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1. Nuclear binding energy and transverse momentum imbalance in neutrino-nucleus reactions

Author

Cai, T., Lu, X. -G., Harewood, L. A., Wret, C., Akbar, F., Andrade, D. A., Ascencio, M. V., Bellantoni, L., Bercellie, A., Betancourt, M., Bodek, A., Bonilla, J. L., Bravar, A., Budd, H., Caceres, G., Carneiro, M. F., Coplowe, D., da Motta, H., Dar, Zubair Ahmad, Díaz, G. A., Felix, J., Fields, L., Filkins, A., Fine, R., Gago, A. M., Gallagher, H., Ghosh, A., Gran, R., Harris, D. A., Henry, S., Jena, S., Jena, D., Kleykamp, J., Kordosky, M., Last, D., Le, T., Lozano, A., Maher, E., Manly, S., Mann, W. A., Mauger, C., McFarland, K. S., Messerly, B., Miller, J., Morfín, J. G., Naples, D., Nelson, J. K., Nguyen, C., Norrick, A., Nuruzzaman, Olivier, A., Paolone, V., Perdue, G. N., Ramírez, M. A., Ransome, R. D., Ruterbories, D., Schellman, H., Salinas, C. J. Solano, Su, H., Sultana, M., Syrotenko, V. S., Valencia, E., Wark, D., Weber, A., Wospakrik, M., Yaeggy, B., and Zazueta, L.

Subjects
High Energy Physics - Experiment
Abstract

We have measured new observables based on the final state kinematic imbalances in the mesonless production of $\nu_\mu+A\rightarrow\mu^-+p+X$ in the $\text{MINER}\nu\text{A}$ tracker. Components of the muon-proton momentum imbalances parallel ($\delta p_\mathrm{Ty}$) and perpendicular($\delta p_\mathrm{Tx}$) to the momentum transfer in the transverse plane are found to be sensitive to the nuclear effects such as Fermi motion, binding energy and non-QE contributions. The QE peak location in $\delta p_\mathrm{Ty}$ is particularly sensitive to the binding energy. Differential cross sections are compared to predictions from different neutrino interaction models. The Fermi gas models presented in this study cannot simultaneously describe features such as QE peak location, width and the non-QE events contributing to the signal process. Correcting the GENIE's binding energy implementation according to theory causes better agreement with data. Hints of proton left-right asymmetry are observed in $\delta p_\mathrm{Tx}$. Better modeling of the binding energy can reduce bias in neutrino energy reconstruction and these observables can be applied in current and future experiments to better constrain nuclear effects., Comment: 14 pages, 12 figures; Added data release file in .root format

Published
2019
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2. Elastic hadron-nucleus scattering in neutrino-nucleus reactions and transverse kinematics measurements

Author

Harewood, L. A. and Gran, R.

Subjects
High Energy Physics - Experiment, High Energy Physics - Phenomenology, Nuclear Theory
Abstract

Rescattering following a neutrino-nucleus reaction changes the number, energy, and direction of detectable hadrons. In turn, this affects the selection and kinematic distributions of subsamples of neutrino events used for interaction or oscillation analysis. This technical note focuses on three forms of two-body rescattering. Elastic hadron+nucleus scattering primarily changes the direction of the hadron with very little energy transfer. Secondly, a hadron+nucleon quasi-elastic process leads to the knockout of a single struck nucleon, possibly with charge exchange between the two hadrons. Also, a pion can be absorbed leading to the ejection of two nucleons. There was an error in the code of the {\small GENIE} neutrino event generator that affects these processes. We present examples of the change with the fixed version of the scattering process, but also compare these specifically to turning off elastic scattering completely, which is similar to other neutrino event generator configurations or a potential Equick-fix to already generated samples. Three examples are taken from current topics of interest: transverse kinematics observables in quasielastic neutrino reactions, the pion angle with respect to the incoming and outgoing lepton for $\Delta$ reactions with a charged pion in the final state, and the angle between two protons in reactions with no pions present. Elastic hadron+nucleus scattering in its unfixed form makes a large distortion in distributions of transverse kinematic imbalances scattering, but only mild distortion in other observables. The distortion of the other two processes is also mild for all distributions considered. The correct form of hadron+nucleus scattering process could play a role in describing the width and center of the sharp peak in the inferred Fermi-motion of the struck nucleon or be benchmarked using (e,e'p) data.

Published
2019

4. The CONFIRM trial protocol: the utility of prostate-specific membrane antigen positron emission tomography/computed tomography in active surveillance for prostate cancer

Author

Bagguley, D, Harewood, L, McKenzie, D, Ptasznik, G, Ong, S, Chengodu, T, Woon, D, Sim, K, Sheldon, J, Lawrentschuk, N, Bagguley, D, Harewood, L, McKenzie, D, Ptasznik, G, Ong, S, Chengodu, T, Woon, D, Sim, K, Sheldon, J, and Lawrentschuk, N

Abstract

OBJECTIVES: Primary objectives: To determine the additive value of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the risk stratification of men with newly diagnosed prostate cancer (PCa) who would have otherwise been deemed suitable for active surveillance (AS). Specifically, we aim to determine if PSMA PET/CT can detect a cohort of men on AS that are in fact high risk and likely to experience unfavourable outcomes should they remain on their current treatment pathway. SECONDARY OBJECTIVES: to determine the additive value of PSMA PET/CT to repeat multiparametric magnetic resonance imaging (mpMRI) of the prostate and explore whether a confirmatory biopsy may be avoided in men with a negative PSMA PET/CT and a negative repeat mpMRI of the prostate (Prostate Imaging-Reporting and Data System score of <3). Furthermore, to develop a nomogram combining clinical, imaging and biomarker data to predict the likelihood of failure on AS in men with high-risk features. Also, a blood sample will be taken to perform a Prostate Health Index test at the time of confirmatory biopsy. Furthermore, a portion of this blood will be stored at a biobank for up to 5 years if a follow-up study on molecular biomarkers and genetic assays in this cohort of men is indicated, based on the results from the CONFIRM trial. PATIENTS AND METHODS: The CONFIRM trial is a prospective, multicentre, pre-test/post-test, cohort study across Victoria, Australia, involving men with newly diagnosed low-risk PCa with high-risk features, considered suitable for AS and undergoing confirmatory biopsy. The trial's goal is to provide high-quality evidence to establish whether PSMA PET/CT has a role in risk-stratifying men deemed suitable for AS despite having high-risk feature(s). RESULTS: The CONFIRM trial will measure the proportion of men deemed unsuitable for ongoing AS based on pathological upgrading and multidisciplinary team recommendation due to PSMA PET

Published
2024

7. The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Author

Risbridger G.P., Clark A.K., Porter L.H., Toivanen R., Bakshi A., Lister N.L., Pook D., Pezaro C.J., Sandhu S., Keerthikumar S., Quezada Urban R., Papargiris M., Kraska J., Madsen H.B., Wang H., Richards M.G., Niranjan B., O'Dea S., Teng L., Wheelahan W., Li Z., Choo N., Ouyang J.F., Thorne H., Devereux L., Hicks R.J., Sengupta S., Harewood L., Iddawala M., Azad A.A., Goad J., Grummet J., Kourambas J., Kwan E.M., Moon D., Murphy D.G., Pedersen J., Clouston D., Norden S., Ryan A., Furic L., Goode D.L., Frydenberg M., Lawrence M.G., Taylor R.A., Risbridger G.P., Clark A.K., Porter L.H., Toivanen R., Bakshi A., Lister N.L., Pook D., Pezaro C.J., Sandhu S., Keerthikumar S., Quezada Urban R., Papargiris M., Kraska J., Madsen H.B., Wang H., Richards M.G., Niranjan B., O'Dea S., Teng L., Wheelahan W., Li Z., Choo N., Ouyang J.F., Thorne H., Devereux L., Hicks R.J., Sengupta S., Harewood L., Iddawala M., Azad A.A., Goad J., Grummet J., Kourambas J., Kwan E.M., Moon D., Murphy D.G., Pedersen J., Clouston D., Norden S., Ryan A., Furic L., Goode D.L., Frydenberg M., Lawrence M.G., and Taylor R.A.

