A volar skin excisional wound model for in situ evaluation of multiple-appendage regeneration and innervation.

Background: Promoting rapid wound healing with functional recovery of all skin appendages is the main goal of regenerative medicine. So far current methodologies, including the commonly used back excisional wound model (BEWM) and paw skin scald wound model, are focused on assessing the regeneration of either hair follicles (HFs) or sweat glands (SwGs). How to achieve de novo appendage regeneration by synchronized evaluation of HFs, SwGs and sebaceous glands (SeGs) is still challenging. Here, we developed a volar skin excisional wound model (VEWM) that is suitable for examining cutaneous wound healing with multiple-appendage restoration, as well as innervation, providing a new research paradigm for the perfect regeneration of skin wounds. Methods: Macroscopic observation, iodine-starch test, morphological staining and qRT-PCR analysis were used to detect the existence of HFs, SwGs, SeGs and distribution of nerve fibres in the volar skin. Wound healing process monitoring, HE/Masson staining, fractal analysis and behavioral response assessment were performed to verify that VEWM could mimic the pathological process and outcomes of human scar formation and sensory function impairment. Results: HFs are limited to the inter-footpads. SwGs are densely distributed in the footpads, scattered in the IFPs. The volar skin is richly innervated. The wound area of the VEWM at 1, 3, 7 and 10 days after the operation is respectively 89.17% ± 2.52%, 71.72% ± 3.79%, 55.09 % ± 4.94% and 35.74% ± 4.05%, and the final scar area accounts for 47.80% ± 6.22% of the initial wound. While the wound area of BEWM at 1, 3, 7 and 10 days after the operation are respectively 61.94% ± 5.34%, 51.26% ± 4.89%, 12.63% ± 2.86% and 6.14% ± 2.84%, and the final scar area accounts for 4.33% ± 2.67% of the initial wound. Fractal analysis of the post-traumatic repair site for VEWM vs human was performed: lacunarity values, 0.040 ± 0.012 vs 0.038 ± 0.014; fractal dimension values, 1.870 ± 0.237 vs 1.903 ± 0.163. Sensory nerve function of normal skin vs post-traumatic repair site was assessed: mechanical threshold, 1.05 ± 0.52 vs 4.90 g ± 0.80; response rate to pinprick, 100% vs 71.67% ± 19.92%, and temperature threshold, 50.34°C ± 3.11°C vs 52.13°C ± 3.54°C. Conclusions: VEWM closely reflects the pathological features of human wound healing and can be applied for skin multiple-appendages regeneration and innervation evaluation.

Defining the impact of platelet-to-lymphocyte ratio on patient survival with gastric neuroendocrine neoplasm: a retrospective cohort analysis.

BACKGROUND: Gastric neuroendocrine neoplasm (g-NEN) is a rare but heterogeneous neoplasm, with an increasing incidence yearly. Conventional prognostic markers of g-NEN remain limited which could only be detected after surgery. There is an urgent need to explore new prognostic markers for g-NEN patients. This study aimed to investigate the prognostic value of platelet-to-lymphocyte, ratio (PLR) and the association between PLR and body mass index (BMI) in patients with gastric neuroendocrine neoplasms (g-NEN). METHODS: A retrospective cohort of patients with g-NEN from January 2001 through June 2016 was examined. The prognostic significance of PLR was determined by multiple regression analysis in different models. Stratified analysis was performed to examine the prognostic value of PLR at different BMI levels. RESULTS: In total, 238 patients were enrolled. Those with higher PLRs tended to undergo open surgery, had larger tumor sizes, were diagnosed more frequently with neuroendocrine carcinoma, and had higher tumor grades. PLR was significantly associated with the survival of patients with g-NEN. With PLR increased per standard deviation, the all-cause mortality risk of patients with g-NEN increased by 67%, 63%, and 54% in the crude (HR = 1.67, 95% CI 1.32-2.12, P < 0.001), minimally adjusted (HR = 1.63, 95% CI 1.28-2.08, P < 0.001), and fully adjusted (HR = 1.54, 95% CI 1.202-1.98, P = 0.001) models, respectively. Patients with higher PLR (quartile 4, ≥ 187) had a 1.8-fold increase in all-cause mortality risk compared with those with lower PLR (quartile 1-3, < 187). Furthermore, there was a significant interaction effect between BMI subgroups and PLR in predicting the survival of patients with g-NEN (PLR regarded as a continuous variable: all P for interaction < 0.05 in the crude, minimally adjusted, and fully adjusted models; PLR regarded as a categorical variable: P for interaction < 0.05 in the fully adjusted model). Patients with g-NEN with the characteristics of higher PLR (quartile 4, ≥ 187) and non-obesity (BMI < 25 kg/m2) had worse survival than others (P < 0.05). CONCLUSION: The inflammation marker PLR has an independent prognostic value for patients with g-NENs, and high PLR combined with non-obesity increases the mortality risk of these patients.

Preoperative albumin levels predict prolonged postoperative ileus in gastrointestinal surgery.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a prolonged state of "pathological" gastrointestinal (GI) tract dysmotility. There are relatively few studies examining the influence of preoperative nutritional status on the development of PPOI in patients who underwent GI surgery. The association between preoperative albumin and PPOI has not been fully studied. We hypothesized that preoperative albumin may be an independent indicator of PPOI. AIM: To analyze the role of preoperative albumin in predicting PPOI and to establish a nomogram for clinical risk evaluation. METHODS: Patients were drawn from a prospective hospital registry database of GI surgery. A total of 311 patients diagnosed with gastric or colorectal cancer between June 2016 and March 2017 were included. Potential predictors of PPOI were analyzed by univariate and multivariable logistic regression analyses, and a nomogram for quantifying the presence of PPOI was developed and internally validated. RESULTS: The overall PPOI rate was 21.54%. Advanced tumor stage and postoperative opioid analgesic administration were associated with PPOI. Preoperative albumin was an independent predictor of PPOI, and an optimal cutoff value of 39.15 was statistically calculated. After adjusting multiple variables, per unit or per SD increase in albumin resulted in a significant decrease in the incidence of PPOI of 8% (OR = 0.92, 95%CI: 0.85-1.00, P = 0.046) or 27% (OR = 0.73, 95%CI: 0.54-0.99, P = 0.046), respectively. Patients with a high level of preoperative albumin (≥ 39.15) tended to experience PPOI compared to those with low levels (< 39.15) (OR = 0.43, 95%CI: 0.24-0.78, P = 0.006). A nomogram for predicting PPOI was developed [area under the curve (AUC) = 0.741] and internally validated by bootstrap resampling (AUC = 0.725, 95%CI: 0.663-0.799). CONCLUSION: Preoperative albumin is an independent predictive factor of PPOI in patients who underwent GI surgery. The nomogram provided a model to screen for early indications in the clinical setting.

RCC2 Interacts with Small GTPase RalA and Regulates Cell Proliferation and Motility in Gastric Cancer.

BACKGROUND: Regulator of chromosome condensation 2 (RCC2), also known as TD-60, is associated with various human malignant cancers. RCC2 has been shown to exhibit guanine exchange factor (GEF) activity and contribute to early mitosis. However, the role and mechanism of RCC2 in gastric cancer remain unclear. MATERIALS AND METHODS: RCC2 expression in gastric cancer was studied using qPCR, Western blotting and immunochemistry staining of clinical specimens, and its roles in the cytobiology, mouse model and related molecular pathways were evaluated using gastric cell lines. RESULTS: RCC2 was frequently overexpressed in gastric cancer. RCC2 knockdown significantly inhibited cell proliferation, migration and invasion in vitro, which was further confirmed by the RCC2 overexpression results in gastric cancer cells. Moreover, RCC2 knockdown inhibited tumor progression in vivo. Further study revealed the interaction between RCC2 and RalA. The level of RalA-GTP was decreased in gastric cancer cells after RCC2 knockdown, while an increased phosphorylation level in MAPK/JNK was found. Furthermore, the changes in the level of RalA-GTP as well as cell proliferation, migration and invasion abilities were further confirmed using RBC8, a specific small-molecule inhibitor of the intracellular actions of Ral GTPases, in gastric cancer cells. CONCLUSION: RCC2 plays an important role in gastric cancer. RCC2 knockdown inhibits cell growth, cell motility and tumor progression, which may act through RalA and affect the MAPK/JNK pathway.

