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Background: Epithelial-mesenchymal transition (EMT) plays a critical role in the recurrence and metastasis of hepatocellular carcinoma (HCC). Some long noncoding (lnc)RNAs are involved in this process through the regulation of EMT-related transcription factors., Methods: In this study, we established a novel EMT-related lncRNA signature in HCC and identified hub lncRNAs that can serve as potential therapeutic targets. Differentially expressed lncRNAs were identified by screening HCC patient data from The Cancer Genome Atlas, and a correlation analysis was performed to identify those associated with EMT. The EMT-related lncRNA signature was established by univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. After verifying the prognostic accuracy of the signature, its relationships to immune cell infiltration and immune checkpoint targets were explored. LINC01116 was identified as a hub lncRNA and its role in HCC was investigated in vitro and in vivo ., Results: A 5-lncRNA signature was developed for HCC and its prognostic accuracy was assessed by survival, time-dependent receiver operating characteristic curve, clinical correlation, and Cox regression analyses. The correlation analysis showed that the lncRNA signature was closely related to immune cell infiltration and 10 immune checkpoint targets and also predicted the prognosis of HCC patients with high accuracy. In vitro and in vivo experiments revealed that LINC01116 stimulated cell proliferation, cell cycle progression, and tumor metastasis. We also found that LINC01116 was closely related to immune regulation., Conclusions: These results demonstrate that LINC01116 is an immune-related oncogene that is associated with both EMT and immune regulation in HCC. Moreover, the EMT-related lncRNA signature that includes LINC01116 can guide risk stratification and clinical decision-making in HCC management.

Objective: Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized., Design: In this retrospective cohort study, the epidemiological, demographic, laboratory, treatment and outcome information of 1,515 COVID-19 patients with available longitudinal amylase records collected from electronic medical system were analyzed to assess the prevalence and clinical significance of hyperamylasemia in this infection. Associated variables with hyperamylasemia in COVID-19 were also analyzed., Results: Of 1,515 patients, 196 (12.9%) developed hyperamylasemia, among whom 19 (1.3%) greater than 3 times upper limit of normal (ULN) and no clinical acute pancreatitis was seen. Multivariable ordered logistic regression implied older age, male, chronic kidney disease, several medications (immunoglobin, systemic corticosteroids, and antifungals), increased creatinine might be associated with hyperamylasemia during hospitalization. Restricted cubic spline analysis indicated hyperamylasemia had a J-shaped association with all-cause mortality and the estimated hazard ratio per standard deviation was 2.85 (2.03-4.00) above ULN. Based on the multivariable mixed-effect cox or logistic regression model taking hospital sites as random effects, elevated serum amylase during hospitalization was identified as an independent risk factor associated with in-hospital death and intensive complications, including sepsis, cardiac injury, acute respiratory distress syndrome, and acute kidney injury., Conclusions: Elevated serum amylase was independently associated with adverse clinical outcomes in COVID-19 patients. Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.

Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in hepatocellular carcinoma is largely unknown. CircRNA microarray was performed to identify abnormally expressed circRNAs in HCC tissue samples. We conducted Kaplan-Meier survival analysis to explore the significance of circUBE2J2 in clinical prognosis. Then, we examined the functions of circUBE2J2 in HCC by cell proliferation, migration, and mouse xenograft assay. We identified miR-370-5P as a circUBE2J2-related microRNA by using biotin-labeled circUBE2J2 probe to perform RNA antisense purification (RAP) assay in HCC cells. The dual luciferase reporter assay and RNA pulldown assays were employed to verify the relationships among circUBE2J2, miRNA-370-5P, and KLF7. Microarray analysis and qRT-PCR verified a circRNA termed circUBE2J2 that was downregulated in HCC. Kaplan-Meier survival analysis showed that downregulated circUBE2J2 was correlated with poorer survival. CircUBE2J2 expression in HCC cells was selectively regulated via luciferase reporter assays; circUBE2J2 and KLF7 were observed to directly bind to miR-370-5P. Furthermore, knockdown of circUBE2J2 in HCC could downregulate KLF7, the target of miR-370-5P, thus promoting the proliferation and migration of HCC cells. Then the related experiment suggested that circUBE2J2 could regulate the expression of KLF7 by sponging miR-370-5p. In summary, we infer that circUBE2J2 may act as a competing endogenous RNA (ceRNA) to regulate KLF7 expression through sponging miR-370-5P and play a regulatory functions in HCC. CircUBE2J2 may be a diagnostic biomarker and potential target for HCC therapy., (© 2021. The Author(s).)

Epigenetic modification plays a crucial regulatory role in the biological processes of eukaryotic cells. The recent characterization of DNA and RNA methylation is still ongoing. Tumor metastasis has long been an unconquerable feature in the fight against cancer. As an inevitable component of the epigenetic regulatory network, 5-methylcytosine is associated with multifarious cellular processes and systemic diseases, including cell migration and cancer metastasis. Recently, gratifying progress has been achieved in determining the molecular interactions between m 5 C writers (DNMTs and NSUNs), demethylases (TETs), readers (YTHDF2, ALYREF and YBX1) and RNAs. However, the underlying mechanism of RNA m 5 C methylation in cell mobility and metastasis remains unclear. The functions of m 5 C writers and readers are believed to regulate gene expression at the post-transcription level and are involved in cellular metabolism and movement. In this review, we emphatically summarize the recent updates on m 5 C components and related regulatory networks. The content will be focused on writers and readers of the RNA m 5 C modification and potential mechanisms in diseases. We will discuss relevant upstream and downstream interacting molecules and their associations with cell migration and metastasis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The DEAD-box helicase family member DDX3X (DBX, DDX3) functions in nearly all stages of RNA metabolism and participates in the progression of many diseases, including virus infection, inflammation, intellectual disabilities and cancer. Over two decades, many studies have gradually unveiled the role of DDX3X in tumorigenesis and tumour progression. In fact, DDX3X possesses numerous functions in cancer biology and is closely related to many well-known molecules. In this review, we describe the function of DDX3X in RNA metabolism, cellular stress response, innate immune response, metabolic stress response in pancreatic β cells and embryo development. Then, we focused on the role of DDX3X in cancer biology and systematically demonstrated its functions in various aspects of tumorigenesis and development. To provide a more intuitive understanding of the role of DDX3X in cancer, we summarized its functions and specific mechanisms in various types of cancer and presented its involvement in cancer-related signalling pathways.

Arsenic is ubiquitously present in the aquatic environment. We investigated the acute toxic effects of arsenite [As(III)] exposure on rare minnows (Gobiocypris rarus) in vivo. The 96-h LC 50 value for exposure to As(III) was 13.73 mg/L. As(III) bioaccumulation in different tissues was measured using inductively-coupled plasma mass spectrometry, and the extent of As(III) accumulation was, from greatest to least, liver > intestine > gills > muscle > kidney > testis > brain. Histological examination revealed that in As(III)-treated fish, numerous cellular and tissue alterations were present in the gill, liver, and intestine tissues. Moreover, transmission electron microscopy showed ultrastructural alterations in hepatocytes. We also performed transcriptome analyses to investigate As(III)-induced toxicity response in the liver of As(III)-treated fish; various oxidative-related genes were differentially expressed, and their expression levels were further validated using qPCR. This study is one of the many steps we aim to take on the way to promote the rare minnow to an international standard laboratory animal.

We demonstrate an enhancement of cyclization against polymerization for the on-surface debrominative coupling reaction, by using the metal-organic Cu-N coordination template to direct the reaction pathways. Experiments performed by using ultrahigh-vacuum scanning tunneling microscopy (UHV-STM), with the substitution of metal-coordination centers, metallic substrates and functional organic ligands, corroborate the template effect of the Cu-N coordination., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Progressive multifocal leukoencephalopathy is a serious condition linked to certain diseases and immunosuppressant therapies, including the α4 integrin antagonist natalizumab. No cases have been reported to date with vedolizumab, a selective antagonist of the α4β7 integrin expressed on gut-homing lymphocytes. This analysis aimed to describe the current and future expected occurrence of progressive multifocal leukoencephalopathy with vedolizumab use, were the risk the same as in other populations in which this disease has been studied., Methods: The expected number of vedolizumab-associated progressive multifocal leukoencephalopathy cases was estimated up to May 19, 2016, and modeled up to 2034. These estimates were based on the cumulative exposure to the drug, assuming an equivalent risk to that of patients treated with natalizumab or those from other reference populations where progressive multifocal leukoencephalopathy has been examined. Future cases were modeled based on similar risks and projected sales., Results: The cumulative vedolizumab exposure was estimated at 54,619 patient-years, with a 95% confidence interval of 0.0 to 6.75 cases per 100,000 patient-years. An estimated 30.2 (95% confidence interval, 19.4-40.9) cases of progressive multifocal leukoencephalopathy would have occurred if vedolizumab had the same risk as that of natalizumab. There would be a 50% chance of the first case occurring by 2018, assuming an equivalent risk to the general population., Conclusions: These analyses indicate that the risk of progressive multifocal leukoencephalopathy with vedolizumab is small, and unlikely to be above 6.75 cases per 100,000 patient-years.

Purpose: Metabolic Syndrome (MetS) is more predominant in overweight, obese and minority populations. This study examined the prevalence of MetS in an exclusively African-American (AA) cohort of breast cancer (BC) survivors; an underrepresented group in previous studies demonstrating negative BC outcomes disparities for females with MetS., Methods: Using a case-control design, overweight/obese AA women with treated Stage I-IIIa BC were matched 1:1 on age, race, sex, and body mass index (BMI) category with non-cancer population controls (n = 444). Three of the following conditions were used to define MetS: HDL cholesterol <50 mg/dL (1.3 mmol/L), serum triglycerides ≥150 mg/dL (1.7 mmol/L), blood glucose ≥100 mg/dL (or on treatment), waist circumference ≥88 cm, or ≥130 mmHg systolic or ≥85 mmHg diastolic blood pressure (or on treatment). Matched-pairs analyses were conducted., Results: For BC cases, most women had self-reported Stage I (n = 76) or Stage II (n = 91) disease and were 6.9 (±5.2) years post-diagnosis. MetS was significantly lower in BC survivors vs. their non-cancer population controls (43.2 vs. 51.4 %, respectively; p < 0.05). The diagnosis of MetS did not differ by BMI stratification. A lower prevalence of ≥2 risk factors (80.2 vs. 85.6 %, p < 0.05) was observed for all cases vs., Conclusions: While MetS occurred less frequently in our BC cases vs. non-cancer controls, our estimates are nearly two times those reported in other BC survivors, suggesting important racial/ethnic differences., Implications for Cancer Survivors: The prognostic implications of MetS among AA BC survivors remain unknown and warrant further investigation.

Background: Acute graft rejection mediated by alloreactive memory CD4 + T cells is a major obstacle to transplantation tolerance. It has been reported that CD8 + T regulatory cells (Tregs) have the ability to induce graft tolerance by restraining the function of activated CD4 + T cells, but not including memory T cells. The aim of this study is to elucidate the effect of CD8 + Tregs on alloreactive memory CD4 + T cells., Methods: We detected Qa-1 expression and performed proliferative assay on memory CD4 + T cells. All memory CD4 + T cells were purified from mice receiving skin allografts. We performed inhibitory and cytotoxic assays on CD8 + Tregs, which were isolated from a T cell vaccination mouse model, and IL-2, IL-4, IL-10 and IFN-γ levels were measured in co-culture supernatants by ELISA. To confirm CD8 + Tregs inhibition of memory CD4 + T cells in-vivo, we utilized a murine model of cardiac allograft transplantation., Results: Memory CD4 + T cells mediated acute allograft rejection, and CD8 + Tregs suppressed the proliferation of memory CD4 + T cells. In vitro, memory CD4 + T cells were inhibited and lysed by CD8 + Tregs. There was a positive correlation between IFN-γ levels, and cell lysis rate induced by CD8 + Tregs. In-vivo studies demonstrated CD8 + Tregs prolonged graft survival times, by inhibiting CD4 + memory T cells, through a Qa-1-peptide-TCR pathway., Conclusions: CD8 + Tregs inhibit CD4 + memory T cell-mediated acute murine cardiac allograft rejection, and further prolong graft survival times. These results provide new insights into immune regulation of organ rejection.

The aim of this study was to investigate the repair function of exogenous Endothelial progenitor cells (EPCs) for brain microvascular damage of the APP/PS1 transgenic mouse model of Alzheimer's disease (AD). This study used a density-gradient centrifugation method to isolate mononuclear cells (MNCs) from mouse bone marrow, which were subsequently seeded and cultured. Cells were characterized by morphology and detection of the surface markers CD34 and CD133 at different time points by immunofluorescence (IF) and flow cytometry (FCM). Then, EPCs were transfected with GFP adenoviral vectors (GFP-EPCs). Wild-type (WT) and APP/PS1 transgenic mice both received GFP-EPCs injection through the tail vein, and using a PBS buffer injection as the control. Seven days later, the animals' brain tissue was isolated. Expression of GFP was detected by quantitative polymerase chain reaction (qPCR) and western-blot (WB), while the fluorescence of GFP within the brains of mice was observed under a fluorescence microscope. Higher mRNA and protein expression of GFP, accompanied with increased green fluorescence, were detected in the brain of GFP-EPCs-injected APP/PS1 mice, as compared with GFP-EPCs-injected WT mice. The results show that the APP/PS1 transgenic mouse model of AD exhibited enhanced penetration of exogenous EPCs into brains than the WT mice.

Purpose: Osteoporosis increases the risk of fracture and is often considered a late effect of breast cancer treatment. We examined the prevalence of compromised bone health in a sample of exclusively African-American (AA) breast cancer survivors since bone mineral density (BMD) varies by race/ethnicity in healthy populations., Methods: Using a case-control design, AA women in a weight loss intervention previously diagnosed and treated for stages I-IIIa breast cancer were matched 1:1 on age, race, sex, and BMI with non-cancer population controls (n = 101 pairs) from National Health and Nutrition Examination Survey (NHANES). Questionnaires and dual-energy x-ray absorptiometry (DXA) scanning were completed, and participants were categorized as having normal bone density, low bone mass, or osteoporosis using the World Health Organization (WHO) definition for femoral neck T-scores., Results: The majority of these overweight/obese survivors were 6.6 (±4.7) years post-diagnosis, had stage II (n = 46) or stage III (n = 16) disease, and treated with chemotherapy (76 %), radiation (72 %), and/or adjuvant hormone therapies (45 %). Mean femoral neck BMD was significantly lower in cases vs. matched non-cancer population controls (0.85 ± 0.15 vs. 0.91 ± 0.14 g/cm(2), respectively; p = 0.007). However, the prevalence of low bone mass and osteoporosis was low and did not significantly differ between groups (n = 101 pairs; p = 0.26), even when restricted to those on adjuvant hormone therapies (n = 45 pairs; p = 0.75). Using conditional logistic regression, controlling for dietary factors and education, the odds of developing compromised bone health in AA breast cancer survivors was insignificant (OR 1.5, 95 % CI 0.52, 5.56)., Conclusions: These null case-control findings challenge the clinical assumption that osteoporosis is highly prevalent among all breast cancer survivors, providing foundational evidence to support differences by race/ethnicity and body weight., Implications for Cancer Survivors: Routine bone density testing and regular patient-provider dialogue is critical in overweight/obese AA breast cancer survivors to ensure that healthy lifestyle factors (e.g., ideal weight, regular weight-bearing exercises, dietary adequacy of calcium and vitamin D) support optimal skeletal health.

Hepatocellular carcinoma (HCC) is associated with a high rate of mortality worldwide. Here, we investigated the effect of combination treatment with suberoylanilide hydroxamic acid (SAHA) and 5-fluorouracil (5-FU) on HCC cells. HepG2, SMMC7721, and BEL7402 cells were treated with SAHA and/or 5-FU and subjected to cell viability, colony formation, and soft agarose assays; cell cycle, apoptosis, and reverse transcription-PCR analyses; western blotting; immunohistochemistry; and xenograft tumorigenicity assay. SAHA and 5-FU inhibited the proliferation of the three cell lines, and combination treatment with SAHA and 5-FU resulted in a combination index <1 and a dose-reduction index value >1, indicating a synergistic effect. Co-treatment with SAHA and 5-FU caused G0/G1 phase arrest and induced caspase-dependent apoptosis, inhibiting tumorigenicity in vitro and in vivo. 5-FU upregulated thymidylate synthase, whereas SAHA downregulated its expression. Our results indicate that SAHA and 5-FU act synergistically to inhibit cell growth and tumorigenicity in HCC via the induction of cell-cycle arrest and apoptosis through a mechanism involving the inhibition of thymidylate synthase, suggesting that combination treatment with 5-FU and SAHA may be beneficial for the treatment of inoperable HCC.

Background/aims: Locoregional chemotherapy continues to be the mainstay for the treatment of unresectable hepatocellular carcinoma (HCC). One of the principal obstacles implicated in its unsuccessful therapy is multidrug resistance (MDR). Former studies have identified the multidrug-resistant nature and possible mechanisms of hepatoma cells both in vitro and in vivo. This work aimed to develop an effective strategy for the treatment of HCC with MDR., Methods: The treatment was exploited to inhibit the MDR cells by co-administration of the recombinant mutant human tumour necrosis factor-alpha (rmhTNF-alpha), a sublethal dose of chemicals [adriamycin (ADM), mitomycin and 5-FU] and hydroxyapatite nanoparticles (nHAPs). Real-time quantitative reverse transcriptase-polymerase chain reaction and electrochemiluminescence Western blot were used to detect the expression of several related genes., Results: The chemicals acted synergistically with rmhTNF-alpha and nHAP in suppressing the growth of hepatoma cells and inducing apoptosis of the cells, with the MDR phenotype reversed, as measured by intracellular ADM retention. Analysis of mRNA and protein revealed that rmhTNF-alpha inhibited the gene expression of XIAP, survivin, Ki67, PCNA, MDR1 and BCRP to some extent. Moreover, the inhibitory effects mentioned above could be as good or better than when nHAP is incorporated into the regimens., Conclusions: rmhTNF-alpha was not only able to restore the chemotherapeutic sensitivity to HepG2/ADM, its xenograft model and clinical samples but also further inhibited the growth of these tumours by a combination of nHAP. These results strongly suggested that chemicals in combination with rmhTNF-alpha and nHAP may be beneficial for the local treatment of advanced HCC.

Interestingly, some lymphoma cells, expressing high levels of transmembrane (tm)TNF-alpha, are resistant to secretory (s)TNF-alpha-induced necrosis but sensitive to tmTNF-alpha-mediated apoptosis. As tmTNF-alpha mediates "forward" as well as "reverse" signaling, we hypothesize that a balanced signaling between forward and reverse directions may play a critical role in determining the fate of cells bearing tmTNF-alpha. Using Raji cells as a model, we first added exogenous tmTNF-alpha on fixed, transfected NIH3T3 cells onto Raji cells to examine tmTNF-alpha forward signaling and its effects, showing that constitutive NF-kappaB activity and cellular inhibitor-of-apoptosis protein 1 transcription were down-regulated, paralleled with Raji cell death. As Raji cells express tmTNF-alpha, an inhibition of their tmTNF-alpha expression by antisense oligonucleotide caused down-regulation of NF-kappaB activity. Conversely, increasing tmTNF-alpha expression by suppressing expression of TNF-alpha-converting enzyme that cleaves tmTNF-alpha led to an enhanced activation of NF-kappaB, indicating that tmTNF-alpha, but not sTNF-alpha, contributes to constitutive NF-kappaB activation. We next transfected Raji cells with a mutant tmTNF-alpha lacking the intracellular domain to competitively suppress reverse signaling via tmTNF-alpha; as expected, constitutive NF-kappaB activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF-alpha enhanced NF-kappaB activation. We conclude that tmTNF-alpha, when highly expressed on tumor cells and acting as a receptor, promotes NF-kappaB activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-alpha, when acting as a ligand, inhibits NF-kappaB activity through forward signaling, which is inclined to induce tumor cell death.

TNF-alpha plays an important role in the pathogenesis of obesity and insulin resistance in which the effect of TNF-alpha signaling via TNF receptor type 1 (TNFR1) largely remains controversial. To delineate the role of TNFR1-mediated TNF-alpha signaling in the pathogenesis of this disorder, a TNFR1 blocking peptide-Fc fusion protein (TNFR1BP-Fc) was used for the present study. Wistar rats were fed a high-fat/high-sucrose (HFS) diet for 16 wk until obesity and insulin resistance developed. In comparison with increased body weight and fat weight, enlarged adipocytes, and hypertriglyceridemia in the obese state, the subsequent 4-wk treatment with TNFR1BP-Fc resulted in significant weight loss characterized by decreased fat pad weight and adipocyte size and reduced plasma triglycerides. Furthermore, obesity-induced insulin resistance, including hyperinsulinemia, elevated C-peptide, higher degree of hyperglycemia after glucose challenge, and less hypoglycemic response to insulin, was markedly improved, and the compensatory hyperplasia and hypertrophy of pancreatic islets were reduced. Interestingly, treatment with TNFR1BP-Fc markedly suppressed systemic TNF-alpha release and its local expression in pancreatic islets and muscle and adipose tissues. In addition, blockage of TNFR1-mediated TNF-alpha signaling in obese rats significantly enhanced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in the muscle and fat tissues. Our results strongly suggest a pivotal role for TNFR1-mediated TNF-alpha signaling in the pathogenesis of obesity and insulin resistance. Thus, TNFR1BP-Fc may be a good candidate for the treatment of this disease.