Highly Effective Pyroelectric Catalysis for Simultaneous Tumor-Targeted Dynamic Therapy and Gentle Photothermal Therapy by Oxygen-Vacancy-Rich CeO2-BaTiO3 Nanorods.

Pyroelectric nanostructures could effectively generate temperature-mediated reactive oxygen species (ROS) through the pyroelectric effect, providing promise for treating hypoxic tumors, and therefore, the synergistic application of photothermal therapy (PTT) and pyroelectric dynamic therapy (PEDT) presents an intriguing approach for cancer therapy. However, this method still faces challenges in improving pyroelectric catalysis and achieving precise tumor localization. In this study, a nano-heterojunction based on CeO2-BaTiO3 nanorods (IR1061@PCBNR) is reported, which exhibits highly effective pyroelectric catalysis for simultaneous tumor-targeted dynamic therapy and gentle photothermal therapy through the utilization of the rich oxygen vacancies. The oxygen vacancies create active sites that facilitate the migration of pyroelectrically-induced charge carriers, improving charge separation and ROS generation. IR1061@PCBNR also demonstrates high tumor penetration while minimizing damage to normal cells. This precise nanomedicine strategy holds great potential for advancing dynamic cancer therapies by overcoming the limitations of conventional approaches. This article is protected by copyright. All rights reserved.

CRKL but not CRKII contributes to hemin-induced erythroid differentiation of CML.

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR-429-CT10 regulation of kinase-like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR-429-CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR-429-CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR-429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR-429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin-induced erythroid differentiation of K562 cells, whereas, miR-429 exhibited opposite effects to CRKL. Mechanistically, miR-429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL-3'-untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR-429 contribute to development, progression and erythropoiesis of CML, miR-429-CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients.

Application Value of 68 Ga-FAPI PET/CT in the Evaluation of Myelofibrotic Diseases.

PURPOSE: Fibroblast activation protein is highly expressed in neoplastic lesions and various fibrotic tissues, making it an attractive target for disease evaluation. 68 Ga-labeled fibroblast activation protein inhibitor (FAPI), a new tumor interstitial imaging agent, holds promise for evaluating myelofibrosis. Therefore, this study aimed to use 68 Ga-FAPI PET/CT for the noninvasive visualization and quantification of the extent of myelofibrosis. PATIENTS AND METHODS: This was a prospective clinical study involving 22 patients with myelofibrosis who underwent 68 Ga-FAPI PET/CT. The uptake of 68 Ga-FAPI was measured in their respective bone marrow and spleen, and the obtained imaging findings were compared with laboratory, cytogenetic, and histopathological data. RESULTS: 68 Ga-FAPI uptake in the bone marrow was significantly and positively correlated with the myelofibrosis grade ( r > 0.8, P < 0.001). 68 Ga-FAPI PET/CT showed visually negative results in patients with grades 0-1 myelofibrosis and positive in those with grades 2-3, but the level of involvement varied. 68 Ga-FAPI PET/CT provides a noninvasive means of visualizing the extent of systemic bone marrow involvement and differentiation between the early and advanced stages of fibrosis. CONCLUSIONS: 68 Ga-FAPI PET/CT shows promise as a method for visualizing and quantifying myelofibrosis, providing suitable sites for bone marrow biopsy. The extent of 68 Ga-FAPI uptake by bone marrow increases with the progression of myelofibrosis, thus it is a simple and noninvasive measurement that can be used to evaluate the progression of myelofibrosis. Nevertheless, although 68 Ga-FAPI PET/CT has demonstrated a potential value in prognostic assessment, further confirmation is needed.

A pilot study of [68Ga]Ga-fibroblast activation protein inhibitor-04 PET/CT in renal cell carcinoma.

OBJECTIVES: As a promising positron emission tomography (PET) tracer, [68Ga]Ga-fibroblast activation protein inhibitor-04([68Ga]Ga-FAPI-04) performs better than 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) at diagnosing primary and metastatic lesions in patients with various types of cancer. We investigated the utility of [68Ga]Ga-FAPI-04 PET/CT for the detection of primary and metastatic lesions in renal cell carcinoma (RCC). [18F]FDG PET/CT were used for comparison. METHODS: Twenty-two patients with suspected RCC or recurrent RCC were enrolled in our study. Among these patients, 14 were newly diagnosed with RCC, 3 had recurrent RCC, and 5 were excluded from further analysis due to having benign renal tumours. Seventeen patients with RCC underwent [68Ga]Ga-FAPI-04 PET/CT, and 6 of them also received [18F]FDG PET/CT. The positive detection rates were calculated and compared with those in patients who underwent both scans. RESULTS: Data from 17 patients with RCC (median age: 60.5 years, interquartile range [IQR]: 54-70 years) were evaluated. The positive detection rate of [68Ga]Ga-FAPI-04 PET/CT for RCC was 64.7% (11/17). Lymph node metastases (n = 44), lung metastasis (n = 1), and bone metastasis (n = 1) were detected. Six patients with RCC underwent [68Ga]Ga-FAPI-04 and [18F]FDG PET/CT. [68Ga]Ga-FAPI-04 PET/CT showed a higher positive detection rate than [18F]FDG PET/CT in detecting RCC (83.3% [5/6] vs. 50% [3/6], P = 0.545). Additionally, [68Ga]Ga-FAPI-04 PET/CT has higher SUVmax (3.20 [IQR: 2.91-5.80 vs. 2.71 [IQR: 2.13-3.10], P = 0.116) and tumour-to-background ratio (TBR) values (1.60 [IQR: 1.33-3.67] vs. 0.86 [0.48-1.21], P = 0.028) than [18F]FDG PET/CT. CONCLUSIONS: These findings suggest that [68Ga]Ga-FAPI-04 PET/CT has potential value in RCC diagnosis. Further studies are warranted to validate these results. ADVANCES IN KNOWLEDGE: Clinical utility of [68Ga]Ga-FAPI-04 in RCC remains unclear, and there are not many similar studies in the literature. We evaluated the role of [68Ga]Ga-FAPI-04 in diagnosing RCC.

Evolutionary proteogenomic landscape from pre-invasive to invasive lung adenocarcinoma.

Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.

Development and validation of an online calculator to predict the pathological nature of colorectal tumors.

BACKGROUND: No single endoscopic feature can reliably predict the pathological nature of colorectal tumors (CRTs). AIM: To establish and validate a simple online calculator to predict the pathological nature of CRTs based on white-light endoscopy. METHODS: This was a single-center study. During the identification stage, 530 consecutive patients with CRTs were enrolled from January 2015 to December 2021 as the derivation group. Logistic regression analysis was performed. A novel online calculator to predict the pathological nature of CRTs based on white-light images was established and verified internally. During the validation stage, two series of 110 images obtained using white-light endoscopy were distributed to 10 endoscopists [five highly experienced endoscopists and five less experienced endoscopists (LEEs)] for external validation before and after systematic training. RESULTS: A total of 750 patients were included, with an average age of 63.6 ± 10.4 years. Early colorectal cancer (ECRC) was detected in 351 (46.8%) patients. Tumor size, left semicolon site, rectal site, acanthosis, depression and an uneven surface were independent risk factors for ECRC. The C-index of the ECRC calculator prediction model was 0.906 (P = 0.225, Hosmer-Lemeshow test). For the LEEs, significant improvement was made in the sensitivity, specificity and accuracy (57.6% vs 75.5%; 72.3% vs 82.4%; 64.2% vs 80.2%; P < 0.05), respectively, after training with the ECRC online calculator prediction model. CONCLUSION: A novel online calculator including tumor size, location, acanthosis, depression, and uneven surface can accurately predict the pathological nature of ECRC.

68 Ga-FAPI PET/CT Detection of Non-FDG-Avid Poorly Differentiated Adenocarcinoma of the Trachea.

ABSTRACT: Primary tracheal adenocarcinoma is relatively rare in clinical practice. We describe the 68 Ga-FAPI-04 and 18 F-FDG PET/CT findings of primary poorly differentiated tracheal adenocarcinoma in a 48-year-old woman. In the present case, the tumor showed increased 68 Ga-FAPI uptake but not significant 18 F-FDG activity.

Influence of Cirrhosis on 68Ga-FAPI PET/CT in Intrahepatic Tumors.

