Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) side chains at a limited number of sites, activity that is strongly implicated with cell invasion associated with cancer metastasis, a consequence of structural modification that loosens the extracellular matrix barrier. Heparanase activity is also implicated in neovascularization, inflammation, and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that HS cleavage by heparanase is required for structural remodeling of the extracellular matrix (ECM), thereby facilitating cell invasion. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors residing in the tumor microenvironment and thereby induces an angiogenic response in vivo. Heparanase up-regulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. These observations, the anticancerous effect of heparanase gene silencing and of heparanase-inhibiting molecules, as well as the unexpected identification of a single functional heparanase suggest that the enzyme is a promising target for anticancer drug development. Progress in the field expanded the scope of heparanase function and its significance in tumor progression and other pathologies such as inflammatory bowel disease and diabetic nephropathy. Notably, while heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity-independent manner. Thus, point-mutated inactive heparanase was noted to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. VEGF) and phosphorylation of selected Src substrates (i.e. EGF receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by elucidation of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity and the identification of a human heparanase splice variant (T5) devoid of enzymatic activity, yet endowed with protumorigenic characteristics. Resolving the heparanase crystal structure will accelerate rational design of effective inhibitory molecules and neutralizing antibodies, paving the way for advanced clinical trials in patients with cancer and other diseases involving heparanase.
This article focuses on contemporary Islamic attitudes towards the question of compensation to a non-relative live organ donor. This article presents the history of the debate on organ transplantation in Islam since the 1950s the key ethical questions. It continues by presenting the opinions of the main-stream ulema such as Tantawi and Qaradawi. The article ends with a conclusion that there must be no compensation made to a non-related live organ donor even a symbolic gift of honor (ikramiyya).
Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis, and angiogenesis. Recently we have demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. Heparanase was shown to up-regulate tissue factor (TF) expression and interact with tissue factor pathway inhibitor (TFPI) on the cell surface, leading to dissociation of TFPI from the cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity. More recently, we have shown that heparanase directly enhances TF activity, resulting in increased factor Xa production and activation of the coagulation system. Data indicate increased levels and possible involvement of heparanase in vascular complications in pregnancy. Taking into account the prometastatic and proangiogenic functions of heparanase, overexpression in human malignancies, and abundance in platelets and placenta, its involvement in the coagulation machinery is an intriguing novel arena for further research.
Phase 1 first-in-human studies with anti-cancer products differ from other phase 1 studies in that they are evaluated in patients rather than healthy volunteers. The rationale design of targeted drugs triggers changes in the design of these studies. Patient populations are more precisely defined and pose a challenge to the efficient inclusion of study patients. Objectives shift from the definition of a maximum tolerated dose to the evaluation of a recommended phase 2 dose. Other challenges related to the efficacy and safety profile of novel targeted anti-cancer drugs call for changes in designing first-in-human studies, such as definitions of biological doses, collection of fresh tumor tissue for surrogate marker analyses, and the management of infusion-related reactions with monoclonal antibodies.
Consequently, the conduct of phase 1 clinical trials in oncology requires changes. Corresponding education with particular focus on phase 1 trials and on the complex drug development process needs to be an integrated part of the medical oncology curriculum for physicians and nursing staff. This is a crucial element for institutions to remain or become clinical research sites for phase 1 studies, and to participate in the drug development process of novel anti-cancer compounds in the future.
While Drs. Wolff, Parkinson, and White fully described the syndrome in 1930, prior case reports had described the essentials. Over the ensuing century this syndrome has captivated the interest of anatomists, clinical cardiologists, and cardiac surgeons. Stanley Kent described lateral muscular connections over the atrioventricular (AV) groove which he felt were the normal AV connections. The normal AV connections were, however, clearly described by His and Tawara. True right-sided AV connections were initially described by Wood et al., while Öhnell first described left free wall pathways. David Scherf is thought to be the first to describe our current understanding of the pathogenesis of the WPW syndrome in terms of a re-entrant circuit involving both the AV node–His axis as well as the accessory pathway. This hypothesis was not universally accepted, and many theories were applied to explain the clinical findings. The basics of our understanding were established by the brilliant work of Pick, Langendorf, and Katz who by using careful deductive analysis of ECGs were able to define the basic pathophysiological processes. Subsequently, Wellens and Durrer applied invasive electrical stimulation to the heart in order to confirm the pathophysiological processes.
