METTL3 protects METTL14 from STUB1-mediated degradation to maintain m6 A homeostasis.

N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.

Diagnostic performance of gadoxetic acid-enhanced abbreviated magnetic resonance imaging protocol in small hepatocellular carcinoma (≤2 cm) in high-risk patients.

BACKGROUND: Biannual Ultrasound showed insufficient sensitivity in detecting small or early-stage hepatocellular carcinoma (HCC). Abbreviated magnetic resonance imaging (A-MRI) protocols with fewer sequences demonstrated higher HCC detection sensitivity than ultrasound with acceptable cost and examination time. PURPOSE: To compare the diagnostic performance of gadoxetic acid-enhanced A-MRI with a full sequence MRI (F-MRI) protocol for small HCC (≤2 cm) in cirrhotic or hepatitis B virus-infected high-risk patients. MATERIAL AND METHODS: Two hundred and four consecutive patients with 166 pathologically confirmed small HCC who underwent preoperative gadoxetic acid-enhanced MRI were retrospectively included. A-MRI set comprised T1-weighted hepatobiliary phase imaging, T2-weighted imaging, diffusion-weighted imaging and apparent diffusion coefficient mapping. Two independent radiologists blinded to clinical data assessed the A-MRI set and F-MRI set. Per-patient HCC and per-lesion HCC diagnostic performance were compared. RESULTS: Per-patient HCC detection sensitivity of A-MRI set was 93.8% and 91.2% for observer 1 and observer 2, and, for the F-MRI set, the per-patient HCC detection sensitivity was 96.6% and 95.2%, respectively. There was no significant difference in per-patient sensitivity, specificity and per-lesion HCC detection sensitivity between the two imaging sets for both readers. (P = 0.06-0.25) The A-MRI set showed higher sensitivity on HCC without arterial phase hyperenhancement, and the F-MRI set demonstrated with higher sensitivity on HCC with arterial phase hyperenhancement (P < 0.05). CONCLUSION: A-MRI using diagnostic criteria including hypointensity on hepatobiliary phase plus mild to moderate hyperintensity on T2-weighted imaging or restricted diffusion demonstrated comparable sensitivity and specificity for small HCC compared to the F-MRI protocol in high-risk patients.

[Status Quo and Development of Immunotherapy for Hepatocellular Carcinoma].

Liver cancer is a serious global health problem and a common cause of cancer-related death. Hepatocellular carcinoma (HCC) is a common pathological type of liver cancer. The clinical symptoms of early HCC tend to be not obvious and 50% of HCC patients are already in the advanced stage by the time they are diagnosed. Systemic therapy is recommended for the treatment of advanced HCC. With the development of molecular targeted drugs (sorafenib and lenvatinib), some progress has been made in the systemic treatment of advanced HCC, but there is only modest benefit for the survival of HCC patients. In recent years, the emergence of immune checkpoint inhibitors has changed the overall outlook of HCC treatment, providing more possibilities for precise treatment of HCC and showing better treatment outcomes. In particular, the combination therapy of atezolizumab and bevacizumab significantly improved the survival outcomes in HCC patients. In addition, adoptive cell therapy, tumor vaccine, oncolytic viruses, and nonspecific immunotherapy have also emerged as strategies for immunotherapy. Herein, the status quo and development of HCC immunotherapy are reviewed.

Microvascular invasion of small hepatocellular carcinoma can be preoperatively predicted by the 3D quantification of MRI.

