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1. HIV-1 viral load outcomes and the evolution of drug-resistance in low-income settings without virological monitoring

Author

Dolling, D. I., Dunn, D. T., and Goodall, R. L.

Subjects
616.97
Abstract

WHO guidelines recommend viral load monitoring for all HIV-1 positive patients on antiretroviral therapy (ART). However, few low-income countries have virological monitoring widely available, and patients may remain on virologically failing regimens. This could compromise future ART through the accumulation of drug resistance mutations and result in worse long-term clinical outcomes. The DART trial was conducted in Uganda and Zimbabwe and compared clinically driven monitoring with or without routine CD4 measurement in ART-naïve adult patients. Annual plasma viral load was retrospectively measured for 1,762 patients. This thesis investigates how no laboratory monitoring impacts virological failure and the development of drug resistance. Time to persistent virological failure was analysed, and analytical weights were calculated to correct for non-random sampling. The long-term durability of first-line ART was remarkable; 21% of patients on an NRTI-NNRTI regimen and 40% on a triple-NRTI regimen experienced persistent virological failure by 240 weeks. Routine CD4 monitoring did not reduce virological failure. Deaths after 48 weeks of ART are widely assumed to be due to virological failure or non-adherence. Analyses revealed that a surprisingly high number of these deaths (40%) occurred without virological criteria for treatment switch being met. Routine CD4 monitoring reduced the rate of death with virological failure but did not impact deaths with virological suppression. Cross-sectional analyses quantified HIV-1 drug resistance at the end of first-line ART. On NRTI-NNRTI regimens, 88% had NRTI resistance, and 66% had NNRTI resistance. Routine CD4 monitoring did not reduce the prevalence or extent of drug resistance. The order and rate of HIV-1 drug resistance mutations were explored using repeated genotypes within patients. On NRTI-NNRTI regimens, NRTI and NNRTI mutations developed at a rate of 0.96 and 0.21 per year respectively. Mutagenic tree models demonstrated that ART regimen influenced the order and rate in which mutations occurred.

Published
2017

3. Light-Induced Transformation of Virus-Like Particles on TiO2

Author

Kohantorabi, M, Ugolotti, A, Sochor, B, Roessler, J, Wagstaffe, M, Meinhardt, A, Beck, E, Dolling, D, Garcia, M, Creutzburg, M, Keller, T, Schwartzkopf, M, Vayalil, S, Thuenauer, R, Guédez, G, Löw, C, Ebert, G, Protzer, U, Hammerschmidt, W, Zeidler, R, Roth, S, Di Valentin, C, Stierle, A, Noei, H, Kohantorabi, Mona, Ugolotti, Aldo, Sochor, Benedikt, Roessler, Johannes, Wagstaffe, Michael, Meinhardt, Alexander, Beck, E. Erik, Dolling, Daniel Silvan, Garcia, Miguel Blanco, Creutzburg, Marcus, Keller, Thomas F., Schwartzkopf, Matthias, Vayalil, Sarathlal Koyiloth, Thuenauer, Roland, Guédez, Gabriela, Löw, Christian, Ebert, Gregor, Protzer, Ulrike, Hammerschmidt, Wolfgang, Zeidler, Reinhard, Roth, Stephan V., Di Valentin, Cristiana, Stierle, Andreas, Noei, Heshmat, Kohantorabi, M, Ugolotti, A, Sochor, B, Roessler, J, Wagstaffe, M, Meinhardt, A, Beck, E, Dolling, D, Garcia, M, Creutzburg, M, Keller, T, Schwartzkopf, M, Vayalil, S, Thuenauer, R, Guédez, G, Löw, C, Ebert, G, Protzer, U, Hammerschmidt, W, Zeidler, R, Roth, S, Di Valentin, C, Stierle, A, Noei, H, Kohantorabi, Mona, Ugolotti, Aldo, Sochor, Benedikt, Roessler, Johannes, Wagstaffe, Michael, Meinhardt, Alexander, Beck, E. Erik, Dolling, Daniel Silvan, Garcia, Miguel Blanco, Creutzburg, Marcus, Keller, Thomas F., Schwartzkopf, Matthias, Vayalil, Sarathlal Koyiloth, Thuenauer, Roland, Guédez, Gabriela, Löw, Christian, Ebert, Gregor, Protzer, Ulrike, Hammerschmidt, Wolfgang, Zeidler, Reinhard, Roth, Stephan V., Di Valentin, Cristiana, Stierle, Andreas, and Noei, Heshmat

Abstract

Titanium dioxide (TiO2) shows significant potential as a self-cleaning material to inactivate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent virus transmission. This study provides insights into the impact of UV-A light on the photocatalytic inactivation of adsorbed SARS-CoV-2 virus-like particles (VLPs) on a TiO2 surface at the molecular and atomic levels. X-ray photoelectron spectroscopy, combined with density functional theory calculations, reveals that spike proteins can adsorb on TiO2 predominantly via their amine and amide functional groups in their amino acids blocks. We employ atomic force microscopy and grazing-incidence small-angle X-ray scattering (GISAXS) to investigate the molecular-scale morphological changes during the inactivation of VLPs on TiO2 under light irradiation. Notably, in situ measurements reveal photoinduced morphological changes of VLPs, resulting in increased particle diameters. These results suggest that the denaturation of structural proteins induced by UV irradiation and oxidation of the virus structure through photocatalytic reactions can take place on the TiO2 surface. The in situ GISAXS measurements under an N-2 atmosphere reveal that the virus morphology remains intact under UV light. This provides evidence that the presence of both oxygen and UV light is necessary to initiate photocatalytic reactions on the surface and subsequently inactivate the adsorbed viruses. The chemical insights into the virus inactivation process obtained in this study contribute significantly to the development of solid materials for the inactivation of enveloped viruses.

Published
2024

7. CD38 in Advanced Prostate Cancers

Author

Guo, C., Crespo, M., Gurel, B., Dolling, D., Rekowski, J., Sharp, A., Petremolo, A., Sumanasuriya, S., Rodrigues, D.N., Ferreira, A., Pereira, R., Figueiredo, I., Mehra, N., Lambros, M.B., Neeb, A., Gil, V., Seed, G., Terstappen, L., Alimonti, A., Drake, C.G., Yuan, W., Bono, J.S. de, Guo, C., Crespo, M., Gurel, B., Dolling, D., Rekowski, J., Sharp, A., Petremolo, A., Sumanasuriya, S., Rodrigues, D.N., Ferreira, A., Pereira, R., Figueiredo, I., Mehra, N., Lambros, M.B., Neeb, A., Gil, V., Seed, G., Terstappen, L., Alimonti, A., Drake, C.G., Yuan, W., and Bono, J.S. de

Abstract

Contains fulltext : 235404.pdf (Publisher’s version ) (Open Access), BACKGROUND: CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. OBJECTIVE: To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38(+) TIIC densities between CSPC and CRPC biopsies were analysed using a negative binomial mixed model. Differences in the proportions of CD38(+) epithelial cells between non-matched benign prostatic epithelium and PC were compared using Fisher's exact test. Differences in the proportions of biopsies containing CD38(+) tumour epithelial cells between matched CSPC and CRPC biopsies were compared by McNemar's test. Univariable and multivariable survival analyses were performed using Cox regression models. RESULTS AND LIMITATIONS: CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adeno

Published
2021

10. Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis

Author

Rescigno, P., Dolling, D., Conteduca, Vincenza, Rediti, Mattia, Bianchini, D., Lolli, Cristian, Mehra, N., Smeenk, S.C., Giorgi, Ugo De, Bono, Johann S. De, Rescigno, P., Dolling, D., Conteduca, Vincenza, Rediti, Mattia, Bianchini, D., Lolli, Cristian, Mehra, N., Smeenk, S.C., Giorgi, Ugo De, and Bono, Johann S. De

Abstract

Contains fulltext : 218771.pdf (Publisher’s version ) (Open Access)

Published
2020

11. Genomics of lethal prostate cancer at diagnosis and castration resistance

Author

Mateo, J, Seed, G, Bertan, C, Rescigno, P, Dolling, D, Figueiredo, I, Miranda, S, Rodrigues, DN, Gurel, B, Clarke, M, Atkin, M, Chandler, R, Messina, C, Sumanasuriya, S, Bianchini, D, Barrero, M, Petermolo, A, Zafeiriou, Z, Fontes, M, Perez-Lopez, R, Tunariu, N, Fulton, B, Jones, R, McGovern, U, Ralph, C, Varughese, M, Parikh, O, Jain, S, Elliott, T, Sandhu, S, Porta, N, Hall, E, Yuan, W, Carreira, S, de Bono, JS, Mateo, J, Seed, G, Bertan, C, Rescigno, P, Dolling, D, Figueiredo, I, Miranda, S, Rodrigues, DN, Gurel, B, Clarke, M, Atkin, M, Chandler, R, Messina, C, Sumanasuriya, S, Bianchini, D, Barrero, M, Petermolo, A, Zafeiriou, Z, Fontes, M, Perez-Lopez, R, Tunariu, N, Fulton, B, Jones, R, McGovern, U, Ralph, C, Varughese, M, Parikh, O, Jain, S, Elliott, T, Sandhu, S, Porta, N, Hall, E, Yuan, W, Carreira, S, and de Bono, JS

Abstract

The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.

