Magnetic resonance imaging features of progressive familial intrahepatic cholestasis type 3.

PURPOSE: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder. This study aimed to present the clinical and magnetic resonance imaging (MRI) features of three patients with PFIC­3. METHODS: The study included three patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing of a targeted-gene panel or by whole-exome sequencing. The clinical, laboratory, histological, molecular, and MRI features of the patients were collected. RESULTS: Three patients (one male and two females) were enrolled. The age when clinical signs and symptoms were first noted was 21, 14, and 39 years, respectively, and the signs and symptoms included pruritus and splenomegaly (in all three patients). Parenchymatous lace-like fibrosis was associated with periportal hyperintensity and periportal halo sign in three patients. Segmental atrophy was observed in two patients, diffuse atrophy was observed in one patient, and liver surface irregularity caused by regenerating nodules was observed in three patients. Magnetic resonance cholangiopancreatography (MRCP) images showed irregular bile duct changes in three patients, focal hilar bile duct stenosis, and local intrahepatic bile duct dilatation. CONCLUSIONS: Imaging studies using MRI and MRCP can support the clinical and laboratory results in cases of PFIC­3 and can also be used as a noninvasive diagnostic option.

Potential role of the intratumoral microbiota in colorectal cancer immunotherapy.

Colorectal cancer (CRC) has been one of the most common malignancies worldwide. Despite the advances in current therapies, the mortality rate of CRC remains high. Among them, immunotherapy has achieved satisfactory results in some CRC patients, however, how to expand the use of immunotherapy in CRC patients remains an urgent challenge. Surprisingly, the intratumoral microbiota has been found in multiple tumor tissues, including CRC. It has been demonstrated that the intratumoral microbiota is associated with the progression and treatment of CRC, and is able to enhance or decrease anti-tumor immune responses via different mechanisms as well as influence the immunotherapy efficacy, providing new potential therapeutic targets for CRC immunotherapy. In this review, we focus on the characteristics of the intratumoral microbiota, its roles in the genesis and development of CRC, its modulation of anti-tumor immune responses and immunotherapy, and propose potential applications of the intratumoral microbiota in CRC immunotherapy. Additionally, we propose possible directions for future research on the intratumoral microbiota related to CRC immunotherapy.

Neural correlates of emotion-label vs. emotion-laden word processing in late bilinguals: evidence from an ERP study.

The brain processes underlying the distinction between emotion-label words (e.g. happy, sad) and emotion-laden words (e.g. successful, failed) remain inconclusive in bilingualism research. The present study aims to directly compare the processing of these two types of emotion words in both the first language (L1) and second language (L2) by recording event-related potentials (ERP) from late Chinese-English bilinguals during a lexical decision task. The results revealed that in the early word processing stages, the N170 emotion effect emerged only for L1 negative emotion-laden words and L2 negative emotion-label words. In addition, larger early posterior negativity (EPN) was elicited by emotion-laden words than emotion-label words in both L1 and L2. In the later processing stages, the N400 emotion effect was evident for L1 emotion words, excluding positive emotion-laden words, while it was absent in L2. Notably, L1 emotion words elicited enhanced N400 and attenuated late positive complex (LPC) compared to those in L2. Taken together, these findings confirmed the engagement of emotion, and highlighted the modulation of emotion word type and valence on word processing in both early and late processing stages. Different neural mechanisms between L1 and L2 in processing written emotion words were elucidated.

Microbes in the tumor microenvironment: New additions to break the tumor immunotherapy dilemma.

Immunotherapies currently used in clinical practice are unsatisfactory in terms of therapeutic response and toxic side effects, and therefore new immunotherapies need to be explored. Intratumoral microbiota (ITM) exists in the tumor environment (TME) and reacts with its components. On the one hand, ITM promotes antigen delivery to tumor cells or provides cross-antigens to promote immune cells to attack tumors. On the other hand, ITM affects the activity of immune cells and stromal cells. We also summarize the dialog pathways by which ITM crosstalks with components within the TME, particularly the interferon pathway. This interaction between ITM and TME provides new ideas for tumor immunotherapy. By analyzing the bidirectional role of ITM in TME and combining it with its experimental and clinical status, we summarized the adjuvant role of ITM in immunotherapy. We explored the potential applications of using ITM as tumor immunotherapy, such as a healthy diet, fecal transplantation, targeted ITM, antibiotics, and probiotics, to provide a new perspective on the use of ITM in tumor immunotherapy.

Tumor size impact on TNM staging which define post-operative complications in rectal cancer.

The purpose of this study was to see how accurate tumor size was at predicting T and N stages in rectal malignancies. Tumor sizes of 40 mm and greater than 40 mm were used to assess post-operative challenges in related to T1-T2 and T3-T4 stages, as well as between node N0 and node N1 and N2 patients. A total of 131 patients were treated for colorectal cancer, with 54 patients < 40 mm and 77 patients > 40 mm receiving Da Vinci colorectal surgery. Conferring to the Clavien-Dindo classification grade III, there's an increase in the percentage of tumors > 40 mm, which also impacts the percentage of intestinal obstruction, anastomotic leakage, GERD, and sepsis with a P < 0.05. A tumor size of more than 40 mm is strongly associated with advanced pT stages. Tumor size may serve in addition to clinical staging and improve the management of rectal cancer.

Selected Electrosynthesis of 3-Aminopyrazoles from α,ß-Alkynic Hydrazones and Secondary Amines.

An available and simple electromediated cyclization method for 3-amino-substituted pyrazoles by using α,ß-alkynic hydrazone and secondary amine is described. The strategy utilizes KI as an electrolyte in an undivided cell with a constant current, generating the desired products in moderate-to-good yield. The method features selective amination at the 3-position of the pyrazole skeleton. The results indicate that α,ß-alkynic hydrazones functionalized with aromatic groups and secondary amines functionalized with electron-rich groups were better tolerated in this transformation.

Akkermania muciniphila: a rising star in tumor immunology.

Tumor is accompanied by complex and dynamic microenvironment development, and the interaction of all its components influences disease progression and response to treatment. Once the tumor microenvironment has been eradicated, various mechanisms can induce the tumors. Microorganisms can maintain the homeostasis of the tumor microenvironment through immune regulation, thereby inhibiting tumor development. Akkermania muciniphila (A. muciniphila), an anaerobic bacterium, can induce tumor immunity, regulate the gastrointestinal microenvironment through metabolites, outer membrane proteins, and some cytokines, and enhance the curative effect through combined immunization. Therefore, a comprehensive understanding of the complex interaction between A. muciniphila and human immunity will facilitate the development of immunotherapeutic strategies in the future and enable patients to obtain a more stable clinical response. This article reviews the most recent developments in the tumor immunity of A. muciniphila.

Dissociation of Hypertension and Renal Damage After Cessation of High-Salt Diet in Dahl Rats.

BACKGROUND: Every year, thousands of patients with hypertension reduce salt consumption in an effort to control their blood pressure. However, hypertension has a self-sustaining character in a significant part of the population. We hypothesized that chronic hypertension leads to irreversible renal damage that remains after removing the trigger, causing an elevation of the initial blood pressure. METHODS: Dahl salt-sensitive rat model was used for chronic, continuous observation of blood pressure. Rats were fed a high salt diet to induce hypertension, and then the diet was switched back to normal sodium content. RESULTS: We found that developed hypertension was irreversible by salt cessation: after a short period of reduction, blood pressure grew even higher than in the high-salt phase. Notably, the self-sustaining phase of hypertension was sensitive to benzamil treatment due to sustaining epithelial sodium channel hyperactivity, as shown with patch-clamp analysis. Glomerular damage and proteinuria were also irreversible. In contrast, some mechanisms, contributing to the development of salt-sensitive hypertension, normalized after salt restriction. Thus, flow cytometry demonstrated that dietary salt reduction in hypertensive animals decreased the number of total CD45+, CD3+CD4+, and CD3+CD8+ cells in renal tissues. Also, we found tubular recovery and improvement of glomerular filtration rate in the postsalt period versus a high-salt diet. CONCLUSIONS: Based on earlier publications and current data, poor response to salt restriction is due to the differential contribution of the factors recognized in the developmental phase of hypertension. We suggest that proteinuria or electrolyte transport can be prioritized over therapeutic targets of inflammatory response.

