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PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗
PubMed2026

Single-organ proteomics in Drosophila melanogaster larva.

The combination of genetic accessibility, organ complexity, evolutionary conservation, and cost-efficiency makes Drosophila melanogaster (Dm) a well-known model system for biomedical and fundamental biological research. Proteomic analysis of single organs enables the identification and quantification of proteins expressed in specific organs. This will help to uncover specific biological functions and unique protein profiles that are not detectable in whole-organism analyses. In this study we have isolated single organs form Dm larvae, and we have performed a deep proteomics mapping by following a minimal manipulation preparation procedure. The combined dataset across all organs comprised 9132 identified proteins. As anticipated, principal component analysis (PCA) revealed clear separation between the proteomes of most organs, confirming distinct protein profiles. These findings demonstrate the applicability of the sample preparation strategy for high-resolution proteomic characterization of individual organs in Drosophila. Given the extensive genetic tools available for this model organism, our approach has the potential to open new avenues for proteomic studies in Drosophila melanogaster and any other biological systems where the sample amount is limiting. SIGNIFICANCE STATEMENT: Drosophila melanogaster is a well-known model system for biomedical and fundamental biological research that serves as a valuable in vivo model organism due to its high degree of evolutionary conservation with higher vertebrates, tractable genetics, and logistical efficiency. However, the proteome of Drosophila at single organ level has been elusive to date, due to several factors like low sensitivity of previous generation mass spectrometers and sample preparation procedures, difficult isolation of some organs. In this study we have applied a compilation of advanced methods including minimal sample manipulation together with simple, straightforward and efficient protein extraction and digestion methods. Obtained peptides were minimally handled to be analyzed by applying specific and sensitive nLC methods coupled on-line to state-of-the-art MS/MS system. Altogether, the applied strategy allowed us to get the first single organ study to date for this animal. These datasets represent a significative resource for future genomic, transcriptomic and proteomic studies in Drosophila, as multi-omic integration requires deep proteomics to translate data into functional biochemistry, and serves as a critical bridge and an indispensable standalone resource across the genomic, transcriptomic, and proteomic landscapes.

Animals↗
PubMed2026

Targeting SIRT6: the design and therapeutic implications of activators and inhibitors.

Sirtuin 6 (SIRT6) is an NAD+-dependent deacylase that maintains genomic stability, regulates metabolism, and influences aging, making it an attractive but challenging therapeutic target. Pharmacological modulation of SIRT6 holds promise for cancer and metabolic disorders, yet its context-dependent functions demand precise intervention strategies. Potent, selective, and drug-like chemical probes are therefore essential to dissect SIRT6 biology and to validate its therapeutic potential. This review critically evaluates recent medicinal chemistry advances in SIRT6 modulation. We focus on structure-guided design strategies and structure-activity relationships (SAR) that have transformed initial hits into optimized leads for both activators and inhibitors, highlighting the remaining challenges in achieving isoform selectivity and drug-like properties.

Sirtuins↗
PubMed2026

The identification of growth-promoting lncRNAs in oral cavity squamous cell carcinoma.

Oral Cavity Squamous Cell Carcinoma (OCSCC) is an aggressive tumor that develops within the mouth of patients. Tumor-suppressor gene loss and genomic arrangements fuel tumorigenesis and transcriptional reprogramming. Understanding how these alterations contribute to OCSCC growth and cell survival may identify new therapeutic vulnerabilities or biomarkers. We profiled the role of long non-coding RNAs (lncRNAs) in the growth of three OCSCC cell lines using a CRISPRi-screen and identified 19 lncRNAs that contribute to OCSCC proliferation. By comparing these lncRNAs to other screens, we find that these lncRNAs are uniquely required in OCSCC and not other malignancies. We show that these lncRNAs are abundantly expressed in OCSCC cells and tumors. Independent testing of candidate lncRNAs confirms their role in supporting OCSCC growth. Our results show that a novel subset of lncRNAs are required for the growth of OCSCC cancer cells and that these lncRNAs are cell lineage specific.

CRISPRi↗
PubMed2026

Genetic overlap between estimated glomerular filtration rate and cardiovascular disease identifies potential targets for cardiorenal syndrome.

Heart and kidney diseases frequently coexist, but the genetic basis of this relationship remains unclear. We analyzed genetic data from large-scale studies to investigate how kidney function (estimated glomerular filtration rate, eGFR) and six common cardiovascular diseases share genetic risk factors. Using MiXeR method, and conjunctional false discovery rate (conjFDR) to identify overlapping genetic regions, we found 478 shared genomic loci between eGFR and cardiovascular diseases. These shared genes are involved in tissue development and structure. We also identified 29 genes that could be targeted by existing medications approved by the US Food and Drug Administration, such as PRKAG2, PDE1A, and IGF1R. Among these, genetically predicted higher level of IGF1R expression is associated with a higher eGFR, which reflects good kidney function and is protective against cardiorenal diseases, such as atrial fibrillation, and myocardial infarction. These findings reveal genetic overlap between kidney function and cardiovascular diseases, highlighting potential targets for understanding and treating cardiorenal syndrome.

Humans↗
PubMed2026

O'nyong-nyong virus adaptive mutations in non-structural protein 1 and 3 enhance RNA replication and overcome FHL1 requirement.

Arthritogenic alphaviruses, like o'nyong-nyong virus (ONNV), cause debilitating musculoskeletal diseases and are geographically expanding. To predict their emergence, we seek to better understand evolutionary mechanisms that enable changes in virus tropism. Here, we identify adaptive mutations in the ONNV non-structural proteins (nsPs) that arose during cellular serial passaging and enabled ONNV to infect non-permissive Lunet cells. Using shotgun proteomics, we show that this human hepatoma cell line lacks the four-and-a-half-LIM domain protein 1 (FHL1), an essential host factor in ONNV RNA replication. Individual single nucleotide mutations in the nsP1 ring-aperture membrane-binding and oligomerization domain, the nsP3 macrodomain, and the nsP3 opal stop codon overcome FHL1 deficiency in Lunet cells by enhanced RNA replication. These findings demonstrate how subtle genomic changes in nsPs can profoundly influence alphavirus replication and tropism.

LIM Domain Proteins↗
PubMed2026

Induced degradation of Ufd1 reveals regulation of cohesin by the VCP/p97Ufd1-Npl4 complex.

The AAA ATPase VCP/p97 has emerged as a critical regulator of ubiquitin and chromatin-associated processes but progress in understanding has been hampered by the complexity of p97 functions and the various p97 cofactors involved. Here, we combined ubiquitin profiling with acutely induced degradation of the Ufd1 subunit of the p97 ubiquitin adapter, Ufd1-Npl4, in human cells. We identified a set of chromatin regulators, HUS1, XRCC1, MORF4L1, and the cohesin subunit RAD21 as targets of p97Ufd1-Npl4 We find that RAD21 is ubiquitylated and targeted by p97Ufd1-Npl4 specifically in S phase to remove a subpopulation of cohesin from chromatin. Acute degradation of Ufd1 in S phase, after replication licensing is completed, impedes replication and leads to replication-associated DNA damage. Our findings suggest that a fraction of cohesin rings need to be removed by p97Ufd1-Npl4 from DNA to allow unhindered replication and reveal a critical function of p97 that ensures genome stability.

Cell Cycle Proteins↗
PubMed2026

Insights into specific and nonspecific butyrate-producing pathways during the in vitro fecal fermentation of butyrylated starch.

Butyrylated starch is a special type-4 resistant starch with butyrate-carrying attribute. In this study, the unique butyrate-producing capability of butyrylated starch was deeply investigated by focusing on its specific and nonspecific butyrate-producing pathways, respectively, using specially designed substrates as controls. In vitro fermentation studies revealed that butyrylated and isobutyrylated starches generated high levels of butyrate and isobutyrate, respectively, highlighting the role of butyryl group metabolism in the specificity of butyrate production. Carboxylesterase assays have demonstrated that butyryl group metabolism is primarily facilitated by carbohydrate esterases expressed in the gut microbiota. Combined with 16S rRNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, it was found that butyrylated starch fermentation did not significantly enhance traditional butyrate synthesis pathways but modified the balance between the butyryl-CoA:acetyl-CoA transferase and butyrate kinase pathways by altering the gut microbiota composition, specifically by upregulating the relative abundance of indicator species such as Bacteroides, the Lachnospiraceae_NK4A136_group, and Parabacteroides. These insights offer theoretical guidance for designing butyrylated starch structures and regulating intestinal health.

Starch↗
PubMed2026

Pervasive hybridization and introgression in Diervilleae (Caprifoliaceae).

