Publications by authors named "Fouad Yousif"

24 Publications

  • Page 1 of 1

Sex differences in oncogenic mutational processes.

Nat Commun 2020 08 28;11(1):4330. Epub 2020 Aug 28.

Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17359-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455744PMC
August 2020

Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia.

Blood 2019 06 28;133(25):2651-2663. Epub 2019 Mar 28.

Moores Cancer Center, University of California San Diego, La Jolla, CA.

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ test, < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1 Patients with GLI1 CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1 CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-09-873695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587306PMC
June 2019

Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer.

Sci Rep 2019 03 5;9(1):3590. Epub 2019 Mar 5.

Department of Medicine, University of Toronto, Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada.

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-39878-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401071PMC
March 2019

Widespread and Functional RNA Circularization in Localized Prostate Cancer.

Cell 2019 02;176(4):831-843.e22

Research Centre of CHU de Québec-Université Laval, Québec City, Québec, Canada.

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.01.025DOI Listing
February 2019

Molecular landmarks of tumor hypoxia across cancer types.

Nat Genet 2019 02 14;51(2):308-318. Epub 2019 Jan 14.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0318-2DOI Listing
February 2019

The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression.

Cell 2018 05 19;173(4):1003-1013.e15. Epub 2018 Apr 19.

Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

The majority of newly diagnosed prostate cancers are slow growing, with a long natural life history. Yet a subset can metastasize with lethal consequences. We reconstructed the phylogenies of 293 localized prostate tumors linked to clinical outcome data. Multiple subclones were detected in 59% of patients, and specific subclonal architectures associate with adverse clinicopathological features. Early tumor development is characterized by point mutations and deletions followed by later subclonal amplifications and changes in trinucleotide mutational signatures. Specific genes are selectively mutated prior to or following subclonal diversification, including MTOR, NKX3-1, and RB1. Patients with low-risk monoclonal tumors rarely relapse after primary therapy (7%), while those with high-risk polyclonal tumors frequently do (61%). The presence of multiple subclones in an index biopsy may be necessary, but not sufficient, for relapse of localized prostate cancer, suggesting that evolution-aware biomarkers should be studied in prospective studies of low-risk tumors suitable for active surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.03.029DOI Listing
May 2018

Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations.

BMC Cancer 2018 01 2;18(1). Epub 2018 Jan 2.

Department of Pathology, Erasmus University Medical Center, Josephine Nefkens Institute building, Be-222, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.

Background: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA).

Methods: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set.

Results: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs.

Conclusions: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-017-3976-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751811PMC
January 2018

Genomic hallmarks of localized, non-indolent prostate cancer.

Nature 2017 01 9;541(7637):359-364. Epub 2017 Jan 9.

Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature20788DOI Listing
January 2017

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.

Nat Commun 2017 01 9;8:13671. Epub 2017 Jan 9.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms13671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227331PMC
January 2017

A four gene signature predicts benefit from anthracyclines: evidence from the BR9601 and MA.5 clinical trials.

Oncotarget 2015 Oct;6(31):31693-701

Transformative Pathology, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.

Chromosome instability (CIN) in solid tumours results in multiple numerical and structural chromosomal aberrations and is associated with poor prognosis in multiple tumour types. Recent evidence demonstrated CEP17 duplication, a CIN marker, is a predictive marker of anthracycline benefit. An analysis of the BR9601 and MA.5 clinical trials was performed to test the role of existing CIN gene expression signatures as predictive markers of anthracycline sensitivity in breast cancer. Univariate analysis demonstrated, high CIN25 expression score was associated with improved distant relapse free survival (DRFS) (HR: 0.74, 95% CI 0.54-0.99, p = 0.046). High tumour CIN70 and CIN25 scores were associated with aggressive clinicopathological phenotype and increased sensitivity to anthracycline therapy compared to low CIN scores. However, in a prospectively planned multivariate analysis only pathological grade, nodal status and tumour size were significant predictors of outcome for CIN25/CIN70. A limited gene signature was generated, patients with low tumour CIN4 scores benefited from anthracycline treatment significantly more than those with high CIN4 scores (HR 0.37, 95% CI 0.20-0.56, p = 0.001). In multivariate analyses the treatment by marker interaction for CIN4/anthracyclines demonstrated hazard ratio of 0.35 (95% CI 0.15-0.80, p = 0.012) for DRFS. This data shows CIN4 is independent predictor of anthracycline benefit for DRFS in breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.5562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741633PMC
October 2015

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

Nat Genet 2015 Jul 25;47(7):736-45. Epub 2015 May 25.

Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3315DOI Listing
July 2015

Description of two new cercariae (an echinostome cercaria and a xiphidiocercaria) procured from Biomphalaria pfeifferi (Krauss) from Nigeria.

J Egypt Soc Parasitol 2014 Aug;44(2):373-80

Department of Environmental Research and Medical Malacology, Theodor Bilharz Research Institute, Giza, Egypt.

During parasitological examination of Biomphalaria pfeifferi snails obtained from Niger state (Nigeria), 2 new types of cercariae were found. They are identified to the level of referring to the major group and described here for the first time. They were examined viable and stained with vital stains as well as fixed in 70% alcohol. They were drawn with a camera lucida and photographed. They are identified as an echinostome cercaria and a xiphidiocercaria. The echinostome is characterized by having a ventral sucker almost double in size the oral one. It has a semicircular structure located beyond the oral sucker. Three pairs of penetration glands are found at the anterior portion of the body. The number of collar spines is relatively large (44-46). The flame cellsare 17 x 2 in number. Two main lateral excretory ducts extend anteriorly, form two typical echinostome loops then pass posteriorly to open together in a diverticulated excretory vesicle. Its tail is relatively long and flattened with 3 fin folds. The tail (640 μm) is longer than the body (475 μm). The xiphidiocercaria belongs to the "ornatae" group. It is relatively small (180.5 x 110 μm) with a long stylet (30 μm). Its oral sucker is one and half times the size of the ventral sucker. Two excretory ducts extend posteriorly in both sides and become dilated and unite to open in a circular excretoryvesicle. Tail is slender shorter than the body and has a dorso-ventral fin fold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12816/0006475DOI Listing
August 2014

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

Nature 2014 Feb 12;506(7488):328-33. Epub 2014 Feb 12.

1] Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991939PMC
February 2014

Educational outcomes of The University of Toronto Visiting Professor Rounds Series.

Can J Ophthalmol 2014 Feb;49(1):96-101

Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ont.

Objective: To assess how the University of Toronto Visiting Professors Rounds Series (UTVPRS) influenced the knowledge, perceptions, and clinical decision making of Canadian ophthalmologists.

Design: Longitudinal cross-sectional.

Participants: Eight hundred and fifty ophthalmologists registered with the Canadian Ophthalmological Society.

Methods: Online surveys, using multiple-choice and reflection questions, were administered before and after online viewing of the University of Toronto Ophthalmology grand rounds as screencasts.

Results: At 18 months, 124 users registered and watched 429 screencasts. Most participants found UTVPRS to be organized and user friendly. Mean prescreencast correct scores were 1008 versus 1288 postscreencast (p = 0.002). Postscreencast, 73% of participants replied in favour of changing future practice.

Conclusions: UTVPRS was well received with demonstrated knowledge gain and potential practice change. The long-term and patient-related outcomes of the results require further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcjo.2013.09.019DOI Listing
February 2014

Schistosoma mansoni cercarial host location and infection under simulated natural conditions in Egypt.

J Egypt Soc Parasitol 2013 Aug;43(2):315-25

Medical Malacology Department, Theodor Bilharz Research Institute, Egypt.

This study was performed in water ditches under simulated natural conditions in Egypt to elucidate the effect of various environmental factors on Schistosoma mansoni cercarial host location and infection of the definitive host (using albino mice). Evaluation of these factors was dependent on both infection rate of exposed mice as well as the schistosome worm load under the same experimental conditions. The seasonal water temperature proved to be a very important factor and this was proven by the infection rate of mice and the worm load recovered were lower in January and April (16 degrees C and 22 degrees C midday water temperature) and much higher in July and October (29 degrees C and 25 degrees C). The daytime factor is similarly important as temperature illustrated by the schistosome infection of mice groups exposed at 8-10 am was much higher than in groups exposed between 1 pm and 3pm (p < 0.001). The greatest infection rate of mice and worm load were obtained when the shedding snails were close to the exposed group of mice. Both criteria increased with the increase of cercarial density in the water. The length of exposure period is also an extremely important factor for schistosome infection, being highest 87.5% (p < 0.001) in3 hours exposure period. Infection rate was found to be 88.2% and 55.6% of shedding snails were located at water surface and midway to the bottom, respectively, and no infection occurred when located at the bottom. The schistosome infection of mice decreased in presence of increasing density of the floating plant Eichhornia crassipes in the ditch water, but low condensation of the submersed plant Ceratophyllum demersum appeared to have stimulating effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12816/0006388DOI Listing
August 2013

