Publications by authors named "Sara Sadeghi"

19 Publications

  • Page 1 of 1

A New Method on Kerma Estimation in Mammography Screenings.

J Biomed Phys Eng 2021 Oct 1;11(5):595-602. Epub 2021 Oct 1.

MD, Faculty of Medicine, Islamic Azad University, Tehran Medical Branch, Tehran, Iran.

Background: Given the extensive use and preferred diagnostic method in common mammography tests for screening and diagnosis of breast cancer, there is concern about the increased dose absorbed by the patient due to the sensitivity of the breast tissue.

Objective: This study aims to evaluate the entrance surface air kerma (ESAK) before irradiation to the patient through its estimation.

Material And Methods: In this descriptive paper, firstly, a phantom was used to measure some data, including ESAK, Kvp, mAs, HVL, and type of filter/target. Secondly, the MultiLayer Perceptron (MLP) neural network model was trained with Levenberg-Marquardt (LM) backpropagation training algorithm and finally, ESAK was estimated.

Results: Based on results obtained from the program in different neuron numbers, it was found that the number of 35 neurons is the most optimal value, offering a regression coefficient of 95.7%. The Mean Squared Error (MSE) for all data was 0.437 mGy and accounting for 4.8% of the output range changes, predicting 95.2% accuracy in the present research.

Conclusion: Using neural networks in ESAK prediction, the method proposed in the present research leads to the possible ESAK estimation of patients before X-Ray. The results suggested that the regression coefficient represented 4.3% difference between the kerma measured by solid-state dosimeter in the radiation field and the value predicted in the research. In comparison with the Monte-Carlo simulation method, this method has better accuracy.
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http://dx.doi.org/10.31661/jbpe.v0i0.1146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546156PMC
October 2021

The Use of Vaginal Lubricants and Ultrasound Gels Can have Deleterious Effects on Sperm Function.

J Hum Reprod Sci 2021 Apr-Jun;14(2):162-166. Epub 2021 Jun 28.

Unidad de Reproducción Humana Asistida. Área de la Mujer. Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Context: Some vaginal lubricants and ultrasound gels are known to be detrimental to sperm function and therefore could negatively affect fertility.

Aims: The aim of the current study was to develop a sperm motility index (SMI) to test the sperm toxicity of ultrasound gels and vaginal lubricants used in reproductive medicine.

Settings And Design: Two ultrasound gels (Aquasonic and Kefus) and five vaginal lubricants (Vaginesil™, Velastisa, K-Y Jelly, Control, and Durex) were studied. Three different concentrations (1%, 5%, and 10%) of each lubricant were tested.

Subjects And Methods: SMI was calculated dividing the percentage of progressively motile sperm in each tested gel by that in the control at 0.5, 1, 2, and 24 h of incubation at 5% of CO and 37°C. SMI values <0.75 indicate sperm toxicity.

Statistical Analysis Used: The main outcome measured was SMI for each concentration and time of incubation.

Results: Only Durex did not show any deleterious effect on sperm quality. The rest of lubricants presented different degrees of toxicity. Vaginesil™ resulted in toxic for all concentrations and incubation periods (SMI < 0.12). Control and Velastisa presented toxicity at 10% after 2 h, while K-Y Jelly showed toxicity at 10% from 1 h of incubation. Regarding ultrasound gels, Aquasonic showed toxic effects after only 0.5 h (SMI = 0.70 ± 0.15), while Kefus showed slightly toxic effects after 2 h (SMI 0.69 ± 0.07).

Conclusions: SMI is an accurate tool to evaluate sperm toxicity. One of the main strengths of the article is the inclusion of representative semen samples and known products used worldwide. This study has a relevant clinical translation since it highlights the importance of evaluating the possible sperm toxicity of simple products used in reproductive medicine.
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http://dx.doi.org/10.4103/jhrs.JHRS_128_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279066PMC
June 2021

Food frequency questionnaire is a valid assessment tool of quercetin and kaempferol intake in Iranian breast cancer patients according to plasma biomarkers.

Nutr Res 2021 09 24;93:1-14. Epub 2021 Jun 24.

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

In epidemiological and clinical studies, the most common nutritional tool to assess dietary flavonol intake is the food frequency questionnaire (FFQ), which needs to contain a detailed list of plant-based foods and be previously validated. Our study aimed to assess the accuracy of dietary flavonol (quercetin, kaempferol, and isorhamnetin) intake from a food frequency questionnaire (FFQ) compared to fasting plasma flavonol concentrations, as biomarkers of exposure, in breast cancer patients. In a consecutive case series, newly diagnosed patients with breast cancer (n = 140) were recruited at Nour-Nejat Hospital, Tabriz, Iran. Flavonol intake was assessed using a validated FFQ. Plasma flavonol concentrations were measured using high-performance liquid chromatography-ultraviolet detection. The accuracy of dietary status was evaluated using a receiver operating characteristic (ROC) and area under the ROC curve (AUC). Dietary status was shown in dichotomous using ROC-cutoff point. The plasma concentrations of quercetin were moderately correlated with dietary intake of quercetin (Spearman's correlation coefficient (r) = 0.188, P < .05; r= 0.330, P < .01) and plasma concentrations of isorhamnetin (r = 0.337, P < .001). A linear correlation between dietary levels and plasma concentrations of kaempferol was attained (r = 0.240, P < .05). Using a ROC-cutoff of 61.9 nmol/L for plasma quercetin (test reference), we were able to differentiate between lower and higher consumers of quercetin with an AUC =0.65 (P < .01, sensitivity = 61.8%, and specificity = 60.0%). Using a plasma kaempferol concentration of 60.1 nmol/L (ROC-cutoff), it was possible to detect significant differences between higher and lower intakes of kaempferol (AUC = 0.64, P < .05). The correlations and diagnostic performance with plasma concentrations could present a significant accuracy rate (validity), which seems acceptable for a nutritional questionnaire (FFQ) to assess intakes intake levels of quercetin and kaempferol. An improvement in the accuracy of the flavonol exposure can provide more precise relationship with health outcomes, which may increase their clinical significance.
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http://dx.doi.org/10.1016/j.nutres.2021.06.004DOI Listing
September 2021

Effect of Sperm Concentration and Storage Temperature on Goat Spermatozoa during Liquid Storage.

Biology (Basel) 2020 Sep 19;9(9). Epub 2020 Sep 19.

Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, 46100 Valencia, Spain.

The use of cooled semen is relatively common in goats. There are a number of advantages of cooled semen doses, including easier handling of artificial insemination (AI) doses, transport, more AI doses per ejaculate, and higher fertility rates in comparison with frozen AI doses. However, cooled semen has a short shelf life. The objective of this study was to examine the effect of temperature and sperm concentration on the in vitro sperm quality during liquid storage for 48 h, including sperm motility and kinetics, response to oxidation, mitochondrial membrane potential (MMP) and DNA fragmentation in goats. Three experiments were performed. In the first, the effects of liquid preservation of semen at different temperatures (5 °C or 17 °C), durations (0, 24 and 48 h) and sperm concentrations (250 × 10 sperm/mL (1:2 dilution rate), 166.7 × 10 sperm/mL (1:3 dilution rate) or 50 × 10 sperm/mL (1:10 dilution rate)) on sperm motility and kinetics were studied. In the second experiment, the effect of temperature, sperm washing and concentration on sperm motility and DNA fragmentation was studied. Finally, the effect of sperm concentration and duration of storage at 5 °C on sperm motility, response to oxidative stress and MMP was examined. We found that refrigerated liquid storage of goat sperm impaired sperm quality, such as motility, MMP and response to oxidation, as storage time increased; however, sperm DNA fragmentation index was not significantly affected. Liquid storage at 5 °C preserved higher total motility than at 17 °C. Moreover, we observed that the reduction of sperm concentration below 500 × 10 sperm/mL did not seem to improve the quality of spermatozoa conserved in milk-based extender in the conditions tested.
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http://dx.doi.org/10.3390/biology9090300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564667PMC
September 2020

Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in Wild-Type Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2019 Aug 8;25(15):4674-4681. Epub 2019 May 8.

Pancreas Centre British Columbia, Vancouver, Canada.

Purpose: Gene fusions involving neuregulin 1 () have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of fusion-positive pancreatic ductal adenocarcinoma is not fully understood.

Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging.

Results: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as wild type by whole-genome sequencing. All wild-type tumors were positive for gene fusions involving the ERBB3 ligand . Two of 3 patients with fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy.

Conclusions: This work adds to a growing body of evidence that gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with wild-type tumors harboring gene fusions may benefit from treatment with afatinib..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0191DOI Listing
August 2019

Effect of different oxidative stress degrees generated by hydrogen peroxide on motility and DNA fragmentation of zebrafish (Danio rerio) spermatozoa.

Reprod Domest Anim 2018 Dec 29;53(6):1498-1505. Epub 2018 Aug 29.

Departament de Biologia Cellular, Biologia Funcional i Antropologia Fisica. Universitat de València, Burjassot, Spain.

An increase in reactive oxygen species (ROS) or decrease in antioxidant barriers can provoke lipid peroxidation of the membranes or DNA damage of the spermatozoa. The aim of this work is to study the effect of the different degrees of oxidative stress generated by H O incubation on total motility, kinetics, and DNA fragmentation of zebrafish (Danio rerio) spermatozoa. For this process, experimental groups were incubated in 50 µM (Low; L) and 200 µM (High; H) H O , respectively, for 20 min at 4ºC. Sperm motility parameters were obtained with a computer-assisted sperm analysis (CASA) system. Sperm DNA fragmentation (SDF) was assessed using the sperm chromatin dispersion test. Both low and high H O concentration groups showed lower motility than control groups. Progressive motility of spermatozoa incubated in the H group dropped rapidly in comparison with other groups. Regarding SDF, the control and L groups had significantly lower values than the H group (25.0% and 31.6% vs. 48.1% fragmented sperm for C, L, and H groups, respectively; p < 0.05). Sperm motility, mostly progressive motility, decreased as H O concentration increased, mainly when time after sperm activation increased. SDF increased as the H O concentration increased. However, measurements of the halo area did not agree with the subjective SDF rate.
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http://dx.doi.org/10.1111/rda.13296DOI Listing
December 2018

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

Cell Rep 2018 04;23(1):194-212.e6

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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http://dx.doi.org/10.1016/j.celrep.2018.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002769PMC
April 2018

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Cell 2017 Oct 5;171(3):540-556.e25. Epub 2017 Oct 5.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
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http://dx.doi.org/10.1016/j.cell.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687509PMC
October 2017

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Cell Rep 2017 03;18(11):2780-2794

Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
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http://dx.doi.org/10.1016/j.celrep.2017.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493145PMC
March 2017

Effect of Melatonin on the Outcome of Assisted Reproductive Technique Cycles in Women with Diminished Ovarian Reserve: A Double-Blinded Randomized Clinical Trial.

Iran J Med Sci 2017 Jan;42(1):73-78

Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.

Diminished ovarian reserve (DOR) significantly decreases the success rate of the assisted reproductive technique (ART). In this study, we assessed the effect of melatonin on the ART outcomes in women with DOR. A double-blinded, randomized, clinical trial was performed on 80 women with DOR as a pilot study in Shiraz, between 2014 and 2015. DOR was defined as the presence of 2 of the following 3 criteria: 1) anti-Müllerian hormone ≤1, 2) follicle-stimulating hormone ≥10, and 3) bilateral antral follicle count ≤6. The women received 3 mg/d melatonin or a placebo since the fifth day of one cycle prior to gonadotropin stimulation and continued the treatment up to the time of ovum pickup. The ART outcomes were compared between the groups using SPSS software. Finally, there were 32 women in the case and 34 in the placebo groups. The mean age and basal ovarian reserve test were the same between the groups. The serum estradiol level on the triggering day was significantly higher in the case group (P=0.005). The mean number of MII oocytes was higher in the case group, but the difference did not reach statistical significance. Number of the patients who had mature MII oocytes (P=0.014), top-quality embryos with grade 1 (P=0.049), and embryos with grades 1 and 2 (P=0.014) was higher among the women who received melatonin. However, the other ART outcomes were not different between the groups. The serum estradiol level was higher and more women with DOR had good-quality oocytes and embryos after receiving melatonin; however, no other outcome was different between the case and control groups. IRCT2014041417264N1.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337768PMC
January 2017

Morphometric comparison by the ISAS CASA-DNAf system of two techniques for the evaluation of DNA fragmentation in human spermatozoa.

Asian J Androl 2016 Nov-Dec;18(6):835-839

Department of Functional Biology and Physical Anthropology, University of Valencia, 46100 Burjassot, Valencia, Spain.

DNA fragmentation has been shown to be one of the causes of male infertility, particularly related to repeated abortions, and different methods have been developed to analyze it. In the present study, two commercial kits based on the SCD technique (Halosperm ® and SDFA) were evaluated by the use of the DNA fragmentation module of the ISAS ® v1 CASA system. Seven semen samples from volunteers were analyzed. To compare the results between techniques, the Kruskal-Wallis test was used. Data were used for calculation of Principal Components (two PCs were obtained), and subsequent subpopulations were identified using the Halo, Halo/Core Ratio, and PC data. Results from both kits were significantly different (P < 0.001). In each case, four subpopulations were obtained, independently of the classification method used. The distribution of subpopulations differed depending on the kit used. From the PC data, a discriminant analysis matrix was obtained and a good a posteriori classification was obtained (97.1% for Halosperm and 96.6% for SDFA). The present results are the first approach on morphometric evaluation of DNA fragmentation from the SCD technique. This approach could be used for the future definition of a classification matrix surpassing the current subjective evaluation of this important sperm factor.
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http://dx.doi.org/10.4103/1008-682X.186875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109872PMC
March 2017

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

N Engl J Med 2015 Jun 10;372(26):2481-98. Epub 2015 Jun 10.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.

Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.

Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.

Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1402121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530011PMC
June 2015

BioBloom tools: fast, accurate and memory-efficient host species sequence screening using bloom filters.

Bioinformatics 2014 Dec 20;30(23):3402-4. Epub 2014 Aug 20.

Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 4S6, Canada.

Large datasets can be screened for sequences from a specific organism, quickly and with low memory requirements, by a data structure that supports time- and memory-efficient set membership queries. Bloom filters offer such queries but require that false positives be controlled. We present BioBloom Tools, a Bloom filter-based sequence-screening tool that is faster than BWA, Bowtie 2 (popular alignment algorithms) and FACS (a membership query algorithm). It delivers accuracies comparable with these tools, controls false positives and has low memory requirements. Availability and implementaion: www.bcgsc.ca/platform/bioinfo/software/biobloomtools.
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http://dx.doi.org/10.1093/bioinformatics/btu558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816029PMC
December 2014

Involvement of orexin-1 receptors in the ventral tegmental area and the nucleus accumbens in antinociception induced by lateral hypothalamus stimulation in rats.

Pharmacol Biochem Behav 2013 Apr 5;105:193-8. Epub 2013 Mar 5.

Cellular and Molecular Research Center and Department of Physiology, Qazvin University of Medical Sciences, Qazvin, Iran.

