An Erythrocyte Membrane-Derived Nanosystem for Efficient Reversal of Endothelial Injury in Sepsis.

Sepsis is caused by a disordered host immune in response to infection and endothelial cells perform a crucial role in boosting immunity reaction in the pathophysiology of sepsis and septic organ failure. The aim of this study is to construct a novel erythrocyte membrane-derived nanosystems to reverse endothelial damage in sepsis. Herein, an innovative nanometer calcium metal-organic framework (Ca-MOF) is generated for the first time by using chelidonic acid as a ligand and calcium chloride as an ion donor for anti-inflammation. Then, zoliflodacin is loaded into Ca-MOF (CMZ) to sterilize and nanoscale erythrocyte membrane vesicles are prepared by modification with a γ3 peptide on the surface (γ3-RM) for precise targeting. Finally, γ3-RM camouflages the nanocore CMZ, to form novel erythrocyte membrane-camouflaged nanoparticle γ3-RCMZ. The superior performance of novel nanosystem results from its suitable biocompatibility, nontoxicity, specific targeting, and anti-inflammatory and bactericidal effects. Its anti-inflammatory mechanism mainly involves inhibiting the Caspase1-nuclear factor kappa-B (Caspase1-NF-κB) pathway and oxidative stress reduction to alleviate endothelial damage. Moreover, the findings have revealed for the first time that the bactericidal drug zoliflodacin also has anti-inflammatory effects in vivo and in vitro. Therefore, the novel nanosystem (γ3-RCMZ) provides a new nanotherapy strategy for sepsis treatment.

Weekly versus triweekly cisplatin treatment in patients with locally advanced nasopharyngeal cancer during concurrent chemoradiotherapy.

BACKGROUND: For patients with locally advanced nasopharyngeal cancer (LA-NPC), concurrent chemoradiotherapy (CCRT) is the standardized treatment. However, whether a weekly or triweekly cisplatin regimen should be used during CCRT is controversial. Therefore, we conducted this meta-analysis to explore differences in the effects and toxicities of the two regimens. METHODS: We searched PubMed, Embase, and the Cochrane Library (until June 10, 2022). We evaluated overall survival (OS), distant metastasis-free survival (DMFS), locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and grade ≥ 3 adverse events. The effect indices were hazard ratios (HRs) and odds ratios (ORs), and Review Manager software 5.4 (RevMan 5.4) was used for computations. RESULTS: We identified 7 studies in our analysis. There was no significant difference in OS (HR = 1.00, 95% CI 0.73-1.38, P = 0.99), DMFS (HR = 0.84, 95% CI 0.58-1.22, P = 0.36), LRFS (HR = 0.91, 95% CI 0.63-1.32, P = 0.62) or DFS (HR = 0.93, 95% CI 0.56-1.56; P = 0.78) between the weekly and triweekly cisplatin regimens. We found that the weekly cisplatin regimen was more likely to cause grade ≥ 3 hematological toxicity events than the triweekly cisplatin regimen. In addition, subgroup analyses revealed that patients undergoing CCRT and CCRT plus adjuvant chemotherapy (AC) had similar OS or DFS. CONCLUSION: Weekly and triweekly cisplatin regimens had similar efficacy for LA-NPC. The triweekly regimen may replace the weekly regimen for LA-NPC because of lower toxicity. Larger data accumulation and more multicenter clinical trials may be needed to verify these results.

Refractory diarrhea in a patient with Sjogren's syndrome: A case report.

We present the case of a 66-year-old man with no abdominal symptoms other than chronic refractory diarrhea. Other causes for diarrhea were excluded. The positive results of anti-SSA antibodies, Schirmer's test, and the biopsy of minor salivary glands confirmed the diagnosis of Sjogren's syndrome. Moreover, during the course of treatment, the patient developed refeeding syndrome. His diarrhea and nutrition resolved with initiation of glucocorticoids. This case highlights that chronic refractory diarrhea can be the chief complaint and most severe symptom in patients with Sjogren's syndrome.

Machine learning models to predict in-hospital mortality in septic patients with diabetes.

Background: Sepsis is a leading cause of morbidity and mortality in hospitalized patients. Up to now, there are no well-established longitudinal networks from molecular mechanisms to clinical phenotypes in sepsis. Adding to the problem, about one of the five patients presented with diabetes. For this subgroup, management is difficult, and prognosis is difficult to evaluate. Methods: From the three databases, a total of 7,001 patients were enrolled on the basis of sepsis-3 standard and diabetes diagnosis. Input variable selection is based on the result of correlation analysis in a handpicking way, and 53 variables were left. A total of 5,727 records were collected from Medical Information Mart for Intensive Care database and randomly split into a training set and an internal validation set at a ratio of 7:3. Then, logistic regression with lasso regularization, Bayes logistic regression, decision tree, random forest, and XGBoost were conducted to build the predictive model by using training set. Then, the models were tested by the internal validation set. The data from eICU Collaborative Research Database (n = 815) and dtChina critical care database (n = 459) were used to test the model performance as the external validation set. Results: In the internal validation set, the accuracy values of logistic regression with lasso regularization, Bayes logistic regression, decision tree, random forest, and XGBoost were 0.878, 0.883, 0.865, 0.883, and 0.882, respectively. Likewise, in the external validation set 1, lasso regularization = 0.879, Bayes logistic regression = 0.877, decision tree = 0.865, random forest = 0.886, and XGBoost = 0.875. In the external validation set 2, lasso regularization = 0.715, Bayes logistic regression = 0.745, decision tree = 0.763, random forest = 0.760, and XGBoost = 0.699. Conclusion: The top three models for internal validation set were Bayes logistic regression, random forest, and XGBoost, whereas the top three models for external validation set 1 were random forest, logistic regression, and Bayes logistic regression. In addition, the top three models for the external validation set 2 were decision tree, random forest, and Bayes logistic regression. Random forest model performed well with the training and three validation sets. The most important features are age, albumin, and lactate.

Effects of the COVID-19 pandemic on elderly patients with head and neck squamous cell carcinoma.

Background: The 2019 novel coronavirus disease (COVID-19) strongly affects health care activities in countries around the world. The diagnosis and treatment of cancer have also been involved, and elderly head and neck squamous carcinoma is one of them. This study aimed to assess the impact of COVID-19 on elderly patients with head and neck squamous cell carcinoma (HNSCC) in our center. Methods: This retrospective study analyzed the clinical characteristics of 400 HNSCC patients over 65 years of age, calculated their treatment interruption rates, and compared the time of delayed diagnosis. Results: The rate of elderly patients with HNSCC with a delayed diagnosis was higher in the "during COVID-19 pandemic" group (DCOV19 group) than in the "during COVID-19 pandemic" group (BCOV19 group), and the difference was statistically significant (p=0.0017). There was a substantial difference in the rate of treatment interruption between the two groups (p=0.002). Conclusions: This is the first study to explore the effect of the COVID-19 pandemic on visits and treatment interruptions in elderly patients with HNSCC. The current impact of the COVID-19 pandemic on HNSCC treatment has resulted in reductions and delays in diagnosing cancer and providing treatment.

A Nomogram to Better Predict the In-Hospital Mortality of Trauma Patients with Sepsis in the Intensive Care Unit.

Background: Trauma has a high incidence and mortality worldwide, and sepsis is one of the main causes of mortality in trauma patients. Therefore, it is essential to identify the risk factors of in-hospital mortality for trauma patients with sepsis. Methods: Data were extracted from the Medical Information Mart for Intensive Care III database and divided into a training set and internal validation set, and another Chinese dataset was used as external validation set. Then, risk factors were estimated using univariate and multivariate logistic regression analyses in the training set. Finally, a nomogram was created to predict the probability of in-hospital mortality for trauma patients with sepsis. Results: A total of 503 patients were enrolled in our study (335 in the training set and 168 in the validation set). Multivariate logistic regression analysis revealed that age (1.047 [1.025-1.071]), respiratory rate (1.258 [1.135-1.394]), PTT (1.026 [1.008-1.044]), ventilation (6.703 [1.528-29.408]), and vasopressor use (3.682 [1.502-9.025]) were independent factors associated with in-hospital mortality. The nomogram for trauma-related sepsis predicted in-hospital mortality with AUC values of 0.8939 in the training set, 0.8200 in the internal validation set, and 0.7779 in the external validation set. Conclusions: The new nomogram has a well predicted value for in-hospital mortality for patients with trauma and sepsis in intensive care units.

