60 research outputs found
PHOX2B-Mediated Regulation of ALK Expression: In Vitro Identification of a Functional Relationship between Two Genes Involved in Neuroblastoma
BACKGROUND: Neuroblastoma (NB) is a severe pediatric tumor originating from neural crest derivatives and accounting for 15% of childhood cancer mortality. The heterogeneous and complex genetic etiology has been confirmed with the identification of mutations in two genes, encoding for the receptor tyrosine kinase Anaplastic Lymphoma Kinase (ALK) and the transcription factor Paired-like Homeobox 2B (PHOX2B), in a limited proportion of NB patients. Interestingly, these two genes are overexpressed in the great majority of primary NB samples and cell lines. These observations led us to test the hypothesis of a regulatory or functional relationship between ALK and PHOX2B underlying NB pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Following this possibility, we first confirmed a striking correlation between the transcription levels of ALK, PHOX2B and its direct target PHOX2A in a panel of NB cell lines. Then, we manipulated their expression in NB cell lines by siRNA-mediated knock-down and forced over-expression of each gene under analysis. Surprisingly, PHOX2B- and PHOX2A-directed siRNAs efficiently downregulated each other as well as ALK gene and, consistently, the enhanced expression of PHOX2B in NB cells yielded an increment of ALK protein. We finally demonstrated that PHOX2B drives ALK gene transcription by directly binding its promoter, which therefore represents a novel PHOX2B target. CONCLUSIONS/SIGNIFICANCE: These findings provide a compelling explanation of the concurrent involvement of these two genes in NB pathogenesis and are going to foster a better understanding of molecular interactions at the base of the disease. Moreover, this work opens new perspectives for NBs refractory to conventional therapies that may benefit from the design of novel therapeutic RNAi-based approaches for multiple gene targets
Episodes of Fall Asleep During Day Time in an Elder Woman with Vascular Dementia: Impact on Cerebral Ischeamic Tolerance and Utility of ECG Holter Monitoring
Here we report the case of an 86-year-old woman with advanced dementia addressed to our service for routinary ECG Holter Monitoring (EHM) for bradycardia in AV block type I. Several day-time episodes of fall-asleep while sitting had been previously reported by the nurse and generally attributed to the dementia itself, without taking into consideration the hypothesis of an AV block. The EHM reading reported several and often subsequent pauses (561), many of them critical, the longest lasting 15,9 s with no changes in clinical condition of the patient. The results of the EHM were reported to the physicians in charge for the patient and subsequently the woman was referred to the arrhythmology unit for pace-maker device implantation. Generalizing our experience, we suggest that advanced dementia, often associated with episodes of fall-asleep, could mask a conduction disturbance causing critical pauses with syncope; therefore we suggest screening those patients for possible arrhythmic disorders. Finally, we remark that in our patient the pauses weren’t associated with a worsening of the patient as seen in the follow-up, and this fact supports the hypothesis that vascular dementia could increase cerebral ischaemic tolerance
Abstract 5620: Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in preclinical settings
Decoupling property of the supersymmetric Higgs sector with four doublets
In supersymmetric standard models with multi Higgs doublet fields,
selfcoupling constants in the Higgs potential come only from the D-terms at the
tree level. We investigate the decoupling property of additional two heavier
Higgs doublet fields in the supersymmetric standard model with four Higgs
doublets. In particular, we study how they can modify the predictions on the
quantities well predicted in the minimal supersymmetric standard model (MSSM),
when the extra doublet fields are rather heavy to be measured at collider
experiments. The B-term mixing between these extra heavy Higgs bosons and the
relatively light MSSM-like Higgs bosons can significantly change the
predictions in the MSSM such as on the masses of MSSM-like Higgs bosons as well
as the mixing angle for the two light CP-even scalar states. We first give
formulae for deviations in the observables of the MSSM in the decoupling region
for the extra two doublet fields. We then examine possible deviations in the
Higgs sector numerically, and discuss their phenomenological implications.Comment: 26 pages, 24 figures, text sligtly modified,version to appear in
Journal of High Energy Physic
Targeting Liposomal Chemotherapy via Both Tumor Cell–Specific and Tumor Vasculature–Specific Ligands Potentiates Therapeutic Efficacy
Editorial of the Special Issue “Targeted Therapies for Cancer”
Cancer, the second leading cause of death worldwide, continues to represent an impressive challenge for researchers and clinicians [...
Novel Immunotherapeutic Approaches for Neuroblastoma and Malignant Melanoma
Neuroblastoma (NB) and malignant melanoma (MM), tumors of pediatric age and adulthood, respectively, share a common origin, both of them deriving from the neural crest cells. Although NB and MM have a different behavior, in respect to age of onset, primary tissue involvement and metastatic spread, the prognosis for high stage-affected patients is still poor, in spite of aggressive treatment strategies and the huge amount of new discovered biological knowledge. For these reasons researchers are continuously attempting to find out new treatment options, which in a near future could be translated to the clinical practice. In the last two decades, a strong effort has been spent in the field of translational research of immunotherapy which led to satisfactory results. Indeed, several immunotherapeutic clinical trials have been performed and some of them also resulted beneficial. Here, we summarize preclinical studies based on immunotherapeutic approaches applied in models of both NB and MM
Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer
Macrophages, cells belonging to the innate immune system, present a high plasticity grade, being able to change their phenotype in response to environmental stimuli. They play central roles during development, homeostatic tissue processes, tissue repair, and immunity. Furthermore, it is recognized that macrophages are involved in chronic inflammation and that they play central roles in inflammatory diseases and cancer. Due to their large involvement in the pathogenesis of several types of human diseases, macrophages are considered to be relevant therapeutic targets. Nanotechnology-based systems have attracted a lot of attention in this field, gaining a pivotal role as useful moieties to target macrophages in diseased tissues. Among the different approaches that can target macrophages, the most radical is represented by their depletion, commonly obtained by means of clodronate-containing liposomal formulations and/or depleting antibodies. These strategies have produced encouraging results in experimental mouse models. In this review, we focus on macrophage targeting, based on the results so far obtained in preclinical models of inflammatory diseases and cancer. Pros and cons of these therapeutic interventions will be highlighted
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