HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody-drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs

When, how and for whom changes in engagement happen:A transition analysis of instructional variables

The pace of our knowledge on online engagement has not been at par with our need to understand the temporal dynamics of online engagement, the transitions between engagement states, and the factors that influence a student being persistently engaged, transitioning to disengagement, or catching up and transitioning to an engaged state. Our study addresses such a gap and investigates how engagement evolves or changes over time, using a person-centered approach to identify for whom the changes happen and when. We take advantage of a novel and innovative multistate Markov model to identify what variables influence such transitions and with what magnitude, i.e., to answer the why. We use a large data set of 1428 enrollments in six courses (238 students). The findings show that online engagement changes differently —across students— and at different magnitudes —according to different instructional variables and previous engagement states. Cognitively engaging instructions helped cognitively engaged students stay engaged while negatively affecting disengaged students. Lectures —a resource that requires less mental energy— helped improve disengaged students. Such differential effects point to the different ways interventions can be applied to different groups, and how different groups may be supported. A balanced, carefully tailored approach is needed to design, intervene, or support students' engagement that takes into account the diversity of engagement states as well as the varied response magnitudes that intervention may incur across diverse students’ profiles

Theoretical Study of Spin-dependent Electron Transport in Atomic Fe Nanocontacts

We present theoretical predictions of spintronic transport phenomena that should be observable in ferromagnetic Fe nanocontacts bridged by chains of Fe atoms. We develop appropriate model Hamiltonians based on semi-empirical considerations and the known electronic structure of bulk Fe derived from ab initio density functional calculations. Our model is shown to provide a satisfactory description of the surface properties of Fe nano-clusters as well as bulk properties. Lippmann-Schwinger and Green's function techniques are used together with Landauer theory to predict the current, magneto-resistance, and spin polarization of the current in Fe nanocontacts bridged by atomic chains under applied bias. Unusual device characteristics are predicted including negative magneto-resistance and spin polarization of the current, as well as spin polarization of the current for anti-parallel magnetization of the Fe nanocontacts under moderate applied bias. We explore the effects that stretching the atomic chain has on the magneto-resistance and spin polarization and predict a cross-over regime in which the spin polarization of the current for parallel magnetization of the contacts switches from negative to positive. We find resonant transmission due to dangling bond formation on tip atoms as the chain is stretched through its breaking point to play an important role in spin-dependent transport in this regime. The physical mechanisms underlying the predicted phenomena are discussed.Comment: 13 pages, 6 figures, Accepted for publication in Physical Review

CDK4/6 inhibition in breast cancer: current practice and future directions

The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes

Los mayores y las nuevas tecnologías de la comunicación

[Resumen] Fundamentos: En una sociedad envejecida es necesario establecer nuevas alternativas que de alguna manera traten de satisfacer las necesidades de las personas mayores, a la vez que incrementen su calidad de vida percibida. En este sentido, las nuevas tecnologías, como la informática, se han convertido en una herramienta básica de nuestra sociedad, de la que los mayores, sin ninguna duda, podrán beneficiarse. El objetivo del presente trabajo es conocer la opinión de los mayores acerca de temas relacionados con la informática e Internet, así como su capacidad de acceso a las nuevas tecnologías y los conocimientos con los que cuentan. Métodos: Se realiza una entrevista estandarizada, de diseño propio, a una muestra de 105 personas mayores con una edad media de 73 años, residentes en la ciudad de A Coruña. Resultados: De los resultados obtenidos se constata que aunque la mayoría de las personas mayores no cuenta con ordenador personal ni ha trabajado con aplicaciones informáticas, les gustaría aprender más sobre este campo. Además, cuando se conectan a Internet lo hacen desde centros sociales y/o educativos, no encontrando excesivos problemas en su manejo y navegación. Conclusiones: Es necesario fomentar el uso de la informática por parte de los mayores, ya que en un futuro puede constituir una herramienta imprescindible en la intervención sobre problemas inherentes al envejecimiento como son el aislamiento o la soledad entre otros.[Abstract] new alternatives, that somehow try to satisfy the needs of elderly people and that at the same time increase their quality of life. On this sense, the new technologies, such as computer science, have become a basic tool of our society, and the elderly, without no doubt will be able to benefit from it. The objective of the present work is to know what the elderly think about themes related to computer science and internet, as well as their capacity of accessing to new technologies, and the knowledge that they have about them. Methods: A standarized interview has been made, it´s self designed, to a sample of 105 elderly people living in the city of A Coruña. Results: Although most elderly people don´t have a personal computer neither have worked with a computer application, would like to learn more about this field. When they are connected to internet they do it from social and/or educative centres, not having great problems neither in its handling or navigation. Conclusions: It´s necessary to promote the use of computer science on the elderly people, since in a future it can constitute an essential tool in the intervention on inherent problems to aging such as isolation or loneliness among others

Expression of a barley cystatin gene in maize enhances resistance against phytophagous mites by altering their cysteine-proteases

Phytocystatins are inhibitors of cysteine-proteases from plants putatively involved in plant defence based on their capability of inhibit heterologous enzymes. We have previously characterised the whole cystatin gene family members from barley (HvCPI-1 to HvCPI-13). The aim of this study was to assess the effects of barley cystatins on two phytophagous spider mites, Tetranychus urticae and Brevipalpus chilensis. The determination of proteolytic activity profile in both mite species showed the presence of the cysteine-proteases, putative targets of cystatins, among other enzymatic activities. All barley cystatins, except HvCPI-1 and HvCPI-7, inhibited in vitro mite cathepsin L- and/or cathepsin B-like activities, HvCPI-6 being the strongest inhibitor for both mite species. Transgenic maize plants expressing HvCPI-6 protein were generated and the functional integrity of the cystatin transgene was confirmed by in vitro inhibitory effect observed against T. urticae and B. chilensis protein extracts. Feeding experiments impaired on transgenic lines performed with T. urticae impaired mite development and reproductive performance. Besides, a significant reduction of cathepsin L-like and/or cathepsin B-like activities was observed when the spider mite fed on maize plants expressing HvCPI-6 cystatin. These findings reveal the potential of barley cystatins as acaricide proteins to protect plants against two important mite pests