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.
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•The phylogenies of 293 localized prostate cancers were reconstructed•Multiple subclones were detected in 59% of patients•Specific genes are selectively mutated early or late in tumor evolution•Subclonal architecture adds prognostic ability to previously developed biomarkers
Tumors evolve during their natural life history. We studied the evolution of newly diagnosed prostate tumors and identified specific genes mutated early or late in a tumor’s life history. Considering subclonality improved predictions of disease aggressivity, identifying those patients who might be good candidates for receiving less treatment.
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.
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).
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.
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.
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.
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.
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.
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.
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 riskv sites could suppress the transmission of the disease.
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.
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.
Abstract 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.
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