Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.
It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important impli-cations for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the hu-man gene pool, thereby enhancing the potential for human evolution. The increase in human popula-tion size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual het-erozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.
Intelligent Design (ID) burst onto the scene in 1996, with the publication of Darwin’s Black Box by Mi-chael Behe. Since then, there has been a plethora of articles written about ID, both pro and con. How-ever, most of the articles critical of ID deal with peripheral issues, such as whether ID is just another form of creationism or whether ID qualifies as science or whether ID should be taught in public schools. It is our view that the central issue is whether the basic claim of ID is correct. Our goal is fourfold: (I) to show that most of the proposed refutations of ID are unconvincing and/or incorrect, (II) to describe the single fundamental error of ID, (III) to discuss the historic tradition surrounding the ID controversy, showing that ID is an example of a “god-of-the-gaps” argument, and (IV) to place the ID controversy in the larger context of proposed proofs for the existence of God, with the emphasis on Jewish tradition.
This paper describes the rapid evolution of modern liver surgery, starting in the middle of the twentieth century. Claude Couinaud studied and described the segmental anatomy of the liver, Thomas Starzl performed the first liver transplantations, and Henri Bismuth introduced the concept of anatomical resections. Hepatic surgery has developed significantly since those early days. To date, innovative techniques are applied, using cutting-edge technologies: Intraoperative ultrasound, techniques of vascular exclusion of the liver, new devices for performing homeostasis and dissection, laparoscopy for resections, and new drugs that allow the resection of previously unresectable tumors. The next stage in liver surgery will probably be the implementation of a multidisciplinary holistic approach to the liver-diseased patient that will ensure the best and most efficient treatments in the future.
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.
I present a realistic view of what Darwinian evolution is in its current form and what it is not. I argue that the Torah is not a source of scientific knowledge and all attempts to reconcile its plain text with the data of science are an exercise in futility. The article argues the position that science and the Torah are incommensurable. I argue against using the Torah for attaining knowledge about the nature of the world, or using science for enhancing or denying the truth of the Torah.
After direct impact of the trauma, crush syndrome is the second most frequent cause of death after mass disasters. However, since crush syndrome is quite rare in daily practice, mistakes are frequent in the treatment of these cases. This paper summarizes the etiopathogenesis of traumatic rhabdomyolysis and of crush syndrome-based acute kidney injury. The clinical and laboratory features, prophylaxis, and treatment of crush cases are summarized as well. The importance of early and energetic fluid resuscitation is underlined for prophylaxis of acute kidney injury. Since there is chaos, and an overwhelming number of victims, logistic drawbacks create a specific problem in the treatment of crush victims after mass disasters. Potential solutions for logistic hurdles and disaster preparedness scenarios have also been provided in this review article.
Patients with type 2 diabetes (T2D) are at increased risk of developing cancer. This evidence arises from numerous epidemiologic studies that relate a positive association between T2D and cancer. In-vitro and several in-vivo experiments have attempted to discern the potential mechanistic factors involved in this relationship. Candidates include hyperinsulinemia, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-2 (IGF-2) signaling. These studies demonstrated that increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce cancer development and progression.
A very troubling issue for health care systems today is that of life-sustaining treatment for patients who have permanently lost their cognitive capacities. These include patients in persistent vegetative state (PVS), or minimally conscious state (MCS), as well as a growing population of patients at the very end stage of dementia. These patients are totally dependent on life-sustaining treatments and are, actually, kept alive “artificially.” This phenomenon raises doubts as to the ethics of sustaining the life of patients who have lost their consciousness and cognitive capacities, and whether there is a moral obligation to do so. The problem is that the main facts concerning the experiences and well-being of such patients and their wishes are unknown. Hence the framework of the four principles—beneficence, non-maleficence, autonomy, and justice—is not applicable in these cases; therefore we examined solidarity as another moral value to which we may resort in dealing with this dilemma.
This article shows that the source of the dilemma is the social attitudes towards loss of cognitive capacities, and the perception of this state as loss of personhood. Consequently, it is suggested that the principle of solidarity—which both sets an obligation to care for the worst-off, and can be used to identify obligations that appeal to an ethos of behavior—can serve as a guiding principle for resolving the dilemma. The value of solidarity can lead society to care for these patients and not deny them basic care and life-sustaining treatment when appropriate.
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.
