Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Transferrin receptor 1 promotes hepatocellular carcinoma progression and metastasis by activating the mTOR signaling pathway.

BACKGROUND: Aberrant iron metabolism is commonly observed in multiple tumor types, including hepatocellular carcinoma (HCC). However, as the key regulator of iron metabolism involved in iron absorption, the role of transferrin receptor (TFRC) in HCC remains elusive. METHODS: The mRNA and protein expression of TFRC were evaluated in paired HCC and adjacent non-tumor specimens. The correlation between TFRC level and clinicopathological features or prognostic significance was also analyzed. The role of TFRC on biological functions was finally studied in vitro and in vivo. RESULTS: The TFRC level was remarkably upregulated in HCC tissues compared to paired peritumor tissues. Overexpressed TFRC positively correlated with serum alpha-fetoprotein, carcinoembryonic antigen, and poor tumor differentiation. Multivariate analysis demonstrated that upregulated TFRC was an independent predictive marker for poorer overall survival and disease-free survival in HCC patients. Loss of TFRC markedly impaired cell proliferation and migration in vitro and notably suppressed HCC growth and metastasis in vivo, while overexpression of TFRC performed an opposite effect. Mechanistically, the mTOR signaling pathway was downregulated with TFRC knockdown, and the mTOR agonist MHY1485 completely reversed the biological inhibition in HCC cells caused by TFRC knockdown. Furthermore, exogenous ferric citrate (FAC) or iron chelator reversed the changed biological functions and signaling pathway expression of HCC cells caused by TFRC knockdown or overexpression, respectively. CONCLUSIONS: Our study indicates that TFRC exerts an oncogenic role in HCC and may become a promising therapeutic target to restrain HCC progression.

Heterogeneous MXene Hybrid-Oriented Exosome Isolation and Metabolic Profiling for Early Screening, Subtyping and Follow-up Evaluation of Bladder Cancer.

Exosome metabolite-based noninvasive liquid biopsy is an emerging research hotspot that tends to substitute current means in clinics. Nanostructure-based mass spectrometry enables continuous exosome isolation and metabolic profiling with superior analysis speed and high efficiency. Herein, we construct a heterogeneous MXene hybrid that possesses ternary binding sites for exosome capture and outstanding matrix performance for metabolite analysis. Upon optimizing experimental conditions, the average extraction of exosomes and their metabolic patterns from a 60 mL urine sample is completed within 45 s (40 samples per batch for 30 min). According to the exosomal metabolic patterns and the subsequently established biomarker panel, we distinguish early bladder cancer (BCa) from healthy controls with an area under the curve (AUC) value greater than 0.995 in model training and validation sets. As well, we realize subtype classification of BCa in the blind test on metabolic patterns, with an AUC value of 0.867. We also explore the significant biomarkers that are sensitive to follow-up patients, which indeed present reverse change levels compared with pathological progression. This study has the potential to guide the development of the liquid biopsy approach.

Coiled-coil domain-containing 154 promotes colorectal cancer proliferation and metastasis via interacting with minichromosome maintenance complex component 2.

Coiled-Coil Domain-Containing (CCDC) is a large class of structural proteins containing left-handed supercoiled structure. The clinical value and the functional implication of CCDC in colorectal cancer (CRC) remain unknown. Based on the genetic, transcriptional, and clinical data from The Cancer Genome Atlas, five of thirty-six CCDC proteins were differentially expressed in the CRC and associated with the survival of patients with CRC. A CCDC-score model was established to evaluate the prognosis of patients. The potential function of Coiled-Coil Domain-Containing 154 (CCDC154) was investigated using bioinformatical methods, which unveiled that high expression of CCDC154 indicates poor survival for patients with CRC and correlates with low infiltration of CD8+ T cells and high infiltration of neutrophils, indicating that CCDC154 enhances tumor growth and metastasis. CCDC154 interacts with Minichromosome Maintenance Complex Component 2 (MCM2) protein and promotes malignant phenotype via MCM2. We validated the expression level and survival prediction value of CCDC154 in clinical samples, and analyzed its co-expression of MCM2, Ki-67 and p53. This work discloses the role of CCDC in clinical setting and CCDC154 functions in CRC.

