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Abstract Background Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. Methods LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. Results TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. Conclusions TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

Abstract Background The prognostic significance of tumor burden score (TBS) in relation to carcinoembryonic antigen (CEA) has not been investigated among patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). This study aimed to develop and validate a simplified model, a combination of TBS and CEA (CTC grade), for predicting the long-term outcomes of postoperative ICC patients. Methods Patients who underwent curative − intent resection of ICC between 2011 and 2019 were identified from a large multi − institutional database. The impact of TBS, CEA, and the CTC grade on overall survival (OS) and recurrence − free survival (RFS) was evaluated in both the derivation and validation cohorts. The receiver operating characteristic curve was utilized for assessing the predictive accuracy of the model. Subgroup analyses were performed across 8th TNM stage system stratified by CTC grade to assess the discriminatory capacity within the same TNM stage. Results A total of 812 patients were included in the derivation cohort and 266 patients in the validation cohort. Survival varied based on CEA (low: 36.7% vs. high: 9.0%) and TBS (low: 40.3% vs. high: 17.6%) in relation to 5 − year survival (both p

Abstract The chromosome 20 long arm (20q) is one of the genomic hotspots where copy number alterations frequently occur in multiple types of tumors. However, it remains elusive which genes are implicated in 20q-related tumorigenesis. Here, by querying TCGA and GEO databases, we observed frequent copy number amplification at 20q and the chromosome subband 20q13.33 was amplificated in multiple cancers. Among those genes at 20q13.33, PSMA7 was found with the strongest correlation with cancers. Further analysis revealed that PSMA7 amplification was the most frequent genetic alteration event conferring adverse prognosis in various cancers. Consistent with the strong positive correlation between PSMA7 amplification and gene expression, elevated PSMA7 expression was observed in 20 of 33 types of cancers with a close link to adverse outcomes in certain tumors. In addition, PSMA7 was essential for the growth of almost 1095 cancer lines. Mechanistically, aberrant PSMA7 most probably influenced the proteasome and protease-related pathways to promote tumorigenesis and might be antagonized by several compounds, e.g., Docetaxel in relevant cancers. The current in-depth pan-cancer analysis refines our understanding of the crucial oncogenic role of copy number amplifications at PSMA7 loci at the novel chromosome amplicon 20q13.33 across different tumors.

Abstract Background Radical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients. Methods Data of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared. Results Two hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child–Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05. Conclusion Surgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

Abstract Background It has been proven that tumor necrosis is associated with poor prognoses in various solid malignant tumors. However, the prognostic effect of tumor necrosis in hepato‐biliary‐pancreatic cancers is still unclear. Therefore, this study was performed to evaluate the associations of tumor necrosis with survival outcomes and clinicopathological features in patients with hepato‐biliary‐pancreatic cancers. Methods Based on the PRISMA statement, eligible studies were identified from PubMed, Embase, Cochrane Library, and Web of Science from inception until January 2023. The pooled hazard ratios (HRs) and 95% confidence intervals (95%CIs) were calculated to assess the connection between tumor necrosis and hepato‐biliary‐pancreatic cancers. We then choose which effects model to use to generate pooled HRs and 95% CIs, depending on data heterogeneity. Results In total, 6497 articles were identified, 10 of which were included in this meta‐analysis. Our results suggested that the presence of tumor necrosis predicted a poorer outcome for overall survival (HR = 1.54, 95% CI = 1.35–1.77, p

