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Beta-adrenoceptor drugs and progression to Parkinson’s disease milestones in a large pooled incident cohort

Publication: NPJ Parkinson’s Disease

Ruwani S. Wijeyekoon, Marta Camacho, David Bäckström, Lars Forsgren, Rachael A. Lawson, Alison J. Yarnall, Angus D. Macleod, Carl E. Counsell, Ole-Bjørn Tysnes, Guido Alves, Jodi Maple-Grødem, Roger A. Barker & Caroline H. Williams-Gray

03 July 2025

Abstract

Beta-adrenoceptor-blockers and agonists have been associated with an increased and decreased risk of Parkinson’s disease (PD), respectively. We aimed to investigate whether these medications are linked to a difference in how patients with PD responded and how their PD progressed.

Data were collected from participants of the the Parkinson’s Incident Cohorts Collaboration (n = 1107) over a period of time and analysed.

Baseline clinical status and progression to Hoehn & Yahr stage 3 (H&Y3) or dementia were compared in beta-blocker or beta-agonist users versus non-users of each drug. Baseline motor and cognitive variables were similar in beta-blocker users (n = 195) versus non-users and beta-agonist users (n = 68) versus non-users, following adjustment for relevant confounders.

Beta-blocker users (n = 156) progressed faster to H&Y3 (p = 0.002), accounting for relevant confounders (Hazard Ratio (HR) = 1.538; p = 0.011), while beta-agonist users (n = 54) progressed similarly to non-users. Neither drug was associated with progression to dementia.

These findings support the possibility that beta-adrenoceptor drugs may have potential to change PD progression.

Further investigation is essential to identify any causative component in the relationship.

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Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer



Publication:Clinical Cancer Research

Harveer Dev, Mark Linch, Krishna Narahari, Toby Milne-Clark, Melissa Cheung, Anne Warren, Alopa Malaviya, Vincent Gnanapragasam, Tatiana Hernandez, Nicholas Bullock, Andrea Machin, Alimu Dayimu, Tamsin Robb, Elizabeth Cromwell, Alex Freeman, Elizabeth A. Harrington, Niedzika Camacho, Silvia Glont, Massimo Squatrito, Asaf Rotem, Luiza Moore, Robert Hanson, Marc Dodd, Shubha Anand, Howard Kynaston, Greg Shaw, Nimish Shah, Simon Pacey

13 June 2025

Purpose:
The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways.
Patients and Methods:

The primary objective was to measure PARP inhibition, and the secondary objectives were to assess safety and feasibility. Participants received olaparib for 2 weeks before prostatectomy and were randomly assigned or not assigned (1:1) to degarelix. We analyzed diagnostic biopsy and radical prostatectomy samples for PARylated protein expression using IHC. Exploratory analyses included tumor gene sequencing, mutation analysis, and RNA sequencing (RNA-seq) using both bulk and single-cell RNA-seq performed on pretreatment and posttreatment tissues.

Results:

PARylated protein expression was significantly reduced in both cohorts, with no drug-related delays in radical prostatectomy. The gene set enrichment analysis identified distinct treatment response signatures related to olaparib in both cohorts and showed downregulation of androgen response genes after olaparib + degarelix treatment.

Transcript profiling revealed an upregulation of the p53 hallmark, which was more pronounced with the combination treatment. Canonical cell-cycle progression hallmarks, including E2Ftargets and the G2–M checkpoint, were suppressed across all cases, correlating with a HR-deficient transcriptional signature. Single-nuclear RNA-seq indicated a greater increase in inflammatory response pathway activity within tumor epithelia after combination treatment.

Conclusions:

Transcriptomic analysis identified common hallmark alterations reflecting the combined impact of PARP inhibitor and androgen blockade on cell-cycle progression. We observed a shared phenotypic response to combination therapy across prostate cancers without known HR repair gene alterations. This suggests alternative mechanisms rather than antiandrogen-induced HR deficiency.

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Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial

Publication: Nature Communications

Jean E. Abraham, Lenka Oplustil O’Connor, Louise Grybowicz, Karen Pinilla Alba, Alimu Dayimu, Nikolaos Demiris, Caron Harvey, Lynsey M. Drewett, Rebecca Lucey, Alexander Fulton, Anne N. Roberts, Joanna R. Worley, Ms Anita Chhabra, Wendi Qian, Jessica Brown, Richard Hardy, Anne-Laure Vallier, Steve Chan, Maria Esther Una Cidon, Elizabeth Sherwin, Amitabha Chakrabarti, Claire Sadler, Jen Barnes, Mojca Persic, Sarah Smith, Sanjay Raj, Annabel Borley, Jeremy P. Braybrooke, Emma Staples, Lucy C. Scott, Cheryl A. Palmer, Margaret Moody, Mark J. Churn, Domenic Pilger, Guido Zagnoli-Vieira, Paul W. G. Wijnhoven, Mukesh B. Mukesh, Rebecca R. Roylance, Philip C. Schouten, Nicola C. Levitt, Karen McAdam, Anne C. Armstrong, Ellen R. Copson, Emma McMurtry, Susan Galbraith, Marc Tischkowitz, Elena Provenzano, Mark J. O’Connor, Helena M. Earl, PARTNER Trial Group

13 May 2025

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity, but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone.

The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20).

The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.

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Early childhood height, weight, and BMI development in children with monogenic obesity: a European multicentre, retrospective, observational study

Publication: The Lancet –  Child & Adolescent Health

Stefanie Zorn, Cornelis Jan de Groot, Stephanie Brandt-Heunemann, Julia von Schnurbein, Ozair Abawi, Rebecca Bounds, Lisa Ruck, Blanca Guijo, Gabriel Á Martos-Moreno,  Clarisse Nicaise, Sophie Courbage, Margit Klehr-Martinelli, Prof Reiner Siebert, Prof Béatrice Dubern, Prof Christine Poitou, Prof Karine Clément, Prof Jesús Argente, Prof Peter Kühnen, Prof Ismaa Sadaf Farooqi, Prof Martin Wabitsch,  Prof Erica van den Akker

17 April 2025

Monogenic defects in the leptin-melanocortin pathway are associated with hyperphagia and severe, early-onset obesity. Early childhood growth patterns in height, weight, and BMI, might serve as phenotypic markers for specific genetic disorders; however, reliable data are scarce. This study aimed to evaluate the natural history of height, weight, and BMI in early childhood in a large European group of individuals with monogenic obesity.

This study identified characteristic early childhood BMI trajectories for different forms of monogenic obesity. From age 6 months onwards, individuals with biallelic variants can be distinguished from those with monoallelic variants and common obesity. A BMI ≥24 kg/m2 at age 2 years had good diagnostic performance for biallelic variants, informing future recommendations for genetic screening for monogenic obesity.

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A redefined indel taxonomy reveals insights into mutational signatures

Publication: Nature Genetics

Gene Ching Chiek Koh, Arjun Scott Nanda, Giuseppe Rinaldi, Soraya Boushaki, Andrea Degasperi, Cherif Badja, Andrew Marcel Pregnall, Salome Jingchen Zhao, Lucia Chmelova, Daniella Black, Laura Heskin, João Dias, Jamie Young, Yasin Memari, Scott Shooter, Jan Czarnecki, Matthew Arthur Brown, Helen Ruth Davies, Xueqing Zou & Serena Nik-Zainal

10 April 2025

In cancer genetics, small insertions and deletions (called InDels) have not been as widely researched as substitutions (both causes of cancer). Researchers created identical ‘CRISPR-edited’ human cell models of ones which were damaged and then replicated (damaged included mismatched repairs and replicative enzymes). The trail that led to these mutations were uncovered and current research was unable to show the cancerous mutations apart from more general mutations.

