The time window for pre-emptive transjugular intrahepatic portosystemic shunt could be extended to 5 days.

As recommended by Baveno VII consensus, the utilization of pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) has been considered as standard therapeutic approach for the management of acute variceal bleeding (AVB) associated with cirrhosis., but the 72-h window for pTIPS is too narrow. This study aimed to compare the clinical outcomes between patients who received <72 h pTIPS and 72 h-5d pTIPS. In this study, a total of 63 cirrhotic patients with AVB who underwent pTIPS between October 2016 and December 2021 were included in this retrospective study. They were divided into <72 h group (n = 32) and 72 h-5d group (n = 31), based on the timing of the intervention. The Kaplan-Meier curves demonstrated that there were no significant differences in the cumulative incidence of death (22.3% ± 7.4% vs. 19.9% ± 7.3%, log-rank P = 0.849), variceal rebleeding (9.7% ± 5.3% vs. 17.8% ± 7.3%, log-rank P = 0.406), OHE (28.5% ± 8.0% vs. 23.9% ± 8.0%, log-rank P = 0.641) and shunt dysfunction (8.6% ± 6.0% vs. 17.4% ± 8.1%, log-rank P = 0.328) between <72 h and 72 h-5d groups. In the total cohort, sarcopenia was identified as an independent risk factor for mortality (HR = 11.268, 95% CI = 1.435-88.462, P = 0.021) and OHE(HR = 12.504, 95% CI = 1.598-97.814, P = 0.016). In conclusion, the clinical outcomes of cirrhotic patients with AVB who underwent pTIPS within the 72-h to 5-day window were found to be comparable to those treated within the 72-h window.

Comparison of specialized stent versus generic stent and bare stent combination for transjugular intrahepatic portosystemic shunt creation.

Transjugular intrahepatic portosystemic shunt (TIPS) creation using the Viatorr stent remains relatively uncommon in underdeveloped and high-burden disease regions in Asia-Pacific, and there is a lack of comparative studies regarding its prognostic effects compared with the generic stent-graft/bare stent combination. The purpose of this retrospective study is to compare the prognostic endpoints of these two treatments in patients who underwent TIPS creation. Clinical data from 145 patients were collected, including 82 in the combination group and 63 in the Viatorr group. Differences in prognostic endpoints (shunt dysfunction, death, overt hepatic encephalopathy [OHE], rebleeding) between the two groups were analyzed using Kaplan-Meier curves. The Cox proportional hazards model was used to identify independent risk factors for post-TIPS shunt dysfunction. The TIPS procedure was successful in all patients. After TIPS creation, both groups showed a significant decrease in porto-caval pressure gradient compared to that before TIPS creation. The stent patency rates at 6, 12, and 18 months were high in both the combination and Viatorr groups (93.7%, 88.5%, and 88.5% vs. 96.7%, 93.4%, and 93.4%, respectively). The stent patency rates was higher in the combination group than in the Viatorr group, although not statistically significant (HR = 2.105, 95% CI 0.640-6.922, Log-rank P = 0.259). There were no significant differences in other prognostic endpoints (death, OHE, rebleeding) between the two groups. The Cox model identified portal vein diameter (HR = 0.807, 95% CI 0.658-0.990, P = 0.040) and portal vein thrombosis (HR = 13.617, 95% CI 1.475-125.678, P = 0.021) as independent risk factors for post-TIPS shunt dysfunction. The shunt patency rates between the Viatorr stent and the generic stent-graft/bare stent combination showed no significant difference and the generic stent-graft/bare stent combination may be a viable alternative in areas where the Viatorr stent is not yet available.

ICA1 affects APP processing through the PICK1-PKCα signaling pathway.

AIMS: Islet cell autoantigen 1 (ICA1) is involved in autoimmune diseases and may affect synaptic plasticity as a neurotransmitter. Databases related to Alzheimer's disease (AD) have shown decreased ICA1 expression in patients with AD. However, the role of ICA1 in AD remains unclear. Here, we report that ICA1 expression is decreased in the brains of patients with AD and an AD mouse model. RESULTS: The ICA1 increased the expression of amyloid precursor protein (APP), disintegrin and metalloprotease 10 (ADAM10), and disintegrin and metalloprotease 17 (ADAM17), but did not affect protein half-life or mRNA levels. Transcriptome sequencing analysis showed that ICA1 regulates the G protein-coupled receptor signaling pathway. The overexpression of ICA1 increased PKCα protein levels and phosphorylation. CONCLUSION: Our results demonstrated that ICA1 shifts APP processing to non-amyloid pathways by regulating the PICK1-PKCα signaling pathway. Thus, this study suggests that ICA1 is a novel target for the treatment of AD.

