Infiltration Of Liver Research Articles

TLR4 AS THE MARKER OF NON-ALCOHOLIC FATTY LIVER DISEASE PROGNOSIS IN PATIENTS WITH INTESTINAL DYSBIOSIS

Introduction. Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases characterized by the fat accumulation in liver cells and is closely associated with metabolic disorders including obesity and insulin resistance. Considerable interest of researchers is focused on the role of the intestinal microbiome in the NAFLD development and occurrence, since a violation of the normal bacteria balance (dysbiosis) can increase inflammatory processes in the liver. Toll-like receptor 4 (TLR4), which responds to components of the bacterial membrane, is an important marker involved in the development of inflammation and progression of NAFLD.The aim of this study was to determine the level of TLR4 in patients with NAFLD and to find the relationship with gut microbiome components. The study included 152 patients diagnosed with NAFLD and 86 control patients without fatty liver infiltration. General clinical, biochemical, enzyme immunoassay, instrumental and bacteriological methods were used to assess the condition of patients.The results showed that the level of TLR4 in patients with NAFLD was significantly higher than in the control group (2.67±3.05 ng/ml vs. 1.23±0.99 ng/ml). A positive correlation was marked between the TLR4 level and biochemical indicators of inflammation, such as ALT, AST, TG and ALP. It confirms the role of TLR4 in the development of inflammatory processes in NAFLD.In addition, patients with NAFLD showed a significant change in the gut microbiome composition – an increase in the number of Firmicutes phylotype bacteria and a higher level of Firmicutes/Bacteroidetes index, which was in positive correlation with TLR4. Small intestinal bacterial overgrowth (SIBO), which may lead to TLR4 activation, was also marked in 50% of NAFLD patients.Conclusion. The study confirms the role of TLR4 as a marker of the potential tole on NAFLD development and its relationship with intestinal dysbiosis, which could be perspective for the looking of new approaches in the prognosis and treatment of this disease. The microbiome correction and the development of TLR4 inhibitors is an essential way for future investigations as promising therapeutic method.

Postbiotics as Antiinflammatory and Immune-Modulating Bioactive Compounds in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Postbiotics, defined as products or metabolic byproducts secreted by live bacteria or released after bacterial lysis, are emerging as promising therapeutic agents for metabolic dysfunction-associated steatotic liver disease (MASLD). This review explores the antiinflammatory and immunomodulatory properties of various postbiotics, including exopolysaccharides, lipoteichoic acid, short-chain fatty acids, hydrogen sulfide, polyamines, tryptophan derivatives, and polyphenol metabolites. These compounds have demonstrated potential in mitigating steatotic liver infiltration, reducing inflammation, and slowing fibrosis progression in preclinical studies. Notably, postbiotics exert their beneficial effects by modulating gut microbiota composition, enhancing intestinal barrier function, optimizing lipid metabolism, reducing hepatic inflammation and steatosis, and exhibiting hepatoprotective properties. However, translating these findings into clinical practice requires well-designed trials to validate efficacy and safety, standardize production and characterization, and explore personalized approaches and synergistic effects with other therapeutic modalities. Despite challenges, the unique biological properties of postbiotics, such as enhanced safety compared to probiotics, make them attractive candidates for developing novel nutritional interventions targeting the multifactorial pathogenesis of MASLD. Further research is needed to establish their clinical utility and potential to improve liver and systemic outcomes in this increasingly prevalent condition.