To address this, a technique called InDel was developed that was able to pick up unusual genetic sequences and very long long genetic sequences that meant they could be classified into 89 subtypes. By using the information collected in the 100K Genomes Project, 37 InDel sequences were found, 27 of these were new. In addition to this new finding, a new mechanism called PRRDetect was developed which allowed tumours to be ‘classified’ possibly having implications for immunotherapy, a way of treating cancerous tumours.

 

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Inherited predisposition to pneumothorax: Estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts

Publication: Thorax

Bryndis Yngvadottir, Lucy Richman, Avgi Andreou, Jessica Woodley, Anita Luharia, Derek Lim, Eamonn R Maher, Stefan J Marciniak

10 April 2025

A condition called Birt-Hogg-Dubé syndrome (BHDS) is the most common single genetic cause of pneumothorax (a collection of air in the pleural space between the lung and the chest wall). Families that are affected have disease causing changes in the FLCN gene. Marciniak et al used large genomic registries (UK Biobank, 100K Genomes Project and East London Genes & Health) to look at the health data of >550,000 individuals and discovered that the frequency of clinically proven loss-of-function FLCN variants is 1 in 2710 to 4190 people. The lifetime risk of pneumothorax in FLCN mutation carriers in the UKB cohort was (28.4%) and BHDS cohort (37.3%) up to the age of 65 years. The lifetime risk of renal cancer was much lower in the UKB group  (1%) than the BHDS patients (32.1%). The findings show the importance of clinical context in managing people with FLCN mutations.

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Machine Learning Achieves Pathologist-Level Celiac Disease Diagnosis

Publication New England Journal of Medicine

Florian Jaeckle, James Denholm, Benjamin Schreiber, Shelley C. Evans, Mike N. Wicks, James Y. H. Chan, Adrian C. Bateman, Sonali Natu, Mark J. Arends, Elizabeth Soilleux

27 March 2025

Diagnosing coeliac disease (CD), an autoimmune disorder that has an estimated global prevalence of around 1%, mainly relies on examination of biopsies of the duodenum under a microscope – called histologic examination. However when pathologists look at the same sample, only 80% of the time do they agree on a CD diagnosis. Jaeckle et al aimed to improve the CD diagnosis by developing an accurate, machine-learning-based diagnostic classifier. Initial results revealed that the model was able to diagnose samples with an accuracy, sensitivity and specificity exceeding 95%. It was concluded that the tool may be able to assist  pathologists in making a CD diagnosis, reducing the time required to make a diagnosis.

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Parallel transmit 7T MRI for adult epilepsy pre-surgical evaluation

Publication: Epilepsia

Krzysztof Klodowski, Minghao Zhang, Jian P. Jen, Daniel J. Scoffings, Robert Morris, Victoria Lupson, Franck Mauconduit, Aurélien Massire, Vincent Gras, Nicolas Boulant, Christopher T. Rodgers, Thomas E. Cope

20 March 2025

The aim of the study was to implement parallel transmit (pTx) 7T magnetic resonance imaging (MRI) in the pre-surgical evaluation of 3T-negative patients with drug-resistant focal epilepsy, and to compare quality to conventional single transmit (specifically, circularly polarized [CP]) 7T MRI.

We implemented a comparative protocol comprising both pTx and CP 7T MRI in consecutive adult candidates for epilepsy surgery who had negative or equivocal 3T MRI imaging. Here we report the outcomes from the first 31 patients. We acquired pTx and CP T1, T2, fluid-attenuated inversion recovery (FLAIR) and edge-enhancing gradient echo (EDGE) images, all in the same three-dimensional (3D) 0.8 mm isotropic space. Two-dimensional (2D) high-resolution T2 and T2*-weighted sequences were acquired only in CP mode due to current technological limitations. Two neuroradiologists, a neurologist, and a neurosurgeon made independent, blinded quality and preference ratings of pTx vs CP images. Quantitative methods were used to assess signal dropout.

