Base by Base

Tumour-Reactive CD8 T Cell Clusters in Human Melanoma

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09754-w

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/tumour-reactive-cd8-t-cell-clusters-in-human-melanoma

️ Episode:
210: Tumour-Reactive CD8 T Cell Clusters in Human Melanoma

️ Season:
1

Article title:
Tumour-reactive heterotypic CD8 T cell clusters from clinical samples

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-26.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering cluster discovery, immunological synapse evidence, antigen-specific competition, ex vivo cytotoxicity and cytokine production, in vivo ACT/PDX results, and the TCF7+ stem-like exhausted T cell state.
- transcript topics: Immunological synapse and proximity requirements; Preservation of cellular clusters during tissue processing; Antigen-specific T cell competitiveness and cluster formation; Clinical heterotypic CD8+ T cell clusters in melanoma (21 samples); Single-cell RNA/TCR analyses of cluster T cells; Ex vivo cytotoxicity and cytokine production by cluster-derived T cells

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- 21 melanoma metastases analyzed; heterotypic CD8+ T cell clusters with tumor cells and/or APCs observed in all samples
- Clusters show relocalization of immune synapse markers (HLA-ABC, CD58, ICAM1) to the T cell–tumor interface
- MART-1-specific T cells outcompete non-specific T cells for cluster formation; up to 11-fold enrichment at 1% input
- Ex vivo killing by cluster-derived T cells is ~9-fold higher than singlets; increased IFN-γ and TNF production
- In vivo ACT/PDX models show tumor control and increased T cell infiltration/activation with cluster-derived T cells
- Clustered CD8+ T cells show a TCF7+ stem-like exhausted state associated with persistence and durability

QC result: Pass.

PERT: Prime Editing tRNAs for Nonsense Mutations

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09732-2

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/pert-prime-editing-trnas-for-nonsense-mutations

️ Episode:
209: PERT: Prime Editing tRNAs for Nonsense Mutations

️ Season:
1

Article title:
Prime editing-installed suppressor tRNAs for disease-agnostic genome editing

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the central scientific narrative: PERT concept and single-locus sup-tRNA installation; cell-model rescues in Batten/Tay-Sachs/NPC1; ClinVar PTC readthrough breadth; in vivo GFP reporter readthrough; Hurler mouse model IDUA restoration and pathology rescue; safety/off-target and delivery considerat
- transcript topics: Disease-agnostic genome editing concept (PERT); Sup-tRNA optimization and design (leader, body, terminator); Single-locus endogenous tRNA installation via prime editing; Cell-model rescues: Batten (TPP1), Tay-Sachs (HEXA), NPC1; ClinVar PTC readthrough across 14,746 mutations; In vivo GFP reporter readthrough and Hurler syndrome mouse model

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- PERT installs an engineered sup-tRNA at a single endogenous genomic locus to enable readthrough of premature termination codons (PTCs).
- In human cell models of Batten (TPP1), Tay–Sachs (HEXA), and Niemann–Pick (NPC1) diseases, treatment with the same prime editor components restored 20–70% of normal enzyme activity
- In a Hurler syndrome mouse model, IDUA enzyme activity was restored ~6% and disease pathology was nearly completely rescued.
- Across ClinVar PTCs (14,746 tested), readthrough was observed for the vast majority, with an average readthrough score of 69% ± 30%.
- Mass spectrometry indicated no detectable readthrough of natural termination codons (NTCs) and no broad perturbations to the transcriptome or proteome.
- In vivo GFP reporter readthrough in a reporter mouse was around 25% full-length GFP production with the PERT approach.

QC result: Pass.

ZAK, Collided Ribosomes, and the Stress Switch

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09772-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/zak-collided-ribosomes-and-the-stress-switch

️ Episode:
208: ZAK, Collided Ribosomes, and the Stress Switch

️ Season:
1

Article title:
ZAK activation at the collided ribosome

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections covering ZAK constitutive ribosome binding, collision sensing via RACK1, RIH and RIM motifs, SAM-domain dimerization as activation switch, SERBP1 regulation, CLIP-seq mapping to ES7/ES6b/c, and downstream MAPK signaling.
- transcript topics: RSR overview and ZAK as central kinase; Constitutive ribosome binding of ZAK to the 40S via pin and ES7-patch; Collision interface: RACK1, RIH, and RIM motifs; SAM-domain dimerization as activation switch; SERBP1 competition at FPxL motif on RACK1; CLIP-seq mapping ES7 and ES6b/c on 18S rRNA

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ZAK activation is triggered by ribosome collisions via SAM-domain dimerization at the collision interface.
- RACK1 acts as the collision scaffold bridging ZAK to both collided ribosomes, with ZAK interacting through RIH and RIM motifs.
- RIH anchors ZAK to RACK1 and is necessary for binding and activation.
- FPxL motif (RIM) is strictly required for ZAK activation on collided ribosomes, but not for initial binding.
- SERBP1 competes for the RACK1 FPxL binding site and acts as a negative regulator of ZAK activation.
- ZAK pin (eS27-pin) anchors ZAK to the 40S subunit via W768; ES7-patch also contributes to ribosome binding.

QC result: Pass.

Semantic Design of de novo Genes with Evo

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09749-7

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/semantic-design-of-de-novo-genes-with-evo

️ Episode:
207: Semantic Design of de novo Genes with Evo

️ Season:
1

Article title:
Semantic design of functional de novo genes from a genomic language model

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-24.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing Evo 1.5 semantic design, contextual autocompletion, toxin–antitoxin designs (T2TA/T3TA), anti-CRISPR designs, and SynGenome, plus limitations and licensing statements.
- transcript topics: Semantic design and genomic context; In-context design and autoregression; Toxin–antitoxin (T2TA) design and validation; Toxin–antitoxin (T3TA) design and validation; Anti-CRISPR (Acr) design and validation; SynGenome database and analyses

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Semantic design uses genomic context to enable function-guided design of de novo genes (Evo 1.5).
- Autocomplete test: Evo 1.5 achieved 85% amino acid recovery for rpoS with 30% input.
- Toxin–antitoxin (T2TA) design yielded functional toxins and antitoxins; EvoRelE1 toxin; EvoAT1–4 antitoxins; EvoAT2 and EvoAT4 show multitoxin neutralization; EvoT3TA design produc
- Anti-CRISPR (Acr) designs produced functional Acrs; 17% of tested Acrs exhibited activity against SpCas9; EvoAcr1–5 validated.
- SynGenome database contains over 120 billion base pairs of AI-generated DNA; ~3.7 million predicted protein structures; Pfam-domain frequencies in SynGenome closely mirror natural
- Limitations include autoregressive generation risks (repetitive/hallucinated sequences) and reliance on genomic context; lab validation remains essential; applicability to human ge

QC result: Pass.

Wild Birds and the North American H5N1 Epizootic

Music:
Enjoy the music based on this article at the end of the episode.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/wild-birds-and-the-north-american-h5n1-epizootic

️ Episode:
206: Wild Birds and the North American H5N1 Epizootic

️ Season:
1

Article title:
Ecology and spread of the North American H5N1 epizootic

Journal:
Nature

DOI:
10.1038/s41586-025-09737-x

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-22.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited substantive narrative segments: introduction to North American H5N1 epizootic, phylogeographic analysis and introductions, flyway diffusion, canonical vs non-canonical hosts, backyard vs commercial spillovers, and surveillance/limitations.
- transcript topics: Introduction and scope of North American H5N1 epizootic; Phylogeographic analysis and number of introductions; Flyway diffusion across Atlantic, Mississippi, Central, and Pacific; Canonical hosts (Anseriformes) vs non-canonical hosts; Persistence times in wild vs domestic birds; Spillovers to backyard/commercial birds and their implications

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Nine introductions into North America from Europe/Asia
- Anseriformes drive transmission; non-canonical hosts are largely dead-ends
- 46–113 independent introductions into domestic birds from wild birds
- Backyard birds infected about 9.6 days earlier than commercial poultry
- Farm-to-farm transmission is a minor component; wild-bird introductions drive spillovers
- Wild birds are the main engine; enhanced wild-bird surveillance is key

QC result: Pass.

Ancient RNA Expression Profiles from the Woolly Mammoth

Music:
Enjoy the music based on this article at the end of the episode.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ancient-rna-expression-profiles-from-the-woolly-mammoth

️ Episode:
205: Ancient RNA Expression Profiles from the Woolly Mammoth

️ Season:
1

Article title:
Ancient RNA Expression Profiles from the Woolly Mammoth

Journal:
Cell

DOI:
10.1016/j.cell.2025.10.025

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-21.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of the article’s main experimental design, data-quality checks, major results, tissue-level interpretation, and preservation rationale, including sample collection/preservation, RNA sequencing and fragment mapping, damage signatures, exonic reads, tissue identity, sex determination, an
- transcript topics: Sample collection and permafrost preservation; RNA sequencing, fragment length, and mapping strategy; Damage signatures and data authenticity (CU deamination, 5' end bias); Exonic mapping and exon-exon junctions indicating mature mRNA; Tissue identity and metabolism (skeletal muscle; slow-twitch markers MYH7, TNNT1, NEB); Genetic sex determination (Y-chromosome transcripts USP9Y) and autosomal DNA

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- RNA recovered from soft tissues of woolly mammoths; 3 of 10 samples showed endogenous mammoth material
- RNA fragments map to exonic regions and span exon-exon junctions, indicating mature mRNA
- Tissue expression profile matches skeletal muscle with slow-twitch fiber markers (MYH7, TNNT1, NEB)
- Genetic sex determined as male via Y-chromosome transcripts such as USP9Y
- Two novel mammoth-specific microRNAs predicted (MPR novel 4 and MPR novel 5) in Afrotherians
- Mir-1 variant with GG unpaired bulge observed, shared among Proboscidians

QC result: Pass.

StealTHY CRISPR: Revealing Hidden Metastasis Regulators

Music:
Enjoy the music based on this article at the end of the episode.

License:
CC BY 4.0 International License (CC BY 4.0)

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/stealthy-crispr-revealing-hidden-metastasis-regulators

️ Episode:
204: StealTHY CRISPR: Revealing Hidden Metastasis Regulators

️ Season:
1

Article title:
Stealthy CRISPR: Revealing Hidden Metastasis Regulators

Journal:
Cell

DOI:
10.1016/j.cell.2025.10.007

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-20.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing stealth platform design, immunogenicity challenges in vivo, iatrogenic clonal dropout, Harakiri purification, AMHR2 axis as a metastasis driver, and translational relevance via TCGA.
- transcript topics: CRISPR immunogenicity in vivo and iatrogenic clonal dropout; Stealth platform design: immune stealth reporters, autologous reporters, Hit-and-Run Cas9; Harakiri selection and ex vivo purification; Preservation of sgRNA library diversity in immunocompetent models; AMHR2 axis as metastasis driver; Dominant negative AMHR2 decoy receptor therapy in humanized/PDX models

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Stealth CRISPR platform uses immune stealth reporters, HiT-and-Run Cas9 delivery, and Harakiri selection to render CRISPR screens immunologically inert
- In immunocompetent models, stealth platform preserves clonal diversity and full sgRNA library integrity
- AMHR2 axis identified as a major driver of metastasis; knockout yields a 20-fold reduction in metastases
- Dominant negative AMHR2 decoy receptor suppresses tumor volume by >80% and essentially abolishes metastasis in humanized/PDX models
- Blocking AMHR2 signaling shifts tumor immune microenvironment: reduced Tregs, increased activated macrophages and cytotoxic T cells; Type I interferon genes and STAT1 pathway upreg
- Human relevance supported via TCGA data showing high AMH expression correlates with poor prognosis in breast cancer

QC result: Pass.

