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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Transjugular Liver Biopsy Following Left Lobe or Lateral Segment Transplantation in Pediatric Patients

Purpose: To evaluate the efficacy and safety of transjugular liver biopsy in pediatric patients with left lobe or lateral segment liver transplant. Materials and Methods: This was a retrospective study of data from 104 transjugular liver biopsies (57 children) using an 18- or 19-G biopsy needle. Transjugular liver biopsy was selected due to coagulopathy and/or ascites in 56 (54%) procedures. The median patient age, body weight, and interval from liver transplantation were 56 months, 16 kg, and 2 months, respectively. Technical success was defined as adequate liver specimens yield determined by the operator at the time of procedure. Complications, the longest length of obtained liver specimens according to needle type, and adequacy for histological diagnosis were analyzed. Result: Biopsy using a biopsy needle was successfully achieved in 103 procedures (99%). In one procedure, liver samples were obtained using biopsy forceps following unsuccessful attempts with a biopsy needle. Major complication occurred in one procedure following biopsies using both a biopsy needle and biopsy forceps. The patient received transfusion to manage decreased blood pressure and hemoglobin levels although post-biopsy venography did not show extravasation. The median longest length of liver specimens using 18-G (n = 63) and 19-G (n = 40) needles were 10 mm (range, 5–20) and 10 mm (range, 5–20), respectively (p = 0.704). Liver specimens were adequate for histological diagnosis in all procedures. Conclusion: Transjugular liver biopsy using a biopsy needle appears to be a safe and effective method to obtain liver specimens for histological diagnosis in pediatric patients with left lobe or lateral segment liver transplant. Level of Evidence: Level 4, case series.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Yap1/Taz are essential for the liver development in zebrafish

Highlights: • Taz is significantly up-regulated in zebrafish yap1 mutants. • yap1{sup −/−}; taz{sup +/−} embryos are defective in digestive organs development. • Mutations in yap1{sup −/−}; taz{sup +/−} impair cell proliferation in liver and movement of LPM. • Taz can substituteYap1's function in liver development in zebrafish. Hippo pathway regulates cell proliferation and differentiation. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are effectors of Hippo pathway. The function of Yap/Taz in embryonic liver development has yet to be reported. Here yap1 and taz were found expressed in liver and other digestive organs in zebrafish embryos, and knockout of yap1 or taz did not lead to visible defects during embryogenesis. Interestingly, Taz was significantly increased in yap1 mutants, which may account for their normal development, albeit losing Yap1. However, yap1{sup −/−}; taz{sup +/-} embryos exhibited smaller digestive organs, and more than half of them showed bilateral livers and pancreas and non-looped intestines. Further analysis revealed that the disrupted gene function in yap1{sup −/−}; taz{sup +/-} embryos did not disturb liver bud formation, but instead impaired cell proliferation in liver and movement of the neighboring lateral plate mesoderm (LPM). Overexpression of wild type yap1 or taz could rescue the defective liver phenotypes in yap1{sup −/−}; taz{sup +/-} embryos, indicating that Yap1 cooperate with Taz to regulate the liver development. In addition, Yap1 was found to function in a Tead-dependent manner in the liver development. Our results suggest that Yap1/Taz regulate LPM movement and promote cell proliferation to ensure proper liver development in zebrafish.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Identification of integrated proteomics and transcriptomics signature of alcohol-associated liver disease using machine learning

Distinguishing between alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC) remains a diagnostic challenge. In this study, we used machine learning with transcriptomics and proteomics data from liver tissue and peripheral mononuclear blood cells (PBMCs) to classify patients with alcohol-associated liver disease. The conditions in the study were AH, AC, and healthy controls. We processed 98 PBMC RNAseq samples, 55 PBMC proteomic samples, 48 liver RNAseq samples, and 53 liver proteomic samples. First, we built separate classification and feature selection pipelines for transcriptomics and proteomics data. The liver tissue models were validated in independent liver tissue datasets. Next, we built integrated gene and protein expression models that allowed us to identify combined gene-protein biomarker panels. For liver tissue, we attained 90% nested-cross validation accuracy in our dataset and 82% accuracy in the independent validation dataset using transcriptomic data. We attained 100% nested-cross validation accuracy in our dataset and 61% accuracy in the independent validation dataset using proteomic data. For PBMCs, we attained 83% and 89% accuracy with transcriptomic and proteomic data, respectively. The integration of the two data types resulted in improved classification accuracy for PBMCs, but not liver tissue. We also identified the following gene-protein matches within the gene-protein biomarker panels: CLEC4M-CLC4M, GSTA1-GSTA2 for liver tissue and SELENBP1-SBP1 for PBMCs. In this study, machine learning models had high classification accuracy for both transcriptomics and proteomics data, across liver tissue and PBMCs. The integration of transcriptomics and proteomics into a multi-omics model yielded improvement in classification accuracy for the PBMC data. The set of integrated gene-protein biomarkers for PBMCs show promise toward developing a liquid biopsy for alcohol-associated liver disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells

Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor ‘SP’600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be benecial for further clinical application of sorafenib in liver cancer treatment.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2019

A Multi-Omics Approach Demonstrates that Spaceflight Leads to Lipid Accumulation in Mouse Livers

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. We analyzed liver transcriptomic and proteomic data from three mouse spaceflight experiments flown aboard the International Space Station (Rodent Research-1 NASA (RR-1 NASA), Rodent Research-1 CASIS (RR-1 CASIS), Rodent Research-3 (RR-3)), and one mouse experiment flown on the Space Shuttle (Commercial Biomedical Testing Module-3 (CBTM-3) aboard STS-135). Despite the differences in genetic background and time of exposure to microgravity it was shown through Oil Red staining and histology that increased lipid accumulation was occurring in the liver of all mice flown in space compared to the ground controls. This led to further pursue the existing GeneLab datasets related to liver omics data from these mice. We were able to discover key conserved pathways across all the mice independent of the flight conditions that were related to increased lipid metabolism, fatty acid metabolism, both lipid and fatty acid processing, lipid catabolic processing, and lipid localization. In addition, key upstream regulators were predicted to be commonly regulated across all conditions which include ESR1, GCG, and NR1I2 being inhibited and INS being activated. Interestingly, estrogen receptor alpha (ESR1) expression has been known to be heavily involved with lipoprotein metabolism. In addition, insulin (INS) is the primary driver for fat metabolism and increased INS has been associated with increased fatty acids in the liver. Through additional proteomic analysis we were able to identify the majority of the key proteins related to lipids for both the RR-1 and RR-3 rodents were being up-regulated in the livers when comparing flight to ground controls. This additional confirmation of the lipid associated activity also showed that the lipid related proteins are heavily involved with lipid metabolism, cholesterol binding, and cholesterol metabolism. Lastly, the analysis also revealed that the circadian clock related pathways in the liver are commonly being increased across all space flight conditions which has also been reported in the literature to potentially cause increased liver damage. The combination of the very strong lipid uptake in the liver and the transcriptomic/proteomic signatures (including the circadian clock pathways) following spaceflight are consistent with early onset of liver disease. Taken together, these data indicate that, activation of lipotoxic pathways could persist during longer duration spaceflight which might result in the development of liver disease

Lipids↗
DOE OSTI2018

TUG1 is involved in liver fibrosis and activation of HSCs by regulating miR-29b

Highlights: • Tug1 is over-expressed in liver fibrosis and activated HSCs. • Tug1 promotes the expression of pro-fibrogenic genes in HSCs. • Tug1 regulates the expression of target genes through down-regulation of miR-29b. • Elevated TUG1 was expressed in liver cirhhosis patients. TUG1 has been shown to be involved in diverse human diseases by regulating gene expression at transcriptional and post-transcriptional levels via interaction with miRNA or proteins. However, the role of TUG1 in liver fibrosis remains unclear. Here, we found that Tug1 is dysregulated in liver fibrosis according to the microarray analysis. Moreover, we investigated the expression files of Tug1 by using CCl{sub 4}-and BDL-induced liver fibrosis model mice as well as in the primary cells isolated from the mice. We demonstrated that Tug1 is over-expressed in the fibrotic livers and activated HSCs, but not injured hepatocytes. In addition, we assessed the function of Tug1 in HSCs and found that Tug1 promotes the expression of α-SMA, Col1α1, Mmp2/9/10 and Timp1. Mechanically, Tug1 promotes the expression of these pro-fibrogenic genes by down-regulating miR-29b, thus accelerating the progression of liver fibrosis. Further study revealed that TUG1was up-regulated in liver tissues of patients with cirrhosis. All together, our data indicate that TUG1 might be a potential therapy target of liver fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Mechanical Response of Porcine Liver Tissue under High Strain Rate Compression

In automobile accidents, abdominal injuries are often life-threatening yet not apparent at the time of initial injury. The liver is the most commonly injured abdominal organ from this type of trauma. In contrast to current safety tests involving crash dummies, a more detailed, efficient approach to predict the risk of human injuries is computational modelling and simulations. Further, the development of accurate computational human models requires knowledge of the mechanical properties of tissues in various stress states, especially in high-impact scenarios. In this study, a polymeric split-Hopkinson pressure bar (PSHPB) was utilized to apply various high strain rates to porcine liver tissue to investigate its material behavior during high strain rate compression. Liver tissues were subjected to high strain rate impacts at 350, 550, 1000, and 1550 s –1 . Tissue directional dependency was also explored by PSHPB testing along three orthogonal directions of liver at a strain rate of 350 s –1 . Histology of samples from each of the three directions was performed to examine the structural properties of porcine liver. Porcine liver tissue showed an inelastic and strain rate-sensitive response at high strain rates. The liver tissue was found lacking directional dependency, which could be explained by the isotropic microstructure observed after staining and imaging. Furthermore, finite element analysis (FEA) of the PSHPB tests revealed the stress profile inside liver tissue and served as a validation of PSHPB methodology. The present findings can assist in the development of more accurate computational models of liver tissue at high-rate impact conditions allowing for understanding of subfailure and failure mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Can MR elastography be used to measure liver stiffness in patients with iron overload?

Untreated hepatic iron overload causes hepatic fibrosis and cirrhosis and can predispose to hepatocellular carcinoma. MR elastography (MRE) provides a non-invasive means to measure liver stiffness, which correlates with liver fibrosis but standard gradient recalled echo (GRE)-based MRE techniques fail in patients with high iron due to very low hepatic signal. Short echo time (TE) 2D spin echo echoplanar imaging (SE-EPI)-based MRE may allow measurement of stiffness in the iron loaded liver. The purpose of this study was to describe the use of such an MRE sequence in patients undergoing liver iron quantification by MRI. In our preliminary study of 43 patients with mean LIC of 9.3 mg/g (range 1.8–21.5 mg/g), liver stiffness measurements could be made in 77% (33/43) of patients with a short TE, SE-EPI based MRE sequence. On average, mean LIC in patients with failed MRE was higher than in those with successful MRE (15.9 mg/g dry weight vs. 7.3 mg/g), but a cut-off value for successful MRE could not be established. Seven patients (21% of those with successful MRE) had liver stiffness values suggestive of the presence of significant fibrosis (> 2.49 kPa). A short TE, SE-EPI based MR elastography sequence allows successful measurement of liver stiffness in a majority of patients with liver iron loading, potentially allowing non-invasive screening for fibrosis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Magnetic resonance elastography SE-EPI vs GRE sequences at 3T in a pediatric population with liver disease

Purpose: The goal of our study is to compare hepatic stiffness measures using gradient-recalled echo (GRE) versus spin-echo echo planar imaging (SE-EPI)-based MR Elastography (MRE) at 3T used to measure hepatic stiffness in a patients with suspected liver diseases. Materials and methods: This retrospective study included 52 patients with liver disease who underwent a 3T MRE exam including both an investigational SE-EPI-based technique and a product GRE-based technique. Regions of interest (ROI) were placed on the elastograms to measure elastography-derived liver stiffness as well as the area included within the ROIs. The mean liver stiffness values and area of ROIs were compared. Results: The mean liver stiffness was 3.72 kilopascal (kPa) ± 1.29 using GRE MRE and 3.78 kPa ± 1.13 using SE-EPI MRE. Measurement of liver stiffness showed excellent agreement between the two pulse sequences with a mean bias of − 0.1 kPa (range − 1.8 to 1.7 kPa) between sequences. The mean measurable ROI area was higher with SE-EPI (313.8 cm{sup 2} ± 213.8) than with the GRE technique (208.6 cm{sup 2} ± 114.8), and the difference was statistically significant (P < 0.05). Conclusions: Our data shows excellent agreement of measured liver stiffness between GRE and SE-EPI-based sequences at 3T. Our results show the advantage of a SE-EPI MRE sequence in terms of image quality, ROI size and acquisition time with equivalent liver stiffness measurements as compared to GRE-MRE sequence.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

NLRP3 inflammasome activation in liver cirrhotic patients

Highlights: • Plasma IL-1β levels were higher in plasma in patients with liver cirrhosis than control. • Plasma IL-18 levels were higher in plasma in patients with liver cirrhosis than control. • Plasma IL-18 were significantly positively associated with Child-Pugh classification. • NLRP3 expression were increased in the livers of patients with cirrhosis. NLRP3 inflammasome activation is involved in the mechanism of liver cirrhosis. In this study, we investigated the levels of plasma IL-1β and IL-18 and their relationship to component traits in patients with liver cirrhosis, and NLRP3 inflammasome expression in liver of patients with liver cirrhosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKα/NF-κB pathway

Highlights: • MALAT1 knockdown inhibits liver cancer cell proliferation. • MALAT1 silence enhances apoptosis and liver cancer cells sensibility to 5-FU incubation. • MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-κB. • MALAT1 knockdown reduces tumor growth in vivo. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis-related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP-ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-κB (p-NF-κB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKα/NF-κB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Brg1 promotes liver fibrosis via activation of hepatic stellate cells

Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFβ/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl{sub 4} administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Matrix stiffness regulate apoptotic cell death in HIV-HCV co-infected hepatocytes: Importance for liver fibrosis progression

Highlights: • HIV-HCV co-infection increases HIV/HCV RNAs levels and apoptosis in hepatocytes. • Fibrotic matrix stiffness enhances HIV/HCV RNAs and apoptosis in hepatocytes. • Apoptotic infected hepatocytes induce pro-fibrotic changes in hepatic stellate cells. HIV-HCV co-infection causes rapid progression of liver fibrosis. These outcomes to liver cirrhosis can be improved, but not stopped by specific antiviral therapies. Due to high significance of HIV-HCV interactions for morbidity and mortality in co-infected patients, our attention was attracted to the multi-component pathogenesis of fibrosis progression as the transition to end-stage liver disease development. In this study, we hypothesize that increased matrix stiffness enhances apoptosis in HCV-HIV-co-infected hepatocytes and that capturing of apoptotic bodies (AB) derived from these infected hepatocytes by hepatic stellate cells (HSC) drives the fibrosis progression. As the source of viruses, JFH1 (HCV genotype 2a) and HIV-1{sub ADA} (either purified or containing in infected macrophage supernatants) were chosen. Using Huh7.5-CYP (RLW) cells and primary human hepatocytes mono-infected with HCV and HIV or co-infected, we have shown that both HCV and HIV RNA levels were increased in co-infected cells, which was accompanied by hepatocyte apoptosis. This apoptosis was attenuated by azidothymidine treatment. The levels of both infections and apoptosis were more prominent in primary hepatocytes cultured on substrates mimicking fibrotic stiffness (24 kPa-stiff) compared to substrates mimicking healthy liver (2.4 kPa-soft). The engulfment of AB from pathogen-exposed hepatocytes activated pro-fibrotic mRNAs in HSC. Overall, the increased matrix stiffness is not only a consequence of liver inflammation/fibrosis, but the condition that further accelerates liver fibrosis development. This is attributed to the switching of HSC to pro-fibrotic phenotype by capturing of excessive amounts of apoptotic HCV- and HIV-infected hepatocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Wogonoside attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis through SOCS1 / P53 / SLC7A11 pathway

Abstract Wogonoside (WG) is a flavonoid chemical component extracted from Scutellaria baicalensis, which exerts therapeutic effects on liver diseases. Ferroptosis, a novel form of programmed cell death, regulates diverse physiological/pathological processes. In this study, we attempted to investigate a novel mechanism by which WG mitigates liver fibrosis by inducing ferroptosis in hepatic stellate cells (HSCs). A CCl 4 ‐induced mouse liver fibrosis model and a rat HSC line were employed for in vivo and in vitro experiments, both treated with WG. Firstly, the levels of the fibrotic markers α‐smooth muscle actin (α‐SMA) and α1(I)collagen (COL1α1) were effectively decreased by WG in CCl 4 ‐induced mice and HSC‐T6 cells. Additionally, mitochondrial condensation and mitochondrial ridge breakage were observed in WG‐treated HSC‐T6 cells. Furthermore, ferroptotic events including depletion of SLC7A11, GPX4 and GSH, and accumulation of iron, ROS and MDA were discovered in WG‐treated HSC‐T6 cells. Intriguingly, these ferroptotic events did not appear in hepatocytes or macrophages. WG‐elicited HSC ferroptosis and ECM reduction were dramatically abrogated by ferrostatin‐1 (Fer‐1), a ferroptosis inhibitor. Importantly, our results confirm that SOCS1/P53/SLC7A11 is a signaling pathway which promotes WG attenuation of liver fibrosis. On the contrary, WG mitigated liver fibrosis and inducted HSC‐T6 cell ferroptosis were hindered by SOCS1 siRNA and pifithrin‐α (PFT‐α). These findings demonstrate that SOCS1/P53/SLC7A11‐mediated HSC ferroptosis is associated with WG alleviating liver fibrosis, which provides a new clue for the treatment of liver fibrosis.

Liu, Guofang↗
DOE OSTI2026

Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

Kelty, Taylor↗
DOE OSTI2022

Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1 + Macrophages and Fibroblasts

Abstract Purpose: The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME). Experimental Design: We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. Results: We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients. Conclusions: We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958–2009

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0–9, 10–19 and 20–29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: –0.02, 95% CI: –0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Microbial communities in the liver and brain are informative for postmortem submersion interval estimation in the late phase of decomposition: A study in mouse cadavers recovered from freshwater

Introduction Bodies recovered from water, especially in the late phase of decomposition, pose difficulties to the investigating authorities. Various methods have been proposed for postmortem submersion interval (PMSI) estimation and drowning identification, but some limitations remain. Many recent studies have proved the value of microbiota succession in viscera for postmortem interval estimation. Nevertheless, the visceral microbiota succession and its application for PMSI estimation and drowning identification require further investigation. Methods In the current study, mouse drowning and CO 2 asphyxia models were developed, and cadavers were immersed in freshwater for 0 to 14 days. Microbial communities in the liver and brain were characterized via 16S rDNA high-throughput sequencing. Results Only livers and brains collected from 5 to 14 days postmortem were qualified for sequencing. There was significant variation between microbiota from liver and brain. Differences in microbiota between the cadavers of mice that had drowned and those only subjected to postmortem submersion decreased over the PMSI. Significant successions in microbial communities were observed among the different subgroups within the late phase of the PMSI in livers and brains. Eighteen taxa in the liver which were mainly related to Clostridium_sensu_stricto and Aeromonas , and 26 taxa in the brain which were mainly belonged to Clostridium_sensu_stricto , Acetobacteroides , and Limnochorda , were selected as potential biomarkers for PMSI estimation based on a random forest algorithm. The PMSI estimation models established yielded accurate prediction results with mean absolute errors ± the standard error of 1.282 ± 0.189 d for the liver and 0.989 ± 0.237 d for the brain. Conclusions The present study provides novel information on visceral postmortem microbiota succession in corpses submerged in freshwater which sheds new light on PMSI estimation based on the liver and brain in forensic practice.

Wang, Linlin↗