Diervilleae (Caprifoliaceae) is a horticulturally important lineage with striking floral diversity and a long history of interspecific crossing, suggesting reticulate evolution. We integrated nuclear SNPs and whole plastome data to reconstruct a phylogenomic backbone for the tribe and to identify hybrids, cultivated accessions, and introgression among lineages. Nuclear and plastid phylogenies consistently recover Weigela and Diervilla as reciprocally monophyletic and resolve four major lineages within Weigela, providing a reproducible framework for revising sectional limits and species boundaries. Cultivated accessions form a well supported clade sister to W. florida and show predominantly W. florida ancestry while retaining contributions from multiple wild lineages, consistent with recurrent crossing, backcrossing, and selection. Analyses of wild populations reveal recurrent hybrids and enable plausible parental combinations to be inferred. Tests across the genome further indicate strong evidence for historical introgression across Diervilleae, with the strongest signals involving W. middendorffiana, W. maximowiczii, and Diervilla. Fossil evidence, divergence time estimation, and paleodistribution modelling together suggest range expansion during the Miocene and Pliocene followed by climate driven contraction, providing a spatiotemporal context for episodic contact, introgression, and the East Asia-North America disjunction.

Hybridization, Genetic↗
PubMed2026

Structural and physicochemical characterisation of branched dextrans produced by an active α-(1→2) branching sucrase from Apilactobacillus kunkeei PDER37.

Recently, branching sucrases encoded in the genomes of certain Lactic Acid Bacteria (LAB) strains have become novel enzymes to obtain branched α-glucans. In this study an active α-(1 → 2) branching sucrase from Apilactobacillus kunkeei PDER37 was expressed, characterised and distinct branched dextrans was obtained with reactions under different sucrose: dextran ratio. Structural characterisation by 1H and 13C NMR analysis demonstrated the branching of the dextran with (1 → 2)-linked α-d-glucose units with no alteration in the final structure depending on sucrose: dextran ratio (D0) but this ratio was effective for the determination of the molecular weights of the branched dextrans (D1, D2 and D3). FTIR analysis further supported the dextran structures and suggested the higher accumulation of the α-Glc units in the branched dextrans. Thermal characterisation of the branched dextrans obtained by TGA and DSC analysis suggested the increased hygroscopicity of the branching units. Both SEM and AFM analysis demonstrated more porous chain like structures in the branched dextrans. This study provides valuable information on the role of active α-(1 → 2) branching sucrase (BS37) for the production of branched dextrans with potential increased physicochemical status applicable for food and other industries.

Dextrans↗
PubMed2026

Proteomics in environmental pollution research: Advances, challenges, and future directions.

Environmental proteomics has emerged as a powerful approach for elucidating the molecular mechanisms underlying pollutant-induced biological effects. Although this field has developed rapidly, the systematic review of recent proteomics applications in environmental pollution research remains limited. This review explored the emerging roles of toxicoproteomics in biomarker discovery and mechanistic elucidation, as well as ecotoxicoproteomics in ecological risk assessment and bioremediation strategies. Here, we review the field, highlighting recent trends such as the integration of proteomics with genomics, transcriptomics, and metabolomics to provide a comprehensive view of biological responses to environmental stressors. We further discuss the growing application of artificial intelligence in improving proteomics data interpretation and accelerating biomarker discovery. In addition, recent technological advances in environmental proteomics are highlighted, including next-generation tissue microarray proteomics, nanoscale proteomics, single-cell proteomics, and spatial proteomics. Despite its potential, proteomics faces challenges, such as high operational costs, computational complexity in analysis, and technical limitations in low-abundance protein detection. We propose that the convergence of proteomics with artificial intelligence and multi-omics approaches offers promising solutions to these challenges, enhancing the practical application of proteomics in environmental monitoring and risk assessment.

Proteomics↗
PubMed2026

Sitosterolemia: evolving strategies for earlier diagnosis.

PURPOSE OF REVIEW: Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8 , resulting in excessive intestinal absorption and impaired biliary excretion of plant sterols. Although historically considered exceptionally rare, recent genetic studies suggest the disorder is substantially underdiagnosed, with marked phenotypic heterogeneity ranging from xanthomas and premature atherosclerosis to hematologic abnormalities, and frequently mimics familial hypercholesterolemia. This review summarizes recent advances in the clinical, biological, and genetic diagnosis of sitosterolemia, with a focus on strategies that may facilitate earlier detection. RECENT FINDINGS: Phytosterol quantification, particularly sitosterol, campesterol, and stigmasterol, remains indispensable for accurate diagnosis. Hematologic abnormalities, including hemolytic anemia, stomatocytosis, and macrothrombocytopenia, are increasingly recognized as valuable diagnostic clues complementing the biochemical approach. Expanded variant catalogs for ABCG5/ABCG8 and genome-wide association studies have revealed potentially polygenic contributions to phytosterol metabolism extending beyond these two genes. However, no specific guidelines have yet been established for cascade screening. SUMMARY: Earlier diagnosis requires integration of clinical, biochemical, hematologic, and genetic data. Plasma phytosterol measurement remains the diagnostic cornerstone. Improved disease awareness, broader access to sterol testing, and expanded genetic screening may reduce diagnostic delays and enable timely management, including ezetimibe and dietary phytosterol restriction.

