Construction of a Prognostic Model Based on Methylation-Related Genes in Patients with Colon Adenocarcinoma.

Purpose: Colon adenocarcinoma (COAD) is the second leading cause of death in the world, and the new incidence rate ranks third among all cancers. Abnormal DNA methylation is related to the occurrence and development of tumors. In this study, we aimed to identify genes associated with abnormal methylation in COAD. Methods: COAD transcriptome data, methylation data and clinical information were downloaded from the TCGA database and GEO database. The differentially expressed genes (DEGs) and methylated genes (DMGs) were analyzed and identified in COAD. PCA analysis was applied to divide COAD into subtypes, and the survival and immune cell infiltration of each subtype were evaluated. Cox and LASSO analyses were performed to construct COAD risk model. GSEA was used to evaluate the enrichment pathways. The Kaplan-Meier was used to analyze the difference in survival. ROC curve was plotted to evaluate the accuracy of the model, and GSE17536 was used to verify the accuracy of the risk model. The risk model is combined with the clinicopathological characteristics of COAD patients to perform multivariate Cox regression analysis to obtain independent risk factors and draw nomograms. Results: In total, 4564 DEGs and 1093 DMGs were screened, among which 298 were found to be overlapping genes. For 220 of these overlapping genes, the methylation was significantly negatively correlated to expression levels. An optimal signature from 4 methylated biomarkers was identified to construct the prognostic model. Conclusion: Our study identified 4 methylated biomarkers in the COAD. Then, we constructed the risk model to provide a theoretical basis and reference value for the research and treatment of COAD.

Ubiquitin-proteasome system reveals clinical subtypes with distinct molecular characteristics and prognoses in gastric cancer.

Modulators in ubiquitin-proteasome system (UPS) has been implicated in regulating cancer-related genes, immune responses, and oncogenesis. However, the global UPS expression pattern and its role in gastric cancer (GC) pathology remain elusive. Herein, we integrated the modulators in UPS and dissected their associations with tumor microenvironment (TME), therapeutic response and prognosis in GC. Ten eligible GC cohorts (n = 2161) were collected in this comprehensive analysis. Unsupervised clustering based on expression profile of ubiquitination regulators was performed to identify distinct expression pattern. Then, pathway activation, and TME characteristics and prognosis were explored for patients in each pattern. Finally, a UPS scoring system in GC, termed UPSGC, is developed for individualized quantification of UPS expression pattern. Two prognosis-distinctive UPS expression patterns were identified and validated. Multiple interdependent characteristics were found in each pattern. Patients in the pattern with poor prognosis were found with activation of EMT, TNFα/NF-κB and IL6/JAK/STAT3 signaling, and more infiltration of immunosuppressive M2 macrophages and Th2 cells in TME. And another pattern was characterized by upregulation of angiogenesis, Notch and Wnt-ß/catenin signaling, as well as enrichment of microvessels in TME. Based on the UPSGC system, two pattern-related clinical subtypes were identified. Finally, the UPSGC subtypes were validated as robust biomarker to predict patient's therapeutic responses and survival outcomes. In conclusion, this study proposes two previously unexplored UPS expression patterns in GC, in which patients have distinct survival outcomes and molecular characteristics. The findings provide new evidences to support the clinical relevance of ubiquitination with personalized therapy.

Interfering HMGB3 release from cancer-associated fibroblasts by miR-200b represses chemoresistance and epithelial-mesenchymal transition of gastric cancer cells.

