Recent Advances in NHC-Catalyzed Chemoselective Activation of Carbonyl Compounds.

N-Heterocyclic carbenes (NHCs) catalysts have been employed as effective tools in the development of various reactions, which have made notable contributions in developing diverse reaction modes and generating significant functionalized molecules. This review provides an overview of the recent advancements in the chemo- and regioselective activation of different aldehydes using NHCs, categorized into five parts based on the different activation modes. A brief conclusion and outlook is provided to stimulate the development of novel activation modes for accessing functional molecules.

Discovery of Novel Chiral Indole Derivatives Containing the Oxazoline Moiety as Potential Antiviral Agents for Plants.

Potato virus Y (PVY) is an important plant virus that has spread worldwide, causing significant economic losses. To search for novel structures as potent antiviral agents, a series of chiral indole derivatives containing oxazoline moieties were designed and synthesized and their anti-PVY activities were evaluated. Biological activity tests demonstrated that many chiral compounds exhibited promising anti-PVY activities and that their absolute configurations exhibited obvious distinctions in antiviral bioactivities. Notably, compound (S)-4v displayed excellent curative and protective efficacy against PVY, with EC50 values of 328.6 and 256.1 µg/mL, respectively, which were superior to those of commercial virucide ningnanmycin (NNM, 437.4 and 397.4 µg/mL, respectively). The preliminary antiviral mechanism was investigated to determine the difference in antiviral activity between the two enantiomers of 4v chiral compounds. Molecular docking indicated a stronger binding affinity between the coating proteins of PVY (PVY-CP) and (S)-4v (-6.5 kcal/mol) compared to (R)-4v (-6.2 kcal/mol). Additionally, compound (S)-4v can increase the chlorophyll content and defense-related enzyme activities more effectively than its enantiomer. Therefore, this study provides an important basis for the development of chiral indole derivatives containing oxazoline moieties as novel agricultural chemicals.

Efficient organized colorectal cancer screening in Shenzhen: a microsimulation modelling study.

BACKGROUND: Colorectal cancer (CRC) is a global health issue with noticeably high incidence and mortality. Microsimulation models offer a time-efficient method to dynamically analyze multiple screening strategies. The study aimed to identify the efficient organized CRC screening strategies for Shenzhen City. METHODS: A microsimulation model named CMOST was employed to simulate CRC screening among 1 million people without migration in Shenzhen, with two CRC developing pathways and real-world participation rates. Initial screening included the National Colorectal Polyp Care score (NCPCS), fecal immunochemical test (FIT), and risk-stratification model (RS model), followed by diagnostic colonoscopy for positive results. Several start-ages (40, 45, 50 years), stop-ages (70, 75, 80 years), and screening intervals (annual, biennial, triennial) were assessed for each strategy. The efficiency of CRC screening was assessed by number of colonoscopies versus life-years gained (LYG). RESULTS: The screening strategies reduced CRC lifetime incidence by 14-27 cases (30.9-59.0%) and mortality by 7-12 deaths (41.5-71.3%), yielded 83-155 LYG, while requiring 920 to 5901 colonoscopies per 1000 individuals. Out of 81 screening, 23 strategies were estimated efficient. Most of the efficient screening strategies started at age 40 (17 out of 23 strategies) and stopped at age 70 (13 out of 23 strategies). Predominant screening intervals identified were annual for NCPCS, biennial for FIT, and triennial for RS models. The incremental colonoscopies to LYG ratios of efficient screening increased with shorter intervals within the same test category. Compared with no screening, when screening at the same start-to-stop age and interval, the additional colonoscopies per LYG increased progressively for FIT, NCPCS and RS model. CONCLUSION: This study identifies efficient CRC screening strategies for the average-risk population in Shenzhen. Most efficient screening strategies indeed start at age 40, but the optimal starting age depends on the chosen willingness-to-pay threshold. Within insufficient colonoscopy resources, efficient FIT and NCPCS screening strategies might be CRC initial screening strategies. We acknowledged the age-dependency bias of the results with NCPCS and RS.

NHC-Catalyzed Chemo- and Enantioselective Reaction between Aldehydes and Enals for Access to Axially Chiral Arylaldehydes.

A chiral carbene-catalyzed chemo- and enantioselective reaction with racemic biaryl aldehydes and α-bromoenals is developed for access to axially chiral 2-arylbenzaldehydes through atroposelective dynamic kinetic resolution (DKR) processes. This atroposelective DKR strategy can tolerate a broad scope of substrates with diverse functionalities. The axially chiral 2-aryl benzaldehyde products generally afford moderate to good yields and enantioselectivities. The axially chiral molecules afforded from the current approach are variable through simple transformations to afford axially chiral functional molecules with excellent optical purities.

Expression of miR-22 profiling in colorectal normal-adenoma-carcinoma sequence.

Colorectal cancer (CRC) is the third most common cancer in the world. MiRNA-22 has emerged as a potential candidate with diagnostic significance; however, its expression profile across the normal-adenoma-carcinoma transition in colorectal remains unexplored. In this study, we evaluated serum miRNA-22 levels in patients with varying stages of CRC. The study cohort comprised 49 healthy controls, 50 patients with polyps, 51 individuals with colorectal adenoma (CRA), and 50 cases of CRC, confirmed through proctocolonoscopy and pathological biopsy. Real-time quantitative polymerase chain reaction was employed to validate the significantly differential expression of serum miRNA-22 among different stages of CRC progression. The 2-ΔΔCT method was utilized to assess the relative changes in serum miRNA-22 expression levels. Our results revealed no significant differences in gender, adenoma grade, location, or TNM classification stage in terms of serum miR-22 expression across the four groups. Notably, both the CRC and CRA groups exhibited higher miR-22 expression levels compared to the control group (p = 0.0001, p = 0.0004), with the CRA and CRC groups displaying higher expression levels than the polyp group (p = 0.02, p = 0.043). Ordered multicategorical logistic regression analysis model revealed the utilization of age, gender, smoking status, and miR-22 expression collectively exhibited the highest value for the area under the curve (AUC = 0.748) in the discrimination between individuals CRC and healthy. The independent factor of expression of miR-22 demonstrated the most notable predictive capacity (AUC = 0.753) when distinguishing between CRA and healthy individuals. Furthermore, the independent expression of miR-22 exhibited discernible potential (AUC = 0.654, 0.636) differentiation between polyps and CRA/ CRC. Notably, the factor of age displayed the most substantial discriminatory power (AUC = 0.741) when distinguishing between polyps and healthy individuals. Our findings provide supportive evidence for considering miR-22 as a potential biomarker for CRC early screening. Nonetheless, the molecular mechanisms of miR-22 regulation in colorectal lesions still need to be investigated.

Cavernous Sinus Syndrome Caused by Noninvasive Fungal Maxillary Sinusitis.

It is rare that cavernous sinus complications are caused by maxillary sinus lesions because the locations of these lesions are some distant from each other. The authors describe an unusual presentation that the primary lesion was located in the maxillary sinus and triggered cavernous sinus syndrome and optic nerve symptoms. The most likely possibility was that the infection traveled retrograde along the vascular plexus. Removal of maxillary sinus lesions and establishment ventilation may achieve source control.

Modifiable Risk Factors in High-Risk Groups of Colorectal Cancer Screening: A Cross-Sectional Study with Propensity Score Method.

Aim: The rising incidence and death rate of colorectal cancer (CRC) have posed a severe danger to the lives and health of residents. Individuals at high risk of CRC are drawing growing attention as the majority of the population impacted by CRC. Hence, it is imperative to examine the detection rates and modifiable factors affecting the populations at high risk for CRC in Shenzhen. Methods: The multi-stage stratified cluster sampling method was used to select residents aged 45-74 years old from September 2020 to December 2021. The community-based CRC screening was attended by a total of 30,921 residents from urban and suburb regions. The association between modifiable risk factors and the detection rate of high-risk groups was analyzed using multinomial logistic regression with the inverse probability treatment weighting (IPTW) based on the propensity score. Results: The cross-sectional analysis included 24,613 people after excluding 6308 people who had missing or invalid fecal occult blood test (FOBT) results. The detection rate for high-risk groups during CRC screening was 28.50%. Higher rate of high-risk groups was detected among those who were male, aged 60 or above, college or above, other marital status, and living in urban (P < 0.05). Demographic characteristics after IPTW showed a weak correlation coefficient with the detection rate of CRC high-risk both in high-risk and general-risk groups (SMD < 0.1), suggesting a balanced group of participants. The results of logistic regression with IPTW indicated that smoking, drinking, obesity, lack of exercise, vegetable or fruit eating infrequently, red meat, processed meat, cereal food and their clustering status were more inclined to be risk indicators of CRC (P < 0.05). Conclusion: The detection rate for high-risk CRC groups was comparatively high in Shenzhen. The distribution characteristics of lifestyle and dietary risk factors of high-risk groups should be given consideration when adopting individualized intervention measures and comprehensive prevention and control strategies.

Corrigendum: Non-alcoholic fatty liver disease is associated with aortic calcification: a cohort study with propensity score matching.

[This corrects the article DOI: 10.3389/fendo.2022.880683.].

Erdheim-Chester disease with bilateral orbital masses and multi-systemic symptoms: two case reports.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic disorder characterized by multisystem xanthogranulomatous infiltration by lipid-laden histiocytes. We report two cases of ECD involving the orbit and describe their clinicopathologic factors, treatments, and prognosis. One was a rare case of ECD complicated with primary thrombocytosis. CASE PRESENTATION: This study describes two patients with bilateral orbital ECD. Both presented with proptosis and visual loss; imaging findings showed bilateral intraorbital masses. Both had different degrees of systemic symptoms (pleural effusion, pericardial effusion, ascites, and heart failure) before the ocular symptoms and did not find the cause before ophthalmic tumor resection and pathological biopsy. The diagnosis of ECD was confirmed after pathological biopsy and detection of BRAFV600E mutation. Patient 2 also with primary thrombocytosis and had a CALR mutation as well as the BRAFV600E mutation. Both patients were recommended to receive targeted therapy. Patient 1 refused targeted therapy for financial reasons and was discharged after local radiotherapy only. The patient had no light perception in either eye and no improvement in systemic symptoms. Patient 2 began targeted treatment after diagnosis and reached the discharge criteria 2 weeks later. He is in good condition at present, but unfortunately, his eyesight has not improved because of the irreversible damage to his visual function. CONCLUSION: ECD is easily misdiagnosed and missed because of its rarity and diverse clinical manifestations. Orbital involvement is common in ECD, and surgery is the most frequently employed approach. Despite the surgical resection is not curative, its significance lies in biopsy to establish diagnosis and/or surgical debulking to relieve mass effect, minimizing further impairment of visual function. Targeted therapy is the most effective treatment for patients with a positive BRAF mutation gene. Evaluation of a concomitant myeloid neoplasm is also critical before initiating targeted therapies for refractory ECD.

The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer.

BACKGROUND: Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway.  METHODS: A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells.  RESULTS: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. CONCLUSIONS: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

Association between Periodontitis and Aortic Calcification: A Cohort Study.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03-4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02-1.36) (P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants <65 years of age (pinteraction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.

Orbital solitary fibrous tumours: clinicopathological characteristics and recurrence prediction.

BACKGROUND: SFTs are thought to have an unpredictable clinical course and currently have no recognized prognostic criterion. Our study aimed to determine the relationship between clinicopathological characteristics and the prognosis of patients with orbital SFTs. METHODS: The clinicopathological features of these patients were extracted from clinical records. The relationships between these features and prognosis were analysed. RESULTS: The positive rates of CD34, CD99, Blc2, and STAT6 expression were 90.3%, 90.3%, 83.9%, and 100%, respectively. The tumour recurrence rate was 38.7%. A higher recurrence rate was observed in patients with Ki67 index ≥ 5 (56.25% vs. 20%, P = 0.038). CONCLUSION: A Ki67 index ≥ 5 was an effective parameter for predicting tumour recurrence of orbital SFTs. Close follow-up is needed for these patients.

Environmental exposure to perchlorate, nitrate and thiocyanate, and thyroid function in Chinese adults: A community-based cross-sectional study.

BACKGROUND: Evidence on environmental exposure to perchlorate, nitrate, and thiocyanate, three thyroidal sodium iodine symporter (NIS) inhibitors, and thyroid function in the Chinese population remains limited. OBJECTIVE: To investigate the associations of environmental exposure to perchlorate, nitrate, and thiocyanate with markers of thyroid function in Chinese adults. METHODS: A total of 2441 non-pregnant adults (mean age 50.4 years and 39.1% male) with a median urinary iodine of 180.1 µg/L from four communities in Shenzhen were included in this cross-sectional study. Urinary perchlorate, nitrate, thiocyanate, and thyroid profiles, including serum free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), total triiodothyronine (TT3), and thyroid stimulating hormone (TSH), were measured. Generalized linear model was applied to investigate the single-analyte associations. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models were used to examine the association between the co-occurrence of three anions and thyroid profile. RESULTS: The median levels of urinary perchlorate, nitrate, and thiocyanate were 5.8 µg/g, 76.4 mg/g, and 274.1 µg/g, respectively. After adjusting for confounders, higher urinary perchlorate was associated with lower serum FT4, TT4, and TT3, and higher serum FT3 and TSH (all P < 0.05). Comparing extreme tertiles, subjects in the highest nitrate tertile had marginally elevated TT3 (ß: 0.02, 95% CI: 0.00-0.04). Each 1-unit increase in log-transformed urinary thiocyanate was associated with a 0.04 (95% CI: 0.02-0.06) pmol/L decrease in serum FT3. The WQS indices were inversely associated with serum FT4, TT4, and FT3 (all P < 0.05). In the BKMR model, the mixture of three anions was inversely associated with serum FT4, TT4, and FT3. CONCLUSIONS: Our study provides evidence that individual and combined environmental exposure to perchlorate, nitrate, and thiocyanate are associated with significant changes in thyroid function markers in the Chinese population with adequate iodine intake.

Diagnostic Accuracy of Transient Elastography and Two-Dimensional Shear Wave Elastography for Staging Liver Fibrosis in Children or Adolescents: A Systematic Review and Meta-Analysis.

BACKGROUND: Few studies comprehensively compared the performance of transient elastography (TE) and two-dimensional shear wave elastography(2D-SWE) to diagnose the stage of liver fibrosis in children and adolescents. We assessed the diagnostic performance of these non-invasive imaging techniques from published studies. METHODS: To evaluate the diagnostic performance of TE and 2D-SWE, we searched the PubMed, Embase, Web of Science, and Cochrane Library databases until November 13, 2021, for studies that diagnosed liver fibrosis in children and adolescents. Pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, and area under the receiver operating characteristic curve were estimated using the bivariate model. We also performed a subgroup analysis of various research characteristics. RESULTS: Twenty-seven studies with 1956 patients were included in the analysis. The sensitivity and specificity of TE and 2D-SWE for detecting liver fibrosis in all stages were greater than 0.82. For the detection of significant fibrosis, advanced fibrosis and cirrhosis, the summary AUC was 0.90 (95% CI: 0.87-0.92), 0.95 (95% CI: 0.93-0.96) and 0.95 (95% CI: 0.93-0.97) for TE, and the summary AUC was 0.92 (95% CI: 0.89-0.94), 0.94 (95% CI: 0.92-0.96) and 0.96 (95% CI: 0.94-0.97) for 2D-SWE, respectively. Both imaging methods detected significant heterogeneity. CONCLUSION: TE and 2D-SWE can provide accurate non-invasive staging of liver fibrosis in children or adolescents and are a promising technology, particularly for advanced liver fibrosis and cirrhosis, with a high potential to replace liver biopsy.

Nasal Sinus Mucoceles Manifesting Ocular Symptoms.

