Ruxolitinib in the treatment of polycythemia vera: patient selection and special considerations.

The discovery of JAK2 V617F mutation in the mid-2000s started to fill the gap between clinical presentation of polycythemia vera (PV), first described by Vaquez at the end of the 19th century, and spontaneous erythroid colony formation, reported by Prchal and Axelrad in the mid-1970s. The knowledge on this mutation brought an important insight to our understanding of PV pathogenesis and led to a revision of the World Health Organization diagnostic criteria in 2008. JAK-STAT is a major signaling pathway implicated in survival and proliferation of hematopoietic precursors. High prevalence of JAK2 V617F mutation among myeloproliferative neoplasms (>95% in PV and ~50% in primary myelofibrosis and essential thrombocythemia) together with its role in constitutively activating JAK-STAT made JAK2 a privileged therapeutic target. Ruxolitinib, a JAK 1 and 2 inhibitor, has already proven to be efficient in relieving symptoms in primary myelofibrosis and PV. In the latter, it also appears to improve microvascular involvement. However, evidence regarding its potential role in altering the natural course of PV and its use as an adjunct to current standard therapies is sparse. Therapeutic advances are needed in PV as phlebotomy, low-dose aspirin, cytoreductive agents, and interferon alpha are the only therapeutic tools available at the moment to influence outcome. Even though several questions are still unanswered, this review aims to serve as an overview article of the potential role of ruxolitinib in PV according to current literature and expert opinion. It should help hematologists to visualize the place of this tyrosine kinase inhibitor in the field of current practice and offer criteria for a careful patient selection

The Role of Plasma Transfusion in Massive Bleeding: Protecting the Endothelial Glycocalyx?

Massive hemorrhage is a leading cause of death worldwide. During the last decade several retrospective and some prospective clinical studies have suggested a beneficial effect of early plasma-based resuscitation on survival in trauma patients. The underlying mechanisms are unknown but appear to involve the ability of plasma to preserve the endothelial glycocalyx. In this mini-review, we summarize current knowledge on glycocalyx structure and function, and present data describing the impact of hemorrhagic shock and resuscitation fluids on glycocalyx. Animal studies show that hemorrhagic shock leads to glycocalyx shedding, endothelial inflammatory changes, and vascular hyper-permeability. In these animal models, plasma administration preserves glycocalyx integrity and functions better than resuscitation with crystalloids or colloids. In addition, we briefly present data on the possible plasma components responsible for these effects. The endothelial glycocalyx is increasingly recognized as a critical component for the physiological vasculo-endothelial function, which is destroyed in hemorrhagic shock. Interventions for preserving an intact glycocalyx shall improve survival of trauma patients

New tools in percutaneous minimally invasive chronic subdural hematomas evacuation

Background: Incidence of chronic subdural hematomas (cSDH) is expected to progressive rise in the next decades. There is no univocal indication of the approach to be used. Furthermore, there is no data about the efficacy of twist drill craniostomy (TDC) in hematomas with membranes. Objective: To describe our modified technique for TDC in patients affected by cSDH with membranes and in treatment with antiplatelets. Methods: We analyzed a group of 37 patients, affected by cSDH with membrane (type D laminar membrane and type G trabecular membrane according to Nakaguchi classification), treated with mushroom TDC using a modified technique. Results: After surgery the average maximum thickness of the common postoperative liquoral subdural collection decreased from 18.8 to 6.21 mm. We documented one acute subdural hematoma (2.7%), asymptomatic and not treated, and one recurrence of cSDH (2.7%) after 2 months that needed re-intervention with single burr hole. Conclusions: We presented a modified twist drill technique, characterized by the introduction of an application of a new device that optimizes both surgical results, clinical outcome and surgical procedure time. The presence of membrane type D and G does not affect the efficacy of drainage, that is negatively related to the presence of clots or acute hematoma. This modified technique is safe, fast, effective and represents a valid first line treatment of an unstable and unpredictable pathology such as cSDH. We suggest performing such technique on a larger patients’ cohort to further validate its effectiveness

Farnesoid X receptor and liver X receptor ligands initiate formation of coated platelets

The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity. We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P-selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin αIIbβ3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D. We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of αIIbβ3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo

Transverse momentum fluctuations and percolation of strings

The behaviour of the transverse momentum fluctuations with the centrality of the collision shown by the Relativistic Heavy Ion Collider data is naturally explained by the clustering of color sources. In this framework, elementary color sources --strings-- overlap forming clusters, so the number of effective sources is modified. These clusters decay into particles with mean transverse momentum that depends on the number of elementary sources that conform each cluster, and the area occupied by the cluster. The transverse momentum fluctuations in this approach correspond to the fluctuations of the transverse momentum of these clusters, and they behave essentially as the number of effective sources.Comment: 16 pages, RevTex, 4 postscript figures. Enhanced version. New figure

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state

Axolotl Nanog activity in mouse embryonic stem cells demonstrates that ground state pluripotency is conserved from urodele amphibians to mammals

Cells in the pluripotent ground state can give rise to somatic cells and germ cells, and the acquisition of pluripotency is dependent on the expression of Nanog. Pluripotency is conserved in the primitive ectoderm of embryos from mammals and urodele amphibians, and here we report the isolation of a Nanog ortholog from axolotls (axNanog). axNanog does not contain a tryptophan repeat domain and is expressed as a monomer in the axolotl animal cap. The monomeric form is sufficient to regulate pluripotency in mouse embryonic stem cells, but axNanog dimers are required to rescue LIF-independent self-renewal. Our results show that protein interactions mediated by Nanog dimerization promote proliferation. More importantly, they demonstrate that the mechanisms governing pluripotency are conserved from urodele amphibians to mammals. © 2010. Published by The Company of Biologists Ltd

Peripheral facial palsy following ventriculoperitoneal shunt. The lesson we have learned

The most frequent complications after shunt surgery are infective and obstructive. Other types are less common, and eventually occur due to technical errors during brain ventricular puncture, opening the intraperitoneal cavity or the tunnelling of the catheter between the two points. Although rare, there are well-reported complications related to the poor positioning of the distal catheter, with perforation of organs and tissues. We report a very rare case of a male patient with normal pressure hydrocephalus submitted to ventriculoperitoneal shunt. During tunnelling of the shunt stylet, a peripheral facial palsy due to injury to the extra cranial segment of the facial nerve occurred. To the best of our knowledge this is the second case described in Literature. The patient and the surgeon should be aware of this very rare but possible complication in shunt surgery being careful to the course of the facial nerve in the mastoid region

Epigenetic reprogramming of breast cancer cells with oocyte extracts

<p>Abstract</p> <p>Background</p> <p>Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis.</p> <p>Results</p> <p>We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts.</p> <p>Conclusions</p> <p>This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.</p