Background: Cancer-associated fibroblasts (CAFs) are vital components of gastric cancer (GC) microenvironments, which impact the aggressive characteristics of GC cells. The objective of this study is to evaluate the influence of High Mobility Group Box (HMGB) on CAF-related GC. Methods: The tissues of 10 GC patients who underwent surgery the Sanya Central Hospital of Hainan Province from July 2018 to July 2019 were collected for the clinical study. Moreover, the GC cell lines, including MGC-803, AGS, and SGC-7901, were used in vitro experiment. We investigated the molecular mechanism of the miR-200b/HMGB3 axis in affecting the chemoresistance and epithelial-mesenchymal transition (EMT) of GC cells induced by CAFs. Cell transfection, Cell Counting Kit-8 (CCK-8), Transwell assay, western blot, enzyme-linked immunosorbent assay (ELISA), and other experiments were employed. Results: We found that miR-200b was down-regulated, yet HMGB3 was up-regulated in CAF-related GC. The CAFs markedly promoted cisplatin (CDDP) resistance, proliferation, invasion, migration, and EMT of GC cells. Gain-assay of miR-200b demonstrated that miR-200b inhibited the HMGB3 release from CAFs. In-vivo experiments confirmed that the growth and EMT of GC cells co-cultured with CAF-miR-200b were significantly reduced. Furthermore, CAFs enhanced the activation of ERK, JNK, and the Wnt/ß-catenin pathways, and those pathways, as well as the malignant behaviors of GC cells, were obviously attenuated by miR-200b or HMGB3 silencing. Conclusions: Collectively, HMGB3 derived from CAFs is negatively regulated by miR-200b and promotes the malignant behaviors of GC cells.

PCDH7 knockdown potentiates colon cancer cells to chemotherapy via inducing ferroptosis and changes in autophagy through restraining MEK1/2/ERK/c-Fos axis.

Chemotherapy is a commonly utilized treatment strategy for colon cancer, a prevalent malignancy. The study intends to probe the function and mechanism of protocadherin 7 (PCDH7) in colon cancer. Gain or loss of functional assays of PCDH7 was performed. MTT and colony formation assay monitored cell proliferation. Transwell measured migration and invasion. Real-time quantitative polymerase chain reaction and western blot verified the profiles of PCDH7 and the MEK1/2/ERK/c-FOS pathway. Western blot was implemented to confirm the profiles of PP1α, MLC2, and p-MLC2 for evaluating the impact of PCDH7 on homotypic cells in cell (hocic) structures. Further, an in-vivo nude mouse model was engineered to figure out the function and mechanism of PCDH7 in tumor cell growth. As indicated by the data, PCDH7 knockdown boosted the cells' sensitivity to chemotherapy. PCDH7 overexpression facilitated their proliferation and invasion, altered autophagy, induced ferroptosis and hocic, and initiated the profile of the MEK1/2/ERK/c-FOS pathway. MEK1/2/ERK inhibition impaired the inhibitory impact of PCDH7 on colon cancer cells' chemotherapy sensitivity and dampened its pro-cancer function in the cells. In-vivo experiments displayed that PCDH7 overexpression stepped up tumor growth and pulmonary metastasis in colon cancer cells. All in all, the research has discovered that PCDH7 knockdown affects autophagy and induces ferroptosis, hence strengthening colon cancer cells' sensitivity to chemotherapy by repressing the MEK1/2/ERK/c-FOS axis.

circIFT80 Functions as a ceRNA for miR-142, miR-568, and miR-634 and Promotes the Progression of Colorectal Cancer by Targeting ß-Catenin.

Colorectal cancer (CRC) is the third most common form of malignant tumor and is characterized by high rates of proliferation and metastases. Circular RNAs (circRNAs) are a form of noncoding and closed loop RNA molecules and play vital roles in the progression of various types of cancer in humans. Here, we used circRNA microarray sequencing technology to analyze the different circRNAs between CRC tissues and normal tissues and explore the role of circIFT80 in progression of colorectal cancer. In this present study, we found that circIFT80 was abnormally overexpression in colorectal cancer tissues and tumor cells. While knockout circIFT80 in HT29 cell or SW480 cells, the proliferation, and migration of the cells were inhibited, the cell cycle was arrested in G2/M phase, and the cell apoptosis was increased. And then, we found circIFT80-positive correlation with CTNNB1 (ß-catenin) by sponging miR-142, miR-568, and miR-634 upregulated the gene expression. These miRNAs which targeted ß-catenin mRNA were confirmed by dual-luciferase reporter system and RNA-pulldown. In addition, xenograft tumor experiments showed that circIFT80 accelerated the tumorigenesis of CRC in vivo. In conclusion, our work reveals the impacts of circIFT80 as ceRNA in the progression of CRC, by which sponging miR-142, miR-568, and miR-634 enhanced the expression levels of ß-catenin and activation Wnt/ß-catenin pathway. Collectively, our data indicate that circIFT80 serves as an oncogene in CRC and represents a novel candidate for diagnosis and treatment.

