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Blumea balsamifera (L.) DC., a perennial herb in the Asteraceae family native to China and Southeast Asia, has a notable history of medicinal use due to its pharmacological properties. Using UPLC–Q–Orbitrap HRMS techniques, we systematically investigated the chemical constituents of this plant. A total of 31 constituents were identified, of which 14 were flavonoid compounds. Significantly, 18 of these compounds were identified in B. balsamifera for the first time. Furthermore, the mass spectrometry fragmentation patterns of significant chemical constituents identified in B. balsamifera were analyzed, providing important insights into their structural characteristics. The in vitro antioxidative potential of the methanol extract of B. balsamifera was assessed using DPPH and ABTS free-radical-scavenging assays, total antioxidative capacity, and reducing power. The antioxidative activity exhibited a direct correlation with the mass concentration of the extract, with IC50 values of 105.1 ± 0.503 μg/mL and 12.49 ± 0.341 μg/mL for DPPH and ABTS, respectively. For total antioxidant capacity, the absorbance was 0.454 ± 0.009 at 400 μg/mL. In addition, the reducing power was 1.099 ± 0.03 at 2000 μg/mL. This study affirms that UPLC–Q–Orbitrap HRMS can effectively discern the chemical constituents in B. balsamifera, primarily its flavonoid compounds, and substantiates its antioxidative properties. This underscores its potential utility as a natural antioxidant in the food, pharmaceutical, and cosmetics sectors. This research provides a valuable theoretical basis and reference value for the comprehensive development and utilization of B. balsamifera and expands our understanding of this medicinally valuable plant.

Purpose: Notch1 has been proven to be aberrantly expressed in colorectal cancer and related to tumor differentiation status. However, few previous studies concentrated on the predictive role of Notch1 expression on the overall survival of patients with colorectal cancer. This study explored expression of Notch1 and its relationship with p65 and prognosis in colorectal cancer.Experimental Design: Two independent study cohorts were involved in the present study. Clinical specimens from 941 eligible patients were constructed into tissue microarrays. The expression of Notch1 and p65 protein was investigated by immunohistochemistry.Results: Statistically significant positive correlations were found between protein expression of Notch1 and p65 in both retrospective and prospective study cohorts. Patients with higher Notch1 expression showed a trend of having shorter survival time, whereas patients with lower Notch1 expression had better survival in both study cohorts. In multivariate analysis, Notch1 expression was proven to be an independent predictor of prognosis. Moreover, the prognostic value of Notch1 might differ according to p65 status.Conclusions: Notch1 is an independent predictor of prognosis for patients with colorectal cancer. In addition, the predictive role of Notch1 on clinical outcome might be modified by p65 status, suggesting that targeting Notch1 and nuclear factor κB (NF-κB) might be a promising strategy for colorectal cancer treatment. Clin Cancer Res; 17(17); 5686–94. ©2011 AACR.

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Noncovalent cross-linked hydrogels with promising mechanical properties are on demand for applications in tissue engineering, flexible electronics, and actuators. However, integrating excellent mechanical properties with facile preparation for the design of hydrogen bond cross-linked hydrogels is still challenging. In this work, an advanced hydrogel was prepared from acrylamide and N-acryloyl phenylalanine by one-pot free-radical copolymerization. Owing to hydrophobicity-assisted multiple hydrogen bonding interactions among phenylalanine derivatives, the hydrogels exhibited fascinating mechanical behaviors: tensile strength of 0.35 MPa, elongation at break of 2100%, tearing energy of 1134 J/m2, and compression strength of 3.56 MPa. The hydrogels also showed robust elasticity and fatigue resistance, and the compression strength did not show any decline, even after 100 successive cycles, as well as promising self-recovery property. In addition, the cytotoxicity test in vitro proved that the hydrogel showed good biocompatibility with normal human liver cells (LO2 cells). The excellent stretchability, robust elasticity, high toughness, fatigue resistance, and biocompatibility of the hydrogel demonstrated its vast potential in the biomedical field and flexible electronic devices.

Chiral framework materials have been developed for many applications including chiral recognition, chiral separation, asymmetric catalysis, and chiroptical materials. Herein, we report that an achiral cucurbit[8]uril-based supramolecular organic framework (SOF-1) with the dynamic rotational conformation of tetraphenylethene units can exhibit adaptive chirality to produce M-SOF-1 or P-SOF-1 with mirror-image circular dichroism (CD) with gabs ≈±10-4 and circularly polarized luminescence (CPL) with glum ≈±10-4 induced by L-/D-phenylalanine in water, respectively. The chirality induction in CD (gabs ≈-10-4 ) and CPL (glum ≈-10-4 ) of P-SOF-1 from achiral SOF-1 can be presented by using a small amount of adenosine-5'-triphosphate disodium (ATP) or adenosine-5'-diphosphate disodium (ADP) (only 0.4 equiv) in water. Furthermore, the adaptive chirality of SOF-1 can be used to determine dipeptide sequences (e.g., Phe-Ala and Ala-Phe) and distinguish polypeptides/proteins (e.g., somatostatin and human insulin) with characteristic CD spectra. Therefore, achiral SOF-1 as an ideal chiroptical platform with adaptive chirality may be applied to determine the enantiopurity of amino acids (e.g., L-/D-phenylalanine), develop aqueous CPL materials, and distinguish biological chiral macromolecules (e.g., peptides/proteins) via chirality induction in water.

Theranostic agents, taking the advantages of both imaging and therapeutic functions, are anticipated to be key components in the development of personalized medicine in which the therapeutic response can be real-time monitored. Herein, three metallacycles with pendent adamantane groups are prepared by coordination-driven self-assembly of PtII ligands with anticancer activities and tetraphenylethylene derivatives with emission. β-Cyclodextrin, which shows good host-guest interactions with adamantane moieties, was added to form amphiphilic supramolecular nanoparticles with the aim to enhance the aqueous solubilities and bioactivities of these metallacycles. Moreover, when rhodamine-modified β-cyclodextrin was used as the carrier, the release of the metallacycles from the nanoparticles could be monitored in situ through the fluorescence changes owing to the efficient fluorescence resonance energy transfer from the metallacycles to rhodamine-modified β-cyclodextrin. In vitro and in vivo studies showed that these nanoparticles not only served as cell imaging contrast agents but also displayed improved anticancer activities, allowing them to serve as potential candidates for cancer theranostics. This study provides a simple and efficient method to prepare theranostic agents by hierarchical supramolecular self-assembly, which will pave the way for image-guided cancer therapy, targeted cancer therapy, and related biomedical fields.

BACKGROUND: The Notch signaling regulates numerous cell growth, differentiation, and death. However, the expression pattern of its ligand Delta-like 4 (DLL4) in tumors is still uncertain. OBJECTIVE: In the present study, we examined DLL4 expression in colorectal cancer as well as assessed its role as a prognostic indicator in the present study. METHODS: DLL4 expression was examined by immunohistochemistry in 289 surgically resected specimens of colorectal cancer and adjacent normal tissues. The relationship between DLL4 expression and clinicopathological characteristics was analyzed. The association of DLL4 expression with the patients’ overall survival rate was assessed by Kaplan-Meier and Cox proportional-hazards regression. RESULTS: Increased DLL4 level was detected in colorectal cancer compared with that of normal tissues. Elevated DLL4 level in colorectal cancer was associated with increased body mass index of patients. Moreover, increased DLL4 level was also found to be correlated with tumor invasion, metastases and unfavorable clinical outcom of patients. CONCLUSIONS: DLL4 level is increased in colorectal cancer, especially in patients with increased body mass index, indicating potential involvement of obesity-related tumorigenesis and development. It might also serve as a novel molecular marker to predicate outcome of patients.

In this work, a near-infrared emissive dipyridyl ligand was synthesized and used to prepare three platinum(II) metallacycles with different shapes via metal-coordination-driven self-assembly with different platinum(II) precursors. These metallacycles were further used for both cell imaging and cancer therapy, offering a new type of theranostic agents towards cancer treatment.

Introduction: Irreversible electroporation (IRE) combined with a catheter-based electrode during endoscopy is a potential alternative treatment method for digestive tract tumors. The aim of this study was to investigate the electrical injury (EI) and thermal injury (TI) to the digestive tract via numerical analyses and to evaluate the role and impact of electrode configurations and pulse settings on the efficacy and outcomes of IRE. Materials and methods: A finite element method was used to solve the numerical model. A digestive tract model having 4-mm-thick walls and two catheter-based electrode configuration models were constructed. The distributions of electric fields, temperature, electrical conductivity, tissue injury and limitation on the pulse number required for IRE were calculated and compared. Results: Electrode length is an important geometric parameter for electrodes in the monopolar model (MPM), while electrode spacing affects the outcomes in the bipolar model (BPM). Increasing the pulse voltage reduces the pulse number required for tissue ablation, while increasing the risk of TI. In total, there were 6 NT-IRE protocols, 12 thermal-IRE protocols and 30 TI protocols. All of the NT-IRE protocols were set in BPMs with a voltage of 0.50 kV. With increasing electrode spacing, the minimum pulse number decreased. However, thermal effects were inevitable in the MPM. Conclusions: The electrode configuration and pulse settings are adjusted to achieve NT-IRE synergistically. The BPM is more reliable for achieving NT-IRE in 4-mm-thick digestive wall. Future in vitro and in vivo studies are needed to support and validate this conclusion.

Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. Thereby, the aim of the present study was to investigate the detailed effects of gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) in colorectal cancer (CRC) cell lines under hypoxia conditions and explore the potential molecular mechanisms. Here, we observed that GRIM-19 expression was downregulated in several CRC cell lines as well as in HCT116 and Caco-2 cells under a hypoxic microenvironment. Additionally, the introduction of GRIM-19 obviously suppressed cell invasive ability and epithelial-mesenchymal transition (EMT) through modulating EMT markers as reflected by the upregulation of E-cadherin along with the downregulation of vimentin and N-cadherin under hypoxic conditions. Moreover, the addition of GRIM-19 repressed hypoxia-induced autophagy through modulating autophagy associated proteins as reflected by the downregulation of LC3-II/LC3-I ratio and Beclin-1 expression, as well as the increased of p62 expression. Interestingly, overexpression of GRIM-19 markedly ameliorated the accumulation of HIF-1α triggered by hypoxia accompanied by an inhibition of vascular endothelial growth factor (VEGF) production and phospho-signal transducer and activator of transcription 3 (p-STAT3) expression. Further data demonstrated that GRIM-19 have a negative feedback effect on the expression of HIF-1α. Mechanistically, re-expression of HIF-1α completely reversed the inhibitory effects of GRIM-19 on hypoxia-induced invasion and EMT. Taken all data together, our findings established that GRIM-19 suppresses hypoxia-triggered invasion and EMT by inhibiting hypoxia-induced autophagy through inactivation HIF-1α/STAT3 signaling pathway, indicating that GRIM-19 may serve as a potential predictive factor and therapeutic target for CRC treatment.

Highlights A series of novel injectable pH-responsive self-healing hydrogels with enhanced adhesive strength were prepared.The hydrogels showed good gastric hemostasis property in a swine gastric hemorrhage model.The hydrogels greatly enhanced gastric wound healing in a swine gastric wound model. Supplementary Information The online version of this article (10.1007/s40820-020-00585-0) contains supplementary material, which is available to authorized users., Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are well-established therapeutics for gastrointestinal neoplasias, but complications after EMR/ESD, including bleeding and perforation, result in additional treatment morbidity and even threaten the lives of patients. Thus, designing biomaterials to treat gastric bleeding and wound healing after endoscopic treatment is highly desired and remains a challenge. Herein, a series of injectable pH-responsive self-healing adhesive hydrogels based on acryloyl-6-aminocaproic acid (AA) and AA-g-N-hydroxysuccinimide (AA-NHS) were developed, and their great potential as endoscopic sprayable bioadhesive materials to efficiently stop hemorrhage and promote the wound healing process was further demonstrated in a swine gastric hemorrhage/wound model. The hydrogels showed a suitable gelation time, an autonomous and efficient self-healing capacity, hemostatic properties, and good biocompatibility. With the introduction of AA-NHS as a micro-cross-linker, the hydrogels exhibited enhanced adhesive strength. A swine gastric hemorrhage in vivo model demonstrated that the hydrogels showed good hemostatic performance by stopping acute arterial bleeding and preventing delayed bleeding. A gastric wound model indicated that the hydrogels showed excellent treatment effects with significantly enhanced wound healing with type I collagen deposition, α-SMA expression, and blood vessel formation. These injectable self-healing adhesive hydrogels exhibited great potential to treat gastric wounds after endoscopic treatment. Supplementary Information The online version of this article (10.1007/s40820-020-00585-0) contains supplementary material, which is available to authorized users.

The aim of this study was to evaluate the feasibility, safety, and efficacy of magnetic anchoring and guidance-assisted endoscopic irreversible electroporation (MAG-IRE) for gastric mucosal ablation. A catheter-based, donut-like, and MAG-assisted electrode was developed. MAG-IRE for gastric mucosal ablation was performed in eight beagle canines. The parameters of one set of IRE was 500 V voltage, 100 μs pulse duration, and 99 pulses. The MAG time, operation time, success rate, and adverse events were measured. Endoscopic examination was performed from 30 min to 28 days post-IRE. Full-thickness gastric tissue was harvested by wedge biopsy for histopathological analysis. 30 (93.75%) of the 32 lesions were successfully ablated by MAG-IRE. The median MAG time was 300 s (IQR 120–422.5 s), and the median operation time was 491.5 s (IQR 358.3–632.5 s). No adverse events occurred. Ulceration was observed, starting from 3 days post-IRE. The mucosa healed 14 to 28 days post-IRE. Hematoxylin–Eosin (H&E) staining showed inflammatory infiltration, edema, and congestion in the ablated mucosa. Masson’s Trichrome staining showed that the gastric wall and blood vessels in the ablation area were intact. TUNEL assay showed diffuse positive cells in ablated mucosa as early as 30 min post-IRE. MAG-IRE for gastric mucosal ablation is feasible, safe, and effective. It can be a potential therapeutic option for minimally invasive treatment of gastric neoplasm.

