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Background and Aim: Endoscopic resection has been successfully used for the removal of digestive submucosal tumors (SMTs). However, the cardia has been considered a challenging location for endoscopic resection due to its narrow lumen and sharp angle. The objective of this study was to establish a clinical scoring model to grade the technical difficulty of endoscopic resection for cardial SMTs., Methods: A total of 246 patients who suffered cardial SMTs and received endoscopic resection were included in this retrospective study. All of them were randomized into the training cohort (n = 123) or internal validation cohort (n = 123). Potential predictors were analyzed using univariate analysis. Then, covariates with P < 0.05 were selected for the multivariate logistic regression model. The β coefficients from the logistic regression model were used to create a scoring system for technical difficulty prediction by rounding the score to the nearest integer of the absolute β coefficient value., Results: The clinical score consisted of the following factors: male gender (2 points), extraluminal growth (3 points), and maximum diameter ≥3 cm (3 points). The scoring model demonstrated good discriminatory power, with an area under the receiver operating characteristic curve of 0.860 and a 95% confidence interval of 0.763-0.958. The model also showed a good goodness of fit in the Hosmer-Lemeshow test (P = 0.979). In the training cohort, the probability of encountering technical difficulty in the easy (score = 0), intermediate (score = 1-3), difficult (score = 4-6), and very difficult (score >6) categories was 0, 6.8%, 33.3%, and 100.0%, respectively; similarly, in the validation cohort, it was 0, 5.6%, 22.2%, and 50.0%, respectively., Conclusions: This scoring system could serve as a valuable tool for clinicians in predicting the technical difficulty of endoscopic resection for cardial SMTs., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor ( MET ) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice., Aim: To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy., Methods: A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA., Results: Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) ( P < 0.001) and higher tumor budding grade ( P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis ( P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM ( P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET -to- CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03)., Conclusion: In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification., Competing Interests: Conflict-of-interest statement: The authors have no relevant financial or non-financial interests to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Accurate recognition of endoscopic instruments facilitates quantitative evaluation and quality control of endoscopic procedures. However, no relevant research has been reported. In this study, we aimed to develop a computer-assisted system, EndoAdd, for automated endoscopic surgical video analysis based on our dataset of endoscopic instrument images., Methods: Large training and validation datasets containing 45,143 images of 10 different endoscopic instruments and a test dataset of 18,375 images collected from several medical centers were used in this research. Annotated image frames were used to train the state-of-the-art object detection model, YOLO-v5, to identify the instruments. Based on the frame-level prediction results, we further developed a hidden Markov model to perform video analysis and generate heatmaps to summarize the videos., Results: EndoAdd achieved high accuracy (>97%) on the test dataset for all 10 endoscopic instrument types. The mean average accuracy, precision, recall, and F1-score were 99.1%, 92.0%, 88.8%, and 89.3%, respectively. The area under the curve values exceeded 0.94 for all instrument types. Heatmaps of endoscopic procedures were generated for both retrospective and real-time analyses., Conclusions: We successfully developed an automated endoscopic video analysis system, EndoAdd, which supports retrospective assessment and real-time monitoring. It can be used for data analysis and quality control of endoscopic procedures in clinical practice.

Background: Calcifying fibrous tumors (CFTs) are rare mesenchymal lesions that can occur in various sites throughout the body, including the tubular gastrointestinal (GI) tract., Aim: To analyze the clinical findings of 36 patients with GI tract CFTs to provide guidance for diagnosis and treatment., Methods: This retrospective study included 36 patients diagnosed with CFTs of the GI tract. We collected demographic and clinical information and conducted regular follow-ups to assess for local recurrence., Results: The stomach was the most commonly involved site, accounting for 72.2% of the 36 CFTs. Endoscopic mucosal resection ( n = 1, 2.8%), endoscopic submucosal dissection ( n = 14, 38.9%), endoscopic full-thickness resection ( n = 16, 44.4%), and submucosal tunneling endoscopic resection ( n = 5, 13.9%) were used to resect calcifying fibrous tumors. Overall, 34 (94.4%) CFTs underwent complete endoscopic resections with a mean procedure time of 39.8 ± 29.8 min. The average maximum diameter of the tumors was 10.6 ± 4.3 cm. No complications, such as bleeding or perforation, occurred during an average hospital stay of 2.9 ± 1.2 d. In addition, two patients developed new growth of CFTs near the primary tumor sites, and none of the patients developed distant metastases during the follow-up period., Conclusion: GI tract CFTs are rare and typically benign tumors that can be effectively managed with endoscopic procedures., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest or financial ties to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Gastric cystica profunda (GCP) represents a rare condition characterized by cystic dilation of gastric glands within the mucosal and/or submucosal layers. GCP is often linked to, or may progress into, early gastric cancer (EGC)., Aim: To provide a comprehensive evaluation of the endoscopic features of GCP while assessing the efficacy of endoscopic treatment, thereby offering guidance for diagnosis and treatment., Methods: This retrospective study involved 104 patients with GCP who underwent endoscopic resection. Alongside demographic and clinical data, regular patient follow-ups were conducted to assess local recurrence., Results: Among the 104 patients diagnosed with GCP who underwent endoscopic resection, 12.5% had a history of previous gastric procedures. The primary site predominantly affected was the cardia (38.5%, n = 40). GCP commonly exhibited intraluminal growth (99%), regular presentation (74.0%), and ulcerative mucosa (61.5%). The leading endoscopic feature was the mucosal lesion type (59.6%, n = 62). The average maximum diameter was 20.9 ± 15.3 mm, with mucosal involvement in 60.6% ( n = 63). Procedures lasted 73.9 ± 57.5 min, achieving complete resection in 91.3% ( n = 95). Recurrence (4.8%) was managed via either surgical intervention ( n = 1) or through endoscopic resection ( n = 4). Final pathology confirmed that 59.6% of GCP cases were associated with EGC. Univariate analysis indicated that elderly males were more susceptible to GCP associated with EGC. Conversely, multivariate analysis identified lesion morphology and endoscopic features as significant risk factors. Survival analysis demonstrated no statistically significant difference in recurrence between GCP with and without EGC ( P = 0.72)., Conclusion: The findings suggested that endoscopic resection might serve as an effective and minimally invasive treatment for GCP with or without EGC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Gastric cancer (GC) stands as a prevalent and deadly global malignancy. Despite its role as a preoperative neoadjuvant therapy, Apatinib's effectiveness is curtailed among GC patients exhibiting elevated YY1 expression. YY1's connection to adverse prognosis, drug resistance, and GC metastasis is established, yet the precise underlying mechanisms remain elusive. This study aims to unravel potential pathogenic pathways attributed to YY1., Design: Utilizing bioinformatics analysis, we conducted differentially expressed genes, functional annotation, and pathway enrichment analyses, and further validation through cellular and animal experiments., Results: Higher YY1 expression correlated with diminished postoperative progression-free survival (PFS) and disease-specific survival (DSS) rates in TCGA analysis, identifying YY1 as an independent DSS indicator in gastric cancer (GC) patients. Notably, YY1 exhibited significantly elevated expression in tumor tissues compared to adjacent normal tissues. Bioinformatics analysis revealed noteworthy differentially expressed genes (DEGs), transcriptional targets, factors, and co-expressed genes associated with YY1. LASSO Cox analysis unveiled Transferrin as a prospective pivotal protein regulated by YY1, with heightened expression linked to adverse DSS and PFS outcomes. YY1's role in governing the p53 signaling pathway and ferroptosis in GC cells was further elucidated. Moreover, YY1 overexpression dampened immune cell infiltration within GC tumors. Additionally, YY1 overexpression hindered GC cell ferroptosis and mediated Apatinib resistance via the p53 pathway. Remarkably, IFN-a demonstrated efficacy in reversing Apatinib resistance and immune suppression in GC tissues., Conclusions: Our findings underscore the pivotal role of YY1 in driving GC progression and influencing prognosis, thus pinpointing it as a promising therapeutic target to enhance patient outcomes., (© 2024. The Author(s).)

