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#预印本

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Oct 9Fri
  1. biorxiv.org45

    Collagen-dependent DDR1 ectodomain shedding regulates proliferative signaling in radiation-resistant glioblastoma

    Radiation-resistant glioblastoma cells in a three-dimensional collagen I matrix show a distinct DDR1 regulatory state: despite higher DDR1 expression, they have reduced DDR1 phosphorylation and enhanced ectodomain shedding, with accumulation of the membrane-associated C-terminal fragment and release of the N-terminal fragment. ADAMTS1 was upregulated in resistant cells, and its knockdown reduced shedding while increasing full-length DDR1, ERK1/2 and RB phosphorylation, cyclin D1, and Ki-67 positivity. The work identifies extracellular-matrix-dependent DDR1 processing as a regulator of proliferative signaling in acquired radiation resistance.

  2. medrxiv.org50

    A spatial AI-based biomarker with independent prognostic value in early low- and intermediate- risk breast cancer

    Clusters of high-grade morphology at the invasive tumour front, detected with the ViT_DG vision-transformer on whole slide images, independently predicted outcome in ER-positive/HER2-negative/lymph-node-negative Grade 1-2 breast cancer. In a Swedish multicentre cohort (6106 patients; 1403 test patients in the primary subgroup), cluster positivity carried a 2.30-fold increased recurrence risk, and cluster-negative patients reached a 10-year breast-cancer recurrence-free interval of 95.3%. The marker also flagged risk (HR 2.86) among patients scored low-risk by the global AI biomarker.

  3. biorxiv.org56

    Cerberus: bidirectional state space blocks improve accuracy and efficiency of regulatory sequence models

    Replacing Borzoi's transformer blocks with Hydra, a bidirectional Mamba-2-based state space block, yields regulatory sequence models that run 5.7-fold faster on 8,192-token inputs and predict binned coverage and fine-mapped eQTLs more accurately. Scaled into Cerberus, an ensemble of eight models over 786 kb of input, the architecture beats Borzoi on GTEx v11 eQTL, sQTL and paQTL benchmarks, with mean eQTL AUPRC of 0.692 versus 0.668 across 48 tissues and effect-size Spearman ρ of 0.379 versus 0.321. Trained blocks show interaction range growing with depth, from a 0.9 kb median half-life in the first block to 79 kb in the seventh.

  4. biorxiv.org50

    Fine-tuning genomic models on rare splicing events identifies a novel biomarker of TDP-43 pathology

    Fine-tuned OpenSpliceAI, a specialized splice site prediction model, outperformed a splicing head on AlphaGenome's frozen backbone for detecting TDP-43 cryptic exons, though fine-tuning all AlphaGenome weights enabled generalization to held-out data. Genome-wide application of fine-tuned OpenSpliceAI identified new cryptic splicing events in CLDN11 and ARHGAP23, validated in FTLD-TDP brain tissue. The CLDN11 cryptic exon is predicted to generate a neoepitope that could serve as an oligodendrocyte-specific biomarker of TDP-43 pathology.

  5. biorxiv.org59

    The adaptive architecture of tRNA dependencies across physiological tumor environments

    tRNA dependencies are environmentally plastic and non-redundant, according to large-scale CRISPRi perturbation mapping across matched in vivo tumor growth and in vitro culture in 16 cancer cell lines from seven tissue types. In vivo, tRNA dependencies showed tissue organization at isodecoder resolution and linked to codon demand at the isoacceptor level, and these relationships reorganized in vitro, unlike aminoacyl-tRNA synthetase dependencies. A shared axis of isoacceptor dependency remodeling ties specific tRNAs to adaptation and to translation of codon-usage-biased programs for proliferation and tumor-microenvironmental stress.

  6. biorxiv.org58

    High-throughput identification of chromatin-opening transcription factors

    Pooled CRISPR activation of endogenous transcription factors in mouse embryonic stem cells reveals which TFs can open chromatin when newly expressed. After screening guides targeting 240 developmental TFs, the authors profiled gene expression and chromatin accessibility in ~140,000 single cells for 60 TFs. Some, like Cdx2 and Sox10, open distal sites on their own, while others require co-TFs through preexisting heterogeneity or hierarchical activation, such as Sox7 inducing Gata6.

  7. biorxiv.org48

    Targeting ribosome biogenesis sensitizes PARPi-resistant triple-negative breast cancer

    Inhibiting ribosome biogenesis with BMH-21 resensitizes PARPi-resistant triple-negative breast cancer to olaparib. The drug combination was synergistic in 4 PARPi-resistant cell lines and in 3 BRCA wild-type TNBC cell lines with intrinsic PARPi resistance, but not in parental cells. In MDAMB231 cells, the combination increased γH2AX-positive cells up to 7.3-fold, SA-β-gal staining 5.6-fold and p21 3.6-fold, findings mirrored with CX-5461. Patient cohort data linked ribosomal pathway activity to MYC, proliferation, DNA damage and senescence.

  8. biorxiv.org56

    Loss of the Y chromosome is transcriptionally silent in clear cell renal cell carcinoma and across cancer entities

    Loss of the Y chromosome is transcriptionally silent in clear cell renal cell carcinoma and across other cancer entities. Across two human ccRCC cohorts (TCGA-KIRC, CPTAC-ccRCC), a murine ccRCC model and five isogenic Y-deficient versus five Y-retaining 786-O clones, transcriptional changes were largely limited to gene dosage effects on MSY and PAR genes, with only modest pathway-level shifts in cell cycle, ribosomal biogenesis and DNA repair. Y-chromosomal genes are therefore unlikely to act as transcriptional drivers of ccRCC or other cancers.

  9. biorxiv.org55

    scPRIME-seq uncovers synchronized multimodal molecular collapse facilitated by pre-neoplastic epigenetic burden in prostate cancer

    scPRIME-seq, a high-throughput platform for simultaneous single-cell profiling of transcriptome, genome and DNA methylome, was applied to 436,908 cells from 29 prostate cancers and 15 benign tissues, resolving 30 cell types along a unified tumorigenic trajectory. The analysis located a tipping point where aneuploidy onset is temporally coupled with global methylomic alterations and transcriptomic rewiring. Early focal epigenetic alterations, including TMEM106A promoter hypermethylation, were present in founder aneuploid clones and benign tissues, pointing to a pre-neoplastic origin of the epigenetic burden and a tumor-permissive microenvironment.

  10. biorxiv.org65

    The Red Blood Cell Surface Defines a Distinct Tumor DNA Compartment for Liquid Biopsy

    Red blood cells tether and retain tumor-derived DNA on their surface, forming a distinct circulating pool of RBC-bound tumor DNA (rtDNA), with desialylation increasing capture in a Toll-like receptor 9-dependent manner. In mice bearing lung cancer xenografts, rtDNA was detected in all animals and tracked tumor burden while plasma tumor DNA was undetectable; in patients with lung cancer, most detected mutant tumor DNA was RBC-associated and concordant with matched tumor tissue. The findings challenge the plasma-centric liquid biopsy paradigm by identifying the RBC surface as a tunable reservoir of tumor DNA.

    Why it matters: It identifies red blood cells, not plasma, as the main circulating compartment of tumor DNA for liquid biopsy.

  11. biorxiv.org60

    STEER-seq: a recombinase based platform for pooled multimodal single-cell perturbation screening

    STEER-seq is a virus-free platform for pooled ORF gain-of-function screening in human induced pluripotent stem cells, using Bxb1-mediated integration at a defined safe-harbour locus so each perturbation is expressed from a single copy in a common genomic context. Joint RNA and chromatin accessibility profiling linked transcription factor responses to chromatin remodelling. In a haematopoietic screen, SPI1 alone drove differentiation to HSC/MPP-like progenitors without exogenous cytokines, and scaling to around 2,000 human coding sequences uncovered factors inducing neural progenitor-, melanocyte- and vascular smooth muscle-like states.

    Why it matters: It removes random viral integration as a confound in pooled gain-of-function screens and works in hiPSCs at ~2,000-ORF scale.

  12. biorxiv.org53

    MYC drives endothelial transformation and dedifferentiation in angiosarcoma

    Endothelial-specific MYC overexpression alone was sufficient to drive angiosarcoma in mice, with the resulting pulmonary tumors showing impaired endothelial differentiation. MYC inactivation in dedifferentiated allografts induced growth arrest and restored endothelial gene expression, showing the plasticity is reversible. MYC-amplified human angiosarcomas were enriched for MYC target and cell-cycle programs and depleted of endothelial lineage signatures, matching the murine findings.

  13. biorxiv.org49

    Multi-Omic and Spatial Profiling Defines Outcome-Associated Tumor States in Head and Neck Adenoid Cystic Carcinoma

    Poor survival in head and neck adenoid cystic carcinoma is marked by loss of myoepithelial tumor cells and expansion of MYC/E2F-driven, actively dividing luminal states, defined by integrating bulk, single-cell, and spatial transcriptomes from 25 HNACC tumors. Both outcome groups share a myoepithelial-like origin, so aggressiveness reflects position along a shared developmental path. A four-gene classifier capturing this state predicted survival in an independent cohort, outperforming larger signatures and flagging aggressive subgroups in two others, supporting prospective risk stratification and proliferative-directed therapy.

  14. biorxiv.org53

    Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism

    In mouse models of pancreatic cancer cachexia, tumors subvert tryptophan metabolism: serotonin is depleted while kynurenine accumulates in tumor, liver, muscle and spleen. Restoring serotonin activity, or blocking kynurenine production or kynurenine-mediated AhR activation, normalized feeding, locomotion and depression-like behavior, but did not change wasting, tumor burden or survival. The behavioral and feeding defects of cachexia are thus separable from its lethal systemic catabolism.

  15. biorxiv.org51

    Single-nucleus multi-omics reveals reversible molecular signatures in skeletal muscle of patients with heart failure with preserved ejection fraction

    Single-nucleus multiome profiling of 140 skeletal muscle biopsies from 95 individuals (25 healthy controls, 70 HFpEF patients) maps molecular signatures of skeletal muscle remodeling in HFpEF, including type 1 fiber and pericyte depletion and type 2x fiber enrichment. Paired biopsies from 45 HFpEF patients before and after a supervised diet and exercise intervention show the chromatin accessibility and transcriptional changes were partially reversible. HFpEF-linked chromatin was enriched for heart failure and cardiometabolic GWAS signals.

  16. biorxiv.org51

    Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling

    Pdk1 expression marks metabolically distinct cancer cell populations in colorectal tumors, and Pdk1-high cells drive tumor growth, 5-fluorouracil chemoresistance and relapse in orthotopic CRC models. These cells show an EMT, stem cell-like phenotype with increased interferon signaling, triggered by mitochondrial DNA release into the cytosol after mitochondrial remodeling. Blocking IFN signaling impairs their tumorigenic and aggressive features, linking metabolic heterogeneity to cell-intrinsic IFN signaling in aggressive CRC.

  17. biorxiv.org52

    Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts

    A NES+SOX4+NOTCH1+ neural-associated program in pancreatic cancer-associated fibroblasts is reversible rather than a fixed identity. Spatial transcriptomics from normal pancreas to invasive carcinoma identified EGF, FGF2 and BDNF as candidate tumor-to-fibroblast signals; EGF and FGF2 induced the program in patient-derived CAFs and fibroblast cell lines, and withdrawal reversed it at protein and transcriptional levels. MAPK/ERK signaling and ETS-family transcription factors drive the state, which pan-cancer single-cell analysis found enriched in CAFs across multiple cancer types.

  18. biorxiv.org41

    Mathematical Modelling of Stochastic Gene Expression Quantifies mRNA Heterogeneity in Cancer Cell Populations with Extrachromosomal DNA

    A stochastic model of gene transcription quantifies mRNA production and decay in cancer cells carrying ecDNA, exploring the space of mRNA distributions possible from a given ecDNA distribution. Applied to single-cell measurements of ecDNA and mRNA counts in cell lines, it estimates transcriptional parameters that are strikingly similar across cell lines and amplification types. Simulating genotoxic therapy, the model predicts the mRNA composition of persisting cells, linking ecDNA-driven heterogeneity to treatment resistance.

  19. biorxiv.org50

    Epstein-Barr virus co-opts ADAR1 to evade PKR activation of the integrated stress response in nasopharyngeal carcinoma

    Epstein-Barr virus requires ADAR1 to maintain latent infection and to undergo lytic reactivation in nasopharyngeal carcinoma, because ADAR1's A-to-I editing of dsRNA prevents PKR from activating the integrated stress response. Without ADAR1, lytic reactivation or synthetic dsRNA triggered PKR-mediated eIF2α phosphorylation, stress granule formation, and cancer cell lethality, with no virion progeny produced. The findings support lytic induction therapy combined with ADAR1 inhibition to kill EBV-positive tumor cells without viral dissemination.

  20. biorxiv.org43

    Inhibitory Nectin-2/TIGIT interactions between CD163+ macrophages and CD8+ T cells in spatially defined immune niches associate with poor outcomes in neuroblastoma

    CD163+ macrophages emerge as the dominant immunosuppressive interaction partner of T cells in neuroblastoma, engaging the TIGIT/PVR/Nectin-2 axis mainly at the tumor edge and in immune cores. Imaging mass cytometry (n=14) and spectral flow cytometry (n=18) on samples from 28 patients revealed T cell-excluded tumor niches and dysfunctional, tissue-resident T cells, with macrophage CD163 and Nectin-2 expression correlating with poor survival. The findings support combining strategies that boost T cell infiltration with blockade of inhibitory signaling.

  21. biorxiv.org40

    Coordinated alterations in SWI/SNF chromatin remodeling complex, mRNA splicing and mRNA methylation as hallmarks of salivary gland adenoid cystic carcinoma (SACC)

    Spatial transcriptomics of salivary gland adenoid cystic carcinoma points to coordinated disruption of epigenetic regulation as a contributor to the disease. The SWI/SNF chromatin remodeling complex, the NineTeen Complex, and the m6A RNA methylation complex were shown to interact directly, and immunohistochemistry on 48 tumor samples showed altered abundance of METTL3, METTL14, WTAP, PRP19, CDC5L and PLRG1 proteins. BRM directly regulates genes encoding subunits of these complexes and some EMT marker genes, and re-analysis revealed broad alterations in transcript usage and splicing events.

  22. medrxiv.org53

    Non-invasive detection of mutagenic exposure to aristolochic acid using ultra-deep sequencing of blood and urine samples

    Duplex sequencing can detect the aristolochic acid mutational signature SBS22a in blood and urine, offering a non-invasive readout of carcinogen exposure before tumors form. In 12 urothelial carcinoma patients, the signature appeared in blood and urine from those with AA-positive tumors and was absent in AA-negative tumors. Single-cell WGS localized the signal to adaptive lymphoid cells, a long-lived systemic reservoir of mutational history.

Oct 8Thu
  1. biorxiv.org43

    A gene-centric analysis of copy number variation reveals tumour suppressor modulation of cancer risk and novel associations with common diseases

    A gene-centric analysis links whole-gene copy number variation to phenotype, showing in GTEx data that predicted expression effects of CNVs are often realised. The approach identified 34 gene deletions associated with cancer incidence, including a germline link between 13q14 deletions and increased cancer risk, and found that the total number of whole-gene losses tracked cancer risk even excluding known cancer genes. Extensions to non-cancer phenotypes uncovered associations with common diseases including asthma and heart attack.

  2. biorxiv.org47

    Heterochromatin protein 1α acts as an essential stabilizer of chromatin packing domains

    Degrading heterochromatin protein 1 alpha (HP1α) unexpectedly caused overall gene downregulation rather than increased transcription, contradicting the canonical view of heterochromatin as purely repressive. Heterochromatic cores of dense chromatin packing domains were disrupted, though some domains persisted, and under hypoxia HP1α-depleted cells showed a dampened transcriptional response. The findings position HP1α crosslinking as essential for packing domain maturation and efficient transcriptional reprogramming.

  3. biorxiv.org45

    Sex-dependent DNA methylation in amyotrophic lateral sclerosis

    A blood-based epigenome-wide association meta-analysis of 8,946 individuals (5,129 males, 3,817 females) from Project MinE and an Australian cohort identified seven sex-dependent ALS-associated differentially methylated positions at P < 9 × 10-8, mapping to KCNQ1, ADPRH, HLA-F, GHRLOS, IRF5, RAD51B and one intergenic region. Sex-stratified case-control analyses alone found no genome-wide significant sex differences; the interaction model did, with the strongest signal at KCNQ1 (P = 3.1 × 10-9). Six of the seven positions survived a four-stratum sensitivity analysis and none appeared in previous conventional ALS methylation analyses, pointing to a distinct sex-conditional component of the ALS blood methylome.

Oct 7Wed
  1. biorxiv.org45

    Dynamic Schlafen 11 (SLFN11) expression revealed by single-cell RNA sequencing of clonal human cancer cells

    SLFN11, a determinant of sensitivity to DNA-damaging therapies, is heterogeneously expressed among individual cells. Immunofluorescence microscopy and single-cell RNA sequencing across eight human cancer cell lines showed cell-to-cell heterogeneity at protein and RNA levels, with SLFN11 coexpressed with a stress-response state and genome maintenance programs and inversely correlated with protein translation pathways. Public single-cell RNA-sequencing datasets of human SCLC tumors confirmed the heterogeneous distribution, indicating dynamic single-cell regulation and a potential reservoir of intrinsic chemotherapy resistance.

  2. biorxiv.org40

    Combined HDAC and ATM inhibition with radiation in preclinical glioblastoma models

    The HDAC inhibitor quisinostat and the ATM inhibitor AZD1390 produced synergistic radiosensitization in patient-derived glioma stem cells in vitro, with quisinostat increasing histone acetylation and suppressing homologous recombination gene transcription while AZD1390 blocked ATM signaling. In an orthotopic glioblastoma model, quisinostat plus radiation significantly prolonged survival over radiation alone, but adding AZD1390 conferred no additional benefit. The finding narrows the promising radiosensitizing combination to HDAC inhibition plus radiation.

  3. biorxiv.org48

    RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression

    RORγ inverse agonism redirected tumour-conditioned emergency myelopoiesis and attenuated established tumour progression in syngeneic tumour models. In treatment-naive gastroesophageal adenocarcinoma patients, elevated circulating neutrophil-to-lymphocyte ratio tracked with circulating RORγ positive neutrophils and tumoural spatial organization of RORγ positive myeloid cells rather than neutrophil abundance. Pharmacologic RORγ inverse agonism altered marrow progenitor composition before tumour-growth divergence and enhanced longitudinal tumour control with PD-L1 blockade, with effects on metastatic establishment depending on tumour conditioning and treatment timing.

  4. biorxiv.org54

    Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control

    Phospholipid acyl chain composition controls KRAS spatial organization and signaling, according to perturbation of lysophosphatidylcholine acyltransferase 3 (LPCAT3), which incorporates polyunsaturated fatty acids into phospholipids. Loss of LPCAT3 depleted polyunsaturated phosphatidylserine species, disrupted KRAS plasma membrane association and nanoclustering, and attenuated MAPK signaling and oncogenic activity in multiple KRAS mutant contexts. Acute restoration of polyunsaturated, but not saturated, lipids rescued nanoclustering, and LPCAT3 inhibition selectively impaired KRAS-dependent proliferation while sensitizing tumor cells to direct KRAS inhibition.

  5. biorxiv.org40

    Disentangling the Crabtree and Warburg effects across syngeneic non-tumor and tumor cells.

    OxPhos insufficiency was the primary bioenergetic hallmark of proliferating malignant cells, distinguishing the Warburg effect from the transient Crabtree effect seen in macrophages. In primary peritoneal macrophages, glucose suppressed OxPhos in a time-dependent way, and lowering glucose or substituting respiratory fuels restored OxPhos and sensitivity to mitochondrial inhibitors. Tumor cells (VM-M3 glioma, CT-2A astrocytoma) showed persistent SLP dependency and resistance to mitochondrial inhibitors even with glucose available. The work argues that normal-versus-cancer metabolism comparisons need long-term steady-state endpoints.

  6. biorxiv.org53

    Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms

    Molecular analysis of 433 microdissected tumor regions from 135 patients with intraductal papillary mucinous neoplasms shows that IPMNs are organized by phenotype, intestinal versus others, rather than by dysplasia grade. Gastric IPMNs progress from low-grade lesions with normal gastric gland polarity to high-grade lesions indistinguishable from pancreatobiliary lesions, while intestinal IPMNs arise through a GNAS-associated route or a KRAS-associated shift from gastric features. Mapping these trajectories enabled phenotype-specific prediction of high-grade dysplasia in mucus aspirated from 94 resected lesions, supporting a fluid-based test to refine surgical decisions.

  7. biorxiv.org51

    Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

    ZFTA-RELA-positive supratentorial ependymomas depend on AHCY, which the fusion upregulates to raise methylation potential, activating CAD via H3K4me3 and repressing ASNS via H3K27me3, shunting aspartate into pyrimidine biosynthesis while creating extracellular asparagine dependency through SLC1A5 stabilization. Inhibiting AHCY genetically or pharmacologically, restricting S-adenosylmethionine, or blocking EZH2 reversed these epigenetic states and suppressed tumor growth in vitro and in vivo.

  8. biorxiv.org47

    The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5 Splice Site Dependent Splicing Regulation

    The spliceosome scaffold component BCAS2/SPF27 drives pancreatic ductal adenocarcinoma progression by regulating alternative splicing at exons with weak splice sites. BCAS2 promotes inclusion of SOS1 exon 21, activating RAC signaling, and elevated BCAS2 expression in PDAC correlates with poor patient outcomes. Splice-switching antisense oligonucleotides that skip SOS1 exon 21 suppressed PDAC proliferation and migration, pointing to a BCAS2/SOS1/RAC axis as a therapeutic vulnerability.

