91 research outputs found
Application of high-throughput cancer genomic approaches for the molecular characterization, patient stratification and identification of evolutionary patterns in different cancer types
No full textCancer genomics refers to the study of the genome and transcriptome from tumour cells and their normal host cells. It aims to understand the genetic basis of tumour cell proliferation and evolution of cancers driven by somatic mutations and selection pressures from the tumour microenvironment, the immune system and therapeutic interventions. Until the emergence of next generation sequencing (NGS) technologies, microarrays were the fundamental tool used in cancer genomics. Using these high-throughput platforms, the characterization and stratification of cancer patients was initially based on the molecular (transcriptional, genomic and epigenetic) profiles derived from single bulk tumour samples. Recently, cancer genomics has further interrogated the inherent complexity of tumours by sequencing multiple cancer specimens from each patient. This approach has uncovered a high degree of heterogeneity within tumours resulting from the Darwinian character of cancer which also explains treatment resistance and is key for personalised treatments.
This introductory section presents my contribution to the cancer genomics field in particular on breast cancer, glioblastoma multiforme (GBM), colorectal carcinoma (CRC) and prostate cancer.
I demonstrated the potential of miRNA profiling to characterise established breast cancer cell lines and primary tumours. Further, I designed and performed a microarray platform comparison study that sustained the transcriptomic and genomic profiling of the largest breast cancer cohort to date. More recently, I uncovered different evolutionary patterns of treatment-naïve breast cancer patients which are recapitulated in plasma cell-free tumour DNA (ctDNA).
Unfortunately, the potential use of ctDNA is limited in GBM patients, thus tumour tissue specimens are necessary to perform brain cancer genomic studies. Using a meticulous multisampling scheme to collect spatially distinct GBM tumour fragments I identified high levels of heterogeneity within individual tumour masses at the genomic and transcriptomic levels. Interestingly, a proportion of GBM patients also bear tumour cells in the subventricular zone (SVZ) away from the primary tumoir mass and for the first time I showed that some GBM tumours grow out from the SVZ to develop large tumour masses while others grow in the SVZ from previously established primary tumours. In addition, I have shown that there are also GBM cells infiltrating the normal brain parenchyma. These residual cancer cells and those in the SVZ, indicate a putative source of treatment resistance.
In colorectal cancer, resistance to cetuximab treatment is nearly inevitable. Using multi-region and longitudinal biopsies I uncovered resistant cancer cells which pre-existed cetuximab therapy and resistant cells which emerged and expanded during treatment. Importantly, treatment response in metastatic CRC patients can be recapitulated using patient derived organoids (PDOs) which could be implemented for personalised medicine. Intriguingly, despite a high metastatic potential, CRC might have a slow progression rate as I uncovered from the disease chronology of one CRC patient.
Lastly, I validated a recurrent epigenetic alteration in prostate cancer and demonstrated that it is a very early event on the progression of this disease.
In summary, this introductory section will describe the application of novel methodologies based on standard cancer genomics tools which have shed light into the molecular classification and evolutionary patterns of different cancer types. The applicability of these findings to personalised cancer treatments will also be discussed
Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics
No full textGlioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients. We present an integrated genomic analysis that uncovers extensive intratumor heterogeneity, with most patients displaying different GB subtypes within the same tumor. Moreover, we reconstructed the phylogeny of the fragments for each patient, identifying copy number alterations in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events during cancer progression. We also characterized the clonal organization of each tumor fragment at the single-molecule level, detecting multiple coexisting cell lineages. Our results reveal the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-specific patterns of cancer evolution, with consequences for treatment design.</p
Gravitational signature of titan's (sub) surface lakes: Discovering the composition of the lakes using a MEMS micro gradiometer mounted on a balloon
No full textAerospace Engineerin
pH-Dependent iron oxide precipitation in a subterranean estuary
No full textAuthor Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Geochemical Exploration 88 (2006): 399-403, doi:10.1016/j.gexplo.2005.08.084.Iron-oxide coated sediment particles in subterranean estuaries can act as a geochemical barrier (“iron curtain”) for various chemical species in groundwater (e.g. phosphate), thus limiting their discharge to coastal waters. Little is known about the factors controlling this Fe-oxide precipitation. Here, we implement a simple reaction network in a 1D reactive transport model (RTM), to investigate the effect of O2 and pH gradients along a flow-line in the subterranean estuary of Waquoit Bay (Cape Cod, Massachusetts) on oxidative precipitation of Fe(II) and subsequent PO4 sorption. Results show that the observed O2 gradient is not the main factor controlling precipitation and that it is the pH gradient at the mixing zone of freshwater (pH 5.5) and seawater (pH 7.9) near the beach face that causes a ~7-fold increase in the rate of oxidative precipitation of Fe(II) at ~15 m. Thus, the pH gradient determines the location and magnitude of the observed iron oxide accumulation and the subsequent removal of PO4 in this subterranean estuary.Financial support was provided by the Netherlands Organisation for Scientific Research (NWO) and WHOI Guest Student Program (grants to C. Spiteri), the Royal Netherlands Academy of Arts and Sciences (KNAW) (fellowship to C.P. Slomp) and US National Science Foundation NSF-OCE0095384 and NSF-OCE0425061 (grants to M.A. Charette)
Validatie van het 3D model van het Grevelingenmeer voor hydrodynamica, waterkwaliteit en primaire productie
No full textIn het kader van de Deltares\u92 bijdrage aan de MIRT1 Grevelingen is het beschikbare 3D modelinstrumentarium voor hydrodynamica (waterbeweging), waterkwaliteit en primaire productie uitgebreid met en gevalideerd voor het jaar 2008. Samen met de eerder uitgevoerde kalibratie voor het jaar 2000 (Deltares, 2008) is hiermee een operationeel modelinstrumentarium beschikbaar voor toepassing in onderzoek en advies door Deltares, andere kennisinstituten en ingenieursbureaus. Het model is opgenomen in het Beheer en Onderhoud van modellen en kan op verzoek uitgeleverd worden. Samen met het kalibratierapport omvat dit validatierapport de onderliggende beschrijving en onderbouwing van het instrumentariu
Contributions to Drug Resistance in Glioblastoma Derived from Malignant Cells in the Sub-Ependymal Zone
No full textGlioblastoma, the most common and aggressive adult brain tumor, is characterized by extreme phenotypic diversity and treatment failure. Through fluorescence-guided resection, we identified fluorescent tissue in the sub-ependymal zone (SEZ) of patients with glioblastoma. Histologic analysis and genomic characterization revealed that the SEZ harbors malignant cells with tumor-initiating capacity, analogous to cells isolated from the fluorescent tumor mass (T). We observed resistance to supramaximal chemotherapy doses along with differential patterns of drug response between T and SEZ in the same tumor. Our results reveal novel insights into glioblastoma growth dynamics, with implications for understanding and limiting treatment resistance
Flow and nutrient dynamics in a subterranean estuary (Waquoit Bay, MA, USA) : field data and reactive transport modeling
No full textAuthor Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 72 (2008): 3398-3412, doi:10.1016/j.gca.2008.04.027.A two-dimensional (2D) reactive transport model is used to investigate the controls on
nutrient (NO3-, NH4+, PO4) dynamics in a coastal aquifer. The model couples density
dependent flow to a reaction network which includes oxic degradation of organic
matter, denitrification, iron oxide reduction, nitrification, Fe2+ oxidation and sorption of PO4 onto iron oxides. Porewater measurements from a well transect at Waquoit
Bay, MA, USA indicate the presence of a reducing plume with high Fe2+, NH4+, DOC
(dissolved organic carbon) and PO4 concentrations overlying a more oxidizing NO3--rich plume. These two plumes travel nearly conservatively until they start to overlap in the intertidal coastal sediments prior to discharge into the bay. In this zone, the aeration of the surface beach sediments drives nitrification and allows the
precipitation of iron oxide, which leads to the removal of PO4 through sorption. Model
simulations suggest that removal of NO3-
through denitrification is inhibited by the
limited overlap between the two freshwater plumes, as well as by the refractory nature
of terrestrial DOC. Submarine groundwater discharge is a significant source of NO3-
to the bay.This research was funded by the Netherlands Organisation for Scientific Research
(NWO) and WHOI Guest Student Program (C. Spiteri), the Royal Netherlands
Academy of Arts and Sciences (KNAW) and the Netherlands Organization for
Scientific Research (NWO VIDI-grant) (C.P. Slomp), the US National Science
Foundation NSF-OCE0095384 and NSF-OCE0425061 (M.A. Charette) and the
Georgia Sea Grant of the National Sea Grant College Program of the U.S. Department
of Commerce’s National Oceanic and Atmospheric Administration under NOAA
Grant #NA04OAR4170033 (C. Meile)
Shutting Down Sharleen
No full textSharleen Spiteri was a sex worker, a drug user, and she was HIV+. In July 1989, Sharleen Spiteri appeared on the national current affairs TV program 60 Minutes and told reporter Jeff McMullen that she tried to get her clients to practice safe sex, but sometimes they wouldn't cooperate. As a result, the NSW government took Sharleen from her flat under police guard, and forcibly detained her in a locked AIDS ward, a mental hospital and a disused nursesâ home. After she was released from detention, Sharleen spent much of the remaining 16 years of her life under 24-hour supervision by health workers. She became the most expensive public patient in NSW history. This program uses the techniques of investigative journalism, including exclusive original interviews with politicians, bureaucrats, health workers, carers, sex workers, nuns and journalists, as well as extensive archival research and material obtained through FOI to uncover the background to Sharleenâs story. It raises important issues about the relationship between the media and public policy, and the clash between individual civil liberties and governmentâs responsibility to protect public interest. Co-producer/author Tom Morton author delivered a paper based on the documentary at Back to the Source, the national Investigative Journalism Conference held at UTS on September 17th-18th 2011. Paper was published in Pacific Journalism Review in 2012. Awards/Competitions/Festivals 2010 Gold Radio Award, New York Festivals: http://www.newyorkfestivals.com/main.php?p=3,1&wp=info&id=405202 Finalist, John Curtin Award for Journalism, Victorian Premierâs Literary Awards, 201
- …