OBJECTIVES: To explore the importance of three-dimensional (3D) quantitative analysis during gadoxetic acid-enhanced magnetic resonance imaging (MRI) of microvascular invasion (MVI) and early recurrence (< 2 years) after surgery of single hepatocellular carcinoma (HCC) ≤ 3 cm. METHODS: Two hundred fourteen patients with pathologically confirmed HCC (training cohort: n = 169; validation cohort: n = 45) were included retrospectively. The 3D quantitative parameters (volume, sphericity, and compacity) and conventional MRI features were analyzed. The significant predictors for MVI were identified using univariate and multivariate logistic regression analyses. Nomograms were constructed from the prediction model, and the relationship between the significant predictors and early recurrence rates was evaluated using the Kaplan-Meier method. RESULTS: Tumor sphericity (odds ratio [OR] = 0.000; p < 0.001), non-smooth tumor margin (OR = 3.353; p = 0.015), and peritumoral hypointensity on hepatobiliary phase (HBP) (OR = 14.067; p = 0.003) were independent significant factors for MVI. When these three factors were combined, the diagnostic specificity of the training and validation cohorts was 97.0 (128/132) and 87.9 (29/33), respectively. The nomogram based on the predictive model performed satisfactorily in the training (C-index: 0.885) and validation (C-index: 0.869) cohorts. Early recurrence rates of patients with two or three significant factors were significantly higher than those with none in the training (29.1% vs. 10.2%, p = 0.007) and validation (36.4% vs. 6.7%, p = 0.037) cohorts. CONCLUSIONS: Lower sphericity combined with non-smooth tumor margin and peritumoral hypointensity on HBP are potential predictive factors for MVI and associated with early recurrence after surgery of HCC ≤ 3 cm. KEY POINTS: • Lower sphericity, non-smooth tumor margin, and peritumoral hypointensity on HBP were important indicators of the occurrence of MVI in HCC. • The combinational model prepared from these findings satisfactorily predicted MVI, and the presence of these predictors was associated with an early recurrence rate after surgical resection in HCC patients. • This model could help clinicians in the preoperative management of small HCC ≤ 3 cm.

Hepatobiliary phase images of gadoxetic acid-enhanced MRI may improve accuracy of predicting the size of hepatocellular carcinoma at pathology.

BACKGROUND: Gadoxetic acid-enhanced magnetic resonance imaging (MRI) has been widely used in clinical practice. However, scientific evidence is lacking for recommending a particular sequence for measuring tumor size. PURPOSE: To retrospectively compare the size of hepatocellular carcinoma (HCC) measured on different gadoxetic acid-enhanced MRI sequences using pathology as a reference. MATERIAL AND METHODS: A total of 217 patients with single HCC who underwent gadoxetic acid-enhanced MRI before surgery were included. The size of the HCC was measured by two abdominal radiologists independently on the following sequences: T1-weighted; T2-weighted; b-500 diffusion-weighted imaging (DWI); and arterial, portal venous, transitional, and hepatobiliary phases. Tumor size measured on MRI was compared with pathological size by using Pearson correlation coefficient, independent-sample t test, and Bland-Altman plot. Agreement between two readers was evaluated with intraclass correlation coefficient (ICC). RESULTS: Correlation between the MR images and pathology was high for both readers (0.899-0.955). Absolute error between MRI and pathologic assessment was lowest on hepatobiliary phase images for both readers (reader 1, 2.8±4.2 mm; reader 2, 3.2±3.4 mm) and highest on arterial phase images for reader 1 (4.9±4.4 mm) and DWI phase images for reader 2 (5.1±4.9 mm). Absolute errors were significantly different for hepatobiliary phase compared with other sequences for both readers (reader 1, P≤0.012; reader 2, P≤0.037). Inter-reader agreements for all sequence measurements were strong (0.971-0.997). CONCLUSION: The performance of gadoxetic acid-enhanced MRI sequences varied with HCC size, and the hepatobiliary phase may be optimal among these sequences.

Feasibility and advantages analyses of wedge resection without mesentery detached approach applied to closure of loop ileostomy.

