Effects of GLP-1 on appetite and weight

Glucagon-like peptide 1 (GLP-1) is a cleavage product of the pre-proglucagon gene which is expressed in the α-cells of the pancreas, the L-cells of the intestine, and neurons located in the caudal brainstem and hypothalamus. GLP-1 is of relevance to appetite and weight maintenance because it has actions on the gastrointestinal tract as well as the direct regulation of appetite. It delays gastric emptying and gut motility in humans. In addition, interventricular injections of GLP-1 inhibit food intake, independent of the presence of food in the stomach or gastric emptying. Peripherally administered GLP-1 also affects the central regulation of feeding. It is therefore the synergistic actions of GLP-1 in the gut and brain, acting on both central and peripheral receptors that seem responsible for the effects of the hormone on satiety.     

Growth-Phase-Dependent Expression of Virulence Factors in an M1T1 Clinical Isolate of Streptococcus pyogenes

The effect of growth phase on expression of virulence-associated factors was studied by Northern hybridization in an M1T1 clinical isolate of Streptococcus pyogenes. Expression of M protein, C5a peptidase, and capsule was maximal in the exponential phase of growth, while streptococcal pyrogenic exotoxins A and B and mitogenic factor were maximally expressed in later phases of growth.     

EVI1 splice variants modulate functional responses in ovarian cancer cells

Amplification of 3q26.2, found in many cancer lineages, is a frequent and early event in ovarian cancer. We previously defined the most frequent region of copy number increase at 3q26.2 to EVI1 (ecotropic viral integration site-1) and MDS1 (myelodysplastic syndrome 1) (aka MECOM), an observation recently confirmed by the cancer genome atlas (TCGA). MECOM is increased at the DNA, RNA, and protein level and likely contributes to patient outcome. Herein, we report that EVI1 is aberrantly spliced, generating multiple variants including a Del^190–515 variant (equivalent to previously reported) expressed in >90% of advanced stage serous epithelial ovarian cancers. Although EVI1^Del190–515 lacks ～70% of exon 7, it binds CtBP1 as well as SMAD3, important mediators of TGFβ signaling, similar to wild type EVI1. This contrasts with EVI1 1–268 which failed to interact with CtBP1. Interestingly, the EVI1^Del190–515 splice variant preferentially localizes to PML nuclear bodies compared to wild type and EVI1^Del427–515. While wild type EVI1 efficiently repressed TGFβ-mediated AP-1 (activator protein-1) and plasminogen activator inhibitor-1 (PAI-1) promoters, EVI1^Del190–515 elicited a slight increase in both promoter activities. Expression of EVI1 and EVI1^Del427–515 (but not EVI1^Del190–515) in OVCAR8 ovarian cancer cells increased cyclin E1 LMW expression and cell cycle progression. Furthermore, knockdown of specific EVI1 splice variants (both MDS1/EVI1 and EVI1^Del190–515) markedly increased claudin-1 mRNA and protein expression in HEY ovarian and MDA-MB-231 breast cancer cells. Changes in claudin-1 were associated with alterations in specific epithelial–mesenchymal transition markers concurrent with reduced migratory potential. Collectively, EVI1 is frequently aberrantly spliced in ovarian cancer with specific forms eliciting altered functions which could potentially contribute to ovarian cancer pathophysiology.     

175Yb labeled polyaminophosphonates as potential agents for bone pain palliation.

Ytterbium-175 (T1/2 = 4.2 d, Ebeta(max) = 480 keV) has radionuclidic properties suitable to be used in palliative therapy of bone metastases. 175Yb can be produced in moderate specific activity and good radionuclidic purity by thermal neutron bombardment of natural Yb target. The analysis of the neutron irradiated sample exhibited the presence of 96.2% 175Yb along with 2.1% 169Yb and 1.7% 177Lu at 6 h post-EOB. Four polyaminomethylene phosphonic acid ligands, ethylenediamine tetramethylene phosphonic acid, propylenediamine tetramethylene phosphonic acid, triethylenetetramine hexamethylene phosphonic acid and diethylenetriamine pentamethylene phosphonic acid were synthesized and radiolabeled with 175Yb. Complexation parameters were optimized to achieve maximum yields (92-99%). All complexes were found to retain their stability at room temperature even after 10d of preparation. Biodistribution studies of the complexes carried out in Wistar rats showed significant bone uptake (3-4.4%/g in tibia at 3h post-injection) with rapid clearance from blood and minimum uptake in soft tissues for all the complexes (bone/blood ratio approximately 40-150 and bone/muscles ratio approximately 40-400 at 3 h post-injection). These studies suggest that 175Yb complexes with the phosphonate ligands have potential for use in palliative treatment of painful bone metastases.