Experimental evaluation of Candonocypris novaezelandiae (Crustacea: Ostracoda) in the biocontrol of Schistosomiasis mansoni transmission.

Asian Pac J Trop Biomed 2013 Apr;3(4):267-72

Department of Environmental Research and Medical Malacology, Theodor Bilharz Research Institute, Warrak El Hadar, Imbaba, Egypt.

Objective: To test Candonocypris novaezelandiae (Baird) (C. novaezelandiae), sub-class Ostracoda, obtained from the Nile, Egypt for its predatory activity on snail, Biomphalaria alexandrina (B. alexandrina), intermediate host of Schistosoma mansoni (S. mansoni) and on the free-living larval stages of this parasite (miracidia and cercariae).

Methods: The predatory activity of C. novaezelandiae was determined on B. alexandrina snail (several densities of eggs, newly hatched and juveniles). This activity was also determined on S. mansoni miracidia and cercariae using different volumes of water and different numbers of larvae. C. novaezelandiae was also tested for its effect on infection of snails and on the cercarial production.

Results: C. novaezelandiae was found to feed on the eggs, newly hatched and juvenile snails, but with significant reduction in the consumption in the presence of other diet like the blue green algae (Nostoc muscorum). This ostracod also showed considerable predatory activity on the free-living larval stages of S. mansoni which was affected by certain environmental factors such as volume of water, density of C. novaezelandiae and number of larvae of the parasite.

Conclusions: The presence of this ostracod in the aquatic habitat led to significant reduction of snail population, infection rate of snails with schistosme miracidia as well as of cercarial production from the infected snails. This may suggest that introducing C. novaezelandiae into the habitat at schistosome risky sites could suppress the transmission of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2221-1691(13)60061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634922PMC
April 2013

Schistosomicidal and molluscicidal activities of aminoalkylamino substituted neo- and norneocryptolepine derivatives.

Pharm Biol 2012 Feb;50(2):134-40

Department of Medical Malacology and Schistosome Biological Supply Centre, Theodor Bilharz Research Institute, Imbaba, Egypt.

Context: The cryptolepines originate from the roots of the climbing shrub Cryptolepis sanguinolenta (Lindi) Schitr(Periplocaeae) which is used in Central and West Africa in traditional medicine for the treatment of malaria.

Objectives: Evaluation for the first time of a series of chloro- and aminoalkylamino derivatives of neo- and norneocryptolepines for potential schistosomicidal and molluscicidal activities.

Materials And Methods: A series of chloro- and aminoalkylamino substituted neo- and norneocryptolepine derivatives were synthesized. They were tested in vitro against viable Schistosoma mansoni Sambon mature worms in culturemedium with fetal serum and antibiotics and in dechlorinated water against the snail vector Biomphalaria alexandrina Ehrenberg. Active compounds were further subjected to determination of their IC50 values.

Results: Results showed that six neocryptolepine and two norneocryptolepine derivatives had in vitro schistosomicidal activity on Egyptian and Puerto Rican strains of S. mansoni. The most effective derivative (2-chloro-5-methyl-N-(2-morpholin-4-ethyl)-5H-indolo[2,3b]quinoline-11-amine) has IC50 and IC90 1.26 and 4.05 μM and 3.54 and 6.83 μM with the Egyptian and Puerto Rican strains of Schistosoma, respectively. All eight derivatives showed molluscicidal activity against the vector snail B. alexandrina. The most active compound (2-chloro-11-(4-methylpiperazin-1-yl)-6H-indolo[2,3-b] quinoline) has LC50 0.6 and LC90 3.9 ppm after 24 h.

Discussion And Conclusions: The findings demonstrate that introducing chloro- and aminoalkylamino side chain initiated both schistosomicidal and molluscicidal activities in these derivatives. The structure–activity relationship of this series of compounds is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13880209.2011.578278DOI Listing
February 2012

Integrated dataset of screening hits against multiple neglected disease pathogens.

PLoS Negl Trop Dis 2011 Dec 20;5(12):e1412. Epub 2011 Dec 20.

Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland.

New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0001412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243694PMC
December 2011

Screening of marine extracts for schistosomicidal activity in vitro. Isolation of the triterpene glycosides echinosides A and B with potential activity from the Sea Cucumbers Actinopyga echinites and Holothuria polii.

Pharm Biol 2012 Apr 2;50(4):490-6. Epub 2011 Dec 2.

Natural Compounds Department, National Research Center, Giza, Egypt.

Context: Praziquantel (PZQ) is the drug available for the treatment of schistosomiasis. The reported reduced cure rates, the failure of treatment after PZQ administration in patients and the existence of resistant parasite strains, reinforce the need to rapidly discover new effective molecules against Schistosoma parasite.

Objective: To screen the methanol extracts of 79 marine organisms for their schistosomicidal activities against Schistosoma mansoni adult worms in vitro and perform bio-assay directed chromatography for the most active extracts to isolate the active compounds.

Materials And Methods: Screening of the marine organisms and bio-assay directed chromatography of the most active extracts together with identification of the active isolates using 1D and 2D NMR analysis, were investigated.

Results: RESULTS indicated that the isolates echinosides A and B from the sea cucumbers Actinopyga echinites Jaeger and Holothuria polii Delle Chiaie (Holothuriidae) were highly active. Their LC(50) values were equal to 0.19 μg/ml and 0.27 μg/ml, respectively. Detailed (1)HNMR data for echinosides A and B are reported here for the first time.

Discussion And Conclusion: These findings demonstrate that the isolated echinosides possess potential in vitro schistosomicidal activity against S. mansoni adult worms. Therefore, echinosides are promising as lead compounds for the development of new schistosomicidal agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13880209.2011.615842DOI Listing
April 2012

Contribution to in vitro screening of Egyptian plants for schistosomicidal activity.

Pharm Biol 2012 Jun 1;50(6):732-9. Epub 2011 Dec 1.

Theodor Bilharz Research Institute, Schistosome Biological Supply Center, Cairo, Imbaba, Egypt.

Context: This study is a continuation of our previous work in which a bioassay screening of 346 methanol extracts from 281 Egyptian plant species was carried out for in vitro schistosomicidal activity.

Objective: Another 309 methanol extracts from 278 plant species were subjected to the bioassay screening using the same technique on viable Schistosoma mansoni Sambon (Schistosomatidae) mature worms in specialized culture medium (Roswell Park Memorial Institute medium 1640) in a trial to discover a source for a schistosomiasis drug from Egyptian flora.

Material And Methods: The methanol plant extracts were tested in vitro against viable S. mansoni mature worms in culture medium. Viability of worms was examined after exposure to 100 μg/ml of the extract in the medium for 24 h. Negative (dimethyl sulfoxide) and positive (praziquantel) controls were simultaneously used. Extracts showing schistosomicidal activity were further subjected to determination of their (Lethal concentration) LC₅₀ and LC₉₀ values.

Results: Confirmed in vitro antischistosomal activity was found in 42 extracts. Of these, 14 plant species possessed considerably high antischistosomal activity (LC₅₀ ≤ 15 µg/ml), viz. Callistemon viminalis (Soland. Ex Gaertn) Cheel, C. rigidus R.Br., C. speciosus (Sims.) DC, C. citrinus Stapf, Eucalyptus citriodora Hook, E. rostrata Dehnh., Eugenia edulis Vell, E. javanica Lam syn. Syzygium samarangense (Blume) Merril, Melaleuca leucadendron (L.) L., M. stypheloides Sm. (all belong to Myrtaceae), Cryptostegia grandiflora R.Br. (Asclepiadaceae), Zilla spinosa (L.) Prantl (Cruciferae), Ficus trijuja L. (Moraceae) and Fagonia mollis Delile (Zygophylacae).

Discussion And Conclusion: These species may represent additional natural sources of bioactive material that deserve further investigation for drug discovery against schistosomiasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13880209.2011.625952DOI Listing
June 2012

Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways.

PLoS Genet 2011 Nov 17;7(11):e1002377. Epub 2011 Nov 17.

Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Canada.

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1002377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219608PMC
November 2011

Capacity building in anthelmintic drug discovery.

Expert Opin Drug Discov 2007 Oct;2(s1):S75-82

Professor and Director, Programme in International Health, Department of Medicine, Biotechnology and Bioengineering Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA +1 414 456 5613 ; +1 414 456 6568 ;

International collaboration in anthelmintic drug discovery holds special challenges compared with local or national discovery projects, and at the same time presents the opportunity to build capacity, forge long lasting inter-institutional relationships and strengthen infrastructure in multinational priority areas. This chapter discusses important issues that should be considered in the context of anthelmintic screening centre development and will give examples (Philippines and Egypt) of the productivity of developing country based screening centres. The positive outcomes of infrastructure building is realised in greater capacities for anthelmintic screening at institutions in the countries where the parasitic diseases are endemic and allows for optimum use of specialised resources for public health priority diseases that may be different from those in Western countries. Support for developing country based screening centres also can help countries optimise product development procedures and policies and can facilitate diffusion of desirable technology in corresponding global regions around the world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/17460441.2.S1.S75DOI Listing
October 2007

Schistosomes: challenges in compound screening.

Expert Opin Drug Discov 2007 Oct;2(s1):S53-61

Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, 20, Avenue Appia - 1211 Geneva 27, Switzerland +41 22 791 1060 ; +41 22 791 4825 ;

Major progress in studying the biology of schistosomes had been achieved since the late 1960s with the successful laboratory cultivation of the parasite's life cycle stages in the vertebrate (in vivo animal models) and snail hosts. This was followed by establishment of in vitro culture techniques for cultivation of the different life cycle stages to understand the mechanisms regulating the parasite's growth, development, transformation, pathogenicity and survival, with prospects to develop and identify relevant candidate diagnostic, immunological and chemotherapeutic targets. Chemotherapeutic measures have been the mainstay in the control of schistosomiasis. The use of praziquantel, a relatively safe and orally administered drug, in targeted or mass treatment programmes had significantly reduced the prevalence of schistosomiasis in disease-endemic countries. However, with only one drug of choice for treatment, parasite resistance remains a major concern. Thus, new drug discovery against schistosomes cannot be overemphasised. Undoubtedly, this will require an integrated system that includes not only rational chemical synthesis and lead optimisation, but also appropriate drug screening strategies. This paper reviews the present state of in vitro and in vivo drug screening strategies against schistosomes. It also highlights the best practices for compound screening in the TDR-designated compound screening centres and details some of the challenges involved in in vitro and in vivo compound screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/17460441.2.S1.S53DOI Listing
October 2007

Origin and diversification of the human parasite Schistosoma mansoni.

Mol Ecol 2005 Oct;14(12):3889-902

Department of Biology, University of New Mexico, Albuquerque, New Mexico 87131 USA.

Schistosoma mansoni is the most widespread of the human-infecting schistosomes, present in 54 countries, predominantly in Africa, but also in Madagascar, the Arabian Peninsula, and the Neotropics. Adult-stage parasites that infect humans are also occasionally recovered from baboons, rodents, and other mammals. Larval stages of the parasite are dependent upon certain species of freshwater snails in the genus Biomphalaria, which largely determine the parasite's geographical range. How S. mansoni genetic diversity is distributed geographically and among isolates using different hosts has never been examined with DNA sequence data. Here we describe the global phylogeography of S. mansoni using more than 2500 bp of mitochondrial DNA (mtDNA) from 143 parasites collected in 53 geographically widespread localities. Considerable within-species mtDNA diversity was found, with 85 unique haplotypes grouping into five distinct lineages. Geographical separation, and not host use, appears to be the most important factor in the diversification of the parasite. East African specimens showed a remarkable amount of variation, comprising three clades and basal members of a fourth, strongly suggesting an East African origin for the parasite 0.30-0.43 million years ago, a time frame that follows the arrival of its snail host. Less but still substantial variation was found in the rest of Africa. A recent colonization of the New World is supported by finding only seven closely related New World haplotypes which have West African affinities. All Brazilian isolates have nearly identical mtDNA haplotypes, suggesting a founder effect from the establishment and spread of the parasite in this large country.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-294X.2005.02709.xDOI Listing
October 2005
-->