Conformal thyroidectomy is a feasible option in papillary thyroid microcarcinoma: a retrospective cohort study with 10-year follow-up results.

BACKGROUND: In recent years, there has been an increasing prevalence of patients with papillary thyroid microcarcinoma (PTMC) without lymph node involvement in medical centers worldwide. For patients who are unable to undergo active surveillance (AS) and are afraid of postoperative complications, conformal thyroidectomy may be a suitable option to ensure both preservation of function and complete removal of the tumor. METHODS: The patients in the cohort during 2010 to 2015 were retrospectively enrolled strictly following the inclusion and exclusion criteria. The observation and control groups were defined based on the surgical approach, with patients in the observation group undergoing conformal thyroidectomy and patients in the control group undergoing lobectomy. Event-free survival (EFS), the interval from initial surgery to the detection of recurrent or metastatic disease, was defined as the primary observation endpoint. RESULTS: A total of 319 patients were included in the study, with 124 patients undergoing conformal thyroidectomy and 195 patients undergoing lobectomy. When compared to lobectomy, conformal thyroidectomy demonstrated reduced hospital stays, shorter operative times, and lower rates of vocal cord paralysis and hypoparathyroidism. Furthermore, the mean bleeding volume during the operation and the rate of permanent hypothyroidism were also lower in the conformal thyroidectomy group than in the lobectomy group. However, there was no statistically significant difference observed in the 5- and 10-year EFS between the two groups. CONCLUSIONS: Conformal thyroidectomy had advantages in perioperative management and short-term complication rates, with an EFS that was not inferior to that of lobectomy. Thus, conformal thyroidectomy is a feasible option for low-risk PTMC patients.

Risk of suicide in patients with thyroid cancer: protocol for a systematic review and meta-analysis.

INTRODUCTION: In recent years, the incidence of thyroid cancer has increased manyfold and young adults, who have a greater financial burden and occupational stress, comprise a large number. Previous studies have shown mixed results, even distinct results, on suicide rates among thyroid cancer survivors. As the overdiagnosis and overtreatment of thyroid cancer has gradually become a topical issue, the study aims to summarise the risk of suicide among patients with thyroid cancer to provide robust evidence of the effects of thyroid cancer on suicide. METHODS AND ANALYSIS: A total of six databases (MEDLINE, Embase, Web of Science Core Collection, PsycINFO, CINAHL and Google Scholar) will be searched according to MeSH, subheadings, and free words, and the planned search date is 31 Jnauary 2024. The search strategy had three parts, such as suicide, cancer and epidemiological studies, moreover, we will collect the detailed suicide information by reviewers' extraction. Standard mortality ratio (SMR) was used as the outcome measure, when SMRs were not available, the risk ratio, HR and detailed number of suicides were extracted to calculate the SMRs. ETHICS AND DISSEMINATION: The Institutional Review Board of Peking University People's Hospital provided ethical approval exemption and approved the data collection and subsequent analyses in accordance with the Declaration of Helsinki as revised in 2013. PROSPERO REGISTRATION NUMBER: CRD42023445542.

Transcriptomic and genomic profiling of multiple primary colorectal cancers reveals intratumor heterogeneity and a distinct immune microenvironment.

This study reported on the intratumor genomic and immunological heterogeneity of different tumor lesions from a single patient with multiple primary colorectal cancer (MPCC). The goal of this study was to explore the molecular and microenvironment characteristics of tumor lesions from different primary sites in a patient with MPCC. A total of three tumor lesions located in the hepatic flexure of the transverse colon, sigmoid colon, and rectum were collected from a 72-year-old male patient with MPCC. All three tumor samples were examined by using whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). The transcriptome data of The Cancer Genome Atlas (TCGA) colon cancer (COAD) dataset were explored to characterize the biological impacts of certain immune cells. Only three nonsynonymous mutations were shared by all of the tumor lesions, whereas a number of single nucleotide variant (SNV) and copy number variation (CNV) mutations were shared by tumor samples from the sigmoid colon and rectum. Transcriptomic analysis showed that tumor lesions derived from the transverse colon had decreased levels of RTK, ERK, and AKT pathway activity, thus suggesting lower oncogenic properties in the transverse lesion compared to the other two samples. Further immune landscape evaluation by using single-cell transcriptomic analysis displayed significant intratumor heterogeneity in MPCC. Specifically, more abundant mucosal-associated invariant T (MAIT) cell infiltration was found in transverse colon tumor lesions. Afterwards, we found that higher MAIT cell infiltration may correlate with a better prognosis of patients with colon cancer (immunohistochemical status was MSI-L/pMMR) by using a publicly available TCGA dataset.

Hallmarks and novel insights for gastrointestinal stromal tumors: A bibliometric analysis.

BACKGROUND: Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field. METHODS: We searched the Web of Science Core Collection without publication data restrictions for GISTs and performed a bibliometric analysis with CiteSpace and VOSviewer software. RESULTS: In sum, 5,911 of 13,776 records were included, and these studies were published in 948 journals and written by 24,965 authors from 4,633 institutions in 100 countries. Referring to published reviews and bibliometric analysis, we classified the future trends in four groups. In epidemiological study, precise incidence and clinicopathological features in different regions and races might become potential hotspots. Novel therapy, such as drugs, modified strategies, radioligand therapy, was persistent hotspots in GIST fields, and ctDNA-guided diagnosis, monitoring, and treatment might meet future clinical needs. The debate over serosa surgery vs. mucosa surgery will remain active for a long time in GIST surgery, and function reserve surgery, biology-based surgery will play an important role in future. Moreover, rare GIST type, like NF-1-associated GIST, Carney triads and SDH mutant GIST, need more studies in pathogenesis and genetic mutation to provide appropriate treatment for this orphan GIST patients. CONCLUSIONS: Potential hotspots in future GIST trends might involve epidemiology, agents, resection therapy and rare type GIST, moreover, researchers could pay more attention in these four fields.

Corrigendum: PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

[This corrects the article DOI: 10.3389/fbioe.2022.1001994.].

Young adults with colon cancer: clinical features and surgical outcomes.

BACKGROUND: The clinicopathological features, surgical outcomes, and long-term survival of patients with young-onset colon cancer (≤ 40 years old) remain controversial. METHODS: The clinicopathologic and follow-up data of patients aged < 40 years with colon cancer between January 2014 and January 2022 were reviewed. The primary objectives were clinical features and surgical outcomes. Long-term survival was investigated as a secondary objective. RESULTS: Seventy patients were included in the study, and no significant rising trend (Z=0, P=1) of these patients was observed over the 8-year study period. Stage IV disease was accompanied by more ulcerative or infiltrating type (84.2% vs. 52.9%, P=0.017) and lymphovascular or perineural invasion (64.7% vs. 25.5%, P=0.003) than stage I-III disease. After a median follow-up time of 41 months (range 8-99 months), the 1-, 3-, and 5-year estimated overall survival (OS) rates were 92.6%, 79.5%, and 76.4%, respectively. The 1-, 3-, and 5-year progression-free survival (PFS) rates were 79.6%, 71.7%, and 71.7%, respectively. Multivariate Cox regression showed that M+ stage (hazard ratio [HR], 3.942; 95% confidence interval [CI], 1.176-13.220, P=0.026) was the only independent risk factor affecting OS. Meanwhile, tumor deposits (HR, 4.807; 95% CI, 1.942-15.488, P=0.009), poor differentiation (HR, 2.925; 95% CI, 1.012-8.454, P=0.047), and M+ stage (HR, 3.540; 95% CI, 1.118-11.202, P=0.032) independently affected PFS. CONCLUSIONS: The differences in the clinical features, surgical outcomes, and long-term survival between young adults and elderly colon cancer patients need further investigation.

Consistency assessment and visualization of recommendations on gastroesophageal reflux disease: a scoping review of clinical practice guidelines.

INTRODUCTION: Gastroesophageal reflux disease (GERD) is a highly prevalent gastrointestinal disorder that causes diverse esophageal and extraesophageal symptoms. Many clinical practice guidelines (CPGs) have been issued around the world to provide practical evidence regarding GERD management. However, some of the recommendations discussed in various CPGs are inconsistent across individual documents. OBJECTIVES: We aimed to summarize the evidence from CPGs on GERD and assess the consistency of the recommendations. PATIENTS AND METHODS: In this scoping review, we identified current CPGs on the clinical management of GERD, which were comprehensively searched for in electronic databases and on relevant scientific websites. The recommendations were extracted using the population­intervention­comparison framework and were subsequently categorized into tables. RESULTS: Ultimately, 24 CPGs were identified. They included 86 recommendations, which were classified into 5 categories: definition, epidemiology, diagnosis, treatment, and complications. Among the identified recommendations, 68 were proposed in at least 2 CPGs, and they were assessed for the consistency of direction and strength. Overall, 32.4% of the recommendations (22/68) were consistent in direction and strength, whereas 60.3% (41/68) were consistent in direction but inconsistent in strength. Moreover, 7.4% (5/68) were inconsistent in direction. These referred to the relationship between GERD and tobacco consumption, Helicobacter pylori infection, diagnostic utility of the 2­week proton pump inhibitor test, cessation of special food, and antireflux surgery for GERD with extraesophageal symptoms. CONCLUSIONS: Most CPG recommendations regarding GERD were consistent in direction, except for 5 discrepancies, for which further well­designed, large­scale research is required to explain the inconsistency.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Corrigendum: Yu et al. PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

[This corrects the article DOI: 10.3389/fbioe.2022.1001994.].

Clinicopathological features and prognosis of colonic and rectal gastrointestinal stromal tumors: A propensity score matching analysis.

Background: Colonic gastrointestinal stromal tumor (cGIST) and rectal gastrointestinal stromal tumor (rGIST) are two rare subtypes of gastrointestinal stromal tumor (GIST). The view that colonic and rectal carcinoma are different is generally accepted; however, whether there is a difference between cGIST and rGIST is still unknown. Here, we aimed to provide evidence for future clinical management and research by comparing the differences between the two types of GIST in the above-mentioned aspects. Methods: Patients were enrolled from three medical centers in China and published literature was collected following the inclusion and exclusion criteria. Propensity score matching was used to eliminate differences between cohorts. Results: Between cGIST and rGIST patients, significant differences were observed in age, tumor size, mitotic index, NIH risk category, growth pattern, and symptoms. Adjuvant therapy is used in a high proportion of cGIST patients, and neoadjuvant therapy is used in a high proportion of rGIST patients. Although local resection is the main surgical method in both cohorts, the proportion is higher in cGIST patients. The overall survival of rGIST patients was better than that of the cGIST patients before propensity score matching (PSM). Interestingly, no significant differences in prognosis were observed after PSM. Conclusions: Although there were significant differences between cGIST and rGIST patients in baseline characteristics, clinicopathological features, treatment choice, and overall survival rate before PSM, no significant differences in long-term survival were observed between the two groups after PSM. In our study, there may be no differences in the tumor entity between cGIST and rGIST.

Development and verification of a prognostic model for colon cancer on pyroptosis-related genes.

Background: Recently, the role of pyroptosis in cancer has attracted people's attention, but its function in colon cancer remains unclear. This study aimed to construct a pyroptosis-related model that can effectively predict the prognosis of patients with colon cancer and explore the potential functions of pyroptosis-related genes. Methods: We identified 40 differentially expressed PRGs between colon cancer and normal colon tissues. The model was established using the least absolute shrinkage and selection operator (LASSO) Cox regression method, and the patients were divided into high- and low-risk groups. Finally, we verified its biological function in vitro based on three PRGs and demonstrated discrepant expression of PRGs within colon cancer and non-tumor tissues at the protein level with immunohistochemistry. Results: A pyroptosis-related prognosis model was constructed, which divided 446 patients with colon cancer into high- and low-risk groups. Kaplan-Meier analysis results showed that the survival of patients with colon cancer in the high-risk group was worse than that in the low-risk group. Finally, we also confirmed that this score is an independent prognostic factor for colon cancer progression. Conclusion: In summary, the model established by three PRGs was a reliable indicator for predicting prognosis, suggesting that pyroptosis might be a noteworthy therapeutic target in CC.

Five-Year Prognosis of Complete Mesocolic Excision in Patients with Colon Cancer: A Prospective, Nonrandomized, Double-Blind Controlled Trial.

BACKGROUND: Previous studies on how complete mesocolic excision (CME) affects prognosis indicate fundamental limitations that prevent the procedure from being completely accepted in practice. This study evaluated 5-year survival in colon cancer patients who underwent CME in a strict quality-controlled trial. STUDY DESIGN: A prospective, nonrandomized, double-blind, controlled trial recruited patients who underwent open radical resection for colon cancer between November 2012 and November 2017. Third-party experts evaluated whether patients had undergone mesocolic dissection and/or central ligation by looking at photographs of both surgical field and specimen, and then divided patients into CME and non-CME (NCME) groups. The primary outcome was the 5-year local recurrence-free survival rate. Clinicopathological and follow-up data were recorded. RESULTS: There were 261 patients with a median follow-up time of 57 months assigned to the CME group, and 129 patients with a median follow-up time of 59 months were assigned to the NCME group. The 5-year local recurrence-free survival rate of patients with Union Internationale Contre le Cancer stage I to III cancer did not differ significantly between the groups. For stage I to III cancer and stage III cancer, the absolute risk reduction of 5-year cumulative death and disease progression after CME were 9.1% (95% CI 1% to 17%; p = 0.033) and 16.1% (95% CI 1% to 31%; p = 0.040), respectively. Meanwhile, CME also could reduce 14% 5-year cumulative incidence recurrence for Union Internationale Contre le Cancer stage III cancer compared with NCME (CME, 27.3% vs NCME, 41.3%; p = 0.042) after adjusting for the effect of non-cancer-related death. CONCLUSIONS: CME should be considered as a standard surgical procedure in affected patients.

PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

Colorectal cancer (CRC) is one of the most common cancers of the digestive tract, and patients with advanced-stage cancer have poor survival despite the use of multidrug conventional chemotherapy regimens. Intra-tumor heterogeneity of cancerous cells is the main obstacle in the way to effective cancer treatments. Therefore, we are looking for novel approaches to eliminate just cancer cells including nanoparticles (NPs). PPy@Fe3O4 NPs were successfully synthesized through a portable method. The characterization of transmission electron microscopy (TEM), Fourier-Transformed infrared spectrometer, and X-ray powder diffraction have further proved successful preparation of PPy@Fe3O4 NPs. NIR irradiation was used to test the photothermal properties of NPs and an infrared camera was used to record their temperature. The direct effects of PPy@Fe3O4 NPs on colorectal cancer cell DLD1 were assessed using CCK8, plate clone, transwell, flow cytometry, and western blotting in CRC cell. The effect of PPy@Fe3O4 NPs on neoplasm growth in nude mice was evaluated in vivo. This study demonstrated that PPy@ Fe3O4 NPs significantly inhibit the growth, migration, and invasion and promote ferroptosis to the untreated controls in colorectal cancer cells. Mechanical exploration revealed that PPy@Fe3O4 NPs inhibit the multiplication, migration, and invasion of CRC cells in vitro by modulating the NF-κB signaling pathway. Importantly, Ferroptosis inhibitors Fer-1 can reverse the changes in metastasis-associated proteins caused by NPs treatment. Collectively, our observations revealed that PPy@Fe3O4 NPs were blockers of tumor progression and metastasis in CRC. This study brought new insights into bioactive NPs, with application potential in curing CRC or other human disorders.

N6-methyladenosine demethylase ALKBH5 suppresses colorectal cancer progression potentially by decreasing PHF20 mRNA methylation.

BACKGROUND: As the most widespread mRNAs modification, N6-methyladenosine (m6 A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear. RESULTS: Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP-seq and RNA-seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5-mediated m6 A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m6 A modification of PHF20 mRNA 3'UTR. CONCLUSIONS: ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5-mediated m6 A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.

Can Dietary Nutrients Prevent Cancer Chemotherapy-Induced Cardiotoxicity? An Evidence Mapping of Human Studies and Animal Models.

Introduction: Chemotherapy has significantly improved cancer survival rates at the cost of irreversible and frequent cardiovascular toxicity. As the main dose-dependent adverse effect, cardiotoxic effects not only limit the usage of chemotherapeutic agents, but also cause the high risk of severe poor prognoses for cancer survivors. Therefore, it is of great significance to seek more effective cardioprotective strategies. Some nutrients have been reported to diminish cardiac oxidative damage associated with chemotherapy. However, the currently available evidence is unclear, which requires a rigorous summary. As such, we conducted a systematic review of all available evidence and demonstrated whether nutrients derived from food could prevent cardiotoxicity caused by chemotherapy. Methods: We searched Medline (via PubMed), Embase and the Cochrane Library from inception to Nov 9, 2021 to identify studies reporting dietary nutrients against cancer chemotherapy-related cardiotoxicity. We performed descriptive summaries on the included studies, and used forest plots to demonstrate the effects of various dietary nutrients. Results: Fifty-seven eligible studies were identified, involving 53 animal studies carried on rats or mice and four human studies in cancer patients. Seven types of dietary nutrients were recognized including polyphenols (mainly extracted from grapes, grape seeds, and tea), allicin (mainly extracted form garlic), lycopene (mainly extracted from tomatoes), polyunsaturated fatty acids, amino acids (mainly referring to glutamine), coenzyme Q10, and trace elements (mainly referring to zinc and selenium). Dietary nutrients ameliorated left ventricular dysfunctions and myocardial oxidative stress at varying degrees, which were caused by chemotherapy. The overall risk of bias of included studies was at moderate to high risk. Conclusion: The results indicated that dietary nutrients might be a potential strategy to protect cardiovascular system exposed to the chemotherapeutic agents, but more human studies are urged in this field.Systematic Review Registration: https://inplasy.com/inplasy-2022-3-0015/.

Establishment of the prediction model and biological mechanism exploration for secondary imatinib-resistant in gastrointestinal stromal tumor.

A gastrointestinal stromal tumor (GIST) is mostly driven by the auto-activated, mutant KIT receptor tyrosine kinase gene or by the platelet-derived growth factor receptor alpha. Inhibition of KIT-signaling is the primary molecular target therapy for GIST, which is performed by the drug imatinib clinically. However, more than half of advanced or metastatic GIST develop secondary resistance to imatinib within 2 years after initiation of treatment, and the mechanism of acquired imatinib-resistant in GIST remains unclear. Therefore, we designed the present study, and firstly analyzed the gene expression profile of imatinib-resistant and sensitive GIST from GEO DataSet and identified 44 differential expressed genes. Then, a model including nine genes with their expressed coefficients was identified as a risk score to predict imatinib-resistant GIST. Internal and external validation of the prediction model was performed through the ROC curve, and the area under the curve was 0.967 (95%CI 0.901-1.000) and 0.917 (95%CI 0.753-1.000), separately. Lastly, the effect of immune, m6A, pyroptosis, and ferroptosis-related genes on imatinib-resistant GIST was also assessed because DNA replication was the most enriched biological function of DEGs after functional annotation, pathway enrichment, and protein-protein interaction network analyses. In conclusion, the present study established a novel model to predict secondary imatinib-resistant GIST. Meanwhile, the bioinformatic mining results provided potential and promising targets for imatinib-resistant therapy.

Assessment of adjuvant chemotherapy benefits after complete mesocolic excision in patients with colon cancer: Reanalysis of data from the ESCME trial.

AIM: The benefits of adjuvant chemotherapy (AC) in colon cancer after complete mesocolic excision (CME) have not been evaluated sufficiently. We reanalysed the ESCME trial data to investigate the survival benefits and establish AC stratified indications. METHODS: The data of Stage II and III colon cancer patients who received CME in the ESCME trial were reanalysed. Patients were divided into AC and non-AC (NAC) groups. The primary outcomes measured were differences in 5-year cancer-specific survival and disease-free survival (DFS) between the groups. RESULTS: Of the 206 patients enrolled in the study, 125 patients (AC, 49; NAC, 76) had Stage II cancer and 111 (AC, 86; NAC, 25) had Stage III cancer. There were no significant differences in the adjusted 5-year cancer-specific survival and DFS between the AC and NAC groups. Poor differentiation (hazard ratio [HR] 2.947; 95% CI 1.218-7.131) and RAS mutation (HR 3.140; 95% CI 1.363-7.234) affected the 5-year DFS significantly in multivariate Cox regression analysis for Stage II and III cancer, respectively. In subgroup analysis, AC significantly improved 5-year DFS (HR 0.369; 95% CI 0.140-0.978) for Stage III cancer with lymphovascular/perineural invasion compared to NAC. CONCLUSION: The current indication and benefits of AC for colon cancer patients after CME should be re-evaluated. AC is more appropriate for Stage III cancer with lymphovascular/perineural invasion.