  9. biorxiv.org42

    An androgen-derived transcriptional state reveals signaling and mitochondrial vulnerabilities in cancer

    An androgen-suppressed transcriptional state (ASTS), derived from dihydrotestosterone treatment of mouse adrenal zona fasciculata cells and projected to human orthologs, marks cancer cell lines with resistance to EGFR-targeted drugs and reduced EGFR dependency. Integration with pharmacogenomic and CRISPR dependency datasets linked higher ASTS to increased dependency on mitochondrial translation and respiratory electron transport. The associations held across lineages and after adjustment for oncogenic drivers and cell-state covariates.

  10. biorxiv.org47

    Disconnect Between Succinate, Succinyl-CoA, and Histone Succinylation in Cells and Gastrointestinal Stromal Tumors with Succinate Dehydrogenase Deficiency

    Succinate dehydrogenase (SDH) deficiency raises succinyl-CoA in multiple models, but histone succinylation does not increase, and lysine malonylation and glutarylation instead decrease. Liquid chromatography high resolution mass spectrometry across the NCI-60 panel, SDH-deficient and SDH-competent models, and GIST patient tumors showed no correlation between succinate to fumarate ratio and succinyl-CoA, and no rise in succinyl-CoA or desuccinylase expression in bulk tumors. Pharmacological desuccinylase inhibition showed very weak or no selective effect on SDH-deficient cell viability, challenging proposed succinylation-based therapeutic targeting.

  11. biorxiv.org52

    A ribosomal pseudouridine drives an oncogenic translation program

    SNORA81-guided pseudouridylation at U4636 in 28S rRNA controls a selective translational program in ovarian cancer cells. Depleting SNORA81 lowers U4636 pseudouridylation without broadly disrupting rRNA processing or bulk translation, but remodels ribosome pausing and polysome association of target mRNAs enriched in cancer-related functions, with matching protein-level changes. The authors term this multilevel cascade the sno-balling effect, linking snoRNA abundance to protein output and cancer cell proliferation.

  12. biorxiv.org58

    Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer

    Loss of the Y chromosome (LOY) affects ~50% of male pancreatic ductal adenocarcinoma patients across two independent cohorts, with enrichment in advanced disease and the basal subtype. Y-chromosome deletion alone in CRISPR-engineered PDAC models induces EMT transcriptional states, mesenchymal morphology and enhanced metastatic ability, via loss of Y-linked chromatin modifiers that reshape DNA methylation at EMT- and basal-defining loci. The work establishes LOY as a causal driver of PDAC progression and a clinically accessible biomarker.

  13. biorxiv.org46

    Artesunate Exploits Glutathione-Dependent Redox Vulnerability in Metastatic Lung Adenocarcinoma

    An in vivo screen of a metabolic drug library in KrasG12D;p53KO lung adenocarcinoma cell lines identified artesunate as a selective inhibitor of metastatic seeding, reducing metastatic burden without affecting primary tumor growth. Artesunate induced oxidative stress with reactive oxygen species and lipid peroxidation, and inhibiting glutathione synthesis specifically sensitized metastasis-derived cells to extensive cell death while primary tumor-derived cells stayed resistant. The work points to glutathione-dependent redox homeostasis as a targetable vulnerability of metastatic cells.

  14. biorxiv.org47

    Analysis of Naturally Arising Simple Deletions in Single Human Colon Crypts with Age

    Simple deletions in single human colon crypts arise mainly through nonhomologous DNA end joining: of 4,264 deletions of two or more nucleotides, about 71% fit NHEJ and under 1.5% fit alternative end joining, while about 58% of all simple deletions are consistent with strand slippage. NHEJ-type simple deletions were roughly 8-fold more frequent than NHEJ-like complex indels, and both lesion classes accumulated about 10-fold across the lifespan from 0.8 months to 90 years in people without radiation or chemotherapy. Radiation treatment increased non-slippage deletions with little effect on slippage deletions.

  15. medrxiv.org44

    Power Calculation for Noninferiority Stepped-Wedge Cluster Randomized Trials

    Simulation studies show that power in noninferiority stepped-wedge cluster randomized trials depends heavily on design choices: for a fixed total sample size, more time periods consistently raised power, more clusters per sequence gave modest gains, and greater between-cluster variability reduced power. Balanced cluster allocation across sequences was more efficient than unbalanced schemes, and Type I error rates were well controlled. The freely available R package swNIsim implements the framework, which handles continuous and binary outcomes, unequal clusters per sequence, varying cluster-period sizes, delayed intervention effects, and adjustment for secular time.

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