Irreversible electroporation (IRE) is an emerging tissue ablation technique. Compared with thermal ablation technique such as radiofrequency, IRE can achieve focal ablation in a shorter time without heat sink effect while sparing the tissue scaffold. IRE has been demonstrated to be a feasible therapeutic modality for the liver, pancreatic, and prostatic cancer. In recent years, several studies regarding of catheter-directed IRE for digestive tract, bronchus, urinary tract, and myocardium have been performed, which preliminarily demonstrated the safety and efficacy of IRE for tissue ablation under endoscopic or interventional technique. This study summarized the research progress of catheter-directed IRE for tissue ablation. The critical technique and future direction of catheter-based IRE are prosp.

The chemical structures and topologies of the crosslinks in supramolecular networks play a crucial role in their properties and functions. Herein, the preparation of a type of poly(N-isopropylacrylamide) (PNIPAAM)-based supramolecular networks crosslinked by emissive hexagonal metallacycles is presented. The topological connections in these networks greatly affect their properties, as evidenced by their differences in absorption, emission, lower critical solution temperature, and modulus along with the variation of crosslinking densities. The integration of PNIPAAM and metallacycles in the networks benefits them improved bioavailability, making them serve as reagents for bacterial imaging and killing. This study provides a strategy to prepare cavity-crosslinked polymer networks for antibacterial applications.

In contrast to what is known about the complicated roles of Notch signalling in human malignancies, the direct target genes of Notch signalling are still unclear. Recently, long noncoding RNAs (lncRNAs) have been found to play various roles in the post-transcriptional regulation of gene expression. In the present study, we investigated the potential role of the Notch-induced lncRNA LUNAR1 in colorectal cancer (CRC). We recruited 196 cases of clinical CRC specimens and investigated LUNAR1 levels in these specimens. The associations of LUNAR1 with tumour aggressiveness and clinical outcomes were evaluated. Moreover, the impact of LUNAR1 on the malignant behaviour of tumour cells was tested in cell lines. Significantly increased expression of LUNAR1 in clinical CRC specimens was detected compared with that in matching normal tissues. LUNAR1 expression in CRC was found to be associated with the tumour aggressiveness, disease-free survival and overall survival of patients. The downregulation of LUNAR1 in SW620 cells inhibited cell proliferation, migration, invasion and tumour growth while inducing apoptosis. Moreover, the inhibition of LUNAR1 can significantly suppress IGF1 signalling in CRC. These results indicated that LUNAR1 was increased in CRC and might promote tumour progression. Thus, LUNAR1 may constitute a promising prognostic marker for the clinical management of CRC.

A series of pyrene or pyrene‐o‐carborane‐appendant selenoviologens (Py‐SeV2+, Py‐Cb‐SeV2+) for enhanced photocatalytic hydrogen evolution reaction (HER) and reduction of alkynes is reported. The efficient photoinduced electron transfer (PET) from electron‐rich pyrene‐o‐carborane heterojunction (Py‐Cb) with intramolecular charge transfer (ICT) characteristic to electron‐deficient selenoviologen (SeV2+) (kET = 1.2 × 1010 s−1) endows the accelerating the generation of selenoviologen radical cation (SeV+•) compared with Py‐SeV2+ and other derivatives. The electrochromic/electrofluorochromic devices’ (ECD and EFCD) measurements and supramolecular assembly/disassembly processes of SeV2+ and cucurbit[8]uril (CB[8]) results show that the PET process can be finely tuned by electrochemical and host–guest chemistry methods. By combination with Pt‐NPs catalyst, the Py‐Cb‐SeV2+‐based system shows high‐efficiency visible‐light‐driven HER and highly selective phenylacetylene reduction due to the efficient PET process.

Proper manipulation of tumorigenic microenvironments has been considered as one of the most effective approaches for tumor therapy, which is still a challenge to be well performed. Herein, a nano-modulator was fabricated to manipulate the hypoxia, glucose, radicals and local temperature in tumor tissue as needed, which consists of hemoglobin (Hb) and ferric ion (Fe3+) co-conjugated polydopamine (PDA) as core, glucose oxidase (GOD) as shell, and folic acid (FA) modified polyethylene glycol (PEG) as corona. The PEG-FA corona not only protected Hb and GOD against protease in blood circulation, but serve as tumor targeting agent for tumor specific accumulation of the nano-modulator. The Hb is in charge of oxygen supply to reverse the hypoxic environment of tumor tissue, which promotes the function of GOD to achieve rapid glucose consumption and hydrogen peroxide generation. The polydopamine was employed to raise local temperature under NIR irradiation, meanwhile to continuously reduce Fe3+ to produce ferrous ions (Fe2+), which further catalyze hydrogen peroxide to cytotoxic hydroxyl radicals via Fenton reaction. Both in vitro and in vivo results showed excellent tumor inhibition and high survival rate of tumor-bearing mice after treatment by our nano-modulator, indicating this synergistic therapy via on-demand manipulation of various tumorigenic microenvironments could be a green approach for tumor treatment with high efficiency and minimum side effects.

Irreversible electroporation (IRE) is an emerging tissue ablation technique, which is safe for sites where thermal-basis techniques are not suitable. The aim of this study is to evaluate the safety and efficacy of magnetic anchoring electrode (MAE)-assisted IRE for normal gastric tissue ablation in a rabbit model. IRE (500 V, 100 μs, 99 pulses, 1 Hz) of the gastric wall was performed in 24 adult New Zealand rabbits with a novel catheter-mounted MAE with fluoroscopy and a surgical approach. Procedure time, procedure-related bleeding, perforation, and other complications were recorded. Animals were sacrificed at 30 min, 1 day, 3 days, 7 days, 14 days, and 28 days post-IRE. The stomach was removed en bloc, and the diameter of each lesion was measured. Histopathological analyses by Hematoxylin–Eosin (H&E), masson trichrome, alpha-smooth muscle action (α-SMA), and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) were performed. Gastric tissue ablation with MAE-assisted IRE was successfully performed without any interruption. No perforation or bleeding was observed during IRE or throughout the follow-up period. A demarcated hemorrhage was found in the ablated area upon gross examination. H&E staining showed complete cell death with inflammatory infiltration, edema, and hemorrhaging. TUNEL presented diffuse positive cells in the ablated area. The tissue scaffold was well preserved without damage as indicated by Masson trichrome staining. Ulceration was observed starting from 3 days post-IRE. The mucosal layer was gradually recovered and regenerated within 14–28 days. No other complication was observed post-IRE. MAE-assisted IRE is safe and effective for normal gastric tissue ablation and the gastric wall recovered in 14–28 days post-IRE.

Aims. There are two treatment modalities for early gastric cancer (EGC)—surgery and endoscopic submucosal dissection (ESD). We aimed to compare the safety and efficacy of ESD with surgery. Method. The article was performed by searching PubMed databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) calculated and P value. Results. 13 studies were identified. The incidence of perforation in two groups was different [OR = 6.18 (95% CI: 1.37–27.98), P=0.02]. The prevalences of synchronous and metachronous cancer in the ESD group were higher than those in the surgery group [OR = 8.52 (95% CI: 1.99–36.56), P = 0.004 and OR = 7.15 (95% CI: 2.95–17.32), P<0.0001]. The recurrence and complete resection rates were different [OR = 6.93 (95% CI: 2.83–16.96), P<0.0001 and OR = 0.32 (95% CI: 0.20–0.52), P<0.00001]. Compared with the surgery group, the hospital stay was shorter [IV = −7.15 (95% CI: −9.08–5.22), P<0.00001], the adverse event rate was lower, and the quality of life (QOL) was better in the ESD group. The difference of bleeding was not found. Conclusion. ESD appears to be preferable for EGC, due to a lower rate of adverse events, shorter hospital stay, cheaper cost, and higher QOL.

// Jianyong Zheng 1 , Yunming Li 2 , Shaojun Zhu 3 , Jipeng Li 1 , Qingchuan Zhao 1 , Gang Ji 1 , Weizhong Wang 1 , Dake Chu 1, 4 1 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China 2 Department of Health Statistics, Fourth Military Medical University. Xi’an, China 3 Department of Pathology, Fourth Military Medical University. Xi’an, China 4 Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, China Correspondence to: Dake Chu, e-mail: chudake@hotmail.com Keywords: NDRG4, colorectal cancer, obesity, disease-free survival, overall survival Received: May 12, 2015 Accepted: October 04, 2015 Published: October 20, 2015 ABSTRACT NDRG4 is a novel candidate tumor suppressor and can inhibit PI3K/AKT signal which is related with energy balance and related carcinogenesis. In the present study, we investigated whether NDRG4 status could modify the association of obesity with clinical outcome of colorectal cancer. For this purpose, a hospital-based prospective study cohort of 226 colorectal cancer patients was involved. NDRG4 mRNA levels were determined by real-time PCR. Association of NDRG4 mRNA expression with disease-free and overall survival was studied first. Then, the association of obesity with clinical outcome was determined according to NDRG4 level. Multivariate Cox proportional hazards model was used to compute hazard ratio, adjusting for covariates including microsatellite instability, KRAS, BRAF and PIK3CA mutation. Results showed that NDRG4 mRNA expression was decreased in tumor specimens and significantly correlated with tumor differentiation, invasion and metastasis. Patients with tumor of reduced NDRG4 mRNA level had unfavorable disease-free and overall survival. Obesity was found to be adversely associated with disease-free and overall survival in tumors with reduced NDRG4 level, not in preserved NDRG4 level group, in both univariate and multivariate analysis. These data provided the first evidence that NDRG4 level in colorectal cancer could effectively stratify the prognostic value of obesity, which would better the understanding of the prognostic role of obesity in colorectal cancer. Our results also support the notion that the host-tumor interactions in colorectal cancer might influence tumor aggressiveness.

The role of NDRG4 in human malignancies is largely unknown. We investigated the role of NDRG4 protein in colorectal cancer and its prognostic value in a hospital-based retrospective training cohort of 272 patients and a prospective validation cohort of 708 patients were. Cell line was transfected with an NDRG4 expression construct to confirm the suppression of PI3K-AKT activity by NDRG4. Appropriate statistical methods were utilized for analysis. Results showed that NDRG4 protein expression was significantly decreased from normal mucosa, chronic colitis, ulcerative colitis, atypical hyperplasia to colorectal cancer. Significant negative correlations were found between NDRG4 staining and p-AKT. Patients with positive NDRG4 staining had favorable survival in both study cohorts. In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival. Moreover, the prognostic role of NDRG4 was stratified by p-AKT. Overexpression of NDRG4 in colorectal cancer cell can significantly suppress PI3K-AKT activity, even after EGF stimulation. These results indicated NDRG4 protein expression was decreased in colorectal cancer. It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity. Therefore, high risk colorectal cancer patients could be better identified based on the combination of NDRG4 and PI3K-AKT activity.

Notch signal has complex roles in human malignancies, which might be attributed to the diversity of Notch receptors. Here, we set out to identify the association of NOTCH4 with colorectal cancer (CRC). In the hospital-based study cohort, we investigated NOTCH4 mRNA levels in primary CRC, as well as its association with clinicopathologic characteristics. Besides, NOTCH4 cDNA and siRNA was transfected into colorectal cancer cell line to elucidate its impact on tumor cell proliferation and migration. Results revealed a statistically significant lower expression of NOTCH4 mRNA in tumor specimens compared with that in control. NOTCH4 level in CRC was found to be related to tumor differentiation, invasion, and node metastasis. Moreover, it was demonstrated that NOTCH4 mRNA level could be an independent prognostic factor for both disease-free and overall survival of CRC patients. Overexpression of NOTCH4 in CRC cell lines suppressed tumor cell proliferation, migration, and invasion, while induced apoptosis. In the opposite, the malignant behavior of CRC cells was enhanced by NOTCH4 knockdown. These results demonstrated for the first time that NOTCH4 expression was decreased in CRC, which could determine tumor proliferation, relapse, and prognosis.

As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real-time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis, and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease-free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer.

MicroRNAs are noncoding RNAs that regulate multiple cellular processes during cancer progression. Among various microRNAs, miR-630 has recently been identified to be implicated in many critical processes in human malignancies. We investigated the expression pattern and prognostic value of miR-630 in human colorectal cancer by utilizing cancer and adjacent normal specimens from 206 patients. Quantitative real-time PCR assay was used to detect the expression of miR-630, and appropriate statistical analysis was used to evaluate the association of miR-630 with overall survival. It was found that miR-630 expression was significantly increased in colorectal cancer specimens compared with that in adjacent normal specimens. It was also proved that miR-630 expression in colorectal cancer was associated with tumor invasion, lymph node metastasis, distant metastasis, and tumor-node-metastasis (TNM) stage. The Kaplan-Meier survival analysis proved that increased miR-630 expression was associated with poor overall survival of patients with colorectal cancer. Multivariate analysis proved that miR-630 was an independent prognostic marker after adjusted for known prognostic factors. These results confirmed the overexpression of miR-630 in human colorectal cancer and its association with tumor progression. It also suggested that miR-630 expression might serve as a prognostic biomarker for patients with colorectal cancer.

Background Recent studies revealed contrasting prognostic roles of body-mass index (BMI) and tumor location in colorectal cancer (CRC). Given that right-sided and left-sided CRC may exhibit inverse impact on outcome and body weight, the present study is to examine whether the prognostic value of BMI and tumor location could be stratified reciprocally. Methods This prospective, observational study recruited 4,086 patients with diagnosed stage III CRC from 5 independent clinical centers in China. verall survival (OS) and disease-specific survival (DSS) was included as the clinical endpoints. The association of patients’ outcome with BMI and tumor location was evaluated hierarchically by Kaplan-Meier and Cox proportional-hazards model. Results Although BMI was not associated with outcome within total patients, this association was significantly modified by tumor location. Among left-sided tumors, obesity and overweight was significantly associated with adverse OS and DSS. In contrast, among right-sided tumors, overweight was significantly associated with more favorable OS and DSS compared with normal-weight group. The association of survival with tumor location did not reach statistical significance either. However, hierarchical analysis by BMI revealed that left-sided tumors were associated with more favorable outcome in normal-weight group, while no statistically significant difference in overweight or obese group. Conclusions BMI and tumor location may have opposing prognostic impact on CRC, stratified by each other, after adjusting for known prognostic factors. These findings are the first to show the interactive prognostic impact of BMI and tumor location, which could be relevant to stratification of patients' management. Clinical trial identification NCT02215642. Legal entity responsible for the study The authors. Funding National Natural Science Foundation of China. Disclosure All authors have declared no conflicts of interest.

Background and Objectives Matrix metalloproteinase-12 (MMP-12) plays an important role in invasion and metastasis of human solid tumor cells. This study aimed to investigate the association of MMP-12 with overall survival in human gastric cancer. Methods Gastric cancer and adjacent normal tissue specimens were collected from 165 patients who had not received neoadjuvant chemotherapy. MMP-12 expression was determined by immunohistochemical staining, and the results were analyzed statistically in relation to the overall survival of the patients. Results MMP-12 expression was increased in gastric cancer compared with that observed in normal tissues. Increased MMP-12 expression was associated with tumor invasion, lymph node metastasis, distant metastasis, and TNM stage. No correlations were detected between MMP-12 expression and age, sex, differentiation status, tumor site, or Lauren classification. Moreover, patients with MMP-12 positive gastric cancer tended to have worse overall survival compared with those patients without MMP-12 expression. Conclusions The study results showed that increased expression of MMP-12 was associated with tumor progression in gastric cancer. It also provided the first evidence for MMP-12 expression in gastric cancer as an independent prognostic factor. J. Surg. Oncol. 2013;107:746–751. © 2012 Wiley Periodicals, Inc.

Members of the NDRG (N-Myc downstream-regulated) gene family have been shown to play a variety of roles in human malignancies. In the present study, we examined the expression of NDRG2 protein in glioma samples of WHO grades I-IV. We also investigated the association between NDRG2 expression and survival. Immunohistochemical analysis was used to measure NDRG2 protein expression in 316 specimens of human glioma and 41 normal control tissues. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. We found that NDRG2 expression was reduced in glioma relative to normal tissue, and that NDRG2 expression decreased with increasing glioma grade. Kaplan-Meier analysis showed that patients without NDRG2 expression had a lower survival rate than other patients. Multivariate analysis showed that NDRG2 expression was an independent prognostic factor for overall survival of patients with glioma. The present study provides the first evidence that NDRG2 expression is decreased in gliomas, indicating that NDRG2 may play an inhibitory role during the development of gliomas. NDRG2 expression may also be a significant and independent prognostic indicator for glioma.

Purpose: Notch1 has been proven to be aberrantly expressed in colorectal cancer and related to tumor differentiation status. However, few previous studies concentrated on the predictive role of Notch1 expression on the overall survival of patients with colorectal cancer. This study explored expression of Notch1 and its relationship with p65 and prognosis in colorectal cancer. Experimental Design: Two independent study cohorts were involved in the present study. Clinical specimens from 941 eligible patients were constructed into tissue microarrays. The expression of Notch1 and p65 protein was investigated by immunohistochemistry. Results: Statistically significant positive correlations were found between protein expression of Notch1 and p65 in both retrospective and prospective study cohorts. Patients with higher Notch1 expression showed a trend of having shorter survival time, whereas patients with lower Notch1 expression had better survival in both study cohorts. In multivariate analysis, Notch1 expression was proven to be an independent predictor of prognosis. Moreover, the prognostic value of Notch1 might differ according to p65 status. Conclusions: Notch1 is an independent predictor of prognosis for patients with colorectal cancer. In addition, the predictive role of Notch1 on clinical outcome might be modified by p65 status, suggesting that targeting Notch1 and nuclear factor κB (NF-κB) might be a promising strategy for colorectal cancer treatment. Clin Cancer Res; 17(17); 5686–94. ©2011 AACR.

Matrix metalloproteinase-9 is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance tumor invasion and metastasis ability. The present study aims to examine MMP-9 expression in human colorectal cancer and to determine its association with clinicopathological characteristics and prognosis. Colorectal cancer and adjacent normal tissues from 192 patients were investigated by immunohistochemical assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival, and overall survival. High level of MMP-9 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. However, no correlations between MMP-9 expression and patient age, sex, tumor location or differentiation status were detected. Disease-free and overall survival were significantly poorer for patients with positive MMP-9 staining than for those with MMP-9-negative tumors. Our findings emphasize the important role of MMP-9 in the invasion and metastasis process in human colorectal cancer. It could also serve as a novel prognostic marker that is independent of, and additive to, the tumor–node–metastasis (TNM) staging system.