Previous studies have demonstrated that chemical stimulation of the lateral hypothalamus (LH) with carbachol has an important role in the induction of antinociception in tail-flick test as a model of acute pain. In this study, we tried to evaluate the involvement of orexin-1 receptors in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) on antinociceptive responses induced by LH stimulation in rats. One hundred twenty adult male albino Wistar rats weighing 200-250g were unilaterally implanted with two separate cannulae into the LH, and VTA or NAc. Antinociceptive effects for two doses of intra-LH carbachol (125 and 250nmol/0.5μl saline), as a cholinergic agonist, were evaluated in this study. In another set of experiments, animals received intra-VTA or -NAc infusions of SB334867 as a selective orexin-A receptor antagonist (0.3, 1, 3 and 10nmol/rat), just 5min before microinjection of an effective dose of carbachol into the LH. In the tail-flick test, antinociceptive responses of drugs were obtained by tail-flick analgesiometer and represented as maximal possible effects (%MPE) at 5, 15, 30, 45 and 60min after their administrations. The results showed that unilateral intra-LH administration of carbachol (125 and 250nmol/rat) induced antinociception in rats (P<0.01). There were no significant differences between the antinociceptive effects of these two doses. In the second part of our study, intra-VTA and intra-accumbal administrations of different doses of SB334867, 5min before microinjection of carbachol, could dose-dependently prevent the development of LH stimulation-induced antinociception in rats. However, this effect was less in the NAc. It is supposed that the orexinergic projections from the LH to the VTA and NAc are direct/indirectly involved in the antinociception induced by LH chemical stimulation, and orexin-1 receptors in the ventral tegmental area have a more substantial role in this phenomenon.
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http://dx.doi.org/10.1016/j.pbb.2013.02.011DOI Listing
April 2013

Length-dependent force characteristics of coiled coils.

Phys Rev E Stat Nonlin Soft Matter Phys 2009 Dec 14;80(6 Pt 1):061909. Epub 2009 Dec 14.

Physics Department, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.

Coiled-coil domains within and between proteins play important structural roles in biology. They consist of two or more alpha helices that form a superhelical structure due to packing of the hydrophobic residues that pattern each helix. A recent continuum model showed that the correspondence between the chirality of the pack to that of the underlying hydrophobic pattern comes about because of the internal deformation energy associated with each helix in forming the superhelix. We have developed a coarse-grained atomistic model for coiled coils that includes the competition between the hydrophobic energy that drives folding and the cost due to deforming each helix. The model exhibits a structural transition from a non-coiled-coil to coiled-coil state as the contribution from the deformation energy changes. Our model is able to reproduce naturally occurring coiled coils and essential features seen in unzipping experiments. We explore the force-extension properties of these model coiled coils as a function helix length and find that shorter coils unfold at lower force than longer ones with the required unfolding force eventually becoming length independent.
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http://dx.doi.org/10.1103/PhysRevE.80.061909DOI Listing
December 2009

Anecortave acetate treatment for retinal angiomatous proliferation: a pilot study.

Retina 2006 Sep;26(7):773-9

LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York 10021, USA.

Purpose: The purpose of this study was to evaluate anecortave acetate treatment of retinal angiomatous proliferation (RAP), a neovascular form of age-related macular degeneration, with specific regard to inhibition of neovascularization and maintenance of vision.

Methods: Thirty-four patients with RAP with any stage of neovascularization were randomized 1:1:1 for treatment with three different quantities (30 mg, 15 mg, 3 mg) of anecortave acetate sterile suspension for juxtascleral administration. Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study chart), intraocular pressure measurement, biomicroscopy, funduscopy, digital fluorescein, and indocyanine green angiography were recorded at baseline and at 3 months. A 6-month retreatment interval was established for this study with a follow-up of 12 months. In selected patients optical coherence tomography was performed. The outcomes were mean changes in visual acuity and lesion size at 1 year.

Results: The detachment of the neurosensory retina and retinal pigment epithelium improved in all eyes, but all neovascular lesions increased in size. Vision loss occurred in the majority of study eyes (22 out of 34 eyes, 64.7%) independent of the concentration administered.

Conclusion: The results suggest that a posterior juxtascleral injection of anecortave acetate reduces capillary permeability in patients with RAP. However, in spite of improvement of the exudation there is a progression of neovascularization and a significant loss of vision in all these patients. Like other monotherapeutic methods used to treat this variant of neovascular age-related macular degeneration, anecortave acetate alone does not appear to benefit these patients. Future studies should investigate a combination form of therapy.
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http://dx.doi.org/10.1097/01.iae.0000244261.52901.67DOI Listing
September 2006
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