Molecular and cellular pathogenesis of melanoma initiation and progression

Melanoma is a malignant tumour of melanocytes, which can spread to other organs of the body resulting in severe and/or lethal malignancies. Melanocytes are pigment producing cells found in deep layer of the epidermis and are originated from melanocytes stem cells through a cellular process called melanogenesis. Several genes, epigenetic and micro-environmental factors are involved in this process via the regulation and maintenance of the balance between melanocytes stem cells proliferation and their differentiation into melanocytes. Dysregulation of this balance through gain or loss of function of key genes implicated in the control and regulation of cell cycle progression and/or differentiation results in melanoma initiation and progression. This review aims at providing a comprehensive overview about the origin of melanocytes, the oncogenic events involved in melanocytes stem cells transformation and the mechanisms implicated in the perpetuation of melanoma malignant phenotype

Targeting RTK signaling pathways in cancer

The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of components of those pathways result in increased proliferation, survival and metastasis. For instance, mutations affecting RTKs, Ras, B-Raf, PI3K and AKT are common in perpetuating the malignancy of several types of cancers and from different tissue origins. Therefore, these signaling pathways became prime targets for cancer therapy. This review aims to provide an overview about the most frequently encountered mutations, the pathogenesis that results from such mutations and the known therapeutic strategies developed to counteract their aberrant functions

Optimal frequency control in microgrid system using fractional order PID controller using Krill Herd algorithm

This paper investigates the use of fractional order Proportional, Integral and Derivative (FOPID) controllers for the frequency and power regulation in a microgrid power system. The proposed microgrid system composes of renewable energy resources such as solar and wind generators, diesel engine generators as a secondary source to support the principle generators, and along with different energy storage devices like fuel cell, battery and flywheel. Due to the intermittent nature of integrated renewable energy like wind turbine and photovoltaic generators, which depend on the weather conditions and climate change this affects the microgrid stability by considered fluctuation in frequency and power deviations which can be improved using the selected controller. The fractional-order controller has five parameters in comparison with the classical PID controller, and that makes it more flexible and robust against the microgrid perturbation. The Fractional Order PID controller parameters are optimized using a new optimization technique called Krill Herd which selected as a suitable optimization method in comparison with other techniques like Particle Swarm Optimization. The results show better performance of this system using the fractional order PID controller-based Krill Herd algorithm by eliminates the fluctuations in frequency and power deviation in comparison with the classical PID controller. The obtained results are compared with the fractional order PID controller optimized using Particle Swarm Optimization. The proposed system is simulated under nominal conditions and using the disconnecting of storage devices like battery and Flywheel system in order to test the robustness of the proposed methods and the obtained results are compared.У статті досліджено використання регуляторів пропорційного, інтегрального та похідного дробового порядку (FOPID) для регулювання частоти та потужності в електромережі. Запропонована мікромережева система складається з поновлюваних джерел енергії, таких як сонячні та вітрогенератори, дизельних генераторів як вторинного джерела для підтримки основних генераторів, а також з різних пристроїв для накопичування енергії, таких як паливна батарея, акумулятор і маховик. Через переривчасту природу інтегрованої відновлювальної енергії, наприклад, вітрогенераторів та фотоелектричних генераторів, які залежать від погодних умов та зміни клімату, це впливає на стабільність мікромережі, враховуючи коливання частоти та відхилення потужності, які можна поліпшити за допомогою вибраного контролера. Контролер дробового порядку має п’ять параметрів порівняно з класичним PID-контролером, що робить його більш гнучким та надійним щодо збурень мікромережі. Параметри PID-контролера дробового порядку оптимізовані за допомогою нової методики оптимізації під назвою «зграя криля», яка обрана як підходящий метод оптимізації порівняно з іншими методами, такими як оптимізація методом рою частинок. Результати показують кращі показники роботи цієї системи за допомогою алгоритму «зграя криля», заснованого на PID-контролері дробового порядку, виключаючи коливання частоти та відхилення потужності порівняно з класичним PID-контролером. Отримані результати порівнюються з PID-контролером дробового порядку, оптимізованим за допомогою оптимізації методом рою частинок. Запропонована система моделюється в номінальному режимі роботи та використовує відключення накопичувальних пристроїв, таких як акумулятор та маховик, щоб перевірити надійність запропонованих методів та порівняти отримані результати

Regulation of tomato fruit ripening

Fruit ripening is a sophisticatedly orchestrated developmental process, unique to plants, that results in major physiological and metabolic changes, ultimately leading to fruit decay and seed dispersal. Because of their strong impact on fruit nutritional and sensory qualities, the ripeningassociated changes have been a matter of sustained investigation aiming at unravelling the molecular and genetic basis of fruit ripening. Tomato rapidly emerged as the model of choice for fleshy fruit research and a wealth of genetic resources and genomics tools have been developed, providing new entries into the regulatory mechanisms involved in the triggering and coordination of the ripening process. Some of the key components participating in the control of tomato fruit ripening have been uncovered, but our knowledge of the network of signalling pathways engaged in this complex developmental process remains fragmentary. This review highlights the main advances and emphasizes issues still to be addressed using the rapidly developing ‘omics’ approaches

Les puces à ADN : outils pour une nouvelle vision de la diversité et des ressources génétiques

À l'aube du troisième millénaire, on assiste à la fusion de différents domaines du savoir pour créer de nouvelles disciplines de recherche. Ainsi, biologie et informatique se sont mariées pour produire la bio-informatique du côté conceptuel et, entre autres, les biopuces au niveau de l'instrumentation. On assiste à un changement d'échelle au niveau de la quantité de locus et du nombre d'échantillons à analyser, et donc de données à acquérir et à traiter. Plus qu'optimiser les techniques de biologie moléculaire (sélection assistée par marqueurs, par ex.), instruments de la genétique, les technologies à grand débit sur lesquelles est fondée la génomique ont dévoilé de nouvelles perspectives et entraînent un changement de paradigme, ouvrant l'ère de la post-génomique. D'analytique, l'approche scientifique évoluera vers une méthodologie systémique. Notre vision, essentiellement descriptive, de la diversité et des ressources génétiques promet de devenir réellement prédictive. (Résumé d'auteur

Tissue-specific cancer stem cells: reality or a mirage?

Equo ne credite, Teucri. Quidquid id est, timeo Danaos et dona ferentes (Do not trust the horse, Trojans! Whatever it is, I fear the Greeks, even bringing gifts) said Laocoön (Virgil, the Aeneid book). Cancer stem cells (CSCs) are populations of cancer cells that can be found in different cancerous tissues and organs, and have properties that are similar to normal stem cells. They are thought to be chemo-resistant and radioresistant and are therefore responsible for cancer recurrence and relapse encountered in cancer patients following chemotherapy and radiotherapy. Although significant progress has been made to characterise CSCs, it is becoming clear that the failure of cancer therapies directed against certain types of aggressive cancers is due to the presence of these malignant cells. Cancer therapies that will rely on a combination of CSCs-targeted therapies, chemotherapy and radiotherapy are more likely to succeed in eradicating aggressive cancers and prevent recurrence in treated patients

Silencing Sl-EBF1 and Sl-EBF2 expression causes constitutive ethylene response phenotype, accelerated plant senescence, and fruit ripening in tomato

The hormone ethylene regulates a wide range of plant developmental processes and EBF (EIN3-binding F-box) proteins were shown to negatively regulate the ethylene signalling pathway via mediating the degradation of EIN3/EIL proteins. The present study reports on the identification of two tomato F-box genes, Sl-EBF1 and Sl-EBF2 from the EBF subfamily. The two genes display contrasting expression patterns in reproductive and vegetative tissues and in response to ethylene and auxin treatment. Sl-EBF1 and Sl-EBF2 genes are actively regulated at crucial stages in the development of the reproductive organs. Their dynamic expression in flowers during bud-to-anthesis and anthesis-to-post-anthesis transitions, and at the onset of fruit ripening, suggests their role in situations where ethylene is required for stimulating flower opening and triggering fruit ripening. VIGS-mediated silencing of a single tomato EBF gene uncovered a compensation mechanism that tends to maintain a threshold level of Sl-EBF expression via enhancing the expression of the second Sl-EBF gene. In line with this compensation, tomato plants silenced for either of the Sl-EBF genes were indistinguishable from control plants, indicating functional redundancy among Sl-EBF genes. By contrast, co-silencing of both Sl-EBFs resulted in ethylene-associated phenotypes. While reports on EBF genes to date have focused on their role in modulating ethylene responses in Arabidopsis, the present study uncovered their role in regulating crucial stages of flower and fruit development in tomato. The data support the hypothesis that protein degradation via the ubiquitin/26S proteasome pathway is a control point of fruit ripening and open new leads for engineering fruit quality

Targeting cellular pathways in glioblastoma multiforme

Glioblastoma multiforme (GBM) is a debilitating disease that is associated with poor prognosis, short median patient survival and a very limited response to therapies. GBM has a very complex pathogenesis that involves mutations and alterations of several key cellular pathways that are involved in cell proliferation, survival, migration and angiogenesis. Therefore, efforts that are directed toward better understanding of GBM pathogenesis are essential to the development of efficient therapies that provide hope and extent patient survival. In this review, we outline the alterations commonly associated with GBM pathogenesis and summarize therapeutic strategies that are aimed at targeting aberrant cellular pathways in GBM

The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro