Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors.

This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure-activity relationship based on the ligand-enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules' binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.

Transcriptome profiling and pathway analysis in squamous cell carcinoma of buccal mucosa.

BACKGROUND: High recurrence and poor overall survival in buccal mucosa squamous cell carcinoma (BMSCC) are not well addressed due to lack of efficient prognostic biomarkers and targeted therapies. To uncover gene candidates for the same, transcriptome profiling has been examined in BMSCC, which is not explored yet. METHODS: We compared 9 BMSCC and 2 normal oral FFPE tissues using Agilent SurePrint G3 Human gene expression v3 microarray chips. The obtained RNA signatures were interrogated in the cancer genome atlas (TCGA) dataset for alteration values and survival data. RESULTS: We found total 237 protein coding RNAs and 85 long non-coding RNAs (lncRNAs) which displayed significant differential expression with criteria of at-least 2 fold change and Benjamini Hochberg FDR < .05. In protein coding RNAs, RUNX3 and EMX2 showed utmost degree of up-regulation and down-regulation, respectively. Likewise, among lncRNAs, ARGFXP2 and lnc-SYCP3-2 displayed highest degree of up-regulation and down-regulation, respectively. Besides, an analysis of the RNA list in TCGA dataset spotted deregulation of 21 genes in both, our cohort and TCGA cohort. Among which, MRTO4 and EIF3J genes, and LINC00310, a lncRNA showed greatest expression alterations. Strikingly, at RNA expression level, up-regulation of two genes, EIF3J and SDCBP, was significantly associated with disease free survival and poor overall survival, respectively. CONCLUSION: Our data documented significant findings to enhance understanding of the disease biology. The proposed RNA candidates (RUNX3, EMX2, MRTO4, EIF3J, SDCBP and LINC00310) may serve as putative therapeutic targets and potential biomarkers for BMSCC diagnosis and prognosis.

Chloroquine fumardiamides as novel quorum sensing inhibitors.

Quorum sensing inhibitors (QSIs) that specifically interfere with bacterial cell-to-cell communication are considered as an alternative approach to conventional antibacterial therapy. In our study, a set of twenty-six fumardiamides with a quinoline head-group were evaluated as potential QSIs. Two strains of Gram-negative Chromobacterium violaceum (violacein-producing strain ATCC31532 and violacein-negative, mini-Tn5 mutant derivative CV026) were used as QS reporters for testing anti-QS and bactericidal activity of various quinoline fumardiamides. The initial screening of eighteen fumardiamides with primaquine, mefloquine and chloroquine scaffolds identified chloroquine derivatives as the most promising QSIs. Tail-group optimization of chloroquine fumardiamides led to the most active compounds 27, 29 and 30 bearing aminoethyl or piperidine moieties. At 400 µM concentration, these compounds inhibited the QS of C. violaceum strains in a manner similar to quercetin (the model QSI), while at the 40 µM concentration their inhibitory effect was twice less than that of quercetin. As none of the compounds displayed a bactericidal effect and that the QS inhibition was specific to the CV026 strain, our findings indicate that the structurally optimized chloroquine derivatives could function as quorum quenching (QQ) agents with a potential to block the signaling without entering the cell. In conclusion, our finding provides an important step toward the further design of agents targeting cell-to-cell communication.

VEGFA isoforms play a vital role in oral cancer progression.

Angiogenesis plays an important role in tumor growth and prognostication. A key angiogenesis stimulator is vascular endothelial growth factor (VEGF). The present investigation aimed to study contribution of VEGFA isoforms in oral cancer progression. Reverse transcription polymerase chain reaction and ELISA were employed to analyze tissue VEGFA isoforms and serum VEGF levels, respectively, in 109 oral cancer cases and 50 controls. VEGF183 and VEGF165 were significantly downregulated in malignant tissues as compared to adjacent normal tissues. VEGF183 and VEGF189 were significantly associated with tumor differentiation and tumor size. VEGF165 was significantly higher in recurrent early stage tumors. Serum VEGF levels were significantly higher in cases as compared to the controls and were associated with tumor differentiation. Serum VEGF levels were significantly higher in patients with recurrent advanced stage tumors. Further, patients with high levels of VEGF165 and serum VEGF levels had the worst prognosis. VEGFA isoform status and serum VEGF levels play a significant role in the progression as well as prognosis of oral cancer.

Loratadine analogues as MAGL inhibitors.

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 µM) and 35-fold higher selectivity over human α/ß-hydrolase-6 (hABHD6, IC50=1.79 µM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 µM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

Revisiting 1,3,4-Oxadiazol-2-ones: Utilization in the Development of ABHD6 Inhibitors.

This article describes our systematic approach to exploring the utility of the 1,3,4-oxadiazol-2-one scaffold in the development of ABHD6 inhibitors. Compound 3-(3-aminobenzyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-169, 52) was identified as a potent inhibitor of hABHD6, with an IC50 value of 216 nM. This compound at 10 µM concentration did not inhibit any other endocannabinoid hydrolases, such as FAAH, MAGL and ABHD12, or bind to the cannabinoid receptors (CB1 and CB2). Moreover, in competitive activity-based protein profiling (ABPP), compound 52 (JZP-169) at 10 µM selectively targeted ABHD6 of the serine hydrolases of mouse brain membrane proteome. Reversibility studies indicated that compound 52 inhibited hABHD6 in an irreversible manner. Finally, homology modelling and molecular docking studies were used to gain insights into the binding of compound 52 to the active site of hABHD6.

Salivary glyco-sialylation changes monitors oral carcinogenesis.

Alterations in cell membrane glycosylation play important role in oral carcinogenesis. The present study evaluated salivary sialylation changes i.e. total sialic acid (TSA), sialidase activity, linkage specific (α2-3 and α2-6) sialoproteins and sialyl transferase (ST) activity in controls, patients with oral precancerous conditions (OPC) and oral cancer. Subjects enrolled included 100 controls, 50 patients with OPC, 100 oral cancer patients, and 30 post treatment follow-ups. TSA was estimated by spectrophotometric method, sialidase activity by spectrofluorometric assay and linkage specific biotinylated lectins (α2-3: sambucus nigra agglutinin and α2-6: maackia amurensis agglutinin) were used to detect α-2,3 and α-2,6 STs and sialoproteins by ELISA and dot blot respectively. An increasing trend of salivary TSA/TP ratio, sialidase activity, α2-3 sialoproteins, α-2,3 and α-2,6 ST activities was observed from controls to patients with OPC to oral cancer patients and levels were significantly elevated in oral cancer patients as compared to the controls. Sialidase activity exhibited significant association with metastasis and infiltration. Sialidase activity, TSA/TP ratio, α-2,3 and α-2,6 ST activities were found to be higher in patients with metastasis as compared to patients without metastasis. A progressive increase in TSA/TP ratio, sialidase activity, α2-3 and α2-6 sialoproteins was observed from controls to early to advanced stage of the disease. Sialidase activity, α2-3 and α2-6 sialoproteins and ST activities were found to be decreased in complete responders; while levels were elevated in non-responders. The results documented utility of salivary sialylation endpoints, a non invasive tool in monitoring of oral carcinogenesis.

Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors.

Prevalence of high-risk human papillomavirus type 16 and 18 in oral and cervical cancers in population from Gujarat, West India.

BACKGROUND: Oral and cervical cancers are major malignancies in men and women, respectively, in India. This study evaluated occurrence of human papillomavirus (HPV) 16 and 18 infections in oral and cervical cancers to estimate HPV-associated burden of these cancers in the population from Gujarat, West India. METHODS: A total of 97 malignant oral carcinoma tissues and 52 cervical carcinoma tissues were analyzed by type-specific PCR for the presence of HPV type 16 and 18 infections. RESULTS: None of the oral cancer patients revealed the presence of HPV type 16 and 18 infection. In cervical cancer, 31 (59.6%) patients were infected with HPV 16 and 18. Of these 31 HPV-positive cervical cancer patients, 28 (90.3%) were infected with HPV 16 and 3 (9.7%) were infected with HPV 18. CONCLUSION: The results suggested that HPV 16 and 18 do not play an important role in oral carcinogenesis in the population from Gujarat, West India. However, HPV 16 is highly prevalent in the cervical cancer patients, which may be considered for planning of prevention programs such as screening and vaccination in women from this region.

Association of Interactions between Metabolic 'Caretaker' Genes, p53, MDM2, and Tobacco Use with the Risk of Oral Cancer: A Multifactor Dimensionality Reduction Approach.