Humans↗
PubMed2026

Targeted Nanoparticle Delivery CRISPR/Cas9: overcoming biological barriers, enhancing stability, and improving therapeutic precision.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a promising gene-editing platform for genetic disorders; however, its in vivo application remains limited by low delivery efficiency and biological barriers. Many CRISPR payloads fail to reach target sites due to extracellular degradation, immune clearance, and intracellular trafficking limitations. This review examines the interplay between biological barriers and nanoparticle engineering strategies for CRISPR/Cas9 delivery. A barrier-oriented engineering approach is proposed as a central framework, encompassing ligand-based surface modification for enhanced targeting and uptake, improved circulation stability via PEGylation and biomimetic coatings, and optimized payload release through endosomal escape strategies. Stimulus-responsive nanoparticle systems further enable spatiotemporal control over payload release. Nuclear targeting strategies, including optimization of nuclear localization signals (NLS) and exploitation of endogenous trafficking pathways, are highlighted as key factors for improving genome-level editing efficiency. Despite these advances, major challenges-including limited intracellular delivery efficiency, insufficient targeting precision, and safety concerns-continue to hinder clinical translation. Future directions highlight artificial intelligence-driven nanoparticle design, personalized delivery systems, and next-generation CRISPR platforms. Overall, an integrated, barrier-oriented engineering strategy is essential for advancing CRISPR/Cas9 delivery toward clinical applications, ultimately advancing global good health and well-being.

CRISPR/Cas9↗
PubMed2026

LitCTL1: A novel C-type lectin involved in the mucosal and cellular immunity of the common periwinkle Littorinalittorea.

C-type lectins (CTLs) are vital pattern-recognition receptors (PRRs) that mediate innate immune responses in mollusks, yet their characterization in Caenogastropoda, the largest gastropod group, remains limited. This study characterizes LitCTL1, a novel secreted single-domain C-type lectin from the common periwinkle, Littorina littorea. The 199-amino acid polypeptide contains a conserved carbohydrate recognition domain with canonical QPD and WND motifs and is predicted to form a homodimer. Uniquely, LitCTL1 was localized in both circulating hemocytes and mucus-secreting epithelial cells of the foot, mantle, and hypobranchial gland - the first report of such dual localization for a molluscan lectin, linking systemic and mucosal defense. Expression analysis revealed that LitCTL1 is constitutively expressed in hemocytes. Functional assays with recombinant LitCTL1 demonstrated its role as a potent opsonin with hemagglutinating activity, significantly enhancing hemocyte spreading and the phagocytosis of zymosan. Genomic analysis reveals that LitCTL1 belongs to a rapidly diversifying, genus-specific expansion distinct from conserved perlucin-like lineages. These results identify LitCTL1 as a key effector molecule in both systemic and mucosal innate immunity, likely reflecting an evolutionary adaptation to the microbial challenges of the intertidal environment.

Animals↗
PubMed2026

Functional characterization of the MdFLZ2 gene in drought and salt stress tolerance in apple.

Drought and salt stress are significant environmental limitations that severely constrain plant growth and productivity, therefore, enhancing stress tolerance is a key goal in crop improvement. The plant-specific FCS-like zinc finger (FLZ) proteins have been identified as important regulators of stress adaptation. In this study, we conducted a genome-wide characterization of the FLZ gene family in apple and functionally characterized MdFLZ2. qRT-PCR analysis revealed that MdFLZ2 was differentially expressed across various tissues and transcriptionally induced by both drought and salt stress. Subcellular localization assays demonstrated that the MdFLZ2 protein is localized to both the nucleus and the cytoplasm. The overexpression of MdFLZ2 in apple calli, Arabidopsis and tomato conferred increased resistance to drought and salt stress. In addition, yeast two-hybrid (Y2H) assays confirmed that MdFLZ2 interacted with MdSnRK1.1, and similar interactions were also detected between other MdFLZ family members and MdSnRK1.1. Collectively, our findings suggest MdFLZ2 as a positive regulator of drought and salt tolerance and highlight its potential to serve as a genetic resource for abiotic stress improvement.

Malus↗
PubMed2026

CNNM2 in schizophrenia: multilevel evidence of genetic susceptibility, magnesium homeostasis, neurodevelopment and cognitive dysfunction.

Schizophrenia (SCZ) is a common psychiatric disorder with a complex, genetically and environmentally influenced etiology, but the specific pathogenesis remains unclear. In recent years, the SCZ susceptibility gene CNNM2 (encoding cyclin M2) located at the 10q24.32-33 locus has received widespread attention. The well-validated SCZ risk interval 10q24.32-33 harbors two independent risk variants: rs11191580 in NT5C2 (significantly associated with CNNM2 mRNA and protein levels) and rs7914558 in CNNM2. Results from functional genomic analyses indicate that lower CNNM2 expression is significantly associated with SCZ. Imaging genetics studies have demonstrated that carriers of risk alleles of CNNM2 SNPs exhibit alterations in brain structure. Animal model studies have revealed that Cnnm2 downregulation in mice leads to impairments in sensorimotor gating and cognitive function. As an Mg2+ transporter, CNNM2 primarily maintains systemic Mg2+ homeostasis. According to clinical studies, a proportion of patients with SCZ exhibit reduced Mg2+ concentrations in plasma and cerebrospinal fluid. CNNM2 dysfunction may contribute to the pathology of SCZ by disrupting Mg2+ homeostasis, thereby affecting neurodevelopment and synaptic plasticity. A systematic consolidation of current evidence supporting the involvement of CNNM2 in SCZ pathogenesis provides a direction for further investigation of the pathological mechanisms underlying this disease, and for identification of novel targets for clinical intervention..

Schizophrenia↗
PubMed2026

Complex evolutionary history of Rosales mediated by extensive incomplete lineage sorting and hybridization.

The angiosperm order Rosales still represents a major challenge for phylogenetic reconstruction. Although its circumscription is now well-defined, phylogenetic relationships among families are still uncertain. Here, we used nuclear, plastid, and mitochondrial genomic data from 33 species representing all nine families to further clarify interfamilial relationships and the group's evolutionary history. We detected significant phylogenetic conflict among the three datasets. Further analyses at the nuclear level identified incomplete lineage sorting (ILS) as the main cause of unstable phylogenetic positions among families. The discordant placements of Rhamnaceae and Elaeagnaceae based on plastid and mitochondrial data are caused by ancient hybridization events, potentially involving differences in organellar inheritance. Our molecular dating confirms earlier suggestions that the ancient rapid diversification of the three Rosaceae subfamilies could be the main reason for the difficulties in resolving their phylogenetic relationships. Our findings provide new insights into the interfamilial relationships of Rosales and demonstrate that the evolutionary history of this order was shaped by ancient and rapid radiation as well as extensive ILS and reticulate evolution. They also suggest that previous attempts to clarify interfamilial relationships in this order were hampered by combining nuclear and organellar sequence data, leading to inconsistent topologies observed across earlier studies.

Phylogeny↗
PubMed2026

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

PURPOSE OF REVIEW: Hereditary hearing loss has historically been approached as a diagnostic category rather than a therapeutically modifiable disease. Recent advances in molecular genetics, cochlear gene delivery, and first-in-human clinical trials are changing that. This review summarizes contemporary progress in the genetics of hearing loss, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice. RECENT FINDINGS: Early clinical trials targeting OTOF -related DFNB9 deafness have demonstrated satisfactory safety profiles and meaningful auditory recovery, establishing the first proof-of-concept for cochlear gene therapy in humans, culminating in the April 2026 FDA approval of Otarmeni. Genetic diagnoses are increasingly informing prognosis, cochlear implant counseling, and therapeutic candidacy. Preclinical research continues to expand toward recessive, dominant, and syndromic hearing loss using gene replacement, antisense, RNA interference, and genome-editing strategies. Substantial challenges remain, including heterogeneous outcome measures, uncertain long-term efficacy, regulatory complexity, and inequitable global access. SUMMARY: The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one. Widespread clinical impact will require advances in vector engineering, equitable implementation, multidisciplinary counseling, and integration with established rehabilitation pathways. For otolaryngologists, genetic literacy is becoming essential to contemporary hearing care.

Humans↗