The formation mechanism of light bridges (LBs) is strongly related to the dynamic evolution of solar active regions (ARs). To study the relationship between LB formation and AR evolution phases, we employ 109 LB samples from 69 ARs in 2014 using observational data from the Helioseismic and Magnetic Imager on board the Solar Dynamics Observatory. LBs are well matched with the weak field lanes (WFLs), except those aligned on the polarity inversion line of δ sunspots. For penumbral intrusion (type-A) and umbral-dot emergence (type-C) LBs, the WFLs represent the splitting of magnetic flux systems. The sunspots tend to decay and split into several parts after type-A and type-C LBs are formed. For sunspot/umbra-merging (type-B) LBs, the declining WFLs are caused by collisions of flux systems. The sunspots merged and remained stable after type-B LBs formed. We conclude that type-B LBs are formed by collisions of flux systems, while type-A and type-C LBs are generated by splits. The time differences ( δ T ) between LBs appearing and ARs peaking have an average value of 1.06, −1.60, and 1.82 days for type-A, B, and C LBs, with the standard deviations of 3.27, 2.17, and 1.89, respectively. A positive value of δ T means that the LB appears after the AR peaks, whereas a negative δ T means it appears before the peak. Type-A LBs tend to form in the decaying phase or around the peak time. Type-B LBs are more likely to be formed in the developing phase. Type-C LBs mostly take shape in the decaying phase of ARs.

Abstract Organoids are three‐dimensional (3D) miniaturized versions of organs or tissues that are derived from cells with stem potential and can self‐organize and differentiate into 3D cell masses, recapitulating the morphology and functions of their in vivo counterparts. Organoid culture is an emerging 3D culture technology, and organoids derived from various organs and tissues, such as the brain, lung, heart, liver, and kidney, have been generated. Compared with traditional bidimensional culture, organoid culture systems have the unique advantage of conserving parental gene expression and mutation characteristics, as well as long‐term maintenance of the function and biological characteristics of the parental cells in vitro. All these features of organoids open up new opportunities for drug discovery, large‐scale drug screening, and precision medicine. Another major application of organoids is disease modeling, and especially various hereditary diseases that are difficult to model in vitro have been modeled with organoids by combining genome editing technologies. Herein, we introduce the development and current advances in the organoid technology field. We focus on the applications of organoids in basic biology and clinical research, and also highlight their limitations and future perspectives. We hope that this review can provide a valuable reference for the developments and applications of organoids.

Lactic acid (LA) is widely used in many industries as a crucial starting material in food products, bio-based materials, and biodegradable polymers. The goals of this research were to isolate LA bacteria from food wastes, assess their potential for LA production, and study their growth characteristics. In this study, six bacterial strains were isolated from food waste and identified using 16S rRNA gene sequencing; namely, Weissella viridescens WJ39, Leuconostoc lactis YS33, Leuconostoc citreum KD42, Leuconostoc mesenteroides VN60, Macrococcus caseolyticus FCI29, and Weissella confusa RG41. W. viridescens WJ39 showed the highest potential for lactic acid production (17.56 g L−1day−1), and the lowest potential was found in L. lactis YS33 (14.09 g L−1day−1). There were significant differences (p < 0.05) in the LA production rates among Weissella spp., Leuconostoc spp., and Macrococcus spp. Moreover, dramatic differences in growth rate were observed among the six strains. W. viridescens WJ39 exhibited the highest growth rate (0.80 h−1), while M. caseolyticus FCI29 exhibited the lowest growth rate (0.57 h−1). W. viridescens WJ39 also exhibited lactic acid production (at a rate around 2 g L−1day−1) in a lab incubation experiment with food waste as a nutrient source. The draft genome of W. viridescens WJ39 with 16 contigs was constructed with an N50 of 215217 bp. The genome size was approximately 1.54 Mb, with a GC content of 41%. A hicD gene, known to catalyze the conversion of pyruvate to D-lactate, was discovered in the genome. This study illustrated the potential for the production of lactic acid from food waste with lactic acid bacteria.

Background: Enhanced recovery after surgery (ERAS) has received increasing attention. Preoperative oral carbohydrate and postoperative early oral feeding (POC-PEOF) as the basic nutrition administration in the ERAS program suffers from low adherence. The role and benefits of administering POC-PEOF in elderly patients with hepatocellular carcinoma (HCC) are unclear. Therefore, the randomized controlled trial evaluated the effects of POC-PEOF in elderly patients with HCC undergoing hepatectomy with inflammation and patient self-reported symptom burden compared with the corresponding outcomes of traditional fasting protocols. Methods: Elderly patients with HCC (n = 126) were randomly assigned to two groups using the sealed envelope technique. Sixty-three patients were included in the intervention (POC-PEOF) group and received POC-PEOF administration, whereas the 63 patients in the control (FAST) group underwent conventional fasting. Acute-phase inflammation markers, patient self-reported symptom burdens, and postoperative outcomes were compared between the two groups. Results: The average age was 69.60 ± 5.00 years in the POC-PEOF group and 70.44 ± 6.15 years in the FAST group. Compared to prolonged fasting, POC-PEOF achieved significant positive results, including lower overall levels of inflammatory response mediators (CRP, IL-6) on postoperative day (POD) 1, POD 3, and POD 5 (P

The lack of meaningful and effective early-stage markers remains the major challenge in the diagnosis of gallbladder cancer (GBC) and a huge barrier to timely treatment. Zinc finger protein 64 (ZFP64), a member of the zinc finger protein family, is considered to be a promising predictor in multiple tumors, but its potential effect in GBC still remains unclear. Here, we identified that ZFP64 was a vital regulatory protein in GBC. We found that ZFP64 expressed higher in GBC gallbladder carcinoma tissues than in normal tissues and was positively correlated with poor prognosis. Furthermore, ZFP64 was responsible for the migration, invasion, proliferation, anti-apoptosis, and epithelial mesenchymal transition (EMT) of GBC cells in vitro and in vivo. Mechanistically, through Co-IP assay, we confirmed that ZFP64 recruits HDAC1 localized to the promoter region of NUMB for deacetylation and therefore inhibits NUMB expression. The downregulation of NUMB enhanced the activation of the Notch1 signaling pathway, which is indispensable for the GBC-promotion effect of ZFP64 on GBC. In conclusion, ZFP64 regulated GBC progression and metastasis through upregulating the Notch1 signaling pathway, and thus ZFP64 is expected to become a new focus for a GBC prognostic marker and targeted therapy.

Abstract Background At present, hepatectomy is still the most common and effective treatment method for intrahepatic cholangiocarcinoma (ICC) patients. However, the postoperative prognosis is poor. Therefore, the prognostic factors for these patients require further exploration. Whether microvascular invasion (MVI) plays a crucial role in the prognosis of ICC patients is still unclear. Moreover, few studies have focused on preoperative predictions of MVI in ICC patients. Methods Clinicopathological data of 704 ICC patients after curative resection were retrospectively collected from 13 hospitals. Independent risk factors were identified by the Cox or logistic proportional hazards model. In addition, the survival curves of the MVI-positive and MVI-negative groups before and after matching were analyzed. Subsequently, 341 patients from a single center (Eastern Hepatobiliary Hospital) in the above multicenter retrospective cohort were used to construct a nomogram prediction model. Then, the model was evaluated by the index of concordance (C-Index) and the calibration curve. Results After propensity score matching (PSM), Child-Pugh grade and MVI were independent risk factors for overall survival (OS) in ICC patients after curative resection. Major hepatectomy and MVI were independent risk factors for recurrence-free survival (RFS). The survival curves of OS and RFS before and after PSM in the MVI-positive groups were significantly different compared with those in the MVI-negative groups. Multivariate logistic regression results demonstrated that age, gamma-glutamyl transpeptidase (GGT), and preoperative image tumor number were independent risk factors for the occurrence of MVI. Furthermore, the prediction model in the form of a nomogram was constructed, which showed good prediction ability for both the training (C-index = 0.7622) and validation (C-index = 0.7591) groups, and the calibration curve showed good consistency with reality. Conclusion MVI is an independent risk factor for the prognosis of ICC patients after curative resection. Age, GGT, and preoperative image tumor number were independent risk factors for the occurrence of MVI in ICC patients. The prediction model constructed further showed good predictive ability in both the training and validation groups with good consistency with reality.

Abstract Background The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC). Methods Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent narrow margin hepatectomy (NMH) using the 1:1 propensity score matching (PSM). Results Among 478 included patients, 195 (40.8%) underwent WMH whereas 283 (59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: median OS 27 vs 17 months, P

BackgroundTo investigate reliable associations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) features and gene expression characteristics in breast cancer (BC) and to develop and validate classifiers for predicting PAM50 subtypes and prognosis from DCE-MRI non-invasively.MethodsTwo radiogenomics cohorts with paired DCE-MRI and RNA-sequencing (RNA-seq) data were collected from local and public databases and divided into discovery (n = 174) and validation cohorts (n = 72). Six external datasets (n = 1,443) were used for prognostic validation. Spatial–temporal features of DCE-MRI were extracted, normalized properly, and associated with gene expression to identify the imaging features that can indicate subtypes and prognosis.ResultsExpression of genes including RBP4, MYBL2, and LINC00993 correlated significantly with DCE-MRI features (q-value < 0.05). Importantly, genes in the cell cycle pathway exhibited a significant association with imaging features (p-value < 0.001). With eight imaging-associated genes (CHEK1, TTK, CDC45, BUB1B, PLK1, E2F1, CDC20, and CDC25A), we developed a radiogenomics prognostic signature that can distinguish BC outcomes in multiple datasets well. High expression of the signature indicated a poor prognosis (p-values < 0.01). Based on DCE-MRI features, we established classifiers to predict BC clinical receptors, PAM50 subtypes, and prognostic gene sets. The imaging-based machine learning classifiers performed well in the independent dataset (areas under the receiver operating characteristic curve (AUCs) of 0.8361, 0.809, 0.7742, and 0.7277 for estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, and obtained radiogenomics signature). Furthermore, we developed a prognostic model directly using DCE-MRI features (p-value < 0.0001).ConclusionsOur results identified the DCE-MRI features that are robust and associated with the gene expression in BC and displayed the possibility of using the features to predict clinical receptors and PAM50 subtypes and to indicate BC prognosis.

This study aimed to develop an effective therapy against M2 macrophages and to investigate the effects of imidazole and mannose modified carboxymethyl chitosan-nanoparticles (MIC-NPs) on tumor growth and antitumor immune responses. MIC-NPs were constructed and analyzed through 1H NMR, nano-laser particle size analyzer, and transmission electron microscopy. The nanoparticles were mainly distributed in 75–85 nm, and zeta potential was 1.5 mV. Cytotoxicity studies in vitro and in vivo indicated that MIC-NPs were safe. The targeting effect of MIC-NPs on M2 macrophages was observed through fluorescence microscope and microplate system. The results demonstrated the uptake of a large amount of FITC-loaded MIC-NPs by M2. Cell growth inhibition experiments showed that MIC-NPs significantly inhibited M2 through cell apoptosis. The evaluation of anti-tumor activity in vivo showed that MIC-NPs could accumulate in the tumor site to exert an anti-tumor effect. Flow cytometry showed that the proportion of M2 macrophages at the tumor site in the experimental group was significantly lower than that in the control group, while the Treg cells and cytotoxic T cells (CTL) were found to be increased. PCR detection showed that the cDNA of FIZZ, MR, TGF-β, and arginase, closely related to M2 macrophages, in the experimental group, was significantly lower than that in the control group, but there was no significant difference in the cDNA of Treg cell characteristic Foxp3 between the two groups. These results suggest that MIC-NPs are expected to provide a new and effective treatment for tumor.

Abstract Background Malignant melanoma is characterized as highly malignant due to its rapid growth and early metastasis. Metastatic melanoma from occult primary is rare. Melanoma of unknown primary in pancreas are even rear. But it is a biologically ill-defined and clinically understudied concept. Case presentation In this report, a 43-year-old man was diagnosed with pancreatic carcinoma. Extended total pancreatectomy together with portal vein reconstruction and extensive lymphadenectomy were performed in our hospital. The patient was diagnosed with pancreatic malignant melanoma after pathological examination. He was still alive 20 months after the operation without any evidence of recurrence. Conclusion The described case highlights the possibility of primary pancreatic malignant melanoma and the treatment strategies of this rare carcinoma.

Abstract Background and Aims The prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection is far from satisfactory; however, the clinical value of adjuvant therapy (AT) remains controversial. This multicenter study aimed to evaluate the clinical value of AT and identify potential patients who would be benefited from AT. Methods Data from ICC patients who underwent radical resection were retrospectively collected from 12 hepatobiliary centers in China between December 2012 and December 2015. Patients were divided into AT and non‐AT groups based on whether AT was administered or not. Overall survival (OS) and disease‐free survival (DFS) were analyzed using the Kaplan‐Meier method before and after 1:2 propensity score matching (PSM). Subgroup analyses were conducted based on the established staging systems. Results A total of 412 patients were enrolled in this study, and 77 patients (18.9%) received AT, including 32 (7.8%) patients who received transarterial chemoembolization (TACE), 21 (5.1%) patients who received chemotherapy, 10 (2.4%) patients who received radiotherapy, and 14 (3.4%) patients who received adjuvant chemoradiotherapy. The median OS and DFS were both longer in the AT group than in the non‐AT group (43.0 months vs 21.0 months, P = .015; 16.0 months vs 11.0 months, P = .045, respectively), and the advantage of AT was confirmed for both the OS and DFS (P = .023; P = .046, respectively) after 1:2 PSM. Furthermore, based on the established nomogram, only “middle‐risk” patients receiving AT cherished a longer median OS (43.0 months vs 20.0 months, P = .033). In subgroup analyses that were stratified by different AT strategies, patients receiving postoperative chemotherapy had a longer median OS (37.0 months vs 21.0 months, P = .039), while patients receiving postoperative TACE had a longer median DFS (50.0 months vs 11.0 months, P = .007). Conclusion With the current data, we conclude that AT benefits ICC patients following radical resection, especially those “middle‐risk” patients, as evaluated by the established nomogram. However, exactly which patients are the most suitable for AT requires further study and validation.

Abstract The introduction of “metamaterials” has had a profound impact on several fields, including electromagnetics. Designing a metamaterial’s structure on demand, however, is still an extremely time-consuming process. As an efficient machine learning method, deep learning has been widely used for data classification and regression in recent years and in fact shown good generalization performance. We have built a deep neural network for on-demand design. With the required reflectance as input, the parameters of the structure are automatically calculated and then output to achieve the purpose of designing on demand. Our network has achieved low mean square errors (MSE), with MSE of 0.005 on both the training and test sets. The results indicate that using deep learning to train the data, the trained model can more accurately guide the design of the structure, thereby speeding up the design process. Compared with the traditional design process, using deep learning to guide the design of metamaterials can achieve faster, more accurate, and more convenient purposes.

Background: To investigate the relationship between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) radiomic features and the expression activity of hallmark pathways and to develop prediction models of pathway-level heterogeneity for breast cancer (BC) patients. Methods: Two radiogenomic cohorts were analyzed (n = 246). Tumor regions were segmented semiautomatically, and 174 imaging features were extracted. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to identify significant imaging-pathway associations. Random forest regression was used to predict pathway enrichment scores. Five-fold cross-validation and grid search were used to determine the optimal preprocessing operation and hyperparameters. Results: We identified 43 pathways, and 101 radiomic features were significantly related in the discovery cohort (p-value < 0.05). The imaging features of the tumor shape and mid-to-late post-contrast stages showed more transcriptional connections. Ten pathways relevant to functions such as cell cycle showed a high correlation with imaging in both cohorts. The prediction model for the mTORC1 signaling pathway achieved the best performance with the mean absolute errors (MAEs) of 27.29 and 28.61% in internal and external test sets, respectively. Conclusions: The DCE-MRI features were associated with hallmark activities and may improve individualized medicine for BC by noninvasively predicting pathway-level heterogeneity.

The authors wish to make the following correction to this paper [...]

Background: This study aimed to reveal the heterogeneity of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of breast cancer (BC) and identify its prognosis values and molecular characteristics. Methods: Two radiogenomics cohorts (n = 246) were collected and tumor regions were segmented semi-automatically. A total of 174 radiomics features were extracted, and the imaging subtypes were identified and validated by unsupervised analysis. A gene-profile-based classifier was developed to predict the imaging subtypes. The prognostic differences and the biological and microenvironment characteristics of subtypes were uncovered by bioinformatics analysis. Results: Three imaging subtypes were identified and showed high reproducibility. The subtypes differed remarkably in tumor sizes and enhancement patterns, exhibiting significantly different disease-free survival (DFS) or overall survival (OS) in the discovery cohort (p = 0.024) and prognosis datasets (p ranged from p ranged from p < 0.05). Conclusions: The imaging subtypes had different clinical outcomes and biological characteristics, which may serve as potential biomarkers.