Background and Aim: Endoscopic resection (ER) has been used to remove submucosal tumors (SMTs) in recent years; however, duodenal ER is associated with high rates of immediate or delayed bleeding and perforation. Whether ER can be recommended for the treatment of duodenal SMTs remains controversial. Therefore, we aimed to investigate the clinical outcomes associated with the ER of duodenal SMTs and to assess possible predictive factors for complications and incomplete resection., Methods: This retrospective study included 141 patients with duodenal SMTs. The therapeutic outcomes from ER and procedure-related complications were analyzed., Results: Of the 141 patients, 78.7% achieved complete resection and nine (6.4%) developed complications. The multivariate analysis suggested that location near the duodenal papilla (P = 0.010) and diameter exceeding 15 mm (P = 0.091) of duodenal SMTs were independent risk factors for complications in ER. Besides, submucosal fibrosis (P = 0.042), location near the duodenal papilla (P = 0.049), and irregular morphology (P = 0.067) were independent risk factors for incomplete resection., Conclusions: ER can be recommended as an effective and minimally invasive treatment for duodenal SMTs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10 -5 ), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families., (© 2023. The Author(s).)

Objective: The gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility disorder characterized by the selective degeneration of inhibitory neurons in the esophageal myenteric plexus. This study aimed to evaluate the composition of the esophageal microbiota in achalasia and explore the potential microbial mechanisms involved in its pathogenesis., Design: The lower esophageal mucosal microbiota was analyzed in patients with achalasia and control participants using 16 S rRNA sequencing. The association between the esophageal microbiota and achalasia was validated by inducing esophageal dysbiosis in C57BL/10 J and C57BL/10ScNJ (TLR4KO) mice via chronic exposure to ampicillin sodium in their drinking water., Results: The esophageal microbiota in EA patients had lower diversity and a predominance of Gram-negative bacteria (Type II microbiota) compared to that in the healthy controls. Additionally, the relative abundance of Rhodobacter decreased significantly in patients with achalasia, which correlated with an enrichment of lipopolysaccharide (LPS) biosynthesis based on the COG database. Antibiotic-treated mice showed an esophageal microbiota characterized by increased abundance of Gram-negative bacteria (Type II microbiome), decreased abundance of Rhodobacter, and enriched LPS biosynthesis. Compared to the control and TLR4KO mice, the antibiotic-treated wild-type mice had higher LES resting pressure, increased LES contraction rate after carbachol stimulation, and decreased relaxation response to L-arginine. Moreover, the number of myenteric neurons decreased, while the number of lamina propria macrophages (LpMs) increased after antibiotic exposure. Furthermore, the TLR4-MYD88-NF-κB pathway was up-regulated, and the production of TNF-α, IL-1β, and IL-6 increased in the antibiotic-treated mice., Conclusions: Patients with achalasia exhibit esophageal dysbiosis, which may induce aberrant esophageal motility., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest or financial ties to disclose., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background and Aims: Stenosis after esophageal endoscopic submucosal dissection (ESD) has a high incidence, and muscular injury is an important risk factor for esophageal stenosis. Hence, this study aimed to classify muscular injury degrees and investigate their association with postoperative stenosis., Methods: This retrospective study included 1033 patients with esophageal mucosal lesions treated with ESD between August 2015 and March 2021. Demographic and clinical parameters were analyzed, and stenosis risk factors were identified using multivariate logistic regression. A novel muscular injury classification system was proposed and used to investigate the association between different muscular injury degrees and postoperative stenosis. Finally, a scoring system was established to predict muscular injury., Results: Of 1033 patients, 118 (11.4%) had esophageal stenosis. The multivariate analysis demonstrated that the history of endoscopic esophageal treatment, circumferential range, and muscular injury were significant risk factors for esophageal stenosis. Patients with type II muscular injuries tended to develop complex stenosis (n = 13 [36.1%], P < .05), and type II muscular injuries were more likely to predispose patients to severe stenosis than type I (73.3% and 92.3%, respectively). The scoring system showed that patients with high scores (3-6) were more likely to have muscular injury. The score model presented good discriminatory power in the internal validation (area under the receiver-operating characteristic curve, .706; 95% confidence interval, .645-.767) and goodness-of-fit in the Hosmer-Lemeshow test (P = .865)., Conclusions: Muscular injury was an independent risk factor for esophageal stenosis. The scoring system demonstrated good performance in predicting muscular injury during ESD., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The multiple metastable excited states provided by excited-state intramolecular proton transfer (ESIPT) molecules are beneficial to bring temperature-dependent and color-tunable long persistent luminescence (LPL). Meanwhile, ESIPT molecules are intrinsically suitable to be modulated as D-π-A structure to obtain both one/two-photon excitation and LPL emission simultaneously. Herein, we report the rational design of a dynamic Cd II coordination polymer (LIFM-106) from ESIPT ligand to achieve the above goals. By comparing LIFM-106 with the counterparts, we established a temperature-regulated competitive relationship between singlet excimer and triplet LPL emission. The optimization of ligand aggregation mode effectively boost the competitiveness of the latter. In result, LIFM-106 shows outstanding one/two-photon excited LPL performance with wide temperature range (100-380 K) and tunable color (green to red). The multichannel radiation process was further elucidated by transient absorption and theoretical calculations, benefiting for the application in anti-counterfeiting systems., (© 2023 Wiley-VCH GmbH.)