OBJECTIVES: To evaluate the feasibility and advantages of wedge resection plus transverse suture without mesentery detached approach applied to loop ileostomy closure by analyzing the surgical data and the incidence of postoperative complications of patients undergoing this procedure. METHODS: We performed a retrospective analysis of the hospitalization data of patients who underwent ileostomy closure surgery and met the research standards from January 2017 to April 2021 in Guangxi Medical University Cancer Hospital; all surgeries were performed by the same surgeon. The perioperative data were statistically analyzed by grouping. RESULTS: In total, 65 patients were enrolled in this study, with 12 in the wedge resection group, 35 in the stapler group, and 18 in the hand suture group. There was no significant difference in operation time between the wedge resection group and stapler group (P > 0.05), but both groups had shorter operation time than that in the hand suture group (P < 0.05). The postoperative exhaustion time of wedge resection group was earlier than that of the others, and cost of surgical consumables in the wedge resection group was significantly lower than that in the stapler group, all with statistically significant differences (P < 0.05). By contrast, there were no statistically significant differences in postoperative complication incidences among the three groups. CONCLUSIONS: The wedge resection plus transverse suture without mesentery detached approach is safe and easy for closure of loop ileostomy in selected patients, and the intestinal motility recovers rapidly postoperatively. It costs less surgical consumables, and is particularly suitable for the currently implemented Diagnosis-Related Groups payment method.

[Relationship Between the Level of Anatomical Risk of Hepatic Alveolar Echinococcosis and Complications after Radical Resection].

Objective: To analyze the impact of high or low levels of anatomical risk of hepatic alveolar echinococcosis (HAE) on complications after radical resection. Methods: The baseline, surgical, and complication data were retrospectively collected from hepatic alveolar echinococcosis patients who underwent radical resection at the Ganzi Branch Hospital, West China Hospital, Sichuan University from 2015 to 2022. The patients were divided into anatomical low-risk (ALR) and anatomical high-risk (AHR) groups based on the PNM staging system designed by the World Health Organization (WHO-PNM). Complications were analyzed according to the Clavien-Dindo classification. Univariate and multivariate logistic regression analyses were performed to assess the effect of high and low risks of lesion anatomy on complications. Results: Radical surgery was performed in 216 HAE patients and 102 of whom were in the AHR group. The median operative time was 230 (175, 300) min, the median intraoperative blood loss was 600 mL, and 129 (59.7%) patients developed complications. The complication rate was 73.5% (75/102) in the AHR group and 47.4% (54/114) in the ALR group, demonstrating statistically significant difference ( P<0.05). The incidence of serious complications was 36.3% (37/102) in the AHR group and 13.2% (15/114) in the ALR group, demonstrating statistically significant difference ( P<0.05). There was significant difference in the proportions of patients having postoperative complications of bile leak, anemia, fever, pleural effusion and ascites between the AHR group and the ALR group ( P<0.05). Multivariate logistic regression analysis suggested that AHR was the only independent risk factor for complications, including bile leak, anemia, fever, and pleural effusion, and severe complications. Conclusion: The anatomical risk of hepatic alveolar echinococcosis is independently associated with the development of multiple postoperative complications, and physicians should choose surgical procedures cautiously according to the actual situation when dealing with patients defined as AHR according to WHO-PNM.

[Mechanism of miRNA-3679 Inhibiting Downstream ZADH2-Target Genes to Promote Hepatocellular Carcinoma Cell Proliferation].

