Microstructural and functional substrates underlying dispositional greed and its link with trait but not state impulsivity.

The interplay between personality traits and impulsivity has long been a central theme in psychology and psychiatry. However, the potential association between Greed Personality Traits (GPT) and impulsivity, encompassing both trait and state impulsivity and future time perspective, remains largely unexplored. To address these issues, we employed questionnaires and an inter-temporal choice task to estimate corresponding trait/state impulsivity and collected multi-modal neuroimaging data (resting-state functional imaging: n = 430; diffusion-weighted imaging: n = 426; task-related functional imaging: n = 53) to investigate the underlying microstructural and functional substrates. Behavioral analyses revealed that GPT mediated the association between time perspective (e.g., present fatalism) and trait impulsivity (e.g., motor impulsivity). Functional imaging analyses further identified that brain activation strengths and patterns related to delay length, particularly in the dorsomedial prefrontal cortex, superior parietal lobule, and cerebellum, were associated with GPT. Moreover, individuals with similar levels of greed exhibited analogous spontaneous brain activity patterns, predominantly in the Default Mode Network (DMN), Fronto-Parietal Network (FPN), and Visual Network (VIS). Diffusion imaging analysis observed specific microstructural characteristics in the spinocerebellar/pontocerebellar fasciculus, internal/external capsule, and corona radiata that support the formation of GPT. Furthermore, the corresponding neural activation pattern, spontaneous neural activity pattern, and analogous functional couplings among the aforementioned brain regions mediated the relationships between time perspective and GPT and between GPT and motor impulsivity. These findings provide novel insights into the possible pathway such as time perspective → dispositional greed → impulsivity and uncover their underlying microstructural and functional substrates.

Happy people are always similar: The evidence from brain morphological and functional inter-subject correlations.

A fundamental question in the study of happiness is whether there is neural evidence to support a well-known hypothesis that happy people are always similar while unfortunate people have their own misfortunes. To investigate this, we employed several happiness-related questionnaires to identify potential components of happiness, and further investigated and confirmed their associations with personality, mood, aggressive behaviors, and amygdala reactivity to fearful faces within a substantial sample size of college students (n = 570). Additionally, we examined the functional and morphological similarities and differences among happy individuals using the inter-subject representational similarity analysis (IS-RSA). IS-RSA emphasizes the geometric properties in a high-dimensional space constructed by brain or behavioral patterns and focuses on individual subjects. Our behavioral findings unveiled two factors of happiness: individual and social, both of which mediated the effect of personality traits on individual aggression. Subsequently, mood mediated the impact of happiness on aggressive behaviors across two subgroup splits. Functional imaging data revealed that individuals with higher levels of happiness exhibited reduced amygdala reactivity to fearful faces, as evidenced by a conventional face-matching task (n = 104). Moreover, IS-RSA demonstrated that these participants manifested similar neural activation patterns when processing fearful faces within the visual pathway, but not within the emotional network (e.g., amygdala). Morphological observations (n = 425) indicated that individuals with similar high happiness levels exhibited comparable gray matter volume patterns within several networks, including the default mode network, fronto-parietal network, visual network, and attention network. Collectively, these findings offer early neural evidence supporting the proposition that happy individuals may share common neural characteristics.

Dual role of CD177 + neutrophils in inflammatory bowel disease: a review.

Inflammatory bowel disease (IBD) represents a group of recurrent chronic inflammatory disorders associated with autoimmune dysregulation, typically characterized by neutrophil infiltration and mucosal inflammatory lesions. Neutrophils, as the earliest immune cells to arrive at inflamed tissues, play a dual role in the onset and progression of mucosal inflammation in IBD. Most of these cells specifically express CD177, a molecule increasingly recognized for its critical role in the pathogenesis of IBD. Under IBD-related inflammatory stimuli, CD177 is highly expressed on neutrophils and promotes their migration. CD177 + neutrophils activate bactericidal and barrier-protective functions at IBD mucosal inflammation sites and regulate the release of inflammatory mediators highly correlated with the severity of inflammation in IBD patients, thus playing a dual role. However, mitigating the detrimental effects of neutrophils in inflammatory bowel disease remains a challenge. Based on these data, we have summarized recent articles on the role of neutrophils in intestinal inflammation, with a particular emphasis on CD177, which mediates the recruitment, transepithelial migration, and activation of neutrophils, as well as their functional consequences. A better understanding of CD177 + neutrophils may contribute to the development of novel therapeutic targets to selectively modulate the protective role of this class of cells in IBD.

Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC.

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

Neurobiological substrates of the dread of future losses.

When anticipating future losses, people respond by exhibiting 1 of 2 starkly distinct behavioral decision patterns: the dread of future losses (DFL) and the preference of future losses (vs. immediate losses). Yet, how to accurately discriminate between those who exhibit dread vs. preference and uncover the potential neurobiological substrates underlying these 2 groups remain understudied. To address this, we designed a novel experimental task in which the DFL group was defined as selecting immediate-loss options >50% in the trials with approximate subjective value in immediate and delayed options (n = 16), otherwise coding as the preference of future losses (PFL). At the behavioral level, DFL exhibited higher weight for delayed losses than immediate losses via the logistic regression model. At the neural level, DFL manifested hypoactivations on subjective valuations of delayed losses, atypical brain pattern when choosing immediate-loss options, and decreased functional coupling between the valuation and choice-systems when making decisions related to immediate-loss alternatives compared with PFL. Moreover, both these brain activations subserving distinct decision processes and their interactions predicted individual decisions and behavioral preferences. Furthermore, morphological analysis also revealed decreased right precuneus volume in DFL compared with PFL, and brain activations related to valuation and choice process mediated the associations between this region volume and behavioral performances. Taken together, these findings help to clarify potential cognitive and neural mechanisms underlying the DFL and provide a clear discrimination strategy.

The Typical Nail Lichen Planus Severity Index: An Outcome Instrument for Typical Nail Lichen Planus.

INTRODUCTION: Despite numerous treatment options for nail lichen planus (NLP), a validated method for measuring the severity of NLP and therapeutic response in clinical trials is absent. The aim of the study was to develop and validate a measurement instrument, Typical Nail Lichen Planus Severity Index (tNLPSI), for typical NLP that could be used in clinical trials. METHODS: A total of 48 patients pathologically confirmed with typical NLP were enrolled in this study. Five dermatologists were trained to use the tNLPSI activity scale and the Physician's Global Assessment (PGA) scale to score samples independently to estimate inter-rater and intra-rater reliability across two sessions. In addition, tNLPSI activity scores were compared with PGA scores to assess the construct validity. RESULTS: The tNLPSI activity scale had excellent internal consistency and inter-rater reliability (Cronbach's alpha 0.990; ICC = 0.954; 95% CI = 0.930-0.971), and the correlations between the different graders' scores indicate good consistency (rp = 0.934-0.968). In addition, the tNLPSI activity scale demonstrated high intra-rater reliability (ICC = 0.996; 95% CI = 0.993-0.998), showing good reproducibility. And tNLPSI activity scores and PGA scores showed good construct validity (Spearman's rho = 0.941 and Spearman's rho = 0.903-0.935, respectively; p < 0.01). CONCLUSION: The tNLPSI activity scale was demonstrated to be consistent, reliable, reproducible, and feasible, making it a potential valuable tool for evaluating the treatment response in typical NLP clinical trials.

Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges.

Hepatectomy is still the major curative treatment for patients with liver malignancies. However, it is still a big challenge to remove the tumors in the central posterior area, especially if their location involves the retrohepatic inferior vena cava and hepatic veins. Ex vivo liver resection and auto-transplantation (ELRA), a hybrid technique of the traditional liver resection and transplantation, has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation. Due to its technical difficulty, ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation. The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases, especially in the advanced alveolar echinococcosis. Recently, the application of ELRA for liver malignances has gained more attention. However, standardization of clinical practice norms and international consensus are still lacking. The prognostic impact in these oncologic patients also needs further evaluation. In this review, we summarized the principles and recent progresses on ELRA.

Early Circulating Tumor DNA Dynamics Predict Neoadjuvant Therapy Response and Recurrence in Colorectal Liver Metastases: A Prospective Study.

BACKGROUND: For patients with colorectal liver metastases (CRLM) who receive neoadjuvant therapy (NAT), reliable indicators that can early and accurately predict treatment response are lacking. This study was conducted to prospectively investigate the potential of early circulating tumor DNA (ctDNA) dynamics as a precise predictor of NAT response and recurrence in CRLM. METHODS: This study prospectively enrolled 34 patients with CRLM who received NAT, with blood samples collected and subjected to deep targeted panel sequencing at two time points: 1 day before the first and the second cycles of NAT. Correlations of ctDNA mean variant allele frequency (mVAF) dynamics and treatment response were assessed. The performance of early ctDNA dynamics in predicting treatment response was assessed and compared with those of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). RESULTS: The baseline ctDNA mVAF was significantly associated with pre-NAT tumor diameter (r = 0.65; P < 0.0001). After one cycle of NAT, the ctDNA mVAF declined remarkably (P < 0.0001). The dynamic change in ctDNA mVAF of 50% or more was significantly correlated with better NAT responses. The discriminatory capacity of ctDNA mVAF changes was superior to that of CEA or CA19-9 in predicting radiologic response (area under the curve [AUC], 0.90 vs 0.71 vs 0.61) and pathologic tumor regression grade (AUC, 0.83 vs 0.64 vs 0.67). The early changes in ctDNA mVAF but not CEA or CA19-9 were an independent indicator of recurrence-free survival (RFS) (hazard ratio, 4.0; P = 0.023). CONCLUSIONS: For CRLM patients receiving NAT, an early ctDNA change is a superior predictor of treatment response and recurrence compared with conventional tumor markers.

27-Hydroxycholesterol promotes metastasis by SULT2A1-dependent alteration in hepatocellular carcinoma.

Oxysterol metabolism plays an important role in the initiation and development of various tumors. However, little is known that the metabolic alternation can promote the metastasis of hepatocellular carcinoma (HCC). In this study, we identify the sulfotransferase family 2A member 1 (SULT2A1) to 27-hydroxycholesterol (27-OHC) metabolic axis as playing a critical role in HCC metastasis. The level of 27-OHC closely corresponded with HCC metastasis instead of proliferation in vitro and in vivo. Also, the expression of SULT2A1 is extremely downregulated in human HCC tissues and is correlated with poor prognosis and tumor metastasis. Gain- and loss-of-function studies reveal that SULT2A1 suppresses the metastasis of HCC by regulating the level of 27-OHC. Further mechanistic studies indicated that SULT2A1-dependent alternation of 27-OHC activates the nuclear factor-κB signaling pathway and promotes HCC metastasis by enhancing Twist1 expression and epithelial-mesenchymal transition. In conclusion, our findings indicate the relationship between the metabolism of 27-OHC and the metastasis of HCC. Moreover, SULT2A1 could act as a potential prognostic biomarker and a therapeutic target for preventing HCC metastasis.

Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC.

BACKGROUND AND AIMS: Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection. APPROACH AND RESULTS: First, in patients with HCC, lenvatinib-treated recurrent tumors had lower programmed death ligand 1 (PD-L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL/6 wild-type mice receiving anti-programmed cell death 1 (PD-1) therapy, PD-L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF receptor 4 (FGFR4) was the most pivotal target in PD-L1 down-regulation by lenvatinib in vitro. Furthermore, lenvatinib reinforced the proteasomal degradation of PD-L1 by blocking the FGFR4-glycogen synthase kinase 3ß axis and rescued the sensitivity of interferon-γ-pretreated HCC cells to T-cell killing by targeting FGFR4. On the other hand, the level of IL-2 increased after anti-PD-1 treatment, but IL-2-mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and the tumor FGFR4 level in C57BL/6-forkhead box protein P3 (Foxp3DTR ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and Foxp3 conferred immune tolerance but better response to the combined therapy in patient cohorts. CONCLUSIONS: Lenvatinib reduced tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4. Levels of FGFR4 expression and Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti-PD-1 combination therapy.

