Validation of a one degree-of-freedom spherical model for kinematics analysis of the human ankle joint

During passive motion, the human tibiotalar (ankle) joint behaves as a single degree-of-freedom (1DOF) system [1,2]. In these conditions, fibres within the ligaments remain nearly isometric throughout the flexion arc and articular surfaces nearly rigid. Relevant theoretical models are showing that the ligaments and the articular surfaces act together as mechanisms to control the passive joint kinematics [3-5]. Kinematic measurements and corresponding model predictions also revealed that the instantaneous screw axes of passive motion pass near to a single point, hereinafter called pivot point [5]. The present study investigates the extent to which this motion is spherical-like

TERT Promoter Mutations in Papillary Thyroid Microcarcinomas

Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs

Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2.

Aberrant reactivation of embryonic pathways occurs commonly in cancer. The transcription factor RUNX2 plays a fundamental role during embryogenesis and is aberrantly reactivated during progression and metastasization of different types of human tumors. In this study, we attempted to dissect the molecular mechanisms governing RUNX2 expression and its aberrant reactivation. We identified a new regulatory enhancer element, located within the RUNX2 gene, which is responsible for the activation of the RUNX2 promoter and for the regulation of its expression in cancer cells. Furthermore, we have shown that treatment with the anticancer compounds histone deacetylase inhibitor (HDACi) results in a profound inhibition of RUNX2 expression, which is determined by the disruption of the transcription-activating complex on the identified enhancer. These data envisage a possible targeting strategy to counteract the oncongenic function of RUNX2 in cancer cells and provide evidence that the cytotoxic activity of HDACi in cancer is not only dependent on the reactivation of silenced oncosuppressors but also on the repression of oncogenic factors that are necessary for survival and progression

Update on Anaplastic Thyroid Carcinoma: Morphological, Molecular, and Genetic Features of the Most Aggressive Thyroid Cancer

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. It shows a wide spectrum of morphological presentations and the diagnosis could be challenging due to its high degree of dedifferentiation. Molecular and genetic features of ATC are widely heterogeneous as well and many efforts have been made to find a common profile in order to clarify its cancerogenetic process. A comprehensive review of the current literature is here performed, focusing on histopathological and genetic features

Update on Anaplastic Thyroid Carcinoma: Morphological, Molecular, and Genetic Features of the Most Aggressive Thyroid Cancer

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. It shows a wide spectrum of morphological presentations and the diagnosis could be challenging due to its high degree of dedifferentiation. Molecular and genetic features of ATC are widely heterogeneous as well and many efforts have been made to find a common profile in order to clarify its cancerogenetic process. A comprehensive review of the current literature is here performed, focusing on histopathological and genetic features