Strong and Ultra-tough Ionic Hydrogel Based on Hyperbranched Macro-Cross-linker: Influence of Topological Structure on Properties.

The application of hydrogels often suffers from their inherent limitation of poor mechanical properties. Here, a carboxyl-functionalized and acryloyl-terminated hyperbranched polycaprolactone (PCL) was synthesized and used as a macro-cross-linker to fabricate a super strong and ultra-tough ionic hydrogel. The terminal acryloyl groups of hyperbranched PCL are chemically incorporated into the network to form covalent cross-links, which contribute to robust networks. Meanwhile, the hydrophobic domains formed by the spontaneous aggregation of PCL chains and coordination bonds between Fe3+ and COO- groups serve as dynamic non-covalent cross-links, which enhance the energy dissipation ability. Especially, the influence of the hyperbranched topological structure of PCL on hydrogel properties has been well investigated, exhibiting superior strengthening and toughening effects compared to the linear one. Moreover, the hyperbranched PCL cross-linker also endowed the ionic hydrogel with higher sensitivity than the linear one when used as a strain sensor. As a result, this well-designed ionic hydrogel possesses high mechanical strength, superior toughness, and well ionic conductivity, exhibiting potential applications in the field of flexible strain sensors.

Altered Signaling Pathways Revealed by Comprehensive Genomic Profiling in Patients With Unknown Primary Tumors.

Purpose: Carcinoma of unknown primary (CUP) is a clinically aggressive disorder with early tumor dissemination. Identifying molecular traits of CUP can be not only beneficial for a better therapeutic approach but also potentially valuable for patients with general metastatic dissemination. Patients and Methods: We retrospectively investigated a total of 35 unique CUP cases. Tumor tissue samples were available in 26 patients, and plasma samples were available in 22 patients. Targeted sequencing was performed with a panel of 416 pan cancer-related genes. Results: A genomic landscape of the CUP cohort showed that TP53 mutation was the most frequently observed mutation while MYC amplification was the most common CNV. Aberrant TP53, RTK-RAS, and PI3K signaling pathways were also prevalent, identified in more than half of the cases with tumor tissue. Around 58% of the CUP cases harbored homologous recombinant repair (HRR) pathway gene alterations. The tumor mutational load of CUP patients with altered HRR pathway displayed a significant increase than that of patients with intact HRR. Clinically actionable mutations were identified in eight patients, which may benefit from targeted therapies. Eight patients were treated with platinum-based chemotherapy, showing different responses, HRR, and LOH status. Conclusion: Collectively, our data have provided much-need insights into the treatment options for patients diagnosed with CUP in the era of precision medicine.

CTCF-activated SNHG16 facilitates gastrointestinal stromal tumor by targeting miR-128-3p/CASC3 axis.

In this study, it was ascertained that SNHG16 was up-regulated in gastrointestinal stromal tumor (GIST) tissues and cells, and was responsible for the aggravated malignant behaviors of GIST cells. CTCF served as a transcription activator responsible for the overexpression of SNHG16 in GIST cells. MiR-128-3p was negatively regulated by SNHG16 and exerted anti-tumor effects. Moreover, CASC3 was the direct target mRNA of miR-128-3p, through which miR-128-3p exerted function influence on GIST cell malignant behaviors. SNHG16 competitively bound with miR-128-3p against CASC3, thus positively regulating CASC3 expression. Finally, functional assays carried out in vitro proved SNHG16 could modulate GIST cell proliferation, migration, invasion and apoptosis via miR-128-3p/CASC3 axis. Animal experiments were also designed and implemented in a rescue way and evidenced that up-regulation of CASC3 countervailed the inhibitory impacts of SNHG16 silence on the progression of GIST. In summary, SNHG16 up-regulated by CTCF facilitated the progression of GIST through miR-128-3p/CASC3.

Comparison of efficacy between montgomery and Jobe technique and arthroscopic bankart repair in treating traumatic recurrent anterior shoulder dislocation.

OBJECTIVE: To compare the clinical efficacy of Montgomery and Jobe technique versus arthroscopic Bankart repair in treating traumatic recurrent anterior shoulder dislocation (ASD). METHODS: A total of 113 patients with traumatic recurrent ASD admitted to our hospital from June 2016 to January 2019 were selected as study subjects, and were divided into Group A and B in accordance with surgical options. The clinical data of the subjects were collected retrospectively. Group A was treated by the Montgomery and Jobe technique, while Group B was treated with arthroscopic Bankart repair. The arthroscopic manifestations were analyzed before and after arthroscopic Bankart repair. Scores of visual analogue scale (VAS) for shoulder joint and American Shoulder and Elbow Surgeons (ASES), Constant-Murley Score (CMS), Rowe Score, and complications were compared between the two groups before and after surgery. RESULTS: Compared with Group A, Group B had a lower score of VAS for the shoulder joint, and higher scores of the range of motion (ROM), functional activities, myodynamia, pain, CMS, vital functions, ASES, and shoulder joint function, and a higher Rowe score after surgery (P < 0.05). The incidence rate (1.75%) of complications in Group B was lower than that (14.29%) in Group A (P < 0.05). CONCLUSION: Arthroscopic Bankart repair is superior to the Montgomery and Jobe technique in treating traumatic recurrent ASD. Arthroscopic Bankart repair, exhibiting a high safety profile, is conducive to improving shoulder joint function and pain.

A laparoscopic pancreaticoduodenectomy for pancreatic adenocarcinoma in a patient with situs inversus totalis.

Situs inversus totalis (SIT) is a congenital disorder in which the thoracic and abdominal viscera organs are mirrored from their normal anatomical position. Thus, the presence of any cancerous mass in one of the visceral organs of patients with SIT represents a great challenge due to the anatomical variation. We report a 52-year-old male with SIT who presented with obstructive jaundice and pancreatic-head mass. After preoperative examinations, it was decided to perform a laparoscopic pancreaticoduodenectomy. In this case, we aim to demonstrate the diagnosis and management of pancreatic cancer in an SIT patient, in addition to presenting the advantages and difficulties of laparoscopic surgery in this case.

Inhibiting the JNK/ERK signaling pathway with geraniol for attenuating the proliferation of human gastric adenocarcinoma AGS cells.

Geraniol, a natural compound found in the essential oils of various aromatic plants, has attracted attention for its probable anticancer effects. The molecular mechanisms of the cell proliferation suppression and apoptosis induction via geraniol in gastric cancer cells (AGS), however, remain unclear. Gastric cancer cells were treated with geraniol, and it was found that the IC50 values were 25 µM/ml, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results showed that 20 and 25 µM geraniol-induced reactive oxygen species (ROS) production (2'-7'dichlorofluorescin diacetate staining) and decreased mitochondrial membrane potential (rhodamine 123 staining) in AGS cells. Then, it effectively inhibited cell growth and induced apoptosis, confirmed through acridine orange/ethidium bromide, 4',6-diamidino-2-phenylindole, and propidium iodide staining and molecular marker analysis in AGS cells. Also, geraniol potently diminished caspase-9, Bax, Bcl-2, and caspase-3 expression in AGS cells. We also evaluated the essential mechanism of the cytotoxic effect of geraniol. Moreover, the present study depicted that geraniol-induced cell death through mitochondrial ROS production and inhibited the phosphorylation form of mitogen-activated protein kinase (p38, MAPK, JNK, and ERK1/2) signaling pathway. Taken together, these results concluded that geraniol has a novel therapeutic property against human stomach cancer.

DNA methylation integratedly modulates the expression of Pit-Oct-Unt transcription factors in esophageal squamous cell carcinoma.

Background: Dysregulation of Pit-Oct-Unc family transcription factors has been implicated in esophageal squamous cell carcinoma (ESCC). In this study, we evaluated the expression and promoter methylation status of Octamer (OCT) transcription factor genes in human ESCC clinical specimens to investigate the mechanism underlying this observation along with the clinical significance. Methods: Total DNA or RNA was extracted from ESCC tissue specimens and the mRNA level of genes encoding the transcription factors OCT1, OCT2, OCT3/OCT4, OCT5, OCT7, OCT9, and OCT11 were evaluated by quantitative PCR. The DNA methylation status of gene promoters was assessed by bisulfite pyrosequencing and next-generation sequencing. The relationship between the expression of these transcription factors and ESCC proliferation was investigated in vitro and in vivo with the colony formation assay and a mouse xenograft tumor model, respectively. We also examined the correlation between OCT gene expression and promoter methylation and clinicopathologic characteristics of ESCC. Results: OCT1 was upregulated whereas OCT4, OCT6, and OCT11 were downregulated in ESCC compared to non-tumor tissue. OCT2, OCT7, and OCT9 were undetected in all samples. OCT1, OCT6, and OCT11 levels were negatively correlated with the methylation of their respective promoters, but there was no relationship between OCT4 expression and promoter methylation status. Conclusion: Changes in promoter methylation rate underlie the observed alterations in OCT1, OCT6, and OCT11 expression in ESCC, whereas another mechanism is likely responsible for the dysregulation of OCT4.