Abstract

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naive primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.Copyright © 2021, The Author(s).

Published
2021

8. The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology

Author

Risbridger, GP, Clark, AK, Porter, LH, Toivanen, R, Bakshi, A, Lister, NL, Pook, D, Pezaro, CJ, Sandhu, S, Keerthikumar, S, Urban, RQ, Papargiris, M, Kraska, J, Madsen, HB, Wang, H, Richards, MG, Niranjan, B, O'Dea, S, Teng, L, Wheelahan, W, Li, Z, Choo, N, Ouyang, JF, Thorne, H, Devereux, L, Hicks, RJ, Sengupta, S, Harewood, L, Iddawala, M, Azad, AA, Goad, J, Grummet, J, Kourambas, J, Kwan, EM, Moon, D, Murphy, DG, Pedersen, J, Clouston, D, Norden, S, Ryan, A, Furic, L, Goode, DL, Frydenberg, M, Lawrence, MG, Taylor, RA, Risbridger, GP, Clark, AK, Porter, LH, Toivanen, R, Bakshi, A, Lister, NL, Pook, D, Pezaro, CJ, Sandhu, S, Keerthikumar, S, Urban, RQ, Papargiris, M, Kraska, J, Madsen, HB, Wang, H, Richards, MG, Niranjan, B, O'Dea, S, Teng, L, Wheelahan, W, Li, Z, Choo, N, Ouyang, JF, Thorne, H, Devereux, L, Hicks, RJ, Sengupta, S, Harewood, L, Iddawala, M, Azad, AA, Goad, J, Grummet, J, Kourambas, J, Kwan, EM, Moon, D, Murphy, DG, Pedersen, J, Clouston, D, Norden, S, Ryan, A, Furic, L, Goode, DL, Frydenberg, M, Lawrence, MG, and Taylor, RA

Abstract

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.

Published
2021

9. FISH mapping of de novo apparently balanced chromosome rearrangements identifies characteristics associated with phenotypic abnormality

Author

Fantes, J.A., Boland, E., Ramsay, J., Donnai, D., Splitt, M., Goodship, J.A., Stewart, H., Whiteford, M., Gautier, P., Harewood, L., Holloway, S., Sharkey, F., Maher, E., van Heyningen, V., Clayton-Smith, J., Fitzpatrick, D.R., and Black, G.C.M.

Subjects
Chromosome abnormalities -- Research, Chromosome mapping -- Analysis, Fluorescence -- Usage, Human genome -- Research, Biological sciences
Abstract

The study employs the fluorescence in situ hybridization (FISH) mapping technique to analyze the de novo, apparently the balanced chromosome rearrangements (ABCR) for determining the various characteristics that leads to phenotypic abnormality in humans.

Published
2008

10. Nucleon binding energy and transverse momentum imbalance in neutrino-nucleus reactions

Author

Cai, T., Lu, X. -G., Harewood, L. A., Wret, C., Akbar, F., Andrade, D. A., Ascencio, M. V., Bellantoni, L., Bercellie, A., Betancourt, M., Bodek, A., Bonilla, J. L., Bravar, A., Budd, H., Caceres, G., Carneiro, M. F., Coplowe, D., da Motta, H., Dar, Zubair Ahmad, D��az, G. A., Felix, J., Fields, L., Filkins, A., Fine, R., Gago, A. M., Gallagher, H., Ghosh, A., Gran, R., Harris, D. A., Henry, S., Jena, S., Jena, D., Kleykamp, J., Kordosky, M., Last, D., Le, T., Lozano, A., Maher, E., Manly, S., Mann, W. A., Mauger, C., McFarland, K. S., Messerly, B., Miller, J., Morf��n, J. G., Naples, D., Nelson, J. K., Nguyen, C., Norrick, A., Nuruzzaman, Olivier, A., Paolone, V., Perdue, G. N., Ram��rez, M. A., Ransome, R. D., Ruterbories, D., Schellman, H., Salinas, C. J. Solano, Su, H., Sultana, M., Syrotenko, V. S., Valencia, E., Wark, D., Weber, A., Wospakrik, M., Yaeggy, B., and Zazueta, L.

