These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.

Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.

Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic micro-RNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LCMSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. Conclusion: S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013;57:2274-2286 T he tumor microenvironment plays an important role in modulating cancer and cancer stem cell progression. 1,2 Recently, mesenchymal stem cells (MSCs), as a pivotal part of the tumor stroma, have attracted great attention for their ability to participate in tumor proliferation 3 and metastasis. 4 Although several lines of evidence demonstrate that MSCs can be activated by cancer cells and contribute to tumor progression, the Abbreviations:: cDNA, complementary DNA; ELISA, enzyme-linked immunosorbent assay; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; LCMSCs, liver cancer-associated MSCs; LN-MSCs, liver normal MSCs; miRNA, microRNA; miR-155, microRNA-155; MMP9, matrix metalloproteinases 9; MSCs, mesenchymal stem cells; qRT-PCR, quantitative real time polymerase chain reaction; siRNA, small interfering RNA; SOCS1, suppressor of cytokine signaling 1; STAT, signal transducer and activator of transcription.From the

Recently, several types of lead halide perovskites have been demonstrated as active layers in resistive switching memory or artificial synaptic devices for neuromorphic computing applications. However, the thermal instability and toxicity of lead halide perovskites severely restricted their further practical applications. Herein, the environmentally friendly and uniform Cs3Cu2I5 perovskite films are introduced to act as the active layer in the Ag/Cs3Cu2I5/ITO memristor. Generally, the Ag ions could react with iodide ions and form AgI x compounds easily, so the Ag/PMMA/Cs3Cu2I5/ITO memristor was designed by employing the ultrathin polymethylmethacrylate (PMMA) layer to avoid the direct contact between the top Ag electrode and Cs3Cu2I5 perovskite films. After optimization, the obtained memristor demonstrated bipolar resistive switching with low operating voltage (< ±1 V), large on/off ratio (102), stable endurance (100 cycles), and long retention (>104 s). Additionally, biological synaptic behaviors including long-term potentiation and long-term depression have been investigated. By using the MNIST handwritten recognition data set, the handwritten recognition rate based on experimental data could reach 94%. In conclusion, our work provides the opportunity of exploring the novel application for the development of next-generation neuromorphic computing based on lead-free halide perovskites.

Emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor-related miRNAs were significantly decreased. Among these miRNAs, miR-125b expression was most strongly suppressed. We also found down-regulation of miR-125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR-125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR-125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR-125b attenuated EMT-associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR-125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR-125b suppressed EMT and EMT-associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR-125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR-125b for liver cancer. Conclusion: miR-125b exerts inhibitory effects on EMT and EMT-associated traits in HCC by SMAD2 and 4. Ectopic expression of miR125b provides a promising strategy to treat HCC. (HEPATOLOGY 2015;62:801-815) H epatocellular carcinoma (HCC) is the fifthmost common cancer in the world and has a high mortality because of a lack of effective treatments. 1 Most HCC patients display symptoms of intrahepatic metastases or postsurgical recurrence with a low survival rate. Emerging evidence suggests that the epithelial-mesenchymal transition (EMT) contributes to tumor metastasis and recurrence, including in liver

Altered hedgehog signaling is implicated in the development of approximately 20-25% of all cancers, especially those of soft tissues. Genetic evidence in mice as well as immunolocalization studies in human breast cancer specimens suggest that deregulated hedgehog signaling may contribute to breast cancer development. Indeed, two recent studies demonstrated that anchorage-dependent growth of some human breast cancer cell lines is impaired by cyclopamine, a potent hedgehog signaling antagonist targeting the Smoothened (SMO) protein. However, specificity of cyclopamine at the dosage required for growth inhibition (> or =10 microM) remained an open question. In this paper we demonstrate that hedgehog signaling antagonists, including cyclopamine, and a second compound, CUR0199691, can inhibit growth of estrogen receptor (ER)-positive and ER-negative tumorigenic breast cancer cells at elevated doses. However, our results indicate that, for most breast cancer cell lines, growth inhibition by these compounds can be independent of detectable Smo gene expression. Rather, our results suggest that cyclopamine and CUR0199691 have unique secondary molecular targets at the dosages required for growth inhibition that are unrelated to hedgehog signaling.

This study analysed the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, group 4 had lower clinical pregnancy and live birth rates as well as the highest ectopic pregnancy rate (29.15% versus 45.91%; 18.67% versus 34.34%; 18.10% versus 5.82%; P<0.05). Group 3 had lower clinical pregnancy and live birth rates per embryo-transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively; P<0.05). Clinical pregnancy rates were similar in frozen-thawed embryo transfers (FET) among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. High serum oestradiol concentration on HCG day did not affect the IVF pregnancy outcome. In combination with the elevated progesterone, high oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes. The aim of this study was to analyse the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to their serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34 nmol/l and oestradiol<19,124 pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, patients in group 4 had lower clinical pregnancy (29.15% versus 45.91%) and live birth rates (18.67% versus 34.34%) as well as the highest ectopic pregnancy rate (18.1% versus 5.82%) (all P<0.05). Those in group 3 had lower clinical pregnancy and live birth rates per embryo transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively, P<0.05). Embryo quality appeared to be unaffected since similar clinical pregnancy rates in frozen-thawed embryo transfer (FET) cycles among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. A high serum oestradiol concentration on the day of HCG administration did not affect the IVF pregnancy outcome. In combination with the elevated progesterone and oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes.

The phylogeny and systematics of cordycipitoid fungi have been extensively studied in the last two decades. However, systematic positions of some taxa in the family Cordycipitaceae have not yet been thoroughly resolved. In this study, a new phylogenetic framework of Cordycipitaceae is reconstructed using multigene (nrSSU, nrLSU, tef-1α, rpb1 and rpb2) sequence data with large-scale taxon sampling. In addition, ITS sequence data of species belonging to the Lecanicillium lineage in the family Cordycipitaceae are used to further determine their phylogenetic placements. Based on molecular phylogenetic data together with morphological evidence, two new genera (Flavocillium and Liangia), 16 new species and four new combinations are introduced. In the new genus Flavocillium, one new species F. bifurcatum and three new combinations previously described as Lecanicillium, namely F. acerosium, F. primulinium and F. subprimulinium, are proposed. The genus Liangia is built by the new species Lia. sinensis with Lecanicillium-like asexual morph, isolated from an entomopathogenic fungus Beauveria yunnanensis. Due to the absence of Paecilomyces hepiali, an economically and medically significant fungus, in the earlier phylogenetic analyses, its systematic position has been puzzling in both business and academic communities for a long time. Here, P. hepiali is recharacterized using the holotype material along with seven additional samples. It is assigned to the genus Samsoniella (Cordycipitaceae, Hypocreales) possessing Cordyceps-like sexual morph and Isaria-like asexual morph, and thus a new combination, namely S. hepiali is proposed. An additional nine new species in Samsoniella are described: S. alpina, S. antleroides, S. cardinalis, S. cristata, S. lanmaoa, S. kunmingensis, S. ramosa, S. tortricidae and S. yunnanensis. Four new species in Cordyceps are described: C. chaetoclavata, C. cocoonihabita, C. shuifuensis and C. subtenuipes. Simplicillium yunnanense, isolated from synnemata of Akanthomyces waltergamsii, is described as a new species.