A1 in papillary thyroid carcinoma. We demonstrated that reduced expression of ALDH5A1 might inhibit the progression of TC by inhibiting cell proliferation, migration and invasion and reversing epithelial-mesenchymal transition (EMT). The findings ensured the interaction relation between ALDH5A1 and EMT in PTC, providing a novel biological marker for PTC and enriching the potential strategies for TC treatment.

New Criterion to Evaluate Acute-on-Chronic Kidney Injury Based on the Creatinine Reference Change.

BACKGROUND: The lack of consensus criteria of acute on chronic kidney injury (ACKI) affects the judgment for its clinical prognosis. METHODS: In this study, we analyzed the data from 711,615 hospitalized adults who had at least 2 serum creatinine (SCr) tests within 30 days. We estimated the reference change value (RCV) of SCr given initial SCr level in adults without known risks of acute kidney injury other than chronic kidney disease (CKD). We proposed a criterion for ACKI based on the RCV of SCr (cROCK), which defined ACKI as a ≥25% increase in SCr in 7 days. We validated cROCK by its association with the risks of in-hospital mortality, death after discharge, and CKD progression in a large cohort of patients with CKD stage 3. RESULTS: In 21,661 patients with CKD stage 3, a total of 3,145 (14.5%), 1,512 (7.0%), and 221 (1.0%) ACKI events were detected by both cROCK and Kidney Disease Improving Global Outcomes (KDIGO), cROCK only, and KDIGO only, respectively. cROCK detected 40% more ACKI events than KDIGO. Compared with patients without ACKI by both definitions, those with cROCK- but not KDIGO-defined ACKI had a significantly increased risk of in-hospital mortality (hazard ratio [HR] 5.53; 95% CI 3.75-8.16), death after discharge (HR 1.51; 95% CI 1.21-1.83), and CKD progression (OR 5.65; 95% CI 3.05-10.48). CONCLUSIONS: RCV-based criterion (cROCK) for ACKI is clinically valid in that it has a substantially improved sensitivity in identifying patients with high risk of adverse outcomes.

A New Criterion for Pediatric AKI Based on the Reference Change Value of Serum Creatinine.

BACKGROUND: Current definitions of AKI do not take into account serum creatinine's high variability in children. METHODS: We analyzed data from 156,075 hospitalized children with at least two creatinine tests within 30 days. We estimated reference change value (RCV) of creatinine on the basis of age and initial creatinine level in children without kidney disease or known AKI risk, and we used these data to develop a model for detecting pediatric AKI on the basis of RCV of creatinine. We defined pediatric AKI according to pediatric reference change value optimized for AKI in children (pROCK) as creatinine increase beyond RCV of creatinine, which was estimated as the greater of 20 µmol/L or 30% of the initial creatinine level. RESULTS: Of 102,817 children with at least two serum creatinine tests within 7 days, 5432 (5.3%) had AKI as defined by pROCK compared with 15,647 (15.2%) and 10,446 (10.2%) as defined by pediatric RIFLE (pRIFLE) and Kidney Disease Improving Global Outcomes (KDIGO), respectively. Children with pROCK-defined AKI had significantly increased risk of death (hazard ratio, 3.56; 95% confidence interval, 3.15 to 4.04) compared with those without AKI. About 66% of patients with pRIFLE-defined AKI and 51% of patients with KDIGO-defined AKI, mostly children with initial creatinine level of <30 µmol/L, were reclassified as non-AKI by pROCK, and mortality risk in these children was comparable with risk in those without AKI by all definitions. CONCLUSIONS: pROCK criterion improves detection of "true" AKI in children compared with earlier definitions that may lead to pediatric AKI overdiagnosis.

[Advances in research on childhood neutropenia].

Neutrophils, an important type of human immune cells, are involved in host defense against infections. Neutropenia refers to a group of diseases manifesting as a reduction in the absolute value of mature neutrophils and is often accompanied by an increased risk of bacterial infection. According to etiology and pathogenesis, neutropenia is classified into congenital and acquired neutropenia. This article reviews the current research status and advances in the etiology of neutropenia in children. A deep understanding of the etiology of neutropenia helps to improve the diagnosis and treatment of this disease.

MiR-384 regulated IRS1 expression and suppressed cell proliferation of human hepatocellular carcinoma.