Objective: To evaluate the effectiveness and safety of endoscopic resection and various suturing methods to treat non-ampullary duodenal submucosal tumors (NAD-SMTs)., Design: We performed a retrospective observational study of patients with NAD-SMTs who underwent endoscopic resection at Zhongshan Hospital, Fudan University, China, between June 2017 and December 2020. Data on patient characteristics, treatments and follow-up results were collected. The association between clinicopathologic characteristics and different suturing methods or adverse events were analyzed., Results: Of 128 patients analyzed, 26 underwent endoscopic mucosal resection (EMR), 64 underwent endoscopic submucosal excavation (ESE), and 38 underwent endoscopic full-thickness resection (EFTR). EMR and ESR are both appropriate for non-full-thickness lesions, whereas ESE is more appropriate for tumors located in the bulb or descending duodenum. Gastric tube drainage is more strongly recommended after ESE. Satisfactory suturing is also vital endoscopic resection of NAD-SMTs. Metallic clips are often used in EMR or ESE of non-full-thickness lesions. The pathological findings revealed that the full-thickness lesions were predominantly gastrointestinal stromal tumors (GIST), Brunner's tumor or lipoma, and the surgeons usually used purse-string sutures to close the wounds. The operation time was longer for purse-string suture closure than metallic clip closure. Eleven patients had complications. Risk factors for adverse events included large-diameter tumor (≥ 2 cm), location in the descending part of the duodenum, involvement of the fourth layer of the duodenal wall, EFTR, and GIST., Conclusions: Endoscopic resection of NAD-SMTs is effective but is associated with a high incidence of complications due to their anatomical peculiarities. Preoperative diagnosis is quite important. Careful selection of treatment and suturing methods are necessary to reduce the risk of adverse effects. Given the increased frequency of severe complications during or following duodenal endoscopic resection, this procedure should be performed by experienced endoscopists., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Optimal bowel preparation is a prerequisite for a successful colonoscopy; however, the rate of inadequate bowel preparation remains relatively high. In this study, we establish a smartphone app that assesses patient bowel preparation using an artificial intelligence (AI)-based prediction system trained on labeled photographs of feces in the toilet and evaluate its impact on bowel preparation quality in colonoscopy outpatients. We conduct a prospective, single-masked, multicenter randomized clinical trial, enrolling outpatients who own a smartphone and are scheduled for a colonoscopy. We screen 578 eligible patients and randomize 524 in a 1:1 ratio to the control or AI-driven app group for bowel preparation. The study endpoints are the percentage of patients with adequate bowel preparation and the total BBPS score, compliance with dietary restrictions and purgative instructions, polyp detection rate, and adenoma detection rate (secondary). The prediction system has an accuracy of 95.15%, a specificity of 97.25%, and an area under the curve of 0.98 in the test dataset. In the full analysis set (n = 500), adequate preparation is significantly higher in the AI-driven app group (88.54 vs. 65.59%; P < 0.001). The mean BBPS score is 6.74 ± 1.25 in the AI-driven app group and 5.97 ± 1.81 in the control group (P < 0.001). The rates of compliance with dietary restrictions (93.68 vs. 83.81%, P = 0.001) and purgative instructions (96.05 vs. 84.62%, P < 0.001) are significantly higher in the AI-driven app group, as is the rate of additional purgative intake (26.88 vs. 17.41%, P = 0.011). Thus, our AI-driven smartphone app significantly improves the quality of bowel preparation and patient compliance., (© 2023. The Author(s).)

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10 -33 ). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A new design was applied for the facile synthesis of pure organic photoluminescent molecules with dual excited-state intramolecular proton transfer (ESIPT) sites. In this novel class of emitters, full-color panel emission from blue, green, and yellow to red, including white light, can be achieved in different solvents as modulated by the enol-keto(1st)-keto(2nd) tautomer emissions. A comprehensive transient photophysical study verifies that keto(1st) and keto(2nd) have a precursor (<0.8 ps)-successor (∼20 ps)-relayed absorbance relationship, and then a fast equilibrium between the two is established, resulting in dual emissions in the nanosecond scale (∼1900 ps). Through the research on copper ions' selective PL response, the dual-ESIPT mechanism was further verified; in addition, the study of solid-state PL changes upon the stimulus of organic vapor manifests the potential application sensitivity of the molecules as dual-ESIPT sensors. Theoretical results including reaction potential energy surface analyses manifest the fact that dual-proton transfer goes along a sequential route with a smaller energy barrier, firmly supporting the experimental results. An intrinsic system that undergoes intramolecular double proton relayed transfer is thus established for the achievement of much broadened optical responses and full-color display, providing reference for the design and application of advanced dual-ESIPT optical materials.