Analysis of Differential Diagnosis of Benign and Malignant Partially Cystic Thyroid Nodules Based on Ultrasound Characterization With a TIRADS Grade-4a or Higher Nodules.

Partially cystic thyroid nodules (PCTNs) are a kind of thyroid nodule with both solid and cystic components, and are usually misdiagnosed as benign nodules. The objective of this study was to determine the ultrasound (US) characterizations with a TIRADS Grade-4a or higher partially cystic thyroid nodules (PCTNs) which are associated with being malignant or benign. In this study, 133 PCTNs with a TIRADS Grade-4a or higher were enrolled; 83 were malignant and 50 were benign. TI-RADS classification can detect malignant PCTNs, and its sensitivity, specificity, positive predictive value, negative predictive value, and accuracy are 39.8%, 96.0%, 94.3%, 49.0%, and 60.9%, respectively. Univariate analyses revealed that nodule shape, margin, and structure were related to PCTNs' being benign and malignant, among which nodules taller-than-wide, with an irregular shape, non-smooth margin, eccentric sharp angle, or edge sharp angle were significantly associated with malignancy while ovoid to round nodules, smooth margins, multiple separation, and eccentric obtuse angle structures were significantly associated with a benign nature. For the solid part of PCTNs, its free margin, echo, and calcification are related to benign and malignant PCTNs. Among them, the free margin of the solid part is non-smooth, hypoechoic, and microcalcification, which are related to malignant PCTNs, while the free margin of the solid part is smooth, isoechoic, macrocalcification, non-calcification and are related to benign PCTNs. Calcification of solid part and free margin are important factors for predicting malignant PCTNs. In addition, nodules' composition, blood flow signal, and other factors had nothing to do with PCTNs' being benign or malignant. In the multivariate Logistic regression analysis, solid part calcification (OR: 17.28; 95%CI: 5.14~58.08) and free margin (OR: 3.18; 95%CI: 1.01~10.00) were revealed to be the strongest independent predictors for malignancy (P<0.05). Our study indicated that understanding the ultrasound characteristics of malignant PCTNs, to avoid misdiagnosed PCTNs patients, is important to make a precise diagnosis and prognosis of PCTNs.

circPTEN1, a circular RNA generated from PTEN, suppresses cancer progression through inhibition of TGF-ß/Smad signaling.

BACKGROUND: PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated. METHODS: We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. RESULTS: We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-ß stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. CONCLUSIONS: Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-ß. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-ß/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.

hsa_circ_0000231 Promotes colorectal cancer cell growth through upregulation of CCND2 by IGF2BP3/miR-375 dual pathway.

BACKGROUND: Circular RNAs (circRNAs) have emerged as vital regulators of the initiation and progression of diverse kinds of human cancers. In this study, we explored the role of hsa_circ_0000231 and its downstream pathway in CRC. METHODS: The expression profile of circRNAs in 5 pairs of CRC tissues and adjacent normal tissues were analyzed by Microarray. Quantitative real-time PCR and in situ hybridization and Base Scope Assay were used to determine the level and prognostic values of hsa_circ_0000231. Then, functional experiments in vitro and in vivo were performed to investigate the effects of hsa_circ_0000231 on cell proliferation. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between hsa_circ_0000231 and IGF2BP3 or has_miR-375. RESULTS: We acquired data through circRNA microarray profiles, showing that the expression of hsa_circ_0000231 was upregulated in CRC primary tissues compared to adjacent normal tissues, which was indicated poor prognosis of patients with CRC. Functional analysis indicated that inhibition of hsa_circ_0000231 in CRC cell lines could suppress CRC cell proliferation as well as tumorigenesis in vitro and in vivo. The mechanistic analysis showed that hsa_circ_0000231 might, on the one hand, act as a competing endogenous RNA of miR-375 to promote cyclin D2 (CCND2) and, on the other hand, bind to the IGF2BP3 protein to prevent CCND2 degradation. CONCLUSIONS: The findings suggested that hsa_circ_0000231 facilitated CRC progression by sponging miR-375 or binding to IGF2BP3 to modulate CCND2, implying that hsa_circ_0000231 might be a potential new diagnostic and therapeutic biomarker of CRC.