Tomentosin induces apoptotic pathway by blocking inflammatory mediators via modulation of cell proteins in AGS gastric cancer cell line.

In this study, we investigated the in vitro effect of tomentosin on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reactive oxygen species by 2',7'-dichlorofluorescein diacetate staining assay, apoptosis (AO/EtBr, propidium iodide, and 4',6-diamidino-2-phenylindole staining, mitochondrial membrane potential), cell adherent, cell migration, inflammation, apoptosis, and oxidative stress from gastric cancer cells (GCCs) AGS. Upon their relative cell proliferative, inflammatory, and apoptotic molecular markers were analyzed by using the enzyme-linked immunosorbent assay and Western blot analysis method. Treatment with tomentosin (IC50 = 20 µM) significantly inhibited cell proliferation and oxidative stress-induced anti-cell proliferative (proliferating cell nuclear antigen and cyclin-D1) also regulated expression, drastically diminished tumor necrosis factor-α, nuclear factor-κB, interleukin-6, and interleukin-1ß expression levels, significantly upregulated Bcl-2 and Bax expression. Thus, this tomentosin can significantly reduce GCC proliferation via cytotoxicity which is stimulated apoptosis markers via morphology staining changes and inhibitory inflammatory markers. The tomentosin-induced oxidative stress may be involved to stimulate apoptotic mechanisms via mitochondria-mediated signaling by the inhibition of inflammation. Taken together, our findings suggest a possible future use of chemotherapeutic agents for pharmacological benefits and as an anti-cancer treatment option.

Long Non-coding RNA MIR4435-2HG Promotes Colorectal Cancer Proliferation and Metastasis Through miR-206/YAP1 Axis.

Objective: Long non-coding RNAs (lncRNAs) are critical to colorectal cancer (CRC) progression. In the current study, the objective was the exploration of the role played by lncRNA MIR4435-2HG in CRC proliferation and metastasis. Methods: lncRNA MIR4435-2HG expression and its association with CRC were analyzed using database and clinical specimens. The influences exerted by MIR4435-2HG on cell proliferating process, invading process, and migrating process of CRC were identified after MIR4435-2HG knockdown. The influences exerted by MIR4435-2HG on tumor growth and metastasis were assessed in vivo. The underlying mechanistic associations between MIR4435-2HG, microRNA miR-206, and the transcription factor Yes-associated protein 1 (YAP1) were assessed using bioinformatics and a luciferase reporter gene assay. Results: MIR4435-2HG was highly expressed in CRC tissue in contrast with that in regular tissues and displayed relations to poor prognosis. MIR4435-2HG knockdown could suppress CRC cell proliferation, invasion, and migration. Moreover, MIR4435-2HG knockdown inhibited CRC growth and liver metastasis in vitro. We found MIR4435-2HG knockdown reduced YAP1, CTGF, AREG, vimentin, Snail, Slug, and Twist expression but enhanced E-cadherin expression. Functionally, MIR4435-2HG acted as a competing endogenous RNA (ceRNA) to upregulate YAP1 by sponging miR-206. Conclusions: MIR4435-2HG promoted CRC growth and metastasis through miR-206/YAP1 axis and is likely to play prognostic marker roles and be therapeutically targeted in CRC.

Hesperidin loaded Zn2+@ SA/PCT nanocomposites inhibit the proliferation and induces the apoptosis in colon cancer cells (HCT116) through the enhancement of pro-apoptotic protein expressions.

Colon carcinoma is a recurring type of cancer that affects the intestine epithelial with a poor survival rate. It was already proven the anticancer property of hesperidin in various cancers but the bioavailability hesperidin is poor, which hinders the hesperidin usage. In this investigation we synthesized hesperidin loaded Zn2+@ SA/PCT nanocomposites and assessed its anticancer potential against colon cancer (HCT116) cells. Hesperidin loaded Zn2+@ SA/PCT nanocomposites were characterized using Fourier transform infrared (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis. The drug releasing capacity and cytotoxic property was assessed via drug releasing assay, MTT assay with HCT116 cells. The anticancer potency of hesperidin nanocomposites were evaluated with TUNEL, DAPI staining, reactive oxygen species (ROS) generation assay and it is confirmed with flow cytometry analysis of MMP disruption in colon cancer (HCT116) cell line. Further the immunoblotting analysis of cysteine proteases Caspases 3, 9, PARP, proapoptotic protein Bax and antiapoptotic protein Bcl2 were performed. The results of FTIR, XRD and electroscopic analyses confirmed the synthesized hesperidin nanocomposites accomplish the properties of potent nanodrug and the MTT assay authentically confirmed that the synthesized hesperidin nanocomposite inhibited the HCT116 cell growth, and the results of fluorescent staining proved that the hesperidin nanocomposite induced the apoptotic mediated cell necrosis via promoting the expression of apoptotic proteins thereby induced the apoptosis in colon cancer (HCT116) cells. Hence, it was concluded that the, hesperidin loaded nanocomposites persuasively inhibited proliferation of colon carcinoma cell and induced apoptosis in in vitro condition.

LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop contributes to the proliferation of gastric cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly investigated in numerous carcinomas containing gastric cancer (GC). The aim of our research is to inquire about the expression profile and role of LBX2-AS1 in GC. METHODS: The expressions of LBX2-AS1, miR-219a-2-3p, FUS and LBX2 were measured by qRT-PCR. Western blot evaluated FUS and LBX2 protein levels. Cell proliferation and apoptosis were, respectively, evaluated by CCK-8, colony formation, EdU, flow cytometry and TUNEL assays. FISH and subcellular fractionation assays examined the position of LBX2-AS1. The binding between genes were certified by RIP, RNA pull-down, ChIP and luciferase reporter assays. Pearson correlation analysis analyzed the association of genes. Kaplan-Meier method detected the relationship of LBX2-AS1 expression with overall survival. RESULTS: The up-regulation of LBX2-AS1 in GC tissues and cells was verified. Function assays proved that LBX2-AS1 down-regulation restricted the proliferation ability. Then, we unveiled the LBX2-AS1/miR-219a-2-3p/FUS axis. Additionally, LBX2-AS1 positively regulated LBX2 mRNA stability via FUS. LBX2 transcriptionally modulated LBX2-AS1. In the end, rescue and in vivo experiments validated the whole regulatory mechanism. CONCLUSION: LBX2-AS1/miR-219a-2-3p/FUS/LBX2 positive feedback loop mainly affected the proliferation and apoptosis abilities of GC cells, offering novel therapeutic targets for the treatment of patients with GC.

Long noncoding RNA TUG1 is a diagnostic factor in lung adenocarcinoma and suppresses apoptosis via epigenetic silencing of BAX.

Lung cancer is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel diagnostic markers and therapeutic targets. Increasing evidences have indicated that long non-coding RNAs (lncRNAs) play an important role in initiation and progression of lung cancer. However, the role of lncRNA Taurine upregulated 1 (TUG1) in lung adenocarcinoma (LAD) progression is not well known. In this study, we determined the diagnostic value of TUG1 in LAD patients, and further uncovered the underlying functional mechanism. Our results showed that TUG1 was significantly upregulated in LAD cells and serum samples. Receiver operator characteristic (ROC) analysis suggested a relatively higher area under the curve (AUC) of TUG1 (0.756) contrast to cyfra21-1 (0.619). In addition, high TUG1 level was associated with enhanced tumor size, degree of differentiation, lymph node metastases, distant metastasis and TNM stage. Cell functional assays showed that knockdown of TUG1 suppressed LAD cell viability and promoted cell apoptosis. We then sought to reveal the underlying regulatory mechanism, and the pro-apoptotic protein BAX was then identified as the downstream target of TUG1. Gain and loss functional assays showed that inhibition of BAX reversed the induced apoptosis by TUG1 knockdown. Finally, RNA immunoprecipitation and Chromatin immunoprecipitation revealed that TUG1 suppressed BAX expression through physically interacting with EZH2. In conclusion, lncRNA TUG1 is a promising diagnostic marker for LAD patients and suppression of TUG1 levels could be a future direction to promote the prognosis of LAD patients.