By designing a tetraphenylethylene (TPE)-based AIEgen-ligand with reduced symmetry, we obtained two alkaline-earth metal-based MOFs (LIFM-102 and LIFM-103) with dense packing structures and low porosity as proved by single-crystal X-ray diffraction and CO 2 sorption data. Excitingly, the desolvated MOFs with rigid environment and reduced lattice free solvent exhibit high quantum yields (QY, 64.9 % and 79.4 %) and excellent two-photon excited photoluminescence (TPA cross-sections, 2946.6 GM and 2899.0 GM), while maintaining the external-stimuli-responsive properties suitable for anticounterfeit fields. The effect of ligand conformation was validated by comparing the structure and fluorescence properties of the samples before and after desolvation and further verified by theoretical calculations. This work expands the study on TPE-cored materials to symmetry-reduced ligand and might bring forward novel structures and excellent photoluminescent properties in the future., (© 2022 Wiley-VCH GmbH.)

Organic LPL (long-persistent luminescence) materials have sparked extensive research interest due to the ultralong-lived triplet states. Although numerous organic LPL materials have been reported, most of the triplet emission was static and monotonous. Therefore, LPL materials with dynamic triplet emission are urgently required. A triamino-s-triazine derivative 1 with dynamic LPL was fabricated. The single-crystal structure shows that the abundant intermolecular interactions and small free volume restrict the molecular motion and avoid the quenchers. Spectral and theoretical calculations upheld the existence of multiple excited states in 1, and the migration of electrons between multiple excited states is very sensitive to external stimuli. By modulating the stimulus, the residence of electrons in different triplet states can be manipulated to achieve RGB LPL. Importantly, blue LPL was achieved by manipulating the anti-Kasha emission. And the red LPL can still be observed at high temperature., (© 2022 Wiley-VCH GmbH.)

Competing Interests: The authors declare that they have no conflict of interest.

Motivation: Taxonomic classification of 16S ribosomal RNA gene amplicon is an efficient and economic approach in microbiome analysis. 16S rRNA sequence databases like SILVA, RDP, EzBioCloud and HOMD used in downstream bioinformatic pipelines have limitations on either the sequence redundancy or the delay on new sequence recruitment. To improve the 16S rRNA gene-based taxonomic classification, we merged these widely used databases and a collection of novel sequences systemically into an integrated resource., Results: MetaSquare version 1.0 is an integrated 16S rRNA sequence database. It is composed of more than 6 million sequences and improves taxonomic classification resolution on both long-read and short-read methods., Availability and Implementation: Accessible at https://hub.docker.com/r/lsbnb/metasquare&#95;db and https://github.com/lsbnb/MetaSquare., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Excited-state intramolecular proton transfer (ESIPT) molecules demonstrating specific enol-keto tautomerism and the related photoluminescence (PL) switch have wide applications in displaying, sensing, imaging, lasing, etc. However, an ESIPT-attributed coordination polymer showing alternative PL between thermally activated fluorescence (TAF) and long persistent luminescence (LPL) has never been explored. Herein, we report the assembly of a dynamic Cd(II) coordination polymer (LIFM-101) from the ESIPT-type ligand, HPI2C (5-(2-(2-hydroxyphenyl)-4,5-diphenyl-1 H -imidazol-1-yl)isophthalic acid). For the first time, TAF and/or color-tuned LPL can be achieved by controlling the temperature under the guidance of ESIPT excited states. Noteworthily, the twisted structure of the HPI2C ligand in LIFM-101 achieves an effective mixture of the higher-energy excited states, leading to ISC (intersystem crossing)/RISC (reverse intersystem crossing) energy transfer between the high-lying keto-triplet state (T n (K*)) and the first singlet state (S 1 (K*)). Meanwhile, experimental and theoretical results manifest the occurrence probability and relevance among RISC, ISC, and internal conversion (IC) in this unique ESIPT-attributed coordination polymer, leading to the unprecedented TAF/LPL switching mechanism, and paving the way for the future design and application of advanced optical materials.

Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative for researchers to understand the resources and methodologies available for various data types and study designs. In this review, we provide an overview of recent methods for identifying rare and common variants and understanding their roles in disease etiology. Additionally, we discuss the strategy, challenge, and promise of gene therapy. As computational and statistical approaches continue to improve, we will have an opportunity to translate human genetic findings into personalized health care.

Introduction: Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterized by constitutive activity of the tyrosine kinase BCR-ABL1. Drug resistance remains one of the major challenges in CML therapy. MicroRNA (miR)-199a-3p plays an important role in many tumours but has rarely been investigated in CML. We aimed to analyse the role and mechanism of miR-199a-3p in regulating imatinib resistance in CML., Methods: The expression of miR-199a-3p and mammalian target of rapamycin (mTOR) in the serum of CML patients and CML cells was examined by quantitative real-time polymerase chain reaction. The levels of apoptosis-related proteins were determined using western blot. The relative cell survival rate and cell proliferation were determined using a CCK-8 assay and a bromodeoxyuridine (BrdU) assay, respectively. Cell cycle and apoptosis were analysed using flow cytometry. Moreover, a dual-luciferase reporter assay was performed to verify the correlation between miR-199a-3p and mTOR., Results: MiR-199a-3p was downregulated in the serum of CML patients and in CML cells, while mTOR was upregulated. Both miR-199a-3p overexpression and mTOR silencing inhibited CML cell proliferation, promoted CML cell apoptosis, and sensitized these cells to imatinib. mTOR silencing reversed the promoting effect of miR-199a-3p inhibition on the proliferation of CML cells and the inhibitory effects on cell apoptosis and sensitivity to imatinib. MiR-199a-3p directly targeted mTOR., Conclusion: MiR-199a-3p suppressed cell propagation, facilitated apoptosis of CML cells, and sensitized CML cells to imatinib by downregulating mTOR signalling., (© 2022 S. Karger AG, Basel.)

BACKGROUND Bacteroides fragilis (B. fragilis) is an uncommon cause of native joint septic arthritis (NJSA). It is an anaerobic gram-negative rod that is normally found in the oral cavity, gastrointestinal tract, genitourinary system, and skin, and thus is rarely isolated from the musculoskeletal system. Risk factors for B. fragilis NJSA include inflammatory arthritis, malignancy, sickle cell disease, and ischemic heart disease. CASE REPORT We discuss a case of a 65-year-old man with coronary artery disease, heart failure, chronic kidney disease, and gout, who presented with 5 days of right knee pain, redness, swelling, and warmth. His history included a corticosteroid injection in the affected knee 2 months prior to presentation. The patient was febrile with a palpable right knee joint effusion on exam. Labs were significant for leukocytosis and elevated inflammatory markers. Synovial fluid was aspirated, which was diagnostic for septic arthritis, with cultures growing B. fragilis. Blood cultures were negative, so the infection was attributed to the prior joint injection. The patient was subsequently taken to the operating room for irrigation and debridement. He was started on metronidazole, but he unfortunately left against medical advice before treatment was complete and was lost to follow-up thereafter. CONCLUSIONS B. fragilis NJSA most often occurs in the setting of bacteremia or contiguous spread from a concomitant infection. Management involves antibiotics such as metronidazole and surgical drainage. Due to the paucity of data on an infection such as in the present case, the optimal duration of metronidazole is not well-established.

Background & Aims: Hepatocellular carcinoma (HCC) is a fatal disease characterized by vast molecular heterogeneity. Although major advances in tumour genetics has led to the identification of new biomarkers, the prognosis of patients with HCC remains dismal., Methods: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot (WB) were used to evaluate meiosis-specific nuclear structural 1 (MNS1) expression in HCC cells. Immunohistochemistry staining was used to evaluate MNS1 expression in HCC tissues. Clinical significance of MNS1 was evaluated by Cox regression analysis. Transwell assays were conducted to assess cells migration ability. Cell counting kit-8 and colony formation assays were performed to detect cells proliferation ability. NOD/SCID/γc(null) (NOG) mice model was adopted to investigate functions of MNS1 in vivo., Results: The expression of MNS1, which is elevated in most HCC tissues, correlated with poor survival in HCC patients. Functional experiments revealed the oncogenic role of MNS1, which promotes HCC growth and metastasis through AKT-dependent modulation of β-catenin. β-Catenin expression was crucial for MNS1's oncogenic effects. MNS1 indirectly translocated β-catenin from the cytoplasm to the nucleus via the MNS1-GSK3β axis., Conclusions: MNS1 promotes HCC growth and metastasis via activating PI3K/AKT signalling and may serve as an important prognostic biomarker as well as potential novel therapeutic target for HCC., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Telomeres are essential for chromosome maintenance. Cdc13 is a single-stranded telomeric DNA binding protein that caps telomeres and regulates telomerase function in yeast. Although specific binding of Cdc13 to telomeric DNA is critical for telomere protection, the detail mechanism how Cdc13-DNA complex protects telomere is unclear. Using two single-molecule methods, tethered particle motion and atomic force microscopy, we demonstrate that specific binding of Cdc13 on single-stranded telomeric DNA shortens duplex DNA into distinct states differed by ∼70-80 base pairs. DNA shortening by Cdc13 is dynamic and independent of duplex DNA sequences or length. Significantly, we found that Pif1 helicase is incapable of removing Cdc13 from the shortened DNA-Cdc13 complex, suggesting that Cdc13 forms structurally stable complex by shortening of the bound DNA. Together our data identified shortening of DNA by Cdc13 and provided an indication for efficient protection of telomere ends by the shortened DNA-Cdc13 complex.

Various epidemiology studies showed the correlation between Alzheimer's disease (AD) and low incidence of cancer. However, the etiology underlying etiology of AD-related carcinogenesis remains largely elusive. Our study focused on characterizing the role of TM2D1 (TM2 domain containing 1) in hepatocellular carcinoma. TM2D1 is also known as β-amyloid peptide binding protein and is critical to the pathogenesis of AD. We found that TM2D1 is increasingly expressed in HCC tumors relative to the peritumoral tissues of the matched tumors and high TM2D1 expression predicts unfavorable clinical outcomes. TM2D1 overexpression induced HCC cell proliferation, migration and invasion, which was related to the epithelial-mesenchymal transition (EMT) observed in these cells. Conversely, TM2D1 depletion led to opposite phenotype in HCC. Mechanistically, we found that TM2D1 promoted Akt and β-catenin hyper-activation, which corresponded with molecular marker change in EMT signaling pathway. Taken together, our results indicated that TM2D1 played an important role in the EMT process in HCC cells by activating AKT and β-catenin signaling and may become a promising therapeutic target in HCC., Competing Interests: None., (AJCR Copyright © 2021.)

Background: Evaluating the need for palliative care and predicting its mortality play important roles in the emergency department., Aim: We developed a screening model for predicting 1-year mortality., Design: A retrospective cohort study was conducted to identify risk factors associated with 1-year mortality. Our risk scores based on these significant risk factors were then developed. Its predictive validity performance was evaluated using area under receiving operating characteristic analysis and leave-one-out cross-validation., Setting and Participants: Patients aged 15 years or older were enrolled from June 2015 to May 2016 in the emergency department., Results: We identified five independent risk factors, each of which was assigned a number of points proportional to its estimated regression coefficient: age (0.05 points per year), qSOFA ⩾ 2 (1), Cancer (4), Eastern Cooperative Oncology Group Performance Status score ⩾ 2 (2), and Do-Not- R esuscitate status (3). The sensitivity, specificity, positive predictive value, and negative predictive value of our screening tool given the cutoff larger than 3 points were 0.99 (0.98-0.99), 0.31 (0.29-0.32), 0.26 (0.24-0.27), and 0.99 (0.98-1.00), respectively. Those with screening scores larger than 9 points corresponding to 64.0% (60.0-67.9%) of 1-year mortality were prioritized for consultation and communication. The area under the receiving operating characteristic curves for the point system was 0.84 (0.83-0.85) for the cross-validation model., Conclusions: A-qCPR risk scores provide a good screening tool for assessing patient prognosis. Routine screening for end-of-life using this tool plays an important role in early and efficient physician-patient communications regarding hospice and palliative needs in the emergency department.