Identification and validation of the clinical prediction model and biomarkers based on chromatin regulators in colon cancer by integrated analysis of bulk- and single-cell RNA sequencing data.

Background: Chromatin regulators (CRs) are implicated in the development of cancer, but a comprehensive investigation of their role in colon adenocarcinoma (COAD) is inadequate. The purpose of this study is to find CRs that can provide recommendations for clinical diagnosis and treatment, and to explore the reasons why they serve as critical CRs. Methods: We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-Expression Network Analysis (WGCNA) screened tumor-associated CRs. LASSO-Cox regression was used to construct the model and to screen key CRs together with support vector machine (SVM), the univariate Cox regression. We used single-cell data to explore the expression of CRs in cells and their communication. Immune infiltration, immune checkpoints, mutation, methylation, and drug sensitivity analyses were performed. Gene expression was verified by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Pan-cancer analysis was used to explore the importance of hub CRs. Results: We finally obtained 32 tumor-associated CRs. The prognostic model was constructed based on RCOR2, PPARGC1A, PKM, RAC3, PHF19, MYBBP1A, ORC1, and EYA2 by the LASSO-Cox regression. Single-cell data revealed that the model was immune-related. Combined with immune infiltration analysis, immune checkpoint analysis, and tumor immune dysfunction and exclusion (TIDE) analysis, the low-score risk group had more immune cell infiltration and better immune response. Mutation and methylation analysis showed that multiple CRs may be mutated and methylated in colon cancer. Drug sensitivity analysis revealed that the low-risk group may be more sensitive to several drugs and PKM was associated with multiple drugs. Combined with machine learning, PKM is perhaps the most critical gene in CRs. Pan-cancer analysis showed that PKM plays a role in the prognosis of cancers. Conclusions: We developed a prognostic model for COAD based on CRs. Increased expression of the core gene PKM is linked with a poor prognosis in several malignancies.

Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application.

Metastasis poses a major challenge in colorectal cancer (CRC) treatment and remains a primary cause of mortality among patients with CRC. Recent investigations have elucidated the involvement of disrupted gut microbiota homeostasis in various facets of CRC metastasis, exerting a pivotal influence in shaping the metastatic microenvironment, triggering epithelial-mesenchymal transition (EMT), and so on. Moreover, therapeutic interventions targeting the gut microbiota demonstrate promise in enhancing the efficacy of conventional treatments for metastatic CRC (mCRC), presenting novel avenues for mCRC clinical management. Grounded in the "seed and soil" hypothesis, this review consolidates insights into the mechanisms by which imbalanced gut microbiota promotes mCRC and highlights recent strides in leveraging gut microbiota modulation for the clinical prevention and treatment of mCRC. Emphasis is placed on the considerable potential of manipulating gut microbiota within clinical settings for managing mCRC.

FANCA facilitates G1/S cell cycle advancement, proliferation, migration and invasion in gastric cancer.

The present study explores the function of FANCA gene, a pivotal member of the Fanconi anaemia (FA) pathway crucial for preserving genomic stability and preventing cancer, particularly in the context of gastric cancer (GC). Using immunohistochemistry, quantitative real-time PCR, and western blot analysis, we evaluate FANCA mRNA and protein expressions in GC cell lines. The relationship between FANCA expression and clinicopathological characteristics is also explored. Various assays, including CCK8, colony formation, wound healing, and Transwell assays, are used to assess functional changes in cells associated with FANCA. Flow cytometry is utilized to evaluate alterations in the cell cycle resulted from FANCA knockdown and overexpression. Our findings show elevated FANCA expression in GC cell lines, with levels correlated with pathologic stage and lymphatic metastasis. FANCA knockdown impedes cell proliferation, migration, and invasion and induces G1/S phase cell cycle arrest. Conversely, FANCA overexpression stimulates cell proliferation, migration, and invasion. In vivo xenograft experiments confirm the promotional role of FANCA in GC tumor progression. Moreover, FANCA overexpression is associated with the activation of cell cycle. Collectively, our results suggest that FANCA drives malignant cell behaviors in GC through the cell cycle pathway, highlighting its potential as a therapeutic target for the treatment of GC.

Multi-omics data-based analysis characterizes molecular alterations of the vesicle genes in human colorectal cancer.