Divergent Evolutionary Dynamics of Benign and Malignant Tumors

Music:
Enjoy the music based on this article at the end of the episode.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/divergent-evolutionary-dynamics-of-benign-and-malignant-tumors

️ Episode:
203: Divergent Evolutionary Dynamics of Benign and Malignant Tumors

️ Season:
1

Article title:
Divergent Evolutionary Dynamics of Benign and Malignant Tumors

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2519203122

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions that present the main comparative oncology findings: definitions of benign vs malignant tumors, the body-mass association, pathwise rate effects, diversification-rate effects, MPGLMM methodology, bird vs mammal differences, genome-architecture implications, and broader implications.
- transcript topics: Benign vs malignant tumor definitions; Body mass and tumor prevalence; Pathwise rate of body size evolution; Diversification rate and tumor prevalence; MPGLMM methodology; Birds vs mammals results

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Both benign and malignant tumor prevalence increase with body mass across birds and mammals.
- Malignant tumor prevalence is negatively associated with the pathwise rate of body size evolution.
- Benign tumor prevalence shows no significant association with the pathwise rate of body size evolution.
- Diversification rate is positively associated with tumor prevalence in birds for both tumor types; no significant association in mammals.
- Bird genome architecture (smaller, more compact genomes) may underlie the observed divergence via genomic instability and chromosomal rearrangements.
- Overall divergence: malignant tumors are constrained by body-size evolution; benign tumors persist with less constraint; distinct macroevolutionary drivers for each tumor type.

QC result: Pass.

Stereo-seq V2: Spatial Total RNA Mapping in FFPE Tissues

Music:
Enjoy the music based on this article at the end of the episode.

License:
CC BY 4.0 International License (CC BY 4.0)

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/stereo-seq-v2-spatial-total-rna-mapping-in-ffpe-tissues

️ Episode:
202: Stereo-seq V2: Spatial Total RNA Mapping in FFPE Tissues

️ Season:
1

Article title:
Stereo-Seq V2: Spatial Total RNA Mapping in FFPE Tissues

Journal:
Cell

DOI:
10.1016/j.cell.2025.08.008

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing FFPE RNA degradation and cross-linking, random-priming with 6N primers, uniform gene-body coverage and 3' bias elimination, 500 nm DNA nano-ball (DNB) arrays for subcellular spatial resolution, total RNA mapping including non-polyadenylated RNAs, DV200 tolerance, and applications
- transcript topics: FFPE RNA degradation and formaldehyde cross-linking; Random-priming with 6N primers vs poly-A capture; Uniform gene-body coverage and 3' bias elimination; DNA nano-ball (DNB) arrays at 500 nm spacing for subcellular resolution; Total RNA mapping including non-polyadenylated RNAs; DV200 tolerance in aged FFPE samples

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Stereo-Seq V2 uses random primers (6N) to capture total RNA from FFPE tissues
- Random priming yields uniform coverage across the entire gene body and removes 3' bias
- Total RNA mapping includes non-polyadenylated RNAs enabling non-coding RNA profiling
- DV200 tolerance: low as 18% in nine-year-old FFPE samples
- Gene detection exceeds poly-A based methods with >23,000 genes missed by poly-A techniques
- Alternative splicing events identified (e.g., GIPC1 exon skipping)

QC result: Pass.

Music:
Enjoy the music based on this article at the end of the episode.

DOI:
10.1038/s41586-025-09521-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

️ Episode:
201: 201: Sex, Smoking, and Somatic Selection in the Bladder

️ Season:
1

Article title:
Sex and smoking bias in the selection of somatic mutations in human bladder

Journal:
Nature

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering ultradeep duplex sequencing of normal urothelium, sex- and smoking-associated clonal selection, TERT promoter mutations, FGFR3 negative selection, natural saturation mutagenesis, TP53 site selectivity, and clinical implications.
- transcript topics: Ultradeep duplex sequencing of normal urothelium; Driver mutations and positive selection in 16 bladder genes; Sex bias: RBM10, CDKN1A, ARID1A truncating mutations higher in men; TERT promoter activating mutations associated with age and smoking; TERT promoter mutations promote clonal expansions rather than global mutation density; FGFR3 truncating mutations under negative selection

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Ultradeep sequencing identified thousands of driver mutations across 16 genes in normal urothelium
- Men have significantly more truncating driver mutations in RBM10, CDKN1A, and ARID1A than women
- Activating TERT promoter mutations detected in normal bladder tissue and associated with age and smoking
- TERT promoter mutations promote clonal expansions rather than globally increasing mutation density in smokers
- FGFR3 truncating mutations exhibit negative selection in normal urothelium
- Natural saturation mutagenesis observed in vivo via ultradeep sequencing, with TP53 site selection

QC result: Pass.