Association Between Liquid Biopsy and Prognosis of Gastric Cancer Patients: A Systematic Review and Meta-Analysis.

Background: Reports regarding liquid biopsy and gastric cancer (GC) have emerged rapidly in recent decades, yet their prognostic value still remains controversial. This study was aimed to assess the impact of liquid biopsy, including circulating tumor cells (CTCs) and cell-free nucleic acids, on GC patients' prognosis. Methods: PubMed, Medline, EMBASE, and ClinicalTrial.gov databases were searched for studies that report GC patient survival data stratified by CTC/circulating tumor DNA (ctDNA)/circulating miRNAs' status. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for patients' overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were recorded or calculated depending on circulating target status. Results: We initially identified 4,221 studies, from which 43 were eligible for further analysis, comprising 3,814 GC patients. Pooled analyses showed that detection of certain CTCs, ctDNA, and circulating miRNA was associated with poorer OS (CTCs: HR = 1.84, 95%CI 1.50-2.26, p < 0.001; ctDNA: HR = 1.78, 95%CI 1.36-2.34, p < 0.001; circulating miRNA: HR = 1.74, 95%CI 1.13-2.69, p < 0.001) and DFS/PFS (CTCs: HR = 3.39, 95%CI 2.21-5.20, p < 0.001; ctDNA: HR = 2.38, 95%CI 1.31-4.32, p = 0.004; circulating miRNA: HR = 3.30, 95%CI 2.39-4.55, p < 0.001) of GC patients, regardless of disease stage and time point at which sample is taken (at baseline or post-treatment). Conclusions: The presence of CTCs and/or cellular components identifies a group of GC with poorer prognosis. Among circulating markers, CTCs demonstrated a stronger and more stable predictive value for late-stage disease and among Mongolian populations with GC. Less data are available for ctDNA and miRNA; however, their presence may also reflect aggressive biology and warrants further prospective study.

Nomogram to predict prolonged postoperative ileus after gastrectomy in gastric cancer.

BACKGROUND: Prolonged postoperative ileus (PPOI) is one of the common complications in gastric cancer patients who underwent gastrectomy. Evidence on the predictors of PPOI after gastrectomy is limited and few prediction models of nomogram are used to estimate the risk of PPOI. We hypothesized that a predictive nomogram can be used for clinical risk estimation of PPOI in gastric cancer patients. AIM: To investigate the risk factors for PPOI and establish a nomogram for clinical risk estimation. METHODS: Between June 2016 and March 2017, the data of 162 patients with gastrectomy were obtained from a prospective and observational registry database. Clinical data of patients who fulfilled the criteria were obtained. Univariate and multivariable logistic regression models were performed to detect the relationship between variables and PPOI. A nomogram for PPOI was developed and verified by bootstrap resampling. The calibration curve was employed to detect the concentricity between the model probability curve and ideal curve. The clinical usefulness of our model was evaluated using the net benefit curve. RESULTS: This study analyzed 14 potential variables of PPOI in 162 gastric cancer patients who underwent gastrectomy. The incidence of PPOI was 19.75% in patients with gastrectomy. Age older than 60 years, open surgery, advanced stage (III-IV), and postoperative use of opioid analgesic were independent risk factors for PPOI. We developed a simple and easy-to-use prediction nomogram of PPOI after gastrectomy. This nomogram had an excellent diagnostic performance [area under the curve (AUC) = 0.836, sensitivity = 84.4%, and specificity = 75.4%]. This nomogram was further validated by bootstrapping for 500 repetitions. The AUC of the bootstrap model was 0.832 (95%CI: 0.741-0.924). This model showed a good fitting and calibration and positive net benefits in decision curve analysis. CONCLUSION: We have developed a prediction nomogram of PPOI for gastric cancer. This novel nomogram might serve as an essential early warning sign of PPOI in gastric cancer patients.

