Receptor C(k)-dependent signaling regulates hTERT gene transcription

BACKGROUND: Available evidence suggests that the regulation of telomerase activity primarily depends on the transcriptional control of the human telomerase reverse transcriptase (hTERT) gene. Although several activators and repressors of hTERT gene transcription have been identified, the exact mechanism by which hTERT transcription is repressed in normal cells and activated in cancer cells remains largely unknown. In an attempt to identify possible novel mechanisms involved in the regulation of hTERT transcription, the present study examined the role of Receptor C(k), a cell surface receptor specific for cholesterol, in the transcription of hTERT gene in normal human peripheral blood mononuclear cells. RESULTS: Activated Receptor C(k )was found to down-regulate hTERT mRNA expression by repressing the transcription of c-myc gene. Receptor C(k)-dependent signaling was also found to down-regulate the mRNA expression of the gene coding for the ligand inducible transcription factor, peroxisome proliferator-activated receptor γ (PPARγ). The ligand activation of PPARγ resulted in the down-regulation of c-myc and hTERT mRNA expression. By using specific activator and inhibitor of protein kinase C (PKC), it was demonstrated that Receptor C(k )dependent down-regulation of hTERT gene transcription involved inhibition of PKC. In addition, 25-hydroxycholesterol was found to contribute to the transcriptional regulation of hTERT gene. CONCLUSION: Taken together, the findings of this study present evidence for a molecular link between cholesterol-activated Receptor C(k )and hTERT transcription, and provide new insights into the regulation of hTERT expression in normal human peripheral blood mononuclear cells

A Case Series Highlighting the Relative Frequencies of the Common, Uncommon and Atypical/Unusual Hematological Findings on Bone Marrow Examination in Cases of Visceral Leishmaniasis

Introduction: Bone marrow aspiration and biopsy still remains as one of the vital tests for confirmation of diagnosis of visceral Leishmaniasis. The aim of the present study is to assess the relative frequency of common, uncommon and atypical hematological findings in cases of Visceral Leishmaniasis. Materials & Methods: A total of 16 cases of Leishmaniasis diagnosed on Bone marrow examination over a period of two years (2008-2010), were retrieved from the archives and the peripheral blood smear, bone marrow aspiration smears and trephine biopsies were examined for the common, uncommon and atypical features as described in the literature. Results: Out of the total of 16 cases, 10 were pediatric and 6 adult cases. The common findings like pancytopenia, peripheral blood monocytosis, increased histiocytes on aspirate smears and granulomas on biopsies were noted in 12/16 (75%), 9/16 (56.25%), 13/16 (81.2%) and 11/16 (69%) cases respectively. Amongst the uncommon findings, hemophagocytosis was noted in 12/ 16 (75%) cases, plasma cells with inclusions in 6/16 (37.5%) and LD bodies in cells other than histiocytes in 4/16 (25%) cases. The atypical findings included organism aggregates noted in 9/16 (56%) cases, Pelger-Heut cells seen in 4/16 (25%) cases and increased focal vascularity on biopsies in 10/16 (62.5%) cases. The average parasite density (APD) on smears was 3+ and the range of positivity was 1+ to 5+. Conclusion: The knowledge of these morphological clues can assist us in searching for LD bodies and correctly diagnosing the condition without excessive dependence on unnecessary and sophisticated tests

Structural and electrical studies on Bi<SUB>2</SUB>VO<SUB>5.5</SUB>/Bi<SUB>4</SUB>Ti<SUB>3</SUB>O<SUB>12</SUB> multilayer thin films

The textured multilayer (ML) thin films of bismuth layered ferroelectric (FE) compounds, Bi2VO5.5 (BVO) and Bi4Ti3O12 (BTO) with different individual layer thicknesses were fabricated via pulsed laser deposition technique on Pt(111)/TiO2/SiO2/Si substrates. X-ray diffraction studies confirmed that BVO and BTO retained their respective crystal structures in these multilayer (ML) thin films. The atomic force microscopy and scanning electron microscopy studies showed smooth and dense microstructures. The polarization hysteresis (P-E) studies on a representative (BVBT30) ML thin film at 300 K confirmed the remnant polarization (2P r ) and coercive field (E c ) to be ~20 &#181; C/cm2 and 250 kV/cm, respectively. The value of P r obtained was greater than that of the single layer thin film of BVO (P r ~5.6 &#181; C/cm2). The room temperature dielectric constant (&#949; r') and the loss (D) for BVBT30 ML measured at 100 kHz were 170 and 0.01, respectively. The frequency and temperature dependent dielectric constant, impedance, modulus and ac conductivity of these ML thin films were studied as a function of frequency (100 Hz-1 MHz) in the 25-300 &#176; C temperature range. Two distinct electrical responses were observed in these films, which were attributed to the grain effects at low temperatures and grain boundary effects at higher temperatures. The frequency dependent electrical conductivity was fitted well with the double power law which evidenced two different types of contributions to the conductivity; the low frequency conductivity being due to the short range translational hopping and the high frequency conductivity was due to the localized or reorientational hopping

Polymorphisms in renin-angiotensin-aldosterone system and vascular endothelial growth factor may cross talk in preeclampsia: a pilot study of maternal and fetal dyads in Indian population

Background: Preeclampsia (PE) is a multi-system disorder complicating 5-7% pregnancies and one of the leading causes of fetal/maternal morbidity and mortality worldwide.Methods: We have analyzed the association of common genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and angiogenesis pathway in preeclamptic/eclamptic mother-fetal dyad samples, as we have hypothesized that there is a cross-talk between the maternal and fetal genotypes. Maternal venous and fetal umbilical vein blood of 50 primigravidae with preeclampsia /eclampsia and 100 matched normotensive controls of north Indian origin were collected.Results: A significant association was observed in the prevalence of VEGFA (vascular endothelial growth factor) polymorphism (rs25648 T>C) with PE. Moreover, difference in the prevalence of the AGT (rs7079 A>C) polymorphism was observed between mild vs. severe PE. Fetal genotypes showed a strong association with respect to RENIN (rs11240688 A>G) and AGT (rs11122576 G>A) to preeclampsia.Conclusions: Preeclamptic mothers and their fetuses have shown association with genes that are interacting partners in the regulation of angiogenesis and it would be interesting to expand the study to include more genes and connected pathways for the better understanding of the interplay of the biological process that goes dysregulated in this multi-systemic disorder.  

A Study on the Expression of BCR-ABL Transcript in Mixed Phenotype Acute Leukemia (MPAL) Cases Using the Reverse Transcriptase Polymerase Reaction Assay (RT-PCR) and its Correlation with Hematological Remission Status Post Initial Induction Therapy

&lt;p&gt;&lt;strong&gt;Introduction&lt;/strong&gt;: The MPAL comprise 2-5% of all acute leukemia. The present WHO 2008 classification has separated two groups in MPAL based on t(9;22) positivity and MLL rearrangement. &lt;strong&gt;Aims &amp;amp; Objectives&lt;/strong&gt;: The aim of the present pilot study is to note the incidence of BCR-ABL transcript in MPAL cases using the RT-PCR assay and to correlate the status with hematological remission post induction. &lt;strong&gt;Materials &amp;amp; Methods&lt;/strong&gt;: A total of 10 MPAL cases classified on Flow-cytometry based on the current WHO 2008 criteria were enrolled. In all the cases Bone marrow or peripheral blood sample in EDTA was processed for molecular studies and the RT-PCR reaction carried out using primers specific to the t (9;22) and t(4;11) translocation. The post induction check marrow slides were also reviewed. &lt;strong&gt;Results&lt;/strong&gt;: Out of the total 10 MPAL cases, 7/10 (70%) were adult and 3/10 (30%) pediatric cases. A total of 4/10 (40%) cases showed positivity for the t(9;22) transcript and none for t (4;11). Of the 4 positive cases, 3/10(30%) were adult cases and 1/10(10%) pediatric case. The BCR-ABL transcript type in adult cases was b3a2 (p210) in 2/3 (66%) and e1a2 (p190) in 1/3 (33.3%) case. The single pediatric case was positive for b3a2 transcript. &lt;strong&gt;Discussion &amp;amp; Conclusion&lt;/strong&gt;: All the 4 positive MPAL cases presented with high TLC and low platelet count (p&amp;lt;0.05). The positive cases also showed hematological remission at post induction check marrow (blasts&amp;lt;5%). This could partly be explained due to good response to the imatinib added to the treatment protocol.&lt;/p&gt

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations