BACKGROUND Trastuzumab is part of the standard treatment for HER-2 positive breast cancer patients, but not all patients respond to trastuzumab. Altered expression levels for microRNAs in cancer cells have been correlated with prognosis and response to chemotherapy. We hypothesized that altered expression levels for miRNAs in plasma are associated with sensitivity to trastuzumab in patients with HER-2 positive breast cancer. METHODS We performed quantitative RT-PCR in plasma samples including breast cancer patients enrolled in a clinical trial of neoadjuvant trastuzumab-based chemotherapy. We analyzed expression levels for miR-210, -21, -29a, and -126 according to the type of response (pCR (n = 18) vs. residual disease (n = 11)). We also compared expression levels of miRNAs in trastuzumab-sensitive and –resistant breast cancer cells derived from BT474 cells and in an independent set of preoperative (n=39) and postoperative plasma (n=30) from 43 breast cancer patients not given any treatment. RESULTS At baseline before neoadjuvant chemotherapy combined with trastuzumab, circulating miR-210 levels were significantly higher in patients who had residual disease than in those who had pathologic CR (P = 0.0359). Mean expression ratio for miR-210 was significantly higher in trastuzumab-resistant BT474 cells and miR-210 expression was significantly higher before surgery than after surgery (P = 0.0297) and in patients whose cancer metastasized to the lymph nodes (P = 0.0030). CONCLUSIONS Circulating miR-210 levels were associated with trastuzumab sensitivity, tumor presence, and lymph node metastases. This suggests that plasma miR-210 may be used to predict and perhaps monitor response to therapies containing trastuzumab.

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BackgroundNon-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion.ResultsWe performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients’ overall survival.ConclusionsThe primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1224-0) contains supplementary material, which is available to authorized users.

Development of improved RNA interference based strategies is of utmost clinical importance. While siRNA-mediated silencing of EphA2, an ovarian cancer oncogene, results in reduction of tumor growth, we present evidence that additional inhibition of EphA2 by a microRNA further ‘boosts’ its anti-tumor effects. We identified miR-520d-3p as a tumor suppressor upstream of EphA2, whose expression correlated with favorable outcomes in two independent patient cohorts comprising of 647 patients. Restoration of miR-520d-3p prominently decreased EphA2 protein levels, and suppressed tumor growth and migration/invasion both in vitro and in vivo. Dual inhibition of EphA2 in vivo using DOPC nano-liposomes loaded with miR-520d-3p and EphA2-siRNA showed synergistic anti-tumor efficiency and greater therapeutic efficacy than either monotherapy alone. This synergy is atleast in part due to miR-520d-3p targeting EphB2, another Eph receptor. Our data emphasize the feasibility of combined miRNA-siRNA therapy, and will have broad implications for innovative gene silencing therapies for cancer and other diseases.

Inflammation is associated with several tumor development and progression. However, these associations are not clear in well-differentiated thyroid carcinomas. We assessed whether NLR is a useful prognostic marker in patients with papillary thyroid carcinomas (PTC). The medical records of all patients who underwent thyroid surgery at a single institution between March 2005 and September 2012 were retrospectively evaluated; as a control group, patients who underwent routine health examinations in 2012 were also evaluated. Differences in mean NLR among patient groups were assessed, and clinical characteristics according to NLR quartile were evaluated in patients with PTC. The association between NLR and disease-free survival (DFS) in PTC patients was determined. NLR was significantly higher in the groups with than without thyroid nodules, but did not differ significantly in patients with benign and malignant thyroid nodules. Mean NLR was significantly higher in patients with solid or mixed thyroid than in patients with cystic nodules (1.75 ± 0.92 vs. 1.65 ± 0.74, p = 0.004). Patient follow-up ranged from 6 to 99 months. At 5-year follow-up, 11 patients had disease-specific events. We found that 5-year DFS rate was significantly worse in stages III and IV patients with NLR ≥1.5 than NLR <1.5 (94.1 vs. 99.3 %, p = 0.013). The univariate Cox hazard proportional hazard model for DFS revealed that higher NLR was independently correlated with poorer prognosis (hazard ratio 8.76; 95 % confidence interval 1.09-70.27, p = 0.041). Higher NLR may be a negative prognostic marker for DFS in patients with PTC, especially those with stages III and IV.

Objective To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy.

Currently, one out of four deaths in the United States is due to cancer; therefore, every major therapeutic advance in cancer has the potential to save many lives. One of the most fascinating discoveries in the area of molecular oncology in the past decade is that, in cancer, alterations in both protein‐coding genes and noncoding RNAs, known as microRNAs (miRNAs), complement each other. In this article, we focus on a novel idea involving the use of small molecules to target overexpressed miRNAs as a new therapy for diseases, particularly cancer, in humans. Clinical Pharmacology & Therapeutics (2010) 87 6, 754–758. doi:

Background: Recently, researchers have tried to predict patient prognosis using biomarker expression in cancer patients. The aim of this study was to develop a nomogram predicting the 5-year recurrence-free probability (RFP) of gastric cancer patients using prognostic biomarker gene expression. Methods: We enrolled 360 patients in the training data set to develop the predictive model and nomogram. We analyzed the patients' general variables and the gene expression levels of 10 prognostic biomarker candidates between the nonrecurrence and recurrence groups. We also performed external validation using 420 patients from the validation data set. Results: The final nomogram was composed of age, sex, and the expression levels of CAPZA, PPase, OCT-1, PRDX4, gamma-enolase, and c-Myc. The five-year RFPs were 89%, 75%, 54% and 32% for the patients in the low-risk, intermediate-risk, high-risk and very-high-risk groups in the development cohort, respectively. In the external validation cohort, the 5-year RFPs were 89%, 75%, 63% and 60%, respectively. The areas under the curve were 0.718 (95% CI, 0.65e0.78) and 0.640 (95% CI, 0.57e0.70) for the training and validation data sets, respectively. The RFP Kaplan-Meier curves were significantly different among the 4 groups in the training and validation data sets (p < 0.0001). Conclusion: This newly developed nomogram using gene expression can predict the 5-year RFP for gastric cancer patients after surgical treatment. We hope that this nomogram will help in the therapeutic decision between endoscopic treatment and gastrectomy.