The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that ...recognize specific cytokines, and is critical in blood formation and immune response. Many of those receptors transmit anti-apoptotic, proliferative and differentiation signals, and their expression and functions are critical for the formation of blood lineages. Several cancers, including blood malignancies, have been associated with constitutive activation of members of the STAT family, which normally require JAK-mediated tyrosine phosphorylation for transcriptional activation. More recently, human myeloproliferative neoplasms were discovered to be associated with a unique acquired somatic mutation in JAK2 (JAK2 V617F), rare exon 12 JAK2 mutations, or thrombopoietin receptor mutations that constitutively activate wild-type JAK2. Prompted by these observations, many studies have explored the possibility that JAKs, cytokine receptors, or other components of the JAK/STAT pathway are mutated or upregulated in several hematological malignancies. This has been observed in certain pediatric acute lymphoblastic leukemias and adult T-cell lymphoblastic leukemias, and overexpression of JAK2 seems to be important in Hodgkin lymphoma. Here we discuss the nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies and present examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage. JAK inhibitors are making their way into the therapeutic arsenal (for example, in myelofibrosis), and we discuss the possibility that other hematological diseases might benefit from treatment with these inhibitors in combination with other agents.
Abstract
The paper studies the influence of light weight aerated autoclaved concrete (AAC) partitioning walls to a medium height reinforced concrete structure, in Bucharest (Romania). The building is ...designed as a framed structure with non-bearing AAC walls placed in certain bays. There is a bearing full bricks masonry wall in one of the bays. Full bricks are used because of its high strength compared to AAC. The aim is to determine the importance of the masonry walls placement, both full bricks and AAC, for the building’s behavior. The analysis points out the structure’s elastic and plastic behavior and also the efforts developed in the non-bearing walls. The bearing masonry wall’s behavior is very important, because the structure is built in a high seismic area. To extend the study, the full bricks wall is replaced with a reinforced concrete one. This is done to see how it impacts the building’s behavior, for both the elastic and plastic stage. The paper concludes that AAC, full bricks and concrete walls placements have a significant influence on the structure.
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in ...which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter‐regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell‐mediated organ‐specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro‐ and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune‐mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Janus kinases (JAKs) are required for cytokine receptor signaling. Since the discovery of the highly prevalent JAK2 V617F mutation in myeloproliferative neoplasms (MPNs), JAK2 became a prime target ...for inhibition. Only one approved JAK2 inhibitor exists, with positive, but not curative effects in MPNs, and promising effects in autoimmune diseases and cancer. On the basis of recent advances in the structural features regulating both normal and mutant JAKs, as well as in small-molecule targeting, we review the current state of JAK2 inhibitor development and present novel avenues of selecting JAK2 inhibitors, with broad and narrow specificities and extend these approaches to other JAKs.
The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome ...whose expression is associated with MS.
To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.
Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association.
43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF.
This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The paper is a study on different types of masonry partitioning walls in a high rise reinforced concrete walls building. It will be built in Bucharest, Romania. The masonry walls are made of ...clay bricks for the first 4 cases studied and aerated concrete blocks for the last 2 cases. They are designed to bare the in plane and perpendicular efforts they are subjected to in the elastic stage. The effect these masonry walls have on the structures is shown. They have an important influence over the buildings natural vibration periods and the slabs reinforcement design and shear stresses. The plastic hinges development is shown for all 6 cases. The pushover diagrams are compared separately for directions X and Y.
Cigarette smoking is the most prominent significant cause of death and morbidity. It is recognised as a risk factor for a number of immune mediated, inflammatory diseases including multiple sclerosis ...(MS). Here, we review the complex immunological effects of smoking on the immune system, which include enhancement of inflammatory responses with a parallel reduction of some immune defences, resulting in an increased susceptibility to infection and a persistent proinflammatory environment.
We discuss the effect of smoking on the susceptibility, clinical course, disability, and mortality in MS, the likely benefits of smoking cessation, and the specific immunological effects of smoking in MS.
In conclusion, smoking is an important environmental risk factor for MS occurrence and outcome, and it acts in significant part through immunological mechanisms.
•Cigarette smoking is a risk factor for the development, severity, progression, and early death in multiple sclerosis.•Many of Its can be explained in significant part by the immunological, proinflammatory effects of smoking.•Components of tobacco smoke other than nicotine are likely to be the strongest enhancers of the inflammatory response.•Smoking cessation, even after MS onset, is an effective lifestyle modification that can reduce disability progression.
The paper studies the influence of adding an aerated autoclaved concrete (AAC) masonry walls story above a reinforced concrete structure of a high building. This structure is situated in a high ...seismic area (0.30g, where g is the gravity acceleration) in Bucharest, Romania. The new story will be lightweight because of the AAC. It is necessary to establish if the existing structure can bare the new story gravity loads and to determine the new building's seismic behaviour. It is also determined if the new AAC masonry walls can bare the seismic loads they are to be subjected to. Both elastic and plastic analysis are present in the study.
This paper studied the behaviour of a medium height, confined masonry walls building, in a medium seismic area (0.25g, where g is the gravity acceleration), in Iasi, Romania. The study focuses on ...different masonry strengths impact on the building's elastic and plastic behaviour. It is important to establish if the structure can bare the gravitational and seismic loads if weaker bricks are used and also how the plastic mechanism is formed if the walls are made of stronger and stiffer masonry. It is also highlighted how the beams stiffness affects the structure ductility and how it can be improved. The building does not have the same stiffness on both X and Y directions, so this will also be taken into account.
Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. ...Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions. Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings. This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth. Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported.
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