Dysbiosis promotes recurrence of adenomatous polyps in the distal colorectum.

BACKGROUND: Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled. AIM: To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps. METHODS: Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student's t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson's correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators. RESULTS: The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella, Plesiomonas, and Cronobacter, was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones. CONCLUSION: These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.

Chlorogenic Acid Inhibits Proliferation, Migration and Invasion of Pancreatic Cancer Cells via AKT/GSK-3ß/ß-catenin Signaling Pathway.

BACKGROUND: Chlorogenic acid (CA, United States Patent No. 10772340), a natural biologically active food ingredient, displays potent antitumor activity against a variety of cancer cells. However, the mechanism underlying its anticancer effect is not well elucidated. OBJECTIVE: In the present study, we hope to dissect the mechanism underlying the anticancer effects of CA in pancreatic cancer cells. METHODS: The cytotoxicity of CA in pancreatic cancer cells was determined by MTT assay. Flow cytometry was performed to evaluate the cells apoptosis, while a clonogenic assay was carried out to check the colony formation of cancer cells. Transwell assay was performed to assess the cells migration and invasion. The protein expression of AKT/GSK-3ß/ß-catenin signaling pathway was detected by Western Blot. RESULTS: Our data indicated that CA inhibited the proliferation of PANC-28 and PANC-1 cells in a dose and time-dependent manner. CA was able to inhibit colony formation, migration, and invasion ability and trigger apoptosis in PANC-28 and PANC-1 cells. Further study showed that CA down-regulated the expression of AKT, p-AKT(Thr308), p-GSK-3ß(Ser9), ß-catenin, N-cadherin, and vimentin while enhancing the expression of cleaved-caspase 3 and cleaved-caspase 7 in PANC-28 and PANC-1 cells. CONCLUSION: Our study provides significant evidence that CA is able to inhibit the growth of pancreatic cancer via the AKT/GSK-3ß/ß-catenin signaling pathway.

Diagnosis, treatment, and genetic characteristics of blastic plasmacytoid dendritic cell neoplasm: A review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and extremely rare hematologic disease with a poor prognosis, involving mainly the skin and bone marrow. The immunophenotype of these tumor cells is characterized by the expression of CD4, CD56, CD123, TCL-1, and CD303. To date, no consensus has been reached on the standard of care for BPDCN. Currently, clinical treatment is mainly based on high-dose chemotherapy combined with hematopoietic stem cell transplantation. However, this treatment method has limitations for elderly, frail, and relapsed/refractory patients. In recent years, breakthroughs in molecular biology and genetics have not only provided new ideas for the diagnosis of BPDCN but also helped develop targeted treatment strategies for this disease. The emergence of targeted drugs has filled the gap left by traditional therapies and shown great clinical promise. This article focuses on the latest advances in genetics and targeted therapies for BPDCN, especially the emerging therapies that may provide new ideas for the clinical treatment of BPDCN.

Knockdown of RhoA Expression Reverts Enzalutamide Resistance via the p38 MAPK Pathway in Castration-resistant Prostate Cancer.

BACKGROUND: Enzalutamide has been approved clinically for the treatment of castrationresistant prostate cancer (CRPC) but is limited by the emergence of resistance. RhoA has been shown to play a vital role in carcinogenesis, invasion, and metastasis. However, the role of RhoA in enzalutamide-resistant prostate cancer (PCa) remains unclear. OBJECTIVES: This study investigated the role of RhoA and the associated mechanisms of RhoA depletion in enzalutamide resistance in CRPC. METHODS: Western blotting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and colony formation assays were used to assess protein expression, survival, and proliferation of PCa cells, respectively. Xenograft experiments and hematoxylin and eosin (H&E) staining were used to detect further effects of RhoA on enzalutamide resistance in vivo. RESULTS: In the present study, the expression of RhoA, ROCK2, p38, p-p38, and AR was upregulated in enzalutamide-resistant PCa cells treated with enzalutamide, and silencing of RhoA or ROCK2 attenuated enzalutamide-resistant cell proliferation and colony formation. Furthermore, the deletion of RhoA dramatically increased the efficacy of enzalutamide in inhibiting 22RV1-derived xenograft tumor growth. Additionally, there was no significant change in ROCK1 expression in C4-2R cells treated with or without enzalutamide. Mechanistically, the knockdown of RhoA expression reverted the resistance to enzalutamide via RhoA/ROCK2/p38 rather than RhoA/ROCK1/p38. CONCLUSION: Our results suggested that RhoA is a promising therapeutic target. As the inhibition of RhoA reverted enzalutamide resistance, it may increase its effectiveness in CRPC.