MicroRNA-126 regulates migration and invasion of gastric cancer by targeting CADM1.

OBJECTIVE: The aberrant expression of microRNAs has been demonstrated to play a crucial role in the initiation and progression of gastric cancer (GC). We here aimed to investigate the mechanism of microRNAs in the regulation of GC pathogenesis. METHODS: Transwell chambers (8-µM pore size; Costar) were used in the in vitro migration and in vision assay. Dual luciferase reporter gene construct and dual luciferase reporter assay to identify the target of miR-126. CADM1 expression was evaluated by immunohistochemical staining. The clinical manifestations, treatments and survival were collected for statistical analysis. RESULTS: Inhibition of miR-126 effectively reduced migration and invasion of gastric cancer cell lines. Bioinformatics and luciferase reporter assay revealed that miR-126 specifically targeted the 3'UTR of cell adhesion molecule 1 (CADM1) and regulated its expression. Down-regulation of CADM1 enhanced migration and invasion of GC cell lines. Furthermore, in tumor tissues obtained from gastric cancer patients, the expression of miR-126 was negatively correlated with CADM1 and the high expression of miR-126 combined with low expression of CADM1 might serve as a risk factor for stage1 gastric cancer patients. CONCLUSIONS: Our study showed that miR-126, by down-regulation CADM1, enhances migration and invasion in GC cells.

Hypoxia/lncRNA-AK123072/EGFR pathway induced metastasis and invasion in gastric cancer.

OBJECTIVE: To investigate the role of long noncoding RNAs (lncRNAs) in hypoxia-induced gastric cancer (GC) metastasis and invasion. METHODS: We investigated the differentially expressed lncRNAs resulting from hypoxia-induced GC and normoxia conditions using microarrays and validated our results through real-time quantitative polymerase chain reaction. The role of the targeting lncRNA was further detected by in vivo and in vitro assays. RESULTS: We found an lncRNA, AK123072, which was up-regulated by hypoxia. AK123072 was frequently up-regulated in GC samples and promoted GC migration and invasion in vivo and in vitro. Furthermore, AK123072 could mediate the metastasis of hypoxia-induced GC cells. Next, we identified EGFR, which was a metastasis-related gene regulated by AK123072. In addition, we found that the expression of EGFR was positively correlated with that of AK123072 in the clinical GC samples used in our study. Furthermore, we found that the EGFR gene CpG island methylation was significantly increased in GC cells depleted of AK123072. Intriguingly, EGFR expression was also increased by hypoxia, and EGFR up-regulation by AK123072 mediated hypoxia-induced GC cell metastasis. CONCLUSION: Our results identified hypoxia/lncRNA-AK123072/EGFR pathway in gastric cancer pathogenesis and this might help in the development of new therapeutics in clinics.

Vascular endothelial growth factor +936C/T polymorphism and gastric cancer risk: A meta-analysis.

The aim of this study was to determine whether the vascular endothelial growth factor (VEGF) +936C/T polymorphism confers susceptibility to gastric cancer (GC) by conducting a meta-analysis. Publications addressing the association between the VEGF +936C/T polymorphism and GC risk were selected from the Pubmed, Embase and CBM databases. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed using RevMan 5.0.25 and STATA 9.2 software. From these data, the odds ratio (OR) with 95% confidence interval (CI) was calculated. Finally, 8 case-control studies were retrieved reporting a total of 2,131 gastrointestinal cancer patients and 2,670 controls. Meta-analysis results showed that there was no significant association between the VEGF +936C/T polymorphism and GC risk in all comparisons of the T allele vs. C allele (OR=1.08, 95% CI 0.90-1.30, P=0.42), CT+TT vs. CC (OR=1.08, 95% CI 0.87-1.34, P=0.49), TT vs. CC+CT (OR=1.14, 95% CI 0.85-1.53, P=0.37), TT vs. CC (OR=1.18, 95% CI 0.87-1.59, P=0.28) and TT vs. CT (OR=1.11, 95% CI 0.79-1.56, P=0.56). This meta-analysis confirms that there is a lack of association between the VEGF +936C/T polymorphism and GC risk.