Novel therapeutic strategies for spinal osteosarcomas

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.This work is funded by a grant (MPP 320133) from the American University of Beirut to Dr. Ali H. Eid

Inflammogenesis of Secondary Spinal Cord Injury

Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine.Grant #NPRP 4-571-3-171 from the Qatar National Research Fund(a member of Qatar Foundation)

Glucocorticoid-induced fetal origins of adult hypertension: Association with epigenetic events

Hypertension is a predominant risk factor for cardiovascular diseases and a major health care burden. Accumulating epidemiological and experimental evidence suggest that adult-onset hypertension may have its origins during early development. Upon exposure to glucocorticoids, the fetus develops hypertension, and the offspring may be programmed to continue the hypertensive trajectory into adulthood. Elevated oxidative stress and deranged nitric oxide system are not only hallmarks of adult hypertension but are also observed earlier in life. Endothelial dysfunction and remodeling of the vasculature, which are robustly associated with increased incidence of hypertension, are likely to have been pre-programmed during fetal life. Apparently, genomic, non-genomic, and epigenomic factors play a significant role in the development of hypertension, including glucocorticoid-driven effects on blood pressure. In this review, we discuss the involvement of the aforementioned participants in the pathophysiology of hypertension and suggest therapeutic opportunities for targeting epigenome modifiers, potentially for personalized medicine. 2015This publication was made possible by grant # NPRP 4-571-3-171 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors.Scopu