Background Gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) is of great diagnostic value for intrahepatic tumors. However, cirrhosis may lead to increased 68Ga-FAPI uptake in background liver, affecting the diagnostic ability of 68Ga-FAPI. Purpose To assess the effect of cirrhosis on liver parenchyma and intrahepatic tumor uptake of 68Ga-FAPI and to compare the ability of 68Ga-FAPI and fluorine 18 (18F)-labeled fluorodeoxyglucose (FDG) PET/CT to depict intrahepatic tumors in patients with cirrhosis. Materials and Methods In this secondary analysis of a prospective trial, patients who underwent both 68Ga-FAPI and 18F-FDG PET/CT and those who underwent only 68Ga-FAPI PET/CT between August 2020 and May 2022 were considered for inclusion in the cirrhotic or noncirrhotic group, respectively. Patients with cirrhosis were chosen via a comprehensive assessment of imaging and clinical data, and patients without cirrhosis were randomly selected. 68Ga-FAPI and 18F-FDG PET/CT data were measured by two radiologists. Between-groups and within-group data were tested with the Mann-Whitney U test and the Wilcoxon signed-rank test, respectively. Results A total of 39 patients with cirrhosis (median age, 58 years [IQR, 50-68]; 29 male; 24 intrahepatic tumors) and 48 patients without cirrhosis (median age, 59 years [IQR, 51-67]; 30 male; 23 intrahepatic tumors) were evaluated. In patients without intrahepatic tumors, the liver 68Ga-FAPI average standardized uptake value (SUVavg) was higher in the cirrhotic group than in the noncirrhotic group (median SUVavg, 1.42 [IQR, 0.55-2.85] vs 0.45 [IQR, 0.41-0.72]; P = .002). However, no difference was observed in the diagnosis of intrahepatic tumor sensitivity (98% vs 93%, respectively). When compared with 18F-FDG, the sensitivity of 68Ga-FAPI PET/CT in the detection of intrahepatic tumors in patients with cirrhosis (41% vs 98%, respectively) and maximum standardized uptake value of tumors (median SUVmax, 2.60 [IQR, 2.14-4.49] vs 6.68 [IQR, 4.65-10.08]; P < .001) were higher. Conclusion The sensitivity of 68Ga-FAPI in the diagnosis of intrahepatic tumors was not affected by cirrhosis, and diagnostic accuracy of 68Ga-FAPI was higher than that of 18F-FDG in patients with cirrhosis. © RSNA, 2023 Supplemental material is available for this article.

NONHSAT021545/miR-330-3p/EREG: A Cooperative Axis in Breast Cancer Prognosis and Treatment.

Lymphatic metastasis is the most common form in breast cancer (BC) progression. Previously, we observed that lnc045874, a most conservative homology of Homo Sapiens NONHSAT021545 (lnc021545), miR-330-3p, and EREG may have some effects in mouse hepatocarcinoma cell lines with different lymphatic metastasis potentials. Through data from TCGA and GEO database analysis, we speculated that miR-330-3p might be a tumor promoter, while EREG could be a tumor suppressor in BC. MiR-330-3p was upregulated, while lnc021545 and EREG were downregulated in 50 BC tissues. MiR-330-3p advanced the metastatic behaviors of BC cells, whereas lnc021545 and EREG resulted in the opposite effects. The three molecules' expressions were correlated respectively and showed that miR-330-3p targeted lnc021545 and EREG to affect their expressions. Lnc021545/miR-330-3p axis affected BC metastasis by regulating EREG in epithelial-to-mesenchymal transition. In 50 BC patients, these three molecules and their cooperation are associated with aggressive tumor phenotypes, patient outcomes, and trastuzumab therapy. We finally discovered that lnc021545, miR-330-3p, and EREG formed a multi-gene co-regulation system that affected the metastasis of BC and the cooperation reflects the synergistic effects of the three molecules, recommending that their cooperation may provide a more accurate index for anti-metastasis therapeutic and prognostic evaluation of BC.

Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes.

The subtypes of duodenal cancer (DC) are complicated and the carcinogenesis process is not well characterized. We present comprehensive characterization of 438 samples from 156 DC patients, covering 2 major and 5 rare subtypes. Proteogenomics reveals LYN amplification at the chromosome 8q gain functioned in the transmit from intraepithelial neoplasia phase to infiltration tumor phase via MAPK signaling, and illustrates the DST mutation improves mTOR signaling in the duodenal adenocarcinoma stage. Proteome-based analysis elucidates stage-specific molecular characterizations and carcinogenesis tracks, and defines the cancer-driving waves of the adenocarcinoma and Brunner's gland subtypes. The drug-targetable alanyl-tRNA synthetase (AARS1) in the high tumor mutation burden/immune infiltration is significantly enhanced in DC progression, and catalyzes the lysine-alanylation of poly-ADP-ribose polymerases (PARP1), which decreases the apoptosis of cancer cells, eventually promoting cell proliferation and tumorigenesis. We assess the proteogenomic landscape of early DC, and provide insights into the molecular features corresponding therapeutic targets.

Integrative proteogenomic characterization of early esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) is malignant while the carcinogenesis is still unclear. Here, we perform a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 ESCC patients, covering 9 histopathological stages and 3 phases. Proteogenomics elucidates cancer-driving waves in ESCC progression, and reveals the molecular characterization of alcohol drinking habit associated signatures. We discover chromosome 3q gain functions in the transmit from nontumor to intraepithelial neoplasia phases, and find TP53 mutation enhances DNA replication in intraepithelial neoplasia phase. The mutations of AKAP9 and MCAF1 upregulate glycolysis and Wnt signaling, respectively, in advanced-stage ESCC phase. Six major tracks related to different clinical features during ESCC progression are identified, which is validated by an independent cohort with another 256 samples. Hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) is considered as a drug target in ESCC progression. This study provides insight into the understanding of ESCC molecular mechanism and the development of therapeutic targets.

Dose-response association of total sedentary behaviour and television watching with risk of depression in adults: A systematic review and meta-analysis.

BACKGROUND: Although sedentary behaviour has been increasingly linked to depression, evidence remains conflicted and meta-analysis of the dose-response associations in adults is lacking. We aimed to explore the quantitative dose-response association of total sedentary behaviour and television watching with depression among adults. METHODS: We systematically searched PubMed, Embase and Web of Science for articles to identify observational studies that assessed the association of total sedentary behaviour and television watching with depression in adults. Summary risk ratios (RRs) and 95 % confidence intervals (CIs) were estimated for the dose-response association by using a fixed or random-effects model. Restricted cubic splines were used to evaluate the possible linear or non-linear relations. RESULTS: We included 16 studies with 221,599 participants in this meta-analysis, 10 for total sedentary behaviour and 6 for television watching. The summary RR of depression for the highest versus lowest total sedentary behaviour and television watching were 1.42 (95 % CI: 1.22-1.67) and 1.26 (95 % CI: 1.14-1.40), respectively. We found a non-linear association between total sedentary behaviour and depression. For participants with total sedentary time 8 h/day and 9 h/day, the risk of depression was increased by 20 % (RR 1.20, 95 % CI 1.09-1.29) and 29 % (RR 1.29, 95 % CI 1.20-1.40), respectively. A linear dose-response association was observed between television watching and depression. For each 1 h/day increase in television watching, risk of depression was increased by 5 % (RR: 1.05, 95 % CI: 1.02-1.09). CONCLUSIONS: Depression may be associated with increased time spent in total sedentary behaviour and television watching.

[68Ga]Ga-FAPI-04 PET/CT on assessing Crohn's disease intestinal lesions.

BACKGROUND: Fibrosis and inflammation are major pathological changes of Crohn's disease (CD). Early detection and accurate severity evaluation of CD are critical for patient's prognosis. Endoscopy is widely used to evaluate CD progression. Herein, we evaluated the efficacy of [68Ga]Ga-FAPI-04 PET/CT to identify lesions and assess the progression of CD. METHODS: All CD patients received computed tomography enterography (CTE), [68Ga]Ga-FAPI-04 PET/CT examination, and ileocolonoscopy within 1 week. Two independent gastroenterologists computed the Crohn's disease activity index (CDAI) of all patients. Two radiology physicians assessed the CTE images separately, and the CTE scores were calculated. Lastly, two nuclear medicine physicians independently examined the [68Ga]Ga-FAPI-04 PET/CT images. Once the FAPI uptake of the intestinal segment was equal or higher relative to the liver (considered FAPI-positive), the target-to-background ratio (TBR) and global FAPI PET/CT score were computed, representing the independent intestinal activity and activity of all intestinal segments, respectively. Levels of fecal calprotectin (FCP) and C-reactive protein (CRP) were determined before the endoscopy. The Crohn's disease endoscopy index of severity (CDEIS) and the simple endoscopic score for Crohn's disease (SES-CD) were calculated during the endoscopy. Finally, all data were obtained and analyzed. RESULTS: There were 74 intestinal segments in 16 patients were assessed. [68Ga]Ga-FAPI-04 PET/CT identified 42 of 45 endoscopically lesioned segments (endoscopic lesions detection sensitivity: 93.3%), while CTE identified 39 of them (endoscopic lesions detection sensitivity: 86.7%). According to the receiver operating characteristic (ROC) analysis, [68Ga]Ga-FAPI-04 PET/CT showed better performance in the detection of endoscopic lesions compared with CTE (P < 0.05). The TBR was significantly associated with the CTE score (r = 0.81; (95% CI): 0.736-0.869; P < 0.0001) and SES-CD values (r = 0.86; (95% CI): 0.776-0.908; P < 0.0001). In addition, the global FAPI PET/CT score was significantly correlated with FCP (r = 0.52; 95% CI, 0.02-0.81; P = 0.039), CRP (r = 0.60; 95% CI, 0.13-0.85; P = 0.014), CDEIS (r = 0.55; 95% CI, 0.06-0.83; P = 0.028), and CDAI (r = 0.81; 95% CI, 0.50-0.93; P < 0.0001). CONCLUSION: In summary, [68Ga]Ga-FAPI-04 PET/CT correlated well with endoscopic, CTE, clinical, and biomarkers of CD. It was also highly sensitive in the detection of different classes of lesions in all intestinal segments, and unlike other examinations, this technique required no patient fasting or bowel preparation. Therefore, [68Ga]Ga-FAPI-04 PET/CT may be a promising method for assessing the activity of CD.

Surveillance Colonoscopies of Synchronous Colorectal Cancer: What Should We Do?

BACKGROUND: The aim of this study is to investigate the occurrence of metachronous neoplasms at 2-year surveillance colonoscopy for synchronous colorectal cancer patients and the relative risk factors. METHODS: Synchronous colorectal cancer patients who underwent surgery or endoscopic resection for colorectal cancer between January 2008 and December 2019 were enrolled. All patients underwent surveillance colonoscopies at least twice within 2 years after operation. Univariate and multivariate analyses were conducted to assess the risk factors for the metachronous neoplasms. RESULTS: Totally 38 patients (male/female: 26/12) were included, with an average age of 64.6 years (±11.5 years) and a mean surveillance interval of 23.47 ± 4.39 months. In 21 of 38 patients (55.3%), metachronous adenoma was detected, including 6 metachronous advanced adenomas. Two patients were detected with metachronous carcinomas. In univariate analysis, male sex, elderly age at diagnosis, and the presence of synchronous adenomas/synchronous advanced adenoma at baseline colonoscopy were associated with the development of metachronous adenoma (P = .037, .047, .013, .039), but not associated with metachronous advanced adenoma (P = 0.455, .746, .503, .269). Patients tends to occur less metachronous advanced adenoma if index colorectal tumors were treated by endoscopic resection (P = .010), but the tendency was not discovered in metachronous adenoma (P = .289). Tumor location (with/ without rectum cancer) was not associated with the development of metachronous lesions (P = .526, .382). On multivariate analysis, the presence of synchronous adenomas at baseline colonoscopy was an independent risk factor for MA during follow-up (odds ratio = 15.0; 95% CI: 1.55-145.22). CONCLUSION: For postoperative synchronous colorectal cancer patients, doctors should design individual surveillance strategies according to sex, baseline colonoscopy, and operative (or endoscopic) approach of resection.

68Ga-FAPI PET/CT in a Patient With Statin-Induced Rhabdomyolysis.

ABSTRACT: Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of muscle cell contents into blood circulation. There is ample clinical evidence that it is one of the adverse effects of statins. 68Ga-FAPI PET/CT was performed on a 78-year-old man with newly diagnosed with mediastinal tumor and statin-induced rhabdomyolysis. 68Ga-FAPI PET/CT showed symmetrical and diffuse increased FAPI uptake in whole-body muscles. Our case indicated that 68Ga-FAPI PET/CT might be valuable in the evaluation of patients with rhabdomyolysis.

The Superiority of 68 Ga-FAPI-04 over 18F-FDG in a Case of Gallbladder Cancer.

A 56-year-old man presented with vague upper abdominal pain for more than 4 months. His abdominal ultrasound and MRI showed thickening of the neck and base of the gallbladder and nodule formation at the base of the gallbladder. 18F-FDG PET/CT revealed intense FDG uptake in the base of the gallbladder and multiple lymph nodes. 68 Ga-FAPI-04 PET/CT not only showed intense FAPI uptake in the above mentioned FDG-avid lesions but also showed intense FAPI uptake in the neck lesion of the gallbladder and some other additional lymph nodes. Finally, histopathological examination confirmed poorly differentiated tubular adenocarcinoma of the neck and base of the gallbladder. Our case illustrated that 68 Ga-FAPI-04 PET/CT may outperform 18F-FDG PET/CT in the detection of gallbladder cancer primary and metastatic lesions.

