Small Liver Research Articles

A novel maladaptive unfolded protein response as a mechanism for small bowel resection-induced liver injury.

The unfolded protein response (UPR) is a complex adaptive signaling pathway activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress (ERS) triggers a cascade of responses that converge upon C/EBP homologous protein (CHOP) to drive inflammation and apoptosis. Herein, we sought to determine whether liver injury and fibrosis after small bowel resection (SBR) were mediated by a maladaptive hepatic ERS/UPR. C57BL/6 mice underwent 50% proximal SBR or sham operation. Markers of liver injury and UPR/ERS pathways were analyzed. These were compared with experimental groups including dietary fat manipulation, tauroursodeoxycholic acid (TUDCA) treatment, distal SBR, and global CHOP knockout (KO). At 10 wk, proximal SBR had elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) (P < 0.005) and greater hepatic tumor necrosis factor-α (TNFα) (P = 0.001) and collagen type 1 α1 (COL1A1) (P = 0.02) than shams. SBR livers had increased CHOP and p-eIF2α, but were absent in activating transcription factor 4 (ATF4) protein expression. Low-fat diet (LFD), TUDCA, and distal SBR groups had decreased liver enzymes, inflammation, and fibrosis (P < 0.05). Importantly, they demonstrated reversal of hepatic UPR with diminished CHOP and robust ATF4 signal. CHOP KO-SBR had decreased ALT but not AST compared with wild-type (WT)-SBR (P = 0.01, P = 0.12). There were no differences in TNFα and COL1A1 (P = 0.09, P = 0.50). SBR-induced liver injury, fibrosis is associated with a novel hepatic UPR/ERS response characterized by increased CHOP and decreased ATF4. LFD, TUDCA, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern. Global CHOP KO only partially attenuated liver injury. This underscores the significance of disruptions to the gut/liver axis after SBR and potentiates targets to mitigate the progression of intestinal failure-associated liver disease.NEW & NOTEWORTHY The unfolded protein response (UPR) is a complex signaling cascade that converges upon C/EBP-homologous protein (CHOP). Under conditions of chronic cellular stress, the UPR shifts from homeostatic to proapoptotic leading to inflammation and cell death. Here, we provide evidence that small bowel resection-induced liver injury and fibrosis are mediated by a maladaptive hepatic UPR. Low-fat diet, TUDCA treatment, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern.

Abstract 197: A systemic model derivation platform for generating 3D neuroendocrine tumor cell spheroids to accelerate cancer research

Abstract The Broad Cancer Cell Line Factory (CCLF) aims to increase the number and representation of in vitro/ex vivo cell models for common and rare cancer types. Neuroendocrine tumor (NET) cell model derivation is one of the CCLFs focus because it lacks well-characterized, publicly available models.Two major barriers existed in deriving NET cell models, including how to collect sufficient patient tumor tissue samples for the model derivation pilot and how to systematically iterate model derivation strategies since there is no prior knowledge for NET cell model generation success. Thus, we partnered with the MD Anderson Cancer Center, the Dana-Farber Cancer Institute, and the Rare Cancer Research Foundation to collect patient tissue samples. All patient’s NET tissues were sequenced with a targeted Pan-Cancer panel to ensure high tumor content. To reduce fibroblast outgrowth, we combined an empirical rich media matrix (HYBRID technology) with a 3D spheroid culture system to initiate one sample in 16-64 conditions. The growing cultures at passage 3-5 were genomically credentialed to ensure the driver events matched with the original patient tissue. So far, we have received more than 70 NET samples. While several derived models are still under culture, we successfully generated 5 genomically verified NET tumor models, including small intestinal, pancreas, and liver subtypes. To phenotypically characterize these NET models, neuroendocrine biomarkers such as chromogranin A, synaptophysin, SSTR2, and VMAT 1/2 were also evaluated using qRT-PCR and ELISA. We observed that these NET spheroid models display long doubling times (2-4 weeks) at later passages which limits their utility for large scale perturbation experiments and model sharing capability with the research community. While we are currently working on several strategies to improve the propagation ability in these models, 1 (out of 5) model has reached passage 15 with a 3 day doubling time. Genomic studies, such as RNAseq, will be performed to address the model transcriptome changes after overcoming growth plateaus. Here we showed that it is feasible to derive NET models from patient biospecimens using our HYBRID strategy. As we expand our NET cohort, we will further refine disease-specific model generation protocols for different NET types. Our goal is to share our model generation experience and make these tumor cell models publicly available to the research community in order to accelerate cancer research. Citation Format: Adel Attari, Madison Liistro, Barbara Van Hare, Jennifer Chan, Emma Coleman, Tim Heffernan, Bianca Amador, Matthew Meyerson, Jesse Boehm, William Sellers, Yuen-Yi (Moony) Tseng. A systemic model derivation platform for generating 3D neuroendocrine tumor cell spheroids to accelerate cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 197.

Abstract 5666: MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation

Abstract Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). MyD88 controls the expression of several key modifier genes in liver tumorigenesis; however, whether and how MyD88 in myofibroblasts contributes to the development of fibrosis-associated liver cancer remain elusive. Here, we used an established hepatocarcinogenesis mouse model involving apparent liver fibrogenesis, in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient (Fib-MyD88 KO) mice developed significantly fewer and smaller liver tumor nodules. MyD88 deficiency in myofibroblasts attenuated liver fibrosis and aerobic glycolysis in hepatocellular carcinoma tissues. Mechanistically, MyD88 signaling in myofibroblasts increased the secretion of CCL20, which promoted aerobic glycolysis in cancer cells. This process was dependent on the CCR6 receptor and ERK/PKM2 signaling. Furthermore, liver tumor growth was greatly relieved when the mice were treated with a CCR6 inhibitor. Our data revealed a critical role for MyD88 in myofibroblasts in the promotion of hepatocellular carcinoma by affecting aerobic glycolysis in cancer cells and might provide a potential molecular therapeutic target for HCC. Citation Format: Qi Yuan, Jinhua Zhang. MyD88 in myofibroblasts regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5666.

Reliability of extracellular contrast versus gadoxetic acid in assessing small liver lesions using liver imaging reporting and data system v.2018 and European association for the study of the liver criteria.

The diagnostic accuracy of Liver Imaging Reporting and Data System (LI-RADS) v.2018 and European Association for the Study of the Liver (EASL) criteria for the diagnosis of HCC have been widely evaluated, but their reliability should be investigated. We aimed to assess and compare the reliability of LI-RADS v.2018 and EASL criteria for the diagnosis of HCC using MRI with extracellular contrast agents (ECAs) and gadoxetic acid (GA) and determine the effect of ancillary features on LI-RADS reliability. Ten readers reviewed MRI studies of 92 focal liver lesions measuring <3 cm acquired with ECAs and GA <1 month apart from two prospective trials, assessing EASL criteria, LI-RADS major and ancillary features, and LI-RADS categorization with and without including ancillary features. Inter-reader agreement for definite HCC diagnosis was substantial and similar for the two contrasts for both EASL and LI-RADS criteria. For ECA-MRI and GA-MRI, respectively, inter-reader agreement was k = 0.72 (95% CI, 0.63-0.81) and k = 0.72 (95% CI, 0.63-0.80); for nonrim hyperenhancement, k = 0.63 (95% CI, 0.54-0.72) and k = 0.57 (95% CI, 0.48-0.66); and for nonperipheral washout, k = 0.49 (95% CI, 0.40-0.59) and k = 0.48 (95% CI, 0.37-0.58) for enhancing capsule. The inter-reader agreement for LI-RADS after applying ancillary features remained in the same range of agreement. Agreement for definite HCC was substantial and similar for both scoring systems and the two contrast agents in small focal liver lesions. Agreement for LI-RADS categorization was lower for both contrast agents, and including LI-RADS ancillary features did not improve agreement.

Automated detection and segmentation of small cell lung cancer liver metastases on CT.

e13555 Background: Small cell lung cancer (SCLC) is a highly malignant cancer that commonly metastasizes throughout the body (mSCLC) and is molecularly classified based on expression of four transcription regulators (NAPY): NeuroD1, ASCL1. POU2F3, and YAP1. Medical imaging is used for treatment monitoring and patient management. Due to the relatively rare occurrence of this disease, large cohorts of data are not available for training. The purpose of this work is to develop a model for automated detection and segmentation of mSCLC liver metastases by leveraging publicly available data and characterize its output against NAPY subtyping. Methods: Two datasets were used: (1) the Liver Tumor Segmentation Challenge (LiTS), a public dataset containing 130 CT scans and (2) 23 patients with mSCLC imaged at our institution with biopsy-confirmed SCLC metastasis to the liver and available NAPY subtyping. N = 12 mSCLC scans underwent ground truth lesion segmentation by an experienced radiologist (&gt; 10yrs) using ITK-Snap. The LiTS dataset was split to 80/12/8 for training/validation/testing. The mSCLC data was reserved for testing. CT scans were resampled to uniform z-spacing of 1mm and Hounsfield range. A liver organ segmentation model based on 2D UNet and liver lesion segmentation model based on DeepLabV3+ were trained using Fast.ai library. Random flipping, rotation, erasing, and variable CT windowing were applied in each batch. Hyperparameters included cross-entropy loss, Adam optimization, batch size 32, input size [512,512], 1e-4 learning rate, 100 epochs, pre-trained weights from ImageNet. The final liver volume was selected as largest 3D-connected component of output and was used as input to lesion segmentation. Segmentation performance was evaluated by Dice Similar Coefficient (DSC). AI-based lesion segmentations were used to extract 106 shape and texture features (PyRadiomics) for association to NAPY subtypes using logistic regression analysis accounting for the clustered nature of lesion data on the patient-level. Results: The liver model achieved median DSC 0.952 (range (0.926-0.964) and 0.958 (range 0.933-0.969) in the LiTs validation and testing sets, respectively. Lesion segmentation results in validation and testing sets achieved median DSC 0.639 (0-0.848) and 0.523 (0-0.878), respectively. This model demonstrated acceptable generalizabilty in the mSCLC patients from our institution with median Dice coefficient 0.696 (0.102-0.882). Overall, the model achieved 62.1% sensitivity and 88.2% PPV with median 1 FP/image (range 0-4) from 53 ground-truth lesions. Sensitivity analysis showed lesions &gt; 2mm3 had excellent detection performance. AI-based Maximum 2D Diameter and GLCM Difference Entropy were significantly associated with NA vs. PY subtypes across 29 lesions with available outcomes. Conclusions: AI-based models have potential for CT-based disease characterization of liver metastases in mSCLC.

Damage control laparotomy outcomes in a major urban trauma centre

BACKGROUND: Damage control laparotomy (DCL) is associated with high mortality. The purpose of this study was to review the outcomes of DCL. METHODS: All patients undergoing DCL for penetrating trauma from May 2015 to July 2017 were reviewed. Data retrieved were demographics, mechanism of injury, vitals, and biochemical parameters. Injury severity was described by the revised trauma score (RTS), penetrating abdominal trauma index (PATI), injury severity score (ISS) and trauma and injury severity score (TRISS). Indications for DCL, length of ICU stay, number of procedures and primary abdominal closure rates, complications and mortality were recorded. RESULTS: Fifty-one patients underwent DCL and 47 patients sustained gunshot injuries. Indications for laparotomy were haemodynamic instability (n = 27) and peritonism in stable patients (n = 22). The medians for the different severity scores were RTS 7.36, ISS 20, and PATI 30. The organs most commonly injured, in decreasing frequency, were small bowel (33), large bowel (25), abdominal vasculature (22), liver (18), stomach (14), kidney (10), diaphragm (10), spleen (9) and pancreas (8). DCL procedures performed were abdominal packing (36), temporary bowel ligation (30), vascular (5) and ureteric (1) shunting. The median number of laparotomies performed per patient was three, with a primary fascial closure rate of 69%. The mortality rate was 29%. CONCLUSION: DCL in our centre is associated with a 29% mortality rate. Severe acidosis, massive blood transfusion in first 24 hours and median PATI score more than 47 are independent risk factors associated with increased mortality.

The situation of parasitic infection in the Patients attending to the Hospital of Hue University of Medicine and Pharmacy from 2015 to 2019

Background: Parasitic and fungal disease is now a public health problem. Objective: To identify the rate of parasite infection at Hue University of Medicine and Pharmacy Hospital from 2015 to 2019. Materials and methods: Retrospective study, survey of laboratory data at the Department of Parasitology from 2015 to 2019. Results: The rates of serum positive for Fasciola sp., Taenia sp., Strongyloides sp., Toxocara sp. was 48.5%, 21.5%, 32.8%, 67.4%, respectively. Infection rates of hookworm, whipworm, strongyloidiasis, small liver fluke, Taenia sp. was 0.8%, 1.7 %, 1.0%, 2.0%, 1.7% respectively. The rate of vaginal yeast, fungal cutaneous infection was 24.2%, 41.1% respectively. Respiratory fungal infection: Candida albicans 31.7%, C. non albicans 21.6%. The rate of fungal infections of the outer ear canal: Aspergillus 54.6%, C. albicans 2.8%, C. non albicans 13%. Conclusion: These results show that the number of parasitic tests is increasing, which corresponds to the importance role of this kind of diseases to the public health. The Parasitology Department play an important role in order for hospital to improve quality to supplying the good service for public health care Key words: protozoa, Parasite, Fungi, Helminth, ELISA