The role of vesicular genes in the development of colorectal cancer (CRC) is crucial. Analyzing alterations in these genes at multi-omics can aid in understanding the molecular pathways behind colorectal carcinogenesis and identifying potential treatment targets. However, studies on the overall alteration of vesicular genes in CRC are still lacking. In this study, we aimed to investigate the relationship between vesicle genetic alterations and CRC progression. To achieve this, we analyzed molecular alterations in CRC vesicle genes at eight levels, including mRNA, protein, and epigenetic levels. Additionally, we examined CRC overall survival-related genes that were obtained from a public database. Our analysis of chromatin structural variants, DNA methylation, chromatin accessibility, and proteins (including phosphorylation, ubiquitination, and malonylation), along with RNA-seq data from the TCGA database, revealed multiple levels of alterations in CRC vesicle genes in the collected tissue samples. We progressively examined the alterations of vesicle genes in mRNA and protein levels in CRC and discovered the hub genes. Further investigation identified the probable essential transcription factors. This study contributes to a thorough knowledge of the connection between vesicle gene alterations at multiple levels and the development of CRC and offers a theoretical framework for the identification of novel treatment targets.

The value of intratumoral microbiota in the diagnosis and prognosis of tumors.

Intratumoral microbiota (ITM) are microorganisms present in tumor cells. ITM participate in tumor development by affecting tumor cells directly and the tumor microenvironment (TME), indirectly. Alterations in ITM instigate changes in tumor DNA, activate oncogenic pathways, induce tumor inflammatory responses, disrupt normal immune activity, and facilitate the secretion of effectors leading to tumor progression, metastasis, or diminished therapeutic effects. ITM varies significantly in different types of cancer cells and disease states. The presence of certain ITM serves as a predictor of various disease states. Thus, ITM predicts tumorigenesis, tumor grade, treatment efficacy, and prognosis, making it a potential tumor biomarker. The present study aimed to determine the mechanisms by which ITM affects tumor development, especially through the TME; highlight the significant potential of ITM in enhancing tumor diagnosis and prognosis; and outline future directions for ITM research, with a focus on the development of innovative tumor markers.

Artificial nonenzymatic antioxidant Prussian blue/KGM-BSA nanocomposite hydrogel dressing as ROS scavenging for diabetic wound healing.

The process of diabetic wound healing was influenced by the excessive proliferation of reactive oxygen species (ROS). Therefore, in the process of healing diabetic wounds, it was crucial to removing ROS. This study designed composited nanoparticles: KBP, consisted by Konjac glucomannan, bovine serum albumin, and Prussian blue. Then they were embedded in Konjac glucomannan and hydroxypropyl trimethylammonium chloride chitosan composite hydrogel (KH), The KBP@KH hydrogel finally achieved excellent efficacy in diabetic wound healing. The in vitro and in vivo experiments demonstrated that KPB nanoparticles exhibited favorable ROS scavenging capability and biosafety. The KBP@KH hydrogel not only effectively eliminated ROS from diabetic wounds, but also exhibited excellent wound adaptability. The KBP@KH hydrogel facilitated angiogenesis and suppressed the production of inflammatory factors. Overall, the KBP@KH hydrogel dressing was characterized by its user-friendly nature, safety, and high efficiency.

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance.

Immune checkpoint inhibitors (ICIs) have been extensively used in immunological therapy primarily due to their ability to prolong patient survival. Although ICIs have achieved success in cancer treatment, the resistance of ICIs should not be overlooked. Ferroptosis is a newly found cell death mode characterized by the accumulation of reactive oxygen species (ROS), glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, which has been demonstrated to be beneficial to immunotherapy and combining ferroptosis and ICIs to exploit new immunotherapies may reverse ICIs resistance. Exosomes act as mediators in cell-to-cell communication that may regulate ferroptosis to influence immunotherapy through the secretion of biological molecules. Thus, utilizing exosomes to target ferroptosis has opened up exciting possibilities for reversing ICIs resistance. In this review, we summarize the mechanisms of ferroptosis improving ICIs therapy and how exosomes regulate ferroptosis through adjusting iron metabolism, blocking the ROS accumulation, controlling ferroptosis defense systems, and influencing classic signaling pathways and how engineered exosomes target ferroptosis and improve ICIs efficiency.

Wogonoside Ameliorates Airway Inflammation and Mucus Hypersecretion via NF-κB/STAT6 Signaling in Ovalbumin-Induced Murine Acute Asthma.

Asthma is recognized as a chronic respiratory illness characterized by airway inflammation and airway hyperresponsiveness. Wogonoside, a flavonoid glycoside, is reported to significantly alleviate the inflammation response and oxidative stress. Herein, this study aimed to investigate the therapeutic effect and underlying mechanism of wogonoside on airway inflammation and mucus hypersecretion in a murine asthma model and in human bronchial epithelial cells (16HBE). BALB/c mice were sensitized and challenged with ovalbumin (OVA). Pulmonary function and the number of cells in the bronchoalveolar lavage fluid (BALF) were examined. Pathological changes in lung tissue in each group were evaluated via hematoxylin and eosin and periodic acid-Schiff staining, and changes in levels of cytokines in BALF and of immunoglobulin E in serum were determined via an enzyme-linked immunosorbent assay. The expression of relevant genes in lung tissue was analyzed via real-time PCR. Western blotting and immunofluorescence were employed to detect the expression of relevant proteins in lung tissue and 16HBE cells. Treatment with 10 and 20 mg/kg wogonoside significantly attenuated the OVA-induced increase of inflammatory cell infiltration, mucus secretion, and goblet cell percentage and improved pulmonary function. Wogonoside treatment reduced the level of T-helper 2 cytokines including interleukin (IL)-4, IL-5, and IL-13 in BALF and of IgE in serum and decreased the mRNA levels of cytokines (IL-4, IL-5, IL-6, IL-13, and IL-1ß and tumor necrosis factor-α), chemokines (CCL-2, CCL-11, and CCL-24), and mucoproteins (MUC5AC, MUC5B, and GOB5) in lung tissues. The expression of MUC5AC and the phosphorylation of STAT6 and NF-κB p65 in lung tissues and 16HBE cells were significantly downregulated after wogonoside treatment. Thus, wogonoside treatment may effectively decrease airway inflammation, airway remodeling, and mucus hypersecretion via blocking NF-κB/STAT6 activation.

The association between tinnitus and risk of cardiovascular events and all-cause mortality: insight from the UK Biobank.

BACKGROUND: The potential influence of tinnitus on cardiovascular disease (CVD) and all-cause mortality has yet to be explored. We aim to examine the correlations between tinnitus and the risk of cardiovascular events and all-cause mortality. METHODS: We conducted a prospective cohort study utilising data from the UK Biobank. The presence of tinnitus was evaluated through a questionnaire. The primary outcome was defined as a composition of cardiovascular events, including myocardial infarction (MI), stroke, and mortality from CVD, as well as all-cause mortality. Cox proportional hazard models were employed to examine the associations between tinnitus and both the primary outcome and its individual components. Sensitivity analyses were conducted to evaluate the robustness of the primary analysis. RESULTS: A total of 140,146 participants were included in the study. The presence of tinnitus was found to be associated with a higher incident rate of the primary outcome (HR = 1.057, 95%CI: 1.017-1.099, p = 0.005), MI (HR = 1.139, 95%CI: 1.061-1.222, p < 0.001) and all-cause mortality (HR = 1.053, 95%CI: 1.003-1.105, p = 0.038) after adjusting for confounders. However, there was no significant association between tinnitus and stroke or mortality from CVD. Subgroup analysis revealed that the association between tinnitus and the primary outcome was significant in females, participants with abnormal BMI, and those without hearing difficulty, depression or anxiety. Sensitivity analyses yielded consistent results. CONCLUSION: The findings from this study contribute to the existing body of evidence suggesting an association between tinnitus and an increased risk of cardiovascular events and all-cause mortality.

Protective Effect of Silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis.

OBJECTIVE: To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia. METHODS: Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1 α, IL-1 ß, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 εmol/L), and low-dose-SIB (100 εmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1 ß were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylineosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay. RESULTS: SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1 α, IL-1 ß, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05). CONCLUSIONS: SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.

A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: Multi-pathway combination therapy with PD-1/PD-L1 inhibitors.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.