Association of sodium intake with adverse left atrial function and left atrioventricular coupling in Chinese.

OBJECTIVES: High sodium intake is strongly associated with hypertension and obesity. This study aims to investigate the relationship between 24-h urinary sodium (a surrogate measure of sodium intake), ambulatory blood pressure parameters, left atrial function, and left atrioventricular coupling. Further, we intend to examine whether blood pressure and BMI might be mediators of the relationship between 24-h urinary sodium and subclinical cardiac function. METHODS: Our study had 398 participants, all of whom were subjected to 24-h urine collection, 24-h ambulatory blood pressure measurement, and cardiac magnetic resonance imaging. RESULTS: The average age of the participants was 55.70 ±â€Š11.30 years old. The mean urinary sodium of the participants was 172.01 ±â€Š80.24 mmol/24 h. After adjusting for age, sex, history of diabetes, smoking status, alcohol consumption, and use of diuretics, 24-h urinary sodium was correlated with multiple ambulatory blood pressure parameters, BMI, left atrial function, and the left atrioventricular coupling index (LACI) (P < 0.05). Mediation analysis showed that BMI explained 16% of the indirect effect of 24-h urinary sodium and left atrial function and 30% of the indirect effect of LACI. Independent of the mediator, 24-h urinary sodium had a significant direct effect on left atrial function and left atrioventricular coupling. CONCLUSIONS: Higher 24-h urinary sodium was associated with a greater BMI as well as poor left atrial function and left atrioventricular coupling, and the BMI mediated the relationship between 24-h urinary sodium and subclinical left cardiac function. Furthermore, and more importantly, 24-h urinary sodium may have directly affected the left atrial function and left atrioventricular coupling independent of intermediary factors.

Extracellular vesicles derived from M2-polarized tumor-associated macrophages promote immune escape in ovarian cancer through NEAT1/miR-101-3p/ZEB1/PD-L1 axis.

Evidence has been presented demonstrating that CD8+ T cells confer anti-cancer effects, which offers a promising approach to enhance immunotherapy. M2-polarized tumor-associated macrophages (TAMs) could transfer RNA to cancer cells by secreting extracellular vesicles (EVs) and stimulate immune escape of cancer cells. Thus, the current study aimed at exploring how EVs derived from M2-polarized TAMs (M2-TAMs) affected the proliferation of ovarian cancer (OC) cells and apoptosis of CD8+ T cells. M2-TAMs were observed in OC tissues, which promoted proliferation of OC cells and CD8+ T cell apoptosis by secreting EVs. OC-associated differentially expressed gene NEAT1 was screened by bioinformatics analysis. The in vitro and in vivo effects of TAM-EVs-NEAT1 and its regulatory mechanism were assessed using gain- and loss-of-function assays in co-culture systems of TAMs-derived EVs, OC cells, and CD8+ T cells and in tumor-bearing mice. NEAT1 was highly expressed in M2-derived EVs and OC cells co-cultured with M2-derived EVs. NEAT1 sponged miR-101-3p to increase ZEB1 and PD-L1 expression. In vitro and in vivo assays confirmed the tumor-supporting effects of NEAT1 delivered by M2-derived EVs on OC cell proliferation and CD8+ T cell apoptosis as well as tumor growth. Collectively, M2-derived EVs containing NEAT1 exerted a tumor-promoting role in OC via the miR-101-3p/ZEB1/PD-L1 axis.

Exosomes from bone mesenchymal stem cells alleviate mifepristone-induced human endometrial stromal cell injury by inhibiting TLR3 via delivering miR-941.

