The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and ...recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.
Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically ...evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs).
MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes.
Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval 95% CI, 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58).
We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality.
Epstein-Barr virus (EBV) infection is closely associated with tumorigenesis and development of nasopharyngeal carcinoma (NPC), but the underlying molecular mechanisms remain poorly understood. It has ...been recently reported that EBV encodes 44 mature miRNAs, some of which were found to promote tumor development by targeting virus-infected host genes or self-viral genes. However, few targets of EBV encoded-miRNAs that are related to NPC development have been identified to date. In this study, we revealed that in NPC cells, EBV-miR-BART10-3p directly targets BTRC gene that encodes βTrCP (beta-transducin repeat containing E3 ubiquitin protein ligase). We found that EBV-miR-BART10-3p expression in clinical samples from a cohort of 106 NPC patients negatively correlated with BTRC expression levels. Over-expression of EBV-miR-BART10-3p and down-regulation of BTRC were associated with poor prognosis in NPC patients. EBV-miR-BART10-3p promoted the invasion and migration cabilities of NPC cells through the targeting of BTRC and regulation of the expression of the downstream substrates β-catenin and Snail. As a result, EBV-miR-BART10-3p facilitated epithelial-mesenchymal transition of NPC. Our study presents an unreported mechanism underlying EBV infection in NPC carcinogenesis, and provides a potential novel biomarker for NPC diagnosis, treatment and prognosis.
MicroRNAs have been considered as a kind of potential novel biomarker for cancer detection due to their remarkable stability in the blood and the characteristics of their expression profile in many ...diseases.
We performed microarray-based serum miRNA profiling on the serum of twenty nasopharyngeal carcinoma patients at diagnosis along with 20 non-cancerous individuals as controls. This was followed by a real-time quantitative Polymerase Chain Reaction (RT-qPCR) in a separate cohort of thirty patients with nasopharyngeal carcinoma and thirty age- matched non-cancerous volunteers. A model for diagnosis was established by a conversion of mathematical calculation formula which has been validated by analyzing 74 cases of patients with nasopharyngeal carcinoma and 57 cases of non-cancerous volunteers.
The profiles showed that 39 and 17 miRNAs are exclusively expressed in the serum of non-cancerous volunteers and of patients with nasopharyngeal carcinoma respectively. 4 miRNAs including miR-17, miR-20a, miR-29c, and miR-223 were found to be expressed differentially in the serum of NPC compared with that of non-cancerous control. Based on this, a diagnosis equation with Ct difference method has been established to distinguish NPC cases and non-cancerous controls and validated with high sensitivity and specificity.
We demonstrate that the serum miRNA-based biomarker model become a novel tool for NPC detection. The circulating 4-miRNA-based method may provide a novel strategy for NPC diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array ...to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and cell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3' untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC.
Previous reports showed that some patients with minimal change disease (MCD) had high serum immunoglobulin E (IgE) levels. This study aimed to explore the proportion of MCD patients with high serum ...IgE levels and evaluate the correlation between serum IgE levels and MCD remission and relapse.
This study enrolled 222 new-onset patients with renal biopsy-confirmed MCD from October 2012 to October 2019 at the First Affiliated Hospital of Zhejiang University in Hangzhou, China. Patients' demographics and clinical parameters were analyzed.
The results indicated that 70.3% of 222 MCD patients had high serum IgE levels (IgE > 100.0 IU/mL). Moreover, 134 patients were treated with glucocorticoids alone and divided into the low- and high-IgE groups, according to the median serum IgE level (523.5 IU/mL). The mean time to complete remission of the low- and high-IgE groups was 29.0 ± 2.2 and 45.7 ± 4.2 days, respectively (log-rank test;
= 0.002). The mean time to total remission was 19.1 ± 1.4 and 31.6 ± 3.2 days of the low- and high-IgE groups, respectively (log-rank test;
< 0.001). The mean time to first relapse in the low- and high-IgE groups was 701.2 ± 65.0 and 425.0 ± 52.6 days, respectively (log-rank test;
= 0.002). Serum IgE ≥ 523.5 IU/mL was an independent correlation factor affecting the patients' remission and relapse.
Serum IgE level was an independent correlation factor for MCD remission and relapse. MCD patients with high serum IgE levels were prone to delayed remissions and early relapses.
Epstein-Barr virus (EBV) infection and chronic inflammation are closely associated with the development and progression of nasopharyngeal carcinoma (NPC) and gastric cancer (GC), and the infiltration ...of inflammatory cells, including tumor-associated macrophages (TAMs), is often observed in these cancers. EBV encodes 44 mature micro RNAs (miRNAs), but the roles of only a few EBV-encoded miRNA targets are known in cancer development, and here, our aim was to elucidate the effects of EBV-miR-BART11 on FOXP1 expression, and potential involvement in inflammation-induced carcinogenesis. We constructed an EBV miRNA-dependent gene regulatory network and predicted that EBV-miR-BART11 is able to target forkhead box P1 (FOXP1), a key molecule involved in monocyte to macrophage differentiation. Here, using luciferase reporter assay, we confirmed that EBV-miR-BART11 directly targets the 3'-untranslated region of FOXP1 gene, inhibits FOXP1 induction of TAM differentiation, and the secretion of inflammatory cytokines into the tumor microenvironment, inducing the proliferation of NPC and GC cells. FOXP1 overexpression hindered monocyte differentiation and inhibited NPC and GC cells growth. Our results demonstrated that EBV-miR-BART11 plays a crucial role in the promotion of inflammation-induced NPC and GC carcinogenesis by inhibiting FOXP1 tumor-suppressive effects. We showed a novel EBV-dependent mechanism that may induce the carcinogenesis of NPC and GC, which may help define new potential biomarkers and targets for NPC and GC diagnosis and treatment.
The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific ...cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically‐induced colitis‐associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation‐induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1‐Smad5‐Id3 axis.
What's new?
It hasn't been clear why chronic inflammation may progress to colitis‐associated cancers (CAC). In this study, the authors found that the inflammatory factor S100A8 contributes to CAC tumorigenesis through the Akt1‐Smad5‐Id3 signaling pathway. Id3 and other Id proteins are transcription factors that play an important role in angiogenesis, inflammation, proliferation, and migration in several common types of cancer. The finding that dysregulated S100A8 expression activates Id3 provides a novel link between inflammation and cancer.
IntroductionCoagulation disorders play a key role in chronic kidney disease, and the formation or elevation of plasma D-dimer levels reflects activation of the coagulation system. However, its ...relationship with the severity and progression of kidney disease in IgA nephropathy (IgAN) remains unclear.MethodsWe assessed 1818 patients with IgAN diagnosed between 2002 and 2019 at the First Affiliated Hospital, Zhejiang University School of Medicine. Plasma D-dimer levels were measured at the time of the renal biopsy. The association between plasma D-dimer levels and kidney disease progression events, defined as a 50% decline in eGFR and end-stage kidney disease (ESKD), was tested using restricted cubic splines and Cox proportional hazard models.ResultsThe median plasma D-dimer level was 220 (170–388.5) µg/L FEU, which was significantly higher than healthy controls 170 (170–202) µg/L FEU. Plasma D-dimer levels were positively correlated with proteinuria (r = 0.211, p < 0.001) and serum galactose-deficient IgA1 (r = 0.226, p = 0.004) and negatively correlated with eGFR (r=-0.127, p < 0.001) and Oxford T (p < 0.001) and C (p = 0.004) scores. After a median follow-up of 25.67 (13.03–47.44) months, 126 (6.93%) patients experienced composite kidney disease progression events. Higher plasma D-dimer levels were associated with an increased risk of kidney disease progression events (hazard ratio, 1.73; 95% confidence interval 95% CI, 1.40–2.23) per ln-transformed plasma D-dimer (p < 0.001), after adjustment for sex, age, proteinuria, Mean arterial pressure (MAP) and Oxford classification scores. In reference to the first tertile of plasma D-dimer, hazard ratios were 1.48 (95% CI, 0.76–2.88) for the second tertile, 3.03 (95% CI, 1.58–5.82) for the third tertile.ConclusionsHigh plasma D-dimer levels were associated with the progression of kidney disease severity in IgA nephropathy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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