Objective: To examine the relationship between miRNA-3679 and hepatocellular carcinoma (HCC) cell lines, and to verify the downstream target genes of miRNA-3679. Methods: PCR was used to determine the expression of miRNA-3679 in liver cancer cell lines, and databases, including ENCORI, miRDB and TargetScan, were used to predict the downstream target genes of miRNA-3679. qPCR of the normal control group (or NC group), miR-3679 inhibitor group and transfection negative control group (or inhibitor NC group) was done to determine the transfection efficiency of the target gene, thereby identifying zinc-binding alcohol dehydrogenase domain containing 2 (ZADH2) as the target gene. Western blot was used to determine the ZADH2 protein expression after miRNA-3679 inhibitor transfection. 5-Ethynyl-2'-deoxyuridine (EdU) staining was done to determine the effect of transfection of miRNA-3679 inhibitor and simultaneous transfection of miRNA-3679 and ZADH2 inhibitors on cell proliferation. Clone formation assay was done to determine the ability of cell clone formation. Flow cytometry was done to examine cell apoptosis. Results: The expression level of miRNA-3679 in HCC cell lines was higher than that in normal human liver cell lines (P<0.05). Through screening conducted with the databases, six genes, including GLUD1, B3GAT1, SLC46A3, MAP2K3, ATF5, and ZADH2, were found to be down-regulated in HCC. qPCR showed that ZADH2 expression increased significantly after transfection with miRNA-3679 inhibitor (P<0.01) and luciferase activity increased after transfection with miR-3679 inhibitor (P<0.01). Western blot results showed that ZADH2 protein expression of the miR-3679 inhibitor group was higher than that of the NC group (P<0.01). EdU analysis showed that the number of positive cells in the miRNA-3679 inhibitor group was lower than that in the NC group and the Inhibitor NC group (P<0.05). The clone count of the miR-3679 inhibitor+si-ZADH2 group was significantly higher than that of the miR-3679 inhibitor group (P<0.01). Flow cytometry showed that the number of apoptotic cells of the miR-3679 inhibitor+si-ZADH2 group was significantly lower than that of the miR-3679 inhibitor group (P<0.01). Conclusion: miRNA-3679 is significantly highly expressed in HCC cells and miRNA-3679 can directly interact with ZADH2 gene and affect its expression. Moreover, miRNA-3679 promotes the proliferation of HCC cells and inhibits their apoptosis by suppressing ZADH2.

Diastereo- and Enantioselective Silver-Catalyzed [3+3] Cycloaddition and Kinetic Resolution of Azomethine Imines with Activated Isocyanides.

In contrast to the well-established [3+2] cycloaddition reactions, the catalytic enantioselective [3+n] (n≥3) cycloaddition reaction of activated isocyanides for the preparation of six-membered or larger ring systems has remained underdeveloped. Herein, we report the first example of highly diastereo- and enantioselective [3+3] cycloaddition of activated isocyanides with azomethine imines. By employing silver catalysis, a wide range of biologically important bicyclic 1,2,4-triazines were obtained in high yields (up to 99 %) with good to excellent stereoselectivities (up to >20 : 1 dr, 99 % ee). In addition, the same catalytic system could be applied to both the late-stage functionalization of complex bioactive molecules and the kinetic resolution of racemic azomethine imines, further highlighting its versatility and synthetic utility.

Torsional Strain-Independent Catalytic Enantioselective Synthesis of Biaryl Atropisomers.

Catalytic asymmetric dynamic kinetic resolution of configurationally labile bridged biaryls is emerging as a powerful strategy for atropisomer synthesis. However, the reported examples suffer from an inherent challenge as the reactivity is highly dependent on the torsional strain of the biaryl substrates, which significantly narrows down the scope and hampers the application. Herein, we report our discovery and development of a torsional strain-independent reaction between biaryl thionolactones and activated isocyanides. By employing auto-tandem silver catalysis, a universal synthesis of both tri- and tetra-ortho-substituted thiazole-containing biaryls was realized in high yields with high enantioselectivities. In addition, these products could be facilely converted to a novel type of bridged biaryls bearing an eight-membered lactone. Mechanistic studies were carried out to elucidate the cause of this unusual torsional strain-independent reactivity.

Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3.

BACKGROUND: Our recent studies have identified that the red nucleus (RN) dual-directionally modulates the development and maintenance of mononeuropathic pain through secreting proinflammatory and anti-inflammatory cytokines. Here, we further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain. METHODS: In this study, male rats with spared nerve injury (SNI) were used as mononeuropathic pain model. Immunohistochemistry, Western blotting, and behavioral testing were used to assess the expressions, cellular distributions, and actions of red nucleus IL-33 and its related downstream signaling molecules. RESULTS: IL-33 and its receptor ST2 were constitutively expressed in the RN in naive rats. After SNI, both IL-33 and ST2 were upregulated significantly at 3 days and peaked at 1 week post-injury, especially in RN neurons, oligodendrocytes, and microglia. Blockade of red nucleus IL-33 with anti-IL-33 neutralizing antibody attenuated SNI-induced mononeuropathic pain, while intrarubral administration of exogenous IL-33 evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 generated an algesic effect in the early development of SNI-induced mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3, suppression of NF-κB, ERK, p38 MAPK, and JAK2/STAT3 with corresponding inhibitors markedly attenuated SNI-induced mononeuropathic pain or IL-33-evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 contributed to SNI-induced mononeuropathic pain by stimulating TNF-α expression, which could be abolished by administration of inhibitors against ERK, p38 MAPK, and JAK2/STAT3, but not NF-κB. CONCLUSIONS: These results suggest that red nucleus IL-33 facilitates the early development of mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3. IL-33 mediates algesic effect partly by inducing TNF-α through activating ERK, p38 MAPK and JAK2/STAT3.

circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression.

Internal tandem duplication (ITD) mutations within FMS-like tyrosine kinase-3 (FLT3) occur in up to 30% of acute myeloid leukemia (AML) patients and confer a very poor prognosis. The oncogenic form of FLT3 is an important therapeutic target, and inhibitors specifically targeting FLT3 kinase can induce complete remission; however, relapse after remission has been observed due to acquired resistance with secondary mutations in FLT3, highlighting the need for new strategies to target FLT3-ITD mutations. Recent studies have reported that the aberrant formations of circular RNAs (circRNAs) are biological tumorigenesis-relevant mechanisms and potential therapeutic targets. Herein, we discovered a circRNA, circMYBL2, derived from the cell-cycle checkpoint gene MYBL2. circMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of polypyrimidine tract-binding protein 1 (PTBP1) to FLT3 messenger RNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD+ cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML.

SmSPL6 Induces Phenolic Acid Biosynthesis and Affects Root Development in Salvia miltiorrhiza.

Salvia miltiorrhiza is a renowned model medicinal plant species for which 15 SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) family genes have been identified; however, the specific functions of SmSPLs have not been well characterized as of yet. For this study, the expression patterns of SmSPL6 were determined through its responses to treatments of exogenous hormones, including indole acetic acid (IAA), gibberellic acid (GA3), methyl jasmonic acid (MeJA), and abscisic acid (ABA). To characterize its functionality, we obtained SmSPL6-ovexpressed transgenic S. miltiorrhiza plants and found that overexpressed SmSPL6 promoted the accumulation of phenolic acids and repressed the biosynthesis of anthocyanin. Meanwhile, the root lengths of the SmSPL6-overexpressed lines were significantly longer than the control; however, both the fresh weights and lateral root numbers decreased. Further investigations indicated that SmSPL6 regulated the biosynthesis of phenolic acid by directly binding to the promoter regions of the enzyme genes Sm4CL9 and SmCYP98A14 and activated their expression. We concluded that SmSPL6 regulates not only the biosynthesis of phenolic acids, but also the development of roots in S. miltiorrhiza.

Stress response of ABI5 to BR stress and its regulation on hypocotyls growth in Arabidopsis thaliana.

Abscisic acid-insensitive 5 (ABI5) is a basic leucine zipper (bZIP) transcription factor that is abundantly expressed in seeds. It plays a central role in regulating the abscisic acid (ABA) signal of seed germination and early seedling growth. Brassinosteroid (BR) is a new type of plant endogenous hormone, which has many physiological functions such as regulating plant growth and development and response to adversity stress. It has recently been discovered that under brassinolide stress, BIN2 (BRASSINOSTEROID INSENSITIVE2) and BES1 (BRI1-EMS-SUPPRESSOR 1) in the BR signaling pathway can inhibit the expression of ABI5 and promote Arabidopsis thaliana seed germination. In order to further explore the function of ABI5 under BR stress, this study analyzed the ABI5 expression characteristics during seed germination, identified Arabidopsis ABI5 gene deletion mutant abi5-1 and analyzed its function under BR stress, the results of which indicated that ABI5 was abundantly expressed in Arabidopsis dry seeds and responded to BR stress during germination. Under normal conditions, there was no significant difference between the hypocotyls of abi5-1 and wild-type seedlings; but under BR stress, the hypocotyls of abi5-1 seedlings were significantly longer than those of wild-type seedlings. These results reveal that ABI5 regulates the growth of Arabidopsis hypocotyls under BR stress, thereby providing a basis for in-depth understanding of the molecular mechanism of ABI5 regulation on plant development.