Acquired evidence indicated that microRNAs (miRNAs) played essential roles in cancer development, including hepatocellular carcinoma (HCC). Functions and mechanisms of miRNAs involved in HCC remain largely unknown. Here, we found that miR-384 was significantly downregulated in HCC cells and tissues by RT-PCR. Gain and loss of function studies revealed that miR-384 significantly suppressed HCC cell proliferation. Insulin receptor substrate 1(IRS1) was identified as a direct and functional target of miR-384. Moreover, miR-384 decreased IRS1 expression, subsequently downregulating cyclin D1 and upregulating p21 and p-Rb expression. In addition, promotion of cell proliferation caused by miR-384-in was counteracted by silencing IRS1 expression with siRNAs. Taken together, our data provided convincing evidence that miR-384 exerted suppressive effect on HCC cell proliferation through the direct inhibition of IRS1 expression, suggesting miR-384 may serve as a potential therapeutic target for HCC.

Oral Bacterial Lysate OM-85: Advances in Pharmacology and Therapeutics.

Background: Bacterial lysates are known for having immunomodulatory properties and have been used mainly for the prevention and treatment of respiratory tract infections (RTIs). However, rigorous studies are needed to confirm the clinical efficacy of bacterial lysates with various bacterial antigen components, preparation methods, administration routes and course of treatment. OM-85, an oral standardized lysate prepared by alkaline lysis of 21 strains from 8 species of common respiratory tract pathogens, is indicated as immunotherapy for prevention of recurrent RTIs and acute infectious exacerbations of chronic bronchitis. OM-85 acts on multiple innate and adaptive immune targets and can restore type 1 helper T (Th1)/Th2 balance. Sporadic studies have shown advances in pharmacology and therapeutics of OM-85, and thus an update review is necessary. Methods: Literature was retrieved by searching PubMed, Web of science, Embase, CNKI, and Full Text Database of Chinese Medical Journals. Results: New roles of OM-85 were discovered in prevention and treatment of lung cancer, pulmonary tuberculosis, SARS-CoV-2 infection, allergic rhinitis, pulmonary fibrosis, atopic dermatitis, and nephrotic syndrome. Pharmacoeconomic values of OM-85 were demonstrated in prophylaxis and treatment of RTIs, chronic obstructive pulmonary disease, asthma, chronic bronchitis, rhinosinusitis and allergic rhinitis. Two consecutive courses of OM-85 (6 or 12 months apart) could prevent recurrent RTIs in children. Maternal OM-85 treatment could offer benefits for offspring. Product-specific response was observed. The efficacy of OM-85 may be associated with patient's characteristics (eg, severity of the disease, age, immune response pattern, malignancy risk stratification). Conclusion: OM-85 can improve effectiveness of standard care for some primary diseases, and carry significant pharmacoeconomic implications. The benefits shown by OM-85 in vitro and in vivo, when extrapolated to humans, are exciting but also require caution. Individualized treatment may need to be considered. It is necessary to compare the efficacy and safety of various bacterial lysate preparations.

Abnormal individualized functional connectivity: A potential stimulation target for pediatric tourette syndrome.

OBJECTIVE: In order to examine whether individualized peak functional connectivity could potentially serve as a target for repetitive transcranial magnetic stimulation (rTMS) therapy, we investigated the location of peak functional connectivity (FC) between the cortical motor area and the key brain region, the globus pallidus internus (GPi), in Tourette syndrome, and explored the relationship between the severity of the disease and these aberrant functional connections. METHODS: The study involved a cohort of 103 children diagnosed with Tourette syndrome and 66 age-matched typically developing children. The GPi was served as the seed, and the study compared individualized peak FC strength in the supplementary motor area (SMA) and premotor area between the two groups. Spatial distribution of peak FC in the motor area and GPi-based voxel-wise FC were also analyzed. RESULTS: Children with Tourette syndrome exhibited lower peak FC in the left SMA when using left GPi as the seed. This reduction in peak FC demonstrated a significant and negative correlation with the Yale Global Tic Severity Scale scores. CONCLUSIONS: SMA-GPi FC is one of the key pathological circuit in Tourette syndrome. SIGNIFICANCE: The individual peak FC location in the left SMA potentially serve as stimulation targets for rTMS treatment of TS.

Acromicric dysplasia caused by a mutation of fibrillin 1 in a family: A case report.

