Hepatitis C virus (HCV) infection usually induces chronic hepatic inflammation, which favors the initiation and progression of hepatocellular carcinoma (HCC). Moreover, microRNA‐155 (miR‐155) plays ...an important role in regulating both inflammation and tumorigenesis. However, little is known about whether and how miR‐155 provides the link between inflammation and cancer. In this study we found that miR‐155 levels were markedly increased in patients infected with HCV. MiR‐155 transcription was regulated by nuclear factor kappa B (NF‐κB), and p300 increased NF‐κB‐dependent miR‐155 expression. The overexpression of miR‐155 significantly inhibited hepatocyte apoptosis and promoted cell proliferation, whereas miR‐155 inhibition induced G0/G1 arrest. Up‐regulated miR‐155 resulted in nuclear accumulation of β‐catenin and a concomitant increase in cyclin D1, c‐myc, and survivin. Gain‐of‐function and loss‐of‐function studies demonstrated that miR‐155 promoted hepatocyte proliferation and tumorigenesis by increasing Wnt signaling in vitro and in vivo, and DKK1 (Wnt pathway inhibitor) overexpression inhibited the biological role of miR‐155 in hepatocytes. Finally, adenomatous polyposis coli (APC), which negatively regulates Wnt signaling, was identified as the direct and functional target of miR‐155. Conclusion: HCV‐induced miR‐155 expression promotes hepatocyte proliferation and tumorigenesis by activating Wnt signaling. The present study provides a better understanding of the relationship between inflammation and tumorigenesis, and thus may be helpful in the development of effective diagnosis and treatment strategies against HCV‐HCC. (HEPATOLOGY 2012;56:1631–1640)
•Heritability and correlation estimation for 33 anatomically defined regions.•Network and cluster analysis for genetic correlation characterize human brain's functional ...architecture.•Composite-linkage disequilibrium score regression reveals correlations between composite phenotypes and complex traits.
Heritability and genetic covariance/correlation quantify the marginal and shared genetic effects across traits. They offer insights on the genetic architecture of complex traits and diseases. To explore how genetic variations contribute to brain function variations, we estimated heritability and genetic correlation across cortical thickness, surface area, and volume of 33 anatomically predefined regions in left and right hemispheres, using summary statistics of genome-wide association analyses of 31,968 participants in the UK Biobank. To characterize the relationships between these regions of interest, we constructed a genetic network for these regions using recursive two-way cut-offs in similarity matrices defined by genetic correlations. The inferred genetic network matches the brain lobe mapping more closely than the network inferred from phenotypic similarities. We further studied the associations between the genetic network for brain regions and 30 complex traits through a novel composite-linkage disequilibrium score regression method. We identified seven significant pairs, which offer insights on the genetic basis for regions of interest mediated by cortical measures.
Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to ...linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.
AsCas12a and LbCas12a nucleases are reported to be promising tools for genome engineering with protospacer adjacent motif (PAM) TTTV as the optimal. However, the C-containing PAM (CTTV, TCTV, TTCV, ...etc.) recognition by Cas12a might induce extra off-target edits at these non-canonical PAM sites.
Here, we identify a novel Cas12a nuclease CeCas12a from Coprococcus eutactus, which is a programmable nuclease with genome-editing efficiencies comparable to AsCas12a and LbCas12a in human cells. Moreover, CeCas12a is revealed to be more stringent for PAM recognition in vitro and in vivo followed by very low off-target editing rates in cells. Notably, CeCas12a renders less off-target edits located at C-containing PAM at multiple sites compared to LbCas12a and AsCas12a, as assessed by targeted sequencing methods.
Our study shows that CeCas12a nuclease is active in human cells and the stringency of PAM recognition could be an important factor shaping off-target editing in gene editing. Thus, CeCas12a provides a promising candidate with distinctive characteristics for research and therapeutic applications.
There have been many controversies about the optimal extent of lymphadenectomy for thoracic esophageal cancer, whether three-field lymphadenectomy is superior to two-field lymphadenectomy with ...respect to the 5-year survival rate and perioperative morbidities and mortality.
A comprehensive search of PubMed and Embase for relevant studies comparing three-field and two-field lymphadenectomies for thoracic esophageal cancer was conducted using the Preferred Reporting Items for Systemic Reviews and Meta-Analyses standards. Hazard ratios (HRs) were extracted from these studies to give pooled estimates of the effect of the two surgical procedures on the 5-year survival rate and perioperative morbidities and mortality.
Thirteen studies were included for analysis. Compared with two-field lymphadenectomy, three-field lymphadenectomy provided a higher 5-year survival rate (HR 0.64, 95% confidence interval CI: 0.56 to 0.73, p = 0.000) and incidence of anastomotic leakage (HR 1.46, 95% CI: 1.19 to 1.79, p = 0.000), with a comparative perioperative mortality (HR 0.64, 95% CI: 0.38 to 1.10, p = 0.110) and incidence of vocal cord palsy (HR 1.12, 95% CI: 0.82 to 1.54, p = 0.470) and pulmonary complications (HR 1.00, 95% CI: 0.89 to 1.12, p = 0.760).
Published evidence indicated that three- field lymphadenectomy could be a priority for thoracic esophageal cancer, especially for tumors with positive lymph nodes. Given the lack of large-sample randomized controlled studies, further evaluations are necessary.
Abstract Background To have a comprehensive investigation of the clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas. Methods Quantitative real-time reverse ...transcriptase PCR (qRT-PCR) and reverse transcriptase PCR (RT-PCR) were simultaneously performed to screen ALK , ROS1 and RET fusions in resected tumor samples from 1139 Chinese lung adenocarcinoma patients, with validation of positive results using fluorescent in situ hybridization. Clinicopathologic characteristics, predominant histologic subtype and cytomorphology were assessed in fusion-positive lung adenocarcinomas and compared to those harboring EGFR , KRAS , HER2 or BRAF mutations. Results There were 58 (5.1%) ALK fusions, 11 (1.0%) ROS1 fusions and 15 (1.3%) RET fusions. Tumors with ROS1 fusions had significantly larger diameter than ROS1 fusion-negative tumors ( P = 0.007), whereas all the 15 tumors harboring RET fusions were ≤3 cm in diameter ( P = 0.001). The three fusion genes were all more prevalent in solid-predominant adenocarcinoma. Compared to fusion-negative lung adenocarcinomas, tumors harboring a fusion gene had significantly higher prevalence of extracellular mucin ( P < 0.001), cribriform pattern ( P < 0.001), signet ring cells ( P < 0.001) and hepatoid cytology ( P < 0.001). No significant difference in relapse-free survival ( P = 0.147) and overall survival ( P = 0.444) was observed between fusion-positive and fusion-negative patients. Conclusions This study showed fusion-positive lung adenocarcinomas had identifiable common and fusion-pattern specific clinicopathologic, histologic and cytologic features, offering implications for fusion genes screening.
The fibroblast growth factor receptor (FGFR)-3 fusion genes have been recently demonstrated in a subset of non-small cell lung cancer (NSCLC). To aid in identification and treatment of these ...patients, we examined the frequency, clinicopathologic characteristics, and treatment outcomes of patients who had NSCLC with or without FGFR fusions.
Fourteen known FGFR fusion variants, including FGFR1, FGFR2, and FGFR3, were detected by RT-PCR and verified by direct sequencing in 1,328 patients with NSCLC. All patients were also analyzed for mutations in EGFR, KRAS, HER2, BRAF, ALK, RET, and ROS1. Clinical characteristics, including age, sex, smoking status, stage, subtypes of lung adenocarcinoma, relapse-free survival, and overall survival, were collected.
Of 1,328 tumors screened, two (0.2%) were BAG4-FGFR1 fusion and 15 (1.1%) were FGFR3-TACC3 fusion. Six of 1,016 patients with lung adenocarcinoma were FGFR3-TACC3 fusions and 11 of 312 lung squamous cell carcinoma harbored BAG4-FGFR1 or FGFR3-TACC3 fusions. Compared with the FGFR fusion-negative group, patients with FGFR fusions were more likely to be smokers (94.1%, 16 of 17 patients, P < 0.001), significantly associated with larger tumor (>3 cm; 88.2%, 15 of 17 patients, P < 0.001) and with a tendency to be more poorly differentiated (53.9%, nine of 17 patients, P = 0.095).