BACKGROUND: The present study investigated the association of interactions between gene polymorphisms in metabolic 'caretaker' genes (Phase I: CYP1A1, CYP2E1; Phase II: GSTM1, GSTT1), the cell cycle regulatory gene, p53, along with its negative controller, MDM-2, and the environment variable (tobacco). A nonparametric model, multifactor dimensionality reduction (MDR), was applied to analyse these interactions. MATERIALS AND METHODS: This case-control study was carried out on 242 subjects. Genomic DNA was extracted from peripheral blood lymphocytes.11 gene variants with an exposure variable (tobacco use) were analysed using MDR to identify the best locus model for gene-gene and gene-environment interactions. Statistical significance was evaluated using a 1000-fold permutation test using MDR permutation testing software (version 1.0 beta 2). The value of p<0.05 was considered statistically significant. RESULTS: The best three-locus model for gene-gene interaction included two of the p53 gene polymorphisms; rs17878362 (intron 3) and rs1042522 (exon 4) and rs6413432 in the Phase I gene, CYP2E1(DraI). The three-locus model to evaluate the gene-environment interaction included two intronic polymorphisms of the p53 gene, that is, rs17878362 (intron 3) and rs1625895 (intron 6), and rs4646903 in the Phase I gene CYP1A1*2C. The interaction graphs revealed independent main effects of the tobacco and p53 polymorphism, rs1042522 (exon 4), and a significant additive interaction effect between rs17878362 (intron 3) and rs1042522 (exon 4). CONCLUSIONS: The nonparametric approach highlighted the potential role of tobacco use and variations in the p53 gene as significant contributors to oral cancer risk. The findings of the present study will help implement preventive strategies in both tobacco use and screening using a molecular pathology approach.

Association of vitamin D receptor gene polymorphisms with breast cancer risk.

BACKGROUND: Recent literature suggests that vitamin D signaling has a protective effect against breast cancer risk. Thus, the aim of the present study was to find the association of vitamin D receptor (VDR) gene polymorphisms with breast cancer risk. MATERIALS AND METHODS: Fok1, Bsm1, Apa1, and Taq1 polymorphisms were performed by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method, and Poly A polymorphism was carried out using PCR-SSCP in 140 breast cancer patients and 155 controls. RESULTS: Odds ratio was significantly higher in both homozygous variant genotypes (LL) of Poly A polymorphism of VDR (odds ratio [OR] = 5.42, 95% confidence interval [CI] = 1.19-23.31, P = 0.02) and heterozygous variant genotypes (SL) of Poly A polymorphism of VDR (OR = 3.89, 95% CI = 1.10-13.7, P = 0.03). Fok1, Bsm1, Apa1, and Taq1 polymorphisms of VDR gene were not significantly associated with breast cancer risk. CONCLUSION: Poly A polymorphism at the 3' untranslated region (UTR) of VDR gene was significantly associated with breast cancer risk in West Indian population.

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid α/ß-Hydrolase Domain 6 (ABHD6).

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/ß-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.

Alterations in p53 Influence hTERT, VEGF and MMPs Expression in Oral Cancer Patients.

BACKGROUND: Mutant p53 is the crucial molecule in the etiopathogenesis of oral cancer. Therefore, we aimed to evaluate the impact of alterations of the p53 gene and its negative feedback regulator, MDM2, on the expression of hTERT, VEGF, and MMPs; the critical genes involved in oral cancer progression. MATERIAL AND METHODS: p53 and MDM2 genotyping were done by PCR-RFLP. p53 mutation analysis was performed using PCR-SSCP and sequencing. hTERT, VEGFA isoforms, MMP2, and MMP9 mRNA levels were analyzed by semi-quantitative Reverse Transcriptase PCR. RESULTS: Arg allele at p53 exon 4 was significantly associated with overexpression of hTERT, MMP2, and MMP9 individually. Expression of hTERT, VEGF A isoforms, MMP2 and MMP9 were significantly altered in the presence of p53 and MDM2 polymorphisms and p53 mutations in a specific combination. Mutant p53, Arg allele at p53 exon 4 locus, and G/G/or T/T genotype at MDM2revealed increased expression of hTERT, VEGF A isoforms, and MMP2/9. CONCLUSION: This study provides evidence that apart from mutant p53, naturally occurring sequence variants in p53codon 72 (Arg72Pro) (rs1042522) and MDM2 (rs2279744) significantly alter the expression of hTERT, VEGF-A isoforms, and MMP2/9 in a specific combination. The differential interaction of codon 72 variants with MDM2, hTERT, VEGF-A isoforms and MMP2/9 play a role in the aggressiveness of oral cancer. The results have important implications for oral cancer progression and should be explored for innovative treatment options.

Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria.

New classes of antibiotics are urgently needed in the fight against multidrug-resistant bacteria. Drug repurposing has emerged as an alternative approach to accelerate antimicrobial research and development. In this study, we screened a library of sphingosine-1-phosphate receptor (S1PR) modulators against Staphylococcus aureus and identified five active compounds. Among them, etrasimod (APD334), an investigational drug for the treatment of ulcerative colitis, displayed the best inhibitory activity against S. aureus when growing as free-floating planktonic cells and within biofilms. In follow-up studies, etrasimod showed bactericidal activity and drastic reduction of viable bacteria within 1 h of exposure. It also displayed a potent activity against other Gram-positive bacteria, including penicillin- and methicillin-resistant S. aureus strains, S. epidermidis, and Enterococcus faecalis, with a minimum inhibitory concentration (MIC) ranging from 5 to 10 µM (2.3-4.6 µg/mL). However, no inhibition of viability was observed against Gram-negative bacteria Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa, showing that etrasimod preferably acts against Gram-positive bacteria. On the other hand, etrasimod was shown to inhibit quorum sensing (QS) signaling in Chromobacterium violaceum, suggesting that it may block the biofilm formation by targeting QS in certain Gram-negative bacteria. Furthermore, etrasimod displayed a synergistic effect with gentamicin against S. aureus, thus showing potential to be used in antibiotic combination therapy. Finally, no in vitro toxicity toward mammalian cells was observed. In conclusion, our study reports for the first time the potential of etrasimod as a repurposed antibacterial compound against Gram-positive bacteria.

Food-Grade Bacteria Combat Pathogens by Blocking AHL-Mediated Quorum Sensing and Biofilm Formation.

Disrupting bacterial quorum sensing (QS) signaling is a promising strategy to combat pathogenic biofilms without the development of antibiotic resistance. Here, we report that food-associated bacteria can interfere with the biofilm formation of a Gram-negative pathogenic bacterium by targeting its AHL (acyl-homoserine lactone) QS system. This was demonstrated by screening metabolic end-products of different lactobacilli and propionibacteria using Gram-negative and biofilm-forming Chromobacterium violaceum as the QS reporter and our anti-QS microscale screening platform with necessary modifications. The method was optimized in terms of the inoculation technique and the concentrations of D-glucose and L-tryptophan, two key factors controlling the synthesis of violacein, a purple pigment indicating the activation of the QS system in C. violaceum. These improvements resulted in ca. 16-times higher violacein yields and enabled revealing anti-QS effects of Lactobacillus acidophilus, Lentilactobacillus kefiri, Lacticaseibacillus rhamnosus and Propionibacterium freudenreichii, including new cheese-associated strains. Our findings also suggest that acetate and propionate excreted by these species are the main factors that interrupt the QS-mediated signaling and subsequent biofilm growth without affecting the cell viability of the C. violaceum reporter. Thus, the present study reports a revised anti-QS screening method to accurately define new bacteria with an ability to combat pathogens in a safe and sustainable way.

New in vitro tools to study human constitutive androstane receptor (CAR) biology: discovery and comparison of human CAR inverse agonists.

The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.

Synthesis and Biological Evaluation of Fingolimod Derivatives as Antibacterial Agents.

We recently identified fingolimod as a potent antibiofilm compound by screening FDA-approved drugs. To study if the antibacterial activity of fingolimod could be further improved and to explore in-depth structure-activity relationships, we synthesized 28 novel fingolimod derivatives and evaluated their efficacy against Staphylococcus aureus grown in planktonic/single cell and biofilms. The most effective derivatives were tested on preformed S. aureus biofilms and against Gram-negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa, using fingolimod as the reference compound. Seven derivatives were more effective against S. aureus, while five other derivatives showed improved activity against P. aeruginosa and/or A. baumannii, with no apparent change in cytotoxicity on human cells. The most interesting derivatives, compounds 43 and 55, displayed a broader spectrum of antibacterial activity, possibly exerted by the change of the para-hydrocarbon chain to a meta position for 43 and by an additional hydroxyl group for 55.

Effectiveness of adjunctive antidepressant treatment for bipolar depression.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

Clinical Significance of BCR-ABL Fusion Gene in Chronic Myeloid Leukemia Patients.

OBJECTIVES: Introduction: The BCR-ABL fusion gene plays a central role in the pathogenesis of CML. The aim of the present study was to evaluate BCR-ABL fusion gene expression in CML patients and to correlate with clinical outcome. Method: A total of 112 CML patients were enrolled for the current study and expression of the BCR-ABL fusion gene was performed using qRT-PCR. Statistical analysis of SPSS correlated the BCR-ABL gene copy number and ratio with distinct parameters. Result: We observed that BCR-ABL gene CN and ratio were significantly higher in adult CML patients as compared to childhood leukemia (p=0.02 and p=0.04, respectively). BCR-ABL CN and ratio were significantly increased in CML patients with leukocytosis (p=0.01 and p=0.008, respectively) and thrombocytosis (p=0.05 and p=0.008, respectively). Further, CN and ratio were compared with three prognostic scores; Sokal, Hasford and EUTOS score. BCR-ABL CN and ratio were higher in high risk category for Sokal and EUTOS (European Treatment and Outcome Study) scores. Conclusion: The current study strengthens clinical importance molecular response and prognosis of CML patients.