第5卷，第4期

James P Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for the development of a revolution in cancer therapy: immune checkpoint blockade. This is a truly well-deserved honor for both Allison and Honjo. The immune system has multiple levels of brakes, known as immune checkpoints, to negatively downregulate activation and function of T cells and other immune cells. Immune checkpoints are important mechanisms for preventing the immune system from attacking the host's own cells.

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Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammalians. Global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. They are somatically associated with known genetic variations.Recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including DNA methylation, histone modifications, nucleosomes changes, non-coding RNAs. The reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the FDA so far.In this review, we discuss the concept of epigenetic changes in diseases, especially cancers, the role of these changes in the onset and progression of cancers and the potential of using this knowledge in designing novel therapeutic strategies.

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Correct folding of nascent peptides occurs in the endoplasmic reticulum (ER). It is a complicate process primarily accomplished by the coordination of multiple redox proteins including members of the protein disulfide isomerase (PDI) family. As a critical member of the PDI family, thioredoxin domain containing protein 5 (TXNDC5) assists the folding of newly synthesized peptides to their mature form through series of disulfide bond exchange reactions. Interestingly, TXNDC5 is frequently found overexpressed in specimens of many human diseases including various types of cancer. In this review, we summarized the biochemical function of TXNDC5 in mammalian cells and the recent progress on the understanding of its role and molecular mechanisms in cancer development. Findings of TXNDC5 in the activation of intracellular signaling pathways, stimulation of cell growth & proliferation, facilitation of cell survival and modulation of extracellular matrix to affect cancer cell invasion and metastasis are reviewed. These published studies suggest that strategies of targeting TXNDC5 can be developed as potentially valuable methods for the treatment of certain types of cancer in patients.

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The in vitro organoid model is a major technological breakthrough that has been established as an important tool in many basic biological and clinical applications. This near-physiological 3D culture system accurately models various biological processes, including tissue renewal, stem cell/niche functions and tissue responses to drugs, mutations or damage. Organoids have the potential value of being an accurate model for disease predictions or drug screening applications and to identify the ideal treatment for that patient. Carcinogenesis can be modeled by mutating specific cancer genes in wild-type organoids; and patient-derived organoids provide an important resource in the development of personalized cancer treatment. Organoids from cancer patients could be used to identify the ideal treatment for a specific patient by growing matched healthy and diseased organoids from human cancer patients which additionally enables clinical screens for drug combinations. Organoids could also provide autologous cells or-in the future-tissue for transplantation. In this review, we discuss the current advances, challenges and potential applications of this technique in gastrointestinal neoplasms.

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Myofibrillar myopathies (MFMs) are rare genetic and slowly progressive neuromuscular disorders. Several pathogenic mutations have been reported in MFM-related genes including DES, CRYAB, MYOT, LDB3 or ZASP, FLNC, BAG3, FHL1 and DNAJB6. Although MFMs is commonly inherited in an autosomal dominant manner, the inheritance pattern and novel mutated genes are not thoroughly elucidated in some cases. Here, we report discovery of a novel nonsense mutation in a 29-year-old Iranian male patient with motor disorders and deformity in his lower limbs. His parents are second cousins. Hereditary Motor Sensory Neuropathy as initial genetic diagnosis was ruled out. Whole exome sequencing using NGS on Illumina Hi-Seq4000 platform was performed to identify the disease and possible mutated gene (s). Our data analysis identified a homozygous nonsense unreported c.C415T (p.R139X) variant on kyphoscoliosis peptidase (KY) gene (NM_178554: exon4). Sanger sequencing of this mutation has been performed for his other related family members. Sequencing and segregation analysis was confirmed the NGS results and autosomal recessive inheritance pattern of the disease.

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To assess the efficacy and short-term outcomes of adherence to statin therapy among coronary heart disease (CHD) patients following their hospital discharge, we enrolled 615 CHD patients who were prescribed statins from The First Affiliated Hospital of Chongqing Medical University in China between February 1st and October 31st of 2013.Statin adherence was evaluated by identifying the proportion of patients who remained adherent or became non-adherent to statin therapy over 4-8 months post-discharge from the hospital. The composite outcomes included all-cause mortality and re-hospitalization with cardiovascular disease. We found that 15.9% patients were non-adherent to their statin therapies and that coronary artery stenosis<75% (OR = 3.433, 95% CI:2.191-5.380, p < 0.001) and adverse effects (OR = 2.542, 95% CI:1.327-4.869, p = 0.005) both clearly contributed to poor adherence. The primary self-reported reasons for non-adherence included a lack of knowledge about the benefits of statin therapy (36.7%), the treatment being halted at the advice of their doctor (19.4%), and the difficulty in obtaining statins (12.2%). Non-adherence to statin therapy was significantly associated with an increased risk of cardiovascular events (OR = 1.741, 95% CI:1.035-2.929, p = 0.037). In conclusion, CHD patients with moderate stenosis or adverse effects tended to have poor statin adherence, and this was significantly associated with increased cardiovascular events. We should strengthen education of the importance of statin therapy for both patients and doctors and facilitate the ability of patients to obtain their statin medication.

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Alzheimer's disease (AD) is characterized by senile plaques (SP) composed of β-amyloid protein (Aβ) and neuro fibrillary tangles (NFTs) composed of intracellular hyperphosphorylated tau. Recently, nuclear receptor subfamily 4 group A member 1 (NR4A1) was implicated in synaptic plasticity, long-term memory formation, suggesting that it may play a role in the pathophysiology of AD. Here, we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice. In addition, NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels, down-regulated ADAM10 expression, and promoted amyloidogenesis as indicated by decreased α-CTF levels and elevated β-CTF levels. Furthermore, a raised level of phospho-tau (p-tau, S396) was accompanied by p-GSK3β (S9) expression reducing, but total tau, p-tau (S262 and T231), CDK5 and ERK remained unchanged in NR4A1-overexpressing cells. Collectively, our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells; as well as NR4A1 accelerates tau hyperphosphorylation by GSK3β signal. Therefore, NR4A1 may play an important role in the pathogenesis of AD.

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In order to explore the molecular mechanisms behind the pathogenesis of acute liver failure (ALF) associated with hepatitis B virus (HBV) infection, the present study aimed to identify potential key genes and pathways involved using samples from patients with HBV-associated ALF. The GSE38941 array dataset was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between 10 liver samples from 10 healthy donors and 17 liver specimens from 4 patients with HBV-associated ALF were analyzed using the Linear Models for Microarray Data package. Gene Ontology and KEGG pathway enrichment analyses of the DEGs were performed, followed by functional annotation of the genes and construction of a protein-protein interaction (PPI) network. Subnetwork modules were subsequently identified and analyzed. In total, 3142 DEGs were identified, of which 1755 were upregulated and 1387 were downregulated. The extracellular exosome, immune response, and inflammatory response pathways may potentially be used as biomarkers of ALF pathogenesis. In total, 17 genes (including CCR5, CXCR4, ALB, C3, VGEFA, and IGF1) were identified as hub genes in the PPI network and may therefore be potential marker genes for HBV-associated ALF.

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Intrahepatic cholestasis of pregnancy (ICP) is related to cholestatic disorder in pregnancy. Total urinary sulfated bile acids (SBAs) were found increased in ICP. We distinguished the metabolic profiling of urinary SBAs in ICP to find potential biomarkers for the diagnosis and grading of ICP. The targeted metabolomics based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze urinary SBAs profiling in mild and severe ICP cases, as well as healthy controls. 16 kinds of urinary SBAs were determined by HPLC-MS/MS. Sulfated dihydroxy glycine bile acid (di-GBA-S), glycine cholic acid 3-sulfate (GCA-3S), sulfated dihydroxy taurine bile acid (di-TBA-S) and taurine cholic acid 3-sulfate (TCA-3S) increased significantly in ICP group compared with the control group. Seven kinds of SBAs were significantly different (p < 0.05) between the ICP group and the control group, with the variable importance in the projection (VIP) value more than one by the orthogonal partial least squares discriminant analysis (OPLS-DA). GCA-3S was well-suited to be used as the biomarker for the diagnosis of ICP with the sensitivity of 100% and specificity of 95.5%. A multi-variable logistic regression containing GCA-3S and di-GBA-S-1 was constructed to distinguish severe ICP from mild ICP, with the sensitivity of 94.4% and specificity of 100%. The developed HPLC-MS/MS method is suitable for the measurement of urinary SBAs profiling. Moreover, the urinary SBAs in the metabolomic profiling have the potential to be used as non-intrusive biomarkers for the diagnosis and grading of ICP.

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Metabolic syndrome (MS) is a cluster of metabolic abnormalities. Obesity and MS are always accompanied by elevated oxidative stress which might affect cellular biomolecules such as DNA. The aim of the present study is to investigate DNA damage profile in obese premenopausal women and its relation to the risk of MS, polycystic ovary syndrome (PCOS) and history of recurrent pre-eclampsia. The study included 90 obese women included cases with MS (n = 30), PCOS (n = 30) and previous history of recurrent preeclampsia (n = 30) and, age-matched healthy non-obese control women (n = 50). The assessment of leukocyte DNA damage was done by comet assay for all cases and controls. Anthropometry and biochemical parameters have been measured. Results showed that mean percent of DNA damage was significantly higher in MS, PCOS as well as in women with the recurrent preeclampsia as compared to healthy controls. The high level of mean DNA damage frequency in obese women was significantly associated with the increased number of metabolic syndrome components. Cases with 2, 3 and 3-5 components showed significantly higher levels of DNA damage than controls. Moreover, cases with 3-5 MS components showed significant higher DNA compared to those with the two components. Regarding PCOS, significant positive association between the mean frequency of DNA damage and waist circumference was observed. The study suggests that metabolic abnormalities, PCOS and recurrent pre-eclampsia might be contributed in development of DNA damage in obese women. DNA damage can serve as an early marker for obesity complications in premenopausal women.

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Mantle cell lymphoma (MCL) is a B-cell malignancy with poor clinical outcome and undefined pathogenesis. Development of clinically relevant cellular models for MCL research is an urgent need. Our preliminary observations lead the development of two novel hypotheses that we tested in this study: 1. multicellular spheroid might be a unique growth mode of early-stage cells in MCL; 2. MCL might be a polyclonal tumor. We made the following original observations that have not been reported: First, we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples. Second, we have established a clinically relevant cellular model of MCL, the JeKo-1-spheroid cell line, that was highly enriched in early-stage sub-clones.JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features. Third, Immunophenotypic analysis has revealed that MCL may be derived from precursor-B (pre-B), immature-B and mature-B cells, not only the mature-B cells as WHO classified in 2016. Fourth, MCL may be a polyclonal disease composed of CD19^-/IgM^e, CD19 ^-/IgM⁺, CD19⁺/IgM⁺ three sub-clones, of which the CD19^-/IgM⁺sub-clone might be the dominant sub-clone with the strongest tumorigenic ability. Fifth, CD19⁺/IgM^-that differentiates MCL and normal B cells may represent a new marker for MCL early detection, minor residual disease monitoring after therapies and prognosis.

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This study aims to determine key genes and pathways that could play important roles in the spermatogenic process of patients with cryptorchidism. The gene expression profile data of GSE25518 was obtained from the Gene Expression Omnibus (GEO) database. Microarray data were analyzed using BRB-Array Tools to identify differentially expressed genes (DEGs) between high azoospermia risk (HAZR) patients and controls. In addition, other analytical methods were deployed, including hierarchical clustering analysis, class comparison between patients with HAZR and the normal control group, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and the construction of a proteineprotein interaction (PPI) network. In total, 1015 upregulated genes and 1650 downregulated genes were identified. GO and KEGG analysis revealed enrichment in terms of changes in the endoplasmic reticulum cellular component and the endoplasmic reticulum protein synthetic process in the HAZR group. Furthermore, the arachidonic acid pathway and mTOR pathway were also identified as important pathways, while RICTOR and GPX8 were indentified as key genes involved in the spermatogenic process of patients with cryptorchidism. In present study, we found that changes in the synthesis of endoplasmic reticulum proteins, arachidonic acid and the mTOR pathway are important in the incidence and spermatogenic process of cryptorchidism. GPX8 and RICTOR were also identified as key genes associated with cryptorchidism. Collectively, these data may provide novel clues with which to explore the precise etiology and mechanism underlying cryptorchidism and cryptorchidism-induced human infertility.

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