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Dev Cell. 2025 Sep 8;60(17):2218-2236. doi: 10.1016/j.devcel.2025.06.032.

ABSTRACT

Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.

PMID:40925326 | DOI:10.1016/j.devcel.2025.06.032

Clin Transplant. 2025 Sep;39(9):e70309. doi: 10.1111/ctr.70309.

ABSTRACT

BACKGROUND: Liver transplantation is the definitive treatment for end-stage liver disease and some cancers. The use of livers from donors following pre-donation cardiac arrest (PDCA), especially with prolonged downtime duration, has been limited outside of the US due to fears over inferior outcomes from ischemic injury. However, PDCA may induce ischemic preconditioning, paradoxically improving post-transplant outcomes. We analyzed the impact of PDCA occurrence and downtime duration on liver transplantation.

METHODS: We used the UNOS registry on adult liver transplantation (2010-2023), and included both donation after brain death (DBD) and donation after circulatory death (DCD) donors. Multivariable regression models were used to analyze the associations. Multiple imputation was used for missing data, and restricted cubic spline modelling to account for non-linear relationships.

RESULTS: Among 74,592 recipients, 32,631 (43.7%) received a liver from a PDCA donor. PDCA occurrence was associated with a small improvement in graft survival (aHR = 0.914, 95% Cl = 0.851-0.982). Interaction terms revealed this benefit was more pronounced among the following donor groups: DCD, moderately raised alanine aminotransferase (ALT), short admission-to-donation time and older donors. These novel associations are all in keeping with a preconditioning effect. Increasing PDCA downtime duration was also associated with a small improvement in graft survival (aHR per doubling = 0.953, 95% Cl = 0.917-0.991). Similar associations were seen with secondary outcomes.

CONCLUSIONS: The use of livers from donors with PDCA, including those with prolonged downtime duration, is a safe and simple approach to expand the donor pool internationally. Interaction terms and non-linear modelling provided clinical evidence for ischemic preconditioning from PDCA, which represents the largest real-world demonstration of this phenomenon.

PMID:40924859 | DOI:10.1111/ctr.70309

Cancer Discov. 2025 Sep 8. doi: 10.1158/2159-8290.CD-25-0526. Online ahead of print.

ABSTRACT

There is growing interest in understanding the mechanisms underlying differences in cancer incidence among species (comparative oncology). The naked mole-rat (NMR) is often referenced as "cancer-resistant" and prior studies focused on identifying mechanisms explaining this. However, efforts to assess this in vivo have been limited. Herein, we provide evidence that the NMR presents as a novel autochthonous model of lung tumor initiation, driven by an introduction of the oncogenic Eml4-Alk fusion protein using CRISPR-mediated genome editing. Whereas in mice the inversion alone is sufficient to drive tumorigenesis, the inversion alone was insufficient to drive tumorigenesis in the NMR lung and tumor development required additional losses of the tumor suppressors p53 and pRb. Our findings suggest that the proposed "resistance" of the NMR to the development of cancer may reflect that the genetic events leading to tumor initiation are likely to be comparable to those present in human cells.

PMID:40920097 | DOI:10.1158/2159-8290.CD-25-0526

Biochem Soc Trans. 2025 Sep 4:BST20243001. doi: 10.1042/BST20243001. Online ahead of print.

ABSTRACT

Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these current treatment options are unable to reverse heart muscle degeneration, with heart transplantation the only cure. The ability to re-muscularise the heart represents a significant unmet clinical need. Although numerous biological pathways driving re-muscularisation have been identified, delivery of therapeutic factors is challenging. Modified mRNA (modRNA) is synthetic mRNA with greater gene packaging capacity, low immunogenic response and allows transient but robust protein expression. In this mini-review, we highlight the emerging discoveries surrounding the application of modRNA in the cardiovascular field. Specifically, we focus on different examples illustrating how modRNA delivery post-myocardial infarction can drive cardiomyocyte proliferation and achieve cardiac regeneration. In addition, we demonstrate how modRNA is being used for protein replacement and Cas delivery for both modelling and therapeutic studies focussed on genetic cardiac diseases. For these applications, in particular Cas delivery, the transient nature of modRNA overexpression is a beneficial property with reduced side effects compared with other modalities. Finally, we preview some of the roadblocks limiting the clinical translation of modRNA and avenues being explored to overcome these. In summary, the flexibility of modRNA combined with its improved safety profile provides a gene overexpression tool capable of integration into all steps of the preclinical and clinical therapeutic pipeline enabling the discovery of improved treatments for HF.

PMID:40905915 | DOI:10.1042/BST20243001

Exp Parasitol. 2025 Sep 2:109009. doi: 10.1016/j.exppara.2025.109009. Online ahead of print.

ABSTRACT

Leishmaniasis is a vector-borne parasitic disease caused by Leishmania spp., for which there is no vaccine and an urgent need for better drugs. The zinc metalloprotease gp63 of Leishmania has been identified as an antigenic structure for vaccine design and a promising target for new antileishmanial agents. In this study, immunoinformatics was used to design a full vaccine construct with the cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes of gp63 from Old and New World Leishmania spp. The vaccine construct comprising of these epitopes, with suitable adjuvant and linker sequences, was found to be thermostable, highly antigenic and non-allergenic. A total of 13 linear B-cell epitopes, and 12 continuous and four discontinuous B-cell epitopes, were further identified using the BepiPred and ElliPro prediction programs, respectively. In addition, molecular docking and molecular dynamics simulation studies were performed to identify new antileishmanial molecules with the potential to target gp63. Nareline - a phytomolecule from the antileishmanial plant Alstonia scholaris - showed the best predictive binding affinity for gp63, forming stable interactions with key residues in the active site of this protein. This study highlights the promising role of gp63 in the search for new vaccines and therapeutic agents to combat leishmaniasis.

PMID:40907690 | DOI:10.1016/j.exppara.2025.109009

Biochem Soc Trans. 2025 Sep 4:BST20243001. doi: 10.1042/BST20243001. Online ahead of print.

ABSTRACT

Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these current treatment options are unable to reverse heart muscle degeneration, with heart transplantation the only cure. The ability to re-muscularise the heart represents a significant unmet clinical need. Although numerous biological pathways driving re-muscularisation have been identified, delivery of therapeutic factors is challenging. Modified mRNA (modRNA) is synthetic mRNA with greater gene packaging capacity, low immunogenic response and allows transient but robust protein expression. In this mini-review, we highlight the emerging discoveries surrounding the application of modRNA in the cardiovascular field. Specifically, we focus on different examples illustrating how modRNA delivery post-myocardial infarction can drive cardiomyocyte proliferation and achieve cardiac regeneration. In addition, we demonstrate how modRNA is being used for protein replacement and Cas delivery for both modelling and therapeutic studies focussed on genetic cardiac diseases. For these applications, in particular Cas delivery, the transient nature of modRNA overexpression is a beneficial property with reduced side effects compared with other modalities. Finally, we preview some of the roadblocks limiting the clinical translation of modRNA and avenues being explored to overcome these. In summary, the flexibility of modRNA combined with its improved safety profile provides a gene overexpression tool capable of integration into all steps of the preclinical and clinical therapeutic pipeline enabling the discovery of improved treatments for HF.

PMID:40905915 | DOI:10.1042/BST20243001

Ann Med Surg (Lond). 2025 Jul 10;87(9):5650-5660. doi: 10.1097/MS9.0000000000003558. eCollection 2025 Sep.

ABSTRACT

In 2022, the presumption of monkeypox (mpox) to be of limited epidemiology shifted when a global outbreak was announced. Being a member of the Orthopoxvirus genus in the Poxviridae family, it'd been reported in over 82 countries with over 17 000 confirmed cases by July 2022, thus showing its capability for spreading rapidly. As the smallpox vaccine offers 85% cross-immunity against mpox, the outbreak highlighted the attenuation of global immunity against orthopoxviruses after the cessation of vaccination campaigns against smallpox. The mortality of this virus is higher in vulnerable populations such as children, pregnant women, the elderly, and immunosuppressed individuals. With treatment methods being limited to off-label use of antivirals, the need for urgent and efficient preventative measures is emphasized. At present, JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic), showing favorable safety, and ACAM2000, a live attenuated virus with a high risk of side effects, are two vaccines that are indicated for mpox immunization. However, neither of them has proven full safety, efficacy, and widespread accessibility against mpox. Hence, the use of mRNA vaccines has emerged as a better alternative to traditional vaccinations, as they leverage synthetic messenger RNA to instruct host cells to produce antigens, eliciting both humoral and cellular immune responses. Though they provided rapid scalability, adaptability to emerging viral variants, and an established safety profile after the COVID-19 pandemic, their usage in preventing mpox remains an area of research. This paper elucidates the potential of mRNA technology to address the unmet needs in mpox prevention. It also highlights the need for genomic surveillance, immunological insights, and innovative delivery systems.

PMID:40901148 | PMC:PMC12401314 | DOI:10.1097/MS9.0000000000003558

Neuropsychobiology. 2025 Sep 2:1-17. doi: 10.1159/000547983. Online ahead of print.

ABSTRACT

INTRODUCTION: Insomnia is one of the most common symptoms of depression, estimated to occur in approximately 75% of adult patients with depression, and it may persist even after remission from depressive episodes. Our objectives were to evaluate the efficacy of mirtazapine in reducing insomnia and depression symptom severity, assess side effects, and compare quality of life before and after intervention in major depressive disorder (MDD) patients with insomnia.

METHODS: This was a single-center, prospective, open-label, quasi-experimental pre-post intervention trial of six weeks. The Hamilton Depression Rating Scale (HDRS), Insomnia Severity Index (ISI), Antidepressant Side-Effect Checklist (ASEC), and World Health Organization Quality of Life (WHOQOL-BREF) tools were used during the assessment.

RESULTS: Out of the 135 recruited patients, 109 (80.7%) completed the trial. On day 14, with a mean dose of 18.9 mg/day, 24.8% of patients experienced remission for insomnia, while 7.3% showed remission for depression. By day 42, with a mean dose of 18.7 mg/day, these figures increased to 62.4% for insomnia and 41.3% for depression. The reduction in the ISI score (mean±SD) from baseline to day 14 and day 42 was 8.74±6.16 and 13.55±5.32, respectively. Similarly, the reduction in the HDRS score from baseline on day 14 and 42 was 10.30±6.89 and 17.78±6.26, respectively. The most commonly reported adverse effects (>10%) included increased appetite, drowsiness, weight gain, dry mouth, headache, and constipation. Regarding QoL, the differences were significant for all four domains with the highest improvement observed in the physical (mean difference 25.67±13.95) and psychological domains (mean difference 26.35±16.42) of QoL.

CONCLUSION: Mirtazapine treatment was associated with significant improvements in depression, insomnia, and all QoL parameters, with increased appetite and weight gain being the most common adverse effects. Further randomized controlled comparator studies will be beneficial for healthcare providers to improve the clinical care of MDD patients with insomnia.

PMID:40892680 | DOI:10.1159/000547983

Elife. 2025 Sep 1;14:RP104238. doi: 10.7554/eLife.104238.

ABSTRACT

E3 ubiquitin ligases engage their substrates via 'degrons' - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and are difficult to inhibit via conventional means, alternative strategies are needed to target them in diseases, and peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide inhibitors of Cdc20, a substrate-recognition subunit and activator of the E3 ubiquitin ligase the anaphase-promoting complex/cyclosome (APC/C) that is essential in mitosis and consequently of interest as an anti-cancer target. APC/C engages substrates via degrons that include the 'destruction box' (D-box) motif. We used a rational design approach to construct binders containing unnatural amino acids aimed at better filling a hydrophobic pocket that contributes to the D-box binding site on the surface of Cdc20. We confirmed binding by thermal-shift assays and surface plasmon resonance and determined the structures of a number of the Cdc20-peptide complexes. Using a cellular thermal shift assay, we confirmed that the D-box peptides also bind to and stabilise Cdc20 in the cell. We found that the D-box peptides inhibit ubiquitination activity of APC/CCdc20 and are more potent than the small-molecule inhibitor Apcin. Lastly, these peptides function as portable degrons capable of driving the degradation of a fused fluorescent protein. Interestingly, we find that although inhibitory activity of the peptides correlates with Cdc20-binding affinity, degradation efficacy does not, which may be due to the complex nature of APC/C regulation and effects of degron binding of subunit recruitment and conformational changes. Our study lays the groundwork for the further development of these peptides as molecular therapeutics for blocking APC/C as well as potentially for harnessing the APC/C for targeted protein degradation.

PMID:40888475 | PMC:PMC12401543 | DOI:10.7554/eLife.104238

Elife. 2025 Sep 1;14:RP104238. doi: 10.7554/eLife.104238.

ABSTRACT

E3 ubiquitin ligases engage their substrates via 'degrons' - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and are difficult to inhibit via conventional means, alternative strategies are needed to target them in diseases, and peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide inhibitors of Cdc20, a substrate-recognition subunit and activator of the E3 ubiquitin ligase the anaphase-promoting complex/cyclosome (APC/C) that is essential in mitosis and consequently of interest as an anti-cancer target. APC/C engages substrates via degrons that include the 'destruction box' (D-box) motif. We used a rational design approach to construct binders containing unnatural amino acids aimed at better filling a hydrophobic pocket that contributes to the D-box binding site on the surface of Cdc20. We confirmed binding by thermal-shift assays and surface plasmon resonance and determined the structures of a number of the Cdc20-peptide complexes. Using a cellular thermal shift assay, we confirmed that the D-box peptides also bind to and stabilise Cdc20 in the cell. We found that the D-box peptides inhibit ubiquitination activity of APC/CCdc20 and are more potent than the small-molecule inhibitor Apcin. Lastly, these peptides function as portable degrons capable of driving the degradation of a fused fluorescent protein. Interestingly, we find that although inhibitory activity of the peptides correlates with Cdc20-binding affinity, degradation efficacy does not, which may be due to the complex nature of APC/C regulation and effects of degron binding of subunit recruitment and conformational changes. Our study lays the groundwork for the further development of these peptides as molecular therapeutics for blocking APC/C as well as potentially for harnessing the APC/C for targeted protein degradation.

PMID:40888475 | DOI:10.7554/eLife.104238

Elife. 2025 Aug 29;14:RP105978. doi: 10.7554/eLife.105978.

ABSTRACT

Self-amplifying RNA (saRNA) holds promise for durable therapeutic gene expression, but its broader utility beyond vaccines is limited by potent innate immune responses triggered during replication. These responses shut down translation, induce cytotoxicity, degrade host mRNAs, and drive cytokine production. While exogenous immunosuppressants can blunt these effects, they complicate treatment and risk systemic side effects. To address this, we engineered 'immune-evasive saRNA' that intrinsically suppresses the innate immune pathways triggered by its own replication. This strategy leverages cap-independent translation to co-express a suite of inhibitors from a single saRNA transcript, targeting key innate immune pathways, including protein kinase R (PKR), oligoadenylate synthase (OAS)/RNase L, and nuclear factor-κB (NF-κB). In primary mouse fibroblast-like synoviocytes, a cell type central to the pathology of joint diseases, immune-evasive saRNA enables sustained transgene expression without external immunosuppressants, substantially reducing cytotoxicity and antiviral cytokine secretion. Crucially, this system offers both concentration-dependent control of expression and on-demand termination via a small-molecule antiviral. Together, these findings establish a framework for developing saRNA therapeutics with an improved tolerability profile that can be switched off once therapeutic outcomes are met, offering a path toward a controllable gene expression platform that fills the therapeutic gap between the transience of mRNA and the permanence of viral vectors.

PMID:40879330 | PMC:PMC12396818 | DOI:10.7554/eLife.105978

Elife. 2025 Aug 29;14:RP105978. doi: 10.7554/eLife.105978.

ABSTRACT

Self-amplifying RNA (saRNA) holds promise for durable therapeutic gene expression, but its broader utility beyond vaccines is limited by potent innate immune responses triggered during replication. These responses shut down translation, induce cytotoxicity, degrade host mRNAs, and drive cytokine production. While exogenous immunosuppressants can blunt these effects, they complicate treatment and risk systemic side effects. To address this, we engineered 'immune-evasive saRNA' that intrinsically suppresses the innate immune pathways triggered by its own replication. This strategy leverages cap-independent translation to co-express a suite of inhibitors from a single saRNA transcript, targeting key innate immune pathways, including protein kinase R (PKR), oligoadenylate synthase (OAS)/RNase L, and nuclear factor-κB (NF-κB). In primary mouse fibroblast-like synoviocytes, a cell type central to the pathology of joint diseases, immune-evasive saRNA enables sustained transgene expression without external immunosuppressants, substantially reducing cytotoxicity and antiviral cytokine secretion. Crucially, this system offers both concentration-dependent control of expression and on-demand termination via a small-molecule antiviral. Together, these findings establish a framework for developing saRNA therapeutics with an improved tolerability profile that can be switched off once therapeutic outcomes are met, offering a path toward a controllable gene expression platform that fills the therapeutic gap between the transience of mRNA and the permanence of viral vectors.

PMID:40879330 | DOI:10.7554/eLife.105978

J Phys Condens Matter. 2025 Aug 27;37(35). doi: 10.1088/1361-648X/adf024.

ABSTRACT

Surface Science Discussions (SSD) is an online seminar series aimed at bringing together worldwide experts and early-career researchers from the surface science community and exchanging knowledge on the recent progress in the field at the international level. The event took place for the first time during the COVID-19 pandemic and continues its mission to this day. In 2024, a Special Issue (SI) featuring articles authored by the Speakers of the first two editions of SSD-2022 and 2023-was published in the Journal of Physics: Condensed Matter. Experimental and theoretical reports constituting the issue reflect current trends in surface science studies, such as the growth, structure and physicochemical properties of supported 2D layers and molecules at surfaces,in operandomodel catalytic studies, application of machine learning to the studies of surface phenomena, and the development of novel surface investigation methods. The editorial provides a brief introduction to surface science, presents the idea behind SSD and the history of the event, and describes the articles comprising the SI, thus constituting a valuable source of information on the actual topics in the field.

PMID:40859653 | DOI:10.1088/1361-648X/adf024

BMC Nephrol. 2025 Aug 22;26(1):481. doi: 10.1186/s12882-025-04409-4.

ABSTRACT

BACKGROUND: Patients with chronic kidney disease (CKD) may experience better health outcomes when they engage in physical activity (PA). The aim of the study was to assess the physical activity level of chronic kidney disease (CKD) patients and its potentials risk factor for health.

METHODS: A cross-sectional study was carried out at Mymensingh Medical College Hospital, Mymensingh, Bangladesh from October 2023 to January 2024. A total of 253 CKD patients aged 18 years and older at moderate to advanced stages were enrolled in the study. The global physical activity questionnaire (GPAQ) was used to measure the physical activity for health of CKD patients. Physical component summary (PCS) and mental component summary (MCS) scores were measured by Short-Form Health Survey (SF-12) questionnaire. Socio-demographic and medical records were also collected. Both logistic regression and descriptive statistics were used for data.

RESULTS: Of 253 participants (62.8% male, mean age 60.1 years), 41.1% did not meet PA recommendations. Median PA durations were 28.57 min/day for moderate PA (MPA), 8.57 min/day for transport, and 11.43 min/day for recreation. Poor physical function (PCS ≤ 41.04) was observed in 85.8% of participants, and 51.0% had depressive disorders (MCS ≤ 45.6). Logistic regression identified younger age [adjusted OR (AOR) 3.29], moderate stage of CKD (AOR 2.39), good physical function (AOR 3.01), absence of depression (AOR 4.87), and family history of CKD (AOR 2.65) were significant predictors of meeting PA recommendations (p < 0.05).

CONCLUSIONS: A substantial proportion of Bangladeshi CKD patients do not meet PA recommendations, with younger age, moderate CKD, better physical function, absence of depression, and family history of CKD predicting higher PA engagement. Targeted interventions addressing these factors, particularly early in CKD progression, are needed to promote PA and improve health outcomes in this population.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40846909 | DOI:10.1186/s12882-025-04409-4

Prev Vet Med. 2025 Aug 14;245:106657. doi: 10.1016/j.prevetmed.2025.106657. Online ahead of print.

ABSTRACT

Anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis. Outbreaks are periodically reported among people and livestock in Bangladesh. From 2009-2020, approximately 4000 suspected human cutaneous anthrax cases were reported. Although annual livestock vaccination against anthrax is one of the primary control methods, we do not know the livestock vaccination practices in Bangladesh. We aimed to determine the knowledge, attitude, and practices of livestock raisers regarding the use of anthrax vaccination. We conducted a cross-sectional survey in four districts with the highest number of suspected human anthrax cases and four districts having no reported cases from October 2017 to March 2018. We randomly selected 81 villages in total; 10-11 villages per district. From each village, 20 households with at least one domestic animal (cattle/buffalo/goat/sheep) were randomly enrolled and the primary livestock raisers were interviewed. Among the 1620 livestock raisers, 36 % had heard of the livestock disease "anthrax" or "Torka" (the local name); 48 % from outbreak districts and 24 % from non-outbreak districts (p < 0.001). Only 11 % of total respondents were aware that anthrax caused human disease. Overall, 25 % of respondents reported vaccinating their livestock for any disease. Among those, only 18 % reported vaccinating against anthrax. Most (73 %) of the livestock raisers who did not vaccinate their animals reported they were unaware of the vaccine against anthrax. Livestock raisers reported being willing to pay an average of 0.12 USD per vaccine for cattle/buffalo, and 0.06 USD for goats/sheep. Although the reported use of livestock vaccination was low in outbreak districts, respondents were more likely to be aware of anthrax. These findings highlight a need for community engagement with targeted education, and risk communication for livestock raisers regarding knowledge of anthrax, the importance of vaccination, and increasing the accessibility of anthrax vaccine in endemic villages.

PMID:40840200 | DOI:10.1016/j.prevetmed.2025.106657

bioRxiv [Preprint]. 2025 Aug 13:2025.01.24.634724. doi: 10.1101/2025.01.24.634724.

ABSTRACT

The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca2+ mobilisation, away from the canonical cAMP-driven signalling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gαs but increased secondary couplings to Gαq and Gαi. These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. A reciprocal effect was observed when looking at reduced expression of endogenous RAMP3, with a loss of sensitivity to GLP-1 in both glucose and insulin tolerance tests in a Ramp3 knockout mouse. The effects of this interaction can then inform selection of models and peptide design when targeting this receptor for therapeutic intervention.

PMID:40832355 | PMC:PMC12363685 | DOI:10.1101/2025.01.24.634724

J Biol Chem. 2025 Aug 18:110604. doi: 10.1016/j.jbc.2025.110604. Online ahead of print.

ABSTRACT

The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca2+ mobilisation, away from the canonical cAMP-driven signalling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gαs but increased secondary couplings to Gαq and Gαi. These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. A reciprocal effect was observed when looking at reduced expression of endogenous RAMP3, with a loss of sensitivity to GLP-1 in both glucose and insulin tolerance tests in a Ramp3 knockout mouse. The effects of this interaction can then inform selection of models and peptide design when targeting this receptor for therapeutic intervention.

PMID:40835007 | DOI:10.1016/j.jbc.2025.110604

J Biol Chem. 2025 Aug 18:110604. doi: 10.1016/j.jbc.2025.110604. Online ahead of print.

ABSTRACT

The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca2+ mobilisation, away from the canonical cAMP-driven signalling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gαs but increased secondary couplings to Gαq and Gαi. These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. A reciprocal effect was observed when looking at reduced expression of endogenous RAMP3, with a loss of sensitivity to GLP-1 in both glucose and insulin tolerance tests in a Ramp3 knockout mouse. The effects of this interaction can then inform selection of models and peptide design when targeting this receptor for therapeutic intervention.

