Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression

Lysophosphatidic acid (LPA) is a potent lipid mediator that acts on a series of specific G protein-coupled receptors, leading to diverse biological actions. Lysophosphatidic acid induces cell proliferation, survival and migration, which are critically required for tumour formation and metastasis. This bioactive lipid is produced by the ectoenzyme lysophospholipase D or autotaxin (ATX), earlier known as an autocrine motility factor. The ATX–LPA signalling axis has emerged as an important player in many types of cancer. Indeed, aberrant expression of ATX and LPA receptors occurs during the development and progression of breast cancer. Importantly, expression of either ATX or LPA receptors in the mammary gland of transgenic mice is sufficient to induce the development of a high frequency of invasive and metastatic mammary cancers. The focus of research now turns to understanding the mechanisms by which ATX and LPA promote mammary tumourigenesis and metastasis. Targeting the ATX–LPA signalling axis for drug development may further improve outcomes in patients with breast cancer

Stat3 Mediates Expression of Autotaxin in Breast Cancer

We determined that signal transducer and activator of transcription 3 (Stat3) is tyrosine phosphorylated in 37% of primary breast tumors and 63% of paired metastatic axillary lymph nodes. Examination of the distribution of tyrosine phosphorylated (pStat3) in primary tumors revealed heterogenous expression within the tumor with the highest levels found in cells on the edge of tumors with relatively lower levels in the central portion of tumors. In order to determine Stat3 target genes that may be involved in migration and metastasis, we identified those genes that were differentially expressed in primary breast cancer samples as a function of pStat3 levels. In addition to known Stat3 transcriptional targets (Twist, Snail, Tenascin-C and IL-8), we identified ENPP2 as a novel Stat3 regulated gene, which encodes autotaxin (ATX), a secreted lysophospholipase which mediates mammary tumorigenesis and cancer cell migration. A positive correlation between nuclear pStat3 and ATX was determined by immunohistochemical analysis of primary breast cancer samples and matched axillary lymph nodes and in several breast cancer derived cell lines. Inhibition of pStat3 or reducing Stat3 expression led to a decrease in ATX levels and cell migration. An association between Stat3 and the ATX promoter, which contains a number of putative Stat3 binding sites, was determined by chromatin immunoprecipitation. These observations suggest that activated Stat3 may regulate the migration of breast cancer cells through the regulation of ATX

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Transgressive segregation in F2 generation of maize hybrids grown for grain and silage

W latach 2005 i 2007, na polach Zakładu Doświadczalno-Dydaktycznego w Gorzyniu filia Swadzim (52o29’ N; 16o46’ E), należącego do Uniwersytetu Przyrodniczego w Poznaniu, przeprowadzono 2 dwuczynnikowe doświadczenia, które miały na celu określenie wielkości spadku plonu ziarna oraz surowca do zakiszania pokolenia F2 mieszańców kukurydzy w porównaniu z pokoleniem F1. Spadek plonu ziarna po wysianiu pokolenia F2 zależał od warunków wegetacji i odmiany. W roku niekorzystnym dla plonowania kukurydzy wyniósł on średnio dla odmian 3,16 t·ha-1, co stanowiło 31,8%, z kolei w roku sprzyjającym uprawie kukurydzy – 2,81 t·ha-1 (23,5%). Po wysiewie pokolenia F2 badanych mieszańców kukurydzy straty z tytułu spadku plonu ziarna znacznie przekraczały koszt zakupu materiału siewnego. W 2005 roku wyniosły one średnio 781,4 zł·ha-1, zaś w 2007 – 1525,3 zł·ha-1. Plony świeżej masy surowca do zakiszania były także niższe po wysiewie pokolenia F2 mieszańców, a spadek plonu wyniósł średnio 6,71 t·ha-1 (21,2%) w 2005 roku oraz 5,68 t·ha-1 (8,8%) w 2007. Surowiec do zakiszania zebrany z pokolenia F2 mieszańców charakteryzował się niższym udziałem kolb w porównaniu z uzyskanym z pokolenia F1.The trials were carried out in 2005 and 2007 at the Experimental Station Swadzim (52o29’ N; 16o46’ E) of the University of Life Sciences in Poznań. The goal of two-factorial trials was to evaluate a decrease in yield of grain and plant raw material for ensiling from F2 maize generation compared with F1. The decrease in grain yield in F2 depended on vegetation conditions and the cultivar. In the unfavorable season for maize growing, the average decrease for cultivar amounted to 3.16 t·ha-1, i.e. 31.8%, while in the favorable season, this was 2.81 t·ha-1 and 23.5%, respectively. The losses caused by a decrease in grain yields in F2 significantly exceeded the cost of seed material. In 2005 these amounted on average up to 781.4 PLN·ha-1, and in 2007 – 1525.3 PLN·ha-1. The yield of raw material for ensiling was also lower from F2 generation and on average amounted to 6.71 t·ha-1 (21.2%) in 2005 and 5.68 t·ha-1 (8.8%) in 2007. Moreover, the raw material for ensiling from F2 had lower cob content compared with F1