DNA molecules are highly compacted in the eukaryotic nucleus where distal regulatory elements reach their targets through three-dimensional chromosomal interactions. G-quadruplexes, stable four-stranded non-canonical DNA structures, can change local chromatin organization through the exclusion of nucleosomes. However, the relationship between G-quadruplexes and higher-order genome organization remains unknown. Here, we found that G-quadruplexes are significantly enriched at boundaries of topological associated domains (TADs). Architectural protein occupancy, which plays critical roles in the formation of TADs, was highly correlated with the content of G-quadruplexes at TAD boundaries. Moreover, adjacent boundaries containing G-quadruplexes frequently interacted with each other because of the high enrichment of architectural protein binding sites. Similar to CCCTC-binding factor (CTCF) binding sites, G-quadruplexes also showed strong insulation ability in the separation of adjacent regions. Additionally, the insulation ability of CTCF binding sites and TAD boundaries was significantly reinforced by G-quadruplexes. Furthermore, G-quadruplex motifs on different strands were associated with the orientation of CTCF binding sites. These findings suggest a potential role for G-quadruplexes in loop extrusion. The enrichment of transcription factor binding sites (TFBSs) around regulatory elements containing G-quadruplexes led to frequent interactions between regulatory elements containing G-quadruplexes. Intriguingly, more than 99% of G-quadruplexes overlapped with TFBSs. The binding sites of CTCF and cohesin proteins were preferentially located surrounding G-quadruplexes. Accordingly, we proposed a new mechanism of long-distance gene regulation in which G-quadruplexes are involved in distal interactions between enhancers and promoters.

Abstract Background The prognostic benefits and safety of extended lymphadenectomy for hilar cholangiocarcinoma remain uncertain. The available evidence is still insufficient concerning its retrospective aspect. The aim of this study is to explore the clinical effect and safety of extended lymphadenectomy compared to regional lymphadenectomy in patients with hilar cholangiocarcinoma. Methods The Relay-HC trial is a prospective, multicenter, and randomized controlled trial. Seven hundred and thirty-four eligible patients with resectable perihilar cholangiocarcinoma across 15 tertiary hospitals in China will be randomly assigned (1:1) to receive either regional lymphadenectomy or extended lymphadenectomy. The primary objective is to determine the overall survival after the two approaches. Secondary objectives of the study include the evaluation of perioperative mortality, postoperative complication, and disease-free survival. This study has been approved by the ethics committee of each participating hospital. Discussion The Relay-HC trial is designed to investigate the prognostic benefits and safety of expanded lymphadenectomy for hilar cholangiocarcinoma. Currently, it has never been investigated in a prospective randomized controlled clinical trial. Trial registration Chinese Clinical Trial Registry (ChiCTR), ChiCTR1800015688. Registered on 15 April 2018.

BackgroundThe clinical value of lymph-node dissection (LND) for intrahepatic carcinoma (ICC) patients with clinically negative lymph node metastasis (LNM) remains unclear; hence we conducted a multi-center study to explore it.MethodsPatients who were diagnosed ICC with clinically negative LNM and underwent hepatectomy with or without LND from December 2012 to December 2015 were retrospectively collected from 12 hepatobiliary centers in China. Overall survival (OS) was analyzed using the Kaplan–Meier method, and then subgroup analysis was conducted stratified by variables related to the prognosis.ResultsA total of 380 patients were eligible including 106 (27.9%) in the LND group and 274 (72.1%) in the non-LND group. Median OS in the LND group was slightly longer than that in the non-LND group (24.0 vs. 18.0 months, P = 0.30), but a significant difference was observed between the two groups (24.0 vs. 14.0 months, P = 0.02) after a well-designed 1:1 propensity score matching without increased severe complications. And, LND was identified to be one of the independent risk factors of OS (HR = 0.66, 95%CI = 0.46–0.95, P = 0.025). Subgroup analysis in the matched cohort showed that patients could benefit more from LND if they were male, age 5 cm, single tumor, mass-forming, no satellite, no MVI, and no perineural invasion (all P < 0.05). Furthermore, only patients with pathologically confirmed positive LNM were found to benefit from postoperative adjuvant therapy (P < 0.001).ConclusionWith the current data, we concluded that LND would benefit the selected ICC patients with clinically negative LNM and might guide the postoperative management.