NDRG2 (N-Myc downstream-regulated gene 2) is aberrantly expressed in colorectal cancer (CRC) and related to tumor differentiation status. In the present study, we investigated the association between NDRG2 mRNA levels in primary CRC to determine whether levels of NDRG2 mRNA could predict relapse and survival. A hospital-based study cohort of 226 CRC patients was involved in the study. NDRG2 mRNA levels were determined by real-time PCR. Correlations of NDRG2 mRNA expression with tumor clinicopathologic features, disease-free survival, and overall survival of the patients were studied. Significant decreased expression of NDRG2 mRNA was detected in tumor specimens. NDRG2 mRNA expression significantly correlated with differentiation status (P < 0.001), lymph node metastasis (P < 0.001), and tumor node metastasis stage (P < 0.001). Patients with reduced level of NDRG2 mRNA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of NDRG2 mRNA. In multivariate analysis, NDRG2 mRNA level was found to be an independent prognostic factor for both disease-free survival and overall survival of CRC patients. The present research provided the first evidence that decreased NDRG2 mRNA expression in primary human CRC might be a powerful, independent predictor of recurrence and outcome. Mol Cancer Ther; 10(1); 47–56. ©2011 AACR.

Intestinal transplantation using living-related donors could potentially reduce the severity of rejection responses against this highly immunogenic organ by better tissue matching and shorter cold ischemia duration, compensating for the shortage of donor grafts. The purpose of this study is to assess the safety of donors receiving living donor small bowel transplantation (LDSBT) in our hospital by reviewing the risk of operations and absorbing capability recovering retrospectively based on the parameters, such as body weight loss, blood loss, blood transfusion, operation time, duration of hospitalization, complications, and d-xylose tolerance test. After a follow-up period (mean 72 months, range: 48-96 months) of four cases of donors performed LDSBT in Xijing Hospital of digestive diseases dated from May 1999 to September 2003, no complication occurred. Therefore, pre-operation angiography, meticulous management of operation and accurate post-operation monitoring were particularly necessary to guarantee the safety of donors.

The significance of Notch2 expression in colorectal cancer (CRC) has not been clearly investigated. We investigated the expression of Notch2 and its relationship with differentiation status and tumor stage by studying clinical CRC specimens with matched adjacent normal tissues and normal control colorectal specimens.Immunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were performed to assess the expression of Notch2 in clinical CRC specimens. Also, Notch2 levels in an induced differentiation model of CRC cell lines were investigated.It was found that Notch2 expression was decreased in cancer tissues compared with adjacent normal tissue and normal control tissues. Also, a tendency for decreased expression was observed when going from well to poorly differentiated carcinomas, as well as going from tumor, node, metastasis system stage I to stage IV. With the differentiation of colon cancer cells, the expression of Notch2 increased. To support this observation, colon cancer cell lines HT29 and SW620 were induced to differentiate in culture, and expression of Notch2 was investigated. A clear increase expression of Notch2 was observed.Notch2 expression correlated closely with CRC and may play a role in tumor inhibition in colon carcinogenesis.

NDRG2, a new member of the N-Myc downstream-regulated gene (NDRG) family, is a focus for study at present. Up to now, its expression and function in carcinoma remain to be elucidated. In this study, using a colorectal cancer tissue array and a series of 213 colorectal cancer samples, the relationship between Ndrg2 and c-MYC expression and tumor differentiation level was investigated. Immunohistochemistry showed that Ndrg2 expression was reduced and that c-Myc was increased in colorectal carcinomas. In addition, Ndrg2 protein levels increased from poorly differentiated to well-differentiated carcinomas (p=0.005). Real-time polymerase chain reaction and Western blots demonstrated quantitatively that NDRG2 mRNA and protein levels were lower in colorectal carcinomas compared to the adjacent tissue and normal tissue from the same individual (p=3x10(-8)). Also, the NDRG2 expression level in adjacent carcinoma tissue was lower than that of normal tissue. However, the expression pattern of c-MYC was the inverse (p=5x10(-8)). Finally, we induced the differentiation of the colorectal carcinoma cell lines HT29, SW480 and SW620 and found that NDRG2 expression increased and that c-MYC expression declined with increasing differentiation. These novel data show a disparity in both the mRNA and protein expression levels of Ndrg2 and c-Myc between colorectal cancers and normal tissues. Taken together, NDRG2 may play a role during the differentiation of colorectal cancer cells, and the function of NDRG2 in the development of colorectal cancer should be further investigated.