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Objective: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1(IS)]) by 12 months., Methods: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study., Results and Conclusions: Of 112 patients enrolled, 66.1% (80% CI, 59.7-72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR(4.5) (BCR-ABL1(IS) ≤ 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP.

The role of anesthesia techniques on perioperative outcomes on a population level has recently gained widespread interest. Although mainly neuraxial vs general anesthesia has been addressed, population-level data on the impact of peripheral nerve blocks (PNBs) are still lacking. Therefore, we investigated the association between PNB use and outcomes using retrospective data on 1,062,152 recipients of hip and knee arthroplasties (total hip arthroplasty [THA]/total knee arthroplasty [TKA]) from the national Premier Perspective database (2006-2013). Multilevel multivariable logistic regression models measured associations between PNB use and outcomes. Complications included cardiac, pulmonary, gastrointestinal and renal complications, cerebrovascular events, infections, wound complications, thromboembolic complications, inpatient falls, and mortality. Resource utilization variables included blood transfusions, intensive care unit admissions, opioid consumption, cost, and length of stay. Overall, 12.5% of patients received a PNB, with an increase over time particularly among TKAs. Peripheral nerve block use was associated with lower odds for most adverse outcomes mainly among patients with THA. Notable beneficial effects were seen for wound complications (odds ratio 0.60 [95% confidence interval, 0.49-0.74]) among THA recipients and pulmonary complications (odds ratio 0.83 [95% confidence interval, 0.72-0.94]) in patients with TKA. Peripheral nerve block use was significantly (P < 0.0001) associated with a -16.2% and -12.7% reduction in opioid consumption for patients with THA and TKA, respectively. In conclusion, our results indicate that PNBs might be associated with superior perioperative population-level outcomes. In light of the inability to establish a causal relationship and the presence of residual confounding, we strongly advocate for further prospective investigation, ideally in multicenter, randomized trials, to establish the potential impact of PNBs on outcomes on a population level.

Aims: Before the era of tyrosine kinase inhibitors (TKIs), the presence of bone marrow fibrosis (MF) in patients with chronic myeloid leukaemia (CML) has been established as a poor prognostic factor. The aim of the present study was to evaluate the effects of imatinib treatment on MF and the prognostic significance of MF at this new era of CML therapy., Methods: The study cohort consisted of 135 patients with CML who were exposed to imatinib. The grades of MF pre and post imatinib together with cytogenetic and molecular responses were evaluated., Results: Severe MF (grade II-III) was observed in 44 (33%) patients prior to imatinib therapy, and in 8 (8%) after 12 months of imatinib treatment (p=0.001). The complete cytogenetic response (CCyR) rates at 12 months did not differ according to the pre-imatinib MF grades, and CCyR rates in patients with grades 0, I, II and III MF were 36/47 (76.5%), 26/33 (78.7%), 12/23 (52.1%) and 7/10 (70%), respectively (p=0.127). There was no significant difference between patients with or without CCyR at 12 months of imatinib regarding grades of MF (p=0.785). The distribution of the major molecular response rates at 18 months according to pre-treatment grades of MF were determined as grade 0 in 38/45 (84.4%), grade I in 21/28 (75%), grade II in 14/21 (66.6%) and grade III in 7/10 (70%) (p=0.112). There was no significant difference in overall survival rates between initial MF mild (grade 0-I) and severe (grade II-III) groups (p=0.278)., Conclusions: According to our findings, MF regresses with imatinib therapy over time, and the MF grades at diagnosis do not have a negative impact on the responses to imatinib treatment. Therefore, the adverse prognostic impact of the MF among patients with CML seems to disappear in the era of the TKIs., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative condition. Major clinical features include progressive dystonia, pigmentary retinopathy, spasticity, and cognitive decline. The typical MRI sign of the disease, known as "eye-of-the-tiger", is what makes differential diagnosis possible. We here describe a 16-year-old male patient with PKAN presenting with severe and sustained jaw-opening dystonia which may be due to heterogeneous etiologies showing poor response to treatment. Herein, long-term follow-up and genetic results of a PKAN case who experienced severe jaw-opening dystonia are presented and discussed., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The aim of the present study is to evaluate the frequency of C609T polymorphism in the NQO1 (NAD(P)H) quinon oxydoreductase) gene and its relation to cytogenetic abnormalities in patients with Myelodysplastic Syndrome (MDS). The study group consisted of 80 patients MDS with 13 of them in the pediatric age group. The frequency of the NQO1 gene polymorphism was compared with a healthy control group involving 423 individuals. Cytogenetic abnormalities were detected in 43 patients (54%). In patients with MDS the overall frequency of the C609T polymorphism was not different than controls. Also, although the frequency of the C609T polymorphism was higher in patients with secondary MDS (sMDS) (OR: 1.893, 95% CI: 0.840-4.265, p=0.238) , 5/del(5q) (OR:1.298, 95% CI: 0.331-5.086,p=0.124), +21(OR:1.817, 95% CI:0.429-7698,p=0.124) and t(8;21) (OR:3.028, 95% CI: 0.604-15.172,p=0.137) groups, the difference did not reach statistical significiance. Our results do not support the view that the C609T polymorphism has a role in the pathogenesis of MDS. Also the frequency of the C609T allele did not seem to be associated with cytogenetic abnormalities.

Background: Extranodal extension (ENE) in lymph node metastases has been shown to worsen the prognosis of papillary thyroid cancer (PTC). Despite the clinical significance of ENE, there are no stringent criteria for its microscopic diagnosis, and its identification is subject to inter-observer variability. The objective of this study was to determine the level of agreement among expert pathologists in the identification of ENE in PTC cases., Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to review 61 scanned slides of representative permanent sections of PTC specimens from Mount Sinai Beth Israel Medical Center in New York. Each slide was evaluated for the presence of ENE. The pathologists were also asked to report the criteria they use to identify ENE., Results: The overall strength of agreement in identifying ENE was only fair (κ = 0.35), and the proportion of observed agreement was 0.68. The proportions of observed agreement for the identification of perinodal structures (fat, nerve, skeletal, and thick-walled vessel involvement) ranged from 0.61 to 0.997., Conclusions: Overall agreement for the identification of ENE is poor. The lack of agreement results from both variation in pathologists' identification of features and disagreement on the histologic criteria for ENE. This lack of concordance may help explain some of the discordant information regarding prognosis in clinical studies when this feature is identified.

Background: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases., Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE., Results: The overall strength of agreement for identifying mETE was slight (κ = 0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (κ = 0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (κ = 0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE., Conclusions: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists' interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature.

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM&#95;005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling., (Copyright © 2015 Elsevier B.V. All rights reserved.)

NEDD4-2 alias NEDD4L (neural precursor cell expressed, developmentally downregulated) gene was reported as a candidate gene for epileptic photo-sensitivity. We aimed to investigate this possible association of NEDD4-2 variants with idiopathic photosensitive epilepsy. Consecutive patients who had been followed up at our epilepsy center and diagnosed with idiopathic epilepsy according to ILAE criteria and clear-cut photoparoxysmal responses in their electroencephalograms and 100 ethnically matched healthy subjects were included in the study. The regions around previously reported three variants, namely, S233L, E271A and H515P were tracked with DHPLC and the samples showing variations were sequenced. 81 patients (63 females) aged between 12-63 years (45 had juvenile myoclonic epilepsy, 11 childhood absence epilepsy, 14 juvenile absence epilepsy, 7 late onset idiopathic generalized epilepsy, 1 unclassified idiopathic generalized epilepsy, and 3 patients with idiopathic photosensitive occipital lobe epilepsy) were included in this study. We found only one heterozygous S233L variant in a 23-year-old man who has photosensitive form of juvenile absence epilepsy and pattern sensitivity to striped carpets. Other two variants were not found in any of the other patients and controls. Our results suggest that three screened NEDD4-2 variants do not play a leading role in the pathogenesis of photosensitive epilepsy in the Turkish population.

Background and Purpose: Global cerebral edema is an independent predictor of mortality and poor outcomes after aneurysmal SAH. Global cerebral edema, a complex disease process, is thought to be associated with an altered cerebral autoregulatory response. We studied the association between cerebral hemodynamics and early global cerebral edema by using CTP., Materials and Methods: We retrospectively studied consecutive patients with aneurysmal SAH with admission CTP performed at days 0-3. Two neuroradiologists classified global cerebral edema and hydrocephalus on NCCT performed concurrently with CTP. Global cerebral edema was defined as diffuse effacement of the sulci and/or basal cisterns or diffuse disruption of the cerebral gray-white matter junction. CTP was postprocessed into CBF and MTT maps by using a standardized method. Quantitative analysis of CTP was performed by using standard protocol with ROI sampling of the cerebral cortex. The Fisher exact test, Mann-Whitney test, and independent-samples t test were used to determine statistical associations., Results: Of the 45 patients included, 42% (19/45) had global cerebral edema and 58% (26/45) did not. Patient groups with and without global cerebral edema were well-matched for demographic and clinical data. Patients with global cerebral edema were more likely to have qualitative global CTP deficits than those without global cerebral edema (P = .001) with an OR = 13.3 (95% CI, 2.09-138.63). Patients with global cerebral edema also had a very strong trend toward statistical significance, with reduced quantitative CBF compared with patients without global cerebral edema (P = .064)., Conclusions: Global perfusion deficits are significantly associated with global cerebral edema in the early phase after aneurysmal SAH, supporting the theory that hemodynamic disturbances occur in global cerebral edema., (© 2015 by American Journal of Neuroradiology.)

A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Human ether-a-go-go related gene (herg) encoding HERG K(+) channel has been demonstrated in many previous studies with its association to cell cycle progression and growth in tumor cells. The upregulated expression of HERG K+ channels was determined in different tumor types. Furthermore, not only full-length transcript herg1 but also a truncated isoform herg1b was shown to be expressed in cancer cells. In this study, the expression levels of herg1 and herg1b and the impact of K897T mutation on their expressions were investigated in pediatric acute myeloid leukemia (pAML). Expression levels of herg1 and herg1b isoforms were analyzed by quantitative real time polymerase chain reaction (PCR) in pAML patients together with healthy donors, and their expressions were confirmed by western blotting. The 2690 A>C nucleotide variation in KCNH2 gene corresponding to K897T amino acid change was analyzed by PCR followed by restriction enzyme digestion. herg1b overexpression was observed in tumor cells compared to healthy controls (P = .0024). However, herg1 expression was higher in healthy control cells than tumor cells (P = .001). The prevalence of polymorphic allele 897T was 26% in our patient group and 897T carriers showed increased herg1b expression compared to wild-type allele carriers. Our results demonstrate the presence of the increased levels of herg1b expression in pAML. In addition, we report for the first time that, pAML subgroup with HERG 897K/K genotype compared to 897K/T and T/T genotypes express increased levels of herg1b. In conclusion, HERG 897K/K genotype with increased level of herg1b expression might well be a prognostic marker for pAML.

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. Lymphocytosis in cases receiving dasatinib therapy has been shown to be associated with pleural effusion (PE) and better outcome. Although patients who gather lymphocytosis during dasatinib have superior responses, there is only little data about the correlation between PE, response rates, and survival. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to compare the responses and outcomes between patients with or without PE. There were 18 patients (44%) who developed PE, in a total of 41 patients, with a median time of 15 months. Lymphocytosis was observed in nine patients (9/41, 22%) with a median duration of 6.5 months of dasatinib treatment. There were fourteen patients with at least one comorbidity that may play a role in the generation of PE. The cumulative MMR and CCyR rates were greater in PE+ patients (p<0.05). The PFS was significantly higher in PE+ group than PE- patients (p=0.013), also the OS was higher among PE+ patients than PE- group (p=0.042). In patients with a grade I/II PE, and durable responses under dasatinib, performing the management strategies for the recovery of effusion, together with continuing dasatinib can be a reasonable choice mainly in countries where third generation TKIs are not available. But alternative treatment strategies such as nilotinib or third generation TKIs can be chosen in patients with grade III/IV PE especially if the quality of life is severely affected., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells., Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis., Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89)., Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.

There is preliminary evidence that the local renin-angiotensin system (RAS) could affect neoplastic hematopoiesis. The aim of this study is to search messenger RNA (mRNA) expressions of the essential RAS elements in myeloid and lymphoid hematological neoplastic disorders. Forty-six patients with newly diagnosed myeloid (AML, biphenotypic leukemia, CML) or lymphoid (CLL, NHL, B-ALL, T-ALL) hematological disorders were included in the study. In the lymphoid group, the median expression values of RENIN, ACE1, ACE2 and ANGIOTENSINOGEN (ANGTS) mRNAs were 1.96%, 0.42%, 0.00% and 0.00%, respectively; in the myeloid group, 0.73%, 1.55%, 0.04% and 0.006%, respectively. In the lymphoid group, RENIN levels were significantly higher (p = 0.001), whereas ACE1 and ACE2 levels were significantly higher in the myeloid group (p values were 0.013 and 0.010, respectively). ANGTS levels were similar in both groups. In patients with non-ALL lymphoid malignancies, RENIN expressions were significantly higher when compared to ALL patients (p = 0.004). All patients with active disease had significantly higher RENIN mRNA expression levels than patients without active disease (2.03% vs 0.30%) (p = 0.034). The result of our present study indicates that the activities of local RAS may differ in distinct disease states such as leukemia and lymphomas.

Objective: Cardiac visceral fat is accepted to be a new marker for cardiometabolic risk due to its association with increased cardiovascular risk factors. This study aimed to compare the expression of 11 beta hydroxysteroid dehydrogenases (11β-HSD)-1, glucocorticoid receptor (GCR), and CD68 in mediastinal and subcutaneous adipose tissues (MAT, and SAT, respectively) and to assess their possible relationships with the development of coronary artery disease (CAD)., Methods and Results: Expression of 11β-HSD-1, GCR, and CD68 mRNA levels were measured by quantitative real-time polymerase chain reaction in MAT and SAT tissues of 37 patients undergoing coronary artery bypass grafting due to CAD (CAD group) and 19 non-CAD patients (controls) undergoing heart valve surgery. 11β-HSD-1 in MAT and SAT and GCR expression in MAT and SAT were found to be significantly increased in CAD group when compared with controls (P<.05, respectively). In CAD group, 11β-HSD-1 mRNA levels were found to be significantly higher in MAT compared to SAT (P<.05). CD68 mRNA levels were significantly higher in MAT of CAD group compared to controls (P<.05). Immunohistochemical analyses demonstrated the presence of CD68+ cells and increased 11β-HSD-1 expression in MAT of CAD group compared to SAT., Conclusion: The present study demonstrate that the mediastinal fat exhibits a pathogenic mRNA profile of 11β-HSD-1, GCR, and CD68. The identification of 11β-HSD-1 expression within the mediastinal fat, along with increased GCR expressions and the presence of CD68+ cells highlight that MAT potentially contributes to the pathogenesis of CAD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Radial scar (RS) is characterized by a fibroelastic core with entrapped ducts and lobules. Association with carcinoma is not uncommon. There is some dilemma as to the need for excisional biopsy or follow-up after RS diagnosis on core biopsy., Aim: To determine the necessity of excisional biopsy after the diagnosis of benign RS by core biopsy., Study Design: A total of 67 RS specimens associated with benign findings on core biopsy obtained between 2003 and 2008 were reviewed. They were grouped by their accompanying histopathologic features found upon subsequent surgical excision: benign, high-risk lesion (HRL), or carcinoma. Demographic features, radiologic findings, and needle gauge were compared within subgroups., Results: After surgical excision, 15 (22.4%) patients in the benign group were upgraded to a HRL, 4 (5.9%) patients were upgraded to carcinoma, and 48 (71.6%) remained benign. We found that malignancy is associated with RS more frequently if the patient is older and postmenopausal. Other variables such as symptoms at presentation, presence and type of abnormality on mammography (Breast Imaging Reporting and Data System score), breast density, size of biopsy needle used, and number of core samples retrieved did not help to predict the presence of carcinoma., Conclusions: The HRL and cancer upgrade rate of RS, requiring further intervention such as surgery or chemoprevention, is 28% in this study. However, we found that age and menopausal status may be taken into consideration when making the decision to follow up or excise the RS diagnosed on core biopsy. There is insufficient data to support the predictive value of any variables. Therefore, RS associated with benign findings on core biopsy should be excised.

T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Objective: T-cell acute lymphoblastic leukemia (T-ALL) is associated with recurrent chromosomal aberrations andabnormal ectopic gene expression during T-cell development. In order to gain insight into the pathogenesis of T-ALLthis study aimed to measure the level of expression of 7 T-cell oncogenes (LMO2, LYL1, TAL1, TLX1, TLX3, BMI1, andCALM-AF10) in pediatric T-ALL patients Material and Methods: LMO2, LYL1, TLX1, TLX3, BMI1, TAL1, and CALM-AF10 expression was measured usingquantitative real-time PCR in 43 pediatric T-ALL patients., Results: A high level of expression of LMO2, LYL1, TAL1, and BMI1 genes was observed in a large group of T-ALL.Several gene expression signatures indicative of leukemic arrest at specific stages of normal thymocyte development(LYL1 and LMO2) were highly expressed during the cortical and mature stages of T-cell development. Furthermore,upregulated TAL1 and BMI1 expression was observed in all phenotypic subgroups. In all, 6 of the patients had TLX1and TLX3 proto-oncogene expression, which does not occur in normal cells, and none of the patients had CALM-AF10fusion gene transcription. Expression of LYL1 alone and LMO2-LYL1 co-expression were associated with mediastinalinvolvement; however, high-level oncogene expression was not predictive of outcome in the present pediatric T-ALLpatient group, but there was a trend towards a poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 protooncogeneexpression., Conclusion: Poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 proto-oncogene expression indicate the needfor extensive study on oncogenic rearrangement and immunophenotypic markers in T-ALL, and their relationship totreatment outcome., Conflict of Interest: None declared.

To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049-129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C-T-C and C-T-T, in the order of loci rs9878047-rs3774207-rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: Photosensitive epilepsy (PSE) is a form of reflex epilepsy characterized by seizures triggered by light. Genetic factors play an important role and some studies have indicated a possible role of the bromodomain-containing protein 2 (BRD2) gene. Our aim was to investigate the relationship between PSE and mutations of the BRD2 gene., Methods: Fifty-four PSE patients with normal findings on neurological examination and neuro-imaging studies were included. All had a clear photoparoxysmal response in the EEG as reported by 2 experienced EEG interpreters. We investigated the BRD2 gene by denaturing high performance liquid chromatography followed by direct DNA sequencing., Results: We failed to detect any mutations of the BRD2 gene. However, several single-nucleotide polymorphisms (SNPs) were observed in the gene; three of them were novel SNPs. The comparison of the patients showing these SNP changes with the remaining patients suggested a link between carrier status and prognosis., Conclusion: Our study did not confirm the presence of the genetic variants previously found to link the BRD2 gene to the idiopathic form of photosensitive epilepsy. SNP changes of the BRD2 gene may be clinically relevant but these findings need to be verified by larger studies., (Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Visceral fat deposition and its associated atherogenic complications are mediated by glucocorticoids. Cardiac visceral fat comprises mediastinal adipose tissue (MAT) and epicardial adipose tissue (EAT), and MAT is a potential biomarker of risk for obese patients., Aim: Our objective was to evaluate the role of EAT and MAT 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and glucocorticoid receptor (GCR) expression in comparison with subcutaneous adipose tissue (SAT) in the development of coronary atherosclerosis in obese patients with coronary artery disease (CAD), and to assess their correlations with CD68 and fatty acids from these tissues., Methods and Results: Expression of 11β-HSD-1 and GCR was measured by qRT-PCR in EAT, MAT and SAT of thirty-one obese patients undergoing coronary artery bypass grafting due to CAD (obese CAD group) and sixteen obese patients without CAD undergoing heart valve surgery (controls). 11β-HSD-1 and GCR expression in MAT were found to be significantly increased in the obese CAD group compared with controls (p < 0.05). In the obese CAD group, 11β-HSD-1 and GCR mRNA levels were strongly correlated in MAT. Stearidonic acid was significantly increased in EAT and MAT of the obese CAD group and arachidonic acid was significantly expressed in MAT of the obese male CAD group (p < 0.05)., Conclusions: We report for the first time the increased expression of 11β-HSD-1 and GCR in MAT compared with EAT and SAT, and also describe the interrelated effects of stearidonic acid, HOMA-IR, plasma cortisol and GCR mRNA levels, explaining 40.2% of the variance in 11β-HSD-1 mRNA levels in MAT of obese CAD patients. These findings support the hypothesis that MAT contributes locally to the development of coronary atherosclerosis via glucocorticoid action.

Background: The fibrotic plaques of Peyronie/s disease and other localized fibrotic conditions have been considered to be the result of an abnormal wound healing process. The potential role of regulatory disorders of apoptosis in abnormal wound healing may also play a role in the development of Peyronie's disease., Objectives: To examine the phenomenon of apoptosis in Peyronie's disease, authors quantified differential levels of gene expression of apoptotic proteins, Fas, Fas Ligand, Bcl-2, p53, Caspase 3 and 8 in Peyronie's plaque and tunica albuginea., Material and Methods: Eight patients with Peyronie's disease undergoing surgical correction of the curvature had biopsy specimens taken from both the Peyronie's plaque and normal tunica albuginea. Messenger RNA expression of the apoptotic proteins in the plaque and normal tunica was measured by reverse transcriptase PCR., Results: Apoptotic gene expression was lower than the housekeeping gene's in half of the tunica albuginea samples and two thirds of the plaque samples. Overall mRNA expressions in the plaque were not significantly different from the normal tunica albuginea., Conclusions: The fibrotic plaques of Peyronie's disease and other localized fibrotic conditions have been considered to be the result of an abnormal wound healing process. The potential role of regulatory disorders of apoptosis in abnormal wound healing may also play a role in the development of Peyronie's disease. In this study, the lower expression of apoptotic genes may cause the persistence of collagen producing cells which were up-regulated for unknown reasons and consequently result in plaque formation. Similar expression levels of apoptotic genes in both tunica albuginea and Peyronie's plaques may be due to the generalized physiopathologic alterations in tunica albuginea that lead to plaque formation at a vulnerable region subjected to recurrent traumas.

TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T-ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T-ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T-ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T-ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology., (© 2012 Blackwell Publishing Ltd.)

Objective: To identify the well-known common translocations and FLT3 mutations in childhood acute myelogenousleukemia (AML) patients in Turkey., Material and Methods: The study included 50 newly diagnosed patients in which t(15;17), t(8;21), and inv(16)chromosomal translocations were identified using real-time PCR and FLT3 gene mutations were identified via direct PCR amplification PCR-RE analysis., Results: In all, t(15;17) chromosomal aberrations were observed in 4 patients (8.0%), t(8;21) chromosomal aberrationswere observed in 12 patients (24.0%), inv(16) chromosomal aberrations were observed in 3 patients (6.0%), and FLT3-ITD mutations were observed in 2 patients (4.0%); FLT3-D835 point mutation heterozygosity was observed in only 1patient (2.0%) patient., Conclusion: Despite of the known literature, a patient with FLT3-ITD and FLT3-D835 double mutation shows a bettersurvival and this might be due to the complementation effect of the t(15;17) translocation. The reportedmutation ratein this article (4%) of FLT3 gene seems to be one of the first results for Turkish population.

Aims: Glutathione S-transferase P1 (GSTP1) plays an important role in cellular protection against oxidative stress and toxic chemicals. Polymorphisms within GSTP1 are associated with alterations in enzyme activity, which may lead to development of lung disease and cancer. In this study, we aimed to investigate the GSTP1 Ile105Val and Ala114Val polymorphisms in patients with small cell lung cancer (SCLC)., Patients/methods: GSTP1 Ile105Val polymorphism in exon 5 and GSTP1 Ala114Val polymorphism in exon 6 were determined by using polymerase chain reaction-restriction fragment length polymorphism techniques in 89 patients with SCLC and 108 control patients with chronic obstructive pulmonary disease (COPD). Genotype frequencies and cigarette smoking intensities were compared among SCLC and COPD patients., Results: There were significantly less SCLC patients with variant exon 6 genotypes than COPD patients (7.9% vs. 20.4%, p=0.007), while the number of patients with variant exon 5 genotypes were comparable among groups. SCLC and COPD patients with variant exon 6 genotype showed trends toward exhibiting reduced cigarette consumption., Conclusions: The variant GSTP1 exon 6 genotype might be conferring protection against SCLC development. Whether this effect is associated with exposure to cigarette smoking needs to be clarified.

Polymorphisms of the x-ray repair cross-complementing group 1 (XRCC1) gene have been reported to be associated with various forms of cancer. We evaluated the possible effects of the Arg194Trp and the Arg399Gln polymorphisms on the risk for chronic lymphocytic leukemia (CLL) in 73 patients and 50 controls. We also analyzed their relation to frequency of sister chromatid exchange (SCE). With respect to codon 194, the allelic frequency of the Arg194Trp polymorphism did not significantly differ between the 2 groups. The proportion of individuals carrying the Arg194Trp polymorphism was not different in the 2 groups. With respect to codon 399, the proportion of the individuals carrying the Arg399Gln allele (90% vs 62%; p=0.000; odds ratio [OR], 5.779; 95% confidence interval [CI], 2.2-15.183) and the allelic frequency of the Arg399Gln polymorphism (56% vs 36%; p=0.002; OR, 2.278; 95% CI, 1.350-3.843) was significantly higher in the patient group. The frequency of the Arg/Gln genotype was significantly higher in the patient group (68.50% vs 52%; p=0.049; OR, 2.007; 95% CI, 0.955-4.217). The mean SCE frequency in the patient group was significantly higher (9.2±4 vs 7.5±2; p=0.02). When different compound genotypes were compared, the coexistence of Arg/Arg genotype in codon 194 with Arg/Arg genotype in codon 399 was significantly more frequent in the control group (30% vs 9%; p=0.004; OR, 0.247; 95% CI, 0.092-0.664). Within the patient group, SCE frequency did not differ between patients with various genotypes. The Arg399Gln polymorphism may be etiologically associated with CLL; however, it does not seem to increase SCE frequency.

In principle mutational records make it possible to estimate frequencies of disease alleles (q) for autosomal recessive disorders using a novel approach based on the calculation of the Homozygosity Index (HI), i.e., the proportion of homozygous patients, which is complementary to the proportion of compound heterozygous patients P(CH). In other words, the rarer the disorder, the higher will be the HI and the lower will be the P(CH). To test this hypothesis we used mutational records of individuals affected with Familial Mediterranean Fever (FMF) and Phenylketonuria (PKU), born to either consanguineous or apparently unrelated parents from six population samples of the Mediterranean region. Despite the unavailability of precise values of the inbreeding coefficient for the general population, which are needed in the case of apparently unrelated parents, our estimates of q are very similar to those of previous descriptive epidemiological studies. Finally, we inferred from simulation studies that the minimum sample size needed to use this approach is 25 patients either with unrelated or first cousin parents. These results show that the HI can be used to produce a ranking order of allele frequencies of autosomal recessive disorders, especially in populations with high rates of consanguineous marriages., (© 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.)

Aims and Background: The SET gene is a target of chromosomal translocations in acute leukemia and encodes a widely expressed multifunctional phosphoprotein. It has been shown that SET is upregulated in BCR-ABL1-positive cell lines, patient-derived chronic myeloid leukemia CD34-positive cells, and some solid tumors., Methods and Study Design: We determined the expression level of SET in 59 pediatric acute lymphoblastic leukemia patients who were BCR-ABL-negative using quantitative real-time reverse-transcriptase-polymerase chain reaction. Results. We showed that SET expression was significantly upregulated in 96.5% of B-acute lymphoblastic leukemia (28 of 29; 16.6 fold) and 93% of T-acute lymphoblastic leukemia (28 of 30; 47.6 fold) patients. This upregulation was not associated with any clinical features or overall and relapse-free survival., Conclusions: Our results showed that SET is significantly overexpressed in pediatric acute lymphoblastic leukemia samples, and an increased level of SET might contribute to leukemic process.

B-lineage acute lymphoblastic leukemia (B-ALL) is a common subtype of acute leukemia in children. PAX5 plays a central role in B-cell development and differentiation. In this study, we analyzed PAX5 expression levels, transactivation domain mutations/deletions in B-ALL patients (n=115) and healthy controls (n=10). Relative PAX5 mRNA levels were significantly increased in B-ALL patients (p<0.0001). PAX5 expression was also evaluated in three different B-ALL subgroups (pro B, Common B and Pre B ALL) and showed stage specific expression levels. Pro B (p=0.04) and pre B (p=0.04) patients showed significantly high PAX5 mRNA levels compared to stage specific controls. At least one deletion of exons 7-8 or 9 has been identified in the 41% of the patients. CD34 positivity in patients and presence of large deletions (Δ7/8/9) showed a significant correlation (p=0.05). None of our patients showed PAX5 point mutations, but two previously identified SNPs (rs3780135 and rs35469494) were detected. Our results support that PAX5 is a critical factor in B-ALL development and aberrant PAX5 expression especially at early stages may leads to leukemic transformation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1(-/-) mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1(-/-) mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1(-/-) mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell-specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus., Competing Interests: The authors have declared that no competing interests exist.

No disease-specific neuronal antibodies have so far been defined in neuro-Behçet's disease (NBD). Immunohistochemistry and immunocytochemistry studies showed antibodies to hippocampal and cerebellar molecular layers and the surface antigens of cultured hippocampal neurons in sera and/or cerebrospinal fluids (CSF) of 13 of 20 NBD and 6 of 20 BD patients but not in multiple sclerosis or headache controls. Screening with a protein macroarray led to identification of stress-induced-phosphoprotein-1 (STIP-1) as an antigenic target. High-titer STIP-1-antibodies were detected in 6 NBD patients' sera but not in controls. These results suggest that neuronal antibodies could be useful as diagnostic biomarkers in NBD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Quantitative PCR (qPCR) for detection of fusion transcripts and overexpressed genes is a promising tool for following minimal residual disease (MRD) in patients with hematological malignancies. Its widespread clinical use has to some extent been hampered by differences in data analysis and presentation that complicate multicenter clinical trials. To address these issues, we designed a highly flexible MRD-reporting software program, in which data from various qPCR platforms can be imported, processed, and presented in a uniform manner to generate intuitively understandable reports. The software was tested in a two-step quality control (QC) study; the first step involved eight centers, whose previous experience with the software ranged from none to extensive. The participants received cDNA from consecutive samples from a BCR-ABL+ chronic myeloid leukemia (CML) patient and an acute myeloid leukemia (AML) patient with both CBFβ-MYH11 and WT1 target genes, they conducted qPCR on their respective hardware platforms and generated a series of reports with pre-defined features. In step two, five centers used the software to report BCR-ABL+ MRD in a harmonized manner, applying their recently obtained CML international scale conversion factors. The QC study demonstrated that this MRD-reporting software is suitable for efficient handling of qPCR data, generation of MRD reports and harmonization of MRD data.

Purpose: Many of commonly used chemotherapeutics in lung cancer treatment are metabolized by glutathione-S transferases (GSTs). The placental isoform of GST (GSTP1) is the most abundant isoform in the lung. Polymorphisms within the GSTP1 may result in alterations in enzyme activity and change sensitivity to platinum-based chemotherapy. We investigated whether the polymorphism within the exons 5 and 6 of GSTP1 gene may change response to therapy, time to tumor progression (TTP) and overall survival in small cell lung cancer (SCLC) patients., Methods: Ninety-four histologically confirmed patients with SCLC were enrolled in this study during 1995-2006. GSTP1 Ile105Val polymorphism in exon 5 and GSTP1 Ala- 114Val polymorphism in exon 6 were determined by using PCR-RFLP techniques. Associations between the GSTP1 polymorphisms and treatment response were evaluated using the chi-square test. Associations between the GSTP1 polymorphisms and TTP and overall survival were compared using Kaplan-Meier survival curves., Results: We found no significant associations between exon 5 and exon 6 GSTP1 gene polymorphisms and response to therapy or overall survival. Patients carrying both variant exon 5 (Ile/Val or Val/Val) and variant exon 6 (Ala/Val) genotypes had significantly shorter TTP (5 vs. 8 months, p = 0.04). Moreover, patients with heterozygote exon 6 variant had presented with extensive-stage disease., Conclusion: No individual effect of variant alleles was found in relation to chemotherapy response, median TTP and overall survival. The carriage of both types of variant alleles may predict worse outcome.

Objective: Metabolic syndrome (MS) is associated with an increased risk of coronary artery disease (CAD) and type 2 diabetes mellitus (DM). In MS, adipose tissue has been shown to function as a paracrine and an endocrine organ secreting various adipocytokines. In the current study, adiponectin, tumor necrosis factor-α (TNF-α) and leptin gene expressions in the epicardial adipose tissue (EAT), paracardial adipose tissue (PAT) and subcutaneous adipose tissue (SAT) were investigated in MS patients with CAD and in non-MS patients without CAD., Methods and Results: Thirty-seven patients with MS undergoing coronary artery bypass grafting due to CAD (MS group) and twenty-three non-MS patients without CAD undergoing heart valve surgery (control group) were recruited prospectively to the study. Relative gene expressions of adiponectin, TNF-α and leptin in EAT, PAT and SAT were compared between two groups of patients. Adiponectin gene expression in EAT and PAT were significantly lower in MS group compared to the control group (p<0.0001, p=0.04, respectively) while SAT adiponectin gene expression did not differ significantly (p=0.64). TNF-α and leptin gene expressions were found to be statistically significantly higher in EAT, PAT and SAT of the MS group (p<0.0001, for all)., Conclusion: Our results demonstrate that TNF-α and leptin gene expressions increase prominently in the EAT, PAT and SAT while adiponectin gene expression decreases significantly in EAT and PAT in MS patients with CAD. These findings suggest that disturbances in expression of adiponectin, TNF-α and leptin in EAT, PAT and SAT might play an important role in MS patients with CAD.

Background: The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by HERG1 (KCNH2, Kv11.1) gene and is most highly expressed in heart and brain. Genetic variations in HERG1 predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia., Methods: We genotyped four single nucleotide polymorphisms (SNPs) in 7q36.1 region (two SNPs, rs1805123 and rs3800779, located on HERG1, and two SNPs, rs885684 and rs956642, at the 3'-downstream intergenic region) and then performed single SNP and haplotype association analyses in 84 patients with schizophrenia and 74 healthy controls after the exclusion of individuals having prolonged or shortened QT interval on electrocardiogram., Results: Our analyses revealed that both genotype and allele frequencies of rs3800779 (c.307+585G>T) were significantly different between populations (P = 0.023 and P = 0.018, respectively). We also identified that two previously undescribed four-marker haplotypes which are nearly allelic opposite of each other and located in chr7:150225599-150302147bp position encompassing HERG1 were either overrepresented (A-A-A-T, the at-risk haplotype, P = 0.0007) or underrepresented (C-A-C-G, the protective haplotype, P = 0.005) in patients compared to controls., Conclusions: Our results indicate that the potassium channel gene HERG1 is related to schizophrenia. Our findings may also implicate the whole family of HERG channels (HERG1, HERG2 and HERG3) in the pathogenesis of psychosis and its treatment.

Background: Complete pathologic response to neoadjuvant chemotherapy (NACT) is predominantly seen in "ERBB2" and "basal-like" tumors using expression profiling. We hypothesize that a similar response could be predicted using semiquantitative immunohistochemistry for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2)., Methods: ER, PR, and HER2 were used to classify 359 tumors treated with NACT into 6 groups: luminal A (strong ER+, HER2 negative), luminal B (weak to moderate ER+, HER2 negative), triple negative (negative for ER, PR, and HER2), ERBB2 (negative for ER and PR, but HER2+), luminal A-HER2 hybrid (strong ER+ and HER2+), and luminal B-HER2 hybrid (weak to moderate ER+ and HER2+). Complete pathologic response was defined as absence of invasive carcinoma in the breast and regional lymph nodes., Results: Thirteen percent (48 of 359) demonstrated complete pathologic response. The highest rate of complete pathologic response was seen in ERBB2 (33%; 19 of 57) and triple negative (30%; 24 of 79) tumor classes. Among the ER+ "molecular" group, the highest rate of complete pathologic response was seen among luminal B-HER2 hybrid tumors, 8% (2 of 24). Remainder of ER+ tumors demonstrated a very low rate of complete pathologic response, 1.5% (3 of 198). The 5-year survival for patients achieving complete pathologic response was 96% compared with 75% in patients that failed to achieve complete pathologic response. The overall survival was worse in the ER-negative group (ERBB2 and triple negative) compared with the ER-positive group., Conclusions: We confirm the recently defined "triple negative paradox," or rather "hormone receptor negative paradox," that despite the best response to NACT, ERBB2 and triple negative tumors show the worst overall survival because of higher relapse among those with residual disease.

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment. NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had both NOTCH1 and FBXW7 mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients. NOTCH1 and FBXW7, NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However, NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.

We aimed to compare the cytogenetic and molecular analyses in the assessment of imatinib mesylate response in patients suffering the chronic phase of chronic myelocytic leukemia who were refractory to alpha-interferon treatment. A total of 117 patients in the chronic phase of chronic myelocytic leukemia were included. The patients were treated with 400 mg/day imatinib mesylate. Bone marrow samples were obtained for the cytogenetic and molecular analyses. Patients without the Ph chromosome were defined as complete cytogenetic responders. Partial cytogenetic response was determined when the Ph chromosome was detected in 1-35% of the cells. Molecular response was determined by quantitative real-time reverse transcriptase polymerase chain reaction (QR-PCR) and defined as no detection of BCR-ABL mRNA. The frequencies of complete and partial cytogenetic response were 29% (n = 34) and 15% (n = 18), respectively. No cytogenetic response was achieved in 56% (n = 65) of the patients. Molecular response was achieved in 62% (n = 21) and 33% (n = 6) of the complete and partial cytogenetic responders, respectively. All of the 65 patients with no cytogenetic response were also molecular nonresponders. We conclude that there is reasonable agreement between the cytogenetic and molecular analyses. Both methods are complementary in the assessment of response to therapy.

Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph(+) CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

Background: Metabolic syndrome is a cluster of different clinical manifestations that are risk factors for atherothrombotic cardiovascular disorders. Fatty-acid-binding protein 4 (FABP4/aP2), which is highly expressed in adipocytes, specifically exerts intracellular lipid trafficking. A high level of fatty-acid-binding protein 4 expression present in obese subjects has also been found in mice and humans, especially in macrophages at atherosclerotic lesions. An in vivo study demonstrated that the inhibitor of aP2 would be a new therapeutic agent for treating metabolic diseases in mice. We have investigated the mRNA expression of fatty-acid-binding protein 4 in human epicardial adipose and ascending aorta tissues of metabolic syndrome and nonmetabolic syndrome patients., Methods: Paired epicardial adipose and ascending aorta tissue samples were obtained from 10 metabolic syndrome patients and 4 nonmetabolic syndrome patients during coronary bypass grafting and aortic valve replacement therapy, respectively. Fatty-acid-binding protein 4 gene expression was determined by quantitative real-time polymerase chain reaction., Results and Conclusions: Fatty-acid-binding protein 4 expression of epicardial adipose tissue was significantly higher in metabolic syndrome patients than in nonmetabolic syndrome controls (P<.05). In metabolic syndrome patients, fatty-acid-binding protein 4 expression in epicardial adipose tissue was 66 times higher than fatty-acid-binding protein 4 expression in ascending aorta tissue. The expression level of fatty-acid-binding protein 4 in epicardial adipose tissue was found to be significantly correlated with waist circumference in all subjects (r=.535, P<.05). Our data showed for the first time that human epicardial adipose and ascending aorta tissues express fatty-acid-binding protein 4 and that its level of expression in epicardial adipose tissues of metabolic syndrome patients is elevated. Increased fatty-acid-binding protein 4 gene expression in epicardial adipose tissues of metabolic syndrome patients led us think that fatty-acid-binding protein 4 might be an important factor in metabolic syndrome.

Introduction: CARD15 gene mutations may present different frequencies in populations and sometimes surgical interventions may become a necessary therapy for inflammatory bowel disease patients. Mutations of 1007fs, G908R, R702W and polymorphisms of P268S, IVS8+158 of the CARD15 gene and their relation with disease-related surgery were investigated in Turkish inflammatory bowel disease patients in this study., Material and Method: 1007fs, G908R, R702W mutations and P268S, IVS8+158 polymorphisms of CARD15 gene were analyzed in 130 inflammatory bowel disease patients (67 Crohn's disease, 63 ulcerative colitis) and 87 healthy controls. After obtaining DNA samples, genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results were evaluated by statistical analysis and accepted as significant if P < 0.05., Results: R702W gene mutation was significantly lower in the inflammatory bowel disease group (1.5%) than the controls (4.8%) (P < 0.05). The overall allele frequency of mutations in the inflammatory bowel disease group (2.7%) was lower than in controls (6.6%) (P < 0.05). Disease-related surgery history was present in 20 Crohn's and 25 ulcerative colitis patients; familial history was present in four Crohn's and five ulcerative colitis patients. Statistically, no relationship was detected between disease-related surgeries and the investigated genetic tests., Conclusion: In Turkish patients, no important relationship was detected between the investigated allele frequencies of the CARD15 gene and inflammatory bowel disease nor between disease-related surgeries and inflammatory bowel disease.

The inhibition of the human ether-à-go-go-related (hERG) K+ channels is the major cause of long QT syndromes inducing fatal cardiac arrhythmias. Ergtoxin 1 (ErgTx1) belongs to scorpion-toxins, which are K+ channel-blockers, and binds to hERG channel with 1:1 stoichiometry and high affinity (Kd approximately 10 nM). Nevertheless, patch-clamp recordings recently demonstrated that ErgTx1 does not establish complete blockade of hERG currents, even at high ErgTx1 concentrations. Such phenomenon is supposed to be consistent with highly dynamic conformational changes of the outer pore domain of hERG. In this study, simultaneous topography and recognition imaging (TREC) on hERG HEK 293 cells was used to visualize binding sites on the extracellular part of hERG channel (on S1-S2 region) for Anti-Kv11.1 (hERG-extracellular-antibody). The recognition maps of hERG channels contained recognition spots, haphazardly distributed and organized in clusters. Recognition images after the addition of ErgTx1 at high concentrations ( approximately 1 microM) revealed subsequent partial disappearance of clusters, indicating that ErgTx1 was bound to the S1-S2 region. These results were supported by AFM force spectroscopy data, showing for the first time that voltage sensing domain (S1-S4) of hERG K+ channel might be one of the multiple binding sites of ErgTx1.

Objectives: Small cell lung cancer (SCLC) has a rapid growth rate and is characterized by early metastases. Tumor growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Whether surveillance of pre- and post-treatment serum VEGF and especially its receptors VEGF-1 and VEGF-2 levels in SCLC patients have impact on clinical outcome is unknown., Methods: From February 2001 to January 2003, 39 consecutive patients with histological proven SCLC were enrolled into the study. Pre-treatment (n: 39) and post-treatment (n: 25) samples of the same patients were collected at the time of their response evaluation. The levels of VEGF and its receptors VEGFR-1 and VEGFR-2 were measured in the serum by quantitative sandwich enzyme immunoassay technique., Results: The median pre-treatment serum VEGF, VEGFR-1, and VEGFR-2 levels which were significantly higher than the normal controls were 1,200 pg/ml (range, 1,414.3 +/- 956.2 pg/ml), 85 pg/ml (range, 97.8 +/- 70.7 pg/ml), and 11,550 pg/ml (range, 14,481 +/- 6,267 pg/ml), respectively. We detected a poor but positive correlation between VEGF and VEGFR-2 (r: 0.46, p: 0.003). Pre-treatment low serum VEGF (<728.5 pg/ml) value (p: 0.02) and good response to treatment (p: 0.008) were found as good prognostic factors by multivariate analysis., Conclusions: Low serum VEGF concentration is a significant and independent prognostic factor in SCLC patients. Surveillance of VEGF and its receptors to predict chemotherapy response is not useful. Whether the levels of serum VEGF and its receptors VEGFR-1 and VEGFR-2 have value in detecting treatment modalities of SCLC need further studies.

Aromatase (P450AROM) converts testosterone to estrogen. This conversion could be important in normal physiology and estradiol-induced tumorigenesis in human pituitary. The objective of this study was to examine the expression of P450AROM in normal human pituitary and determine the gender difference. We examined aromatase expression in 19 normal human pituitary glands [13 males, 6 females, median age: 30 years (interquartile ranges, IQR: 23-63)] obtained from autopsy. We demonstrated aromatase gene expression levels by quantitative RT-PCR and aromatase protein with immunohistochemical staining in normal male and female human pituitary. Although median relative expression level of aromatase mRNA of male individuals [median DeltaCt = 42.6 (IQR: 7.6-93.9)] was higher than the female individuals [median DeltaCt = 3.9 (IQR:0-44.8)], we could not determine a significant gender difference in aromatase mRNA levels (p = 0.2). The difference between the aromatase protein density by immunohistochemistry was not significant between genders (p = 0.78). The aromatase levels were also not correlated with the age of the study subjects (p = 0.42 r = -0.21). The results indicate that aromatase enzyme is present in human pituitary. The amount and the density of the enzyme show a large variance among different individuals. Although higher mRNA expression was observed in male pituitary compared to female pituitary, there was no statistically significant difference for gender or age.