Objective: We aim to investigate the protective effect and underlying mechanisms of BMSCs-exo on human endometrial stromal cells (HESCs) induced by mifepristone in this study. Methods: BMSCs-exo were extracted and then identified by transmission electron microscopy and western-blot assay. RT-PCR assay was used to determine the level of miR-941. MiR-941 mimics or inhibitor were transfected into BMSCs and the exosomes were extracted. Then, Cell activity, apoptosis rate, cell migration and invasion, as well as the expression of angiogenic proteins were determined in HESCs stimulated by mifepristone and BMSCs-exo. Next, Dual-luciferase reporting assay was used to verify the targeted binding of miR-941 to TLR3, and the TLR3 expression in HESCs was detected by RT-PCR and western-blot. Finally, TLR3 was overexpressed to evaluate the effects of miR-941 from BMSCs-exo on cell apoptosis, cell invasion and angiogenesis in HESCs induced by mifepristone. Results: miR-941 was highly expressed in BMSCs-exo. Exosome miR-941 in BMSCs-exo inhibited the cell apoptosis, and promoted cell activity, cell migration, invasion as well as angiogenesis were also improved in HESCs induced by mifepristone. TLR3 was a target of miR-941, which was up-regulated in mifepristonetreated HESCs. We further found that miR-941 derived from BMSCs-exo down-regulated the expression of TLR3 in HESCs treated by mifepristone. In addition, TLR3 overexpression blocked the inhibition of miR-941 on mifepristone-induced cell apoptosis, as well as cell migration and angiogenesis in HESCs. Conclusions: Thus, we concluded that BMSCs-exo has protective effect on mifepristone-induced cell damage by delivering miR-941 which targeted TLR3 and regulated cell activity, migration, and angiogenesis in HESCs.

Significance of TP53 Mutational Status-Associated Signature in the Progression and Prognosis of Endometrial Carcinoma.

Background: TP53 mutations are associated with poor outcome for patients with endometrial carcinoma (EC). However, to date, there have been no studies focused on the construction of TP53 mutational status-associated signature in EC. In this study, we aim to conduct a TP53 mutation-associated prognostic gene signature for EC. Methods: Hence, we explored the mutational landscape of TP53 in patients with EC based on the simple nucleotide variation data downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to establish TP53 mutation-associated prognostic gene signature. The overall survival rate between the high-risk and low-risk groups was compared by the Kaplan-Meier (K-M) method. Results: We found that the TP53 mutation was associated with poor outcome, older age, lower BMI, and higher grade and stage of EC in patients. A TP53 mutational status-associated signature was established based on transcriptome profiling data. Moreover, the patients in TCGA database were categorized into high- and low-risk groups. Kaplan-Meier (K-M) analysis indicated that the patients in the high-risk group have poor survival outcome. Furthermore, receiver operating characteristic (ROC) curves confirmed the robust prognostic prediction efficiency of the TP53 mutational status-associated signature. Finally, the prognostic ability was successfully verified in the other two datasets from cBioPortal database as well as in 60 clinical specimens. Univariate (hazard ratio (HR) = 1.041, 95%CI = 1.031-1.051, p < 0.001) and multivariate (hazard ratio (HR) = 1.029, 95%CI = 1.018-1.040, p < 0.001) Cox regression analyses indicated that the TP53 mutational status-associated signature could be used as an independent prognostic factor for EC patients. Conclusion: In summary, our research constructed a powerful TP53 mutational status-associated signature that could be a potential novel prognostic biomarker and therapeutic target for EC.

Long non-coding RNA NEAT1 facilitates the growth, migration, and invasion of ovarian cancer cells via the let-7 g/MEST/ATGL axis.

BACKGROUND/AIM: Growing evidence indicates a significant role of long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in ovarian cancer, a frequently occurring malignant tumor in women; however, the possible effects of an interplay of NEAT1 with microRNA (miRNA or miR) let-7 g in ovarian cancer are not known. The current study aimed to investigate the role of the NEAT1/let-7 g axis in the growth, migration, and invasion of ovarian cancer cells and explore underlying mechanisms. METHODS: NEAT1 expression levels were examined in clinical tissue samples and cell lines. The relationships between NEAT1, let-7 g, and MEST were then analyzed. Gain- or loss-of-function approaches were used to manipulate NEAT1 and let-7 g. The effects of NEAT1 on cell proliferation, migration, invasion, and apoptosis were evaluated. Mouse xenograft models of ovarian cancer cells were established to verify the function of NEAT1 in vivo. RESULTS: NEAT1 expression was elevated while let-7 g was decreased in ovarian cancer clinical tissue samples and cell lines. A negative correlation existed between NEAT1 and let-7 g, whereby NEAT1 competitively bound to let-7 g and consequently down-regulate let-7 g expression. By this mechanism, the growth, migration, and invasion of ovarian cancer cells were stimulated. In addition, let-7 g targeted mesoderm specific transcript (MEST) and inhibited its expression, leading to promotion of adipose triglyceride lipase (ATGL) expression and inhibition of ovarian cancer cell growth, migration, and invasion. However, the effect of let-7 g was abolished by overexpression of MEST. Furthermore, silencing of NEAT1 decreased the xenograft tumor growth by decreasing MEST while up-regulating let-7 g and ATGL. CONCLUSIONS: Cumulatively, the findings demonstrated that NEAT1 could promote malignant phenotypes of ovarian cancer cells by regulating the let-7 g/MEST/ATGL signaling axis. Therefore, NEAT1 can be regarded as an important molecular target and biomarker for ovarian cancer.