Integrated analysis of probability of type 2 diabetes mellitus with polymorphisms and methylation of SLC30A8 gene: a nested case-control study.

To estimate the associations between single-nucleotide polymorphisms (SNPs) and methylation of SLC30A8 gene and T2DM risk, and the interactions among SNPs, methylation, and environmental factors on T2DM risk. We genotyped 9 SNPs and tested methylation at 46 CpG loci of SLC30A8 in the baseline DNA of 290 T2DM cases and 290 matched controls nested in the Rural Chinese Cohort Study. A conditional logistic regression model was used to estimate the associations between SNPs and SLC30A8 methylation and T2DM risk. Multifactor Dimensionality Reduction analysis was used to estimate the effect of interactions among SNPs, methylation, and environment on T2DM risk. Probability of T2DM was decreased with rs11558471 (GG vs. AA, OR = 0.55, 95% CI 0.32, 0.96), with rs13266634 (TT vs. CC, OR = 0.55, 95% CI 0.32, 0.94), with rs3802177 (AA vs. GG, OR = 0.54, 95%CI 0.31, 0.94), and its probability was increased with rs2466293 of SLC30A8 (GA vs. AA, OR = 1.63, 95% CI 1.08-2.47). Its probability was also significantly associated with methylation of CG9 and CG45 (OR = 0.56 [95% CI 0.33-0.97] and 1.61 [95%CI 1.03--2.51]). T2DM probability was significantly associated with the interaction effect between rs2466293 and hypertension (p = 0.045). T2DM probability was also significantly associated with the combination effects of rs2466293 with BMI, hypertension, and hypertriglyceridemia, with the combination effects of hypertriglyceridemia with rs11558471, rs13266634, and methylation of CG45.

The homeostatic malfunction of a novel feedback pathway formed by lncRNA021545, miR-330-3p and epiregulin contributes in hepatocarcinoma progression via mediating epithelial-mesenchymal transition.

A better understanding of tumor metastasis is urgently required for the treatment and prognosis of hepatocarcinoma patients. Current work contributes a novel ceRNA feedback regulation pathway composed of epiregulin (EREG), microRNA-330-3p (miR-330-3p) and long non-coding RNA 021545 (lncRNA021545) in regulating hepatocarcinoma malignancy via epithelial-mesenchymal transition (EMT) process. Closely correlated, the deficiencies of EREG and lncRNA021545 and the overexpression of miR-330-3p were involved in the clinical progression of hepatocarcinoma. In vitro results showed that 1) lncRNA021545 downregulation promoted, 2) miR-330-3p dysexpression positively correlated, and 3) EREG dysexpression reversely correlated with the migratory and invasive properties of hepatocarcinoma HCCLM3 and Huh7 cell lines. By directly binding to EREG and lncRNA021545, miR-330-3p expression change reversely correlated with their expressions in HCCLM3 and Huh7 cells, which was also confirmed in primary tumors from HCCLM3-xenograft mice in responding to miR-330-3p change. LncRNA021545 and EREG positively regulated each other, and lncRNA021545 negatively regulated miR-330-3p, while, EREG dysregulation unchanged miR-330-3p expression in hepatocarcinoma cells. Furthermore, systemic in vitro cellular characterizations showed that the malfunctions of the three molecules mediated the invasiveness of hepatocarcinoma cells via EMT process through affecting the expressions of E-cadherin, N-cadherin, vimentin, snail and slug, which was further confirmed by in vivo miR-330-3p promotion on the tumorigenicity and metastasis of HCCLM3 bearing nude mice and by in vitro miR-330-3p promotion on the migration and invasion of hepatocarcinoma cells to be antagonized by EREG overexpression through acting on EMT process. Our work indicates, that by forming a circuit signaling feedback pathway, the homeostatic expressions of lncRNA021545, miR-330-3p and EREG are important in liver health. Its collapse resulted from the downregulations of lncRNA021545 and EREG together with miR-330-3p overexpression promote hepatocarcinoma progression by enhancing the invasiveness of tumor cells through EMT activation. These discoveries suggest that miR-330-3p/lncRNA021545/EREG axis plays a critical role in hepatocarcinoma progression and as a candidate for its treatment.