Reduced-energy diet in women with gestational diabetes: the dietary intervention in gestational diabetes DiGest randomized clinical trial

September 10, 2025

Publication: Nature Medicine

19 February 2025

Laura C. Kusinski, Danielle Jones, Nooria Atta, Elizabeth Turner, Suzanne Smith, Linda M. Oude Griep, Kirsten Rennie, Emanuella De Lucia Rolfe, Stephen J. Sharp, Vern Farewell, Helen R. Murphy, Roy Taylor & Claire L. Meek

Abstract

Reduced-energy diets promote weight loss and improve long-term outcomes in type 2 diabetes but are untested in gestational diabetes. We aimed to identify if weight loss in pregnancy improves perinatal outcomes in gestational diabetes. We performed a multicentre parallel, randomized, controlled, double-blind trial of energy restriction in women with singleton pregnancies, gestational diabetes and body mass index ≥25 kg m⁻². Participants were randomized to receive a standard-energy control diet (2,000 kcal d⁻¹) or reduced-energy intervention diet (1,200 kcal d⁻¹) from enrollment (29 weeks) until delivery, provided as weekly diet boxes (40% carbohydrate, 35% fat, 25% protein). The randomization was performed in a 1:1 ratio, stratified by center and blinded to the participants and study team. Primary outcomes were maternal weight change from enrollment to 36 weeks and offspring birth weight. In total, 425 participants were randomized to the control (n = 211) or intervention (n = 214). Outcome data were available for 388 of 425 (90.1%) participants at 36 weeks and 382 of 425 (89.8%) at delivery. There was no evidence of a difference in maternal weight change to 36 weeks between groups (intervention effect −0.20 (95% confidence interval −1.01, 0.61); P > 0.1) and offspring standardized birth weight (intervention effect 0.005 (−0.19, 0.20); P > 0.1). A reduced-energy diet was safe in pregnancy. ISRCTN registration no. 65152174.

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Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis

September 10, 2025

Publication: Diabetes

25 August 2025

Tessa M. Cacciottolo, Katherine Lawler, Kevin M. Méndez-Acevedo, Edson Mendes de Oliveira, Adam Syanda, Elana Henning, Julia M. Keogh, Rebecca Bounds, Miriam Smith, Daniyal Ashraf, David Harman, Adam Duckworth, Edmund M. Godfrey, Laura Watson, Matthew Hoare, Ben Jones, Alastair Baker, Tamir Rashid, Sadaf Farooqi

Abstract

The team, led by Professor Sadaf Farooqi, have identified homozygous loss-of-function mutations in the gene encoding the glucagon receptor (GCGR), in a family in whom three individuals developed early-onset fatty liver disease (and in one case cirrhosis of the liver). While this condition is commonly associated with obesity, the family members had a normal body weight and all other known causes of liver disease were excluded.

In clinical studies, mutation carriers were found to have elevated plasma glucagon levels, α-cell hyperplasia (and/or pancreatic nodules) and elevated serum levels of glucogenic amino acids. Glucagon is known to play a key role in regulating carbohydrate and lipid metabolism acting via its receptors in the liver. In the lab, the team studied hepatocytes (liver cells) derived from stem cells into which they had introduced the patients’ mutations using CRISPR/Cas9 gene editing. They showed that hepatocytes carrying the GCGR mutations could not clear lipid as expected, causing it to accumulate, proving a causal link between the mutations and fatty liver disease in patients.

These findings pave the way for additional mechanistic studies to identify downstream targets which could inform the design of treatments for patients. This work also has a broader relevance as glucagon receptor antagonists have been used in clinical trials of patients with type 2 diabetes in whom elevated glucagon levels contribute to hyperglycemia. In those trials, dose-dependent increases in liver function tests and hepatic fat content suggest that glucagon may have clinically significant effects on human lipid metabolism. While development of some GCGR antagonists has been discontinued due to this increase in liver fat, in view of our findings, increased surveillance is recommended when trialling therapies that impair or inhibit GCGR signaling. In contrast, GCGR agonists are likely to reduce hepatic steatosis, as predicted by studies in mice and now by these studies in humans. Indeed, trials of GCGR agonists in combination with GLP-1R and/or glucose-dependent insulinotropic polypeptide receptor agonists have reported improvements in steatosis in people with obesity and metabolic dysfunction associated steatohepatitis.

Collectively, these results indicate that the relative potency of GCGR agonism may explain the degree to which these drugs impact body composition and hepatic steatosis.

View Publicationhttps://diabetesjournals.org/diabetes/article/doi/10.2337/db25-0209/163277/Glucagon-Receptor-Deficiency-Causes-Early-Onset

The long-term effects of chemotherapy on normal blood cells

July 11, 2025

Publication: Nature Genetics

10 July 2025

Emily Mitchell, My H. Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I. Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E. Machado, E. Joanna Baxter, George Follows, Daniel J. Hodson, Ultan McDermott, Gary J. Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A. Goodell, David Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia & Michael R. Stratton.

Abstract

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3–80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.

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

July 4, 2025

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

June 17, 2025

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

May 14, 2025

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

April 23, 2025

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

April 16, 2025

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

April 16, 2025

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

April 16, 2025

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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Reduced-energy diet in women with gestational diabetes: the dietary intervention in gestational diabetes DiGest randomized clinical trial

Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis

The long-term effects of chemotherapy on normal blood cells

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

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

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

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

A redefined indel taxonomy reveals insights into mutational signatures

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

Machine Learning Achieves Pathologist-Level Celiac Disease Diagnosis

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