Small-for-Size Syndrome: Systemic Review in a Porcine Experimental Model

The small-for-size syndrome (SFSS) is characterized by prolonged hyperbilirubinemia, coagulopathy, and/or encephalopathy caused by a small liver graft that cannot sustain the metabolic demands of the recipient after a partial liver transplant (PLT). Models of PLT in pigs are excellent for studying this syndrome. This review aimed to identify the different porcine models of SFSS in the literature and compare their technical aspects and therapeutics methods focused on portal inflow modulation (PIM). We performed a systematic review of the porcine experimental model and SFSS. The MEDLINE-PubMed, EMBASE, Cochrane Library, LILACS, and SciELO databases were electronically searched and updated until June 20, 2021. The MeSH terms used were ''ORGAN SIZE'' AND ''LIVER TRANSPLANTATION". Thirteen SFSS porcine models were reported. Four were performed with portocaval shunt to PIM and 3 with mesocaval shunt to PIM. A few studies focused on clinical therapeutics to PIM; a study described somatostatin infusion to avoid SFSS. Initially, studies on PIM showed its potentially beneficial effects without mentioning the minimum portal flow that permits liver regeneration. However, an excessive portal diversion could be detrimental to this process. The use of porcine models on SFSS resulted in a better understanding of its pathophysiology and led to the establishment of various types of portal modulation, surgical techniques with different complexities, and pharmaceutical strategies such as somatostatin, making clear that without reducing the portal vein pressure the outcomes are poor. With the improvement of these techniques, SFSS can be avoided.

Detection of Colorectal Liver Metastases Using Near-Infrared Fluorescence Imaging During Hepatectomy: Prospective Single Centre UK Study.

Small superficial colorectal liver metastases (CLM) may be difficult to localise intraoperatively, especially during minimally invasive hepatectomy due to reduced tactile feedback and limitations of ultrasound (US). Near-infrared (NIRF) fluorescence imaging is an emerging technology that permits detection of liver tumours after systemic injection of indocyanine green (ICG). Our aim was to report our experience using NIRF to detect CLM. Patients with small, superficial resectable CLM received a 10-mg IV bolus of ICG the day before hepatectomy. All patients underwent preoperative liver-specific MRI. CLM were localised intraoperatively using a combination of white light/ultrasound (WL-US) and NIRF. Sensitivity and specificity of NIRF were compared with WL-US. Between March 2019 and July 2021, NIRF was utilised in 15 patients who underwent hepatectomy (laparoscopic 13, open 2). Thirty-two lesions were detected by MRI (including 3 disappearing CLM), of which 2 were ICG-negative and not resected (1 haemangioma, 1 disappearing CLM). Of 30 resected lesions, the median tumour diameter was 11mm (range 2-25), median distance from liver surface was 4.5mm (range 0-20) and all were confirmed CLM on histology (R0 resection rate 71%). Twenty-three of thirty (77%) and twenty-seven of thirty (90%) resected CLM were detected by WL-US and NIRF, respectively. Of 7/30 (23%) resected CLM that were WL-US negative, 5 were ICG-positive. Two resected 'disappearing' CLM were ICG-positive, one of which contained viable cancer cells. Overall, NIRF influenced the operative strategy in 6 patients (43%). Near-infrared fluorescence imaging allows detection of small, superficial colorectal liver metastases that are missed by conventional techniques and warrants further study.

A study on predicting cases that would benefit from proton beam therapy in primary liver tumors of less than or equal to 5 cm based on the estimated incidence of hepatic toxicity

BackgroundFor small primary liver tumors, favorable outcomes have been reported with both of proton beam therapy (PBT) and X-ray therapy (XRT). However, no clear criteria have been proposed in the cases for which and when of PBT or XRT has to be used. The aim of this study is to investigate cases that would benefit from PBT based on the predicted rate of hepatic toxicity. Materials and methodsEligible patients were those who underwent PBT for primary liver tumors with a maximum diameter of ≤ 5 cm and Child-Pugh grade A (n = 40). To compare the PBT-plan, the treatment plan using volumetric modulated arc therapy was generated as the XRT-plan. The rate of predicted hepatic toxicity was estimated using five normal tissue complication probability (NTCP) models with three different endpoints. The differences in NTCP values (ΔNTCP) were calculated to determine the relative advantage of PBT. Factors predicting benefits of PBT were analyzed by logistic regression analysis. ResultsFrom the dose-volume histogram comparisons, an advantage of PBT was found in sparing of the normal liver receiving low doses. The factors predicting the benefit of PBT differed depending on the selected NTCP model. From the five models, the total tumor diameter (sum of the target tumors), location (hepatic hilum vs other), and number of tumors (1 vs 2) were significant factors. ConclusionsFrom the radiation-related hepatic toxicity, factors were identified to predict benefits of PBT in primary liver tumors with Child-Pugh grade A, with the maximum tumor diameter of ≤ 5 cm.

Evaluation of short- and medium-term efficacy and complications of ultrasound-guided ablation for small liver cancer.

BACKGROUNDTo ensure clinical efficacy and prolong patient survival, treatments such as surgery and microwave ablation (MWA) are used for early liver cancer. MWA is preferred because it effectively preserves the normal liver tissue and causes transient coagulation necrosis of local liver tumor cells. However, due to technical limitations, the cancerous liver tissue cannot be completely ablated; therefore, the probability of local tumor recurrence is high.AIMTo investigate the clinical efficacy and safety of ultrasound-guided percutaneous MWA in the treatment of small liver cancer.METHODSA total of 118 patients treated for small liver cancer in The Central Hospital of Yongzhou from January 2018 to April 2019 were selected. Sixty-six patients received ultrasound-guided percutaneous MWA (MWA group) and 52 received laparoscopic surgery (laparoscope group). The operation time, blood loss, hospital stay, and medical expenses of both groups were statistically analyzed. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), alpha fetal protein (AFP), carcinoembryonic antigen (CEA), and peripheral blood regulatory T lymphocytes (Treg) levels were evaluated pre- and post-operatively. The cross-sectional area of tumors measured before and after ablation was analyzed statistically; the therapeutic effect was compared between both groups in terms of surgical complications, 2-year progression-free survival rate, and overall survival rate. RESULTSThe operation time, blood loss, hospital stay, and medical expenses in the MWA group were lower than those of the laparoscope group, and the differences were significant (P < 0.05); these parameters, and ALT, AST, TBIL, and ALB levels were compared preoperatively between both groups, and there was no significance (P > 0.05). The operation time, blood loss, hospital stay, and medical expenses for 2 d and 1 wk after surgery, the ALT and AST of the MWA group were lower than those of the laparoscope group, and the difference was significant (P < 0.05). The operation time, blood loss, hospital stay, and medical expenses, and serum AFP, CEA, and Treg levels were measured preoperatively and 4 and 8 wk postoperatively, and there were no significant differences between the two groups (P > 0.05). Compared with preoperative levels, serum AFP, CEA, and Treg levels in both groups were decreased (P < 0.05). The lesion in the MWA group had a maximum area of 4.86 ± 0.90 cm2, 1.24 ± 0.57 cm2, and 0.31 ± 0.11 cm2 preoperatively, 1 and 3 mo postoperatively, respectively. Fifty-eight of them achieved complete response and eight achieved a partial response. After 2 years of follow-up, the progression-free and overall survival rates in the MWA group were 37.88% and 66.67%, respectively, compared with 44.23% and 76.92% in the laparoscope group, with no significant difference (P > 0.05). CONCLUSIONThe effects of ultrasound-guided percutaneous MWA in the treatment of small liver cancer are similar to those of laparoscopic surgery. However, ablation causes less trauma and liver dysfunction.

Integrated analysis of multi-tissues lipidome and gut microbiome reveals microbiota-induced shifts on lipid metabolism in pigs.

Lipid metabolism is very important for meat quality in pigs. Accumulating evidence shows that gut microbiota can contribute to this physiological process. However, the gut microbiota that function in lipid metabolism and adipogenesis remains unclear. Here, we compared the characteristics of fat deposition and gut microbial community between Laiwu pigs and Duroc × (Landrace × Yorkshire) (DLY) pigs. Fecal microbiota transplantation (FMT) was performed to determine the possible impact of gut microbiota on lipid metabolism in pigs. An integrated analysis of the gut microbiome and lipidome of the small intestine, plasma, and liver was conducted to investigate the effects of FMT on host lipid metabolism. The comparative analysis of the gut microbiome showed higher abundance of Bacteroidetes (P = 0.0018) while lower abundance of Firmicutes (P = 0.012) in Laiwu pigs, and the microbial composition can be transferred from Laiwu pigs into DLY pigs. Transmission electron microscope and Oil red-O staining were performed to analyze the effects of FMT on lipid deposition in liver, the main target organ for lipid metabolism. The results showed that FMT significantly increased the number of lipid droplets (P = 0.0035) and lipid accumulation (P = 0.0026) in liver. Furthermore, integrated multi-tissues lipidome analysis demonstrated that the fatty acyls and glycerophospholipids were significantly increased (P < 0.01) in intestine and liver, while glycerolipids and fatty acyls were reduced (P < 0.01) in plasma. In the small intestine, FMT increased (P < 0.01) the relative abundance of polyketides and prenol lipids but reduced (P < 0.01) the saccharolipids. Correlation analysis revealed the potential interactions between microbiota and lipid metabolites. Together, our results indicated that the gut microbiota may regulate the lipid metabolism and enhance the accumulation of lipid droplets in the liver of pigs.

Amino acid balance of microbial-tissue complex in the small intestinal and liver under administration of lead acetate

It is known that the initiating event of liver damage during lead intoxication is the effect of lead on the intestinal microbiome and the metabolic profile of enterocytes. The aim of the study was to reveal the dependence of the concentrations of free amino acids and their derivatives in the liver on the amino acid pool of the microbial-tissue complex of the small intestine. We used rats weighing 120‒140 g, which were injected intragastrically for three weeks with drinking water with lead acetate. Free amino acids and their nitrogen-containing metabolites in the microbial-tissue complex of the intestine and liver were determined by HPLC. Enteral intake of lead acetate with drinking water changes the profile of free amino acids and their derivatives in the microbial-tissue complex of the small intestine, which correlates with a violation of amino acid homeostasis in the liver. The analysis of the correlations of the indicators we determined indicates the essential role of nitrogen-containing metabolites of amino acids ‒ ethanolamine and phosphoethanolamine, taurine, and cystathionine. The direction of the correlation relationship between various nitrogen-containing metabolites of the microbial-tissue complex and the liver can be considered as marker of discoordination of homeostasis.

The Gut‐Brain Connection: The Inflammatory Role of IL‐6 Caused by a Western Diet

IntroductionAn increase in chronic proinflammatory immune activity is recognized as an increasingly fundamental element in relation to neurodegenerative disorders. Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with recent evidence suggesting the Western Diet as a source for systemic inflammation. The communication fusing the gut to brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti‐inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Similarly, IL‐6 is a part of the gut‐brain axis. The levels of IL‐6 expression are affected by the gut microbiota and therefore sought to interplay a key role in cognitive function and decline, which could ultimately lead to several neurodegenerative diseases such as Alzheimer’s. The production of IL‐6 is increased by inflammation and associated with sepsis, endotoxemia and treatment with pro inflammatory cytokines. The release of this cytokine peripherally influences the CNS by a ting on the microglia to stimulate a state of neuroinflammation. During inflammation, proinflammatory cytokine IL‐6 is released from the intestinal mucosa and activates the Vagus nerve afferents. Hence, it could conceivably be hypothesized that IL‐6 activates gastrointestinal submucosal neurons through the brain‐gut axis. The aim of this study is to conduct a systematic review of literature through the search of available online medical databases containing information pertaining to gut dysbiosis and the primary communication between the brain‐gut axis.MethodsA total of 80 articles were retrieved from the databases of Pubmed, Google Scholar and Frontiers. Our method of assessment analyzed prominent keywords in our study pertaining to the small intestines, brain, liver, hepcidin, TMAO, BDNF, iron, astrocytes, WD, microbiota, gut microbiome, gut dysbiosis, iron, inflammation, oxidative stress, IL‐6, and vagus nerve. After reading the full‐text then extracting the findings from each study, our team organized those findings of brain, liver and gut biomolecules in relation to maintaining homeostasis and prevention of inflammation. The databases were assessed fall of 2021 following exportation of articles to a bibliographical database for further screening processes.ResultsThe results of this study indicate the optimal state of a healthy brain is IL‐6, hepcidin, ferritin and iron are at baseline levels. Whereas, in a dysbiosis state likely caused by WD, the brain responds by upregulating IL‐6, hepcidin and ferritin levels.ConclusionsIt would be interesting for a future study to experimentally focus on whether hepcidin upregulation induces the downregulation of iron in the neuron, or if the upregulation of iron in the neuron induces the downregulation of hepcidin in the setting of neuroinflammation.

