Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitinationmediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457-69. Ó2016 AACR.

Background The effect of Helicobacter pylori (H. pylori) eradication on gastric cancer (GC) prevention is controversial. Intestinal metaplasia (IM) seems to be a ''point of no return'' in the precancerous cascade. We performed a meta-analysis of randomized controlled trials (RCTs) to illustrate this issue. Materials and Methods The MEDLINE, EMBASE, Cochrane Library were searched for relevant RCTs that were published in any language up to March 2014. By dividing participants into subgroups based on their baseline diagnoses as group \IM (normal, non-atrophic gastritis, atrophic gastritis) and group CIM(intestinal metaplasia, dysplasia), the relative risk (RR) of GC in each study compared treatment group with control group were pooled using Mantel-Haenszel fixed-effect model and publication bias analyses were performed.Results Ten studies from eight RCTs were included in this analysis, for a total of 7,955 participants. H. pylori treatment compared with control significantly reduced the risk of GC, with a pooled RR of 0.64 (95 % CI, 0.48-0.85). Subgroup analysis for patients with non-atrophic gastritis, atrophic gastritis (\IM) yielded a similar results (RR = 0.25, 95 % CI, 0.08-0.81). But this difference was not observed in patients with intestinal metaplasia, dysplasia (CIM) (RR = 0.88; 95 % CI, 0.59-1.31). Conclusions Our results suggested that patients with Intestinal metaplasia or dysplasia could not benefit from the H. pylori treatment on the risk of GC.

This study aimed to investigate the impact of body mass index (BMI) on the short-term and long-term results of a large cohort of gastric cancer (GC) patients undergoing gastrectomy.Recently, the “obesity paradox” has been proposed, referring to the paradoxically “better” outcomes of overweight and obese patients compared with nonoverweight patients. The associations between BMI and surgical outcomes among patients with GC remain controversial.A single-institution cohort of 1249 GC patients undergoing gastrectomy between 2000 and 2010 were categorized to low-BMI (<18.49 kg/m2), normal-BMI (18.50–24.99 kg/m2), and high-BMI (≥25.00 kg/m2) groups. The postoperative complications were classified according to the Clavien-Dindo system, and their severity was assessed by using the Comprehensive Complication Index (CCI). The impact of BMI on the postoperative complications and overall survival was analyzed.There were 908, 158, and 182 patients in the normal-BMI, low-BMI, and high-BMI groups, respectively. The overall morbidity in the high-BMI group (24.7%) was higher than that in either the low-BMI or the normal-BMI group (20.9% and 15.5%, respectively; P = 0.006), but the mean CCI in the low-BMI group was significantly higher (8.32 ± 19.97) than the mean CCI in the normal-BMI and high-BMI groups (3.76 ± 11.98 and 5.58 ± 13.07, respectively; P < 0.001). The Kaplan–Meier curve and the log-rank test demonstrated that the low-BMI group exhibited the worst survival outcomes compared with the normal-BMI group, whereas the high-BMI group exhibited the best survival outcomes (P < 0.001). In multivariate analysis, BMI was identified as an independent prognostic factor. In the stage-specific subgroup analysis, a low BMI was associated with poorer survival in the cases of stage III–IV diseases.Low BMI was associated with more severe postoperative complications and poorer prognosis. Despite a higher risk of mild postoperative complications, the high-BMI patients exhibited paradoxically “superior” survival outcomes compared with the normal-BMI patients. These findings confirm the “obesity paradox” in GC patients undergoing gastrectomy.

Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial-mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/b-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colonderived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/b-catenin complex, thereby inhibiting the transcriptional activity of b-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane b-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing b-catenin at cell-cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease.

Immune cells contribute to determining the prognosis of gastric cancer. However, their exact role is less clear.We determined the prognostic significance of different immune cells in intratumoral tissue (T), stromal tissue (S), and adjacent normal tissue (N) of 166 gastric cancer cases and their interactions, including CD3+, CD4+, CD8+, CD57+, CD68+, CD66b+, and Foxp3+ cells, and established an effective prognostic nomogram based on the immune reactions.We found high densities of TCD3+, TCD4+, TCD8+, SCD3+, SCD4+, SCD57+, SCD66b+, and NFoxp3+ cells, as well as high TCD8+/SCD8+ ratio, TCD68+/SCD68+ ratio, TCD3+/TFoxp3+ ratio, TCD4+/TFoxp3+ ratio, TCD8+/TFoxp3+ ratio, SCD3+/SFoxp3+ ratio, and SCD4+/SCD8+ ratio were associated with better survival, whereas high densities of TCD66b+, TFoxp3+, SFoxp3+ and NCD66b+ cells as well as high TCD57+/SCD57+ ratio, TCD66b+/SCD66b+ ratio, SCD8+/SFoxp3+ ratio, and TFoxp3+/NFoxp3+ ratio were associated with significantly worse outcome. Multivariate analysis indicated that tumor size, longitudinal tumor location, N stage, TCD68+/SCD68+ ratio, TCD8+/TFoxp3+ ratio, density of TFoxp3+ cells, and TCD66b+/SCD66b+ ratio were independent prognostic factors, which were all selected into the nomogram. The calibration curve for likelihood of survival demonstrated favorable consistency between predictive value of the nomogram and actual observation. The C-index (0.83, 95% CI: 0.78 to 0.87) of our nomogram for predicting prognosis was significantly higher than that of TNM staging system (0.70).Collectively, high TCD68+/SCD68+ ratio and TCD8+/TFoxp3+ ratio were associated with improved overall survival, whereas high density of TFoxp3+ cells and TCD66b+/SCD66b+ ratio demonstrated poor overall survival, which are promising independent predictors for overall survival in gastric cancer.

GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosomelysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM.

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Nutritional and immune status is important to the prognosis of patients with gastric carcinoma (GC). Here, we evaluated the prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) in patients with GC. From January 2005 to December 2011, 1332 patients with GC who underwent gastrectomy were randomly divided into the training (n = 888) and the validation sets (n = 444) by X-tile according to the sample size ratio 2:1. The cut-point of HALP was 56.8 and the patients were subsequently subdivided into HALP < 56.8 and HALP ≥ 56.8 groups in both two sets. Multivariate analysis revealed that gender (p < 0.001, p < 0.001), tumor size (p = 0.003, p = 0.035) and T stage (p < 0.001, p = 0.044) were independently related to HALP both in the training and the validation sets. Kaplan-Meier (p < 0.001, p = 0.003) and Cox regression (p = 0.043, p = 0.042) showed that the prognosis of HALP ≥ 56.8 group was significantly better than that of HALP < 56.8 group both in two sets (p < 0.001, p < 0.001). Nomograms of these two sets based on HALP was more accurate in prognostic prediction than TNM stage alone. Our findings suggested that HALP was closely associated with clinicopathological features and was an independent prognostic factor in GC patients. Nomogram based on HALP could accurately predict the prognosis of GC patients.