Correction: CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models.

[This corrects the article DOI: 10.18632/genesandcancer.24.].

MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies.

KRAS mutation, which occurs in ∼ 95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate the metabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions.

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models.

In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of Her2 positive breast cancer. CDK4/6 controls pathway downstream of Her2, Inhibition of these kinases could represent an important therapeutic approach to augment the effectiveness of standard therapies. In models of acquired resistance to Her2-targeted therapies, Cyclin D1 was inappropriately activated and CDK4/6 inhibition was effective at blocking proliferation by targeting this common pathway associated with resistance. These data were recapitulated in Her2 positive xenografts. Furthermore, in a series of 35 primary breast tumor explants, treatment with PD-0332991 resulted in a greater than 4-fold suppression of the Ki67. The effects of CDK4/6 inhibition were dependent on an intact RB-pathway, and consonantly, loss of RB and high-levels of p16 were associated with resistance to CDK4/6 inhibition. Combination studies illustrated that CDK4/6 inhibition is cooperative with multiple Her2-targeted agents and provides a complementary mechanism of action to T-DM1 to efficiently suppresses the proliferation of residual Her2-positive tumor cell populations that survive T-DM1. Together, these data indicate CDK4/6 is a viable therapeutic target that functions downstream of Her2, and tissue based markers are available to direct rational utilization of CDK4/6 inhibitors in combination with Her2-targeted agents.

The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis.

Our data demonstrate that estrogens, estrogen receptor-α (ERα), and estrogen receptor-ß (ERß) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by determining that αERKO mice have increased adipose tissue inflammation and fibrosis prior to obesity onset. Selective deletion of adipose tissue ERα in adult mice using a novel viral vector technology recapitulated the findings in the total body ERα null mice. Generation of a novel mouse model, lacking ERα specifically from adipocytes (AdipoERα), demonstrated increased markers of fibrosis and inflammation, especially in the males. Additionally, we found that the beneficial effects of estrogens on adipose tissue require adipocyte ERα. Lastly, we determined the role of ERß in regulating inflammation and fibrosis, by breeding the AdipoERα into the ßERKO background and found that in the absence of adipocyte ERα, ERß has a protective role. These data suggest that adipose tissue and adipocyte ERα protects against adiposity, inflammation, and fibrosis in both males and females.

Involving the public in priority setting: a case study using discrete choice experiments.

BACKGROUND: Health-care organizations need to prioritize their resource use and should incorporate the public's preferences into their priority setting process. METHODS: We apply a discrete choice experiment (DCE) to obtain weights, from the public, for use in a priority setting exercise. Ten attributes were chosen: location of care, public consultation, use of technology, service availability, patient involvement, management of care, evidence of effectiveness, health gain, risk avoidance and priority area. From the DCE responses, weighted benefit scores were calculated and used to rank development bids from across a health-care organization. RESULTS: Sixty-eight members of the public completed the DCE. All attributes except risk avoidance were significant. The most important attribute levels were a large health gain to many people: care being provided in teams, using latest or cutting-edge technology and 24 h service availability. Local priorities were valued higher than national priorities. Ninety-five bids were ranked in order of overall score. The ranked list of development bids provided a useful tool to inform prioritization decisions. CONCLUSIONS: DCEs can offer a theoretically valid and practical means of incorporating the views of the public in an accessible, transparent and streamlined decision-making process when health-care organizations are prioritizing their resources.