Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells

Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs

The Second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany

The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016.info:eu-repo/semantics/publishedVersio

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Deliberate termination of life of newborns with spina bifida, a critical reappraisal

Objects: Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. 'Unbearable and hopeless suffering' is the single most cited criterion for this termination, together with the notion that 'there are no other proper medical means to alleviate this suffering'. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective. Methods: First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a 'reference case'. Conclusion: 'Unbearable and hopeless suffering' cannot be applied to newborns with MMC. They are not 'terminally ill' and do have 'prospects of a future'. In these end-of-life decisions, 'quality of life judgments' should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns

Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations

Public health and valorization of genome-based technologies: a new model

<p>Abstract</p> <p>Background</p> <p>The success rate of timely translation of genome-based technologies to commercially feasible products/services with applicability in health care systems is significantly low. We identified both industry and scientists neglect health policy aspects when commercializing their technology, more specifically, Public Health Assessment Tools (PHAT) and early on involvement of decision makers through which market authorization and reimbursements are dependent. While Technology Transfer (TT) aims to facilitate translation of ideas into products, Health Technology Assessment, one component of PHAT, for example, facilitates translation of products/processes into healthcare services and eventually comes up with recommendations for decision makers. We aim to propose a new model of valorization to optimize integration of genome-based technologies into the healthcare system.</p> <p>Methods</p> <p>The method used to develop our model is an adapted version of the Fish Trap Model and the Basic Design Cycle.</p> <p>Results</p> <p>We found although different, similarities exist between TT and PHAT. Realizing the potential of being mutually beneficial justified our proposal of their relative parallel initiation. We observed that the Public Health Genomics Wheel should be included in this relative parallel activity to ensure all societal/policy aspects are dealt with preemptively by both stakeholders. On further analysis, we found out this whole process is dependent on the Value of Information. As a result, we present our LAL (Learning Adapting Leveling) model which proposes, based on market demand; TT and PHAT by consultation/bi-lateral communication should advocate for relevant technologies. This can be achieved by public-private partnerships (PPPs). These widely defined PPPs create the innovation network which is a developing, consultative/collaborative-networking platform between TT and PHAT. This network has iterations and requires learning, assimilating and using knowledge developed and is called absorption capacity. We hypothesize that the higher absorption capacity, higher success possibility. Our model however does not address the phasing out of technology although we believe the same model can be used to simultaneously phase out a technology.</p> <p>Conclusions</p> <p>This model proposes to facilitate optimization/decrease the timeframe of integration in healthcare. It also helps industry and researchers to come to a strategic decision at an early stage, about technology being developed thus, saving on resources, hence minimizing failures.</p

The centrosome and spindle as a ribonucleoprotein complex

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Chromosome Research 19 (2011): 367-376, doi:10.1007/s10577-011-9186-7.The presence of nucleic acids in centrosomes and the spindle have been proposed, observed, and reported since the 1950s. Why did the subject remain, perhaps even until today, such a controversial issue? The explanation is manifold, and includes legitimate concern over contamination from other cellular compartments in biochemical preparations. With a typically high background of cytoplasmic ribosomes, even microscopic images of stained intact cells could be difficult to interpret. Also, evidence for RNA and DNA in centrosomes accumulated for approximately 40 years but was interspersed with contradictory studies, primarily regarding the presence of DNA (reviewed in Johnson and Rosenbaum, 1991; Marshall and Rosenbaum, 2000). Perhaps less tangible but still a likely cause for lingering controversy is that the presence of nucleic acids in the spindle or centrosomes will require us to look differently at these structures from a functional, and more to the point, evolutionary standpoint.This work was supported by grants from the NIH (GM088503) and NSF (MCB0843092) to MCA

GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy