Association Of BCR-ABL Alternative Splice Variants with Disease Progression, Treatment Response and Survival in Chronic Myeloid Leukemia Patients Treated with Firstline imatinib Monotherapy

Background: Alternative RNA splicing has diverse biological effects in heath as well as disease. It also contributes to cancer onset and progression. Chronic Myeloid Leukemia (CML) results due to BCR-ABL fusion oncogene that is created due to chromosomal translocation t [9; 22] [q34; q11]). BCR-ABL is target of tyrosine kinase inhibitors (TKIs). BCR-ABL through alternative splicing can generate b2a2, b3a2 and some other rare splicing variants. BCR-ABL variants may vary in their response to TKI treatment and disease progression potential, which is a major factor contributing to dismal treatment outcome in CML. Objective: The objective of this study is to investigate correlation of BCR-ABL splice variants with TKI treatment outcome and survival in three phases of CML that has rarely been studied previously.Methods: BCR-ABL splice variants were studied using reverse transcriptase PCR (RT-PCR). in 70 CML patients from three phases of CML who were receiving imatinib (TKI) treatment.Results: Frequencies of different BCR/ABL splice variants like b3a2, b2a2 and b3a2+b2a2 were 49 (70%), 15 (21.4%) and 6 (8.6%), respectively. Splice variant b2a2 were more common (53.3%) in chronic phase CML (CP-CML) while b3a2 had higher frequency in advanced phases of CML (44.9%). CML patients with b2a2 transcript had better complete cytogenetic response and major molecular response to TKI treatment overall (100% vs. 24.5%) as well as in CP-CML (100% vs. 85.7%) and superior survival when compared to patients with b3a2 splice variant. All patients who died had male gender, less than 33 years age, b3a2 transcript, advanced phases of CML and imatinib resistance.Conclusions: Splice variant b3a2 was associated with CML progression, poorer survival and inferior treatment outcome as compared to b2a2. Further investigations on BCR-ABL splice variants and their roles in CML pathogenesis can provide deeper insights into CML biology and new targets for BCR-ABL positive leukemia treatment.          Keywords: CML; BCR-ABL splice variants; Progression; Survival; Treatment outcome 

FE65 Binds Teashirt, Inhibiting Expression of the Primate-Specific Caspase-4

The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome

Använda sociala medier i primärvården

Social media websites play an obvious role in involving people to get help and motivation regarding healthcare through social interaction because a huge mass is present on social media websites like Facebook. So there is a need to understand that how social media websites specifically Facebook can involve in healthcare awareness and social interaction at primary care level in Blekinge region.Studien handlar om användningen av sociala medier webbplatser som Facebook i primärvården där vårdgivare kan öka tillgängligheten för människor , skapa vård medvetenhet och hålla dem motiverade genom social interaktion för att slåss med sina hälsoproblem och anta en hälsosam livsstil . Människor blir mer aktiva för att bota och förebygga hälsoproblem som fetma , diabetes och kolesterol genom social interaktion med sina vänner , familj och andra människor som arbetar med samma problem . Studien drar slutsatsen att endast den nationella webbportalen är inte tillräckligt , utan medverkan av sociala medier webbplatser för sjukvård är också fördelaktigt . Ingen tvekan sociala medier webbplatser har nackdelar såsom integritet , patient datasäkerhet , brådskande hantering svar men ändå kan vi inte bortse från vikten av sociala medier i vården . Vid slutet av studien föreslås några förslag för att göra Ronneby Vårdcentral facebook sida effektiv och interaktiv . Föreslagna förslag är effektiva och hjälpsamma i bättre användning av sociala medier för sjukvård . Föreslagna förslag kan genomföra i någon annan vårdcentral för att göra användningen av sociala medier till nytta

Använda sociala medier i primärvården

Social media websites play an obvious role in involving people to get help and motivation regarding healthcare through social interaction because a huge mass is present on social media websites like Facebook. So there is a need to understand that how social media websites specifically Facebook can involve in healthcare awareness and social interaction at primary care level in Blekinge region.Studien handlar om användningen av sociala medier webbplatser som Facebook i primärvården där vårdgivare kan öka tillgängligheten för människor , skapa vård medvetenhet och hålla dem motiverade genom social interaktion för att slåss med sina hälsoproblem och anta en hälsosam livsstil . Människor blir mer aktiva för att bota och förebygga hälsoproblem som fetma , diabetes och kolesterol genom social interaktion med sina vänner , familj och andra människor som arbetar med samma problem . Studien drar slutsatsen att endast den nationella webbportalen är inte tillräckligt , utan medverkan av sociala medier webbplatser för sjukvård är också fördelaktigt . Ingen tvekan sociala medier webbplatser har nackdelar såsom integritet , patient datasäkerhet , brådskande hantering svar men ändå kan vi inte bortse från vikten av sociala medier i vården . Vid slutet av studien föreslås några förslag för att göra Ronneby Vårdcentral facebook sida effektiv och interaktiv . Föreslagna förslag är effektiva och hjälpsamma i bättre användning av sociala medier för sjukvård . Föreslagna förslag kan genomföra i någon annan vårdcentral för att göra användningen av sociala medier till nytta

Increased expression of <it>RXRα </it>in dementia: an early harbinger for the cholesterol dyshomeostasis?

<p>Abstract</p> <p>Background</p> <p>Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE.</p> <p>Results</p> <p>In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions.</p> <p>Conclusions</p> <p>These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.</p

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer's disease

The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer's disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not A beta deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5 and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations