HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Role of Hippo pathway dysregulation from gastrointestinal premalignant lesions to cancer.

BACKGROUND: First identified in Drosophila melanogaster, the Hippo pathway is considered a major regulatory cascade controlling tissue homeostasis and organ development. Hippo signaling components include kinases whose activity regulates YAP and TAZ final effectors. In response to upstream stimuli, YAP and TAZ control transcriptional programs involved in cell proliferation, cytoskeletal reorganization and stemness. MAIN TEXT: While fine tuning of Hippo cascade components is essential for maintaining the balance between proliferative and non-proliferative signals, pathway signaling is frequently dysregulated in gastrointestinal cancers. Also, YAP/TAZ aberrant activation has been described in conditions characterized by chronic inflammation that precede cancer development, suggesting a role of Hippo effectors in triggering carcinogenesis. In this review, we summarize the architecture of the Hippo pathway and discuss the involvement of signaling cascade unbalances in premalignant lesions of the gastrointestinal tract, providing a focus on the underlying molecular mechanisms. CONCLUSIONS: The biology of premalignant Hippo signaling dysregulation needs further investigation in order to elucidate the evolutionary trajectories triggering cancer inititation and develop effective early therapeutic strategies targeting the Hippo/YAP pathway.

Evaluation of Horses' Daytime Activity Budget in a Model of Ethological Stable: A Case Study in Italy.

The increasing interest in animal welfare and the knowledge of equine physiological and ethological needs have led to the development of different types of horses' management and housing systems. The research presented here aimed to assess the daytime activity budget of horses. Focal animal sampling was used as an observational sampling method, and the five animals were observed for a total of 9920 minutes in the paddock and inside the stall. The results showed that horses spent most of the daytime in foraging behaviors, followed by resting behaviors, and locomotion. Social behaviors (s.e. allogrooming, olfactory investigation) were rare, and the stereotypic behaviors (s.e. oral and locomotor stereotypies) occupied 2.74%±2.74% of the total time. The percentage of time spent in foraging, resting, and locomotion, reflects the activity budget observed in free-roaming feral horses. However, the rare occurrence of positive social interactions and the presence of some stereotypies could be aspects to ameliorate. This kind of housing facility could be considered a good alternative to traditional management; indeed, it might offer a better trade-off between the needs of the horse and the management goals from humans.