Molecular dynamic and pharmacological studies on protein-engineered hirudin variants of Hirudinaria manillensis and Hirudo medicinalis.

BACKGROUND AND PURPOSE: Hirudin variants are the most powerful thrombin inhibitors discovered to date, with a lower risk of bleeding than heparin. For anticoagulation, the C-termini of hirudin variants bind to the exocite I of thrombin. Anticoagulant effects of gene-recombinant hirudin are weaker than natural hirudin for the reason of lacking tyrosine O-sulfation at C-terminus. EXPERIMENTAL APPROACH: An integrative pharmacological study was carried out using molecular dynamic, molecular biological and in vivo and in vitro experiments to elucidate the anticoagulant effects of protein-engineered hirudins. KEY RESULTS: Molecular dynamic analysis showed that modifications of the C-termini of hirudin variant 1 of Hirudo medicinalis (HV1) and hirudin variant 2 of Hirudinaria manillensis (HM2) changed the binding energy of the C-termini to human thrombin. The study indicated that Asp61 of HM2 that corresponds to sulfated Tyr63 of HV1 is critical for inhibiting thrombin activities. Further, the anticoagulant effects of HV1 and HM2 were improved when the amino acid residues adjacent to Asp61 were mutated to Asp. These improvements were prolongation of the activated partial thromboplastin time, prothrombin time and thrombin time of human blood, and decreased Ki and IC50 values. In the in vivo experiments, mutations at C-termini of HV1 and HM2 significantly changed partial thromboplastin time, prothrombin and thrombin time CONCLUSION AND IMPLICATIONS: The study indicated that the anticoagulant effects of gene-engineered HM2 are stronger than gene-engineered HV1 and HM2-E60D-I62D has the strongest effects and could be an antithrombotic with better therapeutic effects.

Current Studies on Molecular Mechanisms of Insulin Resistance.

Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor of insulin resistance may be impaired cell signal transduction mediated by the insulin receptor (IR). Several cell-signaling proteins, including IR, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI3K), have been recognized as being important in the impaired insulin signaling pathway since they are associated with a large number of proteins that are strictly regulated and interact with other signaling pathways. Many studies have found a correlation between IR alternative splicing, IRS gene polymorphism, the complicated regulatory function of IRS serine/threonine phosphorylation, and the negative regulatory role of p85 in insulin resistance and diabetes mellitus. This review brings up-to-date knowledge of the roles of signaling proteins in insulin resistance in order to aid in the discovery of prospective targets for insulin resistance treatment.

Ubiquitin-conjugating enzyme E2T(UBE2T) promotes colorectal cancer progression by facilitating ubiquitination and degradation of p53.

OBJECTIVES: The expression level of Ubiquitin-conjugating enzyme E2T (UBE2T) is upregulated in various types of human tumors. We explored the correlation and regulatory mechanism of UBE2T in the development of colorectal cancer (CRC). METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to examine the expression of UBE2T in the CRC tissues and cell lines. Immunohistochemical staining, spearman correlation analysis, and Kaplan Meier-survival analysis were used to demonstrate the correlation between UBE2T high expression level and the clinical characteristics of malignant patients and the overall survival. The proliferation, apoptosis, migration and invasion of CRC cells were analyzed by cell transfection, MTT, colony formation, scratch assay, transwell, and flow cytometry. Furthermore, the expression of cell proliferation and apoptosis related proteins and ubiquitination of p53 were detected by western blot. RESULTS: UBE2T was up-regulated in CRC tissues and cell lines, and high expression level of UBE2T was correlated with the clinical characteristics of malignant of CRC patients (P<0.05), and patients with high expression level of UBE2T had lower overall survival (P=0.0455). In addition, UBE2T could promote the growth, proliferation, invasion and metastasis of CRC cells and inhibit the apoptosis. At the same time, knockdown of UBE2T inhibited the growth of transplanted tumor in mice of subcutaneous CRC model. Moreover, our experimental results proved that UBE2T regulated the expression of downstream related proteins through ubiquitination of p53 protein to promote the occurrence and development of CRC. CONCLUSION: Our study elucidated that high expression of UBE2T would enhance the development of CRC, and then further explored its molecular mechanism both in vitro and in vivo. The results indicated that UBE2T facilitated ubiquitination and degradation of p53, which predicts the possibility of UBE2T as one of molecular diagnosis markers, prognostic indicators and therapeutic drug targets of CRC patients.