JS-K induces reactive oxygen species-dependent anti-cancer effects by targeting mitochondria respiratory chain complexes in gastric cancer.

As a nitric oxide (NO) donor prodrug, JS-K inhibits cancer cell proliferation, induces the differentiation of human leukaemia cells, and triggers apoptotic cell death in various cancer models. However, the anti-cancer effect of JS-K in gastric cancer has not been reported. In this study, we found that JS-K inhibited the proliferation of gastric cancer cells in vitro and in vivo and triggered mitochondrial apoptosis. Moreover, JS-K induced a significant accumulation of reactive oxygen species (ROS), and the clearance of ROS by antioxidant reagents reversed JS-K-induced toxicity in gastric cancer cells and subcutaneous xenografts. Although JS-K triggered significant NO release, NO scavenging had no effect on JS-K-induced toxicity in vivo and in vitro. Therefore, ROS, but not NO, mediated the anti-cancer effects of JS-K in gastric cancer. We also explored the potential mechanism of JS-K-induced ROS accumulation and found that JS-K significantly down-regulated the core proteins of mitochondria respiratory chain (MRC) complex I and IV, resulting in the reduction of MRC complex I and IV activity and the subsequent ROS production. Moreover, JS-K inhibited the expression of antioxidant enzymes, including copper-zinc-containing superoxide dismutase (SOD1) and catalase, which contributed to the decrease of antioxidant enzymes activity and the subsequent inhibition of ROS clearance. Therefore, JS-K may target MRC complex I and IV and antioxidant enzymes to exert ROS-dependent anti-cancer function, leading to the potential usage of JS-K in the prevention and treatment of gastric cancer.

Comparison between laparoscopic and open surgery for large gastrointestinal stromal tumors: A meta-analysis.

AIM: To investigate whether laparoscopic surgery is as safe and feasible as open resection for patients with larger gastrointestinal stromal tumors (GISTs) (≥ 5 cm). METHODS: A systematic search of PubMed, EMBASE, Web of Science and the Cochrane Library database was performed. Relevant studies of laparoscopic and open surgery for GISTs of > 5 cm published before December 2016 were identified from these databases. The quality of the studies was assessed by the Newcastle-Ottawa Quality Assessment Scale. The tumor size, operation time, blood loss, postoperative hospital stay, complication rate, and disease-free survival rate were assessed. The software Stata (version 12.0) was used for the meta-analysis. RESULTS: Five clinical trials comprising 209 patients with GISTs of similar larger sizes were evaluated. The pooled analysis of 100 patients in the laparoscopic resection group and 109 patients in the open resection group demonstrated that laparoscopic surgery was significantly associated with a shorter postoperative hospital stay (P < 0.001) and less blood loss (P = 0.002). Moreover, there were no statistically significant differences in the operation time (P = 0.38), postoperative complication rate (P = 0.88), or disease-free survival rate (P = 0.20) between two groups. CONCLUSION: Our findings revealed that for patients with large GISTs of comparable sizes, laparoscopic surgery did not significantly influence the operation factors or clinical outcomes compared with open surgery. This suggests that laparoscopic resection is as acceptable as open surgery for treatment of large gastric GISTs.

Minimally invasive surgery as a treatment option for gastric cancer with liver metastasis: a comparison with open surgery.

BACKGROUND: As minimally invasive techniques advances, minimally invasive surgery (MIS) has emerged as an alternative modality for advanced gastric cancer. In this study, we compared the short- and long-term surgical outcomes of MIS and conventional open surgery for gastric cancer liver metastasis (GCLM) in terms of safety, feasibility, and efficacy. METHODS: This retrospective study used data from a prospective database at the Chinese People's Liberation Army General Hospital. From January 2006 to June 2016, 53 gastric cancer patients with synchronous liver metastasis accepted radical gastrectomy combined with either or both hepatectomy and radiofrequency ablation for liver metastases. The 53 patients enrolled in the study were divided into two groups: a conventional open surgery group (n = 42) and an MIS group (n = 11). Propensity score matching (PSM) analysis was performed to overcome possible bias. RESULTS: With PSM performed at a 1:3 ratio, 11 patients who received MIS were compared with 33 open surgery cases. Mean operation time was significantly longer for the MIS group compared with the open surgery group (301 vs. 236 min, P = 0.032), while the open surgery group had a larger estimated blood loss than the MIS group (421 vs. 196 ml, P = 0.019). Time to first flatus and postoperative complications, including Clavien-Dindo classification, were similar in the two groups. However, patients undergoing MIS had a significantly shorter time to first sips of water (P = 0.020) and soft diet (P = 0.020) compared with open surgery counterparts. Long-term outcomes were comparable between groups (P = 0.090) after adjustment by PSM analysis. CONCLUSIONS: MIS achieved superior short-term outcomes and comparable long-term outcomes compared with open surgery in GCLM patients. For experienced surgeons, both laparoscopic and robotic methods of MIS are reasonable approaches for the management of highly selected GCLM patients.

Evaluation of hepatectomy and palliative local treatments for gastric cancer patients with liver metastases: a propensity score matching analysis.

BACKGROUND: The optimal treatments for gastric cancer with liver metastases (GCLM) remain controversial. This study aimed to evaluate the efficacy of hepatectomy, RFA and TACE as local treatments for GCLM. METHODS: From 2001 to 2015, 119 consecutive patients who received multidisciplinary treatments based on curative gastrectomy and local treatments (hepatectomy, RFA and TACE) for liver metastases were enrolled in this retrospective cohort study. Patients were divided into Group A (46, hepatectomy) and Group B (73, either or both RFA and TACE). Propensity score matching analysis was employed. RESULTS: The propensity model revealed that hepatectomy was associated with significantly longer OS compared with either or both RFA and TACE (P=0.021). The 1-, 3- and 5-year OS rates were 80.5%, 41.5% and 24.4%, respectively in Group A; and 85.4%, 21.9% and 12.2%, respectively in Group B. Subgroup analyses indicated that hepatectomy was associated with significantly longer long-term survival compared with TACE (P=0.033) and RFA (P=0.010). TACE had a similar efficacy as RFA (P=0.518), but with significantly lower costs (P=0.014) in for patients with metachronous GCLM. CONCLUSION: Hepatectomy is the optimal local treatment for GCLM when surgical R0 resection is intended. TACE attained a similar prognosis as RFA with relatively high cost-effectiveness, particularly for patients with metachronous GCLM.

Predictive factors for lymph node metastasis in early gastric cancer with signet ring cell histology: a meta-analysis.

BACKGROUND: Less invasive surgery is widely used in the treatment of early gastric cancer; however, no definite guidelines exist regarding indications for less invasive surgery to treat early gastric cancer with signet ring cell histology. The aim of this study was to identify risk factors for lymph node metastasis (LNM) in early signet ring cell carcinoma (SRC). An extensive search of PubMed, Embase and the Cochrane library was performed for pertinent articles involving early SRC and LNM. METHODS: Eligible data (gender, depth of invasion, lymphovascular invasion, size, ulceration, macroscopic type and location) were extracted from the included studies and systematically reviewed via a meta-analysis. Review Manager version 5.3 was used to perform the data processing. The Newcastle-Ottawa Scale was utilized to evaluate the quality of the included articles. RESULTS: Fourteen studies were included in the final analysis. After meta-analysis, female gender, submucosal invasion, lymphovascular invasion and size >20 mm were associated with LNM in early SRC. CONCLUSION: Four variables were identified as risk factors for LNM in early SRC. The significance of the results of the present study should be further confirmed in more early SRC patients for future clinical use.

Ring finger protein 43 associates with gastric cancer progression and attenuates the stemness of gastric cancer stem-like cells via the Wnt-ß/catenin signaling pathway.

