Evaluation of bioequivalence and safety analysis of capecitabine tablets and Xeloda® under postprandial dosing conditions in Chinese patients with solid tumor.

OBJECTIVES: To compare the pharmacokinetic and safety of the test group capecitabine tablets (0.5 g) and the reference group capecitabine tablets (0.5 g). METHODS: This study was registered at www.chinadrugtrials.org.cn under the registration number CTR20220138. 48 subjects with solid tumor were recruited and randomized to receive either the test group or the reference group at a dose of 2 g per cycle for three cycles of the entire trial. RESULTS: The point estimate of the geometric mean ratio of Cmax for the subject and reference groups was 1.0670, which was in the range of 80.00%-125.00%. And the upper limit of 95% confidence interval was -0.0450 < 0. The statistics of geometric mean ratio of AUC0-t and AUC0-∞ (test group/reference group) and their 90% confidence intervals were in the range of 80.00%-125.00%, thus the test group was bioequivalent to the reference group under the conditions of this postprandial test. There were no major or serious adverse events. Conclusion: The pharmacokinetic profiles of capecitabine under postprandial conditions were consistent between the two groups. The two groups were bioequivalent and had a similar favorable safety profile in Chinese patients with solid tumor.

Hsa_circ_0014784-induced YAP1 promoted the progression of pancreatic cancer by sponging miR-214-3p.

BACKGROUND: Pancreatic cancer (PC) is one of the most common gastrointestinal tumors globally. Former investigations discovered that circular RNAs (circRNAs) play an important role in PC development. circRNAs belong to a new class of endogenous noncoding RNAs, which have been found to mediate the progression of diverse types of tumors. Nevertheless, the roles of circRNAs and the underlying regulatory mechanisms in PC remain unknown. METHODS: In this study, our team employed next-generation sequencing (NGS) to examine the abnormal circRNA expression in PC tissues. The circRNA expression in PC cell lines and tissues was detected. Then, regulatory mechanism and targets were examined with bioinformatics analysis, luciferase reporting analysis, Transwell migration, 5-ethynyl-2'-deoxyuridine, and CCK-8 analysis. An in vivo experiment was employed to elucidate hsa_circ_0014784 roles in PC tumor growth and metastasis. RESULTS: The results showcased abnormal circRNA expression in PC tissues. Our lab also found that hsa_circ_0014784 expression incremented in PC tissues and cell lines, implying that hsa_circ_0014784 functioned in PC progression. hsa_circ_0014784 downregulation inhibited PC proliferation and invasion in vivo and in vitro. The bioinformatics and luciferase report data validated that both miR-214-3p and YAP1 were hsa_circ_0014784 binding partners. The overexpression of YAP1 reversed the migration, proliferation, and epithelial - mesenchymal transition (EMT) of PC cells and the angiogenic differentiation of HUVECs after miR-214-3p overexpression. CONCLUSION: Taken together, our study found that hsa_circ_0014784 downregulation decremented invasion, proliferation, EMT, and angiogenesis of PC by regulating miR-214-3p/YAP1 signaling.

Drug-drug interaction potential of SH-1028, a third-generation EGFR-TKI: in vitro and clinical trials.

SH-1028 is an irreversible third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Considering the possibility of combination therapy in patients with NSCLC, we investigated the drug-drug interaction (DDI) potential of SH-1028 both in vitro and in clinical trials. The in vitro studies were conducted to determine the potential of SH-1028 as a substrate, inducer, or inhibitor of cytochrome P450 (CYP) subtypes. A phase I drug-drug interaction study in healthy volunteers was performed to evaluate the impact of co-administering rifampicin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of SH-1028. The in vitro experiments showed that SH-1028 was mainly metabolized by CYP3A4. The activities of CYP1A2, 2B6, 2C19, 2D6 and 3A4 enzymes were slightly inhibited in vitro with SH-1028. SH-1028 has no obvious induction effect on CYP1A2 and CYP2B6 activities, but has potential induction effect on CYP3A4 mRNA expression. However, SH-1028 may not induce or inhibit human CYPs significantly at the clinically expected dose (200 mg). The geometric mean ratios of pharmacokinetic parameters and their corresponding 90% confidence intervals for SH-1028 in combination and alone did not fall within the range of 80-125%. It is speculated that itraconazole and rifampicin affect the metabolism of SH-1028. In the clinical application of SH-1028, special attention should be paid to the interaction between SH-1028 and drugs or foods that affect the activity of CYP3A4. (Clinical trial registration number: CTR20210558).