Subjects
Physics, Proton, 010308 nuclear & particles physics, Binding energy, Momentum transfer, FOS: Physical sciences, Computer Science::Digital Libraries, 01 natural sciences, High Energy Physics - Experiment, 3. Good health, Momentum, Nuclear physics, High Energy Physics - Experiment (hep-ex), 0103 physical sciences, Neutrino, 010306 general physics, Nucleon, Fermi gas, Energy (signal processing)
Abstract

We have measured new observables based on the final state kinematic imbalances in the mesonless production of $\nu_\mu+A\rightarrow\mu^-+p+X$ in the $\text{MINER}\nu\text{A}$ tracker. Components of the muon-proton momentum imbalances parallel ($\delta p_\mathrm{Ty}$) and perpendicular($\delta p_\mathrm{Tx}$) to the momentum transfer in the transverse plane are found to be sensitive to the nuclear effects such as Fermi motion, binding energy and non-QE contributions. The QE peak location in $\delta p_\mathrm{Ty}$ is particularly sensitive to the binding energy. Differential cross sections are compared to predictions from different neutrino interaction models. The Fermi gas models presented in this study cannot simultaneously describe features such as QE peak location, width and the non-QE events contributing to the signal process. Correcting the GENIE's binding energy implementation according to theory causes better agreement with data. Hints of proton left-right asymmetry are observed in $\delta p_\mathrm{Tx}$. Better modeling of the binding energy can reduce bias in neutrino energy reconstruction and these observables can be applied in current and future experiments to better constrain nuclear effects., Comment: 14 pages, 12 figures; Added data release file in .root format

Published
2020

11. Use of prostate-specific membrane antigen positron-emission tomography/CT in response assessment following upfront chemohormonal therapy in metastatic prostate cancer

Author

Anton, A, Kamel Hasan, O, Ballok, Z, Bowden, P, Costello, AJ, Harewood, L, Corcoran, NM, Dundee, P, Peters, JS, Lawrentschuk, N, Troy, A, Webb, D, Chan, Y, See, A, Siva, S, Murphy, D, Hofman, MS, Tran, B, Anton, A, Kamel Hasan, O, Ballok, Z, Bowden, P, Costello, AJ, Harewood, L, Corcoran, NM, Dundee, P, Peters, JS, Lawrentschuk, N, Troy, A, Webb, D, Chan, Y, See, A, Siva, S, Murphy, D, Hofman, MS, and Tran, B

Published
2020

24. Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy.

Author

Pook D., Huglo A., Yang R., Henzler C., Li Y., Lopez-Campos F., Castro E., Toivanen R., Azad A., Bolton D., Goad J., Grummet J., Harewood L., Kourambas J., Lawrentschuk N., Moon D., Murphy D.G., Sengupta S., Snow R., Thorne H., Mitchell C., Pedersen J., Clouston D., Norden S., Ryan A., Dehm S.M., Tilley W.D., Pearson R.B., Hannan R.D., Frydenberg M., Furic L., Taylor R.A., Risbridger G.P., Porter L.H., Lister N., Hedwards S., Pezaro C.J., Goode D.L., Rebello R.J., Clark A.K., Van Gramberg J., Hanson A.R., Banks P., Wang H., Niranjan B., Keerthikumar S., Papargiris M., Lawrence M.G., Obinata D., Sandhu S., Selth L.A., Wong S.Q., Pook D., Huglo A., Yang R., Henzler C., Li Y., Lopez-Campos F., Castro E., Toivanen R., Azad A., Bolton D., Goad J., Grummet J., Harewood L., Kourambas J., Lawrentschuk N., Moon D., Murphy D.G., Sengupta S., Snow R., Thorne H., Mitchell C., Pedersen J., Clouston D., Norden S., Ryan A., Dehm S.M., Tilley W.D., Pearson R.B., Hannan R.D., Frydenberg M., Furic L., Taylor R.A., Risbridger G.P., Porter L.H., Lister N., Hedwards S., Pezaro C.J., Goode D.L., Rebello R.J., Clark A.K., Van Gramberg J., Hanson A.R., Banks P., Wang H., Niranjan B., Keerthikumar S., Papargiris M., Lawrence M.G., Obinata D., Sandhu S., Selth L.A., and Wong S.Q.

Abstract

Background: The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC. Objective(s): To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC. Design, setting, and participants: Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system. Intervention(s): The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258). Outcome measurements and statistical analysis: Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments. Results and limitations: Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258. Conclusion(s): This study demonstrates that ribosome-targeting drugs may be effective again

Published
2018

25. Using PSMA PET/CT to assess response in metastatic prostate cancer (mPC) patients (pts) receiving upfront chemohormonal therapy

Author

Anton, A., primary, Ballok, Z., additional, Bowden, P., additional, Costello, T., additional, Harewood, L., additional, Corcoran, N., additional, Dundee, P., additional, Peters, J., additional, Lawrentschuk, N., additional, Troy, A., additional, Webb, D., additional, Chan, Y., additional, See, A., additional, Siva, S., additional, Murphy, D., additional, Hofman, M.S., additional, and Tran, B., additional

Published
2018
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27. Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome

Author

Ansari, M, Rainger, J, Hanson, IM, Williamson, KA, Sharkey, F, Harewood, L, Sandilands, A, Clayton-Smith, J, Dollfus, H, Bitoun, P, Meire, F, Fantes, J, Franco, B, Lorenz, B, Taylor, DS, Stewart, F, Willoughby, CE, McEntagart, M, Khaw, PT, and Clericuzio, C

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Medizin, sense organs, eye diseases
Abstract

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.

Published
2016

29. A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology

Author

Migliavacca, E., Golzio, C., Mannik, K., Blumenthal, I., Oh, E.C., Harewood, L., Kosmicki, J.A., Loviglio, M.N., Giannuzzi, G., Hippolyte, L., Maillard, A.M., Alfaiz, A.A., Haelst, M.M. van, Andrieux, J., Gusella, J.F., Daly, M.J., Beckmann, J.S., Jacquemont, S., Talkowski, M.E., Katsanis, N., Reymond, A., Vulto-van Silfhout, A.T., Vries, B. de, Binsbergen, E. van, et al., Migliavacca, E., Golzio, C., Mannik, K., Blumenthal, I., Oh, E.C., Harewood, L., Kosmicki, J.A., Loviglio, M.N., Giannuzzi, G., Hippolyte, L., Maillard, A.M., Alfaiz, A.A., Haelst, M.M. van, Andrieux, J., Gusella, J.F., Daly, M.J., Beckmann, J.S., Jacquemont, S., Talkowski, M.E., Katsanis, N., Reymond, A., Vulto-van Silfhout, A.T., Vries, B. de, Binsbergen, E. van, and et al.

Abstract

Item does not contain fulltext, The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

Published
2015

35. A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects.

Author

Zajac J.D., Mameghan H., Martyres R.F., Farish S.J., Yue C., Deam D.R., Byron K.A., Beilin J., Harewood L., Frydenberg M., Zajac J.D., Mameghan H., Martyres R.F., Farish S.J., Yue C., Deam D.R., Byron K.A., Beilin J., Harewood L., and Frydenberg M.

Abstract

The development of prostate carcinoma is androgen-dependent. The coding sequence of the androgen receptor (AR) gene contains a CAG repeat polymorphism that has been shown to influence AR activity in vitro. Studies of this polymorphism as a prostate carcinoma risk factor have been conflicting. METHODS. A matched case-control design was used in a clinic-based multicenter study of Australian prostate carcinoma subjects. Cancer subjects were matched by age and locality with controls, all of whom had a serum prostate specific antigen (PSA) level of less than 4 mg/L. Conditional logistic regression was used to determine the relative risk of prostate carcinoma dependent on AR gene CAG number. The association of disease characteristics at diagnosis with the polymorphism also was assessed. RESULTS. Five hundred forty-five cases of prostate carcinoma and 456 matched case-control pairs were recruited. Association studies of disease characteristics at diagnosis showed age at diagnosis to be associated with AR CAG number by univariate (P = 0.004) and multivariate (adjusting for PSA, stage, and grade) linear regression (P = 0.018). No association was observed between the polymorphism and disease stage (TNM-based categories; P = 0.277), histologic grade (P = 0.41), or PSA level at diagnosis (P = 0.48). In the pairwise case-control analysis, the odds ratio of prostate carcinoma for a change of 5 CAG repeats gave an odds ratio of 0.9821 (95% confidence interval, 0.84-1.15). CONCLUSIONS. In this Australian study population, the AR CAG repeat polymorphism was not a risk factor for prostate carcinoma, but a shorter repeat sequence was associated with earlier age at diagnosis. © 2001 American Cancer Society.

Published
2012

36. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Zufferey, F, Sherr, EH, Beckmann, ND, Hanson, E, Maillard, AM, Hippolyte, L, Mace, A, Ferrari, C, Kutalik, Z, Andrieux, J, Aylward, E, Barker, M, Bernier, R, Bouquillon, S, Conus, P, Delobel, B, Faucett, W, Goin-Kochel, RP, Grant, E, Harewood, L, Hunter, JV, Lebon, S, Ledbetter, DH, Martin, CL, Maennik, K, Martinet, D, Mukherjee, P, Ramocki, MB, Spence, SJ, Steinman, KJ, Tjernagel, J, Spiro, JE, Reymond, A, Beckmann, JS, Chung, WK, Jacquemont, S, Zufferey, F, Sherr, EH, Beckmann, ND, Hanson, E, Maillard, AM, Hippolyte, L, Mace, A, Ferrari, C, Kutalik, Z, Andrieux, J, Aylward, E, Barker, M, Bernier, R, Bouquillon, S, Conus, P, Delobel, B, Faucett, W, Goin-Kochel, RP, Grant, E, Harewood, L, Hunter, JV, Lebon, S, Ledbetter, DH, Martin, CL, Maennik, K, Martinet, D, Mukherjee, P, Ramocki, MB, Spence, SJ, Steinman, KJ, Tjernagel, J, Spiro, JE, Reymond, A, Beckmann, JS, Chung, WK, and Jacquemont, S

Abstract

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

37. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Jacquemont, S., Reymond, A., Zufferey, F., Harewood, L., Walters, R.G., Kutalik, Z., Martinet, D., Shen, Y., Valsesia, A., Beckmann, N.D., Thorleifsson, G., Belfiore, M., Bouquillon, S., Campion, D., Leeuw, N. de, Vries, L.B.A. de, Esko, T., Fernandez, B.A., Fernandez-Aranda, F., Fernandez-Real, J.M., Gratacos, M., Guilmatre, A., Hoyer, J., Jarvelin, M.R., Kooy, R.F., Kurg, A., Caignec, C. Le, Mannik, K., Platt, O.S., Sanlaville, D., Haelst, M.M. van, Villatoro Gomez, S., Walha, F., Wu, B.L., Yu, Y., Aboura, A., Addor, M.C., Alembik, Y., Antonarakis, S.E., Arveiler, B., Barth, M., Bednarek, N., Bena, F., Bergmann, S., Beri, M., Bernardini, L., Blaumeiser, B., Bonneau, D., Bottani, A., Boute, O., Brunner, H.G., Cailley, D., Callier, P., Chiesa, J., Chrast, J., Coin, L., Coutton, C., Cuisset, J.M., Cuvellier, J.C., David, A., Freminville, B. de, Delobel, B., Delrue, M.A., Demeer, B., Descamps, D., Didelot, G., Dieterich, K., Disciglio, V., Doco-Fenzy, M., Drunat, S., Duban-Bedu, B., Dubourg, C., El-Sayed Moustafa, J.S., Elliott, P., Faas, B.H.W., Faivre, L., Faudet, A., Fellmann, F., Ferrarini, A., Fisher, R., Flori, E., Forer, L., Gaillard, D., Gerard, M., Gieger, C., Gimelli, S., Gimelli, G., Grabe, H.J., Guichet, A., Guillin, O., Hartikainen, A.L., Heron, D., Hippolyte, L., Holder, M., Homuth, G., Isidor, B., Jaillard, S., Jaros, Z., Jimenez-Murcia, S., Helas, G.J., et al., Jacquemont, S., Reymond, A., Zufferey, F., Harewood, L., Walters, R.G., Kutalik, Z., Martinet, D., Shen, Y., Valsesia, A., Beckmann, N.D., Thorleifsson, G., Belfiore, M., Bouquillon, S., Campion, D., Leeuw, N. de, Vries, L.B.A. de, Esko, T., Fernandez, B.A., Fernandez-Aranda, F., Fernandez-Real, J.M., Gratacos, M., Guilmatre, A., Hoyer, J., Jarvelin, M.R., Kooy, R.F., Kurg, A., Caignec, C. Le, Mannik, K., Platt, O.S., Sanlaville, D., Haelst, M.M. van, Villatoro Gomez, S., Walha, F., Wu, B.L., Yu, Y., Aboura, A., Addor, M.C., Alembik, Y., Antonarakis, S.E., Arveiler, B., Barth, M., Bednarek, N., Bena, F., Bergmann, S., Beri, M., Bernardini, L., Blaumeiser, B., Bonneau, D., Bottani, A., Boute, O., Brunner, H.G., Cailley, D., Callier, P., Chiesa, J., Chrast, J., Coin, L., Coutton, C., Cuisset, J.M., Cuvellier, J.C., David, A., Freminville, B. de, Delobel, B., Delrue, M.A., Demeer, B., Descamps, D., Didelot, G., Dieterich, K., Disciglio, V., Doco-Fenzy, M., Drunat, S., Duban-Bedu, B., Dubourg, C., El-Sayed Moustafa, J.S., Elliott, P., Faas, B.H.W., Faivre, L., Faudet, A., Fellmann, F., Ferrarini, A., Fisher, R., Flori, E., Forer, L., Gaillard, D., Gerard, M., Gieger, C., Gimelli, S., Gimelli, G., Grabe, H.J., Guichet, A., Guillin, O., Hartikainen, A.L., Heron, D., Hippolyte, L., Holder, M., Homuth, G., Isidor, B., Jaillard, S., Jaros, Z., Jimenez-Murcia, S., Helas, G.J., and et al.

Abstract

Contains fulltext : 96105.pdf (publisher's version ) (Closed access), Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI)

Published
2011

38. Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla

Author

Berry, R., primary, Harewood, L., additional, Pei, L., additional, Fisher, M., additional, Brownstein, D., additional, Ross, A., additional, Alaynick, W. A., additional, Moss, J., additional, Hastie, N. D., additional, Hohenstein, P., additional, Davies, J. A., additional, Evans, R. M., additional, and FitzPatrick, D. R., additional

Published
2010
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46. Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis

Author

^@?, J.E., ^@?, D.E.C., ^#, L.A., Cauch-Dudek^*, K., Harewood^*, L., Evrovski^@?, J., Peltekova^@?, V.D., and ^@?, E.

