Mechanisms of RET signaling in cancer: current and future implications for targeted therapy.

De-regulation of RET signaling by oncogenic mutation, gene rearrangement, overexpression or transcriptional up-regulation is implicated in several human cancers of neuroendocrine and epithelial origin (thyroid, breast, lung). Understanding how RET signaling mechanisms associated with these oncogenic events are deregulated, and their impact in the biological processes driving tumor formation and progression, as well as response to treatment, will be crucial to find and develop better targeted therapeutic strategies. In this review we emphasie the distinct mechanisms of RET signaling in cancer and summarise current knowledge on small molecule inhibitors targeting the tyrosine kinase domain of RET as therapeutic drugs in RET-positive cancers.

Comparison of two HIV testing strategies in primary care centres: indicator-condition-guided testing vs. testing of those with non-indicator conditions.

OBJECTIVES: The aim of the study was to compare prospectively indicator-condition (IC)-guided testing versus testing of those with non-indicator conditions (NICs) in four primary care centres (PCCs) in Barcelona, Spain. METHODS: From October 2009 to February 2011, patients aged from 18 to 65 years old who attended a PCC for a new herpes zoster infection, seborrhoeic eczema, mononucleosis syndrome or leucopenia/thrombopenia were included in the IC group, and one in every 10 randomly selected patients consulting for other reasons were included in the NIC group. A proportion of patients in each group were offered an HIV test; those who agreed to be tested were given a rapid finger-stick HIV test (€6 per test). Epidemiological and clinical data were collected and analysed. RESULTS: During the study period, 775 patients attended with one of the four selected ICs, while 66,043 patients presented with an NIC. HIV screening was offered to 89 patients with ICs (offer rate 11.5%), of whom 85 agreed to and completed testing (94.4 and 100% acceptance and completion rates, respectively). In the NIC group, an HIV test was offered to 344 persons (offer rate 5.2%), of whom 313 accepted (90.9%) and 304 completed (97.1%) testing. HIV tests were positive in four persons [prevalence 4.7%; 95% confidence interval (CI) 1.3-11.6%] in the IC group and in one person in the NIC group (prevalence 0.3%; 95% CI 0.01-1.82%; P < 0.009). If every eligible person had taken an HIV test, we would have spent €4650 in the IC group and €396,258 in the NIC group, and an estimated 36 (95% CI 25-49) and 198 persons (95% CI 171-227), respectively, would have been diagnosed with HIV infection. The estimated cost per new HIV diagnosis would have been €129 (95% CI €107-153) in the IC group and €2001 (95% CI €1913-2088) in the NIC group. CONCLUSIONS: Although the number of patients included in the study was small and the results should be treated with caution, IC-guided HIV testing, based on four selected ICs, in PCCs seems to be a more feasible and less expensive strategy to improve diagnosis of HIV infection in Spain than a nontargeted HIV testing strategy.

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.

Estudio comparativo entre dos tipos de entrenamiento para el mantenimiento cognitivo en personas mayores / Comparative study of two cognitive training procedures for elderly people

Este trabajo compara dos procedimientos de entrenamiento en funciones cognitivas con personas mayores. Un total de 65 mujeres y 15 hombres, con edades comprendidas entre 55 y 83 años, fueron evaluados con el Mini Examen Cognoscitivo y el Test Conductual de Memoria Rivermead. Los participantes, fueron asignados al azar a dos grupos de entrenamiento. El grupo informatizado recibió 14 sesiones de entrenamiento de 30 minutos cada una con el software informático “Cómo mejorar tus habilidades mentales”; y el grupo de papel y lápiz recibió las mismas sesiones y utilizó como entrenamiento cognitivo actividades variadas de lápiz y papel. Los resultados muestran una mejoría significativa en las puntuaciones obtenidas en ambos tests. Sin embargo, no se apreciaron diferencias estadísticamente significativas entre ambos grupos de tratamiento

Two cognitive training procedures for elderly people were compared in this study. 65 women and 15 men, aged from 55 to 83, members of a special university course for old people were assessed by the Mini Cognitive Exam and the Rivermead Memory test. Participants were randomly assigned in two different training groups: Pencil and paper group and computer group. The computer group (n = 43) received 14,30-minute training sessions with the software “How to improve your mental skills”. The pencil and paper group (n = 40) received 14,30-minute training sessions with a variety of memory, concentration and attention pencil and paper exercises. Results show significantly higher scores in both tests. However, cross treatment comparison was not statistically significant

Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations.

BACKGROUND: Activating mutations in the RET gene, which encodes a tyrosine kinase receptor, often cause medullary thyroid carcinoma (MTC). Surgical resection is the only curative treatment; no effective systemic treatment is available. We evaluated imatinib, a tyrosine kinase inhibitor currently used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, as a potential drug for systemic treatment of MTC, in 2 MTC-derived cell lines expressing multiple endocrine neoplasia-associated mutant RET receptors. METHODS: We determined RET expression and Y1062 phosphorylation using Western blot analysis and quantitative polymerase chain reaction. We determined the effects on cell proliferation by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and we used fluorescence-activated cell sorter analysis with annexin V/propidium iodide staining to study imatinib-induced cell-cycle arrest, apoptosis, and cell death. RESULTS: Imatinib inhibited RET Y1062 phosphorylation in a dose-dependent manner after 1.5 hours of exposure. After 16 hours both RET Y1062 phosphorylation and protein expression levels were affected. Dose-dependent decreases in cell proliferation of both cell lines after exposure to imatinib with inhibitory concentration of 50% levels of 23 +/- 2 micromol/L and 25 +/- 4 micromol/L were seen. These values are high, compared with those for chronic myelogenous leukemia and gastrointestinal stromal tumors. We further could show that imatinib induced cell-cycle arrest, and apoptotic and nonapoptotic cell death. CONCLUSIONS: Imatinib inhibits RET-mediated MTC cell growth affecting RET protein levels in vitro in a dose-dependent manner. The concentration of imatinib necessary to inhibit RET in vitro, however, makes it impossible to conclude that imatinib monotherapy will be a good option for systemic therapy of MTC.