A phase I study comparing the biosimilarity of the pharmacokinetics and safety of recombinant humanized anti-vascular endothelial growth factor monoclonal antibody injection with Avastin® in healthy Chinese male subjects.

BACKGROUND: The biosimilar landscape for malignancies continues to grow, with several biosimilars for reference product bevacizumab currently available. Bevacizumab has been shown to be well tolerated; however, the safety of recombinant humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody injection remains unclear. This study aimed to compare the pharmacokinetics (PK), safety, and immunogenicity of recombinant humanized anti-VEGF monoclonal antibody injection to that of Avastin® in healthy Chinese male volunteers. METHODS: A randomized, double-blind, single-dose, and parallel-group study was performed on 88 healthy men who randomly (1:1) received either the test drug as an intravenous infusion of 3 mg/kg or Avastin®. The primary PK parameter was area under the serum concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t). Secondary endpoints included maximum observed serum concentration (Cmax), AUC from 0 extrapolated to infinity (AUCinf), safety, and immunogenicity. Serum bevacizumab concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline characteristics were similar among the two groups. The 90% confidence interval (CI) for the geometric mean ratio of AUC0-t, Cmax and AUCinf between the test group and reference group were 91.71%-103.18%, 95.72%-107.49% and 91.03%-103.43%, respectively. These values were within the predefined bioequivalence margin of 80.00%-125.00%, demonstrating the biosimilarity of the test drug and Avastin®. Eighty-one treatment-emergent adverse events were reported, with a comparable incidence among the test group (90.91%) and the reference group (93.18%). No serious adverse events were reported. The incidence of ADA antibodies in the two groups was low and similar. CONCLUSION: In healthy Chinese men, PK similarity of recombinant humanized anti-VEGF monoclonal antibody injection to Avastin® was confirmed, with comparable safety and immunogenicity. Subsequent studies should investigate recombinant humanized anti-VEGF monoclonal antibody injection in patients setting. TRIAL REGISTRATION: Registered 08/10/2019, CTR20191923.

Oseltamivir phosphate for suspension is bioequivalent to TAMIFLU in healthy volunteers: a randomized, open-label clinical study.

PURPOSE: The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and manufactured by Hetero Labs Limited, and the reference product TAMIFLU® in healthy Chinese subjects. METHODS: A single-dose, randomized, two-phase, self-crossed model was adopted. Among 80 healthy subjects, 40 subjects in the fasting group and 40 subjects in the fed group. Subjects in the fasting group were randomized into two sequences according to the proportion of 1:1, each given 75 mg/12.5 mL of Oseltamivir Phosphate for Suspension or TAMIFLU®, and cross-administered after 7 days. Postprandial group is the same as fasting group. RESULTS: The Tmax of TAMIFLU® and Oseltamivir Phosphate for Suspension in the fasting group were 1.50 h and 1.25 h, which in the fed group were both 1.25 h. Geometrically adjusted mean ratios of the PK parameters of Oseltamivir Phosphate for Suspension along with TAMIFLU® under fasting and postprandial conditions were in the range of 80.00-125.00% at the 90% confidence interval (CI). The 90% CI of Cmax, AUC0-t, AUC0-∞ for fasting group and postprandial group were (92.39,106.50), (94.26,100.67), (94.32,100.89) and (93.61,105.83),(95.64,100.19),(96.06,102.66). Among the subjects on medication, a total of 18 subjects reported 27 adverse events, all of which were treatment-emergent adverse events (TEAEs), six of these TEAEs were rated as grade 2 in severity and the rest were as grade 1. The number of TEAEs in the test product and the reference product were 14,13 respectively. CONCLUSION: Two Oseltamivir phosphate for suspensions are safe and bioequivalent.

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration.

PURPOSE: SHC014748M is a potent, novel selective PI3Kδ isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150 mg (100 µCi) [14C] SHC014748M. METHODS: Six healthy Chinese male subjects administrated an oral suspension of 150 mg (100 µCi) [14C] SHC014748M and the samples of blood, urine and feces were collected for measuring. Liquid chromatography-tandem mass spectrometry and liquid scintillation counter were utilized to obtain mass balance and the pharmacokinetic data. RESULTS: The median Tmax for [14C]-radioactivity was 1.6 ± 0.5 h after the oral administration of [14C] SHC014748M and the mean Cmax was 3863 ± 354 ng Eq./mL in plasma, while the mean Cmax, t1/2 values and AUC0-∞ values for total radioactivity in whole blood were 2466 ± 518 ng Eq./mL, 32.2 ± 30.5 h and 66,236 ± 44,232 h * ng Eq./mL, respectively. Fecal excretion was proposed as the predominant elimination route, accounting for a mean of 90.68 ± 11.38% of the administered dose, whereas the mean urine excretion was 6.00 ± 1.48% within 336 h post-dose. The proposed major metabolic pathway of [14C] SHC014748M in the human body were as follows: (I) monooxidation, (II) glucuronide acid conjugation, and (III) monoxide-hydrogenation. CONCLUSIONS: SHC014748M was absorbed, metabolized and excreted with unchanged SHC014748M as its main circulating component in plasma following oral administration. In addition, it was speculated that fecal excretion was the principal excretion pathway; meanwhile, monohydroxy, glucuronide conjugation, oxygen, and hydrogenation were the major clearance pathways of SHC014748M through urine and/or feces. TRIAL REGISTRATION: The trial registration number: CTR20202505.

Metabolism-related lncRNAs signature to predict the prognosis of colon adenocarcinoma.

BACKGROUND: Cell metabolism and long noncoding RNA (lncRNA) played crucial roles in cancer development. However, their association in colon adenocarcinoma (COAD) remains unclear. METHODS: The COAD gene expression data and corresponding clinical data were retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of metabolic genes and lncRNA were identified by comparing tumor and normal colon tissues. Pearson correlation analysis was performed to identify metabolism-associated lncRNA. COAD patients were divided into training cohort and validation cohort by randomization. Then, a univariate Cox regression analysis was introduced to evaluate the correlations between metabolism-related lncRNAs and overall survival (OS) of the patients in the training cohort. The least absolute shrinkage and selection operator (LASSO) method was introduced to determine and establish a prognostic prediction model. Subsequently, survival analysis, receiver operating characteristic (ROC) curve analysis, and Cox regression analysis were generated to estimate the prognostic role of the LncRNA risk score in training, validation, and entire cohorts. RESULTS: We identified 152 differentially expressed metabolism-associated lncRNAs (MRLncRNAs). A prognostic prediction model involving four metabolism-related lncRNAs were established using LASSO. In each cohort, COAD patients in the high-risk group had worse OS compared to those in the low-risk group. The ROC analyses demonstrated that the lncRNA signature performed well in predicting OS. Uni- and multivariate analysis indicated that the lncRNA signature as an independent prognostic factor. Furthermore, a correlation analysis demonstrated that LINC01138 was the most closely lncRNA related to metabolic genes. In vitro assays demonstrated that LINC01138 affects tumor progression in COAD. CONCLUSIONS: In summary, we established a metabolism-associated lncRNAs model to predict the prognosis in COAD patients.

Polystyrene micro(nano)plastics damage the organelles of RBL-2H3 cells and promote MOAP-1 to induce apoptosis.

