J Vasc Access. 2025 Feb 14:11297298251320269. doi: 10.1177/11297298251320269. Online ahead of print.

ABSTRACT

BACKGROUND: This study investigates the relationship between national catheter use among hemodialysis (HD) patients and kidney transplantation (KTX) activity, exploring the hypothesis that higher KTX activity may be associated with increased catheter usage. The rationale is based on the idea that shorter waiting times for transplants in high-activity countries could make central venous catheters (CVCs) more favorable as a temporary bridge to transplantation compared to arteriovenous fistulas or grafts which require longer maturation times.

METHODS: Nine national dialysis and transplant registries (Argentina, Australia, Austria, New Zealand, Portugal, Scotland, Sweden, USA, Turkey) were included in this analysis. The included descriptive analysis of baseline information from included countries, followed by crude association analyses using correlation and regression analyses to explore the relationship between CVC usage and kidney transplants per million inhabitants, considering relevant confounders. Adjusted analyses were performed to account for these confounders, providing a more nuanced understanding of the relationship.

RESULTS: Data from nine different national registries was analyzed. CVC use and KTX activity had a weak to moderate positive correlation (r = 0.23, 95% CI: 0.07, 0.39). In all included countries CVC use increased over time. Adjusting for temporal patterns, country-specific factors, and the proportion of female HD patients, there was still strong evidence for a moderate increase of CVCs among prevalent HD patients with increasing KTX activity.

CONCLUSION: Higher national KTX activity is associated with a moderate increase in CVCs among prevalent HD patients.

PMID:39953649 | DOI:10.1177/11297298251320269

Sci Rep. 2025 Feb 14;15(1):5512. doi: 10.1038/s41598-025-89783-7.

ABSTRACT

The early sequence of respiratory failure events after the onset of sepsis is still unknown. We hypothesize that the lung should signal through circulating extracellular vesicles (EVs) when it is affected by a systemic inflammatory response. Blood samples were obtained from septic patients with (n = 5) and without acute respiratory distress syndrome (ARDS) (n = 13) at 24 h of intensive care unit admission and 3 days later at Sírio-Libanês Hospital. Pulmonary-originated sepsis was not considered. The characteristics of the plasma-isolated EVs were compatible with exosomes. 48 miRNAs were evaluated by real-time PCR. Comparing all samples from patients with sepsis + ARDS to sepsis only, 9 miRNAs are transported in smaller amounts: miR-766 (-35.7, p = 0.002), miR-127 (-23.8, p = 0.001), miR-340 (-13.5, p = 0.006), miR-29b (-12.8, p = 0.001), miR-744 (-7.1, p = 0.05), miR-618 (-4.0, p = 0.02), miR-598 (-3.8, p = 0.035), miR-1260 (-2.5, p = 0.035); and miR-885-5p is expressed at higher levels (9.5; p = 0.028). In paired samples, the set of altered miRNAs is generally different (p < 0.05) between sepsis + ARDS (miR-1183,-1267,-1290,-17,-192,-199a-3p,-25,-485-3p,-518d,-720) or sepsis only (miR-148a,-193a-5p,-199a-3p,-222,-25,-340,744). Bioinformatic analysis showed that when sepsis is associated with ARDS, those differentially expressed miRNAs potentially target messenger RNAs from the Glycoprotein VI/GP6 signaling pathway. Circulating EV-miRNA cargo could be potential biomarkers of lung inflammation during sepsis in patients requiring mechanical ventilation.

PMID:39953195 | DOI:10.1038/s41598-025-89783-7

Nat Rev Rheumatol. 2025 Feb 14. doi: 10.1038/s41584-024-01217-2. Online ahead of print.