PMID:40835007 | DOI:10.1016/j.jbc.2025.110604

JAMA Netw Open. 2025 Aug 1;8(8):e2527805. doi: 10.1001/jamanetworkopen.2025.27805.

ABSTRACT

IMPORTANCE: Cancer is a significant global health concern, with India ranking second in Asia and third in the world in terms of cancer incidence. Regular monitoring and updates on cancer statistics are vital for assessing the impact and burden of the disease and the effectiveness of cancer control measures.

OBJECTIVE: To measure the recent patterns and trends in cancer incidence and mortality across 43 geographic regions in India from 2015 to 2019 and to provide estimates for 2024.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from 43 population-based cancer registries across India, covering varying periods between January 1, 2015, and December 31, 2019. Population at-risk data were obtained from the Census of India, and findings were assessed by registry area. Data were analyzed from May 1 to December 20, 2024.

MAIN OUTCOMES AND MEASURES: Number of cases, crude rates, and age-adjusted rates (per 100 000 population) for cancer incidence and mortality, estimated average annual percent change (AAPC) from time trends, and estimated cancer cases in India for 2024.

RESULTS: Incidence of 708 223 cases with 206 457 deaths from 43 population-based cancer registries were included. The lifetime risk of developing cancer in India was 11.0%, while Mizoram in the Northeastern region reported lifetime risks of 21.1% in males and 18.9% in females. The district of Aizawl reported the highest age-adjusted incidence rate (AAIR) in both males (256.1; 95% CI, 245.2-267.0) and females (217.2; 95% CI, 207.6-226.7). The most common cancers were oral, lung, and prostate in males and breast, cervical, and ovarian in females. Among metropolitan cities (defined as an urban agglomeration with a population of over 1 million), Delhi had the highest overall cancer AAIR for males (146.7; 95% CI, 145.1-148.3), while Srinagar recorded the highest AAIR for lung cancer (39.5; 95% CI, 35.8-43.2). Oral cancer showed significant increases in 14 population-based cancer registries (PBCRs) among males and 4 PBCRs among females; Ahmedabad Urban had an increase of 4.7% (95% CI, 2.9% to 6.6%) in males and 6.9% (95% CI, 4.1% to 9.7%) in females. The estimated AAPC in AAIR (all sites) showed a significant increase over time in Kamrup Urban in males (3.3%; 95% CI, 2.3%-4.3%) and Thiruvananthapuram Taluk in females (3.4%; 95% CI, 3.1%-3.8%). The estimated cancer incidence for 2024 was 1 562 099 cases; estimated cancer mortality, 874 404 cases.

CONCLUSIONS AND RELEVANCE: This cross-sectional study highlighted significant regional disparities in cancer incidence across India and the increasing cancer burden. The findings provide key insights for policymakers to enhance resource allocation and strengthen cancer control strategies nationwide.

PMID:40833697 | DOI:10.1001/jamanetworkopen.2025.27805

bioRxiv [Preprint]. 2025 Aug 13:2025.01.24.634724. doi: 10.1101/2025.01.24.634724.

ABSTRACT

The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca 2+ mobilisation, away from the canonical cAMP-driven signalling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gα s but increased secondary couplings to Gα q and Gα i . These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. A reciprocal effect was observed when looking at reduced expression of endogenous RAMP3, with a loss of sensitivity to GLP-1 in both glucose and insulin tolerance tests in a Ramp3 knockout mouse. The effects of this interaction can then inform selection of models and peptide design when targeting this receptor for therapeutic intervention.

SIGNIFICANCE STATEMENT: G Protein-Coupled Receptors, such as the Glucagon-Like Peptide-1 (GLP-1) Receptor are common drug targets, although not without side effects due to on-target, unwanted signalling outputs. This study identifies an interacting protein which alters its signalling to promote insulin secretion. This may improve the therapeutic potential of GLP-1 mimetics, enhancing effectual signalling over that associated with unwanted effects by directly targeting this receptor complex.

PMID:40832355 | PMC:PMC12363685 | DOI:10.1101/2025.01.24.634724