INTRODUCTION: To describe the ocular symptoms in a series of patients with nasal sinus mucoceles of different locations. METHODS: The authors analyzed the diagnosis and treatment of patients with sinus mucoceles and ocular symptoms who presented to the hospital from February 2010 to April 2020. A total of 61 patients were included in the study. The locations of the mucoceles were the frontal sinus (8 patients), ethmoid sinus (25 patients), and sphenoid sinus (28 patients). The authors selected 1 typical mucocele case from each of the sinuses, including the frontal, ethmoid, and sphenoid sinuses, and analyzed the history, diagnosis, and treatment of mucoceles in each location. RESULTS: The main clinical manifestations were ophthalmic symptoms, such as exophthalmos or displacement, eye pain, blindness or decreased vision, blepharoptosis, and diplopia; no obvious nasal symptoms were noted. Most patients with these symptoms went to an ophthalmologist first. All lesions in this study were found through imaging examinations. Most symptoms improved after surgical interventions. Only 2 of the 61 patients had no improvement in vision because of the long period of vision loss. CONCLUSIONS: Although sinus mucoceles are located in the sinuses, ocular symptoms are more prevalent than nasal symptoms. The earlier the imaging examinations are performed; the sooner lesions are detected, and the patients can be treated.

Diagnostic performance of radiomics in predicting axillary lymph node metastasis in breast cancer: A systematic review and meta-analysis.

Background: This study aimed to perform a meta-analysis to evaluate the diagnostic performance of radiomics in predicting axillary lymph node metastasis (ALNM) and sentinel lymph node metastasis (SLNM) in breast cancer. Materials and methods: Multiple electronic databases were systematically searched to identify relevant studies published before April 29, 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The overall diagnostic odds ratio (DOR), sensitivity, specificity, and area under the curve (AUC) were calculated to evaluate the diagnostic performance of radiomic features for lymph node metastasis (LNM) in patients with breast cancer. Spearman's correlation coefficient was determined to assess the threshold effect, and meta-regression and subgroup analyses were performed to explore the possible causes of heterogeneity. Results: A total of 30 studies with 5611 patients were included in the meta-analysis. Pooled estimates suggesting overall diagnostic accuracy of radiomics in detecting LNM were determined: DOR, 23 (95% CI, 16-33); sensitivity, 0.86 (95% CI, 0.82-0.88); specificity, 0.79 (95% CI, 0.73-0.84); and AUC, 0.90 (95% CI, 0.87-0.92). The meta-analysis showed significant heterogeneity between sensitivity and specificity across the included studies, with no evidence for a threshold effect. Meta-regression and subgroup analyses showed that combined clinical factors, modeling method, region, and imaging modality (magnetic resonance imaging [MRI], ultrasound, computed tomography [CT], and X-ray mammography [MMG]) contributed to the heterogeneity in the sensitivity analysis (P < 0.05). Furthermore, modeling methods, MRI, and MMG contributed to the heterogeneity in the specificity analysis (P < 0.05). Conclusion: Our results show that radiomics has good diagnostic performance in predicting ALNM and SLNM in breast cancer. Thus, we propose this approach as a clinical method for the preoperative identification of LNM.

Platelet-Lymphocyte Ratio, Neutrophil-Lymphocyte Ratio and Their Dynamic Changes with Type 2 Diabetes Mellitus: A Cohort Study in China.

BACKGROUND: This study aimed at investigating the relationships between Platelet-Lymphocyte ratio (PLR) and Neutrophil-Lymphocyte ratio (NLR) and their dynamic changes (∆PLR, ∆NLR) with type 2 diabetes mellitus (T2DM) in a Chinese cohort study. METHODS: This study recruited 41,439 individuals who were diagnosed without T2DM at first health examination and completed at least one follow-up. The relationships between NLR, PLR, ∆PLR, ∆NLR and T2DM risk were analyzed using the Cox regression model with corresponding Hazard Ratios (HRs) and 95% Confidence Intervals (CIs). RESULTS: PLR exhibited significant correlation with T2DM risk in a linear reverse dose-response pattern, the corresponding HRs and 95% CIs were 0.81 (0.72, 0.90), 0.71 (0.63, 0.80) and 0.56 (0.49, 0.64) respectively (Ptrend < 0.001) for Q2, Q3 and Q4 vs Q1 after adjusting for age, gender, BMI, TG, TC, HDL-C, FPG, ALT, AST, heart rate, smoking, family history of diabetes, and alcohol consumption at baseline in Model 3. The significance remained in subgroups of women, <45 years, ≥45 years, BMI ≥ 24, with fatty liver disease, without fatty liver disease and normotension. Comparing with the largest decrease group of NLR (∆NLR < -0.32), the risk of T2DM increased for -0.003 ≤ ∆NLR < 0.31 (HR 1.17, 95% CI 1.01-1.36) and ∆NLR ≥ 0.31 (HR 1.23, 95% CI 1.06-1.43). CONCLUSIONS: Higher PLR could reduce the risk of T2DM. Larger increase of NLR could increase T2DM risk.