FGFR fusions define a molecular subset of NSCLC with distinct clinical characteristics. FGFR is a druggable target and patients with FGFR fusions may benefit from FGFR-targeted therapy, which needs further clinical investigation.
Background. Middle-aged (45-59 years old) patients with major depressive disorder (MDD) have a predilection for dementia and cognitive disorders (CDs); however, the characteristics and mechanisms of ...CDs in these patients remain unclear. There are also known connections between thyroid-stimulating hormone (TSH), brain biochemical metabolism, and cognitive function (CF); however, there is scanty of information about these connections in middle-aged MDD patients. Methods. Cognitive assessment was performed on 30 first-episode, untreated middle-aged patients with MDD and 30 well-matched healthy controls (HCs) using the MATRICS Consensus Cognitive Battery (MCCB). N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in the prefrontal cortex (PFC) and cerebellum were also obtained via proton magnetic resonance spectroscopy (1H-MRS), and the TSH level was measured by chemiluminescence analysis. Results. MDD patients presented significantly lower processing speed, working memory, verbal learning, reasoning problem-solving, visual learning, and composite cognition scores than controls, with a statistically lower NAA/Cr ratio in the right cerebellum. Age was positively related to reasoning problem-solving in the MDD group (r=0.6249, p=0.0220). Education also showed a positive association with visual learning, social cognition, and composite cognition. The 24-item Hamilton Depression Rating Scale (HDRS-24) score was negatively related to all domains of CF. TSH levels were markedly decreased in the MDD group, and a positive connection was determined between the NAA/Cr ratio in the right PFC and the TSH level. Conclusions. Middle-aged MDD patients have multidimensional CDs. There are changes in PFC and cerebellar biochemical metabolism in middle-aged patients with MDD, which may be related to CDs or altered TSH levels.
A highly efficient and enantioselective hydrogenation of diversely substituted C=N‐containing heterocyclic compounds such as 3‐aryl‐1,4‐benzoxazines and 2‐arylquinolines was experimentally explored ...by using 1,1′‐spirobiindane‐7,7′‐diol‐derived chiral phosphoric acids as the catalyst. This method provides straightforward access to the corresponding tetrahydroquinolines and dihydro‐2H‐1,4‐benzothiazines in high yields (85–99 %) with excellent enantioselectivities (91–99 %). The attractive features of this procedure, which include mild reaction conditions, operational simplicity, relatively low catalyst loading (1 mol‐%), and high levels of enantioselectivities, make it a useful approach for the practical synthesis of optically active nitrogen‐containing aromatic heterocycles.
Chiral SPINOL‐derived phosphoric acids are highly enantioselective catalysts for the asymmetric transfer hydrogenation of diversely substituted C=N‐containing heterocyclic compounds (SPA = SPINOL‐derived phosphoric acids). The method provides straightforward access to various optically active tetrahydroquinolines and dihydro‐2H‐1,4‐benzothiazines in high yields with excellent enantioselectivities.
Esophageal squamous cell carcinoma (ESCC) metastasizes in an unpredictable fashion to adjacent lymph nodes, including those along the recurrent laryngeal nerves (RLNs). This study is to apply machine ...learning (ML) for prediction of RLN node metastasis in ESCC.
The dataset contained 3352 surgically treated ESCC patients whose RLN lymph nodes were removed and pathologically evaluated. Using their baseline and pathological features, ML models were established to predict RLN node metastasis on each side with or without the node status of the contralateral side. Models were trained to achieve at least 90% negative predictive value (NPV) in fivefold cross-validation. The importance of each feature was measured by the permutation score.
Tumor metastases were found in 17.0% RLN lymph nodes on the right and 10.8% on the left. In both tasks, the performance of each model was comparable, with a mean area under the curve ranging from 0.731 to 0.739 (without contralateral RLN node status) and from 0.744 to 0.748 (with contralateral status). All models showed approximately 90% NPV scores, suggesting proper generalizability. The pathology status of chest paraesophgeal nodes and tumor depth had the highest impacts on the risk of RLN node metastasis in both models.
This study demonstrated the feasibility of ML in predicting RLN node metastasis in ESCC. These models may potentially be used intraoperatively to spare RLN node dissection in low-risk patients, thereby minimizing adverse events associated with RLN injuries.
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