Using targeted LC‐MS/MS‐based metabolomics to measure a broad constellation of bile acids/salts in disorders of human health

BackgroundBile is an important liver secretion which aids the digestion of fats in the intestine. Bile acids are the major organic solute component of bile and are synthesized from cholesterol in the liver and stored in the gallbladder. After secretion in the intestine, bile acids are re‐absorbed in the distal small intestine (ileum). Imbalances in the reabsorption of bile acids can lead to bile acid diarrhea when bile acid malabsorption occurs. Conversely, when there is an increase in bile acid absorption hepatic disorders such as nonalcoholic fatty liver disease can arise. A wide array of distinct bile acid structures have been identified in vertebrates. Developing and refining experimental tools to identify the role of bile acids in health and disease will enhance our ability to treat complex disorders impacting multiple organ systems.Methods &amp; ResultsWe have expanded our existing reverse‐phase liquid chromatography‐tandem mass spectrometry (LC‐MS/MS)‐based targeted metabolomics method to accommodate a simple‐to‐use standards kit that includes reference standards for 16 bile acids/salts and their corresponding deuterated isotopologs as internal standards. LC‐MS/MS method enhancements include scheduled Selected‐Reaction Monitoring (sSRM) to reduce instrument duty cycle, and carefully tailored chromatographic conditions to resolve the following groups of structurally similar or isobaric bile acids/salts: i) Glycocholic Acid (GCA) and Taurocholic Acid (TCA); ii) Lithocholic Acid (LCA), Glycolithocholic Acid (GLCA), and Taurolithocholic Acid (TLCA); iii) isobaric Cholic Acid (CA) and beta‐Muricholic Acid (b‐MCA); iv) isobaric Ursodeoxycholic Acid (UDCA), Chenodeoxycholic Acid (CDCA), and Deoxycholic Acid (DCA); v) isobaric Glycoursodeoxycholic Acid (GUDCA), Glycochenodeoxycholic Acid (GCDCA), and Glycodeoxycholic Acid (GDCA); and vi) isobaric Tauroursodeoxycholic Acid (TUDCA), Taurochenodeoxycholic Acid (TCDCA), and Taurodeoxycholic Acid (TDCA). Our tissue processing and metabolite extraction procedures have been optimized for hepatic and fecal tissues. Individuals with inactivating mutations in the molecular motor, Myosin Vb, have severe diarrhea and often present with liver cholestasis. We used an animal model of loss of Myosin Vb to determine alterations in bile acid composition in the distal small intestine and liver. Whole segments of the ileum and liver were processed in methanol and analyzed by LC‐MS/MS.ConclusionWe have developed a targeted metabolomics method to accurately identify and quantify bile acids by LC‐MS/MS and this technique can be used to investigate changes in bile acid composition in gastrointestinal disorders.

Experimental silicon intake with drinking water affects the serotonin supply in the digestive tract of laboratory rats

Serotonin plays an important role in the function of the gastrointestinal tract. Currently, the dietary supplementation containing silicon becomes very popular trend, even for the long‐time reception. The effect of dietary silicon intake on serotonin level in small intestine (SI) and liver are not well understood. In this study we checked the impact of water‐soluble silicon compounds intake on the serotonin supply in structures of SI and liver.The study was curry out on 2‐months‐old male rats, which were divided on two groups: control group (n=10) received ad libitum drinking water; experimental group (n=10) received ad libitum the same water containing sodium metasilicate (Na2SiO3x9H2O, 10 mg/liter) for 2 and 9 months. Five animals from each group were sacrificed 2 months after beginning of the experiment, the rest – 9 months later. All manipulations with experimental animals were performed in accordance with the Regulations on Animal Experiments and in Compliance with European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. The liver and pieces of small intestine (10 sm below the hepatoduodenal ligament) were isolated after decapitation and immediately frozen for the luminescence‐histochemical study. The presence of serotonin was detected on 10 µm cryosections using Falck‐Hillarp method modified by Krokhina (1982). The sections were examined under the Leica D1000 fluorescent microscope (360 nm of exciting light length, 525 nm of emission wavelength). Spectrofluorimetry was used to identify and quantify the serotonin levels in cytoplasm of follow structures: epithelial cells of mucous membrane, in the macrophages of the lamina propria of SI, in hepatocytes and luminescent granular cells (LGC) of liver.There are no significant differences in intensity of serotonin fluorescence in investigates structures of SI between control and experimental groups were detected after 2 months from the beginning of experiments. However, in liver the value of serotonin fluorescence intensity in the wall of the central veins and hepatocytes of rats in experimental group was elevated in 1.2 times, in LGC and their microenvironment – 1.5 times (р &lt; 0,05) compared to the control group.The 9‐months silicon supplementation leads to the up‐regulation of serotonin fluorescence intensity in structures of SI: in cytoplasm of epithelial cells of the mucous membrane, in macrophages of the lamina propria and in their microenvironment, by 1.2 and 1.4 times, respectively (p &lt; 0.05). The intensity of serotonin value in cytoplasm of hepatocytes and in the wall of the central veins of liver increased by 1.2 and 1.1 times, respectively (p &lt; 0.05), in LGC and their microenvironment – by 1.3 and 1.7 times, respectively (p &lt; 0.05).We concluded that (i) the liver is a little more sensitive to the intake of silicon with drinking water than the structures of SI; (ii) the silicon supplementation generally increases the intensity of serotonin content in structures of liver and SI, which can be explained by age‐related changes in these organs.