A nomogram to predict in-hospital mortality for post-gastrointestinal resection surgery patients in intensive care units: A retrospective cohort study.

BACKGROUND: The global volume of gastrointestinal surgery has increased steadily. However, there is still a lack of studies focused on the risk factors for post-gastrointestinal resection surgery patients in the intensive care units. METHODS: Post gastrointestinal resection surgery patient data were collected from the Medical Information Mart for Intensive Care (MIMIC-III) database and divided into training set and validation set, then analyzed by Univariate and multiple logistic regression. RESULTS: 795 patients were finally enrolled in our cohort. Multiple logistic regression showed that age (1.029 [1.006-1.053]), temperature (0.337 [0.207-0.547]), respiratory rate (1.133 [1.053-1.218]), mean arterial pressure (1.204 [1.039-1.396]), lactate (1.288 [1.112-1.493]), BUN (1.025 [1.010-1.040]) and vasopressor use (4.777 [2.499-9.130]) were independent factors associated with in-hospital mortality. Our new predicted nomogram achieved a better accuracy than SOFA score, SAPS-Ⅱ score, APACHE-Ⅲ score, and Elixhauser score. CONCLUSION: Our nomogram model could well predict in-hospital mortality for post-GI resection surgery patients receiving intensive care.

A nanodrug system overexpressed circRNA_0001805 alleviates nonalcoholic fatty liver disease via miR-106a-5p/miR-320a and ABCA1/CPT1 axis.

Our study aimed to explore the function of circRNA_0001805 in the pathogenesis of NAFLD and the underlying mechanism. A nanodrug system (GA-RM/GZ/PL) was constructed to overexpress circRNA_0001805 specifically in hepatocytes for the treatment of NAFLD. Fat droplet accumulation in cultured cells and mouse hepatic tissues was detected using Oil Red O or H&E staining. The relative expression of circRNAs, genes associated with lipogenesis was quantified by qRT-PCR. Interactions between circRNA_0001805 and miR-106a-5p/miR-320a, between miR-106a-5p/miR-320a and ABCA1/CPT1 were confirmed by dual-luciferase reporter assay. A novel metalorganic framework nanocarrier (GZ) was prepared from glycyrrhizic acid and zinc ions (Zn2+), and this nanocarrier was loaded with the circRNA_0001805 plasmid to construct a nanocore (GZ/PL). Then, this GZ/PL was coated with a galactose-modified RBC membrane (GA-RM) to generate GA-RM/GZ/PL. CircRNA_0001805 expression was downregulated in FFA-challenged primary hepatocytes, HFD-fed mice and NAFLD patients. Overexpressed circRNA_0001805 attenuated NAFLD development by suppressing lipid metabolism disorder and inflammation. CircRNA_0001805 targeted miR-106a-5p/miR-320a, which served as an upstream inhibitor of ABCA1/CPT1 and collaboratively regulated NAFLD progression. GA-RM/GZ/PL targeted hepatocytes, overexpressed circRNA_0001805, released glycyrrhizic acid to reduce the accumulation of lipids in the liver and played a synergistic role against NAFLD-induced lipid metabolism disorder.

Identification of a Ferroptosis Gene Set That Mediates the Prognosis of Squamous Cell Carcinoma of the Head and Neck.

Squamous cell carcinoma of the head and neck (HNSCC) is one of the six most common malignancies. HNSCC has both a high incidence and poor prognosis, and its prognostic factors remain unclear. Ferroptosis is a newly discovered form of programmed cell death that is iron-dependent. Increasing evidence indicates that targeting ferroptosis may present a new form of anti-tumor treatment. However, the prognostic value of ferroptosis-related genes (FRGs) in HNSCC is unclear. This study was designed to identify molecular markers associated with ferroptosis that influence prognosis in patients with HNSCC. We used HNSCC tumor and normal data from The Cancer Genome Atlas (TCGA) to identify prognosis-related FRGs. An FRG-based prognostic risk score was constructed, and its prognostic value for patients with HNSCC was evaluated using receiver operating characteristic curve (ROC) and nomogram analyses. The model was validated using the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis in patients with HNSCC revealed 11 FRGs that were significantly associated with overall survival (OS). We constructed a ferroptosis risk score model based on five genes and divided the patients into different risk groups based on its median value. Kaplan-Meier curve analysis showed that patients with a higher ferroptosis risk score had shorter OS (TCGA training set: P < 0.001, TCGA validation set: P < 0.05,GEO validation set: P < 0.001), and Gene Expression Profiling Interactive Analysis (GEPIA) further verified the relationships between these five genes and prognosis in patients with HNSCC. Multivariate Cox regression analysis showed that the risk score remained an independent predictor of OS after the exclusion of clinical confounders (HR > 1, P < 0.01). Significant differences in gene function enrichment analysis and immune cell infiltration status were identified between the two groups. The prognostic model can be used to predict the prognosis of patients with HNSCC. Moreover, the five FRGs may affect ferroptosis in HNSCC and thereby represent potential treatment targets. These results provide new directions for HNSCC treatment.

Abnormal m6A modification in non-alcoholic fatty liver disease. / éžé ’ç²¾æ€§è„‚è‚ªæ€§è‚ç— çš„å¼‚å¸¸m6A修饰.

OBJECTIVES: Non-alcoholic fatty liver disease has seriously affected people's health. Recent studies have found that N6-methyladenosine (m6A) methylation is involved in the lipid metabolism process of the body, but the study on the level of m6A modification in NAFLD is still not available. This study aims to explore the changes in the level of RNA m6A methylation modification in NAFLD liver tissues, and to provide experimental and theoretical basis for in-depth study on the role of RNA m6A methylation in the occurrence and development of NAFLD. METHODS: Changes in the m6A level in NAFLD liver tissues were measured by liquid chromatography-mass spectrometry (LC-MS). Total RNA was extracted from liver tissues of NAFLD patients or normal control individuals and subjected to methylated RNA immunoprecipitation (MeRIP) with microarray analysis (including 44 122 mRNAs and 12 496 lncRNAs) to determine the changes in m6A modification levels across the entire transcriptome. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to annotate the differentially modified mRNAs. Finally, 4 mRNAs and 4 lncRNAs were randomly selected to verify the microarray results by MeRIP and real-time transcription polymerase chain reaction. RESULTS: A total of 176 mRNAs and 44 lncRNAs were found to be differentially m6A-modified in the NAFLD group compared with the control group. Among them, 15 mRNAs and 7 lncRNAs were hypermethylated in NAFLD, while 161 mRNAs and 37 lncRNAs were hypomethylated in NAFLD. GO and pathway analysis showed that the differentially modified mRNAs were enriched mainly in biological processes such as carboxylic acid metabolism and transcriptional regulation. CONCLUSIONS: The m6A modification profile is changed in NAFLD liver tissues compared with normal liver tissues, which may functionally impact the pathophysiological progress in NAFLD.

Identification and validation of an immune-related prognostic signature and key gene in papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. The effect of traditional anti-tumor therapy is not ideal for the patients with recurrence, metastasis and radioiodine resistance. The abnormal expression of immune-related genes (IRGs) has critical roles in the etiology of PTC. However, the effect of IRGs on PTC prognosis remains unclear. METHODS: Based on The Cancer Genome Atlas (TCGA) and ImmPort databases, we integrated IRG expression profiles and progression-free intervals (PFIs) of PTC patients. First, we identified the differentially expressed IRGs and transcription factors (TFs) in PTC. Subsequently, an IRG model that can predict the PFI was constructed by using univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses of the differentially expressed IRGs in the TCGA. Additionally, a protein-protein interaction (PPI) network showed the interactions between the differentially expressed genes (DEGs), and the top 30 genes with the highest degree were extracted from the network. Then, the key IRG was identified by the intersection analysis of the PPI network and univariate Cox regression, which was verified the differential expression of by western blotting and immunohistochemistry (IHC). ssGSEA was performed to understand the correlation between the key IRG expression level and immune activity. RESULTS: A total of 355 differentially expressed IRGs and 43 differentially expressed TFs were identified in PTC patients. Then, eight IRGs were finally utilized to construct an IRG model. The respective areas under the curve (AUCs) of the IRG model reached 0.948, 0.820, and 0.831 at 1, 3 and 5 years in the training set. In addition, lactotransferrin (LTF) was determined as the key IRG related to prognosis. The expression level of LTF in tumor tissues was significantly lower than that in normal tissues. And the results of ssGSEA showed the expression level of LTF is closely related to immune activity. CONCLUSIONS: These findings show that the prognostic model and key IRG may become promising molecular markers for the prognosis of PTC patients.

