1,721,195 research outputs found
Retinoid receptors in health and disease: co-regulators and the chromatin connection
No full textRetinoid receptors behave as ligand-dependent transcriptional regulators, repressing transcription in the absence of ligand and activating transcription in its presence. The different effects on transcription are carried out through recruitment of co-regulators: unliganded receptors bind corepressors (NCoR and SMRT) that are found within a complex containing histone deacetylase (HDAC) activity, whereas liganded receptors recruit coactivators with histone acetylase activity (HATs). Chromatin remodeling activities have also shown to be required, suggesting a hierarchy of promoter structure modifications in RA target genes carried out by multiple coregulatory complexes. In this review, we examine the experimental evidence for the model just sketched. We focus on recent findings highlighting new molecular details in receptor-coregulator interactions, including the discovery and initial characterisation of novel complexes with multiple chromatin modifying activities. Finally, we look at the role of aberrant recruitment of the NCoRHDAC complex by altered retinoid receptors in the pathogenesis of acute promyelocytic leukemia. These results point to a crucial role for control of transcription factor coregulator interactions in the regulation of cellular processes, and suggest new molecular targets for cancer therapy
Tranylcypromine Derivatives Useful as Inhibitors Demethylases LSD1 and LSD2
No full textThe present invention relates to tranylcypromine derivatives and to their use as therapeutic
agents, particularly for the prevention and/or treatment of diseases and conditions associated
with the activity of histone demethylases LSD1 and LSD2, such as the diseases characterized by
deregulation of gene transcription, cell differentiation and proliferation, e.g. tumors, viral
infections. The invention also relates to the preparation of these compounds, as well as to
compositions containing them and to therapeutic use thereof
Recurrent varicocele: Role of antegrade sclerotherapy as first choice treatment
No full textOBJECTIVE: To underline the role of antegrade sclerotherapy as first choice treatment in recurrent varicocele. METHODS: In 53 patients, aged 11-38 years, observed over a 30-month period, antegrade sclerotherapy was carried out for the treatment of recurrent varicocele. In seven of these patients, varicocele was bilateral. The right varicocele, however, had not been previously detected and these patients were, therefore, submitted to simultaneous bilateral antegrade sclerotherapy. RESULTS: Antegrade sclerotherapy was feasible in all 53 patients (60 varicoceles) and no significant complications were observed. Unsuccessful results occurred in only two out of the 55 varicoceles observed over a minimum follow-up period of six months. CONCLUSIONS: Whilst antegrade sclerotherapy is recognized as a low-cost, safe and effective method in the management of varicocele, the success rate in recurrent varicocele is even greater than in primary varicocele. If, in the preceding treatment, the internal spermatic vein has presumably been occluded (percutaneous retrograde sclerotherapy, surgical or laparoscopic retroperitoneal ligation of the entire bundle), antegrade sclerotherapy should be considered the treatment of choice
Histone deacetylases and epigenetic therapies of hematological malignancies
No full textHistone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics.To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin lymphoma (HL) and myeloid malignancies.Several agents are also beginning to be tested in combination therapies, either as chemo sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called " epigenetic therapies" , aimed to revert epigenetic alterations found in cancer cells. Herein, we will review HDACi data in hematological malignancies questioning the molecular basis of observed clinical responses, and highlighting some of the concerns raised on the use of these drugs for cancer therapy
New diagnostic and therapeutic aspects of varicocele: Transbrachial retrograde phlebography [NUOVI ASPETTI DIAGNOSTICI E TERAPEUTICI DEL VARICOCELE: LA FLEBOGRAFIA RETROGRADA TRANSBRACHIALE]
No full text[No abstract available
Bilateral varicocele: Single transscrotal approach for Tauber antegrade sclerotherapy
No full textObjective: To describe the results of a new simple technique of single transscrotal approach for Tauber antegrade sclerotherapy in bilateral varicocele. Materials and Methods: During the period March 1998 - June 2001, overall 341 patients were treated for varicocele using Tauber antegrade sclerotherapy. In 39 of these patients, sclerotherapy was performed bilaterally in the same session whilst in 34, rather than making two incisions at the root of the two hemiscrotums, a single incision was made on the median raphe. During this period, the same approach was used in 4 patients with left varicocele and right hydrocele, 2 patients with left varicocele and right epididymis cyst, 1 patient with bilateral varicocele and bilateral hydrocele, 1 patient with bilateral hydrocele and left varicocele. Results: Maximum ray exposure time was 58 seconds (mean 30). Oro-tracheal intubation was not necessary in any of the patients. In 12 patients, besides local anesthesia, additional sedation was given. Slight bleeding of the wound, occurring in 3 patients, was medicated in the out-patient department. Conclusions: Patients prefer a single incision. When the incision is made on the median raphe, no scars remain. In bilateral varicocele, the single approach reduces invasiveness and increases patient satisfaction
Self-renewal of tumor cells : Epigenetic determinants of the cancer stem cell phenotype
No full textAmong the functional subpopulations that coexist within the tumor, 'cancer stem cells' are characterized by increased self-renewal and the ability to derive all of the other subpopulations of tumor cells ('bulk'). The functional heterogeneity among cancer stem cells and bulk cells must reflect distinct cellular epigenetic landscapes, but - due to the difficulty to isolate bona fide cancer stem cells with a high degree of purity - those different epigenetic landscapes, and the molecular mechanisms underlying them, remain largely unknown. Cues of intratumor phenotypic plasticity complicate the interpretation of the cancer stem cell phenotype: we contend that, however, the concept of cancer stem cell has crucial therapeutic implication, and remains a key target for the exploration of the cancer epigenome
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
Full text linkHistone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols
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