A novel goldfish orthotopic xenograft model of hepatocellular carcinoma developed to evaluate antitumor drug efficacy

Tumor xenograft animal models play a crucial role in hepatocellular carcinoma (HCC) research. Mice xenograft models are time consuming, laborious and expensive while zebrafish tumor xenograft models are cost-effective and effortless. However, the development of orthotopic xenograft models for HCC in zebrafish embryos has been challenging due to the small size of zebrafish livers. In this study, we utilized 7-day-old goldfish embryos as hosts and successfully established an orthotopic xenograft model of HCC in goldfish livers. Through injecting fluorescence labeled HCC cells into the liver of goldfish, we could visualize the proliferation and migration of tumor cells in vivo. In addition, we found that the temperature of 36 °C was better for tumor cell survival in goldfish larvae compared to 28 °C, assessed by EdU and TUNEL assays. Moreover, macrophage infiltration in the goldfish liver could be evaluated by neutral red staining. Finally, we evaluated the efficacy of the targeted therapy drug Sorafenib and the traditional Chinese medicine, Huaier granules, alone or in combination in the goldfish HCC orthotopic xenograft model. We found that the combination therapy showed the best efficacy against HCC cells in terms of macrophage infiltration, polarization as well as tumor cells proliferation, metastasis and apoptosis. In conclusion, the proposed goldfish HCC orthotopic xenograft model opens new avenues for HCC related research, including evaluation of tumor progression, cell interactions in the immune microenvironment, drug efficacy, and screening of anti-tumor drugs.

Hepatitis D Virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells

Hepatitis D Virus infection triggers CXCL9-11 upregulation in hepatocytes and liver infiltration of CXCR3+ CD4 T cells

Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF

ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury

Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers. Surprisingly, livers from ZnR/GPR39 knockout (KO) mice exhibited elevated insulin receptor expression and downstream AKT activation. Moreover, ZnR/GPR39 KO mice had higher blood fasting glucose level, pronounced hepatic lipid accumulation, increased hepatocyte oxygen consumption rate (OCR) and reactive oxygen species (ROS) levels. These data suggest that ZnR/GPR39 modulates insulin receptor signaling, a major pathway in hepatic metabolism. Associated with the impaired signaling, ZnR/GPR39 KO livers exhibited increased tissue fibrosis, manifested by marked elevation of collagen expression, compared to wildtype (WT). Additionally, we found alteration of hepatocyte junctional proteins that was accompanied by increased macrophage infiltration and higher liver inflammation in ZnR/GPR39 KO mice. To determine the role of ZnR/GPR39 in ALI, we applied a mild LPS challenge that induced profound decrease in hepatic OCR, also leading to higher ROS generation in ZnR/GPR39 KO hepatocytes, but not in WT. We further found increased serum IL-2 and AST/ALT ratio only in ZnR/GPR39 KO mice. Our findings reveal a role of ZnR/GPR39 in controlling hepatic insulin receptor signaling and mitigating liver fibrosis and inflammation, thus underscoring the important role of ZnR/GPR39 in liver signaling and function.

An observational study of the causes of an isolated elevated alkaline phosphatase level of unclear etiology

BackgroundSerum alkaline phosphatase (ALP) is a commonly obtained laboratory test, but its diagnostic specificity is limited because it is found in multiple tissues. We investigated patients with isolated, elevated, ALP levels without an obvious etiology at presentation to determine the frequency of different causes of an isolated elevated ALP. MethodsThis was a retrospective, cohort study of adults (age >18 years old) from January 1st, 2013, to June 30th, 2020 in both the in- and outpatient setting at the Medical University of South Carolina. 260 patients with an isolated, elevated ALP of unknown etiology (patients with known biliary obstruction, underlying parenchymal liver disease, or pregnancy were excluded) were included. A secondary outcome was mean survival time from the ALP result. ResultsThe most common cause of ALP elevation was due to underlying malignancy (147, 57%), with 61 patients having infiltrative intrahepatic malignancy, 52 patients having bony metastasis, and 34 patients having both hepatic and bone metastasis. Bone disease (75, 29%), unsuspected parenchymal liver disease (18, 7%), non-malignant infiltrative liver disease (7, 2%), and other disorders (13, 5%) accounted for the remainder of the cohort. Notably, 123 of 260 (47%) patients died within an average of 58 months after identification of isolated, elevated ALP. ConclusionsAn isolated, elevated ALP of unclear etiology is associated with several very specific and important disorders, in particular metastatic intrahepatic malignancy - and is uncommonly associated with primary parenchymal liver disease. Providers should be aware of the potential clinical significance of an elevated ALP.

Pattern and extent of intrahepatic infiltration of perihilar cholangiocarcinoma - A case-control study based on liver panoramic digital pathology.

The extent of intrahepatic infiltration of perihilar cholangiocarcinoma (PHCC) remains unclear. This research aimed to explore the pattern and extent of intrahepatic infiltration of PHCC to guide surgical treatment and pathological research. This study included 62 patients diagnosed with PHCC who underwent major hepatectomy. A whole-mount digital liver pathology system (WDLPS) for hepatectomy specimens greater than 10 × 10cm was used to panoramically assess the intrahepatic infiltration extent of PHCC. The distal intrahepatic infiltration (DIHI) and radial liver invasion (RLI) were important parts of intrahepatic infiltration for PHCC explored by WDLPS. The study confirmed that 75.8% of PHCCs had RLI and the infiltration distance in all patients were within 15,000 µm, 62.9% of PHCCs had DIHI greater than 1cm away from the main tumor in liver parenchyma. The recurrence-free survival rates and overall survival rates of patients with DIHI were poorer than the patients without DIHI (P＜0.0001, P=0.0038). Arterial invasion on the resected side could be an excellent predictor. A total of 105 liver lobes were resected from 62 PHCC patients. The invasion rates of the left lateral, left medial, right anterior, and right posterior lobe of PHCC were 79%, 100, 100%, and 69% respectively. The presence of DIHI in most PHCCs was a significant predictor of poor postoperative recurrence and survival. Based on the extent of intrahepatic infiltration, minor hepatectomy was not suitable as the curative surgery for PHCC. Major hepatectomy and liver transplantation were the ideal radical treatment.

Management of HER2-positive and microsatellite instability-high advanced gastric cancer: a case report

Chemotherapy for advanced gastric cancer has progressed significantly in the past few decades. Biomarker-specific drugs, including anti-human epidermal growth factor receptor 2 (HER2) drugs for HER2-positive patients and immune checkpoint inhibitors for those with microsatellite instability-high (MSI-H), have become common. However, patients who are positive for HER2 and have MSI-H are extremely rare, and there are no established treatments for these patients. We present the case of a 75-year-old, male patient with gastric cancer with lymph node metastases and liver infiltration. Biomarker analysis revealed HER2 3 + , loss of MLH1, and MSI-H. After three cycles of S-1, oxaliplatin, and trastuzumab, the primary tumor and metastases shrank markedly. He subsequently underwent gastrectomy and hepatectomy as conversion surgery, achieving a pathologically complete response. He has been recurrence-free for seven months postoperatively. The present case demonstrated the efficacy of trastuzumab-containing chemotherapy followed by conversion surgery in a patient with HER2-positive, MSI-H, advanced gastric cancer.

Laparoscopic Living donor liver transplantation in irresectable intrahepatic cholangiocarcinoma in primary sclerosing cholangitis associated liver cirrhosis

AbstractIntrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor and usually associated with a poor oncological prognosis. The current gold standard is the surgical resection of the tumor with subsequent adjuvant therapy. However, in case of irresectability e.g. in case of liver cirrhosis, a palliative treatment regime is conducted.This report demonstrates the case of an irresectable iCCA in liver cirrhosis due to primary sclerosing cholangitis (PSC) treated by living-donor liver transplantation (LDLT) facilitated by minimal invasive donor hepatectomy. No postoperative complications were observed in the donor and the donor was released on the 6th postoperative day. Further, after a follow-up of 1.5 years, no disease recurrence was detected in the recipient.According to the recent international literature, liver transplantation can be evaluated in case of small solitary iCCA (< 3 cm) in cirrhosis. Less evidence is provided for transplantation in advanced tumors which are surgically not resectable due to advanced liver disease or infiltration of major vessels, however some reports display adequate long-term survival after strict patient selection. The selection criteria comprise the absence of distant metastases and locoregional lymph node metastases as well as partial remission or stable disease after neoadjuvant chemotherapy. Due to no established graft allocation for iCCA in Germany, LDLT is currently the best option to realize transplantation in these patients. Developments in the last decade indicate that LDLT should preferentially be performed in minimal invasive manner (laparoscopic or robotic) as this approach is associated with less overall complications and a shorter hospitalization. The presented case illustrates the possibilities of modern surgery and the introduction of transplant oncology in the modern therapy of patients combining systemic therapy, surgical resection and transplantation to achieve optimal long-term results in patients which were initially indicated for palliative treatment.

Ante Situm Liver Resection for Tumors Invading the Inferior Vena Cava Hepatic Vein Confluence.

Liver malignancy invading the retrohepatic inferior vena cava beyond the cavo-hepatic vein venous confluence can be resected by an ante situm technique first described by Hannoun et al.1 In this approach, a major hepatectomy is performed and the hepatic veins are sectioned to allow the inferior vena cava reconstruction while the liver is cold perfused and the liver remains within the abdominal cavity. The hepatic vein is then reimplanted on the reconstructed inferior vena cava in "a liver autotransplantation fashion." The patient was a 66-year-old with a recurrent adrenocortical carcinoma cancer invading the right liver and the retrohepatic inferior vena cava with intraluminal thrombus extending beyond to the hepatic vein confluence. A right hepatectomy extended to segment 1 and the retrohepatic inferior vena cava was planned because of the intracaval tumoral thrombus and the infiltration of the right liver. The future liver remnant (FLR) (646 cc) to total liver volume (1526 cc) ratios was 42% while the FLR to patient weight ratio was 0.9%. The parenchymal liver transection was performed under a total vascular exclusion, venovenous bypass, and hypothermic perfusion of the left liver.2 The common trunk of the left and middle hepatic veins was sectioned, allowing the liver to be rotated toward the left. Vena cava reconstruction was achieved by a ringed Gore-Tex prosthesis, with reimplantation of the left and middle hepatic veins directly over the prosthesis. Surgery lasted 580 min, total duration of venovenous bypass and liver vascular exclusion was 143 min and 140 min, respectively. Blood loss was 2 liters and 8 red blood cell (RBC) units were transfused. The patient spent 5 days in the ICU, liver function tests normalized by postoperative day 8 and patient was discharged home on postoperative day 20; 1 year later, the patient is alive and disease free under mitotane treatment. The ante situm technique represents a safe surgical option for complex liver resection for malignancy involving the cavo-hepatic venous confluence. Compared with the ex situ liver resection, this technique allows liver remnant outflow reconstruction to be performed while the liver is cold perfused within the abdominal cavity with an intact hepatic pedicle.

Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that threatens human health worldwide. The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containing α-glucan (FLA), in a concanavalin A (ConA)-induced AIH mouse model and to determine the underlying liver-protective mechanism. The results showed that compared with the model group, the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased, and the degree of inflammatory cell infiltration in liver, thymus and spleen was significantly reduced. Quantitative polymerase chain reaction, immunohistochemistry, and Western blotting showed that FLA pre-treatment inhibited the ConA-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2. Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway. Thus, FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes. Up-regulation of NRF2 signaling pathway, down-regulation of TRAF6/NF-κB signaling pathway, and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

Histological Evaluation of the Protective Role of β-glucan Against Cisplatin-Induced Hepatotoxicity

Cisplatin is a commonly used chemotherapeutic agent in the treatment of many cancers. The most important dose-limiting side effect is hepatotoxicity. Some studies have shown that antioxidant treatment with cisplatin reduces the toxic effect. In the present study, we were aimed to investigate the protective effects of antioxidant β-glucan on histological injury caused by cisplatin treatment in the liver. Wistar rats were randomly divided into three groups according to time of sacrifice, 7th day and 14th day (n=20 rats each). Both groups were then divided into four sub-groups Control, Cisplatin (10 mg/kg bw), β-glucan (100 mg/kg bw) and cisplatin+β-glucan (n=5 in each group). The rats were sacrificed at the 7th day and 14th day after the last injection. The liver sections were evaluated under a light microscope after the histological procedure. Histological injury caused by cisplatin in different days were evaluated as as sinusoidal congestion, hydropic degeneration, disorganization of hepatic cords, and mononuclear cellular infiltration in liver. When β-glucan was administered with cisplatin, it was determined that cellular damage caused by cisplatin decreased considerably in the liver in the different days groups. The light microscopic examination showed that the antioxidant beta-glucan protects against hepatotoxicity caused by cisplatin with its free radical scavenging effect. In conclusion, β-glucan may improve patients' quality of life by reducing cisplatin's toxicity on the liver.

Single-cell RNA sequencing unveils metabolic and transcriptional dynamics in CD8+ T cells of Autoimmune Hepatitis murine model, offering insights into potential therapeutic targets.

Abstract Autoimmune hepatitis (AIH) is a chronic liver disorder characterized by immune-mediated hepatocellular damage, potentially leading to liver failure, and necessitating liver transplantation if uncontrolled. Current treatments, primarily immunosuppressive drugs, are hampered by variable efficacy, significant adverse effects, and risks of non-responsiveness or relapse, underscoring the need for novel therapeutic strategies. In AIH, the inflammatory liver infiltrate predominantly consists of α/β T cells; moreover, recent findings highlight a significant contributory role of CD8+ T cells in AIH pathogenesis. Utilizing Traf6ΔTEC mice that exhibit a liver-centric autoimmune response characterized by mTEC (murine thymic epithelial cells) depletion due to conditional Traf6 deletion in thymic epithelial cells, we conducted a single-cell RNA sequencing (scRNA-seq) analysis of CD8+ T cells. This analysis elucidated diverse cellular states and functional dynamics within these cells and a preponderance of exhausted CD8+ T cells. Furthermore, flow cytometry was employed to confirm the presence of identified CD8+ T cell subtypes. Our study identified unique metabolic profiles and transcription factors differentially expressed in CD8+ T cells, shedding light on potential disease-driving mechanisms. These insights lay the groundwork for the discovery of new therapeutics aimed at modulating specific metabolic and transcriptional pathways in autoimmune hepatitis.

Prediction of severe hypertriglyceridemia-associated acute pancreatitis using a nomogram based on CT findings and blood biomarkers.

Hypertriglyceridemia is a common cause of acute pancreatitis (AP). Fatty liver, a manifestation of metabolic syndrome, is related to the severity of AP. The present study aimed to construct an accurate predictive model for severe AP (SAP) by combining the fatty liver infiltration on a computerized tomography (CT) scan with a series of blood biomarkers in patients with hypertriglyceridemia-associated AP (HTG-AP). A total of 213 patients diagnosed with HTG-AP were included in the present retrospective study. Clinical information and imageological findings were retrospectively analyzed. The model was constructed from independent risk factors using univariate analysis, the least absolute shrinkage and selection operator method. Subsequently, the data from the training group of 111 patients with HTG-AP was analyzed using logistic regression analysis. The efficacy of the model was verified using an external validation group of 102 patients through the receiver operating characteristic curve (ROC). Independent predictors, including serum calcium, C-reactive protein, lactate dehydrogenase and liver-to-spleen CT attenuation ratio (L/S ratio), were incorporated into the nomogram model for SAP in HTG-AP. The model achieved a sensitivity of 91.3% and a specificity of 88.6% in the training group. Compared with the Ranson model, the established nomogram model exhibited a better discriminative ability in the training group [area under the curve (AUC): 0.957] and external validation group (AUC: 0.930), as well as better calibration and clinical benefits. The present study demonstrates that the constructed nomogram based on CT findings and blood biomarkers is useful for the accurate prediction of SAP in HTG-AP.