Identification of Genes Related to Immune Infiltration in the Tumor Microenvironment of Cutaneous Melanoma.

Cutaneous melanoma (CM) is the leading cause of skin cancer deaths and is typically diagnosed at an advanced stage, resulting in a poor prognosis. The tumor microenvironment (TME) plays a significant role in tumorigenesis and CM progression, but the dynamic regulation of immune and stromal components is not yet fully understood. In the present study, we quantified the ratio between immune and stromal components and the proportion of tumor-infiltrating immune cells (TICs), based on the ESTIMATE and CIBERSORT computational methods, in 471 cases of skin CM (SKCM) obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were analyzed by univariate Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis to identify prognosis-related genes. The developed prognosis model contains ten genes, which are all vital for patient prognosis. The areas under the curve (AUC) values for the developed prognostic model at 1, 3, 5, and 10 years were 0.832, 0.831, 0.880, and 0.857 in the training dataset, respectively. The GSE54467 dataset was used as a validation set to determine the predictive ability of the prognostic signature. Protein-protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were used to verify "real" hub genes closely related to the TME. These hub genes were verified for differential expression by immunohistochemistry (IHC) analyses. In conclusion, this study might provide potential diagnostic and prognostic biomarkers for CM.

[Corrigendum] FNDC3B promotes epithelial­mesenchymal transition in tongue squamous cell carcinoma cells in a hypoxic microenvironment.

After the publication of the article, and also the publication of a Corrigendum (see doi: 10.3892/or.2020.7744), there are further errors in the published paper that the authors wish to correct in a subsequent corrigendum. In the printed version of Fig. 5, the "NC" images were mistakenly presented in the data panels showing the results of the TCA8113 and TSCCA invasion assay experiments. Furthermore, in Fig. 4A and 6A, the ß­actin control bands were erroneously selected for these figures. The corrected versions of Figs. 4, 5 and 6 are shown opposite and on the next page, incorporating the correct data for Figs. 4A, 5 and 6A. These further corrections do not affect the results and conclusions of this work. The authors all agree to this Corrigendum, and are grateful to the Editor of Oncology Reports for allowing them to have the opportunity to correct these additional errors. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [the original article was published in Oncology Reports 39: 1853­1859, 2018; DOI: 10.3892/or.2018.6231].

Identification of an immune-related signature indicating the dedifferentiation of thyroid cells.

BACKGROUND: Immune cells account for a large proportion of the tumour microenvironment in anaplastic thyroid carcinomas (ATCs). However, the expression pattern of immune-related genes (IRGs) in ATCs is unclear. Our study aimed to identify an immune-related signature indicating the dedifferentiation of thyroid cells. METHODS: We compared the differences in thyroid differentiation score (TDS), infiltration of immune cells and enriched pathways between ATCs and papillary thyroid carcinomas (PTCs) or normal thyroid tissues in the Gene Expression Omnibus database. Univariate and multivariable Cox analyses were used to screen prognosis-associated IRGs in The Cancer Genome Atlas database. After constructing a risk score, we investigated its predictive value for differentiation and survival by applying receiver operating characteristic and Kaplan-Meier curves. We further explored its associations with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy. RESULTS: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower TDS values and higher enrichment of immune cells and activation of the inflammatory response. The quantitative analyses and immunohistochemical staining validated that most ATC cell lines and ATC tissues had higher expression of MMP9 and lower expression of SDC2 than normal thyroid samples and PTC. Higher risk scores indicates dedifferentiation and a worse prognosis. Additionally, the risk score was positively correlated with the immune checkpoint molecules PDL1, CTLA4, IDO1, and HAVCR2 and infiltration of multiple immune cells. Importantly, we found that the samples with higher risk scores tended to have a better response to immunotherapy than those with lower scores. CONCLUSION: Our findings indicate that the risk score may not only contribute to the determination of differentiation and prognosis of thyroid carcinomas but also help the prediction of immune cells infiltration and immunotherapy response.

Elevation of plasma tRNA fragments as a promising biomarker for liver fibrosis in nonalcoholic fatty liver disease.