Treatment of choice for advanced HCC with small future remnant liver volume for a hepatologist?

Treatment of choice for advanced HCC with small future remnant liver volume for a hepatologist?

Atypical anatomic liver resection in patients with small future liver remnant

Atypical anatomic liver resection in patients with small future liver remnant

Identifying key genes in milk fat metabolism by weighted gene co-expression network analysis

Milk fat is the most important and energy-rich substance in milk, and its content and composition are important reference elements in the evaluation of milk quality. However, the current identification of valuable candidate genes affecting milk fat is limited. IlluminaPE150 was used to sequence bovine mammary epithelial cells (BMECs) with high and low milk fat rates (MFP), the weighted gene co-expression network (WGCNA) was used to analyze mRNA expression profile data in this study. As a result, a total of 10,310 genes were used to construct WGCNA, and the genes were classified into 18 modules. Among them, violet (r = 0.74), yellow (r = 0.75) and darkolivegreen (r = − 0.79) modules were significantly associated with MFP, and 39, 181, 75 hub genes were identified, respectively. Combining enrichment analysis and differential genes (DEs), we screened five key candidate DEs related to lipid metabolism, namely PI4K2A, SLC16A1, ATP8A2, VEGFD and ID1, respectively. Relative to the small intestine, liver, kidney, heart, ovary and uterus, the gene expression of PI4K2A is the highest in mammary gland, and is significantly enriched in GO terms and pathways related to milk fat metabolism, such as monocarboxylic acid transport, phospholipid transport, phosphatidylinositol signaling system, inositol phosphate metabolism and MAPK signaling pathway. This study uses WGCNA to form an overall view of MFP, providing a theoretical basis for identifying potential pathways and hub genes that may be involved in milk fat synthesis.

The Apparent Asymmetrical Relationship Between Small Bowel Bacterial Overgrowth, Endotoxemia, and Liver Steatosis and Fibrosis in Cirrhotic and Non-Cirrhotic Patients: A Single-Center Pilot Study

IntroductionGut microbiota are a complex ecosystem harboring our intestine. They maintain human body equilibrium, while their derangement, namely, “dysbiosis“, has been associated with several gastrointestinal diseases, such as liver steatosis (NAFLD) and liver cirrhosis. Small intestinal bacterial overgrowth (SIBO) is an example of dysbiosis of the upper gastrointestinal (GI) tract.AimThe aim of this study is to evaluate the relationship between SIBO and levels of endotoxemia and grade of liver steatosis (LS) and liver fibrosis (LF) in hepatologic patients.Materials and MethodsConsecutive outpatients referred to our hepatology clinic were tested for SIBO by the lactulose breath test (LBT) and peripheral blood levels of endotoxemia; LS grading and LF were assessed by abdominal ultrasound and transient elastography, respectively.ResultsFifty-two consecutive patients (17 with alcohol abuse (4.5 ± 0.8 alcohol units per day), 4 with HCV and 2 with HBV infection, 24 of metabolic origin, 2 of autoimmune origin, and 3 with cholangiopathies; mean age 54.7 ± 8.3 years, 31 F, BMI 24.1 ± 1.1 Kg/m2) and 14 healthy volunteers (HV) (mean age 50.1 ± 4.3 years, 9 F, BMI 23.3 ± 1.1 Kg/m2) were enrolled. SIBO prevalence was significantly higher in cirrhotic (LC) vs. non-cirrhotic (LNC) patients and vs. HV (all, p < 0.05), with a significant positive trend according to Child-Pugh status (all, p < 0.05). SIBO prevalence was not correlated with LS stages (all, p = NS). Consensually, endotoxin levels were significantly higher in LC vs. LNC and vs. HV (all, p < 0.05) and significantly correlated with LF in patients with LC, according to Child-Pugh status (all, p < 0.05).ConclusionThis study shows that SIBO prevalence and relative endotoxin blood levels seem to be significantly associated with the grade of LF vs. LS in LC. SIBO is also present under pre-cirrhotic conditions, but its prevalence seems to correlate with liver disease irreversible derangement.