Nitrogen plays a vital role in biological activities as the basic element of organic molecules and the main nutrient of soil. In the study of nitrogen pollution, the first step is to understand the transformation mechanism of various nitrogen forms. Based on the transformation process and the mechanism of nitrogen in the ecosystem, this review summarizes the research methods of nitrogen source analysis and nitrogen isotope fractionation in soil and water, and categorically reviews the applications of nitrogen source identification in surface water and groundwater. We showed that it is more effective to identify the sources of soil and water nitrogen pollution by combining hydrochemical methods with the multi-isotope approach. The importance of primary nitrogen sources should also be quantified to study groundwater pollution. A new approach to determine the source of oxygen atoms during nitrosation was also presented, and the enrichment principle of δ 18 O-NO 3 - during secondary oxidation was explained. Finally, the contribution of primary ammonium nitrogen to groundwater pollution was discussed, and innovative research ideas were provided.

Previous research suggests that far upstream element-binding protein 1 (FUBP1) plays an important role in various tumors including epatocellular carcinoma (HCC). However, the role of FUBP1 in liver cancer remains controversial, and the regulatory pathway by FUBP1 awaits to be determined. This study aims to identify the role of FUBP1 in HCC progression. Our result shows that the high level of FUBP1 expression in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion, and metastasis by activating transforming growth factor-β (TGF-β)/Smad pathway and enhancing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Inhibitor of Thrombospondin-1 (LSKL) could inhibit HCC proliferation and invasion in vitro and in vivo by blocking the activation of TGF-β/Smad pathway mediated by thrombospondin-1 (THBS1). Our study identified the critical role of FUBP1-THBS1-TGF-β signaling axis in HCC and provides potentially new therapeutic modalities in HCC., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Metal-organic frameworks (MOFs) with long persistent luminescence (LPL) have attracted widespread attention due to potential applications in displays, anticounterfeiting, and so on. However, MOFs often have large pore size, which restricts the formation of efficient inter- and intramolecular interactions to realize LPL. Herein, a new approach to achieving LPL in MOFs by multifold interpenetration of discrete frameworks is reported. By comparison between threefold- and twofold-interpenetrating MOFs, it was found that the former, which have higher multiplicity and denser frameworks, can be endowed with enhanced inter- and intramolecular interactions, and thus enhanced LPL is obtained. Meanwhile, metal-cluster and heavy-halogen effects could also cause variations in LPL duration and color., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Liver cancer is a lethal disease that is associated with poor prognosis. In order to identify the functionally important genes associated with liver cancer that may reveal novel therapeutic avenues, we performed integrated analysis to profile miRNA and mRNA expression levels for liver tumors compared to normal samples in The Cancer Genome Atlas (TCGA) database. We identified 405 differentially expressed genes and 233 differentially expressed miRNAs in tumor samples compared with controls. In addition, we also performed the pathway analysis and found that mitogen-activated protein kinases (MAPKs) and G-protein coupled receptor (GPCR) pathway were two of the top significant pathway nodes dysregulated in liver cancer. Furthermore, by examining these signaling networks, we discovered that FOS (Fos proto-oncogene, AP-1 transcription factor subunit), LAMC2 (laminin subunit gamma 2), and CALML3 (calmodulin like 3) were the most significant gene nodes with high degrees involved in liver cancer. The expression and disease prediction accuracy of FOS, LAMC2, CALML3, and their interacting miRNAs were further performed using a HCC cohort. Finally, we investigated the prognostic significance of FOS in another HCC cohort. Patients with higher FOS expression displayed significantly shorter time to recurrence (TTR) and overall survival (OS) compared with patients with lower expression. Collectively, our study demonstrates that FOS is a potential prognostic marker for liver cancer that may reveal a novel therapeutic avenue in this lethal disease., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Jin-Wu Hu et al.)

Background: To evaluate the feasibility of predicting tumor recurrence of hepatocellular carcinoma (HCC) patients after curative hepatectomy by detection of circulating tumor DNA (ctDNA) through droplet digital PCR (ddPCR)., Methods: HCC patients receiving surgical treatment were enrolled and peripheral blood samples before and after hepatectomy were collected. Four hotspot mutants, TP53 -rs28934571 (c.747G>T), TRET -rs1242535815 (c.1-124C>T), CTNNB1 -rs121913412 (c.121A>G) and CTNNB1 -rs121913407 (c.133T>C) were selected to detect ctDNA and the mutant allele frequency (MAF) was calculated accordingly. The matched peripheral blood mononuclear cells (PBMCs) were used for Sanger sequencing. The clinicopathologic information of the patients was retrospectively analyzed and the predictive abilities for postoperative recurrence of different clinicopathologic parameters and ctDNA were compared., Results: Eighty-one patients were enrolled and 70.4% (57/81) of them had detectable ctDNA before hepatectomy. Positive preoperative ctDNA status was related to larger tumor size (P=0.001), multiple tumor lesions (P=0.001), microvascular invasion (MVI) (P<0.001), advanced BCLC stages (P<0.001) and shorter disease free survival (DFS) (P<<0.001) and overall survival (OS) (P<<0.001). Multivariate analysis showed that detectable ctDNA was the independent risk factor for postoperative recurrence. Moreover, receiver operating characteristic (ROC) curves proved that ctDNA possessed the second largest area under the curve (AUC) in foretelling postoperative recurrence right after BCLC stage. For patients after surgery, the alterations of MAF were also correlated to postsurgical recurrence. Patients with increased MAF had more incidences of MVI (P=0.016) and recurrence (P<0.001). At the same time, Kaplan-Meier curves revealed a significant shorter DFS and OS in the patients with increased MAF compared to the patients with decreased MAF (P<0.001 and P=0.0045, respectively) and ROC curves showed MAF to possess the greatest AUC among all the indices for postoperative recurrence., Conclusions: Digital droplets PCR assessment of specific gene combination through ctDNA possesses potential prognostic value in HCC patients undergoing surgical treatment., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

There are some controversies about the involvement of microRNA (miR)-19a-3p in hepatocellular carcinoma (HCC) biology, even though many studies have shown that it plays an important role in cancer. In this study, we found that miR-19a-3p is usually overexpressed in HCC tissues compared with corresponding peritumorous tissues, and its expression was associated with tumor size and poor overall survival. MiR-19a-3p promoted cell proliferation significantly, and more cells were found in the S phase. In vivo, miR-19a-3p promoted liver tumor growth, and more HCC cells were found in the active cell cycle. Sequencing and bioinformatics analysis predicted that PIK3IP1 is a likely target gene of miR-19a-3p, and we next confirmed it by luciferase and rescue assays. Altogether, our data showed an important role of PIK3IP1 downregulation by miR-19a-3p in HCC progression, and the miR-19a-3p-PIK3IP1-AKT pathway may be a potential therapeutic target., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Organ donation after brain death followed by circulatory death is practiced in China. This study evaluated the application of normothermic regional perfusion to protect the liver grafts from these donors from warm ischemia in a large transplant center in China., Materials and Methods: This prospective study involved 19 liver transplants from brain death followed by circulatory death donors that were conducted between December 2014 and June 2017. We evaluated the baseline characteristics of the donors and recipients and compared outcomes of both groups. Graft and recipient survival and postoperative complications were also analyzed., Results: Although the normothermic regional perfusion group consisted of marginal donors with prolonged warm ischemia and recipients with higher Model for End-Stage Liver Disease scores (P < .05), postoperative tests indicated no differences in liverfunction recovery in both groups. Furthermore, total bilirubin decreased significantly faster in the normothermic regional perfusion group than in the control group (P < .05). Both groups showed similar 1-year recipient survival rates. No recipients in the normothermic regional perfusion group had any biliary complications, whereas 2 recipients in the control group developed ischemic cholangiopathy and received invasive treatment during follow-up., Conclusions: In situ normothermic regional perfusion demonstrated a significant benefit in grafts from brain death followed by circulatory death donors and could potentially increase both the number and quality of donated organs.

Utilization of next-generation sequencing (NGS) to identify potential therapeutic targets and then prescribe matched agents provides new hope for patients with advanced cancer, such as hepatocellular carcinoma (HCC). However, intratumoral heterogeneity (ITH) challenges precise genomic profiling and may lead to target treatment failure. This study aims to evaluate whether and to what extent would genetic profiling be biased by ITH in HCC. We datamined publications focusing on the ITH of HCC and extracted the sequencing and clinicopathological information to make data reanalysis. Potential therapeutic targets and driver genes in HCC were specially pooled as reference to analyze the bias effect of ITH on genetic profiling. Five studies which analyzed ITH using NGS of multi-site samples were enrolled, with a total of 207 tumor samples from 36 HCC patients. The ITH ranged from 5.21% to 88.27% and no correlations between ITH extent and sample numbers, sequencing depth, or clinicopathological parameters were observed. In total, 72 therapeutic and 15 candidate driver genes were pooled as reference. Totally, 38.8% HCCs were found to be drugable in single-site sample, of which only 19.4% might be biased by ITH. Of the driver genes, 86% could be detected in single-site sample. HCC is a highly heterogeneous disease. While ITH indeed hinders comprehensive and precise HCC genome profiling, it has limited influences on identification of actionable and driver mutations. Single-site sampling/biopsy assayed with targeted deep sequencing might be efficient in the clinical management of HCC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Gastrointestinal Oncology. All rights reserved.)

Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.

The design of white-light phosphors is attractive in solid-state lighting (SSL) and related fields. A new strategy in obtaining white light emission (WLE) from dual-way photon energy conversion in a series of dye@MOF (LIFM-WZ-6) systems is presented. Besides the traditional UV-excited one-photon absorption (OPA) pathway, white-light modulation can also be gained from the combination of NIR-excited green and red emissions of MOF backbone and encapsulated dyes via two-photon absorption (TPA) pathway. As a result, down-conversion OPA white light was obtained for RhB + @LIFM-WZ-6 (0.1 wt %), BR-2 + @LIFM-WZ-6 (2 wt %), and APFG + @LIFM-WZ-6 (0.1 wt %) samples under 365 nm excitation. RhB + @LIFM-WZ-6 (0.05 wt %), BR-2 + @LIFM-WZ-6 (1 wt %) and APFG + @LIFM-WZ-6 (0.05 wt %) exhibit up-conversion TPA white light under the excitation of 800, 790, and 730 nm, respectively. This new WLE generation strategy combines different photon energy conversion mechanisms together., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new Eu-MOF was designed from an amino-functionalized ligand and Eu(iii) ions under solvothermal conditions. It is a highly porous, water-stable, and luminescent material, exhibiting pH sensing in the acidic range of pH = 7-3 with selective detection for Cd 2+ by an enhanced fluorescence of ∼23-fold against a series of metal ions. Gas adsorption performance shows that Eu-MOF exhibits a high CO 2 /N 2 (15/85) selectivity of 109.4 at 273 K and 1 atm. This performance was superior to that of most reported Ln-MOFs owing to its appropriate pore size, dipole-dipole interaction and donor-acceptor Lewis affinities.

Background: Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC., Methods: We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain-of-function (overexpression) and loss-of-function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3-specific inhibitor AT-406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer., Results: BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial-mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT-406 can inhibit HCC cell proliferation and reduce pulmonary metastases., Conclusion: BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer., (© 2018 Wiley Periodicals, Inc.)