LINC00461 Promoted Endometrial Carcinoma Growth and Migration by Targeting MicroRNA-219-5p/Cyclooxygenase-2 Signaling Axis.

Endometrial carcinoma (EC) ranks as the most common female genital cancer in developed countries. Lately, more and more long noncoding RNAs (lncRNAs) have been identified as vital regulators in numerous physiological and pathological processes, including EC. However, the expression pattern and precise functions of different lncRNAs in EC remain unclear. In this study, we reported LINC00461 was upregulated in EC patient tissues and cell lines. In addition, LINC00461 knockdown could remarkably suppress cell proliferation, cell cycle progression, cell migration, and promote cell apoptosis in EC cells. We discovered LINC00461 could sponge microRNA-219-5p (miR-219-5p) and suppress its expression, thereby upregulating expression level of miR-219-5p's target, cyclooxygenase-2 (COX-2). In vivo animal models, LINC00461 knockdown inhibited tumor growth by increasing miR-219-5p level and reducing COX-2 expression, thus confirming LINC00461 functions as an oncogene in EC. In this study, a novel regulatory role of LINC00461/miR-219-5p/COX-2 axis was systematically investigated in context of EC, with the aim to provide promising intervention targets for EC therapy from bench to clinic. [Formula: see text].

DNA methylation subtypes for ovarian cancer prognosis.

Ovarian cancer is one of three major malignancies of the female reproductive system. DNA methylation (MET) is closely related to ovarian cancer occurrence and development, and as such, elucidation of effective MET subtype markers may guide individualized treatment and improve ovarian cancer prognosis. To identify potential markers, we downloaded a total of 571 ovarian cancer MET samples from The Cancer Genome Atlas (TCGA), and established a Cox proportional hazards model using the MET spectrum and clinical pathological parameters. A total of 250 prognosis-related MET loci were obtained by Cox regression, and six molecular subtypes were screened by consensus clustering of CpG loci with a significant difference in both univariate and multivariate analyses. There was a remarkable MET difference between most subtypes. Cluster 2 had the highest MET level and demonstrated the best prognosis, while Clusters 4 and 5 had MET levels significantly lower than those of the other subtypes and demonstrated very poor prognosis. All Cluster 5 samples were at a high grade, while the percentage of stage IV samples in Cluster 4 was greater than in the other subtypes. We obtained five CpG loci using a coexpression network: cg27625732, cg00431050, cg22197830, cg03152385, and cg22809047. Our cluster analysis showed that prognosis in patients with hypomethylation was significantly worse than in patients with hypermethylation. These MET molecular subtypes can be used not only to evaluate ovarian cancer prognosis, but also to fully distinguish the tumor stage and histological grade in patients with ovarian cancer.

In situ apolipoprotein E-enriched corona guides dihydroartemisinin-decorating nanoparticles towards LDLr-mediated tumor-homing chemotherapy.

The therapeutic efficiency of active targeting nanoparticulate drug delivery systems (nano-DDS) is highly compromised by the plasma proteins adsorption on nanoparticles (NPs) surface, which significantly hinders cell membrane receptors to recognize the designed ligands, and provokes the off-target toxicity and rapid clearance of NPs in vivo. Herein, we report a novel dihydroartemisinin (DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E (apoE) on the NPs surface. The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA (PPD) NPs circulation capability in blood, facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention (EPR) effect and low-density lipoprotein receptor (LDLr)-mediated target transport, and ultimately improve the in vivo antitumor activity. Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.

Comprehensive analysis of angiogenesis-related genes and pathways in early diabetic retinopathy.

BACKGROUND: Angiogenesis is an important parameter in the development of diabetic retinopathy (DR), and it is indicative of an early stage evolving into a late phase. Therefore, examining the role of angiogenic factors in early DR is crucial to understanding the mechanism of neovascularization. METHODS: The present study identified hub genes and pathways associated with angiogenesis in early DR using bioinformatics analysis. Genes from published literature and Gene Expression Omnibus (GEO) were collected and analysed. RESULTS: We collected 73 genes from 70 published studies in PubMed, which were referred to as DR-related gene set 1 (DRgset1). The gene expression profile of GSE12610 was downloaded, and 578 differentially expressed genes (DEGs) between diabetic and normal samples were identified. DEGs and DRgset1 were further combined to create DR-related gene set 2 (DRgset2). After an enrichment analysis, we identified 12 GO terms and 2 pathways associated with neovascularization in DRgset1, and 8 GO terms and 2 pathways in DRgset2. We found 39 new genes associated with angiogenesis and verified 8 candidate angiogenesis-related genes in DR cells using real-time PCR: PIK3CB, ALDH3A1, ITGA7, FGF23, THBS1, COL1A1, MAPK13, and AIF1. We identified 10 hub genes associated with neovascularization by constructing a protein-protein interaction (PPI) network: TNF, VEGFA, PIK3CB, TGFB1, EDN1, MMP9, TLR4, PDGFB, MMP2, and THBS1. CONCLUSIONS: The present study analysed angiogenesis-related genes and pathways in early DR in a comprehensive and systematic manner. PIK3CB, ALDH3A1, ITGA7, FGF23, THBS1, COL1A1, MAPK13, and AIF1 may be the candidate genes to further explore the mechanisms of angiogenesis in early DR. TNF, PIK3CB, TGFB1, EDN1, MMP9, TLR4, PDGFB, MMP2, and THBS1 may be new targets for early neovascularization therapy in the future.

CircRNA hsa_circ_0002577 accelerates endometrial cancer progression through activating IGF1R/PI3K/Akt pathway.

BACKGROUND: Endometrial cancer (EC) is a common gynecologic malignancy worldwide. This study investigated the regulatory effects of circular RNA (circRNA) hsa_circ_0002577 on the tumorigenesis of EC. METHODS: Tumor samples and adjacent normal tissues were obtained from 84 EC patients. Recombinant lentiviral vectors expressing hsa_circ_0002577 (Lv-circRNA), short hairpin RNAs against hsa_circ_0002577 (sh-circRNA), miR-625-5p mimics, miR-625-5p inhibitor, lentiviral vectors expressing insulin-like growth factor 1 receptor (IGF1R) and their corresponding controls were transfected into EC cells as designated. A mouse xenograft model was established in BALB/c mice by inoculating Ishikawa cells transfected with sh-circRNA or control sequence. RESULTS: Hsa_circ_0002577 was upregulated in EC tissue samples and cells as compared to normal controls. EC patients with higher expression of hsa_circ_0002577 showed poorer overall survival and more advanced tumor stage. EC cells transfected with Lv-circRNA showed promoted proliferation, migration, and invasion, whereas the delivery of sh-circRNA exerted an opposite effect. Further analyses showed that hsa_circ_0002577 acted as a miR-625-5p sponge in EC cells. IGF1R was a potential downstream target of miR-625-5p. The expression of IGF1R in EC tissues was significantly higher than that in matched controls. Hsa_circ_0002577 accelerated EC development by inducing IGF1R expression and activating PI3K/Akt signaling pathway. Also, the knockdown of hsa_circ_0002577 delayed tumor growth and metastasis in the inoculated mice. CONCLUSION: Our study showed that circRNA hsa_circ_002577 accelerated EC progression by acting as a miR-625-5p sponge, upregulating IGF1R and activating the PI3K/Akt pathway, suggesting the potential therapeutic use of hsa_circ_002577 in EC treatment. TRIAL REGISTRATION: Not Applicable.

Inhibition of Rac1 reverses enzalutamide resistance in castration-resistant prostate cancer.