The ubiquity of microplastics increases the exposure risks and health threats to humans. In this study, rat basophilic leukemia (RBL-2H3) cells were exposed to polystyrene particles (PS-particles) of 50 nm, 500 nm and 5 µm to investigate organelle damage and the mechanism of cell death. PS-particles induced oxidative stress, which in turn led to mitochondrial and lysosomal damage, arrested the cell cycle in the G0/G1 phase, and finally caused apoptosis. Anti-apoptotic genes (Bcl-2) were down regulated, and pro-apoptotic genes (Bax) and a key gene (caspase-3) in apoptosis were upregulated. The molecular mechanism of apoptosis was further explored via the combination of transcriptome sequencing, RT-qPCR verification and small interfering RNA (siRNA) technology. The modulator of apoptosis-1 (MOAP-1) was significantly upregulated, and apoptosis was abolished by knocking down MOAP-1. This finding clarifies that PS-particles promote MOAP-1 to induce apoptosis. Hence, PS-particles may promote the binding of MOAP-1 and Bax, which ultimately activates caspase-3 and causes apoptosis through the mitochondrial pathway. The 50-nm PS-particles resulted in the most serious mitochondrial damage and apoptosis. Eventually, PS-particles cause oxidative stress, damage organelles and induce apoptosis by promoting MOAP-1. Altogether, our study emphasizes the need to assess the cytotoxicity of micro(nano)plastics and helps to predict the health risks.

GPX2 stabilized by PCBP2 induces autophagy to protect Het-1A esophageal cells from apoptosis and inflammation.

The implantation of esophageal stent loaded with iodine-125 (125I) is one of the critical approaches for the treatment of advanced esophageal cancer, but one common complication after stent implantation is benign hyperplasia associated restenosis. The aim of the current study is to understand the role of glutathione peroxidase 2 (GPX2), a key member of the GPX family of antioxidant enzymes. Initially, we detected the increased levels of GPX2 and GPX1 in esophageal benign hyperplasia tissues. Further, we evaluated the effects of GPX2 in response to H2O2 induced apoptosis and LPS induced inflammation. We observed that GPX2 expression was also significantly increased in Het-1A. Silencing of GPX2 significantly increased H2O2-induced apoptosis and LPS-induced inflammation, but GPX2 overexpression did the opposite, suggesting a protective effect by GPX2. In addition, we identified that the protective effect of GPX2 is through the activation of autophagy, and PCBP2, a poly (rC) binding protein, binds to and stabilizes GPX2 mRNA. These findings reveal a role of GPX2 in esophageal hyperplasia, allowing for a better understanding of the underlying molecular mechanism, which could lead to identification of potential treatment for clinical benign restenosis following stent implantation with 125I.

Endocarditis-associated rapidly progressive glomerulonephritis mimicking vasculitis: a diagnostic and treatment challenge.

BACKGROUND: Infective endocarditis (IE)-associated rapidly progressive glomerulonephritis (RPGN) is rarely reported. Sporadic case reports have noted the diagnostic and therapeutic challenge in IE-associated glomerulonephritis because it may masquerade as idiopathic vasculitis. METHODS: Patients with clinical diagnosis of IE-related RPGN in a tertiary hospital in China between January 2004 and May 2021 were identified and retrospectively reviewed. RESULTS: Twenty-four patients with IE-associated RPGN were identified. All patients presented with fever and multiorgan system involvement on top of heart and kidneys, spleen (79%, 19/24), skin (63%, 15/24), lung (33%, 8/24) and nervous system (17%, 4/24). Six of the 24 patients (25%) were initially suspected to have ANCA-associated or IgA vasculitis. Forty-five percent of patients are seropositive for ANCA. Renal histology showed mesangial and/or endocapillary hypercellularity with extensive crescents in most patients. C3-dominant deposition was the predominant pattern on immunofluorescence and pauci-immune necrotising crescentic glomerulonephritis was observed in one case. All patients received antibiotics with or without surgery. Six patients received immunosuppressive therapy before antibiotics due to misdiagnosis and seven patients received immunosuppressive therapy after antibiotics due to persistence of renal failure. Three of the 24 patients died due to severe infection. All the surviving patients had partial or complete recovery of renal function. CONCLUSION: IE-associated RPGN is rare and the differential diagnosis from idiopathic vasculitis can be challenging due to overlaps in clinical manifestations, ANCA positivity and absence of typical presentations of IE. The prognosis is generally good if antibiotics and surgery are not delayed. The decision on introducing immunoruppressive treatment should be made carefully on a case by case basis when kidney function does not improve appropriately after proper anti-infective therapy.Key messagesInfective endocarditis associated RPGN is rare and differentiating it from idiopathic vasculitis can be challenging due to overlap in clinical manifestations, ANCA positivity and occasional absence of typical manifestations of infective endocarditis.Kidney function usually responds to antibiotic therapy alone.Immunosuppressive therapy may be beneficial in carefully selected patients whose kidney function does not improve with antibiotics alone.