Accumulating evidence suggests that long non-coding RNA (lncRNA) plays important roles in some malignant tumors. However, the mechanism underlying how lncRNA regulates hepatocellular carcinoma (HCC) process remains largely unknown. In this study, we explored the potential role of lncRNA 00607 as a novel tumor suppressor in HCC. In this study, we examined the regulation of lncRNA 00607 by the important inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also determined the expression of LINC000607 in 159 HCC tumors and paired adjacent tissues. Effects of LINC000607 in HCC proliferation and apoptosis were examined in vitro in HCC cell lines and in vivo tumor xenografts. Furthermore, we also examine underlying mechanism by which lncRNA 00607 regulates NF-κB p65 and how LIN00607 exerts its tumor suppressor role in HCC. We found that lncRNA 00607 expression level is lower in HCC tumors compared with matched normal liver tissue, and its low expression predicts worse prognosis in HCC. Functionally, lncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity. Mechanistically, lncRNA 00607 inhibits the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC. Taken together, the findings of this study show that the TNF-α/IL-6-lncRNA 00607-NF-κB p65/p53 signaling axis represents a novel therapeutic avenue in cancer chemotherapy.

Chronic alcoholism seriously damages the central nervous system and leads to impaired learning and memory. Cell damage in chronic alcoholism is strongly associated with elevated levels of hydrogen sulfide (H 2 S) and calcium ion overload. Aminooxyacetic acid is a cystathionine-β-synthase activity inhibitor that can reduce H 2 S formation in the brain. This study sought to observe the effect of aminooxyacetic acid on learning and memory in a chronic alcoholism rat model. Rats were randomly divided into three groups. Rats in the control group were given pure water for 28 days. Rats in the model group were given 6% alcohol for 28 days to establish an alcoholism rat model. Rats in the aminooxyacetic acid remedy group were also given 6% alcohol for 28 days and were also intraperitoneally injected daily with aminooxyacetic acid (5 mg/kg) from day 15 to day 28. Learning and memory was tested using the Morris water maze test. The ultrastructure of mitochondria in the hippocampus was observed by electron microscopy. H 2 S levels in the hippocampus were measured indirectly by spectrophotometry, and ATPase activity was measured using a commercial kit. The expression of myelin basic protein was determined by immunohistochemistry and western blotting. Compared with the control group, latency and swimming distance were prolonged in the navigation test on days 2, 3, and 4 in the model group. In the spatial probe test on day 5, the number of platform crosses was reduced in the model group. Cristae cracks, swelling or deformation of mitochondria appeared in the hippocampus, the hippocampal H 2 S level was increased, the mitochondrial ATPase activity was decreased, and the expression of myelin basic protein in the hippocampus was down-regulated in the model group compared with the control group. All the above indexes were ameliorated in the aminooxyacetic acid remedy group compared with the model group. These findings indicate that aminooxyacetic acid can improve learning and memory in a chronic alcoholism rat model, which may be associated with reduction of hippocampal H 2 S level and mitochondrial ATPase activity, and up-regulation of myelin basic protein levels in the hippocampus., Competing Interests: The authors declare that there are no conflicts of interest associated with this manuscript

Background: This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression., Methods: Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation., Results: NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.76, overall survival [OS] 2.26, 95% CI 1.44-3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner., Conclusions: NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.

Objective: This study intended to screen differentially expressed genes and pathways in Brown Adipose Tissue (BAT) of obese mice after the intervention of hypoxia by mRNA expression profile microarray, exploring the mechanism of hypoxia activated BAT., Methods: Thirty C57BL/6J male mice were divided into the normal diet control group (N, n =8), high-fat diet control group (OB, n =8) and high-fat diet hypoxia group (H, n =8). Group H was intervened by hypoxia exposure in the oxygen concentration of 11.2% of the normal oxygen and hypoxia for 8 h/d, 6 d/w of 4 weeks. Blood lipid and blood glucose were detected after intervention; RNA microarray scan and bioinformation analysis were done of BAT from scapula. Genes significantly ( P ≤ 0.05) regulated more than 1.5 fold were chosen to do Gene Ontology and enrichment analysis by KOBAS 2.0, and confirmation of genes participating in key biological process (BP) and pathway was done by real time qPCR., Results: After intervention, the body weight and blood lipid and glucose levels in group H were significantly lower than those of group OB. Comparing with group N, 802 genes were significantly up-regulated and 1 175genes were down-regulated. The BP of these genes mainly concerned with glucose and lipid metabolic process and inflammatory reaction. Comparing with group OB, 297 genes were significantly up-regulated and 228 genes were down-regulated. These genes participated in glucose and lipid metabolic process, lipid transport, muscle system process and cardiovascular system development. The pathways of regulating BAT by hypoxia exposure mainly concentrated on the HIF-1, PI3K-AKT, FoxO and ErbB signaling pathways., Conclusions: A series of genes and pathways in BAT could be adjusted by hypoxia exposure, so that hypoxia could improve the activity of BAT, promoting obese organism to lose weight.

The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-γ-induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo . Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study., Methods: Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution., Results: With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant., Conclusion: These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile., Trial Registration: ClinicalTrials.gov NCT00794508., Funding: Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.

Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological event post liver surgery or transplantation and significantly influences the prognosis of liver function. The mechanisms of IRI remain unclear, and effective methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabolism, mitochondria, oxidative stress, intracellular calcium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide (NO) in protecting against liver IRI has recently been reported. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhancing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for controlling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI.

Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA(-/-) mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA(-/-) mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34(+) cells transduced with 1-5 × 10(7) TU/ml had 1-3 vector copies/cell and expressed 1-2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis.

A duplex-triplex switchable DNA nanomachine was fabricated and has been applied for the demonstration of intracellular acidification and apoptosis of Ramos cells, with graphene oxide (GO) not only as transporter but also as fluorescence quencher. The machine constructed with triplex-forming oligonucleotide exhibited duplex-triplex transition at different pH conditions. By virtue of the remarkable difference in affinity of GO with single-stranded DNA and triplex DNA, and the super fluorescence quenching efficiency of GO, the nanomachine functions as a pH sensor based on fluorescence resonance energy transfer. Moreover, taking advantage of the excellent transporter property of GO, the duplex-triplex/GO nanomachine was used to sense pH changes inside Ramos cells during apoptosis. Fluorescence images showed different results between living and apoptotic cells, illustrating the potential of DNA scaffolds responsive to more complex pH triggers in living systems.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.