ORCID Profile
0000-0002-5399-9431
Current Organisations
Johns Hopkins Bloomberg School of Public Health
,
University of New South Wales
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Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2011
DOI: 10.1158/1078-0432.CCR-10-3314
Abstract: Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor s les, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe lification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res 17(8) 2538–48. ©2011 AACR.
Publisher: MDPI AG
Date: 04-2011
Publisher: Public Library of Science (PLoS)
Date: 12-11-2013
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NEURON.2018.02.028
Abstract: Animals rely on mechanosensory feedback from proprioceptors to control locomotory body movements. Unexpectedly, we found that this movement control requires visual opsins. Disrupting the Drosophila opsins NINAE or Rh6 impaired larval locomotion and body contractions, independently of light and vision. Opsins were detected in chordotonal proprioceptors along the larval body, localizing to their ciliated dendrites. Loss of opsins impaired mechanically evoked proprioceptor spiking and cilium ultrastructure. Without NINAE or Rh6, NOMPC mechanotransduction channels leaked from proprioceptor cilia and ciliary Inactive (Iav) channels partly disappeared. Locomotion is shown to require opsins in proprioceptors, and the receptors are found to express the opsin gene Rh7, in addition to ninaE and Rh6. Besides implicating opsins in movement control, this documents roles of non-ciliary, rhabdomeric opsins in cilium organization, providing a model for a key transition in opsin evolution and suggesting that structural roles of rhabdomeric opsins preceded their use for light detection.
Publisher: Frontiers Media SA
Date: 28-03-2022
DOI: 10.3389/FNBEH.2022.819146
Abstract: The analysis of kinematics, locomotion, and spatial tasks relies on the accurate detection of animal positions and pose. Pose and position can be assessed with video analysis programs, the “trackers.” Most available trackers represent animals as single points in space (no pose information available) or use markers to build a skeletal representation of pose. Markers are either physical objects attached to the body (white balls, stickers, or paint) or they are defined in silico using recognizable body structures (e.g., joints, limbs, color patterns). Physical markers often cannot be used if the animals are small, lack prominent body structures on which the markers can be placed, or live in environments such as aquatic ones that might detach the marker. Here, we introduce a marker-free pose-estimator (LACE L imbless A nimal tra C k E r) that builds the pose of the animal de novo from its contour. LACE detects the contour of the animal and derives the body mid-line, building a pseudo-skeleton by defining vertices and edges. By applying LACE to analyse the pose of larval Drosophila melanogaster and adult zebrafish, we illustrate that LACE allows to quantify, for ex le, genetic alterations of peristaltic movements and gender-specific locomotion patterns that are associated with different body shapes. As illustrated by these ex les, LACE provides a versatile method for assessing position, pose and movement patterns, even in animals without limbs.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.CUB.2019.07.036
Abstract: Rhodopsins, the major light-detecting molecules of animal visual systems [1], consist of opsin apoproteins that covalently bind a retinal chromophore with a conserved lysine residue [1, 2]. In addition to capturing photons, this chromophore contributes to rhodopsin maturation [3, 4], trafficking [3, 4], and stabilization [5], and defects in chromophore synthesis and recycling can cause dysfunction of the retina and dystrophy [6-9]. Indications that opsin apoproteins alone might have biological roles have come from archaebacteria and platyhelminths, which present opsin-like proteins that lack the chromophore binding site and are deemed to function independently of light [10, 11]. Light-independent sensory roles have been documented for Drosophila opsins [12-15], yet also these unconventional opsin functions are thought to require chromophore binding [12, 13, 15]. Unconjugated opsin apoproteins act as phospholipid scramblases in mammalian photoreceptor disks [16], yet chromophore-independent roles of opsin apoproteins outside of eyes have, to the best of our knowledge, hitherto not been described. Drosophila chordotonal mechanoreceptors require opsins [13, 15], and we find that their function remains uncompromised by nutrient carotenoid depletion. Disrupting carotenoid uptake and cleavage also left the mechanoreceptors unaffected, and manipulating the chromophore attachment site of the fly's major visual opsin Rh1 impaired photoreceptor, but not mechanoreceptor, function. Notwithstanding this chromophore independence, some proteins that process and recycle the chromophore in the retina are also required in mechanoreceptors, including visual cycle components that recycle the chromophore upon its photoisomerization. Our results thus establish biological function for unconjugated opsin apoproteins outside of eyes and, in addition, document chromophore-independent roles for chromophore pathway components.
Publisher: SAGE Publications
Date: 2012
DOI: 10.4137/CMO.S5855
Abstract: The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically erse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2013
DOI: 10.1007/S40265-013-0049-8
Abstract: Previously characterized by a median overall survival of between 6 and 12 months, metastatic melanoma now has a number of novel and effective treatment options. The ability to target the mitogen-activated protein kinase (MAPK) pathway with BRAF (v-raf murine sarcoma viral oncogene homolog B1) or MEK (mitogen-activated protein kinase kinase) inhibitors can result in rapid clinical benefit, but is too often associated with limited durability of response. Resistance inevitably develops either via reactivation of the MAPK pathway or via bypass signalling pathways, such as the PI3K (phosphoinositide 3-kinase) pathway. Combination strategies are thus appealing with an aim to overcome potential resistance mechanisms. Already, the combination of the BRAF inhibitor, dabrafenib, along with the MEK inhibitor, trametinib, has shown promising results clinically and with an improved toxicity profile. Other combination strategies with agents that target the PI3K pathway, angiogenesis, and the immune system are in development or already underway, although potential overlapping toxicities require close monitoring. The currently available molecularly targeted agents that target the MAPK pathway and development of combination therapies for treatment of metastatic melanoma are discussed in further detail.
Publisher: SAGE Publications
Date: 19-12-2011
Abstract: Historically, patients with advanced cutaneous melanoma have a poor prognosis and limited treatment options. The discovery of selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation as an oncogenic mutation in cutaneous melanoma and the importance of the mitogen-activated protein kinase (MAPK) pathway in its tumourigenesis have changed the treatment paradigm for melanoma. Selective BRAF inhibitors and now MEK inhibitors have demonstrated response rates far higher than standard chemotherapeutic options and we review the phase I–III results for these agents in this article. The understanding of mechanisms of resistance that may occur upstream, downstream, at the BRAF level or bypassing the MAPK pathway provides a platform for rational drug development and combination therapies.
Publisher: Baishideng Publishing Group Inc.
Date: 2012
Publisher: Wiley
Date: 29-07-2015
DOI: 10.1002/JCPH.560
Abstract: Two multicenter, single-arm, single-infusion, open-label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rif in (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m(2) intravenous 4-hour infusion for the ketoconazole study or a 14 mg/m(2) intravenous 4-hour infusion for the rif in study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rif in (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rif in, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half-life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rif in, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rif in. The use of romidepsin with rif in and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 08-03-2019
DOI: 10.1038/S41598-019-40459-Z
Abstract: Sensing environmental temperatures is essential for the survival of ectothermic organisms. In Drosophila , two of the most used methodologies to study temperature preferences (T P ) and the genes involved in thermosensation are two-choice assays and temperature gradients. Whereas two-choice assays reveal a relative T P , temperature gradients can identify the absolute T p . One drawback of gradients is that small ectothermic animals are susceptible to cold-trapping: a physiological inability to move at the cold area of the gradient. Often cold-trapping cannot be avoided, biasing the resulting T P to lower temperatures. Two mathematical models were previously developed to correct for cold-trapping. These models, however, focus on group behaviour which can lead to overestimation of cold-trapping due to group aggregation. Here we present a mathematical model that simulates the behaviour of in idual Drosophila in temperature gradients. The model takes the spatial dimension and temperature difference of the gradient into account, as well as the rearing temperature of the flies. Furthermore, it allows the quantification of cold-trapping and reveals unbiased T P. Additionally, our model reveals that flies have a range of tolerable temperatures, and this measure is more informative about the behaviour than commonly used T P . Online simulation is hosted at igloo.uni-goettingen.de . The code can be accessed at erotonin/igloo .
Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2018
DOI: 10.1101/400069
Abstract: Sensing environmental temperatures is essential for the survival of ectothermic organisms. In Drosophila, two methodologies are used to study temperature preferences (T P ) and the genes involved in thermosensation: two-choice assays and temperature gradients. Whereas two-choice assays reveal a relative T P , temperature gradients can identify the absolute T p . One drawback of gradients is that small ectothermic animals are susceptible to cold-trapping: a physiological inability to move at the cold area of the gradient. Often cold-trapping cannot be avoided, biasing the resulting T P to lower temperatures. Two mathematical models were previously developed to correct for cold-trapping. These models, however, focus on group behaviour which can lead to overestimation of cold-trapping due to group aggregation. Here we present a mathematical model that estimates the behaviour of in idual Drosophila in temperature gradients. The model takes the spatial dimension and temperature difference of the gradient into account, as well as the rearing temperature of the flies. Furthermore, it allows quantifying cold-trapping, reveals true T P , and differentiates between temperature preference and tolerance. Online simulation is hosted at igloo.uni-goettingen.de . The code can be accessed at erotonin/igloo .
Publisher: S. Karger AG
Date: 14-10-2014
DOI: 10.1159/000368161
Abstract: b i Objective: /i /b Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. b i Methods: /i /b Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. b i Results: /i /b Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. b i Conclusion: /i /b As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits. © 2014 S. Karger AG, Basel
Publisher: Wiley
Date: 04-02-2014
DOI: 10.1002/IJC.28730
Abstract: Human papillomavirus (HPV) causes most cases of anal cancers. In this study, we analyzed biopsy material from 112 patients with anal cancers in Australia for the presence of HPV DNA by the INNO LiPA HPV genotyping assay. There were 82% (92) males and 18% (20) females. The mean age at diagnosis was significantly (p = 0.006) younger for males (52.5 years) than females (66 years). HIV-infected males were diagnosed at a much earlier mean age (48.2 years) than HIV negative (56.3 years) males (p = 0.05). HPV DNA was detected in 96.4% (108) of cases. HPV type 16 was the commonest, at 75% (81) of s les and being the sole genotype detected in 61% (66). Overall, 79% (85) of cases had at least one genotype targeted by the bivalent HPV (bHPV) vaccine, 90% (97) by the quadrivalent HPV (qHPV) vaccine and 96% (104) by the nonavalent HPV (nHPV) vaccine. The qHPV vaccine, which is now offered to all secondary school students in Australia, may prevent anal cancers in Australia. However, given the mean age of onset of this condition, the vaccine is unlikely to have a significant impact for several decades. Further research is necessary to prove additional protective effects of the nHPV vaccine.
Publisher: Frontiers Media SA
Date: 30-08-2013
Abstract: The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.
Location: United States of America
Location: No location found
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Charlotte Lemech.