Temporal dynamics of nitric oxide wave in early vasculogenesis.

Endothelium-derived nitric oxide (NO) is a mediator of angiogenesis. However, NO-mediated regulation of vasculogenesis remains largely unknown. In the present study, we show that the inhibition of NO significantly attenuated endothelial migration, ring formation, and tube formation. The contribution of nitric oxide synthase (NOS) enzymes during early vasculogenesis was assessed by evaluating endothelial NOS (eNOS) and inducible NOS (iNOS) mRNA expression during HH10-HH13 stages of chick embryo development. iNOS but not eNOS was expressed at HH12 and HH13 stages. We hypothesized that vasculogenic events are controlled by NOS-independent reduction of nitrite to NO under hypoxia during the very early phases of development. Semi-quantitative polymerase chain reaction analysis of hypoxia-inducible factor-1α (HIF-1α) showed higher expression at HH10 stage, after which a decrease was observed. This observation was in correlation with the nitrite reductase (NR) activity at HH10 stage. We observed a sodium nitrite-induced increase in NO levels at HH10, reaching a gradual decrease at HH13. The possible involvement of a HIF/NF-κB/iNOS signaling pathway in the process of early vasculogenesis is suggested by the inverse relationship observed between nitrite reduction and NOS activation between HH10 and HH13 stages. Further, we detected that NR-mediated NO production was inhibited by several NR inhibitors at the HH10 stage, whereas the inhibitors eventually became less effective at later stages. These findings suggest that the temporal dynamics of the NO source switches from NR to NOS in the extraembryonic area vasculosa, where both nitrite reduction and NOS activity are defined by hypoxia.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Systems level insights into the impact of airborne exposure on SARS-CoV-2 pathogenesis and COVID-19 outcome - A multi-omics big data study.

Coronavirus disease 2019 (COVID-19) is a viral pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that led to more than 800,00 deaths and continues to be a major threat worldwide. The scientific community has been studying the risk factors associated with SARS-CoV-2 infection and pathogenesis. Recent studies highlight the possible contribution of atmospheric air pollution, specifically particulate matter (PM) exposure as a co-factor in COVID-19 severity. Hence, meaningful translation of suitable omics datasets of SARS-CoV-2 infection and PM exposure is warranted to understand the possible involvement of airborne exposome on COVID-19 outcome. Publicly available transcriptomic data (microarray and RNA-Seq) related to COVID-19 lung biopsy, SARS-CoV-2 infection in epithelial cells and PM exposure (lung tissue, epithelial and endothelial cells) were obtained in addition with proteome and interactome datasets. System-wide pathway/network analysis was done through appropriate software tools and data resources. The primary findings are; 1. There is no robust difference in the expression of SARS-CoV-2 entry factors upon particulate exposure, 2. The upstream pathways associated with upregulated genes during SARS-CoV-2 infection considerably overlap with that of PM exposure, 3. Similar pathways were differentially expressed during SARS-CoV-2 infection and PM exposure, 4. SARS-CoV-2 interacting host factors were predicted to be associated with the molecular impact of PM exposure and 5. Differentially expressed pathways during PM exposure may increase COVID-19 severity. Based on the observed molecular mechanisms (direct and indirect effects) the current study suggests that airborne PM exposure has to be considered as an additional co-factor in the outcome of COVID-19.

Repurposing of thalidomide and its derivatives for the treatment of SARS-coV-2 infections: Hints on molecular action.

AIMS: The SARS-coV-2 pandemic continues to cause an unprecedented global destabilization requiring urgent attention towards drug and vaccine development. Thalidomide, a drug with known anti-inflammatory and immunomodulatory effects has been indicated to be effective in treating a SARS-coV-2 pneumonia patient. Here, we study the possible mechanisms through which thalidomide might affect coronavirus disease-19 (COVID-19). METHODS: The present study explores the possibility of repurposing thalidomide for the treatment of SARS-coV-2 pneumonia by reanalysing transcriptomes of SARS-coV-2 infected tissues with thalidomide and lenalidomide induced transcriptomic changes in transformed lung and haematopoietic models as procured from databases, and further comparing them with the transcriptome of primary endothelial cells. RESULTS: Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signalling, NOD-like receptor signalling, Toll-like receptor signalling, leucocyte differentiation and innate immunity, the processes that are aberrantly regulated in severe COVID-19 patients. CONCLUSION: The present study indicates thalidomide analogues as a better fit for treating severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the COVID-19.

Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q.

BACKGROUND: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification. METHODS: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival. RESULTS: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group. CONCLUSIONS: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.

Ectopic release of nitric oxide modulates the onset of cardiac development in avian model.

Heart development is one of the earliest developmental events, and its pumping action is directly linked to the intensity of development of other organs. Heart contractions mediate the circulation of the nutrients and signalling molecules to the focal points of developing embryos. In the present study, we used in vivo, ex vivo, in vitro, and in silico methods for chick embryo model to characterize and identify molecular targets under the influence of ectopic nitric oxide in reference to cardiogenesis. Spermine NONOate (SpNO) treatment of 10 µM increased the percentage of chick embryos having beating heart at 40th h of incubation by 2.2-fold (p < 0.001). In an ex vivo chick embryo culture, SpNO increased the percentage of embryos having beats by 1.56-fold (p < 0.05) compared with control after 2 h of treatment. Total body weight of SpNO-treated chick embryos at the Hamburger and Hamilton (HH) stage 29 was increased by 1.22-fold (p < 0.005). Cardiac field potential (FP) recordings of chick embryo at HH29 showed 2.5-fold (p < 0.001) increased in the amplitude, 3.2-fold (p < 0.001) increased in frequency of SpNO-treated embryos over that of the control group, whereas FP duration was unaffected. In cultured cardiac progenitors cells (CPCs), SpNO treatment decreased apoptosis and cell death by twofold (p < 0.001) and 1.7-fold (p < 0.001), respectively. Transcriptome analysis of chick embryonic heart isolated from HH15 stage pre-treated with SpNO at HH8 stage showed upregulation of genes involved in heart morphogenesis, heart contraction, cardiac cell development, calcium signalling, structure, and development whereas downregulated genes were enriched under the terms extracellular matrix, wnt pathway, and BMP pathway. The key upstream molecules predicted to be activated were p38 MAPK, MEF2C, TBX5, and GATA4 while KDM5α, DNMT3A, and HNF1α were predicted to be inhibited. This study suggests that the ectopic nitric oxide modulates the onset of cardiac development.

Interactome of miRNAs and transcriptome of human umbilical cord endothelial cells exposed to short-term simulated microgravity.

Adaptation of humans in low gravity conditions is a matter of utmost importance when efforts are on to a gigantic leap in human space expeditions for tourism and formation of space colonies. In this connection, cardiovascular adaptation in low gravity is a critical component of human space exploration. Deep high-throughput sequencing approach allowed us to analyze the miRNA and mRNA expression profiles in human umbilical cord vein endothelial cells (HUVEC), cultured under gravity (G), and stimulated microgravity (MG) achieved with a clinostat. The present study identified totally 1870 miRNAs differentially expressed in HUVEC under MG condition when compared to the cells subjected to unitary G conditions. The functional association of identified miRNAs targeting specific mRNAs revealed that miRNAs, hsa-mir-496, hsa-mir-151a, hsa-miR-296-3p, hsa-mir-148a, hsa-miR-365b-5p, hsa-miR-3687, hsa-mir-454, hsa-miR-155-5p, and hsa-miR-145-5p differentially regulated the genes involved in cell adhesion, angiogenesis, cell cycle, JAK-STAT signaling, MAPK signaling, nitric oxide signaling, VEGF signaling, and wound healing pathways. Further, the q-PCR based experimental studies of upregulated and downregulated miRNA and mRNAs demonstrate that the above reported miRNAs influence the cell proliferation and vascular functions of the HUVEC in MG conditions effectively. Consensus on the interactome results indicates restricted fluctuations in the transcriptome of the HUVEC exposed to short-term MG that could lead to higher levels of endothelial functions like angiogenesis and vascular patterning.

An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate.

OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.

Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity.

Thalidomide is an infamous teratogen and it is continuously being explored for its anticancer properties. Fibroblast growth factor receptors (FGFRs) are implicated in embryo development and cancer pathophysiology. With striking similarities observed between FGFR implicated conditions and thalidomide embryopathy, we hypothesized thalidomide targets FGFRs. We utilized three different cell lines and chicken embryo model to investigate the effects of thalidomide and analogs on FGFR expression. We performed molecular docking, KINOMEscan analysis, and kinase activity assays to study the drug-protein interactions. The expression of FGFR1 and FGFR2 was differentially regulated by all the three drugs in cells as well as in developing organs. Transcriptome analysis of thalidomide-treated chick embryo strongly suggests the modulation of FGFR signaling and key transcription factors. Corroboration with previous studies suggests that thalidomide might affect FGFR expression through the transcription factor, E2F1. At the protein level, molecular docking predicted all three analogs to interact with lysine residue at 517th and 508th positions of FGFR2 and FGFR3, respectively. This lysine coordinates the ATP binding site of FGFR, thus hinting at the possible perturbation of FGFR activity by thalidomide. Kinome analysis revealed that kinase activities of FGFR2 and FGFR3 (G697C) reduced by 31% and 65%, respectively, in the presence of 10 µM thalidomide. Further, we checked and confirmed that the analogs inhibited the FGFR2 kinase activity in a dose-dependent manner. This study suggests that FGFRs could be potential targets of thalidomide and the two analogs, and also endorses the link between the teratogenicity and antitumor activities of the drugs.

Mechanistic insights into the differential effects of thalidomide and lenalidomide in metastatic prostate cancer.

AIM: To understand why thalidomide and lenalidomide exhibit different responses in metastatic prostate cancer (mPCa) treatment. METHODS: We analyzed the perturbation signatures of thalidomide, lenalidomide, flutamide treated mPCa cell line from Library of Integrated Network-based Cellular Signatures database and transcriptome of docetaxel-treated mPCa patients. RESULTS: Flutamide and docetaxel downregulated 'Steroid Biosynthesis', 'Cell cycle' and PCa specific transcription factor networks. Thalidomide inhibited 'Cell cycle' and 'E2F network', possibly accounting for its synergistic effects with docetaxel. Conversely, lenalidomide promoted 'Cell cycle' and 'Cholesterol biosynthesis'. CONCLUSION: Hence, we propose that lenalidomide upregulates cholesterol synthesis followed by enhanced rate of cell cycle, thereby nurturing a hyperproliferative tumor microenvironment. In summary, this study offers a possible explanation for the differential outcomes in the treatment of mPCa with thalidomide and lenalidomide.

Thalidomide remodels developing heart in chick embryo: discovery of a thalidomide mediated hematoma in heart muscle.

Despite of medical disaster caused by thalidomide in 1960s, the drug came to clinical use again for the treatment of erythema nodosum leprosum (ENL) and multiple myeloma. Recently, a new generation of children affected by thalidomide intake by their mothers during pregnancy has been identified in Brazil. In the past few years, there is the great enhancement in our understanding of the molecular mechanisms and targets of thalidomide with the help of modern OMICS technologies. However, understanding of cardiac-specific anomalies in fetus due to thalidomide intake by the respective mother has not been explored fully. At organ level, thalidomide causes congenital heart diseases, limb deformities in addition to ocular, and neural and ear abnormalities. The period of morning sickness and cardiogenesis is synchronized in pregnant women. Therefore, thalidomide intake during the first trimester could affect cardiogenesis severely. Thalidomide intake in pregnant women either causes miscarriage or heart abnormalities such as patent ductus arteriosus, ventricular septal defect (VSD), atrial septal defect (ASD), and pulmonary stenosis in survivors. In the present study, we identified a novel morphological defect (lump) in the heart of thalidomide-treated chick embryos. We characterized the lump at morphological, histo-pathological, oxidative stress, electro-physiological, and gene expression level. To our knowledge, here, we report the very first electrophysiological characterization of embryonic heart affected by thalidomide treatment.

A proteome-wide systems toxicological approach deciphers the interaction network of chemotherapeutic drugs in the cardiovascular milieu.

Onco-cardiology is critical for the management of cancer therapeutics since many of the anti-cancer agents are associated with cardiotoxicity. Therefore, the major aim of the current study is to employ a novel in silico method combined with experimental validation to explore off-targets and prioritize the enriched molecular pathways related to the specific cardiovascular events other than their intended targets by deriving relationship between drug-target-pathways and cardiovascular complications in order to help onco-cardiologists for the management of strategies to minimize cardiotoxicity. A systems biological understanding of the multi-target effects of a drug requires prior knowledge of proteome-wide binding profiles. In order to achieve the above, we have utilized PharmMapper, a web-based tool that uses a reverse pharmacophore mapping approach (spatial arrangement of features essential for a molecule to interact with a specific target receptor), along with KEGG for exploring the pathway relationship. In the validation part of the study, predicted protein targets and signalling pathways were strengthened with existing datasets of DrugBank and antibody arrays specific to vascular endothelial growth factor (VEGF) signalling in the case of 5-fluorouracil as direct experimental evidence. The current systems toxicological method illustrates the potential of the above big-data in supporting the knowledge of onco-cardiological indications which may lead to the generation of a decision making catalogue in future therapeutic prescription.

Oxidative environment causes molecular remodeling in embryonic heart-a metabolomic and lipidomic fingerprinting analysis.

Environmental factors including pollution affect human health, and the unifying factor in determining toxicity and pathogenesis for a wide array of environmental factors is oxidative stress. Here, we created the oxidative environment with 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH) and consequent cardiac remodeling in chick embryos. The metabolite fingerprint of heart tissue was obtained from Fourier transform infrared (FTIR) spectroscopic analysis. The global lipidomic analysis was done using electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) by precursor ion scanning and neutral loss scanning methods. Further, the fatty acid levels were quantified in AAPH-treated H9c2 cardiomyoblasts with gas chromatography-mass spectrometry (GC-MS). Lipidomic fingerprinting study indicated that majority of differentially expressed phospholipids species in heart tissue belonged to ether phosphatidylcholine (ePC) species, and we conclude that excess oxidative environment may alter the phospholipid metabolism at earlier stages of cardiac remodeling.

Transcriptomic Analysis of Thalidomide Challenged Chick Embryo Suggests Possible Link between Impaired Vasculogenesis and Defective Organogenesis.

Since the conception of thalidomide as a teratogen, approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8), which is the most vulnerable stage for thalidomide-induced deformities. We observed that thalidomide affected the early vasculogenesis through interfering with the blood island formation extending the effect to organogenesis. The transcriptome analyses of the embryos collected on sixth day of incubation showed that liver, eye, and blood tissue associated genes were down regulated due to thalidomide treatment. The conserved gene coexpression module also indicated that the genes involved in lens development were heavily affected. Further, the Gene Ontology analysis explored that the pathways of eye development, retinol metabolism, and cartilage development were dampened, consistent with the observed deformities of various organs. The study concludes that thalidomide exerts its toxic teratogenic effects through interfering with early extra-embryonic vasculogenesis and ultimately gives an erroneous transcriptomic pattern to organogenesis.

Disturbed flow mediated modulation of shear forces on endothelial plane: A proposed model for studying endothelium around atherosclerotic plaques.

Disturbed fluid flow or modulated shear stress is associated with vascular conditions such as atherosclerosis, thrombosis, and aneurysm. In vitro simulation of the fluid flow around the plaque micro-environment remains a challenging approach. Currently available models have limitations such as complications in protocols, high cost, incompetence of co-culture and not being suitable for massive expression studies. Hence, the present study aimed to develop a simple, versatile model based on Computational Fluid Dynamics (CFD) simulation. Current observations of CFD have shown the regions of modulated shear stress by the disturbed fluid flow. To execute and validate the model in real sense, cell morphology, cytoskeletal arrangement, cell death, reactive oxygen species (ROS) profile, nitric oxide production and disturbed flow markers under the above condition were assessed. Endothelium at disturbed flow region which had been exposed to low shear stress and swirling flow pattern showed morphological and expression similarities with the pathological disturbed flow environment reported previously. Altogether, the proposed model can serve as a platform to simulate the real time micro-environment of disturbed flow associated with eccentric plaque shapes and the possibilities of studying its downstream events.

The expression dynamics of mechanosensitive genes in extra-embryonic vasculature after heart starts to beat in chick embryo.

BACKGROUND: Fluid flow plays an important role in vascular development. However, the detailed mechanisms, particularly the link between flow and modulation of gene expression during vascular development, remain unexplored. In chick embryo, the key events of vascular development from initiation of heart beat to establishment of effective blood flow occur between the stages HH10 and HH13. Therefore, we propose a novel in vivo model to study the flow experienced by developing endothelium. OBJECTIVE: Using this model, we aimed to capture the transcriptome dynamics of the pre- and post-flow conditions. METHODS: RNA was isolated from extra embryonic area vasculosa (EE-AV) pooled from three chick embryos between HH10-HH13 and RNA sequencing was performed. RESULTS: The whole transcriptome sequencing of chick identified up-regulation of some of the previously well-known mechanosensitive genes including NFR2, HAND1, CTGF and KDR. GO analyses of the up-regulated genes revealed enrichment of several biological processes including heart development, extracellular matrix organization, cell-matrix adhesion, cell migration, blood vessel development, patterning of blood vessels, collagen fibril organization. Genes encoding for gap junctions proteins which are involved in vascular remodeling and arterial-venous differentiation, and genes involved in cell-cell adhesion, and ECM interactions were significantly up-regulated. Validation of selected genes through semi quantitative PCR was performed. CONCLUSION: The study indicates that shear stress plays a major role in development. Through appropriate validation, this platform can serve as an in vivo model to study conditions of disturbed flow in pathology as well as normal flow during development.

Harvesting clues from genome wide transcriptome analysis for exploring thalidomide mediated anomalies in eye development of chick embryo: Nitric oxide rectifies the thalidomide mediated anomalies by swinging back the system to normal transcriptome pattern.

Thalidomide, the notorious teratogen is known to cause various developmental abnormalities, among which a range of eye deformations are very common. From the clinical point of view, it is necessary to pinpoint the mechanisms of teratogens that tune the gene expression. However, to our knowledge, the molecular basis of eye deformities under thalidomide treatmenthas not been reported so far. Present study focuses on the possible mechanism by which thalidomide affects eye development and the role of Nitric Oxide in recovering thalidomide-mediated anomalies of eye development using chick embryo and zebrafish models with transcriptome analysis. Transcriptome analysis showed that 403 genes were up-regulated and 223 genes were down-regulated significantly in thalidomide pre-treated embryos. 8% of the significantly modulated genes have been implicated in eye development including Pax6, OTX2, Dkk1 and Shh. A wide range of biological process and molecular function was affected by thalidomide exposure. Biological Processes including structural constituent of eye lens and Molecular functions such as visual perception and retinal metabolic process formed strong annotation clustersindicating the adverse effects of thalidomide on eye development and function. Here, we have discussed the whole embryo transcriptome with the expression of PAX6, SOX2, and CRYAAgenes from developing eyes. Our experimental data showing structural and functional aspects includingeye size, lens transparency and optic nerve activity and bioinformatics analyses of transcriptome suggest that NO could partially protect thalidomide treated embryos from its devastating effects on eye development and function.

Genetic association between the DRD4 promoter polymorphism and clozapine-induced sialorrhea.

The use of clozapine, an effective antipsychotic drug used in treatment-resistant schizophrenia, is associated with adverse effects. Sialorrhea is one such effect, which can be distressing for many patients. Studies on the pharmacogenetics of the adverse effects of clozapine are limited. The aim of the present study was to determine whether clozapine-induced sialorrhea is associated with a 120 base-pairs (bp) tandem duplication polymorphism in the dopamine receptor subtype D4 (DRD4) gene. Ninety-five patients, mean age 35.43±9.43 years, with treatment-resistant schizophrenia and on clozapine were included in the study. Development of sialorrhea in response to the drug, as manifested by drooling of saliva, was documented in 45 (47.4%) patients. Genotyping of the patients was carried out to detect the presence of the polymorphism of interest. Clozapine-induced sialorrhea was found to be associated significantly with the 120-bp duplication in DRD4. The association was found to fit a log-additive model with an odds ratio of 2.95 (95% confidence interval 1.51-5.75; P=0.0006). Thus, the presence of the 120-bp duplication in DRD4 appears to confer a risk for sialorrhea in response to clozapine therapy. The underlying pathophysiology and clinical significance of this phenomenon warrant further investigation.