Histopathological effect of Buccholzia coricea on some liver and kidneys in alloxan-induced diabetic Wistar rats

Liver and kidneys are vital organs that play several important roles such as detoxification, storage of blood, blood filtration and purification, urine excretion and secretion of hormones among others. This study was conducted to determine the histopathological effects of Buccholzia coricea on the liver and kidneys of female wistar rats, Twenty-five female wistar rats were divided into five groups of five rats per group. The five rats in group one served as the normal control group and were fed with food and water without inducement and treatment. Test group two, the positive control were induced with alloxan (150 mg/kg) without any treatment throughout the study. Test group three, the known drug group were induced with diabetes (150 mg/kg) and administered metformin daily. Test group four were induced with diabetes and were treated with low dose of 250 mg/kg of Buccholzia coriacea seed extract daily throughout the study. Test group five were induced with diabetes and were treated with high dose of 1000 mg/kg of Buccholzia coriacea seed extract daily throughout the study for 14 days and the animal models were checked daily with glucometer to ascertain their blood sugar level before the animals were sacrificed and organs harvested and preserved for histological analysis. At the end of the 14 days, hematoxylin and eosin staining methods of histological methods were used. The results of the histology of the five groups showed that group one had normal liver and kidney tissues. Group two showed cytoplasmic vacoulation and cellular infiltration of liver but an inflammation of the kidney tissue. Group three had mild sinusoidal dilation in the liver and distention of the renal tubules with reduced inflammation of the kidney tissue. Group four had cytoplasmic vacoulation of liver and reduced inflammatory activities of the kidney tissue. Group five had mild cellular degeneration of liver, hemorrhage and inflammation of the kidney tissue. Thus, Buccholzia coriacea can improve the functioning of the liver and kidneys of a diabetic rats when it is consumed below 1000mg and its equivalent daily by mitigation of the histopathological alterations by alloxan-induced diabetes. Buccholzia coriacea is a natural panacea in the management of diabetes-related organ damage.

Porphyromonas gingivalis Strain W83 Infection Induces Liver Injury in Experimental Alcohol-Associated Liver Disease (ALD) in Mice

The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.

Abstract A009: Addressing obesity’s impact on the PTEN mutant endometrium

Abstract Obesity is a rising epidemic in the United States, with approximately 50% of adult women predicted to be obese by 2030. Obesity is a risk factor for endometrial hyperplasia (EH), which is characterized by the benign overgrowth of the endometrial epithelium and is considered a precursor lesion for endometrial cancer (EC). Somatic PTEN mutations are commonly observed in EH and EC, with PTEN loss being one of the earliest mutations observed in the progression to EC. Previous obesity work in our lab utilized high-fat diet (HFD)-induced obese WT mice and found that obesity affected different cell types within the endometrium, including non-tumor prone cells. Our preliminary findings suggest that 60% HFD prolongs the estrus stage of the estrus cycle in WT mice. The aims of this study are to determine the cell-specific effects of obesity on the endometrial epithelia carrying PTEN mutations. Female PTENfl/fl; Pax8Cre/+ mutant and Pax8Cre+/+ control mice on a C57BL/6J background were fed either a 60% HFD or it’s sucrose-matched control diet (CD) for a minimum of 22 weeks. Weekly mouse and food weights were collected. Mice were tested for glucose tolerance after being on diet for at least 4.5 months. Uterus and blood were collected at estrus stage. Uteri were processed for single-cell RNA seq. PTENfl/fl; Pax8Cre/+ mice on both the HFD and CD had a diminished weight gain compared to Pax8Cre+/+ mice on the same diet. HFD-treated mice exhibited hyperphagia, weighed significantly more than the CD mice, and demonstrated glucose intolerance. H&E staining of the adipose tissue and liver revealed adipocyte hypertrophy and fatty liver infiltration in HFD mice. IHC of PTENfl/fl; Pax8Cre/+ uteri confirmed epithelial-specific loss of PTEN and displayed endometrial hyperplasia. PTENfl/fl; Pax8Cre/+ uteri had an influx of Ly6G+ neutrophils invading the endometrial epithelium compared to the Pax8Cre+/+ mice. Strikingly in PTENfl/+; Pax8Cre/+ we observe clonal loss of PTEN immunoreactivity in a subset of endometrial glands with similar phenotypic features. We propose that obesity’s impact on non-tumor cell types within the endometrium will be shaped by early genetic mutations in tumor-prone epithelia. Citation Format: Hilary J. Skalski, Shannon K. Harkins, Amelia R. Arendt, Madison MacLachlan, Katelyn Becker, Marc Wegener, Marie Adams, Galen Hostetter, Ronald L. Chandler. Addressing obesity’s impact on the PTEN mutant endometrium [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A009.