BACKGROUND: Acromicric dysplasia (AD) is a rare skeletal dysplasia. Its incidence is < 1/1000000, and only approximately 60 cases are reported worldwide. It is a disease characterized by severe short stature, short hands and feet, facial abnormalities, normal intelligence, and bone abnormalities. Unlike other skeletal dysplasia, AD has a mild clinical phenotype, mainly characterized by short stature. Extensive endocrine examination has not revealed a potential cause. The clinical effect of growth hormone therapy is still uncertain. CASE SUMMARY: We report a clinical phenotype of AD associated with mutations in the fibrillin 1 (FBN1) (OMIM 102370) gene c.5183C>T (p. Ala1728Val) in three people from a Chinese family. A 4-year-old member of the family first visited the hospital because of slow growth and short stature for 2 years, but no abnormalities were found after a series of laboratory tests, echocardiography, pituitary magnetic resonance imaging, and ophthalmological examination. Recombinant human growth hormone (rhGH) was used to treat the patient for > 5 years. The efficacy of rhGH was apparent in the first year of treatment; the height increased from -3.64 standard deviation score (SDS) to -2.88 SDS, while the efficacy weakened from the second year. However, long-term follow-up is required to clarify the efficacy of rhGH. CONCLUSION: FBN1-related AD has genetic heterogeneity and/or clinical variability, which brings challenges to the evaluation of clinical treatment. rhGH is effective for treatment of AD, but long-term follow-up is needed to clarify the effect.

Identification of a 3-Gene Prognostic Index for Papillary Thyroid Carcinoma.

The accurate determination of the risk of cancer recurrence is a critical unmet need in managing thyroid cancer (TC). Although numerous studies have successfully demonstrated the use of high throughput molecular diagnostics in TC prediction, it has not been successfully applied in routine clinical use, particularly in Chinese patients. In our study, we objective to screen for characteristic genes specific to PTC and establish an accurate model for diagnosis and prognostic evaluation of PTC. We screen the differentially expressed genes by Python 3.6 in The Cancer Genome Atlas (TCGA) database. We discovered a three-gene signature Gap junction protein beta 4 (GJB4), Ripply transcriptional repressor 3 (RIPPLY3), and Adrenoceptor alpha 1B (ADRA1B) that had a statistically significant difference. Then we used Gene Expression Omnibus (GEO) database to establish a diagnostic and prognostic model to verify the three-gene signature. For experimental validation, immunohistochemistry in tissue microarrays showed that thyroid samples' proteins expressed by this three-gene are differentially expressed. Our protocol discovered a robust three-gene signature that can distinguish prognosis, which will have daily clinical application.

Design and development of a new type of phimosis dilatation retractor for children.

BACKGROUND: Phimosis is one of the most common diseases in children. Early selection of appropriate treatment for phimosis in children is beneficial to the development of their reproductive organs and significantly improves the prognosis of phimosis in children. Although traditional circumcision is the most widely used, it has many disadvantages, including postoperative bleeding and incision infection, pain, obvious scars on the surgical incision, and unsatisfactory appearance. In addition, there is much controversy regarding treatment options and timing at home and abroad. Surgical procedures such as circumcision and cerclage for children with excessively long foreskin will greatly affect the normal life of children after the operation. Young children need general anesthesia, but this anesthesia carries a great risk. AIM: To design a new children phimosis dilatation retractor for children phimosis. METHODS: The children phimosis was dilated with an elastic dilation frame, in order to expand the foreskin mouth and expose the penis head, and after that, the phimosis was cured. RESULTS: A new type of phimosis dilatation retractor was designed, which can gently dilate the prepuce at multiple angles and in multiple directions at the same time. It has obtained the national patent for clinical application. CONCLUSION: The phimosis dilatation retractor based on the principle of elastically expanding the prepuce can achieve the purpose of expanding the phimosis. The clinical application shows that the effect of the children phimosis retractor is significant, which is worth promoting.

Network Pharmacology to Explore the Molecular Mechanisms of Prunella vulgaris for Treating Hashimoto's Thyroiditis.

Purpose: Prunella vulgaris (PV), a traditional Chinese medicine, has been used to treat patients with thyroid disease for centuries in China. The purpose of the present study was to investigate its bioactive ingredients and mechanisms against Hashimoto's thyroiditis (HT) using network pharmacology and molecular docking technology to provide some basis for experimental research. Methods: Ingredients of the PV formula were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Additionally, HT-related genes were retrieved from the UniProt and GeneCards databases. Cytoscape constructed networks for visualization. A protein-protein interaction (PPI) network analysis was constructed, and a PPI network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These key targets of PV were enriched and analyzed by molecular docking verification, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Results: The compound-target network included 11 compounds and 66 target genes. Key targets contained Jun proto-oncogene (JUN), hsp90aa1.1 (AKI), mitogen-activated protein kinase 1 (MAPK1), and tumor protein p53 (TP53). The main pathways included the AGE-RAGE signaling pathway, the TNF signaling pathway, the PI3K-Akt signaling pathway, and the mitogen-activated protein kinase signaling pathway. The molecular docking results revealed that the main compound identified in the Prunella vulgaris was luteolin, followed by kaempferol, which had a strong affinity for HT. Conclusion: Molecular docking studies indicated that luteolin and kaempferol were bioactive compounds of PV and might play an essential role in treating HT by regulating multiple signaling pathways.

Interaction between CD9 and PI3K­p85 activates the PI3K/AKT signaling pathway in B­lineage acute lymphoblastic leukemia.

Our previous study has shown that CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the cytotoxicity of chemotherapeutic drugs in the B­lineage acute lymphoblastic leukemia (B­ALL) cell line SUP­B15. In this study, we further investigated the molecular mechanism underlying the effects of CD9 on leukemic cell progression and the efficacy of chemotherapeutic agents in B­ALL cells. Using the CD9­knockdown SUP­B15 cells, we demonstrated that the silencing of the CD9 gene significantly reduced the expression of phosphorylated­phosphatidylinositol­3 kinase (p­PI3K), phosphorylated­protein kinase B (p­AKT), P­glycoprotein (P­gp), multidrug resistance­associated protein 1 (MRP1), breast cancer resistance protein (BCRP), matrix metalloproteinase 2 (MMP2) and phosphorylated­focal adhesion kinase (p­FAK). In addition, glutathione S­transferase (GST) pull­down assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vitro, while co­immunoprecipitation assay showed the binding between CD9 and both PI3K­p85α and PI3K­p85ß in vivo. Furthermore, the PI3K/AKT inhibitor LY294002 mirrored the effects of CD9 knockdown in SUP­B15 cells. Taken together, these findings demonstrated that CD9 activates the PI3K/AKT signaling pathway through direct interaction with PI3K­p85 in B­ALL cells. Our data provide evidence for the inhibition of the PI3K/AKT pathway as a novel therapeutic option in CD9 antigen­positive B­ALL.

Prioritizing Susceptible Genes for Thyroid Cancer Based on Gene Interaction Network.

Thyroid cancer ranks second in the incidence rate of endocrine malignant cancer. Thyroid cancer is usually asymptomatic at the initial stage, which makes patients easily miss the early treatment time. Combining genetic testing with imaging can greatly improve the diagnostic efficiency of thyroid cancer. Researchers have discovered many genes related to thyroid cancer. However, the effects of these genes on thyroid cancer are different. We hypothesize that there is a stronger interaction between the core genes that cause thyroid cancer. Based on this hypothesis, we constructed an interaction network of thyroid cancer-related genes. We traversed the network through random walks, and sorted thyroid cancer-related genes through ADNN which is fusion of Adaboost and deep neural network (DNN). In addition, we discovered more thyroid cancer-related genes by ADNN. In order to verify the accuracy of ADNN, we conducted a fivefold cross-validation. ADNN achieved AUC of 0.85 and AUPR of 0.81, which are more accurate than other methods.

Significance of DMBT1 in Papillary Thyroid Carcinoma Concurrent With Hashimoto's Thyroiditis.

BACKGROUND: Papillary thyroid carcinoma (PTC) concurrent with Hashimoto's thyroiditis (HT) was associated with a better clinical prognosis. This study aimed to investigate a potential mRNA gene that affects the development of PTC, which helps PTC concurrent with HT patients have a better prognosis. MATERIAL/METHODS: PTC data were obtained from The Cancer Genome Atlas (TCGA) database. And the validation data of tissue specimens were collected from Guangzhou First People's Hospital. The thyroid tissue sections were hybridized with deleted in malignant brain tumor 1 (DMBT1) probes by situ hybridization. Survival rates were analyzed using Kaplan-Meier curves, and the log-rank test was used to compare group survival rates. Prognosis clinicopathological factors were analyzed by Cox regression. Gene Ontology (GO) and Kyoto Gene and Genomic Encyclopedia (KEGG) pathway enrichment analyses were performed using single-sample gene set enrichment analysis (ssGSEA). Finally, the correlation of deletion in DMBT1 expression with overall immune status, tumor purity, and human leukocyte antigen (HLA) gene expression profile was analyzed. RESULTS: HT was significantly associated with sex, tumor foci, extrathyroidal extension (ETE), residual tumor, and tumor stage (T stage). Moreover, PTC concurrent with HT had a lower risk of recurrence versus non-HT groups. A total of 136 differentially expressed mRNAs (DEMs) were identified between HT and non-HT groups. Among them, the expression level of DMBT1 in HT groups was statistically higher than that in non-HT groups. A significant association with ETE and recurrence was revealed in the high expression and the low expression of DMBT1. Furthermore, DMBT1 was an independent predictor of survival. The overall immune activity of high expression of DMBT1 was higher than that of the low-expression group. CONCLUSIONS: The PTC patients with HT had better behavior features and prognosis than those with simple PTC. DMBT1 in PTC-HT patients was a potential possible factor that inhibits tumors. High expression of DMBT1 may improve PTC prognosis by immune-related pathways.

Higher Red Blood Cell Distribution Width is a Poor Prognostic Factor for Patients with Chronic Myeloid Leukemia.

PURPOSE: Red blood cell distribution width (RDW) has been considered as a potential indicator of the effects of treatment or as a prognostic indicator for various malignancies. Most chronic myeloid leukemia (CML) patients are in the chronic phase, but some have transformed to accelerated phase or blast phase (blast crisis). However, the clinical significance of RDW in CML remains limited. PATIENTS AND METHODS: In the present study, detailed clinical information and the RDW of 168 healthy people and 153 CML patients (106 patients for the training cohort and 47 patients for the validation cohort) were retrospectively assessed. RESULTS: Multivariate analysis demonstrated that patient age (OR, 1.081; 95CI% 1.039~1.125; p < 0.001), platelet counts (OR, 0.997; 95CI% 0.994~0.999; p = 0.001) and RDW at admission (OR,1.469; 95CI% 1.121~1.925; p = 0.005) were significantly associated with the patients with advanced phase. Among CML patients in the chronic phase, higher RDW was significantly associated with overall survival (OS; p = 0.0008) and the event-free survival (EFS; p = 0.0221) among CML patients with chronic phase, but not with Transformation-free survival (TFS; p = 0.0821). Furthermore, higher RDW was associated with higher mortality compared to patients with low RDW (CML-associated deaths; p < 0.0001). In addition, a decline in RDW is associated with the treatment of CML patients with tyrosine kinase inhibitors, especially at 6 and 12 months after the start of treatment. CONCLUSION: Higher RDW is a potential prognostic biomarker for chronic CML patients.

Frequency-Specific Regional Homogeneity Alterations in Tourette Syndrome.

Tourette syndrome (TS) is a developmental neuropsychiatric disorder with onset during childhood. Because of its complex spectrum of phenotypes, the underlying pathophysiology of TS is still unclear. Resting-state functional magnetic resonance imaging demonstrated aberrant spontaneous neural synchronization in conventional frequency band (0.01-0.08 Hz) in TS. No published studies have reported abnormalities of local synchronization across different frequency bands. We estimated the alterations of local synchronization across five bands ranging from 0 to 0.25 Hz. Seventy-nine children with TS and 63 age-, sex-, and handedness-matched healthy children were recruited. Frequency-specific regional homogeneity (ReHo) and independent component analysis were used to identify functional alterations between TS and healthy children. TS patients showed significantly increased ReHo in the left precentral gyrus and decreased ReHo in the right operculum. Abnormal ReHo alterations of the superior frontal gyrus, superior parietal gyrus, anterior cingulate gyrus, putamen, superior temporal gyrus, and operculum were observed in different frequency bands. TS patients showed increased connectivity of the right superior frontal gyrus within the left executive control network. In addition, a significantly negative correlation was found between Yale Global Tic Severity Scale (YGTSS) vocal score and ReHo values of the right operculum in the highest frequency bands (0.198-0.25 Hz), while a significant positive correlation was found between YGTSS motor score and altered connectivity of the right superior frontal gyrus. The present study revealed frequency-specific abnormal alterations of ReHo in the whole brain and altered connectivity within the executive control network of TS children. Its neural importance and clinical practicability require further investigation.