Ultrasmall Metal TPZ Complexes with Deep Tumor Penetration for Enhancing Radiofrequency Ablation Therapy and Inducing Antitumor Immune Responses.

Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small satellite lesions after insufficient RFA (iRFA) are difficult to remove, often leading to metastasis and recurrence. Here, Fe-TPZ nanoparticles are designed by metal ion and (TPZ) ligand complexation for synergistic enhancement of RFA residual tumor therapy. Fe-TPZ nanoparticles are cleaved in the acidic microenvironment of the tumor to generate Fe2+ and TPZ. TPZ, an anoxia-dependent drug, is activated in residual tumors and generates free radicals to cause tumor cell death. Elevated Fe2+ undergoes a redox reaction with glutathione (GSH), inducing a strong Fenton effect and promoting the production of the highly toxic hydroxyl radical (•OH). In addition, the ROS/GSH imbalance induced by this treatment promotes immunogenic cell death (ICD), which triggers the release of damage-associated molecular patterns, macrophage polarization, and lymphocyte infiltration, thus triggering a systemic antitumor immune response and noteworthy prevention of tumor metastasis. Overall, this integrated treatment program driven by multiple microenvironment-dependent pathways overcomes the limitations of the RFA monotherapy approach and thus improves tumor prognosis. Furthermore, these findings aim to provide new research ideas for regulating the tumor immune microenvironment.

Impact of Sarcopenia on Prognosis in Primary Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Single Center Retrospective Study.

Objective: This study aimed to investigate the prognostic effect of sarcopenia on primary hepatocellular carcinoma (HCC) patients after transcatheter arterial chemoembolization (TACE). Methods: This retrospective study enrolled 265 patients diagnosed with HCC who underwent TACE between April 2014 and February 2021. The patients were divided into two groups: the sarcopenia group (n=133) and the non-sarcopenia group (n=132). The study analyzed the differences in overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier curves. The independent risk factors for OS and PFS were determined using univariate and multivariate Cox regression analysis. Based on these factors, the study constructed a prognostic risk grading system. Results: At 3 and 6 months post-TACE, the prognoses of the sarcopenia group were worse than that of the non-sarcopenia group according to the mRECIST criteria. Kaplan-Meier curves showed that the cumulative OS and PFS rate in the non-sarcopenia group were significantly higher compared to the sarcopenia group (HR=3.319, 95%CI: 2.283-4.824, Log-rank P < 0.001; HR=0.631, 95%CI: 0.486-0.820, Log-rank P < 0.001). Sarcopenia, maximal tumor diameter, and AFP ≥ 200 ng/mL were independent risk factors for OS and PFS. The prognostic risk grading system based on sarcopenia, AFP ≥ 200 ng/mL, and maximal tumor diameter≥8.9 cm showed significant differences in prognosis between risk groups. Conclusion: Sarcopenia had excellent predictive value for OS and PFS in patients after TACE, and AFP ≥ 200 ng/mL and maximal tumor diameter were also independent risk factors for a poor prognosis. The prognostic risk grading system based on sarcopenia, AFP, and maximal tumor diameter had good guiding value for the prognosis of patients.

CSTB accelerates the progression of hepatocellular carcinoma via the ERK/AKT/mTOR signaling pathway.

