arteriovenous-metabolomics-to-measure-vivo-metabolite-exchange-brown

Arteriovenous Metabolomics to Measure <em>In Vivo</em> Metabolite Exchange in Brown Adipose Tissue

Brown adipose tissue (BAT) plays a crucial role in regulating metabolic homeostasis through a unique energy expenditure process known as non-shivering ...

Failure of mitotic checkpoint machinery leads to the chromosomal missegregation and nuclear endoreduplication, thereby driving the emergence of aneuploidy and tetraploidy population. Although abnormal nuclear ploidy and the resulting impairment of mitotic checkpoint function are typical physiological event leading to human hepatocellular carcinoma, any mutational change of mitotic checkpoint regulators has not yet been discovered. Therefore, we investigated the mutation of p31(comet), a recently identified mitotic checkpoint regulator, in human hepatocellular carcinoma. Of 51 human hepatocellular carcinoma tissue and 6 cell lines tested, five samples exhibited nucleotide sequence variations dispersed on four sites within the entire coding sequence. Among these sites with sequence substitutions, three were found to be missense mutation accompanied with amino acid change but one was a silent mutation. Of these sequence substitutions, two were present in both tumor and non-tumor liver tissues, suggesting the possibility of polymorphism. The present findings indicate that p31(comet) does not have an impact on the formation of aneuploidy and tetraploidy found in human hepatocellular carcinoma.

Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma.

Chronic oxidative stress from reactive oxygen species (ROS) produced by the mitochondria promotes hepatocarcinogenesis and tumor progression. However, the exact mechanism by which mitochondrial ROS contributes to tumor cell invasion is not known. We investigated the role of ROS modulator 1 (Romo1) in hepatocellular carcinoma (HCC) development and tumor cell invasiveness.

Overexpression of Romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells.

At present, surgical treatment is the only curative option for gallbladder (GB) cancer. Many efforts therefore have been made to improve resectability and the survival rate. However, GB cancer has a low incidence, and no randomized, controlled trials have been conducted to establish the optimal treatment modalities. The present guidelines include recent recommendations based on current understanding and highlight controversial issues that require further research. For T1a GB cancer, the optimal treatment modality is simple cholecystectomy, which can be carried out as either a laparotomy or a laparoscopic surgery. For T1b GB cancer, either simple or an extended cholecystectomy is appropriate. An extended cholecystectomy is generally recommended for patients with GB cancer at stage T2 or above. In extended cholecystectomy, a wedge resection of the GB bed or a segmentectomy IVb/V can be performed and the optimal extent of lymph node dissection should include the cystic duct lymph node, the common bile duct lymph node, the lymph nodes around the hepatoduodenal ligament (the hepatic artery and portal vein lymph nodes), and the posterior superior pancreaticoduodenal lymph node. Depending on patient status and disease severity, surgeons may decide to perform palliative surgeries.

Practical guidelines for the surgical treatment of gallbladder cancer.

Despite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence.

Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma.

Alterations in mitochondrial respiration contribute to the development and progression of cancer via abnormal biogenesis, including generation of reactive oxygen species. Ubiquinol-cytochrome c reductase hinge protein (UQCRH) consists of the cytochrome bc1 complex serving respiration in mitochondria. In the present study, we analyzed UQCRH abnormalities in hepatocellular carcinoma (HCC) and its association with clinical outcomes of patients. UQCRH expression in HCC was determined via semiquantitative and quantitative real-time reverse transcriptase polymerase chain reaction of 96 surgically resected HCC tissues positive for hepatitis B virus surface antigen. UQCRH was frequently overexpressed in HCC tissues (46.8%, based on 2.1-fold cutoff). UQCRH overexpression was observed in HCCs with larger tumor size, poorer differentiation, or vascular invasion. Kaplan-Meier analysis revealed significantly shorter overall (P = 0.005) and recurrence-free survival (P = 0.027) in patients with tumors overexpressing UQCRH. The prognostic impact of UQCRH was significant in subgroups of patients divided according to the α-fetoprotein (AFP) level. The patient subgroup with higher AFP levels (≥20 ng/mL) exhibited significant differences in 5-year overall (18.5% vs. 67.9%) and recurrence-free survival rates (11.1% vs. 46.4%) between groups with and without UQCRH overexpression. In contrast, no marked survival differences were observed between subgroups with lower AFP levels (<20 ng/mL). Multivariate analysis defined UQCRH as an independent poor prognostic factor. Conclusively, our results indicate that UQCRH overexpression is correlated with poor outcomes of HCC patients. Furthermore, in patients grouped as high risk based on elevated AFP, lack of UQCRH overexpression could be a useful indicator for clinical treatment.

The mitochondrial hinge protein, UQCRH, is a novel prognostic factor for hepatocellular carcinoma.

The application of laparoscopy for liver surgery is rapidly increasing and the past few years have demonstrated a shift in paradigm with a trend towards more extended and complex resections. The development of instruments and technical refinements with the effective use of magnified caudal laparoscopic views have contributed to the ability to overcome the limitation of laparoscopic liver resection. The Endoscopic and Laparoscopic Surgeons of Asia (ELSA) Visionary Summit 2017 and the 3 Expert Forum of Asia-Pacific Laparoscopic Hepatectomy organized hepatobiliary pancreatic sessions in order to exchange surgical tips and tricks and discuss the current status and future perspectives of laparoscopic hepatectomy. This report summarizes the oral presentations given at the 3 Expert Forum of Asia-Pacific Laparoscopic Hepatectomy.

Highlights of the Third Expert Forum of Asia-Pacific Laparoscopic Hepatectomy; Endoscopic and Laparoscopic Surgeons of Asia (ELSA) Visionary Summit 2017.

Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes transfer of methyl groups to the arginine residues of proteins and is involved in diverse cellular and biological responses. While the participation of PRMT5 in cancer progression has been increasingly documented, its association with the invasive phenotype currently remains poorly understood. In the present study, we revealed that PRMT5 is overexpressed in human hepatocellular carcinoma (HCC) and in colon cancer and its depletion leads to the suppression of cell invasive activity via the reduction of the expression of MMP-2. Real-time quantitative RT-PCR analysis of 120 HCC patient tissues revealed the overexpression of PRMT5 in HCC and the association of PRMT5 with aggressive clinicopathological parameters, such as poorer differentiation (P=0.004), more frequent hepatic vein invasion (P=0.019), larger tumor size (P=0.011) and higher α-fetoprotein levels (P=0.020). Similarly to the data obtained with HCC, overexpression of PRMT5 was also displayed in colon cancer tissues, compared to matched non-tumor regions. Consistent with the significant association of the overexpression of PRMT5 with hepatic vein invasion in patient specimens, PRMT5 depletion via siRNA transfection led to a marked reduction in the invasion rate in both HCC and colon cancer cells. Reduced invasion associated with PRMT5 depletion was accompanied by a decrease in the expression of MMP-2. Collectively, our results indicated that PRMT5 overexpression in HCC and colon cancer cells contributed to their acquisition of aggressive characteristics, such as invasiveness, thus presenting a promising therapeutic target for the treatment of these diseases.

Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells.

Although several prediction models for the occurrence of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) exist, all were established using Western cohorts. Large-scale external validation studies in Eastern cohorts that consider demographic variables including lower body mass index (BMI) are scarce. The purpose of this study was to externally validate POPF prediction models using nationwide large-scale Korean cohorts.

Clinical validation of scoring systems of postoperative pancreatic fistula after pancreatoduodenectomy: applicability to Eastern cohorts?

IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort.

Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study.

The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location.

Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a Japan-Korea collaborative study.

This study was performed to investigate the oncologic role of lymph node (LN) management and to propose a surgical strategy for treating intrahepatic cholangiocarcinoma (IHCC).

Should Lymph Nodes Be Retrieved in Patients with Intrahepatic Cholangiocarcinoma? A Collaborative Korea-Japan Study.

Aberrant production of reactive oxygen species (ROS) leads to tissue damage accumulation, which is associated with a myriad of human pathologies. Although several sensors have been developed for ROS quantification, their applications for ROS-related human physiologies and pathologies still remain problematic due to the unstable nature of ROS. Herein, we developed Trx1-cpYFP-fRMsr (TYfR), a genetically-encoded fluorescent biosensor with the remarkable specificity and sensitivity toward fMetRO (free Methionine-R-sulfoxide), allowing for dynamic quantification of physiological levels of fMetRO, a novel indicator of ROS and methionine redox status in vitro and in vivo. Moreover, using the sensor, we observed a significant fMetRO enrichment in serum from patients with acute coronary syndrome, one of the most severe cardiovascular diseases, which becomes more evident following percutaneous coronary intervention. Collectively, this study proposes that fMetRO is a novel biomarker of tissue damage accumulation in ROS-associated human pathologies, and that TYfR is a promising tool for quantifying fMetRO with potentials in versatile applications.

Development of a novel fluorescent biosensor for dynamic monitoring of metabolic methionine redox status in cells and tissues.

Methionine oxidation is involved in regulating the protein activity and often leads to protein malfunction. However, tools for quantitative analyses of protein-specific methionine oxidation are currently unavailable. In this work, we developed a biological sensor that quantifies oxidized methionine in the form of methionine--sulfoxide in target proteins. The biosensor "tpMetROG" consists of methionine sulfoxide reductase B (MsrB), circularly permuted yellow fluorescent protein (cpYFP), thioredoxin, and protein G. Protein G binds to the constant region of antibodies against target proteins, specifically capturing them. Then, MsrB reduces the oxidized methionine in these proteins, leading to cpYFP fluorescence changes. We assessed this biosensor for quantitative analysis of methionine--sulfoxide in various proteins, such as calmodulin, IDLO, LegP, Sacde, and actin. We further developed an immunosorbent assay using the biosensor to quantify methionine oxidation in specific proteins such as calmodulin in animal tissues. The biosensor-linked immunosorbent assay proves to be an indispensable tool for detecting methionine oxidation in a protein-specific manner. This is a versatile tool for studying the redox biology of methionine oxidation in proteins.

Biosensor-Linked Immunosorbent Assay for the Quantification of Methionine Oxidation in Target Proteins.

Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.

Article	Year
Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma. Experimental & molecular medicine\| PubMed ID: 17934339	2007
Overexpression of Romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells. Gastroenterology\| PubMed ID: 22749933	2012
Practical guidelines for the surgical treatment of gallbladder cancer. Journal of Korean medical science\| PubMed ID: 25368485	2014
Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma. BMC genomics\| PubMed ID: 25888140	2015
The mitochondrial hinge protein, UQCRH, is a novel prognostic factor for hepatocellular carcinoma. Cancer medicine\| PubMed ID: 28332314	2017
Highlights of the Third Expert Forum of Asia-Pacific Laparoscopic Hepatectomy; Endoscopic and Laparoscopic Surgeons of Asia (ELSA) Visionary Summit 2017. Annals of hepato-biliary-pancreatic surgery\| PubMed ID: 29536050	2018
Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells. Oncology reports\| PubMed ID: 29749478	2018
Clinical validation of scoring systems of postoperative pancreatic fistula after pancreatoduodenectomy: applicability to Eastern cohorts? Hepatobiliary surgery and nutrition\| PubMed ID: 31245401	2019
Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study. HPB : the official journal of the International Hepato Pancreato Biliary Association\| PubMed ID: 31837945	2020
Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a Japan-Korea collaborative study. Journal of hepato-biliary-pancreatic sciences\| PubMed ID: 32511838	2020
Should Lymph Nodes Be Retrieved in Patients with Intrahepatic Cholangiocarcinoma? A Collaborative Korea-Japan Study. Cancers\| PubMed ID: 33503932	2021
Development of a novel fluorescent biosensor for dynamic monitoring of metabolic methionine redox status in cells and tissues. Biosensors & bioelectronics\| PubMed ID: 33571808	2021
Biosensor-Linked Immunosorbent Assay for the Quantification of Methionine Oxidation in Target Proteins. ACS sensors\| PubMed ID: 34936330	2022
MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation. Cell reports\| PubMed ID: 36351405	2022

Dong Wook Choi

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