Abstract

Background & Aims: Hepatic osteodystrophy is a complication of primary biliary cirrhosis (PBC). Allelic polymorphisms of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD) in normal cohorts and those with primary osteoporosis. We sought to establish the prevalence of reduced bone mass in PBC, correlate BMD with VDR gene polymorphisms, and identify risk factors for the development of hepatic osteodystrophy. Methods: Seventy-two female patients with PBC were evaluated prospectively. Clinical information, BMD assessment, disease severity, and osteoporosis risk factors were documented, and multivariate regression modeling was performed. Results: Twenty-four percent of the patients were osteoporotic at the lumbar spine and 32% at the femur. Severe bone loss (z score <-2.0) occurs 4 times more frequently in patients with PBC compared with controls. Body weight (P = 0.003) and postmenopausal status (P = 0.012) correlated independently with BMD. VDR genotype (P = 0.01) correlated with lower BMD at the spine only. Conclusions: Osteoporosis is a common complication of PBC. VDR genotype predicts lower BMD in patients with PBC. Studies are warranted to investigate the mechanism(s) by which VDR as well as other candidate genes may contribute to the development of hepatic osteodystrophy in PBC. GASTROENTEROLOGY 2000;118:145-151

Published
2000
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48. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011

49. Topographic analysis of pancreatic cancer by TMA and digital spatial profiling reveals biological complexity with potential therapeutic implications.

Author

Bingham V, Harewood L, McQuaid S, Craig SG, Revolta JF, Kim CS, Srivastava S, Quezada-Marín J, Humphries MP, and Salto-Tellez M

Subjects
Humans, High-Throughput Nucleotide Sequencing, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Retrospective Studies, Transcriptome, Male, Female, Middle Aged, Aged, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Tissue Array Analysis
Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-β axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer., (© 2024. The Author(s).)

Published
2024
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50. The CONFIRM trial protocol: the utility of prostate-specific membrane antigen positron emission tomography/computed tomography in active surveillance for prostate cancer.

Author

Bagguley D, Harewood L, McKenzie D, Ptasznik G, Ong S, Chengodu T, Woon D, Sim K, Sheldon J, and Lawrentschuk N

Subjects
Humans, Male, Cohort Studies, Follow-Up Studies, Prospective Studies, Prostate pathology, Victoria, Watchful Waiting, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms therapy, Prostatic Neoplasms pathology
Abstract

Objectives: Primary objectives: To determine the additive value of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the risk stratification of men with newly diagnosed prostate cancer (PCa) who would have otherwise been deemed suitable for active surveillance (AS). Specifically, we aim to determine if PSMA PET/CT can detect a cohort of men on AS that are in fact high risk and likely to experience unfavourable outcomes should they remain on their current treatment pathway., Secondary Objectives: to determine the additive value of PSMA PET/CT to repeat multiparametric magnetic resonance imaging (mpMRI) of the prostate and explore whether a confirmatory biopsy may be avoided in men with a negative PSMA PET/CT and a negative repeat mpMRI of the prostate (Prostate Imaging-Reporting and Data System score of <3). Furthermore, to develop a nomogram combining clinical, imaging and biomarker data to predict the likelihood of failure on AS in men with high-risk features. Also, a blood sample will be taken to perform a Prostate Health Index test at the time of confirmatory biopsy. Furthermore, a portion of this blood will be stored at a biobank for up to 5 years if a follow-up study on molecular biomarkers and genetic assays in this cohort of men is indicated, based on the results from the CONFIRM trial., Patients and Methods: The CONFIRM trial is a prospective, multicentre, pre-test/post-test, cohort study across Victoria, Australia, involving men with newly diagnosed low-risk PCa with high-risk features, considered suitable for AS and undergoing confirmatory biopsy. The trial's goal is to provide high-quality evidence to establish whether PSMA PET/CT has a role in risk-stratifying men deemed suitable for AS despite having high-risk feature(s)., Results: The CONFIRM trial will measure the proportion of men deemed unsuitable for ongoing AS based on pathological upgrading and multidisciplinary team recommendation due to PSMA PET/CT scan and PSMA-targeted confirmatory biopsy. Additionally, the positive and negative predictive values, sensitivity, and specificity of PSMA PET/CT will be calculated in isolation and combined with repeat mpMRI of the prostate., Conclusions: This trial will provide robust prospective data to determine if PSMA-PET/CT and standard of care (prostate biopsy ± repeat mpMRI) can improve diagnostic certainty in men undergoing confirmatory biopsy for low-grade PCa with high-risk features., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Published
2024
Full Text
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