Effect of thrombopoietin receptor agonist on health-related quality of life and platelet transfusion burden for patients with myelodysplastic syndromes: a systematic review and meta-analysis.

Thrombocytopenia is a common and unsolved problem in myelodysplastic syndrome (MDS) patients; we aimed to summarize the evidence of TPO-RA treatment for heath-related quality of life (HRQoL) and platelet transfusion burden of MDS patients. We searched Pubmed, Web of Science, EMBASE, and CENTRAL for randomized clinical trials (RCTs) comparing TPO-RA to placebo in MDS published until July 31, 2021. A random-effect model was used. Eight RCTs with 908 patients were identified. Only three RCTs involving eltrombopag reported HRQoL, and all three studies treated HRQoL as a secondary outcome. In these three RCTs, the HRQoL instruments used in each study were different. However, this outcome cannot be meta-analyzed because some studies did not provide complete data. Subsequent clinical trials should pay more attention to this. Compared to placebo, TPO-RA did not affect platelet transfusion incidence 0.83 (95% CI 0.60-1.15). There was no evidence for subgroup differences in the analyses of different types of TPO-RA, different additional agent, and different types of MDS risk groups. However, platelet transfusion units (RR = 0.68, 95% CI 0.53 to 0.84) were significantly decreased. The RR of patients who did not require platelet transfusion for 56 or more consecutive days was not different between groups (RR = 0.98, 95% CI 0.41 to 2.34). TPO-RA may decrease platelet transfusion units in MDS patients with thrombocytopenia. But the significance of this finding should be interpreted with caution, because too few studies were meta-analyzed.

Clinicopathological and prognostic significance of HER2 status in surgically resected colorectal liver metastases.

BACKGROUND: The clinicopathological and prognostic significance of human epidermal growth factor receptor 2 (HER2) status in surgically resected colorectal liver metastases (CRLM) remains uncertain. METHODS: HER2 expression was evaluated by immunohistochemical (IHC) in two CRLM tissue microarrays (TMAs). For samples with an IHC score of 2+ or 3+, fluorescence in situ hybridization (FISH) was performed to assess HER2 amplification. The association of HER2 amplification with clinicopathological parameters and prognosis was assessed using Fisher's exact test and Kaplan-Meier method, respectively. RESULTS: HER2 expression was consistent between primary tumor and liver metastases in 66.9% (85/127) cases (r = 0.643, p = 0.001). After FISH validation, HER2 amplification was identified in 6.25% (13/208) patients. HER2 amplification was significantly associated with age (p = 0.017), bilobar involvement (p = 0.005) and left-sided RAS/RAF wild-type status (p = 0.002). In the overall cohort, HER2 amplification was correlated with significantly worse relapse-free survival (RFS). Further stratification revealed that among left-sided RAS/RAF wild-type cases, HER2 amplification was significantly associated with worse overall survival (OS) (30.2 vs. 50.9 months, p = 0.040) and RFS (5.77 vs. 19.97 months, p = 0.017). CONCLUSION: HER2 amplification is more enriched in CRLMs with younger age, left-sided RAS/RAF wild-type, and bilobar involvement. Moreover, HER2 amplification predicts a poorer prognosis especially in left-sided RAS/RAF wild-type CRLMs.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

Left Hepatic Vein Preferential Approach Based on Anatomy Is Safe and Feasible for Laparoscopic Living Donor Left Lateral Sectionectomy.