Enzalutamide, an androgen receptor inhibitor, has been clinically approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) in the United States. However, patients only benefit from enzalutamide for a short period of time as resistance may develop. Therefore, it is vital to develop a novel strategy to overcome enzalutamide resistance. Ras-related C3 botulinum toxin substrate 1 (Rac1), which is commonly upregulated in human cancer types, has been recognized as a key molecular component in tumorigenesis, invasion and metastasis. However, the role of Rac1 in enzalutamide-resistance in prostate cancer (PCa) remains unknown. In the present study, Rac1 was demonstrated to be upregulated in enzalutamide-resistant PCa cells, and Rac1 knockdown inhibited enzalutamide-resistant cell proliferation and colony formation. Western blotting results indicated that enzalutamide treatment downregulated the expression levels of JNK and activated transcription factor 2, as well as enhanced the Bax/Bcl-2 ratio and induced cleavage of poly-ADP ribose polymerase. Moreover, knockdown of Rac1 in MR49F cells significantly inhibited cell migration and invasion via the downregulation of Snail and the upregulation of E-cadherin. The results of a nude mouse xenograft tumor model using 22RV1 cells demonstrated that enzalutamide inhibited tumor growth after Rac1 knockdown dramatically, compared to vehicle and single treatment groups. Therefore, the present study provided novel evidence that Rac1 may serve a crucial role in enzalutamide resistance, and that targeting Rac1 may be a potential approach for the treatment of CRPC.

MYORG Mutation Heterozygosity Is Associated With Brain Calcification.

BACKGROUND: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications. OBJECTIVES: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. METHODS: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 through September 2019. Mutational analysis of MYORG was performed in 435 primary familial brain calcification probands who were negative for mutations in the other four known primary familial brain calcification-causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1). RESULTS: Biallelic MYORG mutations were identified in 14 primary familial brain calcification patients from 10 unrelated families. Interestingly, 12 heterozygous carriers from seven of these families also exhibited mild-to-moderate brain calcifications. Moreover, single heterozygous mutations were detected in an additional 9 probands and in 7 of their family members affected with brain calcifications. In our cohort, clinical and imaging penetrance of individuals with biallelic mutations were 100%, whereas among individuals with heterozygous mutations, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 carriers had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG mutations, individuals with heterozygous mutations had brain calcifications with much lower calcification scores (P < 2e-16). CONCLUSIONS: Presence of brain calcifications in individuals with heterozygous MYORG mutations suggested a semidominant inheritance pattern with incomplete penetrance. This finding further expanded the genotype-phenotype correlations of MYORG-related primary familial brain calcification. © 2020 International Parkinson and Movement Disorder Society.

Plasma D-Dimer Level and the Failure of Forearm Autologous Arteriovenous Fistula in Patients With End-Stage Renal Disease.

Failed autologous arteriovenous fistula (AVF) is a major issue in the creation of functional hemodialysis vascular access. To date, the relationship between D-dimer and AVF failure is still uncertain. Hence, we conducted a retrospective cohort study to explore the patency rate of forearm AVFs and to clarify whether plasma D-dimer level can predict the failure of AVFs. In this study, 290 ESRD patients (the mean age 54.1 ± 14.6 years, 63.8% of them were males) receiving forearm AVFs surgery were consecutively enrolled with a median follow-up time of 34 months. Primary patency rates and risk factors associated with AVFs failure were explored by the Kaplan-Meier method or Cox proportional hazards model. Patients were divided into two groups based on the median level of D-dimer (group 1 <1.1 mg/L and group 2 ≥1.1 mg/L). The Kaplan-Meier survival analysis demonstrated that the patency of AVF in group 1 was similar in group 2, which were 92.4% versus 88.9%, 84.8% versus 84.0%, 80.0% versus 79.2%, 76.7% versus 78.5%, and 76.7% versus 78.5% at 12, 24, 36, 48, and 60 months (Log-rank test, P = 0.8), respectively. In the crude analysis, D-dimer (per 1 mg/L increase) was independently associated with AVFs failure, with OR of 1.08 (95% CI, 1.02-1.15). However, after adjusting for potential confounders, the D-dimer (per 1 mg/L increase) was not associated with the AVFs failure (OR = 1.06, 95% CI = 0.99-1.13). This study did not find that the plasma D-dimer level can predict the failure of forearm AVFs.

Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China.

