Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. APPROACH AND RESULTS: Intestinal PPARα was activated and fatty acid-binding protein 1 (FABP1) up-regulated in humans with obesity and high-fat diet (HFD)-fed mice as revealed by using human intestine specimens or HFD/high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed C57BL/6N mice and PPARA -humanized, peroxisome proliferator response element-luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double-knockout ( Ppara/Fabp1ΔIE ) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA -humanized, but not Ppara -null, mice. CONCLUSIONS: Intestinal PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.

Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC. APPROACH AND RESULTS: Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. CONCLUSIONS: This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.

De novo Creation and Assessment of a Prognostic Fat-Age-Inflammation Index "FAIN" in Patients With Cancer: A Multicenter Cohort Study.

Background and Aims: Malnutrition is highly prevalent and is related to multiple impaired clinical outcomes in cancer patients. This study aimed to de novo create an objective, nutrition-related index specially for prognostic purposes in oncology populations. Methods: We performed a multicenter cohort study including 14,134 cancer patients. The prognostic impact for each baseline characteristic was estimated by calculating Harrell's C-index. The optimal parameters reflecting the nutritional and inflammatory impact on patients' overall survival were selected to develop the fat-age-inflammation (FAIN) index. The associations of the FAIN with the nutritional status, physical performance, quality of life, short-term outcomes and mortality of patients were comprehensively evaluated. Independent external validation was performed to further assess the prognostic value of the FAIN. Results: The study enrolled 7,468 men and 6,666 women with a median age of 57 years and a median follow-up of 42 months. The FAIN index was defined as: (triceps skinfold thickness + albumin) / [age + 5 × (neutrophil count/lymphocyte count)]. There were significant associations of the FAIN with the nutritional status, physical performance, quality of life and short-term outcomes. The FAIN also showed better discrimination performance than the Nutritional Risk Index, the Prognostic Nutritional Index and the Controlling Nutritional Status index (all P < 0.05). In multivariable-adjusted models, the FAIN was independently associated with a reduced death hazard both as a continuous variable (HR = 0.57, 95%CI = 0.47-0.68) and per one standard deviation (HR = 0.83, 95%CI = 0.78-0.88). External validation in a multicenter lung cancer cohort (n = 227) further confirmed the prognostic value of the FAIN. Conclusions: This study created and assessed the prognostic FAIN index, which might act as a feasible option to monitor the nutritional status and help develop intervention strategies to optimize the survival outcomes of cancer patients.

Several anthropometric measurements and cancer mortality: predictor screening, threshold determination, and joint analysis in a multicenter cohort of 12138 adults.

BACKGROUND: Anthropometric measurements (AMs) are cost-effective surrogates for evaluating body size. This study aimed to identify the optimal prognostic AMs, their thresholds, and their joint associations with cancer mortality. METHODS: We performed an observational cohort study including 12138 patients with cancer at five institutions in China. Information on demographics, disease, nutritional status, and AMs, including the body mass index, mid-arm muscle circumference, mid-arm circumference, handgrip strength, calf circumference (CC), and triceps-skinfold thickness (TSF), was collected and screened as mortality predictors. The optimal stratification was used to determine the thresholds to categorize those prognostic AMs, and their associations with mortality were estimated independently and jointly by calculating multivariable-adjusted hazard ratios (HRs). RESULTS: The study included 5744 females and 6394 males with a mean age of 56.9 years. The CC and TSF were identified as better mortality predictors than other AMs. The optimal thresholds were women 30 cm and men 32.8 cm for the CC, and women 21.8 mm and men 13.6 mm for the TSF. Patients in the low CC or low TSF group had a 13% (HR = 1.13, 95% CI = 1.03-1.23) and 22% (HR = 1.22, 95% CI = 1.12-1.32) greater mortality risk compared with their normal CC/TSF counterparties, respectively. Concurrent low CC and low TSF showed potential joint effect on mortality risk (HR = 1.39, 95% CI = 1.25-1.55). CONCLUSIONS: These findings support the importance of assessing the CC and TSF simultaneously in hospitalized cancer patients to guide interventions to optimize their long-term outcomes.