Hepatocellular carcinoma (HCC) is a significant contributor to global cancer-related deaths, leading to high mortality rates. However, the pathogenesis of HCC remains unclear. In this research, by the bioinformatics data analysis, we found that elevated CSTB expression correlated with advanced disease and predicted diminished overall survival (OS) in HCC patients. We subsequently verified the oncogenic role of CSTB as well as the potential underlying mechanisms in HCC through a series of in vitro experiments, such as CCK-8 assays, cloning assays, flow cytometry, Transwell assays, and western blotting. Our findings illustrated that the silencing of CSTB effectively suppressed cellular proliferation by inducing cell cycle arrest in the G2 phase and impaired HCC cell invasion and migration by stimulating epithelial-mesenchymal transition (EMT). Additionally, we analyzed the pathways enriched in HCC using RNA sequencing and found that the ERK/AKT/mTOR signaling pathway was related to increased CSTB expression in HCC. Finally, we confirmed the tumorigenic role of CSTB via in vivo experiments. Thus, our findings revealed that silencing CSTB inhibited the HCC progression via the ERK/AKT/mTOR signaling pathway, highlighting new perspectives for investigating the mechanisms of HCC.

scCAN: Clustering With Adaptive Neighbor-Based Imputation Method for Single-Cell RNA-Seq Data.

Single-cell RNA sequencing (scRNA-seq) is widely used to study cellular heterogeneity in different samples. However, due to technical deficiencies, dropout events often result in zero gene expression values in the gene expression matrix. In this paper, we propose a new imputation method called scCAN, based on adaptive neighborhood clustering, to estimate the zero value of dropouts. Our method continuously updates cell-cell similarity information by simultaneously learning similarity relationships, clustering structures, and imposing new rank constraints on the Laplacian matrix of the similarity matrix, improving the imputation of dropout zero values. To evaluate the performance of this method, we used four simulated and eight real scRNA-seq data for downstream analyses, including cell clustering, recovered gene expression, and reconstructed cell trajectories. Our method improves the performance of the downstream analysis and is better than other imputation methods.

Synergistic Effects of Nanoscale CaO2 Combined with PD-1 Inhibitors in the Treatment of Hepatocellular Carcinoma: A Promising Combination.

Purpose: To explore the effect of calcium peroxide nanoparticles (CaO2 NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism. Methods: Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO2 NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO2 NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO2 NPs group (intra-tumoral injection of CaO2 NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO2 NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4+ and CD8+ T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO2 NPs combined with PD-1 inhibitors on survival time. Results: The results of in vivo mechanism study showed that CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO2 NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8+ and CD4+ T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups. Conclusion: CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.

Enhanced Gasdermin-E-mediated Pyroptosis in Alzheimer's Disease.

Amyloid ß protein (Aß) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aß induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aß treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aß and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.

Circular RNA hsa_circ_0067842 facilitates tumor metastasis and immune escape in breast cancer through HuR/CMTM6/PD-L1 axis.

BACKGROUND: Circular RNAs (circRNAs) have been shown to play diverse biological functions in the progression of multiple diseases. However, the impacts of circRNAs on breast cancer (BC) progression remains unclear. Therefore, the objective of this paper is to investigate the role and mechanisms of a functional circRNA in BC metastasis and immune escape. METHODS: This study used a circRNA microarray and identified a novel circRNA hsa_circ_0067842. The validation and characteristics of hsa_circ_0067842 were investigated using qRT-PCR, sanger sequencing, RNase R treatment, actinomycin D treatment and fluorescence in situ hybridization (FISH). Gain- and loss-of-function assays were performed to evaluate the biological function of hsa_circ_0067842 in BC progression and immune escape. Mechanistically, the interaction between hsa_circ_0067842 and HuR was explored by RNA pull down, mass spectrometry (MS), subcellular component protein extraction and immunofluorescence (IF). The regulatory mechanisms of hsa_circ_0067842/HuR/CMTM6/PD-L1 axis were investigated by qRT-PCR, western blot, FISH, immunoprecipitation and rescue assays. RESULTS: The expression of hsa_circ_0067842 was upregulated in BC tissues and cells, which was found to be significantly associated with poor prognosis, regardless of other clinical covariates. Function assays showed that hsa_circ_0067842 promoted the migration and invasion capacities of BC cells. Moreover, co-culture experiment with peripheral blood mononuclear cells (PBMCs) showed that hsa_circ_0067842 played a role in the immune escape of BC cells. Mechanistically, our study showed that hsa_circ_0067842 interacted with HuR, affecting its nuclear translocation, thus enhancing the stability of CMTM6. CMTM6 not only enhances the migration and invasion ability of BC cells, but also affects the ubiquitination of PD-L1 and inhibits its degradation. CONCLUSION: Collectively, our results demonstrated that hsa_circ_0067842 promoted BC progression through the HuR/CMTM6/PD-L1 axis, providing new insight and a potential target for BC prognosis and therapy.