ABSTRACT

Systemic sclerosis (SSc) remains a challenging and enigmatic systemic autoimmune disease, owing to its complex pathogenesis, clinical and molecular heterogeneity, and the lack of effective disease-modifying treatments. Despite a century of research in SSc, the interconnections among microvascular dysfunction, autoimmune phenomena and tissue fibrosis in SSc remain unclear. The absence of validated biomarkers and reliable animal models complicates diagnosis and treatment, contributing to high morbidity and mortality. Advances in the past 5 years, such as single-cell RNA sequencing, next-generation sequencing, spatial biology, transcriptomics, genomics, proteomics, metabolomics, microbiome profiling and artificial intelligence, offer new avenues for identifying the early pathogenetic events that, once treated, could change the clinical history of SSc. Collaborative global efforts to integrate these approaches are crucial to developing a comprehensive, mechanistic understanding and enabling personalized therapies. Challenges include disease classification, clinical heterogeneity and the establishment of robust biomarkers for disease activity and progression. Innovative clinical trial designs and patient-centred approaches are essential for developing effective treatments. Emerging therapies, including cell-based and fibroblast-targeting treatments, show promise. Global cooperation, standardized protocols and interdisciplinary research are vital for advancing SSc research and improving patient outcomes. The integration of advanced research techniques holds the potential for important breakthroughs in the diagnosis, treatment and care of individuals with SSc.

PMID:39953141 | DOI:10.1038/s41584-024-01217-2

Nat Commun. 2025 Feb 14;16(1):1643. doi: 10.1038/s41467-025-56901-y.

ABSTRACT

C4 photosynthesis exemplifies convergent evolution of complex traits. Herein, we construct chromosome-scale genome assemblies and perform multi-omics analysis for five Flaveria species, which represent evolutionary stages from C3 to C4 photosynthesis. Chromosome-scale genome sequence analyses reveal a gradual increase in genome size during the evolution of C4 photosynthesis attributed to the expansion of transposable elements. Systematic annotation of genes encoding C4 enzymes and transporters identify additional copies of three C4 enzyme genes through retrotranspositions in C4 species. C4 genes exhibit elevated mRNA and protein abundances, reduced protein-to-RNA ratios, and comparable translation efficiencies in C4 species, highlighting a critical role of transcriptional regulation in C4 evolution. Furthermore, we observe an increased abundance of ethylene response factor (ERF) transcription factors and cognate cis-regulatory elements associated with C4 genes regulation. Altogether, our study provides valuable genomic resources for the Flaveria genus and sheds lights on evolutionary and regulatory mechanisms underlying C4 photosynthesis.

PMID:39952962 | DOI:10.1038/s41467-025-56901-y

Pharmacol Rev. 2025 Jan;77(1):100001. doi: 10.1124/pharmrev.123.001140. Epub 2024 Nov 22.

ABSTRACT

For most vertebrates, bitter perception plays a critical role in the detection of potentially harmful substances in food items. The detection of bitter compounds is facilitated by specialized receptors located in the taste buds of the oral cavity. This work focuses on these receptors, including their sensitivities, structure-function relationships, agonists, and antagonists. The existence of numerous bitter taste receptor variants in the human population and the fact that several of them profoundly affect individual perceptions of bitter tastes are discussed as well. Moreover, the identification of bitter taste receptors in numerous tissues outside the oral cavity and their multiple proposed roles in these tissues are described briefly. Although this work is mainly focused on human bitter taste receptors, it is imperative to compare human bitter taste with bitter taste of other animals to understand which forces might have shaped the evolution of bitter taste receptors and their functions and to distinguish apparently typical human features from rather general ones. For readers who are not very familiar with the gustatory system, short descriptions of taste anatomy, signal transduction, and oral bitter taste receptor expression are included in the beginning of this article. SIGNIFICANCE STATEMENT: Apart from their role as sensors for potentially harmful substances in the oral cavity, the numerous additional roles of bitter taste receptors in tissues outside the gustatory system have recently received much attention. For careful assessment of their functions inside and outside the taste system, a solid knowledge of the specific and general pharmacological features of these receptors and the growing toolbox available for studying them is imperative and provided in this work.

PMID:39952694 | DOI:10.1124/pharmrev.123.001140

Annu Rev Plant Biol. 2025 Feb 14. doi: 10.1146/annurev-arplant-083123-050311. Online ahead of print.

ABSTRACT

The target of rapamycin (TOR) is a central regulator of growth, development, and stress adaptation in plants. This review delves into the molecular intricacies of TOR signaling, highlighting its conservation and specificity across eukaryotic lineages. We explore the molecular architecture of TOR complexes, their regulation by a myriad of upstream signals, and their consequential impacts on plant physiology. The roles of TOR in orchestrating nutrient sensing, hormonal cues, and environmental signals are highlighted, illustrating its pivotal function in modulating plant growth and development. Furthermore, we examine the impact of TOR on plant responses to various biotic and abiotic stresses, underscoring its potential as a target for agricultural improvements. This synthesis of current knowledge on plant TOR signaling sheds light on the complex interplay between growth promotion and stress adaptation, offering a foundation for future research and applications in plant biology.

PMID:39952681 | DOI:10.1146/annurev-arplant-083123-050311

Adv Med Sci. 2025 Feb 12:S1896-1126(25)00009-4. doi: 10.1016/j.advms.2025.01.009. Online ahead of print.

NO ABSTRACT

PMID:39952431 | DOI:10.1016/j.advms.2025.01.009

J Adv Res. 2025 Feb 12:S2090-1232(25)00111-0. doi: 10.1016/j.jare.2025.02.013. Online ahead of print.

ABSTRACT

BACKGROUND: Despite notable advancements in AML therapy in recent years, a substantial proportion of patients remain refractory or at high risk of recurrence with limited efficacy. Therefore, it's urgent to develop novel drugs for treating AML.

METHODS: The small molecule drug library was utilized to screen for drugs that elicit the inflammatory death of AML cells. Cell viability, cell morphological analysis, western blotting, and RNA-seq were used to determine the pathway of Mebendazole (MBD)-induced AML cell death. Cell cycle analysis, protein expression profiling, molecular docking, western blotting and lentivirus overexpression were used to analyze the target protein of MBD in AML cells. The anti-AML activity of MBD in vivo was evaluated using tumor xenograft models constructed by AML cell lines and patient-derived primary AML cells.

RESULTS: In this study, we have identified Mebendazole (MBD), a conventional anthelmintic drug known for its low toxicity and cost, as a potent agent that exerts significant anti-AML effects in vitro. Furthermore, we have observed its inhibitory effects on the invasion of AML cell lines and primary AML cells in xenograft mouse models, while noting its negligible toxic side effects in normal mice in vivo. Mechanically, MBD inhibits the cell cycle in G2/M phase by inhibiting tubulin α1A (TUBA1A) and promotes ZBP-1 mediated PANoptosis in AML cells. Our results confirm that MBD exerts anti-AML activity in preclinical models.

CONCLUSION: These results highlight the remarkable clinical translational potential of MBD, providing new potential medicine for AML patients. In addition, TUBA1A can be used potential novel therapeutic target in tumors with abnormal TUBA1A expression.

PMID:39952321 | DOI:10.1016/j.jare.2025.02.013

Stem Cell Reports. 2025 Feb 8:102419. doi: 10.1016/j.stemcr.2025.102419. Online ahead of print.

ABSTRACT

Naive human pluripotent stem cells (hPSCs) model the pre-implantation epiblast. However, parent-specific epigenetic marks (imprints) are eroded in naive hPSCs, which represents an important deviation from the epiblast in vivo. To track the dynamics of imprint erasure during naive resetting in real time, we established a dual-colored fluorescent reporter at both alleles of the imprinted SNRPN locus. During primed-to-naive resetting, SNRPN expression becomes biallelic in most naive cells, and biallelic SNRPN expression is irreversible upon re-priming. We utilized this live-cell reporter to evaluate chemical and genetic strategies to minimize imprint erasure. Decreasing the level of MEK/ERK inhibition or overexpressing the KRAB zinc-finger protein ZFP57 protected a subset of imprints during naive resetting. Combining these two strategies protected imprint levels to a further extent than either strategy alone. This study offers an experimental tool to track and enhance imprint stability during transitions between human pluripotent states in vitro.

PMID:39952244 | DOI:10.1016/j.stemcr.2025.102419

Food Chem. 2025 Feb 10;475:143323. doi: 10.1016/j.foodchem.2025.143323. Online ahead of print.

ABSTRACT

Triterpenoid saponins, bioactive compounds with pharmaceutical relevance and functional food potential, are abundant in tea plants (Camellia sinensis), yet their structural diversity and tissue-specific distribution remain insufficiently explored. Using high-resolution mass spectrometry, Feature-based Molecular Networking, and imaging mass spectrometry (IMS), we profiled 52 tea saponins, including two novel trisaccharide saponins with unique glycosylation patterns. Aerial tissues, particularly buds and leaves, were enriched with cinnamoyl-decorated tetrasaccharide saponins, whereas roots predominantly accumulated di- and trisaccharide saponins, with significant cultivar-specific variation. IMS further revealed a compartmentalized root distribution, with di- and trisaccharide saponins localized in the epidermis and cortex, while tetrasaccharide saponins were concentrated in the stele. These findings advance understanding of the structural complexity and spatial accumulation of tea saponins, offering insights for bioactive compound extraction and informing breeding strategies to enhance saponin yield and diversity.

PMID:39952190 | DOI:10.1016/j.foodchem.2025.143323

Sci Adv. 2025 Feb 14;11(7):eadp4008. doi: 10.1126/sciadv.adp4008. Epub 2025 Feb 14.

ABSTRACT

Chimeric antigen receptor (CAR) T cells offer a promising cancer treatment, yet challenges such as limited T cell persistence hinder efficacy. Given its critical role in modulating T cell responses, it is crucial to understand how the CAR signaling architecture influences T cell function. Here, we designed a combinatorial CAR signaling domain library and performed repeated antigen stimulation assays, pooled screens, and single-cell sequencing to systematically investigate the impact of modifying CAR signaling domains on T cell activation and persistence. Our data reveal the predominant influence of membrane-proximal domains in driving T cell phenotype. Notably, CD40 costimulation was crucial for fostering robust and lasting T cell responses. Furthermore, we correlated in vitro generated CAR T cell phenotypes with clinical outcomes in patients treated with CAR T therapy, establishing the foundation for a clinically informed screening approach. This work deepens our understanding of CAR T cell biology and may guide future CAR engineering efforts.

PMID:39951542 | DOI:10.1126/sciadv.adp4008

J Virol. 2025 Feb 14:e0147824. doi: 10.1128/jvi.01478-24. Online ahead of print.

ABSTRACT

Influenza A viruses with fewer amino acids in the neuraminidase (NA) stalk domain are primarily isolated from chickens rather than wild ducks, indicating that a shortened NA stalk is considered an adaptation marker of avian influenza viruses (AIVs) to chickens. Experimental passages of an H7N7 nonpathogenic AIV (rgVac2-P0) in chickens resulted in a highly pathogenic variant (Vac2-P3L4) with a 34-amino-acid deletion in the NA stalk, encompassing five potential N-glycosylation sites. To investigate how amino acid truncation and deglycosylation in the NA stalk contribute to increased pathogenicity, a virus with glycosylation-deficient mutations at these sites (rgVac2-P3L4/P0NAΔGlyco) was constructed. Contrary to expectations, chickens inoculated with rgVac2-P3L4/P0NAΔGlyco exhibited variable clinical outcomes, attributed to the genetic instability of the virus. A single mutation stabilized the virus, and the mutant (rgVac2-P3L4/P0NAΔGlyco-Y65H) resulted in higher pathogenicity compared with a virus with restored glycosylation (rgVac2-P3L4/P0NA-Y65H). Glycan occupancy analysis revealed 3-4 glycans at the five potential sites. In functional analysis, glycosylation-deficient mutants, similar to the short-stalk NA virus, showed significantly reduced erythrocyte elution activity. Additionally, mutational analysis indicated variable contributions of N-glycans to elution activity across the sites. Moreover, the functionally most contributing sites of the five potential N-glycosylation motifs were consistently included in the amino acid deletions of the stalk-truncated NA in N7-subtyped field isolates, despite the varying truncation position or length. These findings suggest that the loss of glycosylation is functionally equivalent to a reduction in amino acids, and it plays a crucial role in enhancing pathogenicity in chickens and affecting NA function.IMPORTANCEAvian influenza poses significant economic challenges to the poultry industry and presents potential risks to human health. Understanding the molecular mechanisms that facilitate the emergence of chicken-adapted avian influenza viruses (AIVs) from non-pathogenic duck-origin influenza viruses is crucial for improving AIV monitoring systems in poultry and controlling this disease. Amino acid deletions in the neuraminidase (NA) stalk domain serve as one of the molecular markers for AIV adaptation to Galliformes. This study highlights the critical role of N-glycosylation in the NA stalk domain in the pathogenesis of high pathogenicity avian influenza viruses in chickens. The findings propose a novel theory that the loss of glycosylation at the NA stalk domain, rather than a reduction in stalk length, is responsible for both NA function and increased virus pathogenicity in chickens.

PMID:39950775 | DOI:10.1128/jvi.01478-24

Genetics. 2025 Feb 14:iyae215. doi: 10.1093/genetics/iyae215. Online ahead of print.

