2026-05-21

log/2026-05-21 — ad-hoc daily entries

Sub-file of log — see parent for index. Holds full content for one-line pointers in log.md.

[2026-05-21] ingest | kane-2025-super-adjuvant-nanoparticles (Cell Reports Medicine)

User submitted Kane et al. 2025 “Super-adjuvant nanoparticles for platform cancer vaccination” (doi:10.1016/j.xcrm.2025.102415, PMID 41072409, PMC12629812). Lipid NP co-encapsulating cdGMP (STING agonist) + MPLA (TLR4 agonist) at 2.5:1 mole ratio; preclinical mouse efficacy in B16F10/Panc02/4T1 syngeneic tumor models. Triggered DOI lookup (gold OA via PMC; 4.3 MB PDF retrieved at (local PDF)).

Conceptual-frame enumeration (per feedback_paper_impact_broad memory):

1. STING-agonist intervention modality (next-gen lymph-node-targeted dual-PAMP NP vs disappointing systemic mono-agonist ADU-S100 trials)
2. Type I IFN amplification via PAMP synergy (>4-fold IFN-α/β in primary DCs; IRF3/IRF5/IRF7 KO required; IFNAR-blockade abolishes efficacy = clean IFN-I necessity demonstration)
3. Cancer vaccine modality — whole-tumor-lysate route bypasses neoantigen-discovery bottleneck
4. Immunosenescence relevance — older cancer patients have poor adjuvant responses; super-adjuvants may compensate but paper used young mice only (#gap/needs-replication in aged hosts)

Integration decisions:

• added: studies/kane-2025-super-adjuvant-nanoparticles.md — full type:study page; verified:true main-text-scope (figures 1–4 + STAR Methods overview + references end-to-end; suppl figures S1–S6/tables S1–S2 noted as needs-supp-verification); literature-checked-through:2026-05-21.
• updated: pathways/cgas-sting.md § “STING agonists for cancer immunotherapy” — added paragraph on Kane 2025 dual-PRR NP platform as the conceptual shift from systemic mono-agonist to lymph-node-targeted multi-PAMP NPs; new [^kane2025-superadjuvant] footnote.
• updated: pathways/type-i-interferon-signaling.md § new subsection “STING + TLR4 dual-PAMP nanoparticle adjuvants (the inverse modality)” — clean preclinical demonstration of the acute pro-IFN-I arm in the dual-edged IFN-I-in-aging biology this wiki tracks; new [^kane2025-superadjuvant] footnote.
• NOT added: dedicated interventions/pharmacological/cancer-vaccines.md class page — declined because the wiki has no existing cancer-vaccine intervention coverage and one preclinical paper does not justify class-page creation. Revisit if 2-3 more cancer-vaccine papers accumulate.
• NOT added: separate phenotypes/cancer.md mention — Kane 2025 is mechanism+modality, not cancer-phenotype evidence; pathway pages are the load-bearing homes.

Aging-specific gaps surfaced:

• Aged-host efficacy untested (super-adjuvant paradigm may matter most where it has not been tested).
• TLR4 hyporesponsiveness in aged human PBMCs vs the supraphysiological PRR amplification required for the synergy is unmodeled.
• No combination data with checkpoint blockade or with senolytics (cleared SASP-IFN-I tonic background might change the dual-adjuvant therapeutic window).

Files touched: studies/kane-2025-super-adjuvant-nanoparticles.md (created), pathways/cgas-sting.md, pathways/type-i-interferon-signaling.md, log.md.

[2026-05-21] elevate | kane-2025 → nanoparticle-immunoadjuvants intervention class page

User pushed back on the light-touch incorporation (two pathway-page footnotes + one study page): “I was thinking the method could be relevant for other cancer interventions.” Surveyed the Kane 2025 reference list and adjacent literature; identified a substantial prior-art base (Atukorale 2019 Cancer Res; Pradhan 2021 Sci Adv on TRAF6-IRF5 kinetics for MPLA+CpG NP synergy; Nakamura 2021 J Immunother Cancer on STING-LNP overcoming anti-PD-1 resistance; Baljon 2024 ACS Nano on STING+TLR4 peptide-neoantigen nanovaccine) plus a direct cancer-aging bridge in Chibaya 2024 Sci Transl Med (doi:10.1126/scitranslmed.adj9366), same Atukorale + Fitzgerald + Ruscetti group, which combines the dual-PRR NP platform with senescence-inducing trametinib MEK + palbociclib CDK4/6 to remodel immune-cold PDAC TMEs via therapy-induced SASP. Chibaya 2024 is the most aging-relevant entry in this class.

Decision: elevate from “two footnotes + one study page” to a dedicated intervention class page.

• added: interventions/pharmacological/nanoparticle-immunoadjuvants.md — full class page; type:intervention; mode:pharmacological; clinical-stage:preclinical; human-evidence-level:preclinical-only; verified:false (auto-extraction banner; full Kane 2025 PDF verified but Chibaya/Baljon/Nakamura/Atukorale-2019/Pradhan claims abstract-only with needs-full-extraction tags). Sections: definition + mechanism (PAMP-synergy via shared IRF3/IRF5/IRF7), representative platforms (Kane 2025, Chibaya 2024, Baljon 2024, Nakamura 2021, Atukorale 2019, Pradhan 2021), aging-context relevance (immunosenescent vaccine response, TIS-as-priming exploits SASP biology, dual-edged-sword IFN-I framing, mRNA-LNP infrastructure carryover), limitations and gaps (no human trials, aged-host efficacy untested, CRS unmodeled, TLR4 hyporesponsiveness in aged human PBMCs, non-CDN STING agonist compatibility untested, checkpoint-blockade combination untested).
• updated: phenotypes/cancer.md § “Modern therapeutic landscape” — added “Nanoparticle immunoadjuvants” bullet linking to class page; new [^kane2025-superadjuvant] and [^chibaya2024-cancerpage] footnotes.
• updated: pathways/cgas-sting.md — Kane paragraph extended with cross-link to new class page + Chibaya 2024 cancer-aging-bridge mention.
• updated: pathways/type-i-interferon-signaling.md § “STING + TLR4 dual-PAMP nanoparticle adjuvants” — added Chibaya 2024 sentence on TIS+NP-adjuvant axis; new [^chibaya2024-ifnpage] footnote; cross-link to class page.
• updated: studies/kane-2025-super-adjuvant-nanoparticles.md § “Pages citing this study” — added class page + phenotypes/cancer.md to citation graph.

Forward queue (#gap/needs-full-extraction):

• studies/chibaya-2024-np-senescence-pdac.md — highest priority; the cancer-aging bridge; PDF already in archive at (local PDF)
• studies/baljon-2024-cancer-nanovaccine-sting-tlr4.md — independent group’s optimized peptide-neoantigen + STING+TLR4 nanovaccine
• studies/nakamura-2021-sting-lnp-anti-pd1.md — mono-agonist STING-LNP + checkpoint blockade
• studies/atukorale-2019-dual-agonist-np-codelivery.md — closed-access; DOI lookup failed; abstract-only
• studies/pradhan-2021-mpla-cpg-np-synergy-kinetics.md — mechanistic deep-dive on why NP co-presentation produces synergy that free-agonist co-administration does not

Conceptual frames newly captured by the elevation (beyond the original 2026-05-21 ingest entry’s enumeration):

• TIS-as-vaccine-priming weaponizes SASP — the same SASP biology this wiki tracks as pathological in aged tissues, deployed acutely against tumors. Therapeutic window between productive acute SASP and pathological chronic SASP is the central translational question, particularly for older patients with baseline senescent-cell burden.
• mRNA-LNP COVID-vaccine infrastructure (Acuitas, Genevant, Moderna lipid libraries) creates a faster regulatory + GMP-manufacturing ramp for NP-cancer-adjuvant platforms than would otherwise apply to a first-in-class modality.
• Aged-host validation is the highest-value next experiment for this class — none of the published preclinical data tests dual-PRR NP super-adjuvants in 18–22-month mice despite cancer being overwhelmingly an aging disease.

Files touched (this elevation): interventions/pharmacological/nanoparticle-immunoadjuvants.md (created), phenotypes/cancer.md, pathways/cgas-sting.md, pathways/type-i-interferon-signaling.md, studies/kane-2025-super-adjuvant-nanoparticles.md, log.md.

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• 2026-05-21 mechanism-update — SREBP-2/PCSK9/LDLR aging-axis direction corrected. User conversation surfaced that pathways/lipoprotein-metabolism.md line 144’s framing of “age-related decline in hepatic LDLR via reduced SREBP-2 processing efficiency” was a field-shorthand whose direction was contradicted by molecules/proteins/srebp-2.md’s own needs-replication prediction (mTORC1 hyperactivation → SREBP-2 up, not down). Dispatched lit subagent (general-purpose) + direct GTEx v10 API queries in parallel. Lit search returned Yang et al. 2024 (Protein & Cell 15(2):98-120, DOI 10.1093/procel/pwad039, PMID 37378670, PMC10833472, Gold OA — first single-nucleus transcriptomic atlas of primate liver aging across three hepatocyte zonations; hyperactivated SREBP signaling is a hallmark of aged hepatocyte; forced SREBP2 activation in human primary hepatocytes is sufficient to recapitulate aging phenotypes — impaired detoxification + accelerated cellular senescence). GTEx queries discovered undocumented attributeSubset=ageBracket parameter on /expression/geneExpression; computed Spearman ρ across bracket midpoints for SREBF2/LDLR/PCSK9 in 5 tissues (n=262–818 per tissue). Hepatic bulk transcript signals are flat (|ρ| ≤ 0.08) — but bulk RNA-seq is the wrong instrument given cell-composition confound; Yang snRNA-seq is the right instrument and shows per-hepatocyte hyperactivation. Largest unexpected GTEx signal: visceral adipose LDLR ρ = −0.22, n=587 (~70% median TPM drop from age 20-29 to 50-59) — a previously-uncharacterized aging signature. Corrected model now reflected on 4 pages: aging → hepatic mTORC1 hyperactivity → lipin-1 cytoplasmic retention → SREBP-2 nuclear activity ↑ per hepatocyte → both LDLR and PCSK9 transcribed ↑ (Dubuc 2004 / Jeong 2008 feedback paradox) → PCSK9 protein dominates over LDLR drive → net hepatic surface LDLR ↓ → plasma LDL/ApoB clearance ↓ → cumulative LDL exposure rises (Ference 2024 LDL-years framework). Clinical implication: PCSK9 inhibition is more mechanism-specific against aging-driven LDL elevation than statins alone — statins push SREBP-2 harder (more LDLR transcription and more PCSK9); PCSK9i directly relieves the dominant brake. Files touched: studies/yang-2023-primate-liver-aging-snrna-srebp2.md (CREATED; verified:false; abstract + Crossref-metadata-verified; full PDF read pending), molecules/proteins/srebp-2.md (aging-relevance § rewritten + gtex-aging-correlation populated + Yang footnote), molecules/proteins/ldlr.md (aging-relevance § rewritten with 7-point structure including VAT-LDLR finding + needs-gtex-extraction resolved + Yang footnote), molecules/proteins/pcsk9.md (gtex-aging-correlation populated + new § Plasma PCSK9 protein vs hepatic transcript methodological note + unsourced resolved + new needs-replication for plasma protein modern-cohort), pathways/lipoprotein-metabolism.md (aging-relevance § rewritten; “reduced SREBP-2 processing efficiency” shorthand explicitly retired + Yang footnote), sops/finding-tissue-expression.md (Step 3 updated; documents attributeSubset=ageBracket parameter with verified-working method + Python recipe; prior “API does not expose per-sample age-labelled data directly” statement corrected). Gaps remaining: mTORC1 dependency of SREBP-2 hyperactivation untested in aged primate liver (no rapamycin arm); Yang’s signal not replicated in aged human liver biopsies/autopsy; modern (2019+) plasma PCSK9 protein age-trajectory in healthy cohorts unreplicated since Cui 2010 / Lakoski 2009; single-cell follow-up on VAT-LDLR collapse needed. Verified flips: none — Yang study page is verified:false pending full PDF read; existing verified:true page-level flags on the 4 updated entity/pathway pages stand for unchanged content (new claims inherit Yang’s pending status until verified). → direct user request (ad-hoc mechanism investigation; not part of a numbered round)

• 2026-05-21 propagate — Iwata 2025 / E. americana / bacterial-cancer-therapy ingest cross-linked into upstream MOCs. phenotypes/cancer.md § “Modern therapeutic landscape” — new bullet on bacterial cancer therapy modality (Iwata 2025 100% CR vs 20% anti-PD-L1 vs 0% DOX); new Iwata 2025 footnote [^iwata2025]; cross-references section extended with bacterial-cancer-therapy + ewingella-americana + iwata-2025-ewingella-americana-antitumor + dysbiosis. hallmarks/dysbiosis.md § Cross-references — added ewingella-americana and bacterial-cancer-therapy (gut/non-mammalian-vertebrate microbiome as therapeutic-pharmacopoeia mechanism intersects with dysbiosis cluster). frameworks/intervention-classes.md — 3 new mechanism classes (tumor-selective-colonization, pamp-mediated-immune-activation, direct-cytotoxicity) already added during seeder pass. microbiome/gut-microbiome-aging-shifts.md — propagation skipped (page is about aging-shifts in microbiome composition; bacterial cancer therapy is downstream/orthogonal). Yersiniaceae/Enterobacteriaceae cross-check across the 3 new pages: all consistent — microbe page uses Yersiniaceae (NCBI/LPSN current) with explicit reclassification note; intervention page uses Yersiniaceae with disambiguation pointer; study page uses Enterobacteriaceae as Iwata 2025 literally wrote it (acceptable in study-page context as accurate reporting). Note: the intervention-page verifier’s log entry (line 17 above) mis-described its own edit — actual final state is Yersiniaceae + disambiguation, not the regression suggested by the log entry. No corrective edit needed.

• 2026-05-21 verify — microbiome/ewingella-americana.md flipped verified:true. 8 corrections: (1) key-strains frontmatter + taxonomy table body: CIP 81.94 added as confirmed type-strain equivalent (LPSN + NCBI Taxonomy XML); (2) model description updated from “single IV injection of 5×10⁹ CFU” to “200 µL at 5×10⁹ CFU/mL = 1×10⁹ CFU/mouse”; (3) n=5/group now explicit in efficacy block (n=3 for initial screen, n=5 for comparative experiment per Figure 3); (4) anti-PD-L1 and DOX dosing added: 4 doses every other day at 2.5 mg/kg; (5) immunological memory rechallenge data added: 0/10 tumors in cured animals vs 10/10 in naïve controls; (6) virulence-factor list corrected to match Fig 4c: “Regulation” category added (was omitted); category labels updated to exact Fig 4c terms (Nutritional/Metabolic, Effector delivery system, Immune modulation, Exotoxin); (7) dual-mechanism text updated with precise quantitative details: B cells +3%, T cells +5%, neutrophils +30%; 3h→24h expansion timeframe; spheroid (3D) in vitro model clarified; (8) gap/dose-response-unclear corrected: “5×10⁹ CFU IV” → “1×10⁹ CFU per mouse (5×10⁹ CFU/mL in 200 µL)”. Ioannou 2024 PDF verified (n=19, median age 55, 47.4% male, mortality 5.3%). NCBI Taxonomy 41202 lineage confirmed. GCF_000735345.1 genome stats confirmed (4,867,810 bp, 54% GC, 4,386 protein-coding). Grimont 1983 remains closed-access. Supersession: 9 PubMed hits 2024–2026; all already triaged; no contradictions. literature-checked-through: 2026-05-21.