Published
2020

13. Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Author

Mehra, N., Dolling, D., Sumanasuriya, S., Christova, R., Pope, L., Carreira, S., Seed, G., Yuan, W., Goodall, J., Hall, E., Flohr, P., Boysen, G., Bianchini, D., Sartor, O., Eisenberger, M.A., Fizazi, K., Oudard, S., Chadjaa, M., Mace, S., and Bono, J.S. de

Subjects
Male, Time Factors, PROSELICA, Circulating cell-free DNA, Docetaxel, Drug Administration Schedule, Article, Circulating Tumor DNA, Taxane chemotherapy, Biomarkers, Tumor, Humans, Prospective Studies, Neoplasm Metastasis, cfDNA, Aged, Cabazitaxel, Prostatic Neoplasms, Middle Aged, Prostate-Specific Antigen, Antineoplastic Agents, Phytogenic, Progression-Free Survival, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Kallikreins, Taxoids, FIRSTANA, Cell-Free Nucleic Acids, Biomarkers
Abstract

Background Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR] = 1.54; 95% confidence interval [CI]: 1.15–2.08; p = 0.004), and shorter OS on taxane therapy (HR = 1.53; 95% CI: 1.18–1.97; p = 0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p = 0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA., Take Home Message Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.

Published
2018

14. Fluctuating wall pressures near separation in highly swept turbulent interactions

Author

Schmisseur, J. D and Dolling, D. S

Subjects
Fluid Mechanics And Heat Transfer
Abstract

Fluctuating wall pressures have been measured in Mach 5 interactions generated by sharp, upswept fins at angles of attack of 16 to 28 deg. The results show that rms pressure distributions, like the mean, can be collapsed in conical coordinates. The wall pressure signal near separation is intermittent and is qualitatively similar to that measured in unswept interactions and other swept flows. However, the dominant separation shock frequencies in the swept flows are up to an order of magnitude higher than those in unswept interactions under identical incoming flow conditions. In light of the present observations, it appears that an earlier remark, by Gilson and Dolling, that separation is characterized by a shuddering compression system, in contrast to a translating separation shock is erroneous due to a combination of weak shock strength and inadequate spatial resolution. Furthermore, although the maximum rms pressure near separation increases with increasing interaction strength, as in swept compression ramp flows, comparison of data from the two flow types indicates that the appropriate correlating parameter is the interaction sweepback angle.

Published
1994

15. Unsteady Phenomena in Shock Wave/Boundary Layer Interaction

Author

Dolling, D. S

Subjects
Fluid Mechanics And Heat Transfer
Abstract

A brief review is given of the unsteadiness of shock wave/turbulent boundary layer interaction. The focus is on interactions generated by swept and unswept compression ramps, by flares, steps and incident shock waves, by cylinders and blunt fins, and by glancing shock waves. The effects of Mach number, Reynolds number, and separated flow scale are discussed as are the physical causes of the unsteadiness. The implications that the unsteadiness has for interpreting time-average surface and flowfield data, and for comparisons of such experimental data with computation, is also briefly discussed. Finally, some suggestions for future work are given. It is clear that there are large gaps in the data base and that many aspects of such phenomena are poorly understood. Much work remains to be done.

Published
1993

16. Control of unsteady shock-induced turbulent boundary layer separation upstream of blunt fins

Author

Kleifges, K and Dolling, D. S

Subjects
Aerodynamics
Abstract

Fluctuating wall pressure measurements have been made on centerline upstream of blunt fins in a Mach 5 turbulent boundary layer. Standard time series analysis and conditional sampling algorithms have been used to examine the effects of leading edge sweepback, leading edge shape, and fin root modifications on the fluctuating pressures. Leading edge sweep considerably reduces the mean and rms pressure loading at the fin root, the extent of the region of unsteady separation shock motion, and the separation length. The frequency of pressure fluctuations in the intermittent region increases with leading edge sweepback, while the spectral content of pressure fluctuations in the separated region is virtually unchanged by leading edge sweep. A swept hemicylindrically blunted root fillet reduces the centerline upstream influence and intermittent region length by 50 percent, and reduces the mean and rms pressure loading at the fin root by about 75 percent and 95 percent respectively. Experiments using hemicylindrical, wedge shaped and flat leading edges show that while separated flow scales increase with increasing 'bluntness', intermittent region length and root loading decrease, and separation shock frequency increases.

Published
1993

17. Flowfield dynamics in blunt fin-induced shock wave/turbulent boundary layer interactions

Author

Brusniak, L and Dolling, D. S

Subjects
Aerodynamics
Abstract

Fluctuating wall pressure measurements were made on centerline upstream of a blunt fin in a Much 5 turbulent boundary layer. By examining the ensemble average wall pressure distributions for different fixed shock foot positions, it was shown that local fluctuating wall pressure measurements are due to a distinct pressure distribution, P(i), which undergoes a stretching and flattening effect as its upstream boundary translates aperiodically between the upstream influence and separation lines. The locations of the maxima and minima in the centerline wall standard deviation distribution can be accurately predicted using this distribution, providing quantitative confirmation of the model. This model also explains the observed cross-correlations and ensemble average measurements within the interaction. Using the P(i) model, wall pressure signals from under the separated flow region were able to reproduce the position-time history of the separation shock foot. The negative time delay peak in the cross-correlation between the predicted and actual shock foot histories shows that the separated region fluctuations precede shock foot motion.

Published
1993

18. Computation of turbulent, separated, unswept compression ramp interactions

Author

Marshall, T. A and Dolling, D. S

Subjects
Aerodynamics
Abstract

Examination of the literature shows that the comparison between experiment and computation for highly separated unswept compression ramp flows is generally poor, irrespective of the turbulence model used. In general, the upstream influence is not correct, the wall pressure rise through separation is too steep, and the pressures under the separated shear layer are too high. In the current study, the objective is to determine if these discrepancies might be attributed more to other factors such as flowfield unsteadiness or three-dimensionality, rather than to inadequate turbulence modeling. To examine this possibility, multichannel wall pressure fluctuations were measured under the unsteady separation shock wave in a 28-deg unswept compression ramp flow at Mach 5. The results show that the large scale, low frequency separation shock unsteadiness controls the distribution of time-averaged surface properties and that neglect of the unsteadiness is probably the primary cause of the discrepancy between experiment and computation.

Published
1992

19. An experimental examination of the effects of incoming boundary layer modifications on the dynamics of a turbulent compression corner interaction

Author

Mcclure, W. B and Dolling, D. S

Subjects
Aerodynamics
Abstract

This experimental study examines the effects of modifications to the incoming turbulent boundary layer on the highly separated shock wave/boundary layer interaction generated by an unswept compression corner. Particular focus is placed on the motion of the unsteady separation shock wave. The flowfield was generated by a 28 deg ramp in a Mach 5 flow with a freestream Reynolds number of 50 x 10 exp 6/m. The incoming turbulent boundary layer transitioned naturally and developed under near-adiabatic wall conditions. Modification of the flow entering the interaction was effected through either a single plate boundary layer manipulator (BLM) or riblets. The BLM reduced the length of separation by 35-45 percent and reduced the streamwise extent of the separation shock motion by 36-74 percent. Examination of the flowfield downstream of the BLM showed this result to be due to the inviscid preturning of the flow by the BLM, and not by changes to the boundary layer dynamics. The riblets had no measurable effect on the compression corner interaction.

Published
1992

20. Unsteady separation in sharp fin-induced shock wave/turbulent boundary layer interaction at Mach 5

Author

Schmisseur, J. D and Dolling, D. S

Subjects
Aerodynamics
Abstract

Fluctuating wall-pressure measurements are made in shock-wave/turbulent-boundary-layer interactions generated by sharp/unswept fins at angles of attack of 16, 18, 20, 22, 24, 26, and 28 degrees at Mach 5. The experiment was conducted under approximately adiabatic wall temperature conditions. The mean and rms pressure distributions can be collapsed in conical coordinates. The wall-pressure signal near separation is intermittent for all angles of attack (16-28 deg) and is qualitatively similar to that measured in unswept flows. However, the shock frequencies are higher - about 5 kHz compared to 0.5-1 kHz. Over the range of sweepbacks examined, from 25-55 deg, the spectral content of the fluctuating pressures does not change. Thus, the increase in separation-shock frequency from 1 to 5 kHz occurs at lower interaction sweepback and is not a continuous process with increasing sweepback. Power spectra at the position of maximum rms in the intermittent region for interactions in different incoming boundary layers have the same center frequency. The maximum rms in the intermittent region correlates with interaction sweepback, not with overall inviscid pressure rise.

Published
1992

21. Abstract GS3-02: PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib

Author

Dowsett, M, primary, Jacobs, S, additional, Johnston, S, additional, Bliss, J, additional, Wheatley, D, additional, Holcombe, C, additional, Stein, R, additional, McIntosh, S, additional, Barry, P, additional, Dolling, D, additional, Snowdon, C, additional, Perry, S, additional, Batten, L, additional, Dodson, A, additional, Martins, V, additional, Modi, A, additional, Cornman, C, additional, Puhalla, S, additional, Wolmark, N, additional, Julian, T, additional, Pogue-Geile, K, additional, Robidoux, A, additional, Provencher, L, additional, Boileau, JF, additional, Shalaby, I, additional, Thirlwell, M, additional, Fisher, K, additional, Huang Bartlett, C, additional, Koehler, M, additional, Osborne, K, additional, and Rimawi, M, additional

Published
2019
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22. PI3K/AKT pathway deleterious mutations in lethal prostate cancer

Author

Rescigno, P., primary, Rediti, M., additional, Dolling, D., additional, Rodrigues, D.N., additional, Bianchini, D., additional, Riisnaes, R., additional, Messina, C., additional, Barrero, M., additional, Petremolo, A., additional, Sharp, A., additional, Sumanasuriya, S., additional, Seed, G., additional, Figueiredo, I., additional, Miranda, S., additional, Goodall, J., additional, Mateo, J., additional, Chandler, R., additional, Yuan, W., additional, Carreira, S., additional, and de Bono, J.S., additional

Published
2018
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24. Reply to Vincenza Conteduca, Giorgia Gurioli, and Ugo De Giorgi's Letter to the Editor re: Niven Mehra, David Dolling, Semini Sumanasuriya, et al. Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA). Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.02.013

Author

Mehra, N., Dolling, D., Bono, J. de, Mehra, N., Dolling, D., and Bono, J. de

Abstract

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Published
2018

25. Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials

Author

Sundar, R., McVeigh, T., Dolling, D., Petruckevitch, A., Diamantis, N., Ang, J.E., Chenard-Poirier, M., Collins, D., Lim, J., Ameratunga, M., Khan, K., Kaye, S.B., Banerji, U., Lopez, J., George, A.J., Bono, J.S. de, Graaf, W.T.A. van der, Sundar, R., McVeigh, T., Dolling, D., Petruckevitch, A., Diamantis, N., Ang, J.E., Chenard-Poirier, M., Collins, D., Lim, J., Ameratunga, M., Khan, K., Kaye, S.B., Banerji, U., Lopez, J., George, A.J., Bono, J.S. de, and Graaf, W.T.A. van der

Abstract

Item does not contain fulltext, BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.

Published
2018

26. Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Author

Mateo, J, Cheng, HH, Beltran, H, Dolling, D, Xu, W, Pritchard, CC, Mossop, H, Rescigno, P, Perez-Lopez, R, Sailer, V, Kolinsky, M, Balasopoulou, A, Bertan, C, Nanus, DM, Tagawa, ST, Thorne, H, Montgomery, B, Carreira, S, Sandhu, S, Rubin, MA, Nelson, PS, de Bono, JS, Mateo, J, Cheng, HH, Beltran, H, Dolling, D, Xu, W, Pritchard, CC, Mossop, H, Rescigno, P, Perez-Lopez, R, Sailer, V, Kolinsky, M, Balasopoulou, A, Bertan, C, Nanus, DM, Tagawa, ST, Thorne, H, Montgomery, B, Carreira, S, Sandhu, S, Rubin, MA, Nelson, PS, and de Bono, JS

Abstract

BACKGROUND: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE: To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. RESULTS AND LIMITATIONS: The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm-]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p=0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm- (5.1 mo), and RRs were similar (gDDRm+=61%; gDDRm-=54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+=8.3 mo, gDDRm-=8.3 mo; gDDRm+=46%, gDDRm-=56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28-1.25; p=0.17). Results are limited by the retrospective nature of the analysis. CONCLUSIONS: mPC patients with gDDRm appeared to benefit from standard therapies s

Published
2018

28. Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study

Author

Gafos, M., Brodnicki, E., Desai, M., McCormack, S., Nutland, W., Wayal, S., White, E., Wood, G., Barber, T., Bell, G., Clarke, A., Dolling, D., Dunn, D., Fox, J., Haddow, L., Lacey, C., Nardone, A., Quinn, K., Rae, C., Reeves, I., Rayment, M., White, D., Apea, V., Ayap, W., Dewsnap, C., Collaco-Moraes, Y., Schembri, G., Sowunmi, Y., Horne, R., Proud Study Team , ., and Law, M

Subjects
Science, Medicine, humanities
Abstract

Background\ud \ud PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design.\ud \ud Methods\ud \ud Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants.\ud \ud Results\ud \ud Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported ‘being deferred’ as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design.\ud \ud Conclusion\ud \ud The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study.

Published
2017

31. Neutrophil to Lymphocyte Ratio in Castration-Resistant Prostate Cancer Patients Treated With Daily Oral Corticosteroids

Author

Mehra, N., Sharp, A., Lorente, D., Dolling, D., Sumanasuriya, S., Johnson, B., Dearnaley, D., Parker, C., Bono, J. de, Mehra, N., Sharp, A., Lorente, D., Dolling, D., Sumanasuriya, S., Johnson, B., Dearnaley, D., Parker, C., and Bono, J. de