Hsa_circRNA_002144 promotes growth and metastasis of colorectal cancer through regulating miR-615-5p/LARP1/mTOR pathway.

CircRNAs (circular RNAs), recently identified as a critical regulator in tumorigenesis, participate in CRC (colorectal cancer) growth. However, the role of hsa_circRNA_002144 in CRC was poorly understood. Firstly, hsa_circRNA_002144 showed significantly elevation in both of CRC tissues and cell lines, and suggested closely associated with poor prognosis in patients. Secondly, data from functional assays revealed that silence of hsa_circRNA_002144 inhibited CRC progression with reduced cell viability, proliferation, migration and invasion, while enhanced cell apoptosis. In addition, in vivo CRC growth and metastasis were also suppressed by knockdown of hsa_circRNA_002144. However, CRC progression was promoted with over-expression of hsa_circRNA_002144. Thirdly, hsa_circRNA_002144 colocalized with miR-615-5p in the cytoplasm of CRC cells, and decreased miR-615-5p expression. Moreover, miR-615-5p could target LARP1 (La ribonucleoprotein 1, translational regulator). Lastly, the suppressive effects of hsa_circRNA_002144 knockdown on CRC progression were reversed by LARP1 over-expression. In conclusion, hsa_circRNA_002144 could sponge miR-615-5p to promote CRC progression through the regulation of LARP1, providing a therapeutic target for cancer intervention.

Development and validation of a hypoxia-immune-based microenvironment gene signature for risk stratification in gastric cancer.

BACKGROUND: Increasing evidences have found that the clinical importance of the interaction between hypoxia and immune status in gastric cancer microenvironment. However, reliable prognostic signatures based on combination of hypoxia and immune status have not been well-established. This study aimed to develop a hypoxia-immune-based gene signature for risk stratification in gastric cancer. METHODS: Hypoxia and immune status was estimated with transcriptomic profiles for a discovery cohort from GEO database using the t-SNE and ESTIMATE algorithms, respectively. The Cox regression model with the LASSO method was applied to identify prognostic genes and to develop a hypoxia-immune-based gene signature. The TCGA cohort and two independent cohorts from GEO database were used for external validation. RESULTS: Low hypoxia status (p < 0.001) and high immune status (p = 0.005) were identified as favorable factors for patients' overall survival. By using the LASSO model, four genes, including CXCR6, PPP1R14A and TAGLN, were identified to construct a gene signature for risk stratification. In the discovery cohort (n = 357), patients with low risk yielded better outcomes than those with high risk regarding overall survival across and within TNM stage subgroups. Multivariate analysis identified the hypoxia-immune-based gene signature as an independent prognostic factor (p < 0.001). A nomogram integrating the gene signature and known risk factors yielded better performance and net benefits in calibration and decision curve analyses. Similar results were validated in the TCGA (n = 321) and two independent GEO (n = 300 and n = 136, respectively) cohorts. CONCLUSIONS: The hypoxia-immune-based gene signature represents a promising tool for risk stratification tool in gastric cancer. It might serve as a prognostic classifier for clinical decision-making regarding individualized prognostication and treatment, and follow-up scheduling.

Recurrence-Associated Long Non-coding RNA LNAPPCC Facilitates Colon Cancer Progression via Forming a Positive Feedback Loop with PCDH7.

Long non-coding RNAs (lncRNAs) gradually show critical regulatory roles in many malignancies. However, the lncRNAs implicated in colon cancer recurrence are largely unknown. In this study, we searched the lncRNAs associated with metastasis and recurrence of colon cancer using GEO datasets. We focused on a novel lncRNA long non-coding RNA associated with poor prognosis of colon cancer (LNAPPCC), which is highly expressed in colon cancer. Increased expression of LNAPPCC is positively associated with metastasis, recurrence, and poor survival of colon cancer patients. LNAPPCC promotes colon cancer cell proliferation, migration, and in vivo xenograft growth and liver metastasis. Mechanistic investigations revealed that LNAPPCC binds EZH2, represses the binding of EZH2 to PCDH7 promoter, downregulates histone H3K27me3 level in PCDH7 promoter, and activates PCDH7 expression. Intriguingly, we also found that PCDH7 activates ERK/c-FOS signaling, increases the binding of c-FOS to LNAPPCC promoter, and activates LNAPPCC expression. Therefore, LNAPPCC and PCDH7 form a positive regulatory loop via EZH2 and ERK/c-FOS. The positive correlations between the expression of LNAPPCC, PCDH7, phosphorylated ERK, and phosphorylated c-FOS are detected in colon cancer tissues. Furthermore, depletion of PCDH7 or the adding of ERK inhibitor abolished the oncogenic roles of LNAPPCC in colon cancer. In summary, this study identified a novel lncRNA LNAPPCC that is highly expressed in colon cancer and associated with poor prognosis of colon cancer patients. LNAPPCC exerts oncogenic roles in colon cancer via forming a positive feedback loop with PCDH7. Targeting LNAPPCC/EZH2/PCDH7/ERK/c-FOS signaling axis represents a potential therapeutic strategy for colon cancer.

Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death in the world. Despite cisplatin is a commonly used chemotherapeutic drug for the colorectal cancer treatment, resistance of cancer cells to cisplatin restricts its clinical efficacy. It is important to explore the potential mechanisms and take strategies to sensitize colorectal cancer cells to cisplatin treatment. METHODS: Differences of TRIM32 and miR-519d expression between colorectal cancer cells and human normal colon epithelial cells were evaluated by qRT-PCR and Western blot assays. Cytotoxicity of cisplatin against colorectal cancer cells was tested by CCK-8 assay. Generation of reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis was measured by flow cytometry. Dual-luciferase reporter assay was used to validate the association between miR-519d and TRIM32. RESULTS: Significant increase of TRIM32 expression in colorectal cancer tissues and cell lines was observed. TRIM32 negatively regulated the cisplatin sensitivity in colorectal cancer cells. Mechanically, overexpression of TRIM32 was induced by decrease of miR-519d. Exogenous miR-519d can inhibit the expression of TRIM32 and thus promoted the cisplatin-induced apoptosis through the mitochondrial pathway. CONCLUSION: Overexpression of TRIM32 was induced by the absence of miR-519d in colorectal cancer. MiR-519d can be used as a sensitizer during the cisplatin-based chemotherapy of colorectal cancer.

Using nomograms to predict prognostic factors in young colorectal mucinous and signet-ring cell adenocarcinoma patients.

Due to insufficient quantitative evaluation of the clinic-pathological features and prognosis of young colorectal cancer (CRC) with mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRC), the aim of our study was to develop a nomogram to identify the prognostic predictors for overall survival (OS) in this patient population. We retrospectively evaluated the patient records of MAC and SRC patients aged ≤ 40 years. Kaplan-Meier analysis and log-rank testing were performed to estimate OS. A nomogram predicting OS was created for risk quantitation and decision tree analysis was performed for patient grouping. With a median follow-up of 36.5 months, we included a total of 90 young CRC patients for analysis. The overall cumulate 5-year OS rate was 57.7% (95% confidence interval (CI): 45.1-68.5%). The estimated 5-year OS was 62.9% (95% CI: 48.5-74.3%) for MAC and 37.3% (95% CI: 14.4-61.2%) for SRC (P=0.021). The recurrence rate was significantly greater in the SRC group compared with the mucinous group (52.4 compared with 26.1%, P=0.047). In the multivariate Cox regression model, preoperative carcinoembryonic antigen (CEA) levels and cycles of adjuvant chemotherapy (CT) were found to be an independent prognostic factor for OS (hazard ratio (HR): 2.43; 95% CI: 1.13-5.62, P=0.024; HR: 0.21; 95% CI: 0.083-0.57, P=0.002, respectively). Nomograms predicting 3- and 5-year OS were established that performed well (concordance index (c-indexes) of 0.636, 95% CI: 0.549-723) for OS. For MAC and SRC disease, a greater proportion of young patients present with advanced disease, and the prognosis for young SRC patients is poorer than MAC. Furthermore, preoperative CEA levels and cycles of adjuvant CT seem to independently affect the OS in this patient population.

Effect and Mechanism of Sophoridine to suppress Hepatocellular carcinoma in vitro and vivo.

AIM: The aim of this study is to explain effect and mechanism of Sophoridine to suppress Hepatocellular carcinoma in vitro and vivo. METHODS: In vitro experiment, the HepG2 cells were divided into 5 groups: 0µg/mL Sophoridine treated group (0 µg/mL group); 10µg/mL matrine treated group (10µg/mL group); 20µg/mL matrine treated group (20µg/mL group) and 10µg/mL Paclitaxel treated group (Positive drug group). Measuring the cell proliferation of difference groups by MTS assay; evaluating cell apoptosis of difference by flow cytometry; the cell invasion and migration abilities of difference HepG2 cells were measured by transwell and wound healing testing; measuring the relative proteins expression in difference groups. In vovo experiment, the nude mice were divided into 5 groups: 0µg/mL, 5µg/mL, 10µg/mL, 20µg/mL and Positive drug groups, after executing, taking the tumor tissue from nude mice of difference groups, measuring the tumor volume and weight; evaluating the PTEN protein expression in tumor tissue by Immunohistochemistry (IHC). RESULTS: In the cell experiments, Compared with 0µg/mL group, cell proliferation rates were significantly reduced, cell aopotosis were significantly increased and invasion and wound healing abilities were significantly decreased in marine treated groups with dose-dependent (P<0.05, respectively). In the nude mice experiment, the tumor volume and weight of matrine treated groups were significantly decreased compared with 0 µg/mL group with dose-dependent (P<0.05, respectively). And the PTEN protein expression of Sophoridine treated groups were significantly decreased compared with 0µg/mL group with dose-dependent (P<0.05, respectively). CONCLUSION: Sophoridine had anti-cance effects to suppress HepG2 activities by regulation PTEN/PI3K/AKT, Caspase-3/-9 and MMP-2/-9 signaling pathway.

A propensity score-matching analysis comparing the oncological outcomes of laparoscopic and open gastrectomy in patients with gastric carcinoma.

PURPOSE: To compare the oncological outcomes of patients with laparoscopy-assisted gastrectomy with those with open resection to remove nonmetastatic gastric cancer. METHODS: A total of 532 patients were initially enrolled. Propensity score matching was applied to assemble a study cohort. The primary objective was overall survival (OS). Cancer-specific survival (CSS) and disease-free survival (DFS) were secondary objectives. RESULTS: A total of 388 patients were matched for analysis. The morbidity, number of lymph nodes harvested and surgical margins were similar between the two groups. OS following laparoscopic gastrectomy was similar to open resection. Neither CSS nor DFS following laparoscopic gastrectomy was inferior compared with open resection Conclusion: Laparoscopic gastrectomy for gastric cancer is feasible and safe with acceptable oncological outcomes. Further prospective multicenter trials are warranted before incorporating laparoscopic gastrectomy into routine surgical practice.

Chinese herb derived-Rocaglamide A is a potent inhibitor of pancreatic cancer cells.

Pancreatic cancer ranks No.1 in mortality rate worldwide. This study aims to identify the novel anti-pancreatic cancer drugs. Human pancreatic carcinoma cell lines were purchased from ATCC. CPE-based screening assay was used to examine the cell viability. Patient derived tumor xenografts in SCID mice was established. The Caspase-3 and 7 activities were measured using the Caspase Glo 3/7 Assay kit. Soft agar colony formation assay was used to evaluate the colony formation. Wound healing assay was employed to determine the cell migration. We screened a Chinese herbal product library and found three "hits" that kill cancer cells at nanomolar to micromolar concentrations. One of these compounds, rocaglamide, was found to be potent inhibitors of a wide spectrum of pancreatic cancer cell lines. Furthermore, Rocaglamide reduced the tumor size in a patient-derived pancreatic cancer xenograft mouse model without noticeable toxicity in vivo. Rocaglamide also inhibits pancreatic cancer cell migration and invasion. In conclusion, these data support that Rocaglamide may be a promising anti-pancreatic cancer drug.

Bioinspired Mechanical Gradients in Cellulose Nanofibril/Polymer Nanopapers.

Mechanical gradients are important as tough joints, for strain field engineering in printable electronics, for actuators, and for biological studies, yet they are difficult to prepare and quantitatively characterize. We demonstrate the additive fabrication of gradient bioinspired nanocomposites based on stiff, renewable cellulose nanofibrils that are bottom-up toughened via a tailor-made copolymer. Direct filament writing of different nanocomposite hydrogels in patterns, and subsequent healing of the filaments into continuous films while drying leads to a variety of linear, parabolic and striped bulk gradients. In situ digital image correlation under tensile deformation reveals important differences in the strain fields regarding asymmetry and step heights of the patterns. We envisage that merging top-down and bottom-up structuring of nanocellulose hybrids opens avenues for aperiodic and multiscale, bioinspired nanocomposites with optimized combinations of stiffness and toughness.

Supramolecular Engineering of Hierarchically Self-Assembled, Bioinspired, Cholesteric Nanocomposites Formed by Cellulose Nanocrystals and Polymers.

Natural composites are hierarchically structured by combination of ordered colloidal and molecular length scales. They inspire future, biomimetic, and lightweight nanocomposites, in which extraordinary mechanical properties are in reach by understanding and mastering hierarchical structure formation as tools to engineer multiscale deformation mechanisms. Here we describe a hierarchically self-assembled, cholesteric nanocomposite with well-defined colloid-based helical structure and supramolecular hydrogen bonds engineered on the molecular level in the polymer matrix. We use reversible addition-fragmentation transfer polymerization to synthesize well-defined hydrophilic, nonionic polymers with a varying functionalization density of 4-fold hydrogen-bonding ureidopyrimidinone (UPy) motifs. We show that these copolymers can be coassembled with cellulose nanocrystals (CNC), a sustainable, stiff, rod-like reinforcement, to give ordered cholesteric phases with characteristic photonic stop bands. The dimensions of the helical pitch are controlled by the ratio of polymer/CNC, confirming a smooth integration into the colloidal structure. With respect to the effect of the supramolecular motifs, we demonstrate that those regulate the swelling when exposing the biomimetic hybrids to water, and they allow engineering the photonic response. Moreover, the amount of hydrogen bonds and the polymer fraction are decisive in defining the mechanical properties. An Ashby plot comparing previous ordered CNC-based nanocomposites with our new hierarchical ones reveals that molecular engineering allows us to span an unprecedented mechanical property range from highest inelastic deformation (strain up to ∼13%) to highest stiffness (E ∼ 15 GPa) and combinations of both. We envisage that further rational design of the molecular interactions will provide efficient tools for enhancing the multifunctional property profiles of such bioinspired nanocomposites.

Increased expression of SOX4 is associated with colorectal cancer progression.

Sex-determining region Y-related high-mobility group box 4 (SOX4) has been proven to serve as a critical role in cancer progression. However, the pathological role of SOX4 in colorectal cancer (CRC) remains unknown. The aim of this study was to investigate the role of SOX4 in CRC. In this study, we investigated the expression of SOX4 in CRC tissues by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot. We also evaluated the effect of SOX4 on cell proliferation and invasion by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and transwell assay. The SOX4 messenger RNA (mRNA) and protein expression were markedly higher in CRC tissues compared with adjacent normal mucosa tissues. Inhibition of SOX4 could suppress CRC cell proliferation, and invasion in vitro. Our findings indicate that targeting SOX4 might provide a new therapeutic modality for the treatment of CRC patients.