Increased expression of autophagy-related gene 5 indicates poor prognosis in patients with hepatocellular carcinoma.

OBJECTIVES: As a critical component of the autophagic machinery, autophagy-related gene 5 (ATG5) is essential for autophagosome formation. Autophagy participates in the transformation and progression of various malignant tumors, but the role of ATG5 in hepatocellular carcinoma (HCC) remains to be illustrated. In this study we aimed to investigate the prognostic significance of ATG5 in HCC. METHODS: ATG5 expression was evaluated in 89 pairs of HCC tissues and adjacent non-tumor tissues. The relationship between ATG5 expression and patients' clinicopathological characteristics and prognosis were evaluated. Moreover, subgroup analyses were performed regarding patients' age and number of tumors. Nomograms estimating overall survival (OS) and disease-free survival (DFS) were conducted. RESULTS: ATG5 expression was increased in HCC specimens rather than adjacent non-tumor tissues. The upregulated ATG5 expression was positively associated with serum α-fetoprotein (AFP) level. Moreover, cases with a strong ATG5 expression had a poorer disease-free survival (DFS) and overall survival (OS) than those with a weak ATG5 expression. Multivariate analysis showed that a strong expression of ATG5 was related to a poor OS and DFS in patients with HCC. Further analysis indicated that cases with a higher ATG5 expression had a poorer OS and DFS in the young patients (≤55 years) and those with solitary tumor. The nomogram suggested that there was a coherence between nomogram prediction and the actual situation of patient survival related to ATG5. CONCLUSION: ATG5 promotes tumor progression in HCC, making it a potential biomarker in the diagnosis and a therapeutic target of HCC.

Synergistic Photochemo Effects Based on Light-Activatable Dual Prodrug Nanoparticles for Effective Cancer Therapy.

Ferroptosis is identified as a novel type of cell death with distinct properties involved in physical conditions and various diseases, including cancers. It is considered that ferroptosis provides a promising therapeutic strategy for optimizing oncotherapy. Although erastin is an effective ferroptosis trigger, the potential of its clinical application is largely restricted by its poor water solubility and concomitant limitations. To address this issue, an innovative nanoplatform (PE@PTGA) that integrated protoporphyrin IX (PpIX) and erastin coated with amphiphilic polymers (PTGA) to evoke ferroptosis and apoptosis is constructed and exemplified using an orthotopic hepatocellular carcinoma (HCC) xenograft mouse model as a paradigm. The self-assembled nanoparticles can enter HCC cells and release PpIX and erastin. With light stimulation, PpIX exerts hyperthermia and reactive oxygen species to inhibit the proliferation of HCC cells. Besides, the accumulated reactive oxygen species (ROS) can further promote erastin-induced ferroptosis in HCC cells. In vitro and in vivo studies reveal that PE@PTGA synergistically inhibits tumor development by stimulating both ferroptosis- and apoptosis-related pathways. Moreover, PE@PTGA has low toxicity and satisfactory biocompatibility, suggesting its promising clinical benefit in cancer treatments.

Diagnostic and economic value of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 in gastrointestinal cancers.

BACKGROUND: The diagnostic and economic value of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA72-4 for gastrointestinal malignant tumors lacked evaluation in a larger scale. AIM: To reassess the diagnostic and economic value of the three tumor biomarkers. METHODS: A retrospective analysis of all 32857 subjects who underwent CEA, CA19-9, CA72-4, gastroscopy and colonoscopy from October 2006 to May 2018 was conducted. Then, we assessed the discrimination and clinical usefulness. Total cost, cost per capita and cost-effectiveness ratios were used to evaluate the economic value of two schemes (gastrointestinal endoscopy for all people without blood tests vs both gastroscopy and colonoscopy when blood tests were positive). RESULTS: The analysis of 32857 subjects showed that CEA was a qualified biomarker for colorectal cancer (CRC), while the diagnostic efficiencies of CA72-4 were catastrophic for all gastrointestinal cancers (GICs). Regarding early diagnosis, only CEA could be used for early CRC. The combination of biomarkers didn't greatly increase the area under the curve. The economic indicators of CEA were superior to those of CA19-9, CA72-4 and any combination. At the threshold of 1.8 µg/L to 10.4 µg/L, all four indicators of CEA were lower than those in the scheme that conducted gas-trointestinal endoscopy only. Subgroup analysis implied that the health checkup of CEA for people above 65 years old was economically valuable. CONCLUSION: CEA had qualified diagnostic value for CRC and superior economic value for GICs, especially for elderly health checkup subjects. CA72-4 was not suitable as a diagnostic biomarker.

PRP19 Enhances Esophageal Squamous Cell Carcinoma Progression by Reprogramming SREBF1-Dependent Fatty Acid Metabolism.

Lipid metabolism reprogramming is a recognized hallmark of cancer cells. Identification of the underlying regulators of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) could uncover potential therapeutic targets to improve treatment. Here, we demonstrated that pre-mRNA processing factor 19 (PRP19) mediates reprogramming of lipid metabolism in ESCC. Expression of PRP19 was significantly upregulated in multiple ESCC cohorts and was correlated with poor clinical prognosis. PRP19 promoted ESCC proliferation in vitro and in vivo. Upregulation of PRP19 enhanced fatty acid synthesis through sterol regulatory element-binding protein 1 (SREBF1), a major transcription factor of lipid synthase. Moreover, PRP19 enhanced the stability of SREBF1 mRNA in an N6-methyladenosine-dependent manner. Overall, this study shows that PRP19-mediated fatty acid metabolism is crucial for ESCC progression. Targeting PRP19 is a potential therapeutic approach to reverse metabolic reprogramming in patients with ESCC. SIGNIFICANCE: Upregulation of pre-mRNA processing factor 19 (PRP19) contributes to esophageal squamous cell carcinoma progression by reprogramming SREBF1-dependent fatty acid metabolism, identifying PRP19 as a potential prognostic biomarker and therapeutic target.

Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer.

Background: Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysis‒cholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment. Methods: Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo. Results: Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysis‒cholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model. Conclusions: Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.

A novel murine model of combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Primary liver cancer (PLC) is a common gastrointestinal malignancy worldwide. While hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two major pathologic types of PLC, combined HCC and ICC (cHCC-ICC) is a relatively rare subtype that shares both hepatocyte and cholangiocyte differentiation. However, the molecular feature of this unique tumor remains elusive because of its low incidence and lack of a suitable animal model. Herein, we generated a novel spontaneous cHCC-ICC model using a Sleeping Beauty-dependent transposon plasmid co-expressing oncogenic Myc and AKT1 and a CRISPR-Cas9 plasmid expressing single-guide RNA targeting p53 into mouse hepatocytes via in situ electroporation. The histological and transcriptional analysis confirmed that this model exhibits cHCC-ICC features and activates pathways committing cHCC-ICC formation, such as TGF-ß, WNT, and NF-κB. Using this model, we further screened and identified LAMB1, a protein involved in cell adhesion and migration, as a potential therapeutic target for cHCC-ICC. In conclusion, our work presents a novel genetic cHCC-ICC model and provides new insights into cHCC-ICC.

Nalidixic acid potentiates the antitumor activity in sorafenib-resistant hepatocellular carcinoma via the tumor immune microenvironment analysis.

Sorafenib resistance is often developed and impedes the benefits of clinical therapy in hepatocellular carcinoma (HCC) patients. However, the relationship between sorafenib resistance and tumor immune environment and adjuvant drugs for sorafenib-resistant HCC are not systemically identified. This study first analyzed the expression profiles of sorafenib-resistant HCC cells to explore immune cell infiltration levels and differentially expressed immune-related genes (DEIRGs). The prognostic value of DEIRGs was analyzed using Cox regression and Kaplan-Meier analysis based on The Cancer Genome Atlas. The primary immune cells infiltrated in sorafenib-resistant HCC mice were explored using flow cytometry (FCM). Finally, small-molecule drugs for sorafenib-resistant HCC treatment were screened and validated by experiments. The CIBERSORT algorithm and mice model showed that macrophages and neutrophils are highly infiltrated, while CD8+ T cells are downregulated in sorafenib-resistant HCC. Totally, 34 DEIRGs were obtained from sorafenib-resistant and control groups, which were highly enriched in immune-associated biological processes and pathways. NR6A1, CXCL5, C3, and TGFB1 were further identified as prognostic markers for HCC patients. Finally, nalidixic acid was identified as a promising antagonist for sorafenib-resistant HCC treatment. Collectively, our study reveals the tumor immune microenvironment changes and explores a promising adjuvant drug to overcome sorafenib resistance in HCC.

Sorafenib-Loaded Cu2-xSe Nanoparticles Boost Photothermal-Synergistic Targeted Therapy against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for the predominant form of liver malignancy and presents a leading cause of cancer-related death globally. Sorafenib (SOR), a first-line targeted drug for advanced HCC treatment, has a battery of untoward side effects. Photothermal therapy (PTT) has been utilized as an effective adjuvant in synergy with other approaches. However, little is known about the tumoricidal efficacy of combining SOR with PTT for HCC. Herein, a novel versatile nanoparticle, Cu2-xSe@SOR@PEG (CSP), that is based on a photothermal Cu2-xSe core and SOR for simultaneously reinforcing PTT and reducing the adverse effects of SOR was constructed. The synthesized CSP exhibited a remarkably enhanced therapeutic effect upon 808 nm laser irradiation via dampening HCC cell propagation and metastasis and propelling cell apoptosis. The intravenous administration of CSP substantially suppressed tumor growth in a xenograft tumor mouse model. It was noted that the CSP manifested low toxicity and excellent biocompatibility. Together, this work indicates a promising and versatile tool that is based on synergistic PTT and molecular-targeted therapy for HCC management.

Iridium Complex-Loaded Sorafenib Nanocomposites for Synergistic Chemo-photodynamic Therapy of Hepatocellular Carcinoma.

Although sorafenib, a multi-kinase inhibitor, has provided noteworthy benefits in patients with hepatocellular carcinoma (HCC), the inevitable side effects, narrow therapeutic window, and low bioavailability seriously affect its clinical application. To be clinically distinctive, innovative drugs must meet the needs of reaching tumor tissues and cause limited side effects to normal organs and tissues. Recently, photodynamic therapy, utilizing a combination of a photosensitizer and light irradiation, was selectively accumulated at the tumor site and taken up effectively via inducing apoptosis or necrosis of cancer cells. In this study, a nano-chemo-phototherapy drug was fabricated to compose an iridium-based photosensitizer combined with sorafenib (IPS) via a self-assembly process. Compared to the free iridium photosensitizer or sorafenib, the IPS exhibited significantly improved therapeutic efficacy against tumor cells because of the increased cellular uptake and the subsequent simultaneous release of sorafenib and generation of reactive oxygen species production upon 532 nm laser irradiation. To evaluate the effect of synergistic treatment, cytotoxicity detection, live/dead staining, cell proliferative and apoptotic assay, and Western blot were performed. The IPS exhibited sufficient biocompatibility by hemolysis and serum biochemical tests. Also, the results suggested that IPS significantly inhibited HCC cell proliferation and promoted cell apoptosis. More importantly, marked anti-tumor growth effects via inhibiting cell proliferation and promoting tumor cell death were observed in an orthotopic xenograft HCC model. Therefore, our newly proposed nanotheranostic agent for combined chemotherapeutic and photodynamic therapy notably improves the therapeutic effect of sorafenib and has the potential to be a new alternative option for HCC treatment.

microRNA-106b-5p Promotes Cell Growth and Sensitizes Chemosensitivity to Sorafenib by Targeting the BTG3/Bcl-xL/p27 Signaling Pathway in Hepatocellular Carcinoma.

microRNAs (miRNAs) and miRNA-mediated regulatory networks are promising candidates in the prevention and treatment of cancer, but the role of specific miRNAs involved in hepatocellular carcinoma (HCC) remains to be elusive. Herein, we found that miR-106b-5p is upregulated in both HCC patients' tumor tissues and HCC cell lines. The miR-106b-5p expression level was positively correlated with α-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), and tumor size. Overexpression of miR-106b-5p promoted cell proliferation, migration, cell cycle G1/S transition, and tumor growth, while decreased miR-106b-5p expression had opposite effects. Mechanistic studies showed that B-cell translocation gene 3 (BTG3), a known antiproliferative protein, was a direct target of miR-106b-5p, whose expression level is inversely correlated with miR-106b-5p expression. Moreover, miR-106b-5p positively regulates cell proliferation in a BTG3-dependent manner, resulting in upregulation of Bcl-xL, cyclin E1, and CDK2, as well as downregulation of p27. More importantly, we also demonstrated that miR-106b-5p enhances the resistance to sorafenib treatment in a BTG3-dependent manner. The in vivo findings showed that mice treated with a miR-106b-5p sponge presented a smaller tumor burden than controls, while the mice injected cells treated with miR-106b-5p had more considerable tumor burden than controls. Altogether, these data suggest that miR-106b-5p promotes cell proliferation and cell cycle and increases HCC cells' resistance to sorafenib through the BTG3/Bcl-xL/p27 signaling pathway.

Prp19 Facilitated p21-Dependent Senescence of Hepatocellular Carcinoma Cells.

Introduction: Evidence suggests that the role of senescence in the development of cancer is context-dependent. An orthologue of human pre-mRNA processing factor 19 (Prp19) attenuates the senescence of human endothelial cells. Prp19 has been reported to be involved in the progression of hepatocellular carcinoma (HCC). This work aims to investigate the effect of Prp19 on the senescence of HCC. Materials and Methods: Senescence of L02 cells and HCC cells under different stimuli was detected through cell cycle analysis, SA-ß-gal staining, and senescence associated secretory phenotype analysis. The relationship between Prp19 and senescence-related proteins was evaluated using real-time RT-PCR, western blot assay, and immunohistochemistry. Subcutaneous xenograft tumors in nude mice were used to evaluate the role of Prp19 on senescence in vivo. Data analysis was carried out using GraphPad Prism 6. Results: Prp19 facilitated the senescence of L02 cells and HCC cells under different stresses. Prp19 positively modulated p21 expression in the mRNA level. Downregulation of Prp19 promoted the growth of subcutaneous xenograft tumors generated by HCC cell lines. Conclusions: Prp19 may promote senescence of HCC cells via regulating p21 expression.

IRF-2 inhibits cancer proliferation by promoting AMER-1 transcription in human gastric cancer.

BACKGROUND: Interferon regulatory factor 2 (IRF-2) acts as an anti-oncogene in gastric cancer (GC); however, the underlying mechanism remains unknown. METHODS: This study determined the expression of IRF-2 in GC tissues and adjacent non-tumor tissues using immunohistochemistry (IHC) and explored the predictive value of IRF-2 for the prognoses of GC patients. Cell function and xenograft tumor growth experiments in nude mice were performed to test tumor proliferation ability, both in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) assay was used to verify the direct target of IRF-2. RESULTS: We found that IRF-2 expression was downregulated in GC tissues and was negatively correlated with the prognoses of GC patients. IRF-2 negatively affected GC cell proliferation both in vitro and in vivo. ChIP-Seq assay showed that IRF-2 could directly activate AMER-1 transcription and regulate the Wnt/ß-catenin signaling pathway, which was validated using IHC, in both tissue microarray and xenografted tumor tissues, western blot analysis, and cell function experiments. CONCLUSIONS: Increased expression of IRF-2 can inhibit tumor growth and affect the prognoses of patients by directly regulating AMER-1 transcription in GC and inhibiting the Wnt/ß-catenin signaling pathway.

Efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation: Chinese sub-cohort analysis of a phase III, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To conduct a sub-cohort analysis to evaluate the efficacy and safety of linaclotide in Chinese patients with constipation-predominant irritable bowel syndrome (IBS-C) using data from a completed trial (NCT01880424). METHODS: In this phase III, double-blind, placebo-controlled trial, IBS-C patients were randomized to receive linaclotide (290 µg/d) or placebo for 12 weeks. Efficacy was assessed with two co-primary responder end-points (12-wk abdominal pain/discomfort: ≥30% reduction in either score with neither deteriorating from baseline for ≥6 wks; 12-wk IBS degree of relief: score ≤2 for ≥ 6 wks), seven secondary endpoints and several additional end-points. RESULTS: In total, 659 Chinese IBS-C patients received linaclotide (n = 327) or placebo (n = 332). The 12-week abdominal pain/discomfort end-point was met in 62.1% and 53.3% of the linaclotide-treated and placebo-treated patients, respectively (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.05-1.96, P = 0.023); the 12-week IBS degree of relief end-point was achieved in 32.7% and 16.9% of the patients treated with linaclotide and placebo, respectively (OR 2.40, 95% CI 1.66-3.47, P < 0.001). The linaclotide-treated patients had a shorter time to the first spontaneous bowel movement than the placebo-treated patients (23.6 h vs 43.7 h, P < 0.001). Linaclotide produced significantly greater improvement than placebo in all secondary end-points from the first 2 weeks (all P < 0.001). Diarrhea was reported in 8.3% of linaclotide-treated patients and 1.2% of placebo-treated patients. CONCLUSION: Linaclotide (290 µg/d) was efficacious and well-tolerated in Chinese IBS-C patients with a rapid onset of effect.

Pre-mRNA processing factor 19 functions in DNA damage repair and radioresistance by modulating cyclin D1 in hepatocellular carcinoma.

Pre-mRNA processing factor 19 (PRP19) is elevated in hepatocellular carcinoma (HCC); however, little is known about its function in DNA damage repair in HCC. In this study, analysis of The Cancer Genome Atlas data and our tumor models after ionizing radiation (IR) treatment indicated that increased expression of PRP19 was positively correlated with DNA damage repair. Gain of PRP19 expression induced by plasmids resulted in decreases in apoptosis and double-strand breaks (DSBs), and an increase in cell survival after IR. Loss of PRP19 expression induced by small interfering RNAs resulted in the accumulation of apoptosis and DSBs, and a decrease in cell survival. Mechanistically, the effect of PRP19 on DNA damage repair was mediated by the modulation of cyclin D1 expression in HCC. PRP19 controlled the translation of cyclin D1 by modulating eukaryotic initiation factor 4E. PRP19 affected the DNA damage repair ability of cyclin D1 by interacting with the WD40 domain. The combination of PRP19 and cyclin D1 was more valuable than each single marker for predicting the prognosis of patients. Taken together, the present results demonstrate that PRP19 promotes DNA damage repair by modulating cyclin D1 expression and function, thereby contributing to the radioresistance in HCC.

Efficacy and safety of lubiprostone for the treatment of functional constipation in Chinese adult patients: A multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Functional constipation is a gastrointestinal disorder prevalent around the world. Lubiprostone is the first locally acting type-2 chloride channel activator to be used for treating constipation. This study aimed to evaluate the efficacy and safety of lubiprostone in Chinese adults with functional constipation. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Patients with functional constipation were randomized to receive either lubiprostone (24 mcg twice daily) or placebo for 4 weeks. The primary end-point was the frequency of spontaneous bowel movements (SBMs) during the first week of treatment. The secondary end-points included the median time of the first SBM, SBM frequency at weeks 2, 3 and 4, weekly response rate of SBMs, the stool consistency score and average number of complete spontaneous bowel movements (CSBMs) per week. RESULTS: In total, 259 patients were randomized, with 130 in the lubiprostone group and 129 in the placebo group. SBM frequency was higher in the lubiprostone group (4.88 ± 4.09/wk) than that in the placebo group (3.22 ± 2.01/wk) at week 1 (P < 0.0001). SBM frequency was also higher in the lubiprostone group at weeks 2, 3 and 4. The average number of CSBMs and the stool consistency score in the lubiprostone group were significantly higher than that in the placebo group at each week. No drug-related serious adverse events (AEs) occurred. The most commonly reported AE was nausea. CONCLUSION: Lubiprostone was superior to placebo in treating Chinese patients with functional constipation, together with good safety profile.