Abstract

Item does not contain fulltext, BACKGROUND: The neutrophil to lymphocyte ratio (NLR) has been shown to be highly prognostic across many tumor types, and predictive of treatment outcome in advanced prostate cancer, and has been postulated to be an indirect measure of tumor inflammation. We evaluated the effect of low-dose steroids on NLR in men suffering from castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The NLR was evaluated in a prospective randomized phase II trial that compared prednisolone 5 mg twice daily and dexamethasone 0.5 mg daily administered to 75 chemotherapy and abiraterone/enzalutamide-naive CRPC patients. NLR was examined at baseline (BL), after 6 and 12 weeks of corticosteroid treatment; associations with >50% prostate-specific antigen (PSA) response, duration of response (PSA progression-free interval), and overall survival (OS) were tested using logistic regression and Cox regression analysis. RESULTS: The median NLR for all evaluable patients was 2.6 at BL; 2.9 at 6 weeks; and 4.0 at 12 weeks. After low-dose corticosteroid initiation, 46 patients had a decline in PSA with 24 confirmed responders. BL NLR (log10) associated with a PSA response (odds ratio, .029, 95% confidence interval [CI], .002-.493; P = .014), and with the extent of the PSA decline (P = .009). A favorable BL NLR (less than median) associated with a 5.5-fold higher odds of a PSA >50% response (95% CI, 1.3-23.9; P = .02). Higher BL NLR (log10) associated with a shorter time to PSA progression (hazard ratio [HR], 9.5; 95% CI, 2.3-39.9; P = .002). In multivariate analysis BL NLR as a discrete variable was independently associated with PSA progression (HR, 3.5; 95% CI, 1.5-8.1; P = .003). NLR at 6 weeks was also associated with duration of benefit; in the favorable NLR category time to PSA progression was 10.8 months, for those who converted to an unfavorable (greater than median) category 4.5 months, and for those remaining in a unfavorable category only 1.5 months (95% CI, 0.5-2.5; P = .003).

Published
2017

32. Experimental Study of Shear-Layer/Acoustics Coupling in Mach 5 Cavity Flow

Author

Unalmis, O. H., Clemens, N. T., and Dolling, D. S.

Subjects
Shear flow -- Analysis, Sound-waves -- Analysis, Aerodynamics, Hypersonic -- Analysis, Aerospace and defense industries, Business
Abstract

Simultaneous planar laser imaging and fluctuating-pressure measurements were made in a high-Reynoldsnumber, Mach 5 cavity flow, with cavity length-to-depth ratios of 3, 4, 5, 6, and 7. Instantaneous planar laser scattering images show no evidence for coherent structures that are induced by the cavity acoustics. Furthermore, both the pressure measurements and imaging suggest that the rear-wall shock is caused by the impingement of shear-layer turbulent structures. Analysis of the fluctuating-pressure data suggests that the shock frequencies and the duration of the impingement shock are not sensitive to cavity length-to-depth ratio. Ensemble-average velocity profiles in the shear layer, conditioned on the front-wall pressure, suggest that the deflection of the shear layer is not measurably correlated with the cavity oscillation cycle. In addition, spectral analysis of the fluctuating pressures shows that the cavity oscillation frequencies are accurately predicted using simple closed-box acoustic theory. These results suggest that the present cavity flow exhibits substantially less coupling between the cavity pressure fluctuations and the shear-layer fluid dynamics as compared to similar flows at lower Mach numbers.

