No abstract

The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.

BackgroundNo consensus definition of macrosomia currently exists among researchers and obstetricians. We aimed to identify a definition of macrosomia that is more predictive of maternal and perinatal mortality and morbidity in low- and middle-income countries.MethodsWe conducted a secondary data analysis using WHO Global Survey on Maternal and Perinatal Health data on Africa and Latin America from 2004 to 2005 and Asia from 2007 to 2008. We compared adverse outcomes, which were assessed by the composite maternal mortality and morbidity index (MMMI) and perinatal mortality and morbidity index (PMMI) in subgroups with birthweight (3000–3499 g [reference group], 3500–3999 g, 4000–4099 g, 4100–4199 g, 4200–4299 g, 4300–4399 g, 4400–4499 g, 4500–4999 g) or country-specific birthweight percentile for gestational age (50th–74th percentile [reference group], 75th–89th, 90th–94th, 95th–96th, and ≥97th percentile). Two-level logistic regression models were used to estimate odds ratios of MMMI and PMMI.ResultsA total of 246,659 singleton term births from 363 facilities in 23 low- and middle-income countries were included. Adjusted odds ratios (aORs) for intrapartum caesarean sections exceeded 2.0 when birthweight was greater than 4000 g (2 · 00 [95 % CI: 1 · 68, 2 · 39], 2 · 42 [95 % CI: 2 · 02, 2 · 89], 2 · 01 [95 % CI: 1 · 74, 2 · 33] in Africa, Asia and Latin America, respectively). aORs of MMMI reached 2.0 when birthweight was greater than 4000 g, 4500 g in Asia and Africa, respectively. aORs of PMMI approached to 2.0 (1 · 78 [95 % CI: 1 · 16, 2 · 74]) when birthweight was greater than 4500 g in Latin America. When birthweight was at the 90th percentile or higher, aORs of MMMI and PMMI increased, but none exceeded 2.0.ConclusionsThe population-specific definition of macrosomia using birthweight cut-off points irrespective of gestational age (4500 g in Africa and Latin America, 4000 g in Asia) is more predictive of maternal and perinatal adverse outcomes, and simpler to apply compared to the definition based on birthweight percentile for a given gestational age.Electronic supplementary materialThe online version of this article (doi:10.1186/s12884-015-0765-z) contains supplementary material, which is available to authorized users.

JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.

The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. Ó2016 AACR.