ABSTRACT

Studying mutation in healthy somatic tissues is the key for understanding the genesis of cancer and other genetic diseases. Mutation rate varies from site to site in the human genome by up to 100-fold and is influenced by numerous epigenetic and genetic factors including GC content, trinucleotide sequence context, and DNAse accessibility. These factors influence mutation at both local and regional scales and are often interrelated with one another, meaning that predicting mutability or uncovering its drivers requires modelling multiple factors and scales simultaneously. Historically, most investigations have focused either on analyzing the local sequence scale through triplet signatures or on examining the impact of epigenetic processes at larger scales, but not both concurrently. Additionally, sequencing technology limitations have restricted analyses of healthy mutations to coding regions (RNA-seq) or to those that have been influenced by selection (e.g. bulk samples from cancer tissue). Here, we leverage single-cell mutations and present a comprehensive analysis of epigenetic and genetic factors at multiple scales in the germline and 3 healthy somatic tissues. We create models that predict mutability with on average 2% error and find up to 63-fold variation among sites within the same tissue. We observe varying degrees of similarity between tissues: the mutability of genomic positions was 93.4% similar between liver and germline tissues, but sites in germline and skin were only 85.9% similar. We observe both universal and tissue-specific mutagenic processes in healthy tissues, with implications for understanding the maintenance of germline vs soma and the mechanisms underlying early tumorigenesis.

PMID:39950507 | DOI:10.1093/genetics/iyae215

Plant Cell Environ. 2025 Feb 14. doi: 10.1111/pce.15429. Online ahead of print.

ABSTRACT

Plant-microbe interactions have been studied extensively in legumes, but the influence of host developmental stages on its microbiome remains poorly understood. The rhizospheric region enriched with microbial diversity presents an optimal environment to investigate this relationship. We employed a multi-omics meta-analysis approach to identify the rhizospheric bacteria co-existing with legumes at different developmental stages. The data from eight different legume species across various geographical locations, soil conditions and developmental stages (vegetative, reproductive and maturation) were included in the study. A total of 10 developmental stage-specific marker bacteria were identified and found to be positively associated with plant growth phenotypes. The functional profiling elucidated the expression of these marker bacterial genes, indicating the active presence of marker bacteria. Co-expression network analysis revealed the involvement of gene clusters in biological processes such as cobalt and nitrogen metabolism. Further, pathway enrichment analysis illustrated the role of these bacteria in plant metabolic pathways, such as biosynthesis of various plant secondary metabolites, biotin metabolism and carbon fixation in photosynthetic organisms. Our study identified a positive relationship between marker bacteria and the host plant, suggesting their crucial role in legume growth and development that could further aid in crop improvement strategies.

PMID:39950378 | DOI:10.1111/pce.15429

F1000Res. 2024 Dec 20;13:1545. doi: 10.12688/f1000research.160121.1. eCollection 2024.

ABSTRACT

ADNP is a multifunctional protein involved in chromatin remodeling, transcription, and microtubule interaction, playing a critical role in brain development, with mutations linked to ADNP-Related Disorder. Here we have characterized seven ADNP commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

PMID:39949964 | PMC:PMC11822250 | DOI:10.12688/f1000research.160121.1

Chin Herb Med. 2024 Nov 9;17(1):178-188. doi: 10.1016/j.chmed.2024.11.003. eCollection 2025 Jan.

ABSTRACT

OBJECTIVE: Benzylisoquinoline alkaloids (BIAs) have pharmacological functions and clinical use. BIAs are mainly distributed in plant species across the order Ranunculales and the genus Phellodendron from Sapindales. The BIA biosynthesis has been intensively investigated in Ranunculales species. However, the accumulation mechanism of BIAs in Phellodendron is largely unknown. The aim of this study is to unravel the biosynthetic pathways of BIAs in Phellodendron amurens.

METHODS: The transcriptome and metabolome data from 18 different tissues of P. amurense were meticulously sequenced and subsequently subjected to a thorough analysis. Weighted gene co-expression network analysis (WGCNA), a powerful systems biology approach that facilitates the construction and subsequent analysis of co-expression networks, was utilized to identify candidate genes involved in BIAs biosynthesis. Following this, recombinant plasmids containing candidate genes were expressed in Escherichia coli, a widely used prokaryotic expression system. The purpose of this genetic engineering endeavor was to express the candidate genes within the bacteria, thereby enabling the assessment of the resultant enzyme activity.