The symbiosis between cnidarian hosts and photosynthetic dinoflagellates of the family Symbiodiniaceae (i.e., zooxanthellae) provides the energy foundation of coral reef ecosystems in oligotrophic waters. The structure of symbiont biota and the dominant species of algal symbiont partly shape the environmental adaptability of coral symbiotes. In this study, the algal symbiont cells were isolated from the tentacles of Galaxea fascicularis, a hermatypic coral with obvious differentiation in heat resistance, and were cultured in vitro with an improved L1 medium. An algal monoclonal cell line was established using separated algal culture drops and soft agar plating method, and named by GF19C1 as it was identified as Cladocopium sp. C1 (Symbiodiniaceae) based on its ITS1, ITS2, and the non-coding region of the plastid psbA minicircle (psbAncr) sequences. Most GF19C1 cells were at the coccoid stage of the gymnodinioid, their markedly thickened (ca. two times) cell wall suggests that they developed into vegetative cysts and have sexual and asexual reproductive potential. The average diameter of GF19C1 cells decreased significantly, probably due to the increasing mitotic rate. The chloroplasts volume density of GF19C1 was significantly lower than that of their symbiotic congeners, while the surface area density of thylakoids relative to volumes of chloroplasts was not significantly changed. The volume fraction of vacuoles increased by nearly fivefold, but there was no significant change in mitochondria and accumulation bodies. Light-temperature orthogonal experiments showed that, GF19C1 growth preferred the temperature 25 ± 1°C (at which it is maintained post-isolation) rather than 28 ± 1°C under the light intensity of 42 ± 2 or 62 ± 2 μmol photons m–2 s–1, indicating an inertia for temperature adaptation. The optimum salinity for GF19C1 growth ranged between 28–32 ppt. The monoclonal culture techniques established in this study were critical to clarify the physiological and ecological characteristics of various algal symbiont species, and will be instrumental to further reveal the roles of algal symbionts in the adaptive differentiation of coral-zooxanthellae holobionts in future studies.

In our previous experiment, we found that there were abnormal levels of circRNA-089763 in the plasma exosomes of patients with postoperative cognitive dysfunction (POCD) after cardiac surgery. Therefore, the aim of this study was to further investigate the relationship between plasma circRNA-089763 level and POCD in elderly patients after non-cardiac surgery. A prospective cohort study was conducted to select elderly patients undergoing elective non-cardiac surgery. A total of 72 patients were enrolled in this study, and cognitive functions were assessed 1 day before and 3 days after surgery by a series of neuropsychological measurements. Next, patients were divided into POCD and non-POCD (NPOCD) groups according to the Z score method. Blood was collected the day before and 3 days after surgery, and the plasma circRNA-089763 level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the difference and correlation in plasma circRNA-089763 levels between the POCD and NPOCD groups were analyzed. On the third day after surgery, the incidence of POCD was 30.56%. The relative level of circRNA-089763 in the POCD group was 2.41 times higher than that in the NPOCD group (t = 4.711, p < 0.001), patients in POCD group had higher age (t = 5.971, p < 0.001), higher American Society of Anesthesiologists classification (χ2 = 14.726, p < 0.001), less years of education (t = 2.449, p = 0.017), more intraoperative blood loss (t = 3.196, p = 0.002), and higher visual analog scale (VAS) scores (t = 10.45, p < 0.001). The binary logistic regression analysis showed that the circRNA-089763 level, age, and intraoperative blood loss were independently associated with POCD (OR: 2.75, 95% CI: 1.261–5.999, p = 0.011; OR: 1.32, 95% CI: 1.114–1.565, p = 0.001; OR: 1.017, 95% CI: 1.004–1.03, p = 0.011). These results demonstrated that the circRNA-089763 plasma level was related to POCD after non-cardiac surgery in elderly patients.

