RANKL inhibitors for osteosarcoma treatment: hope and caution

Chen and collaborators propose RANKL blockade for the treatment and prevention of aggressive RANKL-overexpressing osteosarcoma (OS) in humans. Here we comment the main findings, putative applications and concerns. OS is the most common primary bone cancer, which occurs primarily in children and adolescents, severely affecting survivors’ quality of life. Current treatment for newly diagnosed OS includes three main components: preoperative chemotherapy, surgical resection, and postoperative chemotherapy (1). This strategy has improved the outcome of patients with localized OS. However, patients with advanced, metastatic, and recurrent OSs continue to experience a quite poor prognosis. After aggressive treatment with both surgery and chemotherapy, the 5-year survival rate for OS patients with localized disease is about 65%, whereas it is less than 20% for patients with metastases. The use of adjuvant chemotherapy provides no survival advantage for patients with pulmonary metastases (2). So that, it is of particular importance to develop molecularly targeted therapy to treat patients with this metastatic bone malignancy, on the basis of in-depth understanding of signaling mechanisms involved in OS tumorigenesis

Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor kappa B ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second-and third-generation bisphosphonates were developed, particularly zoledronic add (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours

European Network of Breast Development and Cancer turned 10 years: a growing family of mammary gland researchers

The European Network for Breast Development and Cancer (ENBDC), a worldwide network (http://www.enbdc.org/), celebrated its tenth anniversary with a fantastic meeting last March 15-17, 2018 in Weggis with 76 attendees

Adaptación curricular por competencias como medida educativa inclusiva. Exposición de un caso con amplias dificultades de comunicación y lenguaje en Educación Infantil

La comunicación en el ser humano es la clave del aprendizaje, progreso y evolución social, por lo que la carencia de la misma puede portear serias dificultades en el desarrollo psicológico, educativo y social de los niños y niñas. En la etapa de Educación Infantil es cuando podemos detectar de forma temprana estas dificultades comunicativas, por lo que la rápida prevención, diagnóstico e intervención de las mismas facilitarán dar respuesta educativa de la manera más adecuada posible. En este trabajo, tratamos de exponer un caso real de un niño con amplias dificultades de comunicación y lenguaje en Educación Infantil y cómo la medida más adecuada para dar respuesta a sus necesidades específicas de apoyo educativo es una adaptación curricular por competencias desde una perspectiva inclusiva, enfoque que defiende una educación de calidad e igualitaria para todos, para lo cual la metodología más idónea sería el trabajo por proyectos

Una medida innovadora para la atención a la diversidad. La adaptación curricular por competencias

En la actualidad, las instituciones educativas se están adaptando a una nueva forma de diseñar y planificar el currículo. Este proceso es lento y complejo, ya que después de haberse familiarizado con las pautas establecidas por la anterior ley educativa, la nueva concepción del currículo implica una programación basada en las competencias básicas. Asimismo, la atención a la diversidad del alumnado debe seguir preservando el derecho a una educación de calidad, siguiendo las directrices de una filosofía inclusiva, democrática y compensatoria. Teniendo en cuenta estas directrices, en este artículo exponemos la adaptación curricular por competencias como medida de atención al alumnado que precisa concreciones del currículo más significativas. Partimos del hecho de la necesidad de saber elaborar programaciones didácticas por competencias y a partir de éstas concretizar la medida de atención educativa a la que hacemos mención. En nuestra opinión, la adaptación curricular por competencias puede favorecer el desarrollo integral del alumnado con necesidades específicas de apoyo educativo, empleando una metodología de trabajo por proyectos que permita desarrollar las competencia básicas, pues se basa en un proceso de enseñanza y aprendizaje globalizado y experimental que permite un aprendizaje más significativo para el alumno/a

Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability

Poly(ADP-ribose) polymerase (PARP)-1, a detector of single-strand breaks, plays a key role in the cellular response to DNA damage. PARP-1–deficient mice are hypersensitive to genotoxic agents and display genomic instability due to a DNA repair defect in the base excision repair pathway. A previous report suggested that PARP-1–deficient mice also had a severe telomeric dysfunction consisting of telomere shortening and increased end-to-end fusions (d'Adda di Fagagna, F., M.P. Hande, W.-M. Tong, P.M. Lansdorp, Z.-Q. Wang, and S.P. Jackson. 1999. Nat. Genet. 23:76–80). In contrast to that, and using a panoply of techniques, including quantitative telomeric (Q)-FISH, we did not find significant differences in telomere length between wild-type and PARP-1−/− littermate mice or PARP-1−/− primary cells. Similarly, there were no differences in the length of the G-strand overhang. Q-FISH and spectral karyotyping analyses of primary PARP-1−/− cells showed a frequency of 2 end-to-end fusions per 100 metaphases, much lower than that described previously (d'Adda di Fagagna et al., 1999). This low frequency of end-to-end fusions in PARP-1−/− primary cells is accordant with the absence of severe proliferative defects in PARP-1−/− mice. The results presented here indicate that PARP-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1−/− primary cells can be explained by the repair defect associated to PARP-1 deficiency. Finally, no interaction between PARP-1 and the telomerase reverse transcriptase subunit, Tert, was found using the two-hybrid assay

Qualitative and quantitative characterization of exosomes secreted by rat hepatocytes

Comunicaciones a congreso

Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands

Rank signaling pathway regulates mammary gland homeostasis and epithelial cell differentiation. Although Rank receptor is expressed by basal cells and luminal progenitors, its role in each individual cell lineage remains unclear. By combining temporal/lineage specific Rank genetic deletion with lineage tracing techniques, we found that loss of luminal Rank reduces the luminal progenitor pool and leads to aberrant alveolar-like differentiation with high protein translation capacity in virgin mammary glands. These Rank-deleted luminal cells are unable to expand during the first pregnancy, leading to lactation failure and impairment of protein synthesis potential in the parous stage. The unfit parous Rank-deleted luminal cells in the alveoli are progressively replaced by Rank-proficient cells early during the second pregnancy, thereby restoring lactation. Transcriptomic analysis and functional assays point to the awakening of basal bipotency after pregnancy by the induction of Rank/NF-kappa B signaling in basal parous cell to restore lactation and tissue homeostasis. Rocha and co-authors show that loss of luminal Rank signaling causes abnormal alveolar differentiation and lactation failure. Subsequent pregnancies activate bipotency in basal cells, replacing unfit luminal cells, and restoring lactation