RESULTS: The synonymous substitutions per synonymous site for paralogs indicated that at least one whole genome duplication event has occurred. The potential BIA biosynthetic pathway of P. amurense was proposed, and two PR10/Bet v1 members, 14 CYP450s, and 33 methyltransferases were selected as related to BIA biosynthesis. One PR10/Bet v1 was identified as norcoclaurine synthase, which could catalyze dopamine and 4-hydroxyphenylacetaldehyde into (S)-norcoclaurine.

CONCLUSION: Our studies provide important insights into the biosynthesis and evolution of BIAs in non-Ranunculales species.

PMID:39949809 | PMC:PMC11814251 | DOI:10.1016/j.chmed.2024.11.003

Front Immunol. 2025 Jan 30;16:1494446. doi: 10.3389/fimmu.2025.1494446. eCollection 2025.

ABSTRACT

INTRODUCTION: New biomarkers are urgently needed to detect pancreatic ductal adenocarcinoma (PDAC) at an earlier stage for individualized treatment strategies and to improve outcomes. Autoantibodies (AAbs) in principle make attractive biomarkers as they arise early in disease, report on disease-associated perturbations in cellular proteomes, and are static in response to other common stimuli, yet are measurable in the periphery, potentially well in advance of the onset of clinical symptoms.

METHODS: Here, we used high-throughput, custom cancer antigen microarrays to identify a clinically relevant autoantibody biomarker combination able to differentially detect PDAC. Specifically, we quantified the serological AAb profiles of 94 PDAC, chronic pancreatitis (CP), other pancreatic- (PC) and prostate cancers (PRC), non-ulcer dyspepsia patients (DYS), and healthy controls (HC).

RESULTS: Combinatorial ROC curve analysis on the training cohort data from the cancer antigen microarrays identified the most effective biomarker combination as CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Additionally, differential expression analysis on the samples run on the iOme™ array identified 4 biomarkers (ALX1-GPA33-LIP1-SUB1) upregulated in PDAC against diseased and healthy controls. Identified AAbs were validated in silico using public immunohistochemistry datasets and experimentally using a custom PDAC protein microarray comprising the 11 optimal AAb biomarker panel. The clinical utility of the biomarker panel was tested in an independent cohort comprising 223 PDAC, PC, PRC, colorectal cancer (CRC), and HC samples. Combinatorial ROC curve analysis on the validation data identified the most effective biomarker combination to be CEACAM1-DPPA2-DPPA3-MAGEA4-SRC-TPBG-XAGE3 with an AUC = 85·0% (SE = 0·828, SP = 0·684). Subsequently, the specificity of the 11-biomarker panel was validated against other cancers (PDAC vs PC: AUC = 70·3%; PDAC vs CRC: AUC = 84·3%; PDAC vs PRC: AUC = 80·2%) and healthy controls (PDAC vs HC: AUC = 80·9%), confirming that this novel AAb biomarker panel is able to selectively detect PDAC amongst other confounding diseases.

CONCLUSION: This AAb panel may therefore have the potential to form the basis of a novel diagnostic test for PDAC.

PMID:39949781 | PMC:PMC11821970 | DOI:10.3389/fimmu.2025.1494446

Front Cell Dev Biol. 2025 Jan 30;12:1490902. doi: 10.3389/fcell.2024.1490902. eCollection 2024.

ABSTRACT

Mitophagy is a critically important survival mechanism in which toxic, aged, or defective mitochondria are segregated into mitophagosomes, which shuttle the damaged mitochondrial segments to the lysosome and proteasome for destruction. Cancer cells rely on mitophagy under conditions of high oxidative stress or increased energy demand. Oxidative stress can generate a large volume of damaged mitochondria, overwhelming lysosomal removal. Accumulated damaged mitochondria are toxic and their proper removal is crucial for maintaining mitochondrial health. We propose a new cancer cell mechanism for survival that is activated when the demand for segregating and eliminating damaged mitochondria exceeds the capacity of the lysosome or proteasome. Specifically, we show that tumor cells subjected to oxidative stress by carbonyl cyanide-3-chlorophenylhdrazone (CCCP) eliminate damaged mitochondria segments by bypassing the lysosome to export them outside the cell via extracellular vesicles (EVs), a process termed "secretory mitophagy". PINK1, the initiator of mitophagy, remains associated with the damaged mitochondria that exported in EVs. Using several types of cancer cells, we show that tumor cells treated with CCCP can be induced to switch over to secretory mitophagy by treatment with Bafilomycin A1, which blocks the fusion of mitophagosomes with lysosomes. Under these conditions, an increased number of PINK1 + EVs are exported. This is associated with greater cell survival by a given CCCP dose, enhanced mitochondrial ATP production, and reduced mitochondrial oxidative damage (membrane depolarization). Our data supports the hypothesis that secretory mitophagy is a previously unexplored process by which cancer cells adapt to survive therapeutic or hypoxic stress. Ultimately, our findings may inform new prevention strategies targeting pre-malignant lesions and therapeutic approaches designed to sensitize tumor cells to oxidative stress-inducing therapies.