Outcome of Atezolizumab Plus Bevacizumab Combination Therapy in High-Risk Patients with Advanced Hepatocellular Carcinoma.

Real-world data regarding treatment with atezolizumab plus bevacizumab in high-risk patients with advanced HCC are lacking. In this multicenter retrospective cohort study, a total of 215 patients with advanced HCC received atezolizumab plus bevacizumab treatment at four tertiary hospitals. High-risk patients were those with grade Vp4 portal vein thrombus, bile duct invasion, or more than 50% liver infiltration. In total, 98 (45.6%) were the high-risk population, 186 (86.5%) were considered to be Child-Pugh class A, and 128 (59.5%) had previously received neoadjuvant or concomitant radiation treatment. Median overall survival (OS) was 11.25 months (95% CI, 9.50-13.10), and the median progression-free survival (PFS) was 8.00 months (95% CI, 6.82-9.18). In the high-risk population, the median OS was 10 months (95% CI, 8.19-11.82) and the median PFS was 6.50 months (95% CI, 3.93-9.08). In the high-risk population, multivariate analysis indicated that radiation therapy and lower ALBI grade were associated with better OS and PFS. A total of 177 (82.3%) patients experienced adverse events of any grade, the most common being proteinuria (23.7%). Atezolizumab plus bevacizumab treatment showed consistent efficacy and tolerability in both the total and high-risk population. Radiation therapy combined with atezolizumab plus bevacizumab treatment might be helpful to improve PFS and OS in high-risk populations.

Microscopic Growth Pattern of Metastatic Colorectal Carcinomas, Morphological Findings of the Non-Neoplastic Liver, andTheir Relationship With Prognosis and Survival.

Introduction. Various clinicopathological, radiological, and molecular parameters are predictive of prognosis in patients with colorectal carcinoma and distant organ metastases continue to have a significant place among them. Recent studies reveal that not only the presence of metastases but also the histopathological growth pattern of the metastatic tumor significantly affects prognosis. This study aimed to investigate the prognostic significance of the histopathological growth patterns of metastatic tumors, the morphological findings in the peritumoral non-neoplastic liver, and its relationship with survival in patients who have metastatic colorectal carcinoma. Materials and Method. Hematoxylin and eosin-stained slides of the tumors were re-examined in terms of histopathological diagnosis, growth pattern, presence and degree of peritumoral lymphocytic infiltration, steatosis, cholestasis, and peritumoral ductular reaction in the non-neoplastic liver. Results. In terms of histopathological growth patterns, 24 (47%) tumors showed replacement, 19 (37%) showed desmoplastic and 8 (16%) showed pushing growth pattern. In terms of total survival, there was a significant difference (P = .011) between desmoplastic and replacement growth patterns, and the survival period was shorter in patients with replacement growth patterns. Conclusion. Recent studies show that histopathological growth patterns in metastatic liver tumors may be a promising prognostic and predictive parameter. It is important to include this parameter in the pathology reports as it does not require additional equipment for evaluation in routine pathology practice, does not bring additional costs, or takes a long time to evaluate. This feature can be evaluated standardly by every pathologist.