Association of Soluble Klotho Level with Adverse Outcomes in Patients on Maintenance Hemodialysis.

BACKGROUND: The predictive value of soluble Klotho (sKlotho) for adverse outcomes in patients on maintenance hemodialysis (MHD) is controversial. In this study, we aimed to clarify the potential association of sKlotho levels with adverse outcomes in this patient population. MATERIALS: A total of 211 patients on MHD were identified and stratified according to the median sKlotho level. Patients were followed up for adverse outcomes including cardiovascular (CV) morbidity and all-cause mortality. RESULTS: During the 36-month follow-up, 75 patients [51 CV events (including 16 CV deaths) and 40 deaths] experienced adverse outcomes. After stratification according to median sKlotho level, patients with a lower sKlotho level had a greater risk of CV events (38.2% vs. 19.5%, p = 0.006), all-cause mortality (28.4% vs. 11.6%, p = 0.003), and combined adverse outcomes (51.0% vs. 24.2%, p < 0.001). Similar observations were made from analyses using Kaplan-Meier survival curves. Cox regression analysis showed that a low sKlotho level was strongly correlated with CV morbidity [1.942 (1.030-3.661), p = 0.040)], all-cause mortality [2.073 (1.023-4.203), p = 0.043], and combined adverse outcomes [1.818 (1.092-3.026), p = 0.021] in fully adjusted models. CONCLUSIONS: The sKlotho level was an independent predictive factor of adverse outcomes including CV morbidity and mortality in patients on MHD.

The prognostic value of soluble Klotho in patients with haemodialysis: a systematic review and meta-analysis.

AIM: The correlation between soluble Klotho (sKlotho) levels and clinical outcomes remains inconclusive for patients undergoing maintenance haemodialysis (MHD). We aimed to evaluate the potential predictive significance of sKlotho in this population by conducting a meta-analysis. METHODS: PubMed, Embase, Web of Science and Cochrane Library were comprehensively searched for studies concerning the association between sKlotho level and clinical outcomes including cardiovascular (CV) events and all-cause mortality. The pooled hazard ratios (HR) and 95% confidence intervals (CI) were generated using either random or fixed effects models. Sensitivity and subgroup analyses were used to explore heterogeneity sources. RESULTS: Eight prospective studies with 992 MHD participants were included and reduced sKlotho levels predicted more adverse outcomes in this meta-analysis. The pooled HRs and 95% CIs related to CV events, mortality, or composite outcomes were 1.73 (95% CI 1.08-2.76, p = 0.02), 2.34 (95% CI 1.34-2.07, p = 0.003) or 1.75 (95% CI 1.19-2.57, p = 0.005). Moderate heterogeneity was observed in the composite adverse outcomes (I 2 = 57%, p = 0.05). Age and sKlotho level were the main sources of heterogeneities in the subgroup analysis. CONCLUSION: Lower sKlotho levels were associated with more CV events and all-cause mortality, suggesting that sKlotho may have predictive value in CKD patients receiving haemodialysis.

MicroRNA-3690 promotes cell proliferation and cell cycle progression by altering DKK3 expression in human thyroid cancer.

An increasing amount of evidence has demonstrated the importance of microRNAs (miRNAs/miRs) in the tumorigenesis of malignant types of cancer, and data retrieved from The Cancer Genome Atlas database revealed that miR-3690 was upregulated in thyroid cancer (TC). The present study focused on the biological function and mechanism of miR-3690 in TC, demonstrating that miR-3690 expression was significantly elevated in TC cells and clinical tissues. Functional studies indicated that miR-3690 acted as an oncogene in TC by promoting cell proliferation, colony formation and cell cycle progression in association with the increased expression of cyclin E and c-myc. Mechanistically, prediction software indicated that Dickkopf-related protein 3 (DKK3) was a target of miR-3690, which was confirmed by the results of luciferase reporter assays and western blotting. DKK3 silencing abrogated the functions of miR-3690-in on TC cell proliferation. Collectively, the findings of the present study demonstrated that miR-3690 promoted TC cell proliferation and indicated miR-3690 as a potential biomarker and therapeutic target for TC.