Fibrotic tissue remodelling in nonalcoholic fatty liver disease (NAFLD) will probably emerge as the leading cause of end-stage liver disease in the coming decades, but the ability to diagnose liver fibrosis in NAFLD patients noninvasively is limited. The abnormal expression of tRNA-derived small RNA (tsRNA) in plasma provides a novel idea for noninvasive diagnosis of various diseases, however, the relationship between tsRNAs and NAFLD is still unknown. Here, we took advantage of small RNA-Seq technology to profile tsRNAs in NAFLD patients and found the ubiquitous presence of hepatic tsRNAs secreted into circulating blood. Verification in a cohort of 114 patients with NAFLD and 42 patients without NAFLD revealed that three tsRNAs (tRF-Val-CAC-005, tiRNA-His-GTG-001, and tRF-Ala-CGC-006) were significantly elevated in the plasma of NAFLD patients, and the expression level are associated with NAFLD activity score (calculated from 0 to 8) and fibrosis stage (scored from 0 to 4). In mouse models, we further found that increased plasma levels of these three tsRNAs were positively correlated with the degree of liver fibrosis. Our study potentially identifies a new class of NAFLD biomarkers and reveal the possible existence of tsRNAs in the blood that can be used to predict fibrogenesis risk in patients diagnosed with NAFLD.

[Corrigendum] FNDC3B promotes epithelial-mesenchymal transition in tongue squamous cell carcinoma cells in a hypoxic microenvironment.

During the preparation of the above article, the authors inadvertently selected an incorrect pair of data panels for Fig. 5B. Essentially, in the published version of Fig. 5B, the images were presented incorrectly for the NC migration and KD#3 migration and invasion data panels associated with the TSCCA cell Transwell assay experiments. Furthermore, in Fig. 7A, the GAPDH control bands were erroneously selected for the figure. Figs. 5 and 7 as they should have appeared in the Journal are shown opposite, incorporating the correct data for Figs. 5B and 7A. These errors did not affect either the results or the conclusions of this work. The authors all agree to this Corrigendum, and thank the Editor of Oncology Reports for allowing them to have the opportunity to present their corrected data. Furthermore, the authors apologize to the readership for any inconvenience these errors may have caused. [the original article was published in Oncology Reports 39: 1853­1859, 2018; DOI: 10.3892/or.2018.6231].

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.

Genetic analysis for germline mutations of RET proto-oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next-generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch-wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87-year-old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P < .05). In conclusion, the V292M RET variant could be classified as 'likely benign' according to ACMG (2015). The compound variant V292M/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.

Long noncoding RNA CCAT1 inhibits miR-613 to promote nonalcoholic fatty liver disease via increasing LXRα transcription.

Nonalcoholic fatty liver disease (NAFLD) is regarded as a threat to public health; however, the pathologic mechanism of NAFLD is not fully understood. We attempted to identify abnormally expressed long noncoding RNA (lncRNAs) and messenger RNA that may affect the occurrence and development of NAFLD in this study. The expression of differentially expressed lncRNAs in NAFLD was determined in oleic acid (OA)-treated L02 cells, and the functions of CCAT1 in lipid droplet formation were evaluated in vitro. Differentially expressed genes (DEGs) were analyzed by microarray analysis, and DEGs related to CCTA1 were selected and verified by weighted correlation network analysis. The dynamic effects of LXRα and CCTA1 on lipid droplet formation and predicted binding was examined. The binding between miR-631 and CCAT1 and LXRα was verified. The dynamic effects of miR-613 inhibition and CCTA1 silencing on lipid droplet formation were examined. The expression and correlations of miR-631, CCAT1, and LXRα were determined in tissue samples. As the results show, CCAT1 was induced by OA and upregulated in NAFLD clinical samples. CCAT1 silencing significantly suppressed lipid droplet accumulation in vitro. LXRα was positively correlated with CCAT1. By inhibiting miR-613, CCAT1 increased the transcription of LXRα and promoted LXRα expression. The expression of LXRα was significantly increased in NAFLD tissues and was positively correlated with CCAT1. In conclusion, CCAT1 increases LXRα transcription by serving as a competing endogenous RNA for miR-613 in an LXRE-dependent manner, thereby promoting lipid droplet formation and NAFLD. CCAT1 and LXRα might be potent targets for NAFLD treatment.