We assess the safety and feasibility of the left hepatic vein preferential approach (LHVPA) based on left hepatic vein (LHV) anatomy for living donor laparoscopic left lateral sectionectomy (LLLS). Data from 50 donors who underwent LLLS in Huashan Hospital from October 2016 to November 2019 were analyzed retrospectively. On the basis of the classification of the LHV anatomy, the vein was defined as the direct import type, upper branch type, or indirect import type. A subgroup analysis was performed to compare the outcomes between the LHVPA and non-LHVPA groups. All 50 patients underwent pure LLLS. The mean operative duration was 157.5 ± 29.7 minutes. The intraoperative blood loss was 160.4 ± 97.5 mL. No complications more severe than grade 3 occurred. LHVPA was applied in 13 patients, whereas non-LHVPA was applied in 10 patients with the direct import type and upper branch type anatomy. The operative duration was shorter in the LHVPA group than the non-LHVPA group (142.7 ± 22.0 versus 173.0 ± 22.8 minutes; P = 0.01). Intraoperative blood loss was reduced in the LHVPA group compared with the non-LHVPA group (116.2 ± 45.6 versus 170.0 ± 63.3 mL; P = 0.02). The length of the LHV reserved extrahepatically in the LHVPA group was longer than in the non-LHVPA group (4.3 ± 0.2 versus 3.3 ± 0.3 mm; P = 0.01). Fewer reconstructions of the LHV in the direct import type anatomy were required for the LHVPA group than for the non-LHVPA group (0/8 versus 4/6). LHVPA based on the LHV anatomy is recommended in LLLS because it can further increase the safety and the efficiency of surgery for suitable donors.

Platelet transcriptome profiles provide potential therapeutic targets for elderly acute myelocytic leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time. METHODS: Platelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95. RESULTS: We found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients. CONCLUSIONS: In summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.

Volume changes of subcortical structures in patients with post-hepatitis B cirrhosis: A magnetic resonance imaging study. / ä¹™åž‹è‚ç‚ŽåŽè‚ç¡¬åŒ–æ‚£è€ è„‘çš®å±‚ä¸‹ç»“æž„ä½“ç§¯æ”¹å˜çš„MRIç ”ç©¶.

OBJECTIVES: To investigate volume changes of subcortical structures in patients with post-hepatitis B cirrhosis. METHODS: Thirty patients with post-hepatitis B cirrhosis (the cirrhosis group) and 24 age- and sex-matched healthy controls (the control group) were enrolled in this prospective study. All subjects underwent neuropsychological tests, blood biochemical determinations, and cerebral MRI. Volumes of 18 selected subcortical structures were automatically segmented and analyzed by the FreeSurfer. In the cirrhosis group, the relationships between abnormal subcortical volumes and clinical index or neurocognitive performance were investigated. The relationships between globus pallidus volumes and pallidal hyperintensity were also examined. RESULTS: Compared with the healthy controls, patients with post-hepatitis B cirrhosis displayed smaller bilateral putamen, amygdala, and nucleus accumbens volumes and larger bilateral globus pallidus volumes (P<0.001 or P=0.001). In the cirrhosis group, the volumes of left putamen and amygdala were negatively correlated with the number connection test-A (NCT-A)(left putamen r=-0.410, P=0.034; left amygdala r=-0.439, P=0.022), and the volumes of bilateral globus pallidus were positively correlated with pallidal index (PI) (left globus pallidus r=0.889, P<0.001; right globus pallidus r=0.900, P<0.001). CONCLUSIONS: Abnormalities of subcortical volumes appear bilaterally symmetrical in patients with post-hepatitis B cirrhosis. Atrophy of left putamen and amygdala might contribute to poor neurocognitive performance, and the manganese deposition might contribute to the increased globus pallidus volumes in patients with post-hepatitis B cirrhosis.

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis.

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis.

Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein-binding protein-associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. CONCLUSION: These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515-528).