Manajemen Program Siaran Lokal Aceh TV Dalam Upaya Penyebarluasan Syariat Islam Dan Pelestarian Budaya Lokal

Managing broadcasting management is not easy. Managing the broadcasting business is a difficult and challenging. This research aims to analyze the activity of management and organizational performance ACEH TV television media in an effort to disseminate the Islamic Sharia and Preservation of Local Culture in Aceh. This research is descriptive qualitative. Informants of this research is managing director, program director, executive producer, cameraman / reporter, as well as additional informants Regional Chairman of the Indonesian Broadcasting Commission (KPID) Aceh, Aceh Province Department of Islamic Law, and local media observers. The location of this research is in Banda Aceh, Aceh province. Sampling was done purposively. Data collected through observation, interviews, and documentation. Data were analyzed by analysis of an interactive model of Miles and Huberman. The results showed that the ACEH TV as the medium of television that is broadcasting management ACEH have done according to a local television broadcasting standard. Agenda setting function of mass media performed in the ACEH TV dissemination of Islamic Shariah in Aceh and local culture to influence the people of Aceh to implement Islamic Sharia and also maintain the culture and local wisdom Aceh. It can be seen from all the programs that are aired ACEH TV is a program of local cultural nuances of Islamic law. There are still some shortcomings in running broadcasting broadcasting technology such as lack of equipment that is increasingly sophisticated. The results of image editing is very simple, and some programs presenter still looks stiff when in front of the camera

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

En oncologie, les 18 membres de la famille des déacétylases d’histone (HDAC) représentent des cibles thérapeutiques d’intérêt croissant. En effet, de nombreuses molécules pharmacologiques ciblant l’activité enzymatique de ces protéines (HDACi) montrent des effets anti-tumoraux intéressants in vitro et in vivo ainsi que dans de nombreux essais cliniques sur des patients souffrant de pathologies cancéreuses solides et hématologiques. A ce jour, 4 de ces molécules (Vorinostat®, l’Istodax®, Beleodaq® et le Farydak®) sont d’ailleurs approuvées par la FDA et l’EMA pour le traitement de patients souffrant, notamment, de différents types de lymphomes et de myélomes. Aujourd’hui, les oncologues s’intéressent au développement d’inhibiteurs d’HDAC plus sélectifs avec comme objectifs de maintenir et d’améliorer l’effet anti-tumoral tout en diminuant la toxicité et en réduisant les potentiels effets non désirés. Dans cette optique, il convient de déterminer plus finement les relations qu’il existe entre l’inhibition spécifique d’une HDAC et les effets anti- tumoraux observés et ce, afin d’identifier la (les) HDAC d’intérêt à cibler en thérapie anti-cancéreuse. Dans ce travail, nous nous sommes focalisés sur le rôle et les mécanismes d’action de l’histone déacétylase 5 (HDAC5) dans les cellules cancéreuses. Nos résultats démontrent que l’inhibition sélective d’HDAC5 module l’expression de protéines du complexe I de la chaîne respiratoire mitochondriale, de protéines pro- et anti- oxydantes et des protéines impliquées dans le métabolisme de métaux tel que le métabolisme de stockage du fer labile. Par conséquent, la déplétion d’HDAC5 induit une production accrue d’espèces réactives de l’oxygène (ROS) mitochondriaux accentués par la présence accrue de fer labile intracellulaire disponible pour la réaction de Fenton. Cette accumulation accrue de ROS induit une mort cellulaire par apoptose et un processus d’autophagie de type mitophagie (dégradation sélective des mitochondries endommagées et productrice de ROS). La déplétion d’HDAC5 dans des cellules cancéreuses modifie également le métabolisme énergétique dépendant du glucose et de la glutamine. Nous avons effectivement observé d’une part, une augmentation de l’import du glucose dirigé vers la voie des pentoses phosphates assurant une production de NADPH, force réductrice du glutathion permettant ainsi de contrecarrer le stress oxydant et d’autre part, une glutamino-dépendance nécessaire au maintien des besoins énergétiques de la cellule. Par conséquent, des cellules déplétées en HDAC5 dont l’apport en glucose ou en glutamine est contrecarré par des inhibiteurs métaboliques utilisés en clinique, meurent de manière significative par apoptose in vitro et diminuent la croissance de tumeurs in vivo, suggérant que des stratégies combinatoires couplant l’inhibition sélective d’HDAC5 à des inhibiteurs du métabolisme énergétique actuellement testés en essai clinique pourraient être proposées comme nouvelle stratégie combinatoire en thérapie anti-cancéreuse

Glucose-dependent metabolic reprogramming in HDAC5-depleted cancer cells

Histone deacetylases (HDAC) is a family of eighteen enzymes, which modulates the acetylation level of histones and non-histone proteins to regulate gene expression and chromatin structure. Broad-spectrum inhibitors of these enzymes such as SAHA can inhibit tumor growth both in vitro and in vivo and are currently used as anti-cancer agents in clinic. For many years, we are investigating the specific role of individual HDAC members in cancer biology and we have recently demonstrated that specific depletion of HDAC5 using siRNA technology reduced cancer cells proliferation and survival (PEIXOTO et al., 2012). The goal of this study is to further understand the molecular mechanisms of action of HDAC5 in cancer cells. Screening transcriptomic study demonstrated that HDAC5 depletion induces a down-regulation of subunits of the complex I of the mitochondrial respiratory chain (NDUFB5-NDUFA3) as well as anti-oxydant proteins (Ferritin, Metalothionein,¿) through modulation of mRNA stability. Therefore, HDAC5 depletion causes a significant increase of ROS production inducing both apoptosis and mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). This HDAC5 depletion-induced mitochondrial dysfunction provokes metabolic adaptation associated with increased importance of glycolysis and glucose. Indeed, interference with glucose supply in HDAC5-depleted cancer cells significantly increases apoptotic cell death suggesting that glucose deprivation might be combined to HDAC5 inhibition as a therapeutic strategy to kill cancer cells. Our study demonstrated for the first time that specific HDAC5 inhibition induces metabolic reprogramming and provides insight into a valuable experimental strategy for manipulation of specific HDAC5 inhibition and glucose metabolism in therapy against cancer. Acknowledgements This work fiancially suppoted by a grant of F.R.S .-FNRS (contract n° 7.4515.12F). E Hendrick is recipient of a Televie fellowship. References PEIXOTO et al., (2012) Cell Death and Differentiation. 7:1239-52

Role of HDAC5 depletion induced autophagy on cancer cell death

Introduction: Histone deacetylases (HDAC) is a family of eighteen enzymes which modulates the acetylation level of histones and non-histone proteins to regulate gene expression and chromatin structure. Broad spectrum inhibitors of these enzymes can inhibit tumor growth both in vitro and in vivo and are currently used in clinic as anti-cancer agents. For many years, we are investigating the specific role of individual HDAC members in cancer biology and we have recently demonstrated that depletion of HDAC5 using siRNA technology triggered cancer cells to both autophagy and apoptosis. The study of autophagy in cancer is a new research field that has recently generated tremendous attention due to the recognition that autophagy can have either pro-survival or pro-death functions depending on its level of activation. In addition, more and more studies indicate that a complex relationship exists between autophagy and apoptosis, and that the interplay between these two processes determines whether a cell will live or die. - Aims: The aim of this study is to further understand the role of autophagy induced by HDAC5 depletion. Current investigations include determining the molecular mechanisms of HDAC5 depletion-mediated autophagy and exploring regulatory relationships between autophagy and apoptosis on cancer cell death in absence of HDAC5. - Methods and results : The set up of the autophagy in absence of HDAC5 occurs trough a non-canonical pathway which depends on the JNK activation. This activation could be induced by an inappropriate ROS production. Indeed, a transcriptomic analysis performed in HDAC5 depleted Hela cells highlighted a deregulation of a set of genes implicated in ROS detoxification. This deregulation has been validated by FACS analysis. - Conclusion: Through this study we determined the molecular mechanism implicated in the autophagy induction after HDAC5 silencing. This phenomenon appears dependent of an accumulation of ROS into the cells that activates JNK and mediate cell death by autophagy and apoptosis. Now, in we hope to determine whether manipulation of autophagy may provide a useful way to increase the efficacy of treatments with HDAC inhibitors, and limit tumor progression