COMMD3 Expression Affects Angiogenesis through the HIF1α/VEGF/NF-κB Signaling Pathway in Hepatocellular Carcinoma In Vitro and In Vivo.

Background: High expression of copper metabolizing MURR1 domain (COMMD3) is significantly correlated with poor prognosis in hepatocellular carcinoma (HCC) patients. Here, we explored the mechanism by which COMMD3 affects HCC angiogenesis through the HIF1α/VEGF/NF-κB signaling pathway. Methods: SK-Hep1 and Hep-3B cell lines were transfected by COMMD3 overexpression and RNA interference lentivirus and verified using RT-qPCR and western blotting techniques. Using RNA sequencing, we analyzed differentially expressed genes in COMMD3-overexpressed and COMMD3-knockdown HCC cells. Altogether, colony formation assay, wound healing assay, transwell cell invasion assay, flow cytometry apoptosis experiments, HUVEC tube formation detection, phalloidin staining assay, western blotting, immunohistochemical staining, and a nude mouse xenograft model were used for experimental verification. Results: Lentivirus COMMD3 overexpression and knockdown were successfully established in HCC cells. COMMD3 overexpression significantly promoted the proliferation, angiogenesis, migration, and invasion capacities of HCC cells with no obvious effect on apoptosis versus controls while COMMD3 knockdown showed the opposite trend. The expression and protein levels of COMMD3 as well as HIF1α, VEGF, and NF-κB were increased in COMMD3-overexpressing HCC cells versus control cells, while they were reduced after COMMD3 knockdown. In addition, RNA-seq indicated that COMMD3 is an indispensable gene for HCC angiogenesis through HIF1α and NF-κB signaling pathways. Conclusion: This study showed that low expression of COMMD3 can inhibit HCC angiogenesis by suppressing the HIF1α/VEGF/NF-κB pathway. This implicates COMMD3 as a potential biomarker for improving the therapeutic outcome of HCC.

Discovery and validation of tissue-specific DNA methylation as noninvasive diagnostic markers for colorectal cancer.

BACKGROUND: Noninvasive diagnostic markers that are capable of distinguishing patients with colorectal cancer (CRC) from healthy individuals or patients with other cancer types are lacking. We report the discovery and validation of a panel of methylation-based markers that specifically detect CRC. METHODS: This was a large-scale discovery study based on publicly available datasets coupled with a validation study where multiple types of specimens from six cohorts with CRC, other cancer types, and healthy individuals were used to identify and validate the tissue-specific methylation patterns of CRC and assess their diagnostic performance. RESULTS: In the discovery and validation cohort (N = 9307), ten hypermethylated CpG sites located in three genes, C20orf194, LIFR, and ZNF304, were identified as CRC-specific markers. Different analyses have suggested that these CpG sites are CRC-specific hypermethylated and play a role in transcriptional silencing of corresponding genes. A random forest model based on ten markers achieved high accuracy rates between 85.7 and 94.3% and AUCs between 0.941 and 0.970 in predicting CRC in three independent datasets and a low misclassification rate in ten other cancer types. In the in-house validation cohort (N = 354), these markers achieved consistent discriminative capabilities. In the cfDNA pilot cohort (N = 14), hypermethylation of these markers was observed in cfDNA samples from CRC patients. In the cfDNA validation cohort (N = 155), the two-gene panel yielded a sensitivity of 69.5%, specificity of 91.7%, and AUC of 0.806. CONCLUSIONS: Hypermethylation of the ten CpG sites is a CRC-specific alteration in tissue and has the potential use as a noninvasive cfDNA marker to diagnose CRC.