Intestinal MYC modulates obesity-related metabolic dysfunction.

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

A fusion decision system to identify and grade malnutrition in cancer patients: Machine learning reveals feasible workflow from representative real-world data.

BACKGROUND AND AIMS: Most nutritional assessment tools are based on pre-defined questionnaires or consensus guidelines. However, it has been postulated that population data can be used directly to develop a solution for assessing malnutrition. This study established a machine learning (ML)-based, individualized decision system to identify and grade malnutrition using large-scale data from cancer patients. METHODS: This was an observational, nationwide, multicenter cohort study that included 14134 cancer patients from five institutions in four different geographic regions of China. Multi-stage K-means clustering was performed to isolate and grade malnutrition based on 17 core nutritional features. The effectiveness of the identified clusters for reflecting clinical characteristics, nutritional status and patient outcomes was comprehensively evaluated. The study population was randomly split for model derivation and validation. Multiple ML algorithms were developed, validated and compared to screen for optimal models to implement the cluster prediction. RESULTS: A well-nourished cluster (n = 8193, 58.0%) and a malnourished cluster with three phenotype-specific severity levels (mild = 2195, 15.5%; moderate = 2491, 17.6%; severe = 1255, 8.9%) were identified. The clusters showed moderate agreement with the Patient-Generated Subjective Global Assessment and the Global Leadership Initiative on Malnutrition criteria. The severity of malnutrition was negatively associated with the nutritional status, physical status, quality of life, and short-term outcomes, and was monotonically correlated with reduced overall survival. A multinomial logistic regression was found to be the optimal ML algorithm, and models built based on this algorithm showed almost perfect performance to predict the clusters in the validation data. CONCLUSIONS: This study developed a fusion decision system that can be used to facilitate the identification and severity grading of malnutrition in patients with cancer. Moreover, the study workflow is flexible, and might provide a generalizable solution for the artificial intelligence-based assessment of malnutrition in a wider variety of scenarios.

Comparison of the AWGS and optimal stratification-defined handgrip strength thresholds for predicting survival in patients with lung cancer.

OBJECTIVES: Handgrip strength (HGS) is related to cancer mortality. The aim of this study was to compare the performance of the Asian Working Group for Sarcopenia 2019 (AWGS)- and optimal stratification (OS)-defined HGS thresholds for predicting the survival of patients with lung cancer (LC). METHODS: We performed an observational cohort study including 3230 patients with LC admitted to five institutions in China from November 2011 to January 2019. Comprehensive baseline and follow-up information was documented. Sex-specific thresholds for identifying patients with a low HGS were defined based on the AWGS (<28 kg in men and <18 kg in women) and the OS. The associations of a low HGS with survival were estimated by calculating multivariable-adjusted hazard ratios (HRs), and the relationships were flexibly modeled using restricted cubic splines. RESULTS: The study included 1041 women and 2189 men with a mean age of 60 y and a median follow-up time of 761 d. The OS-calculated HGS thresholds were <31.2 kg in men and <22.4 kg in women. There were significant associations between a low HGS defined by the AWGS (n = 1392; 43.1%) or the OS (n = 2034; 63%) and various nutritional characteristics. An AWGS-defined low HGS was associated with prolonged hospitalization. The OS-defined low HGS group was associated with a 23% greater death hazard than the normal HGS group (HR, 1.23; 95% confidence interval, 1.08-1.40). An n-shaped non-linear association was observed between the HGS and survival in women (P = 0.003). CONCLUSIONS: The OS-defined HGS thresholds show better performance than the AWGS for predicting the survival of patients with LC. Additionally, the HGS had n-shaped associations with the overall mortality among female patients with LC.

IL-11 activated by lnc-ATB promotes cell proliferation and invasion in esophageal squamous cell cancer.

IL-11 exerts important functions involved in tumorigenesis and cancer progression. However, the underlying functional role of IL-11 in esophageal squamous cell cancer (ESCC) is not well known. In this paper, we demonstrated that IL-11 expression was increased in esophageal cancer compared with normal tissues, whereas knockdown of IL-11 could inhibit the proliferation and invasion of Eca109 and KYSE410 ESCC cells. Besides, we found that the stability and expression of IL-11 was regulated by lnc-ATB in Eca109 and KYSE410 ESCC cells. More importantly, we found that knockdown of IL-11 partly abolished lnc-ATB-mediated the proliferation and invasion of Eca109 and KYSE410 ESCC cells. Collectively, these results indicated that IL-11 mediated by lnc-ATB increased the proliferation and invasion of ESCC cells, which may provide a promising therapeutic option for suppressing ESCC progression.

Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells.

Increasing evidence shows that aberrant epigenetic regulation of tumor suppressor genes is a contributing factor to their altered expression in esophageal squamous cell carcinoma (ESCC). In the current study, we investigate the role of DOK7 in ESCC cells. We found that enforced expression of DOK7 inhibited the proliferation and invasion of ESCC cells. We also found that treatment of ESCC cells with the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-azadC), induced the demethylation of DOK7 in promoter and DOK7 expression. Moreover, silencing DNMT3A decreased methylation of DOK7 and increased DOK7 expression, followed by repressing the proliferation and invasion of ESCC cells. Collectively, our data indicated that silencing DNMT3A inhibits proliferation and invasion in ESCC cells by inducing demethylation of DOK7.

miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN.

Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. The mechanism of chemo-resistance is still poorly understood, however, mounting evidence supports a role for microRNAs (miRNAs) in modulating key cellular pathways mediating response to chemotherapy. microRNA-21 (miR-21) has been implicated in many cancers and contributed to chemo-resistance, but its role in gastric cancer drug resistance still remains unexplored. The aim of this study was to investigate whether miR-21 mediated resistance of the gastric cancer cell line SGC7901 to the chemotherapeutic agent cisplatin (DDP). Our study found that the expression of miR-21 upregulated in the cisplatin resistant cell line SGC7901/DDP compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by cisplatin, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by cisplatin. In addition, miR-21 induced cell survival and cisplatin resistance through downregulating the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN) and activation of Akt pathway. Inhibition of Akt using PI3K inhibitor LY 294002 could abrogate miR-21 induced cell survival. These results suggest that miR-21 may provide a novel mechanism for understanding cisplatin resistance in gastric cancer by modulating PTEN/PI3K/Akt pathway.

Post-TACE combination therapy of heparin and octreotide results in decreased tumor metastasis in extrahepatic tumorigenesis.

Primary hepatocarcinoma is the most common type of malignant tumor and a leading cause of cancer mortality. Standard treatment for patients with advanced primary hepatocarcinoma for whom surgery is not recommended includes transcatheter arterial chemoembolization (TACE). Within these patients 44% develop metastasis within 1 year. Thus, understanding the events underlying the recurrent tumors and developing therapies in conjunction with TACE would be of great benefit. Reducing tumor angiogenesis by combining the somatostatin analog octreotide with small doses of heparin is one approach in decreasing metastasis rates by targeting VEGF and heparinase, respectively. Given this, we investigated whether a heparin and octreotide combination treatment administered post-TACE would decrease the tumor metastasizing rate in primary hepatocarcinoma. A total of 147 patients diagnosed with primary hepatocarcinoma were admitted to the study and received 2-4 TACE treatments and were monitored for 1 year. Of these 84 received the heparin plus octreotide combination treatment and 63 did not (control group). All patients were monitored for adverse reactions, coagulation ability, and tumor metastasis. We found a significant decrease in the incidence of tumor metastasis in patients receiving the combination treatment post-TACE for up to 1 year with no significant toxic or adverse effects. Thus, we propose using the combination treatment of heparin and octreotide post-TACE in the treatment of recurrent tumorigenesis in primary hepatocarcinoma.