BACKGROUND: Primary familial brain calcification (PFBC) is a rare calcifying disorder of the brain with extensive clinical and genetic heterogeneity. Its prevalence is underestimated due to clinical selection bias (compared with symptomatic PFBC patients, asymptomatic ones are less likely to undergo genetic testing). METHODS: A total of 273 PFBC probands were enrolled in a multicenter retrospective cohort study by two different approaches. In Group I (nonsystematic approach), 37 probands diagnosed at our clinic were enrolled. In Group II (systematic approach), 236 probands were enrolled by searching the medical imaging databases of 50 other hospitals using specific keywords. Genetic testing of four genes known to be causative of autosomal dominant PFBC was performed in all probands using cDNA. All identified variants were further confirmed using genomic DNA and classified according to ACMG-AMP recommendations. RESULTS: Thirty-two variants including 22 novel variants were detected in 37 probands. Among these probands, 83.8% (31/37) were asymptomatic. Two probands with homozygous pathogenic SLC20A2 variants presented more severe brain calcification and symptoms. Based on the variant detection rate of probands in Group II, we extrapolated an overall minimal prevalence of PFBC of 6.6 per 1,000, much higher than previously reported (2.1 per 1000). CONCLUSIONS: We identified a higher proportion of genetically confirmed PFBC probands who were asymptomatic. These patients would be overlooked due to clinical selection bias, leading to underestimation of the disease prevalence. Considering that PFBC patients with biallelic variants had more severe phenotypes, this specific condition should be focused on in genetic counseling.

Expression levels of miR-205 and miR-506 in colon cancer tissues and their relationships with clinicopathological features.

The study intended to investigate the expression levels of micro ribonucleic acid (miR)-205 and miR-506 in colon cancer tissues and their relationships with clinicopathological features. The expression levels of miR-205 and miR-506 in colon cancer tissues and para-carcinoma normal colonic mucosa tissues were detected via fluorescence reverse transcription quantitative polymerase chain reaction (RT-qPCR), and the expression levels of the two miRNAs in plasma of colon cancer patients and healthy control population were also detected. Moreover, the relationships of the two miRNAs with clinicopathological features of patients with colon cancer were analyzed. The expression levels of the two miRNAs in colon cancer tissues were higher than those in para-carcinoma normal colonic mucosa tissues, and also significantly higher in plasma of the colon cancer patients than those in the healthy control population. The differences were statistically significant (P<0.05). The expression level of miR-205 was associated with tumor-node-metastasis (TNM) staging and lymph node metastasis, while the expression level of miR-506 was associated with lymph node metastasis. The differences were statistically significant (P<0.05). The expression levels of miR-205 in the colon cancer tissues and plasma in patients had no significant correlation (r=0.467, P=0.081). There was a positive correlation between the expression levels of miR-506 in the colon cancer tissues and plasma in patients (r=0.599, P=0.038). The expression levels of miR-205 and miR-506 are upregulated in the colon cancer patients, both of which may be closely related to the occurrence and development of colon cancer, and may become potential tumor markers as well as relevant therapeutic targets.

Methylation of DACT2 contributes to the progression of breast cancer through activating WNT signaling pathway.

The activation of the Wnt/ß-catenin signaling pathway has been demonstrated to play important roles in breast carcinogenesis and to be associated with a poorer prognosis in breast cancer patients. However, genetic mutation is not the major reason for Wnt/ß-catenin activation in breast cancer. Dishevelled-associated antagonist of ß-catenin homolog 2 (DACT2) is a negative regulator of ß-catenin and acts as a tumor suppressor in numerous cancer types; however, the expression change and potential role of DACT2 in breast cancer is unknown. The present study detected the expression and function of DACT2 in breast cancer progression. It was identified that the expression of DACT2 significantly decreased in breast cancer tissues compared with paired adjacent normal breast tissues. Additional investigation demonstrated that the hypermethylation of DACT2 gene promoter contributes to the loss of the gene in breast cancer. It was also demonstrated that DACT2 is a tumor suppressor in breast cancer and inhibits the proliferation and invasion of breast cancer cells by repressing the expression of ß-catenin target genes associated with tumor growth and metastasis. The present study indicates that the loss of DACT2 may contribute to breast cancer progression and provides a promising therapeutic target for the treatment of breast cancer.