PMID:39949610 | PMC:PMC11821619 | DOI:10.3389/fcell.2024.1490902

Endocr Oncol. 2025 Feb 5;5(1):e240025. doi: 10.1530/EO-24-0025. eCollection 2025 Jan.

ABSTRACT

Neuroendocrine tumors (NETs) occur sporadically or as part of rare endocrine tumor syndromes (RETSs) such as multiple endocrine neoplasia 1 and von Hippel-Lindau syndromes. Due to their relative rarity and lack of model systems, NETs and RETSs are difficult to study, hindering advancements in therapeutic development. Causal or mechanistic mathematical modeling is widely deployed in disease areas such as breast and prostate cancers, aiding the understanding of observations and streamlining in vitro and in vivo modeling efforts. Mathematical modeling, while not yet widely utilized in NET research, offers an opportunity to accelerate NET research and therapy development. To illustrate this, we highlight examples of how mathematical modeling associated with more common endocrine cancers has been successfully used in the preclinical, translational and clinical settings. We also provide a scope of the limited work that has been done in NETs and map how these techniques can be utilized in NET research to address specific outstanding challenges in the field. Finally, we include practical details such as hardware and data requirements, present advantages and disadvantages of various mathematical modeling approaches and discuss challenges of using mathematical modeling. Through a cross-disciplinary approach, we believe that many currently difficult problems can be made more tractable by applying mathematical modeling and that the field of rare diseases in endocrine oncology is well poised to take advantage of these techniques.

PMID:39949335 | PMC:PMC11825163 | DOI:10.1530/EO-24-0025

Euro Surveill. 2025 Feb;30(6). doi: 10.2807/1560-7917.ES.2025.30.6.2400166.

ABSTRACT

BackgroundThe global dissemination of ceftriaxone-resistant Neisseria gonorrhoeae FC428-like strains poses a public health concern. To assess and follow their spread, establishing effective antimicrobial resistance (AMR) surveillance systems is essential.AimThis study aimed to track ceftriaxone-resistant FC428-like strains in parts of China, using a molecular screening tool.MethodsSamples were collected from Sichuan, Zhejiang, Shanghai, and Guangdong provinces between 2019 and 2021. We employed a rapid molecular tool - the high-resolution melting analysis-based FC428 (HRM-FC428) assay, to screen for FC428-like strains. All FC428-like strains detected were further characterised by genotyping and PCR-sequencing.ResultsOf 1,042 tested samples, 44 harboured the penA-60.001 allele linked to ceftriaxone resistance, revealing a 4.2% prevalence of FC428-like strains. The HRM-FC428 assay additionally uncovered six strains with mosaic penA-195.001 or penA-232.001 alleles, both bearing the A311V mutation, a ceftriaxone resistance marker. During the study, the prevalence of FC428-like strains among overall samples appeared to increase, with rates of 2.8% (11/395) in 2019, 4.2% (16/378) in 2020, and 6.3% (17/269) in 2021. Some strains' sequence types (ST)s were identified across provinces (e.g. ST1903, ST1600) and most strains (24/44) were ST1903, an ST also reported in other regions/countries, suggesting local evolution and global transmission.ConclusionOur work underscores the value of culture-independent antimicrobial resistance monitoring and validates the use of molecular diagnostic tools, like the HRM-FC428 assay for this purpose. This study offers insights into the complex landscape of ceftriaxone-resistant N. gonorrhoeae, emphasising the importance of continued surveillance and global collaboration to mitigate this growing public health threat.

PMID:39949323 | DOI:10.2807/1560-7917.ES.2025.30.6.2400166