Published
2001

35. Detection of drug resistance mutations at low plasma HIV-1 RNA load in a European multicentre cohort study

Author

Prosperi, Mc1, Mackie, N, Di Giambenedetto, S, Zazzi, M, Camacho, R, Fanti, I, Torti, C, Sönnerborg, A, Kaiser, R, Codoñer, Fm, Van Laethem, K, Bansi, L, van de Vijver DA, Geretti, Am, De Luca, A, Giacometti A, SEHERE c. o. n. s. o. r. t. i. u. m., Butini, L, del Gobbo, R, Menzo, S, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Maggiolo, F, Callegaro, A, Calza, L, Carla Re, M, Pristerà, R, Turconi, P, Mandas, A, Tini, S, Zoncada, A, Paolini, E, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Colao, G, Tosti, A, Di Biagio, A, Setti, M, Bruzzone, B, Penco, G, Trezzi, M, Orani, A, Pardelli, R, De Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, d'Arminio Monforte, A, Cicconi, P, Rusconi, S, Gismondo, Mr, Micheli, V, Biondi, Ml, Gianotti, N, Capetti, A, Meraviglia, P, Boeri, E, Mussini, C, Pecorari, M, Soria, A, Vecchi, L, Santirocchi, M, Brustia, D, Ravanini, P, Bello, Fd, Romano, N, Mancuso, S, Calzetti, C, Maserati, R, Filice, G, Baldanti, F, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, R, Vatteroni, L, Vivarelli, A, Dionisio, D, Nerli, A, Lenzi, L, Magnani, G, Ortolani, P, Andreoni, M, Palamara, G, Fimiani, C, Palmisano, L, Fadda, G, Vullo, Vincenzo, Turriziani, O, Montano, M, Cenderello, G, Gonnelli, A, Palumbo, M, Ghisetti, V, Bonora, S, Foglie, Pd, Rossi, C, Grossi, P, Seminari, E, Poletti, F, Mondino, V, Malena, M, Lattuada, E, Lengauer, T, Däumer, M, Hoffmann, D, Schülter, E, Müller, C, Oette, M, Reuter, S, Esser, S, Fätkenheuer, G, Rockstroh, J, Incardona, F, Rosen Zvi, M, Clotet, B, Thalme, A, Svedhem, V, Bratt, G, Gargiulo, F, Lapadula, G, Manca, N, Paraninfo, G, Quiros Roldan, E, Carosi, G, Castelnuovo, F, Vandamme, Am, Van Wijngaerden, E, Ainsworth, J, Anderson, J, Babiker, A, Dunn, D, Easterbrook, P, Fisher, M, Gazzard, B, Garrett, N, Gilson, R, Gompels, M, Hill, T, Johnson, M, Leen, C, Orkin, C, Phillips, A, Pillay, D, Porter, K, Post, F, Sabin, C, Sadiq, T, Schwenk, A, Walsh, J, Delpech, V, Palfreeman, A, Glabay, A, Lynch, J, Hand, J, de Souza, C, Perry, N, Tilbury, S, Churchill, D, Nelson, M, Waxman, M, Mandalia, S, Kall, M, Korat, H, Taylor, C, Ibrahim, F, Campbell, L, James, L, Brima, N, Williams, I, Youle, M, Lampe, F, Smith, C, Grabowska, H, Chaloner, C, Puradiredja, Di, Weber, J, Ramzan, F, Carder, M, Wilson, A, Dooley, D, Asboe, D, Pozniak, A, Cameron, S, Cane, P, Chadwick, D, Clark, D, Collins, S, Lazarus, L, Dolling, D, Fearnhill, E, Castro, H, Coughlin, K, Zuckerman, M, Booth, C, Goldberg, D, Hale, A, Kaye, S, Kellam, P, Leigh Brown, A, Smit, E, Templeton, K, Tilston, P, Tong, W, Zhang, H, Ushiro Lumb, I, Oliver, T, Bibby, D, Mitchell, S, Mbisa, T, Wildfire, A, Tandy, R, Shepherd, J, Maclean, A, Bennett, D, Hopkins, M, Garcia Diaz, A, Kirk, S, Sloot, P. M., Virology, Prosperi, M, Mackie, N, di Giambenedetto, S, Zazzi, M, Camacho, R, Fanti, I, Torti, C, Sönnerborg, A, Kaiser, R, Codoñer, F, van laethem, K, Bansi, L, van de Vijver, D, Geretti, A, de luca, A, and Mancuso, S

Subjects
Male, Drug Resistance, HIV Infections, Drug resistance, Cohort Studies, 0302 clinical medicine, Genotype, HIV Infection, Pharmacology (medical), 030212 general & internal medicine, Viral, 0303 health sciences, Proteolytic enzymes, Genotypic testing, HIV, Viral load, Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Europe, Female, HIV-1, Humans, RNA, Viral, Viral Proteins, Drug Resistance, Viral, Mutation, Missense, Viral Load, Pharmacology, Infectious Diseases, 3. Good health, Cohort, Cohort study, Human, Microbiology (medical), Biology, Settore MED/17 - MALATTIE INFETTIVE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Viral Protein, 030306 microbiology, Anti-HIV Agent, Virology, Reverse transcriptase, Regimen, genotypic testing, viral load, Immunology, Mutation, RNA, Missense, Cohort Studie
Abstract

Background and objectives: Guidelines indicate a plasma HIV-1 RNA load of 500-1000 copies/mL as the minimal threshold for antiretroviral drug resistance testing. Resistance testing at lower viral load levels may be useful to guide timely treatment switches, although data on the clinical utility of this remain limited. We report here the influence of viral load levels on the probability of detecting drug resistance mutations (DRMs) and other mutations by routine genotypic testing in a large multicentre European cohort, with a focus on tests performed at a viral load

Published
2011

39. Experimental Studies of Transitional Boundary Layer Shock Wave Interactions

Author

TEXAS UNIV AT AUSTIN CENTER FOR AEROMECHANICS RESEARCH, Clemens, N. T., Dolling, D. S., Murphree, Z. R., Yueceil, K. B., TEXAS UNIV AT AUSTIN CENTER FOR AEROMECHANICS RESEARCH, Clemens, N. T., Dolling, D. S., Murphree, Z. R., and Yueceil, K. B.

Abstract

Transitional shock wave/boundary layer interactions are studied with planar imaging techniques. The interaction is generated by a cylinder mounted on a flat plate in a Mach 5 flow. Planar laser scattering (PLS) and particle image velocimetry (PIV) are used to visualize the flow structure. Images are obtained in streamwise-spanwise planes (plan view). Earlier work focused on investigating similar interactions with tripped boundary layers, whereas the current work focuses on the case where transition occurs naturally. One goal of this preliminary study was to see if repeatable interactions could be generated. Imaging was conducted for three downstream locations of the cylinder. The PLS imaging revealed that the transitional interactions resulting from an untripped boundary layer are similar to those generated by tripping. In general it is observed that the separated flow region of transitional interactions exhibits larger variations in their scale and shape than fully turbulent interactions. When the cylinder is farthest upstream (5.3 diameters from leading edge) two types of separation shock are seen: an apparently laminar shock along the plate centerline and a turbulent one in the outboard region. As the cylinder is moved downstream (10.7 diameters), this dual structure is not as apparent, which is consistent with the upstream boundary layer becoming more turbulent. Finally, at 16 diameters downstream the interaction exhibits extreme variations in its shape, which we believe to be caused by sidewall interference. The PIV measurements largely confirm these qualitative observations.

Published
2006

40. Exploratory Experimental Study of Transitional Shock Wave Boundary Layer Interactions

Author

TEXAS UNIV AT AUSTIN DEPT OF AEROSPACE ENGINEERING AND ENGINEERING MECHANICS, Dolling, D. S., Clemens, N. C., Hood, E., TEXAS UNIV AT AUSTIN DEPT OF AEROSPACE ENGINEERING AND ENGINEERING MECHANICS, Dolling, D. S., Clemens, N. C., and Hood, E.

Abstract

An exploratory investigation has been made of transitional shock wave boundary layer interactions. In this case, the interaction is induced by a circular cylinder perpendicular to a flat plate. The tests were conducted in the Mach 5 blowdown tunnel of The University of Texas at Austin. The primary goal of this initial, exploratory study was to determine if repeatable transitional interactions could be generated. Measurements included surface flow visualization using the kerosene-lampblack technique and high speed schlieren imaging. Consistent with earlier experiments the current work shows that as the cylinder is shifted upstream on the plate and the interaction start moves into an area where the incoming boundary layer is transitional, rather than turbulent, the separated flow and overall interaction scales increase significantly.

Published
2003

44. Separation shock motion in fin, cylinder, and compression ramp - Induced turbulent interactions

Author

Dolling, D. S and Brusniak, L

Subjects
Aerodynamics
Abstract

In conjunction with new experimental results at Mach 5, an examination has been made of published data on unsteadiness of shock-induced turbulent boundary-layer separation. The data are all wall pressure fluctuation measurements made under the unsteady separation shock and are from interactions induced by compression ramps, blunt and sharp fins, and circular cylinders. There is little evidence of a link between the separation shock zero-crossing frequency and characteristic frequency of the incoming boundary layer. The low shock frequencies and low shock speeds, and the trends with changes in model geometric parameters and incoming boundary layer, suggest that turbulent or global fluctuations at the upstream boundary of the separated flow drive the shock motion.

Published
1989

45. Unsteady shock-induced turbulent separation in Mach 5 cylinder interactions

Author

Dolling, D. S and Smith, D. R

Subjects
Aerodynamics
Abstract

Wall pressure fluctuations have been determined under the unsteady separation shock in interactions generated by unswept circular cylinders, using a nominal freestream Mach number of 5 and a freestream unit Reynolds number of 53 x 10 to the 6th/m. The distributions of shock frequency and period were calculated using a conditional sampling algorithm. The shock frequency distributions were all found to be broadband, with frequencies being typically 1-2 kHz. The results support the previous suggestion that pressure fluctuations in the separated flow drive the shock motion.

Published
1988

46. Driving mechanism of unsteady separation shock motion in hypersonic interactive flow

Author

Dolling, D. S and Narlo, J. C., II

Subjects
Aerodynamics
Abstract

Wall pressure fluctuations were measured under the steady separation shock waves in Mach 5 turbulent interactions induced by unswept circular cylinders on a flat plate. The wall temperature was adiabatic. A conditional sampling algorithm was developed to examine the statistics of the shock wave motion. The same algorithm was used to examine data taken in earlier studies in the Princeton University Mach 3 blowdown tunnel. In these earlier studies, hemicylindrically blunted fins of different leading-edge diameters were tested in boundary layers which developed on the tunnel floor and on a flat plate. A description of the algorithm, the reasons why it was developed and the sensitivity of the results to the threshold settings, are discussed. The results from the algorithm, together with cross correlations and power spectral density estimates suggests that the shock motion is driven by the low-frequency unsteadiness of the downstream separated, vortical flow.

Published
1987

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