GPx8 regulates apoptosis and autophagy in esophageal squamous cell carcinoma through the IRE1/JNK pathway.

Glutathione peroxidase 8 (GPx8) belongs to a family of enzymes that have a critical role in controlling levels of reactive oxygen species (ROS). GPX family members have been associated with several cancers. Here, we examined the role of GPx8 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining and western blot analysis were used to study the clinical significance of GPx8 in ESCC tissue. GPx8 was further evaluated in cells by MTT assay and colony formation. RT-PCR, western blot, immunofluorescence staining, TUNEL assay, TEM, and flow cytometry were used to assess the molecular mechanism underlying endoplasmic reticulum (ER) stress associated with GPx8 in ESCC cells. Xenografted tumor growth was used to assess the in vivo role of GPx8. We found that GPx8 was overexpressed in both ESCC cell lines and tumor tissue. GPx8 knockdown significantly suppressed ESCC proliferation and induced autophagy and apoptosis in ESCC cell lines, whereas GPx8 overexpression led to increased proliferation and inhibition of apoptosis. GPx8-mediated inhibition of apoptosis was associated with the ER stress pathway through inositol-requiring enzyme 1 (IRE1) and Jun N-terminal kinase (JNK). Knockdown of GPx8 in xenograft models of ESCC resulted in a significant reduction in tumor weight and volume, which was further reduced with IRE1 or JNK inhibitors. Our study suggests that GPx8 regulates apoptosis and autophagy in ESCC through the IRE1/JNK pathway in response to ER stress. Targeting this pathway might be a potential therapeutic strategy for ESCC.

Pharmacokinetic and pharmacodynamic evaluation of the new prolonged-release leuprorelin acetate microspheres for injection compared with Enantone® in healthy Chinese male volunteers.

PURPOSE: To compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg). METHOD: 48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®. RESULTS: There were no significant differences in Cmax, AUC0-t and AUC0-48 between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate. CONCLUSION: The pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.

HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma.

HP1BP3, an ubiquitously expressed nuclear protein belonging to the H1 histone family of proteins, plays an important role in cell growth and viability. Recently, it was reported that HP1BP3 exclusively regulates miRNA biogenesis by enhancing transcriptional miRNA processing. Although HP1BP3 has previously been implicated in common cancer types, the mechanistic functions and effects of HP1BP3 and its role in the prognosis of esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we report that ESCC tissues and cell lines show increased endogenous expression of HP1BP3. Knockdown of HP1BP3 in TE-1 cells significantly inhibited tumor growth and metastasis in vivo emphasizing its role in cell proliferation and invasion. In contrast, overexpression of HP1BP3 significantly enhanced tumor growth and metastasis in Eca-109 cells. Further, we found that HP1BP3 regulates these functions by upregulating miR-23a, which directly binds to the 3'UTR region of TRAF5 downstream to alter cell survival and proliferation. Our findings describe a role for HP1BP3 in promoting tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal cancer. This study provides novel insights into the potential of targeting miRNAs for therapy and as clinical markers for cancer progression.

TRIM11 suppresses ferritinophagy and gemcitabine sensitivity through UBE2N/TAX1BP1 signaling in pancreatic ductal adenocarcinoma.

Gemcitabine is first-line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif-containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto-polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real-time polymease chain reaction, and immunohistochemical staining. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N-TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC.

Long non-coding RNA BCAR4 aggravated proliferation and migration in esophageal squamous cell carcinoma by negatively regulating p53/p21 signaling pathway.

Long non-coding RNA breast cancer antiestrogen resistance 4 (lncRNA BCAR4) is an independent factor on the survival prognosis of patients with multiple cancers. However, the role of lncRNA BCAR4 in esophageal squamous cell cancer (ESCC) remains unknown. Here, we unraveled that lncRNA BCAR4 was upregulated in ESCC and predicted poor prognosis. Functionally, lncRNA BCAR4 knockdown induced cell apoptosis and G1/S arrest, while inhibited cell proliferation and migration in vitro; conversely, overexpressing lncRNA BCAR4 promoted proliferation and metastasis. Mechanistically, lncRNA BCAR4 sponged miR-139-3p to upregulate ELAVL1, thereby inhibiting p53/p21 pathway in ESCC cells. In conclusion, lncRNA BCAR4 promotes ESCC tumorigenesis via regulating p53/p21 signaling pathway and develops a brand-new biomarker and medicine target for ESCC.

Integrative bioinformatics analysis identifies LINC01614 as a potential prognostic signature in esophageal cancer.

BACKGROUND: Esophageal cancer (EC) is one of the most common gastrointestinal cancers and the incidence is on the increase in recent years. The aim of the present study was to assess novel long non-coding RNA (lncRNA) biomarkers for the prognosis of EC through the analysis of gene expression microarrays. METHODS: Three datasets (GSE53622, GSE53624, and GSE53625) were downloaded from the Gene Expression Omnibus (GEO) database and EC patients' clinical information were from The Cancer Genome Atlas (TCGA) databases. Differentially expressed genes (DEGs) were screened by comparing tumor tissues with normal tissues using limma R package. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database was used to obtain the novel lncRNAs and their co-expression genes in EC and these were visualized with the Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database was used to analyze the functions enrichment of selected DEGs. Cell Counting Kit-8 (CCK8) and Transwell assays were used to further confirm the function of target lncRNAs. RESULTS: We identified 24 differentially expressed (DE) lncRNAs and 659 DE mRNAs from the intersection of GEO and TCGA databases. And we found that only LINC01614 was concerned with a candidate prognostic signature in EC. "Extracellular matrix (ECM)-receptor interaction" and "PI3K-Akt signaling pathway" were observed, and we constructed a lncRNA-mRNA co-expression network for EC that includes LINC01614 and 64 mRNAs. The results of CCK8 and Transwell assays showed that suppression of LINC01614 inhibited EC cell proliferation and migration. CONCLUSIONS: Our study might provide LINC01614 as a novel lncRNA biomarker for diagnosis and prognosis in EC.

TMEM88 Modulates Lipid Synthesis and Metabolism Cytokine by Regulating Wnt/ß-Catenin Signaling Pathway in Non-Alcoholic Fatty Liver Disease.

Objective: To clarify the molecular mechanism of TMEM88 regulating lipid synthesis and metabolism cytokine in NAFLD. Methods: In vivo, NAFLD model mice were fed by a Methionine and Choline-Deficient (MCD) diet. H&E staining and immunohistochemistry experiments were used to analyze the mice liver tissue. RT-qPCR and Western blotting were used to detect the lipid synthesis and metabolism cytokine. In vitro, pEGFP-C1-TMEM88 and TMEM88 siRNA were transfected respectively in free fat acid (FFA) induced AML-12 cells, and the expression level of SREBP-1c, PPAR-α, FASN, and ACOX-1 were evaluated by RT-qPCR and Western blotting. Results: The study found that the secretion of PPAR-α and its downstream target ACOX-1 were upregulated, and the secretion of SREBP-1c and its downstream target FASN were downregulated after transfecting with pEGFP-C1-TMEM88. But when TMEM88 was inhibited, the experimental results were opposite to the aforementioned conclusions. The data suggested that it may be related to the occurrence, development, and end of NAFLD. Additionally, the study proved that TMEM88 can inhibit Wnt/ß-catenin signaling pathway. Meanwhile, TMEM88 can accelerate the apoptotic rate of FFA-induced AML-12 cells. Conclusion: Overall, the study proved that TMEM88 takes part in regulating the secretion of lipid synthesis and metabolism cytokine through the Wnt/ß-catenin signaling pathway in AML-12 cells. Therefore, TMEM88 may be involved in the progress of NAFLD. Further research will bring new ideas for the study of NAFLD.

Baicalein attenuates cardiac hypertrophy in mice via suppressing oxidative stress and activating autophagy in cardiomyocytes.

Baicalein is a natural flavonoid extracted from the root of Scutellaria baicalensis that exhibits a variety of pharmacological activities. In this study, we investigated the molecular mechanisms underlying the protective effect of baicalein against cardiac hypertrophy in vivo and in vitro. Cardiac hypertrophy was induced in mice by injection of isoproterenol (ISO, 30 mg·kg-1·d-1) for 15 days. The mice received caudal vein injection of baicalein (25 mg/kg) on 3rd, 6th, 9th, 12th, and 15th days. We showed that baicalein administration significantly attenuated ISO-induced cardiac hypertrophy and restored cardiac function. The protective effect of baicalein against cardiac hypertrophy was also observed in neonatal rat cardiomyocytes treated with ISO (10 µM). In cardiomyocytes, ISO treatment markedly increased reactive oxygen species (ROS) and inhibited autophagy, which were greatly alleviated by pretreatment with baicalein (30 µM). We found that baicalein pretreatment increased the expression of catalase and the mitophagy receptor FUN14 domain containing 1 (FUNDC1) to clear ROS and promote autophagy, thus attenuated ISO-induced cardiac hypertrophy. Furthermore, we revealed that baicalein bound to the transcription factor FOXO3a directly, promoting its transcription activity, and transactivated catalase and FUNDC1. In summary, our data provide new evidence for baicalein and FOXO3a in the regulation of ISO-induced cardiac hypertrophy. Baicalein has great potential for the treatment of cardiac hypertrophy.

A randomized Phase I pharmacokinetic trial comparing the potential biosimilar trastuzumab (SIBP-01) with the reference product (Herceptin®) in healthy Chinese male volunteers.

OBJECTIVES: This study aimed to evaluate the bioequivalence, safety, tolerability and immunogenicity of the biosimilar trastuzumab (SIBP-01) compared to Herceptin®. METHODS: In this Phase I randomized double-blind parallel-group trial, 100 healthy male volunteers were randomized in a1:1 ratio to receive a single 6 mg•kg-1 intravenous dose of SIBP-01 or Herceptin®. Serum concentrationswere analyzed using a validated ELISA. RESULTS: The two groups had similar baseline characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t and AUCinf between the trial group and the reference group were 93.55%-104.27%, 91.98%-102.35% and 91.88%-102.34%, respectively; the geometric mean ratios (90% CI) of AUC0-t and AUCinf in the sensitivity analysis were 92.29%-102.63% and 91.81%-102.16%, respectively. These values were within the prespecified equivalence margins, establishing the bioequivalence of SIBP-1 and Herceptin®. AEs were similar across all subjects in the SIBP-01 and Herceptin® arms, with treatment-related AEs reported by 72.00% and 80.00%, respectively. In each group, there was one AE that caused a subject to discontinue the study. EXPERT OPINION: Trastuzumab (Herceptin®) is significantly more effective than chemotherapy in reducing exacerbations and tumor cell growth, and its adverse events are far lower than chemotherapy. Herceptin®is very expensive for most patients in China. The protein molecular primary structure of the biosimilar trastuzumab (SIBP-01) is consistent with Herceptin®, with highly similar high level structure, biologocal activity and purity.But there are few studies comparing the bioequivalence of SIBP-01 and Herceptin® in healthy subjects and cancer patients 2. CONCLUSIONS: This study showed the PK similarity of SIBP-01 to Herceptin®. SIBP-01 was safe and well tolerated in healthy male volunteers, with no significant differences from the reference drug in safety or immunogenicity 4.