Circular RNAs (circRNAs) are considered as functional biomolecules with tissue/development-specific expression patterns. Generally, a single gene may generate multiple circRNA variants by alternative splicing, which contain different combinations of exons and/or introns. Due to the low abundance of circRNAs as well as overlapped with their linear counterparts, circRNA enrichment protocol is needed prior to sequencing. Compared with numerous algorithms, which use back-splicing reads for detection and functional characterization of circRNAs, original bioinformatic analyzing tools have been developed to large-scale determination of full-length circRNAs and accurate quantification. This review provides insights into the complexity of circRNA biogenesis and surveys the recent progresses in the experimental and bioinformatic methodologies that focus on accurately full-length circRNAs identification.

High‐resolution climate models have been shown to improve the statistics of tropical storms (TCs) and hurricanes compared to low‐resolution models. The impact of increasing horizontal resolution in the TC simulation is investigated exclusively using a series of Atmospheric Global Climate Model (AGCM) runs with idealized aquaplanet steady‐state boundary conditions and a fixed operational storm‐tracking algorithm. The results show that increasing horizontal resolution helps to detect more hurricanes, simulate stronger extreme rainfall, and emulate better storm structures in the models. However, increasing model resolution does not necessarily produce stronger hurricanes in terms of maximum wind speed, minimum sea‐level pressure, and mean precipitation, as the increased number of storms simulated by high‐resolution models is mainly associated with weaker storms. The spatial scale at which the analyses are conducted appears to have more important control on these meteorological statistics compared to horizontal resolution of the model grid. When the simulations are analyzed on common low‐resolution grids, the statistics of the hurricanes, particularly the hurricane counts, show reduced sensitivity to the horizontal grid resolution and signs of scale invariance.

We used a lake thermal physics model recently coupled into the Community Earth System Model 1 (CESM1) to study the effects of lake distribution in present and future climate. Under present climate, correcting the large underestimation of lake area in CESM1 (denoted CCSM4 in the configuration used here) caused 1 °C spring decreases and fall increases in surface air temperature throughout large areas of Canada and the US. Simulated summer surface diurnal air temperature range decreased by up to 4 °C, reducing CCSM4 biases. These changes were much larger than those resulting from prescribed lake disappearance in some present-day permafrost regions under doubled-CO2 conditions. Correcting the underestimation of lake area in present climate caused widespread high-latitude summer cooling at 850 hPa. Significant remote changes included decreases in the strength of fall Southern Ocean westerlies. We found significantly different winter responses when separately analysing 45-yr subperiods, indicating that relatively long simulations are required to discern the impacts of surface changes on remote conditions. We also investigated the surface forcing of lakes using idealised aqua-planet experiments which showed that surface changes of 2 °C in the Northern Hemisphere extra-tropics could cause substantial changes in precipitation and winds in the tropics and Southern Hemisphere. Shifts in the Inter-Tropical Convergence Zone were opposite in sign to those predicted by some previous studies. Zonal mean circulation changes were consistent in character but much larger than those occurring in the lake distribution experiments, due to the larger magnitude and more uniform surface forcing in the idealised aqua-planet experiments.

Extreme precipitation is generally underestimated by current climate models relative to observations of present-day rainfall distributions. Possible causes of this systematic error include the convective parameterization in these models that have been designed to reproduce measurements of climatological mean precipitation. One possible approach to improve the interaction of subgrid-scale physical processes and large-scale climate is to replace the conventional convective parameterizations with a high-resolution cloud-system resolving model. A ‘super-parameterized’ Community Atmosphere Model (SP‑CAM) utilizing this approach is used in this study to investigate the distribution of extreme precipitation in the United States. Results show that SP-CAM better simulates the distributions of both light and intense precipitation compared to the standard version of CAM based upon conventional parameterizations. The improvements are mostly seen in regions dominated by convective precipitation, suggesting that super-parameterization provides a better representation of subgrid convective processes.