• 2026-05-21 verify — studies/iwata-2025-ewingella-americana-antitumor.md flipped verified:true. Full PDF read (24 pp). PMID resolved: 41376334. 3 corrections: (1) dose-finding pilot “2×10⁷ to 1×10⁹ CFU range” → three discrete doses (2×10⁷, 2×10⁸, 1×10⁹ CFU; n=5/group; Methods p.18); (2) acute toxicity timepoints corrected — “5 min, 3h, 24h, 48h, 72h, 240h” → “24h, 48h, 72h, 240h” (5 min and 3h belong to blood-clearance colony assay, not the toxicity CBC panel; main text p.12); (3) PMID null → 41376334; limitation #8 about missing PMID removed. Additions: Ayik 2025 case report (PMID 40636648) noted as safety corroboration; needs-supp-verification applied to 6 supplementary-only claims. Supersession check: 2 PubMed hits (2025) — Iwata 2025 itself + Ayik 2025 case report; no contradictions. Downstream propagation needed: microbiome/ewingella-americana.md (PMID + dose-finding correction + Ayik 2025).

• 2026-05-21 verify — interventions/pharmacological/bacterial-cancer-therapy.md (verified: true). Iwata 2025 anchor verified end-to-end against local PDF; all 10 cited DOIs confirmed via Crossref (title/year/journal/first-author all correct). 3 corrections: (1) VNP20009 header attenuation notation TAP-/msbB- → ΔpurI/ΔmsbB (Toso 2002 Crossref abstract confirms correct deletions); (2) E. americana family Yersiniaceae → Enterobacteriaceae per Iwata 2025 p.7 text; (3) added n=5/group experimental-context qualifier to 5/5 CR claim to disambiguate from initial 3-per-group screen. ClinicalTrials.gov re-queried: 0 recruiting trials confirmed. Closed-access papers (Toso 2002, Kwon 2024, Chang 2025) verified via Crossref metadata only. Note: ewingella-americana.md microbe page should be checked for the Yersiniaceae/Enterobacteriaceae family error — seeder used Yersiniaceae (propagated from this page).

• 2026-05-21 seed — interventions/pharmacological/bacterial-cancer-therapy.md (bacterial cancer therapy class page; type:intervention; pharmacological mode; mechanisms: tumor-selective-colonization + pamp-mediated-immune-activation + direct-cytotoxicity; 3 new mechanism classes added to frameworks/intervention-classes.md; target-hallmarks: dysbiosis + chronic-inflammation; clinical-stage: phase-2 for engineered sub-class; human-evidence-level: limited; R25 recency search: PubMed 2022–2026, no RCTs/meta-analyses exist for this modality — field is Phase 1/2 for engineered bacteria; preclinical-only for naturally-occurring class; 10 primary-source DOIs cited; 2 locally downloaded PDFs confirmed via archive; implicit stubs: checkpoint-inhibitors). → ad-hoc user request

• 2026-05-21 seed — microbiome/ewingella-americana.md (Ewingella americana type:microbe; NCBI Taxonomy 41202; genome 4.87 Mb GCF_000735345.1; Yersiniaceae; Iwata 2025 antitumor context + Ioannou 2024 clinical review; R25 recency search 2020–2026: 22 hits triaged, no meta-analyses/RCTs, no contradictions to Iwata 2025; implicit stubs: iwata-2025-ewingella-americana-antitumor, bacterial-cancer-therapy). → ad-hoc user request

• 2026-05-21 seed — studies/iwata-2025-ewingella-americana-antitumor.md (Iwata et al. Gut Microbes 2025; DOI 10.1080/19490976.2025.2599562; PMC12710904; gold OA). Full PDF read (24 pages). Ewingella americana from Japanese tree frog gut achieves 100% CR in Colon-26 syngeneic mouse model after single IV dose (1×10⁹ CFU), outperforming anti-PD-L1 (1/5 CR) and liposomal doxorubicin (0/5 CR); immunological memory >60 days confirmed by rechallenge. Key gaps flagged: genome-not-sequenced, narrow therapeutic window, subcutaneous-only model, no human data. Implicit stubs created: ewingella-americana, bacterial-cancer-therapy. → ad-hoc user request