7T revealed previously-unseen structural lesions in nine patients (29%), confirmed 3T-equivocal lesions in four patients (13%), and disproved 3T-equivocal lesions in four patients (13%). Lesions were better visualized on pTx than CP in 57% of cases, and never better visualized on CP. Clinical management was altered by 7T in 18 cases (58%). Nine cases were offered surgical resection and one laser interstitial thermal therapy (LITT). Three cases were removed from the surgical pathway because of bilateral or extensive lesions. Five cases were offered stereo-electroencephalography (sEEG) with better targeting (in three because the 7T lesion was deemed equivocal by the multi-disciplinary team (MDT), and in two because the lesion was extensive). Blinded comparison confirmed significantly better overall quality of pTx FLAIR images (F(2, 184) = 13.7, p = 2.88 × 10−6), whereas pTx MP2RAGE images were subjectively non-inferior and had improved temporal lobe coverage with quantitatively less signal drop-out.

pTx-7T is implementable in a clinical pathway, changed management in 58% of patients where 3T + FDG-PET had not enabled resection, and is superior to single transmit 7T MRI.

Key points

  • We scanned 31 patients with parallel transmit and conventional 7T magnetic resonance imaging (MRI), finding previously-unreported structural lesions in nine patients (29% of cases).
  • In 13% of cases, 7T MRI showed that an equivocal lesion at 3T MRI was likely significant
  • In 13% of cases, 7T MRI showed that an equivocal lesion at 3T MRI could be disregarded.
  • Both qualitative and quantitative quality assessments indicate superiority of pTx images over circularly polarized (CP).
  • Future clinical implementations of 7T MRI for epilepsy should utilize parallel transmit where possible.

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Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

Publication: Nature

Douglas P. Loesch, Manik Garg, Dorota Matelska, Dimitrios Vitsios, Xiao Jiang, Scott C. Ritchie, Benjamin B Sun, Heiko Runz, Christopher D. Whelan, Ruey R. Holman, Robert J. Mentz, Filipe A. Moura, Stephen D. Wiviott, Marc S Sabatine, Miriam S Udler, Ingrid A. Gause-Nilsson, Slavé Petrovski, Jan Oscarsson, Abhishek Nag, Dirk S. Paul & Michael Inouye.

03 March 2025

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal (https://public.cgr.astrazeneca.com/t2d-pgs/v1/).

 

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Endoscopic, ultrasound-guided, radiofrequency ablation of aldosterone-producing adenomas (FABULAS): a UK, multicentre, prospective, proof-of-concept trial

Publication: The Lancet

Giulia Argentesi, Xilin Wu, Alexander Ney, Emily Goodchild, Kate Laycock, Yun-Ni Lee, Russell Senanayake, James MacFarlane, Elizabeth Ng, Jessica Kearney, Sam O’Toole, Jackie Salsbury, Nick Carroll, Daniel Gillett, John A Tadross, Alison Marker, Edmund M Godfrey, George Goodchild, Jonathan P Bestwich, Prof Mark Gurnell, Heok Cheow, Prof Stephen P. Periera, Prof William M Drake, Prof Morris J Brown, FABULAS Study Group

07 February 2025

Five percent of all cases of hypertension are caused by the potentially curable cause – unilateral aldosterone-producing adrenal adenomas (APAs). Very often their localisation (via adrenal vein sampling – AVS) and removal (by laparoscopic adrenalectomy) are not appealing to patients. Another, less invasive,  method of detecting and treating APAs has been discovered by the FABULAS Study Group. Over a five year testing period, 44 patients were screened and 28 recruited. The recruited patients  underwent ablations using the new EUS-RFA technology with positive outcomes; complete or partial biochemical cure in 21 participants and complete or partial cure of hypertension in 12 participants after a 3 month period. These findings appear to offer a safe alternative to total adrenalectomy for the treatment of left sided APAs and could potentially cure primary aldosteronism and hypertension when most of the APA is ablated.

The NIHR Cambridge BRC is part of the NIHR and hosted by Cambridge University Hospitals NHS Foundation Trust in partnership with the University of Cambridge. We are at the heart of the Cambridge Biomedical Campus, Europe’s largest health research area.

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