BACKGROUND: Ring finger protein 43 (RNF43) is a member of the transmembrane E3 ubiquitin ligase family that was originally found in stem cells and plays important roles in tumor formation and progression. Our previous study indicated that RNF43 might be a tumor suppressor protein in gastric cancer. Given its antagonistic relationship with leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), one of the gastric cancer stem cell markers, investigation of the potential role of RNF43 in gastric stem cancer cells is necessary. METHODS: Immunohistochemistry staining, western blot analysis, and quantitative reverse transcription polymerase chain reaction were used to determine the mRNA and protein expression level of RNF43 and other Wnt pathway factors. Gastric cancer stem-like cells were obtained from gastric cancer tumor and cell lines by tumorsphere culture. The adeno-associated virus system was used to upregulate RNF43 expression in cancer cells. Functional experiments including tumorsphere formation, chemotherapy resistance, surface marker detection, and tumor xenograft assay were performed to measure stem-like properties in gastric cancer stem-like cells after RNF43 overexpression. RESULTS: RNF43 loss was significantly associated with TNM stage, distant metastasis, and Lauren classification, and predicted worse prognosis in gastric cancer patients. RNF43 expression was even lower in tumorspheres derived from tumor tissues or cell lines compared with adherent cancer cells and normal gastric cells. Overexpression of RNF43 in gastric cancer cells impaired their stem-like properties, including sphere formation ability, chemoresistance in vitro, and tumorigenicity in vivo. Moreover, Wnt pathway-related proteins were decreased in RNF43-overexpressing cells, while Wnt pathway activators could reverse the trend to some extent. CONCLUSIONS: Our findings indicated that RNF43 might not only participate in gastric cancer progression, but also attenuate the stemness of gastric cancer stem-like cells through the Wnt/ß-catenin pathway.

Predictive Factors for Lymph Node Metastasis in Undifferentiated Early Gastric Cancer: a Systematic Review and Meta-analysis.

OBJECTIVES: Less invasive surgery is gaining popularity for the treatment of early gastric cancer (EGC), but there are no definitive guidelines for the use of less invasive surgery for the treatment of undifferentiated EGC. The aims of this meta-analysis were to identify potential predictive factors for lymph node metastasis (LNM) in undifferentiated EGC and to guide the personalized therapeutic modality for patients with undifferentiated EGC. METHODS: An extensive search of the PubMed, Embase, and Cochrane Library databases was performed to identify relevant articles involving undifferentiated EGC and LNM. Eligible data were systematically reviewed through a meta-analysis using Review Manager 5.3. RESULTS: In total, 23 studies were included in this analysis. The meta-analysis found that the variables sex (female), age (greater than 60 years), tumor size (greater than 20 mm), depth of invasion (submucosal invasion), presence of lymphovascular involvement, presence of ulcer findings, histology type (non-signet ring carcinoma), and tumor location (not in the middle part of the stomach) were significantly associated with LNM. CONCLUSIONS: Eight variables were identified as predictive factors for LNM in undifferentiated EGC. The significance of these variables should be further confirmed during the process of LNM in undifferentiated EGC patients for future clinical application.

A systematic review and meta-analysis of robot-assisted versus laparoscopically assisted gastrectomy for gastric cancer.

BACKGROUND: Robotic-assisted gastrectomy (RAG) has been used for gastric cancer since 2002. This meta-analysis was carried out to evaluate whether RAG is safer and more effective than conventional laparoscopically assisted gastrectomy (LAG) for gastric cancer. METHODS: We performed a manual search for these 2 types of operations (RAG and LAG) in the PubMed, Embase, and the Cochrane Library databases up to April 30, 2016. Twelve nonrandomized controlled trials that reported on RAG and LAG for gastric cancer were included. Outcomes evaluated included operation time, number of retrieved lymph nodes, blood loss, length of the resection margin, complications, and postoperative hospital stay. RESULTS: A total of 3744 patients in 12 studies were included (1134 patients in the RAG group and 2610 patients in the LAG group). The operation time was significantly shorter in the LAG group [weighted mean difference (WMD) 42.0 (95% confidence interval, 95% CI 28.11-55.89) minutes; P < .00001], while the loss of blood volume was lower in the RAG group (P = .01). The number of retrieved lymph nodes, duration of postoperative stay, length of the proximal resection margin, length of the distal resection margin, and postoperative complications were similar between groups. CONCLUSION: We conclude that RAG is a safe and appropriate treatment for gastric cancer patients in comparison to LAG. Nevertheless, RAG is not superior to LAG. Future research on RAG should focus on comparing the differences in retrieved lymph nodes in different tiers, evaluating the postoperative recovery and reducing the cost of the treatment.

Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer.

Colon cancer is the third most common malignancy worldwide, and chemotherapy is a widely used strategy in clinical therapy. Chemotherapy-resistant of colon cancer is the main cause of recurrence and progression. Novel drugs with efficacy and safety in treating colon cancer are urgently needed. Shikonin, a naphthoquinone derived from the roots of the herbal plant Lithospermum erythrorhizon, has been determined to be a potent anti-tumor agent. The aim of the present study was to detect the underlying anti-tumor mechanism of shikonin in colon cancer. We found that shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo. Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins. Shikonin increased the generation of intracellular ROS, which played an upstream role in shikonin-induced apoptosis. Our data indicated that generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade were components of the programmed event of shikonin-induced apoptosis in colon cancer cells. In addition, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models, showing safety in the control of colon cancer cell growth in vitro and in vivo. Taken together, our findings suggest that shikonin might serve as a potential novel therapeutic drug in the treatment of human colon cancer.

Diagnostic and prognostic value of circulating tumor DNA in gastric cancer: a meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has offered a minimally invasive approach for detection and measurement of gastric cancer (GC). However, its diagnostic and prognostic value in gastric cancer still remains unclear. RESULTS: A total of 16 studies comprising 1193 GC patients met our inclusion criteria. The pooled sensitivity and specificity were 0.62 (95% confidence intervals (CI) 0.59-0.65) and 0.95 (95% CI 0.93-0.96), respectively. The AUSROC (area under SROC) curve was 0.94 (95% CI 0.89-0.98). The results showed that the presence of certain ctDNA markers was associated with larger tumor size (OR: 0.26, 95% CI 0.11-0.61, p = 0.002), TNM stage (I + II/III + IV, OR: 0.11, 95% CI 0.07-0.17, p = 0.000), as well as H. pylori infection. (H.p negative/H.p positive, OR: 0.57, 95% CI 0.36-0.91, p = 0.018). Moreover, there was also a significant association between the presence of ctDNA and worse overall survival (HR 1.77, 95% CI 1.38-2.28, p < 0.001), as well as disease-free survival (HR 4.36, 95% CI 3.08-6.16, p < 0.001). MATERIALS AND METHODS: Pubmed, Embase, Cochrane Library and Web of Science databases were searched for relating literature published up until November 30, 2016. Diagnostic accuracy variables were pooled by the Meta-Disc software. Engauge Digitizer and Stata software were applied for prognostic data extraction and analysis. CONCLUSIONS: Our meta-analysis indicates the detection of certain ctDNA targets is significantly associated with poor prognosis of GC patients, with high specificity and relatively moderate sensitivity.

Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species.

The prognosis of gastric cancer remains poor due to clinical drug resistance. Novel drugs are urgently needed. Shikonin (SHK), a natural naphthoquinone, has been reported to trigger cell death and overcome drug resistance in anti-tumour therapy. In this study, we investigated the effectiveness and molecular mechanisms of SHK in treatment with gastric cancer. In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells. SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis. We confirmed that SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade, but also in a caspase-independent manner which mediates the nuclear translocation of apoptosis-inducing factor and Endonuclease G. Furthermore, we demonstrated that SHK enhanced the chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin in vitro and in vivo. Taken together, our data show that SHK may be a novel therapeutic agent in the clinical treatment of gastric cancer.

Increased Expression of 58-kDa Microspherule Protein (MSP58) in Human Gastric Cancer Promotes Cell Proliferation and Correlates with Poor Patient Survival.

BACKGROUND: Gastric cancer (GC) is one of the most frequently occurring malignancies with poor prognosis because of its huge heterogeneity and limited available therapeutic options. The nucleolar 58-kDa microspherule protein (MSP58) is involved in a variety of cellular processes. Though MSP58 was identified as a candidate oncogene in many cancer types, it has both oncogenic and tumor suppressive properties. The oncogenic effect of MSP58 in GC is currently unclear. The present study identified MSP58 expression in GCs and investigated its role in tumor proliferation and patient survival. METHODS: MSP58 expression in GCs was identified using western blotting and immunochemistry methods and correlations with clinicopathological features. Patient survival was calculated by multivariate survival analysis. Small interference RNA transfection, CCK8, and clonogenic assays were performed to investigate the roles of MSP58 in cell proliferation. RESULTS: MSP58 was highly expressed in MGC803, BGC823, and NCI-N87 cell lines compared with normal gastric mucosa cells. The study thus provided evidence that knockdown of MSP58 expression significantly suppressed cell proliferation and colony-forming ability. Immunohistochemical analysis showed MSP58 was highly expressed in 51.5% of GC tissues and in 11.9% of normal corresponding mucosal tissues. Significant positive correlations between MSP58 expression and differentiation grade, depth of invasion, and pathological tumor node metastasis (TNM) stage was further identified. The overall 5-year survival rate for the MSP58-positive group was lower than that of the MSP58-negative group. Depth of invasion, lymph node metastasis, and MSP58 expression were found to be independent prognostic factors. CONCLUSIONS: These findings suggested that MSP58 plays an important role in tumorigenesis and progression and may help predict the prognosis of GC patients.

[Clinicopathologic features and prognostic analysis of 104 patients with gastric neuroendocrine neoplasms].

OBJECTIVE: To investigate the clinicopathologic features and prognostic factors of gastric neuroendocrine neoplasms(gNENs). METHODS: Clinicopathologic data of 104 patients with gastric neuroendocrine neoplasms admitted in Chinese PLA General Hospital between January 2000 and December 2014 were analyzed retrospectively. Tumor proliferation activity classification (G1, G2 and G3) and TNM staging were observed. The clinicopathologic features of the whole group were collected and the univariate and multivariate analysis were determined by Log-rank and Cox proportional hazard model to detect the prognosis-determining features. RESULTS: Of all the patients, 66 cases(63.5%) were neuroendocrine carcinoma, 25 cases(24.0%) were mixed adenoendocrine carcinoma and 12 cases (11.5%) were neuroendocrine tumor. For G grades, 92 cases (88.5%) were G3 grade, 8 cases(7.7%) were G2 grade and 4 cases (3.8%) were G1 grade. TNM staging results showed that stageI( was found in 6 cases (5.8%), stageII(A in 6 cases (5.8%), stageII(B in 9 cases (8.7%), stage III(A in 8 cases (7.7%), stage III(B in 55 cases (52.9%) and stageIIII( in 20 cases (19.2%). For T stage, 7 cases (6.7%) were T1, 12 cases (11.5%) were T2, 24 cases (23.1%) were T3, and 61 cases (58.7%) were T4. Lymph node metastasis occurred in 73 cases (70.2%) and distant metastasis occurred in 20 cases(19.2%). Eighty-six patients were followed up for 6 to 186 months. The median survival was 33.0 months(95% CI: 28.3 to 36.6), and 1-, 3-, and 5-year survival rates were 80%, 49% and 31%. Clinicopathologic features which were considered statistically significant on univariate analysis were selected to Cox proportional hazard model. Univariate analysis showed that risk factors of reducing survival rate included tumor size, pathological type, proliferation activity grades, and depth of invasion (all P<0.05), as well as chromogranin A expression, tumor staging, lymph node metastasis and distant metastasis(all P<0.01). The multivariate analysis showed that the stage of gNEN was the independent risk factor of the prognosis (RR=14.213, 95% CI: 1.316 to 153.524, P=0.029). CONCLUSION: Late staging is the main clinical feature and a prognostic factor for gNENs.