Comprehensive immunogenomic landscape analysis of prognosis-related genes in head and neck cancer.

Head and neck cancer is the sixth most common malignancy around the world, and 90% of cases are squamous cell carcinomas. In this study, we performed a systematic investigation of the immunogenomic landscape to identify prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC). We analyzed the expression profiles of immune-related genes (IRGs) and clinical characteristics by interrogating RNA-seq data from 527 HNSCC patients in the cancer genome atlas (TCGA) dataset, including 41 HPV+ and 486 HPV- samples. We found that differentially expressed immune genes were closely associated with patient prognosis in HNSCC by comparing the differences in gene expression between cancer and normal samples and performing survival analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the biological functions of the differentially expressed immunogenomic prognosis-related genes. Two additional cohorts from the Oncomine database were used for validation. 65, 56 differentially expressed IRGs was associated with clinical prognosis in total and HPV- samples, respectively. Furthermore, we extracted 10, 11 prognosis-related IRGs from 65, 56 differentially expressed IRGs, respectively. They were significantly correlated with clinical prognosis and used to construct the prognosis prediction models. The multivariable ROC curves (specifically, the AUC) were used to measure the accuracy of the prognostic models. These genes were mainly enriched in several gene ontology (GO) terms related to immunocyte migration and receptor and ligand activity. KEGG pathway analysis revealed enrichment of pathways related to cytokine-cytokine receptor interactions, which are primarily involved in biological processes. In addition, we identified 63 differentially expressed transcription factors (TFs) from 4784 differentially expressed genes, and 16 edges involving 18 nodes were formed in the regulatory network between differentially expressed TFs and the high-risk survival-associated IRGs. B cell and CD4 T cell infiltration levels were significantly negatively correlated with the expression of prognosis-related immune genes regardless of HPV status. In conclusion, this comprehensive analysis identified the prognostic IRGs as potential biomarkers, and the model generated in this study may enable an accurate prediction of survival.

Transcriptome analysis reveals the link between lncRNA-mRNA co-expression network and tumor immune microenvironment and overall survival in head and neck squamous cell carcinoma.

BACKGROUND: As the sixth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) develops visceral metastases during the advanced stage of the disease and exhibits a low five-year survival rate. The importance of tumor microenvironment (TME) in tumor initiation and metastasis is widely recognized. In addition, accumulating evidence indicates that long non-coding RNA (lncRNA) is involved in crosstalk between TME and tumor cells. However, the lncRNA-associated regulators modulating the HNSCC microenvironment and progression remain largely unknown. METHODS: The publicly available transcriptome data and matched clinical HNSCC data were collected from The Cancer Genome Atlas (TCGA). Immune scores (ISs) and stromal scores (SSs) of HNSCC TME were calculated using ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) was conducted to determine the co-expressed lncRNAs and protein-coding mRNAs. RESULTS: Results showed that the high IS HNSCC male patient subgroup exhibited improved survival. Additionally, we identified 169 lncRNAs and 825 protein-coding mRNAs that were differentially expressed in high IS HNSCC samples, with the up-regulated mRNAs displaying enrichment in immune-related biological processes. Notably, we identified a high co-expression lncRNA-mRNA module (i.e., purple module) that showed strong correlation with ISs. This module contained 79 lncRNAs and 442 mRNAs, including 26 lncRNAs and 215 mRNAs showing association between expression and male HNSCC survival. Consistently, 207 of the 215 mRNAs were up-regulated in high IS HNSCC group and were enriched in immune-related signaling pathways. Based on bioinformatics analyses and previous functional assays, certain lncRNAs (e.g., AL365361.1 and PCED1B-AS1) in the purple module likely contributed to the modification of tumor immune microenvironment (TIME) in the high IS HNSCC patients, achieved by regulating transcription of abundant immune-related genes (e.g., CCR7 and TLR8). CONCLUSIONS: In summary, we ascertained a HNSCC male patient subgroup that displayed high ISs and good survival probability. We identified hundreds of genes with specific expression patterns in this HNSCC subgroup as well as a highly co-expressed lncRNA-mRNA module with great potential for the modulation of TIME of HNSCC. Our study provides evidence of a link between the lncRNA-associated gene network, TIME, and HNSCC progression, and highlights potential therapeutic targets for this disease.