PCP4 Promotes Alzheimer's Disease Pathogenesis by Affecting Amyloid-ß Protein Precursor Processing.

BACKGROUND: Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer's disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. OBJECTIVE: To explore the role of PCP4 in amyloid-ß protein precursor (AßPP) processing in AD. METHODS: In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AßPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. RESULTS: We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AßPP. The production of amyloid-ß protein (Aß) was also promoted by PCP4. The upregulation of endogenous AßPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aß deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. CONCLUSION: Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AßPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aß pathology.

Transcriptional activation of CSTB gene expression by transcription factor Sp3.

CSTB has been reported to be associated with the pathogenesis of many malignant tumors, especially hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated is largely unknown. We initially cloned and analyzed the promoter region of the CSTB gene by luciferase assay and the Sp3 binding site (CCCCGCCCCGCG) was found in it. The results of electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments verified that the transcription factor, Sp3 could bind to the " CCCCGCCCCGCG ″ site of the CSTB gene promoter. We showed that the overexpression of Sp3 significantly increased the endogenous mRNA and protein expression levels of CSTB, whereas knockdown of Sp3 decreased the mRNA and protein expression levels according to quantitative real-time PCR (qRT‒PCR) and western blotting. In conclusion, CSTB gene expression is closely regulated by transcription factor Sp3, which may be a potential mechanism for the dysregulation of CSTB expression in HCC.

Endovascular treatment of aorto-iliac occlusive disease with TASC II C and D lesions: 10 year's experience of clinical technique.

OBJECTIVES: The purpose of this study was to evaluate the therapeutic efficacy and safety of endovascular treatment aorto-iliac occlusive disease (AIOD) with TransAtlantic Inter-Society Consensus II (TASC II) C and D lesions. In addition, 10 years of experience with interventional procedures and treatment options in our center were also worthy of further discussion. METHODS: Between January 2011 and December 2020, a total of 26 consecutive AIOD patients with TASC-II C and D lesions treated endovascular approach were enrolled in this study. Patients' demographic and clinical data were collected, and the safety and efficacy of endovascular therapy were evaluated. In addition, operation procedures were also described. RESULTS: The mean age of patients was 62.2 ± 7 years (49-57 years), and the mean body mass index of patients was 24.2 ± 2.6 kg/m2. Fifteen patients (57.7%) were Rutherford 4, 5 each (19.2%) were Rutherford 3 and 5, and 1 (3.8%) was Rutherford 2. No other serious complications occurred except death in 3 patients. Most of the patients (73.1%) had a history of smoking, and hypertension and hyperlipidemia were common comorbidities. Endovascular therapy was successfully performed in 25 patients, and the technical success rate was 96.2%. The patient's ankle-brachial index improved significantly postoperatively compared with preoperatively (preoperative 0.33 ± 0.14 vs 1.0 ± 0.09, P < 0.001). The primary patency rates were 100%, 95.7%, and 91.3% at 1, 3, and 5 years, while the secondary patency rates were 100%. No treatment-related deaths or serious complications occurred. CONCLUSIONS: Endovascular treatment of AIOD patients with TASC-II C and D lesions might be safe and have a high rate of middle-term and long-term primary patency.

Ratiometric fluorescent detection of exosomal piRNA-823 based on Au NCs/UiO-66-NH2 and target-triggered rolling circle amplification.

piR-823 is a newly discovered colorectal cancer marker with high diagnostic efficacy. However, the current quantification methods have complicated operations and high cost, which restrict its clinical application. Herein, a metal-organic framework (MOF) with a UiO-66 prototype structure which supports gold nanoclusters (Au NCs), Au NCs/UiO-66-NH2, were prepared as a model nanobiosensing platform for ratiometric detection of exosomal piR-823. The rolling circle amplification process provides high sensitivity and the ratiometric detection process ensures good accuracy of the sensor. Such biosensor showed a wide linear range of 0.04-4 pM, and a low detection limit of 10.2 fM towards piR-823. In addition, piR-823 can be used as an effective supplement to carcinoembryonic antigen (CEA) in clinical diagnosis of colorectal cancer. This study not only provides a potentially valuable ratio fluorescence platform involving enzyme catalytic reaction, but also offers a design blueprint for further expansion of nanotechnology in the diverse biological analysis.

Toward Better Structure and Constraint to Mine Negative Sequential Patterns.

Nonoccurring behavior (NOB) studies have attracted the growing attention of scholars as a crucial part of behavioral science. As an effective method to discover both NOB and occurring behaviors (OB), negative sequential pattern (NSP) mining is successfully used in analyzing medical treatment and abnormal behavior patterns. At this time, NSP mining is still an active and challenging research domain. Most of the algorithms are inefficient in practice. Briefly, the key weaknesses of NSP mining are: 1) an inefficient positive sequential pattern (PSP) mining process, 2) a strict constraint of negative containment, and 3) the lack of an effective Negative Sequential Candidate (NSC) generation method. To address these weaknesses, we propose a highly efficient algorithm with improved techniques, named sc-NSP, to mine NSP efficiently. We first propose an improved PrefixSpan algorithm in the PSP mining process, which connects to a bitmap storage structure instead of the original structure. Second, sc-NSP loosens the frequency constraint and exploits the NSC generation method of positive and negative sequential patterns mining (PNSP) (a classic NSP mining method). Furthermore, a novel pruning strategy is designed to reduce the computational complexity of sc-NSP. Finally, sc-NSP obtains the support of NSC by using the most efficient bitwise-based calculation operation. Theoretical analyses show that sc-NSP performs particularly well on data sets with a large number of elements and items in sequence. Comparison and extensive experiments along with case studies on health data show that sc-NSP is 10 times more efficient than other state-of-the-art methods, and the number of NSPs obtained is 5 times greater than other methods.

An Efficient Method for Modeling Nonoccurring Behaviors by Negative Sequential Patterns With Loose Constraints.

The sequence analysis handles sequential discrete events and behaviors, which can be represented by temporal point processes (TPPs). However, TPP models only occurring events and behaviors. This article explores an efficient method for the negative sequential pattern (NSP) mining to leverage TPP in modeling both frequently occurring and nonoccurring events and behaviors. NSP mining is good at the challenging modeling of nonoccurrences of events and behaviors and their combinations with occurring events, with existing methods built on incorporating various constraints into NSP representations, e.g., simplifying NSP formulations and reducing computational costs. Such constraints restrict the flexibility of NSPs, and nonoccurring behaviors (NOBs) cannot be comprehensively exposed. This article addresses this issue by loosening some inflexible constraints in NSP mining and solves a series of consequent challenges. First, we provide a new definition of negative containment with the set theory according to the loose constraints. Second, an efficient method quickly calculates the supports of negative sequences. Our method only uses the information about the corresponding positive sequential patterns (PSPs) and avoids additional database scans. Finally, a novel and efficient algorithm, NegI-NSP, is proposed to efficiently identify highly valuable NSPs. Theoretical analyses, comparisons, and experiments on four synthetic and two real-life data sets clearly show that NegI-NSP can efficiently discover more useful NOBs.

GPSAdb: a comprehensive web resource for interactive exploration of genetic perturbation RNA-seq datasets.

Gene knock-out/down methods are commonly used to explore the functions of genes of interest, but a database that systematically collects perturbed data is not available currently. Manual curation of all the available human cell line perturbed RNA-seq datasets enabled us to develop a comprehensive human perturbation database (GPSAdb, https://www.gpsadb.com/). The current version of GPSAdb collected 3048 RNA-seq datasets associated with 1458 genes, which were knocked out/down by siRNA, shRNA, CRISPR/Cas9, or CRISPRi. The database provides full exploration of these datasets and generated 6096 new perturbed gene sets (up and down separately). GPSAdb integrated the gene sets and developed an online tool, genetic perturbation similarity analysis (GPSA), to identify candidate causal perturbations from differential gene expression data. In summary, GPSAdb is a powerful platform that aims to assist life science researchers to easily access and analyze public perturbed data and explore differential gene expression data in depth.

Astrocyte-Ablation of Mtnr1b Increases Anxiety-Like Behavior in Adult Male Mice.

BACKGROUND: Astrocytes are essential for synaptic transmission, and their dysfunction can result in neuropsychiatric disorders such as anxiety and depression. Many studies have shown that global knockout of Melatonin receptor 2 (Mtnr1b) is associated with the development of various mental disorders. AIM: This study aimed to investigate the effects of astrocyte ablation of Mtnr1b on cognitive function and anxiety-like behavior in mice, as well as the potential biological mechanisms. METHODS: A conditional Cre-loxP system allowing deletion of Mtnr1b from astrocytes was developed to investigate the specific role Mtnr1b. Control and Mtnr1b cKO𝐺𝑓𝑎𝑝 mice were selected for cognitive function behavioral testing (Morris water maze test, novel object recognition test) and emotion-related behavioral testing (open field, elevated plus maze). After testing, brain tissue was collected and examined by immunofluorescence for the expression of neuronal nuclei (NeuN), glutamate decarboxylase 67 (GAD67), and vesicular glutamate transporter 1 (vGluT1). RNA-seq was performed on hippocampal tissue from control and Mtnr1b cKO𝐺𝑓𝑎𝑝 mice to identify differentially expressed genes. Additional confirmation of differential gene expression was performed using real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: Mtnr1b cKO𝐺𝑓𝑎𝑝 mice were not significantly different from control mice in the Morris water maze and novel object recognition tests. Results from the open field and elevated plus maze tests showed that Mtnr1b cKO𝐺𝑓𝑎𝑝 mice exhibited significantly more anxiety-like behavior than did controls. Immunofluorescence revealed that the number of mature neurons did not differ significantly between Mtnr1b cKO𝐺𝑓𝑎𝑝 mice and controls. The expression of GAD67 in the hippocampal CA1 and CA3 areas of Mtnr1b cKO𝐺𝑓𝑎𝑝 mice was significantly lower than in the control group, but no significant difference was detected for vGluT1 expression. RNA-seq and qRT-PCR results showed that Mtnr1b knockout in astrocytes led to a decrease in the levels of gamma-aminobutyric acid sub-type A (GABAA) receptors and Kir2.2. CONCLUSIONS: The astrocyte-specific knockout in Mtnr1b cKO𝐺𝑓𝑎𝑝 mice results in anxiety-like behavior, which is caused by down-regulation of gamma-aminobutyric acid-ergic (GABAergic) synaptic function.

Evaluation of Transarterial Chemoembolization Protocol with Drug-Eluting Beads in Combination with Lipiodol for Hepatocellular Carcinoma: A Single-Center Controlled Study.

Objectives: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) and lipiodol (DEB-Lipiodol TACE) in the treatment of unresectable hepatocellular carcinoma (HCC) patients. Materials and Methods: The medical records of consecutive unresectable HCC patients who underwent DEB-TACE or DEB-Lipiodol TACE from June 2016 to July 2021 were retrospectively evaluated. Therapeutic response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared among the groups. Results: Three hundred and twenty-seven patients were enrolled in the study, including 293 patients in the DEB-TACE group and 34 patients in the DEB-Lipiodol TACE group. The objective response rate in the DEB-Lipiodol TACE group was 17.6%, significantly higher than that in the DEB-TACE group (5.8%, P=0.011). Similarly, DEB-Lipiodol TACE group also had a higher disease control rate (91.2% vs 68.6%, P=0.006). Median OS was 13 months (95% CI: 11.0 months and 15.0 months) and 22 months (95% CI: 17.3 months and 26.7 months) in the DEB-TACE group and DEB-Lipiodol TACE group, respectively (P=0.041). Meanwhile, median PFS was 7 months (95% CI: 5.2 months and 8.8 months) in the DEB-TACE group and 12 months (95% CI: 7.9 months and 16.1 months) in the DEB-Lipiodol TACE group (P=0.174). There was no statistically significant difference in AEs incidence among the two groups (P > 0.05). Conclusions: DEB-Lipiodol TACE was safe, well tolerated, and had a better efficacy compared with DEB-TACE in unresectable HCC patients.