MetaHMEI: meta-learning for prediction of few-shot histone modifying enzyme inhibitors.

MOTIVATION: Histones are the chief protein components of chromatin, and the chemical modifications on histones crucially influence the transcriptional state of related genes. Histone modifying enzyme (HME), responsible for adding or removing the chemical labels, has emerged as a very important class of drug target, with a few HME inhibitors launched as anti-cancerous drugs and tens of molecules under clinical trials. To accelerate the drug discovery process of HME inhibitors, machine learning-based predictive models have been developed to enrich the active molecules from vast chemical space. However, the number of compounds with known activity distributed largely unbalanced among different HMEs, particularly with many targets of less than a hundred active samples. In this case, it is difficult to build effective virtual screening models directly based on machine learning. RESULTS: To this end, we propose a new Meta-learning-based Histone Modifying Enzymes Inhibitor prediction method (MetaHMEI). Our proposed MetaHMEI first uses a self-supervised pre-training approach to obtain high-quality molecular substructure embeddings from a large unlabeled chemical dataset. Then, MetaHMEI exploits a Transformer-based encoder and meta-learning framework to build a prediction model. MetaHMEI allows the effective transfer of the prior knowledge learned from HMEs with sufficient samples to HMEs with a small number of samples, so the proposed model can produce accurate predictions for HMEs with limited data. Extensive experimental results on our collected and curated HMEs datasets show that MetaHMEI is better than other methods in the case of few-shot learning. Furthermore, we applied MetaHMEI in the virtual screening process of histone JMJD3 inhibitors and successfully obtained three small molecule inhibitors, further supporting the validity of our model.

Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

A LASSO Cox Regression Predictive Model for Patients Undergoing Surgery for Pancreatic Body and Tail Adenocarcinoma Patients: Comparative Long-Term Survival Analysis of Radical Antegrade Modular Pancreatosplenectomy (RAMPS) and Standard Retrograde Pancreatosplenectomy (SPRS).

PURPOSE: This study was designed to assess the advantages of radical antegrade modular pancreatosplenectomy (RAMPS) over standard retrograde pancreatosplenectomy (SPRS) in terms of disease-free survival (DFS) by comparing clinical outcomes. METHODS: Clinical data from 154 patients who underwent distal pancreatectomy at Tianjin Medical University Cancer Institute and Hospital between January 2015 and August 2018 were collected. We compared the preoperative conditions, postoperative complications, and survival outcomes of patients who underwent two different surgical procedures. By creating a LASSO-Cox model, we determined the parameters affecting DFS and the risk ratios of the two surgical procedures on DFS. RESULTS: The R0 resection rate (85.23% vs. 68.18%, P = 0.003), negative posterior margin rate (96.59% vs. 75.76%, P < 0.001), and tumor bed recurrence rate (15.29% vs. 40.00%, P = 0.001) significantly differed between the RAMPS and SPRS groups. The 1-, 3-, and 5-year survival and DFS rates of the RAMPS group were significantly better than those of the SPRS group (P < 0.05). Disease-free survival analysis based on Kaplan-Meier curves revealed that RAMPS was superior to SPRS (P < 0.001). CONCLUSIONS: We recommend RAMPS as the preferred procedure for treating ductal adenocarcinoma of the pancreatic body and tail due to its enhanced lymph node repair capacity and visualization of posterior pancreatic sections, which can increase DFS in patients.

Ratiometric electrochemical aptasensor based on split aptamer and Au-rGO for detection of aflatoxin M1.

A novel ratiometric electrochemical aptasensor based on split aptamer and Au-reduced graphene oxide (Au-rGO) nanomaterials was proposed to detect aflatoxin M1 (AFM1). In this work, Au-rGO nanomaterials were coated on the electrode through the electrodeposition method to increase the aptamer enrichment. We split the aptamer of AFM1 into 2 sequences (S1 and S2), where S1 was immobilized on the electrode due to the Au-S bond, and S2 was tagged with methylene blue (MB) and acted as a response signal. A complementary strand to S1 (CS1) labeled with ferrocene (Fc) was introduced as another reporter. In the presence of AFM1, CS1 was released from the electrode surface due to the formation of the S1-AFM1-S2 complex, leading to a decrease in Fc and an increase in the MB signal. The developed ratiometric aptasensor exhibited a linear range of 0.03 µg L-1 to 2.00 µg L-1, with a detection limit of 0.015 µg L-1 for AFM1 detection. The ratiometric aptasensor also showed a linear relationship from 0.2 µg L-1 to 1.00 µg L-1, with a detection limit of 0.05 µg L-1 in natural milk after sample pretreatment, indicating the successful application of the developed ratiometric aptasensor. Our proposed strategy provides a new way to construct aptasensors with high sensitivity and selectivity.

Synergistic toxicity induced by the co-exposure of tenuazonic acid and patulin in Caenorhabditis elegans: Daf-16 plays an important regulatory role.

Tenuazonic acid (TeA) and patulin (PAT), as the naturally occurring mycotoxins with various toxic effects, are often detected in environment and food chain, has attracted more and more attention due to their widespread and high contaminations as well as the coexistence, which leads to potential human and animals' risks. However, their combined toxicity has not been reported yet. In our study, C. elegans was used to evaluate the type of combined toxicity caused by TeA+PAT and its related mechanisms. The results showed that TeA and PAT can induce synergistic toxic effects based on Combination Index (CI) evaluation model (Chou-Talalay method), that is, the body length, brood size as well as the levels of ROS, CAT and ATP were significantly affected in TeA+PAT-treated group compared with those in TeA- or PAT-treated group. Besides, the expressions of oxidative (daf-2, daf-16, cyp-35a2, ctl-1, ctl-3, pmk-1, jnk-1, skn-1) and intestinal (fat-5, pod-2, egl-8, pkc-3, ajm-1, nhx-2) stress-related genes were disrupted, among which daf-16 displayed the most significant alternation. Further study on daf-16 gene defective C. elegans showed that the damages to the mutant nematodes were significantly attenuated. Since daf-2, daf-16, jnk-1 and pmk-1 are evolutionarily conserved, our findings could hint synergistic toxic effects of TeA+PAT on higher organisms.

Disparity Analysis of Clinical Features and Prognostic Evaluation of Hemophagocytic Lymphohistiocytosis in Pediatric and Adult Patients: A Retrospective Multicenter Study of 525 Cases in HHLWG.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder with rapid progression and high mortality. There have been few large cohort study comparisons of pediatric and adult HLH until now. This study was designed to explore the disparity of clinical presentations and evaluate the prognosis in pediatric and adult HLH patients. METHODS: Totally, 525 newly diagnosed HLH patients were included and divided into 4 groups according to age: <6, 6-18, 18-60, and >60 years (geriatric patients). Mann-Whitney U test, Kruskal-Wallis test, χ2 test, and Bonferroni's adjustment were used to explore the difference between age groups. Overall survival (OS) was estimated by using Kaplan-Meier method. The Cox proportional hazard model was used to analyze the univariable and multivariable association between prognostic factors and OS. RESULTS: Geriatric patients had the lowest levels of hemoglobin, platelet, albumin, and the highest level of creatinine, while patients <6 years of age had the lowest values of fibrinogen, IgA, IgM and highest values of triglyceride. The trigger of HLH in patients <18 years of age was mainly EBV infection. However, lymphoma and non-EBV-driven infection were the more frequent drivers in patients aged 18-60 and >60 years, respectively. Geriatric patients were associated with highest mortality (58.8%), and 5-year OS was 43%. By contrast, 5-year OS of patients <6, 6-18, and 18-60 years was 86.1%, 74%, and 58.9%, respectively. Additionally, among patients with different etiologies (EBV, non-EBV-driven infection, and uncertain causes) and treatment regimens (HLH-04, HLH-94, and glucocorticoid regimen), geriatric patients showed lowest 5-year OS. Multivariate analysis revealed that creatinine and alanine aminotransferase were independent risk factors affecting the survival of patients aged 0-6 years, while albumin and IgG were independent factors affecting survival of geriatric patients. CONCLUSION: Our study showed a wide heterogeneity of clinical presentations, etiology distribution, prognostic factors, and survival outcomes in pediatric and adult HLH patients.

Taraxasterol alleviates aflatoxin B1-induced liver damage in broiler chickens via regulation of oxidative stress, apoptosis and autophagy.

Aflatoxin B1 (AFB1) is the most dangerous and abundant mycotoxin, which is toxic to almost all animals, and poultry is more sensitive to AFB1 toxicity. Ingesting AFB1-contaminated feed can cause significant liver damage and brings serious harm to poultry, which greatly restricts the development of the poultry industry. The present research was implemented to explore the intervention effect and its mechanism of taraxasterol on liver damage induced by AFB1 in broiler chickens. The liver damage model in broiler chickens was established by feeding 0.5 mg/kg AFB1 feed, and taraxasterol (25, 50 and 100 mg/kg BW, respectively) was given in the drinking water for 21 days. The growth performance, liver function, oxidative stress, apoptosis and autophagy were evaluated. The results showed that taraxasterol increased BW and reduced feed-to-gain ratio of broiler chickens induced by AFB1. Taraxasterol improved the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), total bilirubin (TBIL) and alkaline phosphatase (ALP), and attenuated hepatic histopathological changes induced by AFB1. Meantime, taraxasterol down-regulated cytochrome P450 (CYP450) enzyme system CYP1A1 and CYP2A6 mRNA expression, inhibited the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), and enhanced the activities of antioxidant enzymes glutathione (GSH) and catalase (CAT) and the content of antioxidant superoxide dismutase (SOD) of the liver in broiler chickens induced by AFB1. Furthermore, taraxasterol up-regulated the mRNA and protein expression of hepatic nuclear factor E2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), and down-regulated the expression of hepatic kelch like ECH associated protein 1 (Keap1) induced by AFB1 in Keap1/Nrf2 signaling pathway. The ultrastructural observation and RT-qPCR results found that taraxasterol inhibited apoptosis of hepatocytes, up-regulated the expression of B-cell lymphoma-2 (Bcl-2) mRNA and down-regulated the expression of Bax and caspase3 mRNA. Further, taraxasterol restored the autophagy of hepatocytes and down-regulated the mRNA expression of phosphatidylinositol 3-kinase K (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in AFB1-induced liver of broiler chickens. The above results indicate that taraxasterol alleviates liver damage induced by AFB1 in broiler chickens through regulation of Keap1/Nrf2 signaling pathway to exert its antioxidant effect, mitochondrial apoptosis pathway to improve anti-apoptotic ability and PI3K/AKT/mTOR pathway to restore autophagy.

[Protective mechanism of tetramethylpyrazine on cardiovascular system].

Tetramethylpyrazine is the main component of Ligusticum chuanxiong. Studies have found that tetramethylpyrazine has a good protective effect against cardiovascular diseases. In the heart, tetramethylpyrazine can reduce myocardial ischemia/reperfusion injury by inhibiting oxidative stress, regulating autophagy, and inhibiting cardiomyocyte apoptosis. Tetramethylpyrazine can also reduce the damage of cardiomyocytes caused by inflammation, relieve the fibrosis and hypertrophy of cardiomyocytes in infarcted myocardium, and inhibit the expansion of the cardiac cavity after myocardial infarction. In addition, tetramethylpyrazine also has a protective effect on the improvement of familial dilated cardiomyopathy. Besides, the mechanisms of tetramethylpyrazine on blood vessels are more abundant. It can inhibit endothelial cell apoptosis by reducing oxidative stress, maintain vascular endothelial function and homeostasis by inhibiting inflammation and glycocalyx degradation, and protect vascular endothelial cells by reducing iron overload. Tetramethylpyrazine also has a certain inhibitory effect on thrombosis. It can play an anti-thrombotic effect by reducing inflammatory factors and adhesion molecules, inhibiting platelet aggregation, and suppressing the expression of fibrinogen and von Willebrand factor. In addition, tetramethylpyrazine can also reduce the level of blood lipid in apolipoprotein E-deficient mice, inhibit the subcutaneous deposition of lipids, inhibit the transformation of macrophages into foam cells, and inhibit the proliferation and migration of vascular smooth muscle cells, thereby reducing the formation of atherosclerotic plaque. In combination with network pharmacology, the protective mechanism of tetramethylpyrazine on the cardiovascular system may be mainly achieved through the regulation of phosphatidylinositol 3 kinase/protein kinase B(PI3K/Akt), hypoxia-inducible factor 1(HIF-1), and mitogen-activated protein kinase(MAPK) pathways. Tetramethylpyrazine hydrochloride and sodium chloride injection has been approved for clinical application, but some adverse reactions have been found in clinical application, which need to be paid attention to.

Matrix-associated mycotoxins in foods, cereals and feedstuffs: A review on occurrence, detection, transformation and future challenges.

Matrix-associated mycotoxins that bind with macromolecular components through covalent or non-covalent interactions easily occur in various cereals, cereal-based products, and cereal-based feedstuff. They are "masked" by macro-components, causing the underestimation of total exposure risk of mycotoxins. Most of the current reports focus on the free and modified mycotoxins, while the matrix-associated forms are ignored but still can exert toxic effects after ingestion. In this paper, current researches and future prospects of matrix-associated mycotoxins are reviewed. Especially, a focus is set on the transformation of matrix-associated mycotoxins with their free forms during metabolism and food processing. Enzymes, temperature and pH levels during food processing can induce the interconversion of matrix-associated mycotoxins with free mycotoxins. Furthermore, the analytical methods targeted on matrix-associated mycotoxins are discussed. Due to the lack of efficient methods releasing the mycotoxins from matrix, the standard analytical methods has not developed so far. Also, we further analyzed the challenges of matrix-associated mycotoxins about variety, occurrence, toxicity and transformation, exposure assessment, which contributes to establish preventive measures to control their hazards for consumers. Overall, this overview is significant for perfecting risk assessment, as well as developing effective prevention and control actions to matrix-associated mycotoxins.

Immunomodulatory effects of Inonotus obliquus polysaccharide on splenic lymphocytes infected with Toxoplasma gondii via NF-κB and MAPKs pathways.

CONTEXT: As a medicinal and edible fungus, Inonotus obliquus has been traditionally used to prevent and treat various ailments. Inonotus obliquus polysaccharide (IOP) isolated from I. obliquus processes many biological activities, our series of in vivo studies have shown that IOP protects against Toxoplasma gondii infection. OBJECTIVE: This study aimed to investigate the in vitro immunomodulatory effects and its mechanisms of IOP on mouse splenic lymphocytes infected with T. gondii. MATERIALS AND METHODS: Mouse splenic lymphocytes were infected with T. gondii tachyzoites, and treated with different concentrations of IOP. The levels of cytokines and chemokines were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The expression of toll-like receptor 2 (TLR2) and TLR4, and the modulation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways were determined by Western blot. RESULTS: IOP significantly decreased the over-release of cytokine interleukin-1 beta (IL-1ß), IL-4, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) in supernatant from T. gondii-infected splenic lymphocytes. IOP also effectively inhibited the overexpression of cytokines and chemokine macrophage inflammatory protein-1 (MIP-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA. Furthermore, IOP down-regulated TLR2 and TLR4 expressions and inhibited the over-phosphorylation of NF-κB p65 and inhibitor κBα (IκBα) in NF-κB signaling pathway and p38, c-Jun N-terminal kinase (JNK) in MAPKs signaling pathway. By observing the effect of IOP on TNF-α secretion after pretreatment with specific inhibitors, it was further confirmed that IOP was involved in the regulation of NF-κB, p38, and JNK signaling pathways. CONCLUSIONS: These data indicate that IOP can inhibit the excessive inflammatory response caused by T. gondii infection through modulating NF-κB, p38, and JNK signaling pathways, and thus plays the in vitro anti-T. gondii role.

Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers.

BACKGROUND: Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients. METHODS: Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed. RESULTS: IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response. CONCLUSIONS: NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

A multifunctional near-infrared fluorescent sensing material based on core-shell upconversion nanoparticles@magnetic nanoparticles and molecularly imprinted polymers for detection of deltamethrin.

The construction of multifunctional sensors has attracted considerable attention due to their multifunctional properties, such as high sensitivity and rapid detection. Herein, near-infrared multifunctional fluorescent sensing materials based on core-shell upconversion nanoparticle@magnetic nanoparticle and molecularly imprinted polymers were synthesized for rapid detection of deltamethrin. The difunctional core-shell upconversion nanoparticle@magnetic nanoparticle was introduced as the optical signal and rapid separator. Firstly, the difunctional core-shell materials were prepared through solvothermal method. Then, molecularly imprinted polymers (MIPs) as recognition elements for deltamethrin were coated on the surface of upconversion nanoparticle@magnetic nanoparticle through polymerization. The structure and recognition characterizations of multifunctional fluorescent sensing materials were evaluated. Under optimal condition, the imprinting factor of sensing materials was 3.63, and the fluorescence intensity of sensing materials decreased linearly with increasing concentration of deltamethrin from 0.001 to 1 mg L-1 with a detection limit of 0.749 µg L-1, and a relative standard deviation of 3.10% was obtained with 5 mg L-1 deltamethrin. The sensing materials showed a high selectivity and were successfully utilized for the detection of deltamethrin in grapes and cabbages; the results showed that the recoveries for two samples obtained were 95.6-102% and 91.8-105%.

A simple mesoporous silica nanoparticle-based fluorescence aptasensor for the detection of zearalenone in grain and cereal products.

Zearalenone (ZEN) is a type of estrogenic mycotoxin commonly occurring in cereals. The aim of this study was to design a simple, rapid, inexpensive and ultrasensitive fluorescence assay for the determination of ZEN. Here, amino-modified mesoporous silica nanoparticles (MSNs-NH2) were synthesized to be the positive charge-rich reactor. A 6-carboxy-fluorescein-labeled aptamer (aptamer-FAM) was designed as the signal probe, ZEN-capture probe and negative charge reactor. In the absence of ZEN, the negatively charged aptamer-FAM combined with the positively charged MSNs-NH2 in an electrostatic manner. In the presence of ZEN, the fluorescence intensity in the supernatant increased significantly because the aptamer-FAM could bind to ZEN instead of MSNs-NH2. Under the optimal experimental conditions, this assay exhibited excellent specificity, repeatability and a wide linearity range of 0.005-150 ng/mL, with a detection limit of 0.012 ng/mL. Additionally, it showed high recovery (83.3-101.5%) for the spiked samples. There was no statistically significant difference in the ZEN concentrations detected by the proposed assay and HPLC in naturally contaminated samples. Overall, this design provides a new strategy for the rapid, inexpensive and sensitive detection of ZEN, and it could be applied to develop fluorometric assays for different targets by the selection of appropriate aptamers. Graphical abstract.

Oxidative DNA damage and multi-organ pathologies in male mice subchronically treated with aflatoxin B1.

Although the acute and/or chronic exposure to AFB1 has been widely investigated, the study on the toxic effects resulted from the subchronic exposure of AFB1 which is more close to the real scenario in view of the regional and seasonal characters of aflatoxin-producing strains is still limited. To understand the subchronically toxic effects of AFB1, we studied the AFB1-induced oxidative damage, reproductive impairment as well as their potential correlations and mechanisms at the molecular level. Generally, our results showed that subchronic exposure of AFB1 gave rise to pathological and oxidative damages in mice, disrupted oxidation-reduction homeostasis, activated mitochondrial apoptotic and p53-regulated signaling pathways, induced DNA and chromosomal damages and increased the rate of sperm malformation. Importantly, reproductive toxic effects were detected in AFB1-treated mice under a subchronic exposure, which was evidenced by the ascended sperm malformation. Based on our pilot study, it's speculated that the partial mechanism of reproductive toxicity may be the oxidative damages, especially DNA damages directly induced by AFB1. In short, our study demonstrated that severe damages can be caused even by a subchronic exposure as well as hinted that reproductive toxicity also should be taken into consideration when conducting risk assessments of the subchronic exposure of AFB1.

[Application and Research of Digital Twin Technology in Safety and Health Monitoring of the Elderly in Community].

In this paper, through the research of digital twin technology, combined with the application of vision sensor, artificial intelligence chip and deep learning algorithm technology, the real-time monitoring and alarm system of elderly fall and abnormal posture based on digital twin technology is developed. The system collects the data of the posture and behavior of the elderly, and then presents them in the cloud by digital mapping after the calculation and analysis of artificial intelligence chip. Once the safety threshold is deviated, the alarm can be activated to avoid or mitigate the injury caused by the fall of the elderly. Through product validation and trial operation of Tianbao Nursing Home in Hongkou District of Shanghai, the user can set alarm thresholds in different time periods and regions, thus achieving the preset purpose of the product.

Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma.

Metastasis is a serious risk that may occur during the treatment of hepatocellular carcinoma (HCC), preventing many patients from being surgical candidates and contributing to poor prognosis. Hypoxia has been proved an important factor of metastasis through the epithelial-mesenchymal transition (EMT) pathway. Acetyl-CoA synthase 2 (ACSS2) provides an acetyl group for the acetylation of hypoxia-inducible factor (HIF)-2α, and this epigenetic modification affects the activity of HIF-2α and the subsequent EMT process. Here, we showed that ACSS2 expression was negatively correlated with HCC malignancy. Knockdown of ACSS2 increased the invasion and migration ability of HCC cells and promoted EMT without increasing the total protein level of HIF-2α, even in hypoxic conditions. The immunoprecipitation assay revealed downregulated acetylation levels of HIF-2α after ACSS2 knockdown in hypoxic conditions, which resulted in enhanced HIF-2α activity. Finally, decreased expression of ACSS2 was found to be related to advanced stage and poor overall survival and disease-free survival rates in a cohort of patients with HCC. In conclusion, ACSS2 plays an important role in the acetylation process of HIF-2α, which effectively modifies the activity of HIF-2α under hypoxic conditions and greatly impacts on the prognosis of patients with HCC.

Surgery for Duodenal Gastrointestinal Stromal Tumors: A Single-Center Experience.

BACKGROUND: The duodenal gastrointestinal stromal tumors (GISTs) are an extremely rare subset of GISTs. The optimal surgical procedure remains not well defined. AIMS: We assessed the surgical approach and long-term outcomes of patients with duodenal GISTs who underwent limited resection (LR) versus pancreaticoduodenectomy (PD). METHODS: From November 2005 to January 2016, 64 consecutive patients with duodenal GISTs in a single center were retrospectively analyzed. Overall survival (OS), recurrence-free survival (RFS), and perioperative outcomes were analyzed according to the different surgical type. RESULTS: A total of 41 patients (64.1%) underwent LR, while 23 patients (35.9%) underwent PD. All patients had negative surgical margins (R0). Median tumor size was larger for PD (6 cm) versus LR (4 cm) (P = 0.041). PD also had more complications than LR (PD, 69.6 vs. LR, 31.7%) (P = 0.002). The 3-year and 5-year RFS was 62.9 and 44.3%, respectively. The 3-year and 5-year OS was 85.7 and 59.5%, respectively. The multivariate analysis demonstrated the only unfavorable predictive factor was tumor size >5 cm for RFS and OS. Although the complication rate in the PD group was higher than in the LR group, OS and RFS were not affected by the complication (P = 0.492 for OS, P = 0.512 for RFS). PD versus LR was not associated with RFS and OS. Adjuvant imatinib mesylate (IM) did not improve the survival of the patients after operation. CONCLUSIONS: Survival of duodenal GISTs is mainly dependent on tumor biology rather than surgical procedure. LR should be the surgical procedure of choice for duodenal GISTs when technically feasible and no anatomical constrains. LR shows comparable survival and lower risk of postoperative complications compared by PD. The administration of IM both as adjuvant and neoadjuvant therapy for duodenal GISTs needs large population and prospective study to evaluate its effect.

Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30.

We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP-activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib.

HIF-2α regulates CDCP1 to promote PKCδ-mediated migration in hepatocellular carcinoma.

Overexpression of CUB domain-containing protein 1 (CDCP1), a transmembrane glycoprotein and major substrate of Src family kinases (SFKs), always indicates unfavorable outcomes in various cancers. The characteristics of CDCP1 in hepatocellular carcinoma (HCC) have not been assessed. Most recently, CDCP1 was identified as a specific target gene of HIF-2α in clear cell renal carcinoma (CC-RCC). However, considering the role of HIF-2α in the progression of HCC is highly controversial, it is necessary to figure out whether HIF-2α and CDCP1 play a significant part in the metastasis of HCC. Our results showed that HIF-2α and CDCP1 were both induced by hypoxia, and the activation of CDCP1 was HIF-2α dependent. CDCP1 was governed by HIF-2α at mRNA and protein levels in HCC cell lines. Moreover, knocking down of HIF-2α not only inhibited cell invasion but also impaired the expression of Tyr(311) phosphorylation of protein kinase Cδ (PKCδ) which is a downstream factor of CDCP1 and has been reported to induce malignant migration in various tumors. Analysis of human HCC samples showed a negative correlation of CDCP1 expression with disease-free survival, and CDCP1 was an independent prognostic factors of disease-free survival. Taken together, these data demonstrated that HIF-2α could promote HCC cell migration by regulating CDCP1, and targeting HIF-2α-CDCP1-PKCδ pathway might be effective to inhibit HCC metastasis.

Acinar cell carcinoma: a report of 19 cases with a brief review of the literature.

BACKGROUND: Acinar cell carcinoma (ACC) is a relatively rare pancreatic neoplasm with poorly defined prognosis. This study aimed to investigate this rare pancreatic neoplasm through comparing patients with ACC to pancreatic ductal cell adenocarcinoma (DCA). METHODS: Tianjin Medical University Cancer Institute and Hospital pathology database was reviewed from 1995 to 2015, and 19 patients with pathologically confirmed ACC were enrolled while 19 conventional DCA patients assigned randomly as control. Retrospective review and follow-up were performed for each patient. Regression methods were used to identify differences between ACC and DCA. RESULTS: In our study, most patients suffered from abdominal or back pain, and no lipase hypersecretion syndrome was observed. For ACC, resected cases had better survival than those without resection, and earlier staging was related to longer survival. Resection with postoperative adjuvant therapy had a better outcome than surgery alone. Twelve cases developed recurrence. Compared to DCA, ACC had earlier staging and better survival. The overall 1-, 2-, and 5-year survival rates for patients with ACC were 73.7, 26.3, and 5 %, respectively. CONCLUSIONS: ACC carries a better prognosis than DCA and a similarly high recurrence rate, while surgical resection proved the best first-line approach for it. A well-planned neoadjuvant or adjuvant chemoradiotherapy indeed benefit the patients with ACC.