Sealy and his colleagues at Duke University Medical Center were the first to successfully surgically divide an accessory pathway and ushered in the modern era of therapy for these patients. Morady and Scheinman were the first to successfully ablate an accessory pathway (posteroseptal) using high-energy direct-current shocks. Subsequently Jackman, Kuck, Morady, and a number of groups proved the remarkable safety and efficiency of catheter ablation for pathways in all locations using radiofrequency energy. More recently, Gollob et al. first described the gene responsible for a familial form of WPW. The current ability to cure patients with WPW is due to the splendid contributions of individuals from diverse disciplines throughout the world.
Evaluation of patients after penetrating neck injury has evolved over time. Previously, location of injury and symptoms were used to determine management. The contemporary management of penetrating neck injuries relies on physical examination. Patients with hard signs of vascular or aerodigestive tract injury require immediate operation, regardless of location of injury. Those with no signs can be observed. For the remainder with soft signs multidetector, computed tomographic angiography (MDCTA) is a highly sensitive and specific screening modality for evaluating the vasculature and aerodigestive structures in the neck. Utilizing MDCTA, the patient can be safely directed towards operative intervention, observation, or further investigation.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood. Recent studies have shown that CPVT is caused by mutations in the cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 (CASQ2) genes. Both proteins are key contributors to the intracellular Ca2+ handling process, and play a pivotal role in Ca2+ release from the SR to the cytosol during systole. Although the molecular pathogenesis of CPVT is not entirely clear, it was suggested that the CPVT mutations promote excessive SR Ca2+ leak, which initiates delayed afterdepolarizations (DADs) and triggered arrhythmias in cardiac myocytes. The recent breakthrough discovery of induced pluripotent stem cells (iPSC) generated from somatic cells (e.g., fibroblasts, keratinocytes), now enables researches to investigate mutated cardiomyocytes generated from the patient's iPSC. To this end, in the present article we review recent studies on CPVT iPSC-derived cardiomyocytes, thus demonstrating in the mutated cells catecholamine-induced DADs and triggered arrhythmias.
Late onset is a key unifying feature of human neurodegenerative maladies such as Alzheimer’s and Parkinson’s diseases and prion disorders. While sporadic cases typically emerge during the patient’s seventh decade of life or later, mutation-linked, familial cases manifest during the fifth or sixth decade. This common temporal emergence pattern raises the prospect that slowing aging may prevent the accumulation of toxic protein aggregates that lead to the development of these disorders, postpone the onset of these maladies, and alleviate their symptoms once emerged. Invertebrate-based studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway, protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer’s model mice from the behavioral and biochemical impairments associated with the disease. Here I review the recent advances in the field, describe the known mechanistic links between toxic protein aggregation and the aging process, and delineate the future therapeutic potential of IIS reduction as a treatment for various neurodegenerative disorders.
Life expectancy has been increasing in the last few decades in the Western world and is accompanied by higher occurrence of age-related diseases like metabolic, cardiovascular, and renal diseases and also with a decline in immune functions. In HIV-infected people, due to the use of combination antiretroviral therapy cART, life expectancy has increased. As a result, non-AIDS conditions which are age-associated have become more prevalent and appear earlier, resulting in accelerated aging in HIV patients. These non-AIDS conditions in HIV patients are associated with CD4+ T cell counts: lower counts are associated with higher rates of liver, cardiovascular, renal, and neurocognitive disorders. The effect of viral load and cART on the earlier occurrence of age-associated diseases is less significant than the CD4 count effect. Thus, the loss of immune functions in HIV-infected patients may enhance aging.
For patients with acute coronary syndrome (ACS), the first priority is to alert emergency services. In addition to an ECG (ideally taken during the first medical contact at the patient’s home), the key of live saving is the immediate antithrombotic therapy with acetylsalicylic acid (ASA) and (unless contraindicated) an injection of unfractionated heparin or bivalirudin as an alternative anticoagulant. Dual antiplatelet therapy (ASA combined with other antiplatelet drugs, like thienopyridines) should be started as soon as possible in the ambulance or at the latest in the hospital. For clopidogrel, a loading dose of 600 mg is the standard. To avoid the risk of an unknown low or missing clopidogrel-response, prasugrel is recommended instead, administrating a loading dose of 60 mg, if no contraindication (s/p stroke or TIA) exists. When PCI is planned, the ambulance must head directly to the nearest hospital with continuous (24/7) PCI service within 90 (to 120) minutes. The maintenance dose for clopidogrel is 75 mg/d; a daily double-dose has not proven to be superior, even in “low responders”. For prasugrel, the maintenance dose is usually 10 mg/d. To avoid bleeding complications in patients ≥75 y and/or <60 kg, a prasugrel maintenance dose of 5 mg/d is recommended. The ESC guidelines recommend DAPT for 1 year after ACS – independent of the type of ACS and independent of whether any or which coronary stent has been implanted. With DAPT, the patient – and not the stent – is treated.