[The Predictive Value of Perioperative Inflammatory Indicatorsin Prognosis of the Intrahepatic Cholangiocarcinoma Patients after Hepatectomy].

OBJECTIVE: To evaluate the effect of perioperative inflammatory indicators on the prognosis of the patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy. METHODS: The clinical data of 231 ICC patients in the West China Hospital of Sichuan University from December 2006 to December 2016 were retrospectively collected. Neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) and platelet-to-lymphocyte ratio (PLR) of patients during the perioperative period (pre-operation, postoperative day 3 and day 5) were analyzed. The X-tile software was used to determine the optimal cut-off values of NLR, d-NLR and PLR in pre-operation, postoperative day 3 and day 5. Based on the cut-off values, all patients were divided into high level group and low level group, and Kaplan-Meier methods were used to analyze the correlations of NLR, d-NLR and PLR with the disease-free survival (DFS) and overall survival (OS) of patients. Univariate and multivariate Cox regression models were applied to assess the prognostic values of NLR, d-NLR and PLR. Nomogram was established to predict the prognosis for ICC patients, and the predicting accuracy was evaluated by the Consistency index ( C-index). RESULTS: A total of 231 ICC patients including 115 males and 116 females were enrolled into this study, and the proportion of patients aged <60 years was 57.1%. Among the patients enrolled, 161 patients (69.7%) recurred and 156 patients (67.5%) died after hepatectomy. The median time of DFS and OS were 8.9 and 12.5 months respectively. The Kaplan-Meier curves showed that d-NLR and NLR levels in pre-operation, postoperative day 3 and day 5, together with the preoperative PLR level were correlated with the time of DFS ( P<0.05). Meanwhile, d-NLR and PLR levels in pre-operation, postoperative day 3 and day 5, together with the NLR level in pre-operation and postoperative day 3 were correlated with the time of OS ( P<0.05). Univariate and multivariate Cox regression model analysis suggested that high level of the preoperative NLR and d-NLR, together with the high level of NLR on postoperative day 3 were the independent influencing factors of poor DFS. High level of the preoperative NLR and d-NLR, together with the high level of NLR on postoperative day 3 were the independent influencing factors of OS. The level of PLR level was not correlated with DFS and OS. The C-index values of nomogram for predicting DFS and OS were 0.738 (95% confidence interval: 0.699-0.777) and 0.778 (95% confidence interval: 0.758-0.818), respectively. CONCLUSION: High level of the preoperative NLR, preoperative d-NLR and NLR on postoperative day 3 in ICC patients indicate poor prognosis, and PLR has no prognostic value for ICC patients after hepatectomy.

ANKRD49 inhibits etoposide-induced intrinsic apoptosis of GC-1 cells by modulating NF-κB signaling.

Spermatogenesis is a complicated process that is tightly regulated by the well-coordinated expression of a series of genes in the testes. Ankyrin repeat domain-containing protein 49 (ANKRD49), an evolutionarily conserved protein highly expressed in the testes, is mainly found in spermatogonia, spermatocytes, and round spermatids. However, the exact function of ANKRD49 in spermatogenesis has remained elusive. In this study, we sought to investigate the role of ANKRD49 in apoptosis and determine the mechanism underlying this process in male germ cell-derived GC-1 cells. Nuclear staining with Hoechst 33258 and annexin V-FITC/PI, as well as analysis of caspase 3 activity, mitochondrial membrane potential, and apoptotic protein expression, showed that etoposide-induced apoptosis was attenuated by ANKRD49 overexpression but promoted by RNA interference-induced ANKRD49 knockdown. Furthermore, assessment of the levels of caspase 9, caspase 8, and proteins of the Bcl-2 family revealed ANKRD49 to be involved in an intrinsic apoptosis pathway. Examination of the subcellular distribution of the NF-κB p65 subunit after treatment with an NF-κB signaling inhibitor or p65 small interfering RNA demonstrated that ANKRD49 modulated etoposide-induced GC-1 cell apoptosis via the NF-κB pathway. Taken together, these results suggest that ANKRD49 plays an important role in reducing intrinsic apoptosis of GC-1 cells by modulating the NF-κB signaling pathway.

Synthesis and antidepressant-like activity of novel alkoxy-piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.

Synthesis and antidepressant effect of novel aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

A series of novel aralkyl piperazine and piperidine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the selective compound were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compound 19a exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, Ki = 12 nM; 5-HT7, Ki = 3.2 nM) coupled with potent serotonin reuptake inhibition (IC50 = 14 nM) and showed a marked antidepressant-like effect in the FST and TST models.

Difference analysis in prevalence of incidental pancreatic cystic lesions between computed tomography and magnetic resonance imaging.

BACKGROUND: The purpose was to investigate the difference of detection rate of incidental pancreatic cystic lesions (PCLs) with computed tomography (CT) and magnetic resonance imaging (MRI) and to compare the difference between CT and MRI and to explore the effect of this difference on surgical resection. METHODS: We reviewed the diagnostic reports for incidental PCLs between 2013 and 2016. Images of PCLs would be re-evaluated. Clinical and imaging data were recorded. The chi-square and independent t-test were conducted for categorical and continuous variables. RESULTS: The prevalence of PCLs was 1.91% (1038/54210) and 3.36% (1282/38099) on CT and MRI respectively, and increased with increasing age (P < 0.001). No significant differences were found in the annual prevalence of PCLs on CT (P = 0.796) and MRI (P = 0.213) from 2013 to 2016 while the number of examinations was increasing every year. The annual detection rate of MRI for small PCLs (< 20 mm) was significantly higher than CT (P < 0.001), but was not significantly different for large PCLs (≥20 mm). The rate of surgical resection of PCLs (≥20 mm) in MRI group was higher than CT (55.2% vs. 37.0%, P < 0.001). CONCLUSIONS: The detection rate of PCLs on CT and MRI tended to be stable despite increasing scan volumes. Female had a slightly more frequency of PCLs than male. MRI detected more small PCLs(< 20 mm) and had higher impact on surgical resection of large PCL(≥20 mm) compared with CT.

Global identification and characterization of lncRNAs that control inflammation in malignant cholangiocytes.

BACKGROUND: Long noncoding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, and associated with chronic inflammation and damage to the biliary epithelium. This study determined whether lncRNAs were dysregulated and participated in disease diagnosis or pivotal inflammation pathways through a genome-wide lncRNA screening and functional analysis. RESULTS: We firstly identified a large number of lncRNAs abnormally expressed between 9 pairs of cancerous and adjacent tissues of CCA, and between intra-hepatic CCA and extra-hepatic CCA through a genome-wide profiling. A set of aberrant differentially expressed lncRNAs were further validated in a training set (16 pairs) and a test set (11 pairs) of CCA patient samples. Following assessment of the diagnostic value of the 7 differentially expressed lncRNAs, we confirmed the optimal combination of H19, C3P1, AC005550.3, PVT1, and LPAL2 with area under the curve of 0.8828 [95% CI: 0.7441-1.021, P < 0.001], with 93.75% sensitivity and 81.25% specificity, at the cutoff point of - 0.2884 to distinguish the CCA tissue from the normal ones, suggesting that specific lncRNAs may have potential for detecting CCA. More importantly, the genome-wide locus and lncRNA/mRNA co-expression analyses revealed a set of lncRNAs that participated in inflammation and oxidative stress response pathways by regulating genes in cis or in trans. Finally, APOC1P1, PVT1, and LPAL2 were validated to regulate the migration and some pivotal inflammation genes under the CCA pathogenesis. CONCLUSIONS: Our findings are the first to show that lncRNAs may not only be potential biomarkers of CCA progression but also respond to inflammation in CCA.