Towards an integrated cellular and molecular: definition of breast cancers

Breast cancer is a major health problem as well as scientifically poorly understood. Our knowledge of breast cancer is however rapidly progressing in several directions. First, genomic studies are establishing a new molecular classification of breast cancers. Molecular subtypes have been identified and are being associated with the histoclinical forms of breast cancers. Second, genetic alterations are discovered and classified, generating new potential therapeutical targets. Third, mammary stem cells have been identified in the normal mammary epithelium. Their altered counterparts have been identified in tumors and are being characterized. These combined studies allow a new integrated cellular and molecular definition of breast cancers and a conceptual basis that will help the management of the disease.     

Analysis of gene order data supports vertical inheritance of the leukotoxin operon and genome rearrangements in the 5' flanking region in genus <Emphasis Type="Italic">Mannheimia</Emphasis>

Background  

The Mannheimia subclades belong to the same bacterial genus, but have taken divergent paths toward their distinct lifestyles. For example, M. haemolytica + M. glucosida are potential pathogens of the respiratory tract in the mammalian suborder Ruminantia, whereas M. ruminalis, the supposed sister group, lives as a commensal in the ovine rumen. We have tested the hypothesis that vertical inheritance of the leukotoxin (lktCABD) operon has occurred from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades by exploring gene order data.     

Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.     

Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.     

Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.     

Abundance of two threatened woodpecker species in relation to the proportion of spruce plantations in native pine forests of western Norway

In a comparative study we investigated woodpecker abundance in forest landscapes with different proportion of native pine forest and spruce plantations in western Norway. In 100 circular study plots of 100ha each we recorded 38 white-backed –Dendrocopos leucotos, 22 grey-headed –Picus canus, 13 great spotted –Dendrocopos major, 6 green –Picus viridis, and 2 lesser spotted –Dendrocopos minor woodpeckers in the breeding season. The mean number of recorded woodpecker species peaked at 20–40% spruce plantations. The two most common species in the study, the white-backed and the grey-headed woodpeckers are both Red-listed species in Norway and among the rarest woodpeckers in Europe. The white-backed woodpecker preferred plots with higher than average proportions of standing dead trees and deciduous trees, and low proportions of spruce plantations in the plots. The grey-headed woodpecker preferred plots in the western (coastal) parts of the study area with presence of large aspen Populus tremula trees. Logistic regression models did not reveal any clear threshold values with respect to proportion of spruce plantations in plots, although both woodpecker species were extremely rare in plots with >60% spruce plantations. We recommend spruce plantations to be kept at moderate levels to ensure viable populations of woodpeckers in western Norway.     

Mesenchymal stem cell therapy to rebuild cartilage

Disorders affecting cartilage touch almost the whole population and are one of the leading causes of invalidity in adults. To repair cartilage, therapeutic approaches initially focused on the implantation of autologous chondrocytes, but this technique proved unsatisfactory because of the limited number of chondrocytes obtained at harvest. The discovery that several adult human tissues contain mesenchymal stem cells (MSCs) capable of differentiating into chondrocytes raised the possibility of injecting MSCs to repair cartilages. The important data published recently on the factors controlling chondrocyte commitment must be thoroughly considered to make further progress towards this therapeutic approach. The potential application of MSC therapy provides new hope for the development of innovative treatments for the repair of cartilage disorders.     

A plasminogen-like protein, present in the apical extracellular environment of thyroid epithelial cells, degrades thyroglobulin in vitro

The prothyroid hormone, thyroglobulin (Tg), is stored at high concentrations in the thyroid follicular lumen as a soluble 19S homo-dimer and as heavier soluble (27S and 37S) and insoluble (Tgm) forms. Follicular degradation of Tg may contribute to maintaining Tg concentrations compatible with follicle integrity. Here, we report on the presence of a plasminogen-like protein in the follicular lumen of normal human thyroids and its synthesis and apical secretion by cultured epithelial thyroid cells. Since all the main luminal forms of Tg are cleaved by this plasminogen-like protein, we suggest that it contributes to Tg degradation in the follicular lumen.