DQIS — Register of Scientific Objections v35

DQIS — Register of Scientific Objections (v35, current cleaned version — June/July 2026). Supplementary document to the DQIS Consolidated Framework v36 (concept DOI 10.5281/zenodo.19855263). A live register of the scientific objections identified during preparation for academic validation of DQIS — Distributed Quorum-Based Independent Immune Surveillance. 39 objections are mapped across mathematical, biological, engineering, clinical, empirical, and structural categories. The register is adversarial by design: each objection carries a severity, a "does it dismantle the theory?" assessment, and — where resolved — the mechanism or measurement that resolved it. Two objections were re-evaluated (v35.4) with a laboratory-excluded logic: since no wet-lab is available, status reflects the strength achievable with the means at hand (computation on real data), and the "needs wet-lab confirmation" caveat is recorded separately. Status distribution (v35, 39 objections). ~13 RESOLVED/ADDRESSED · 9 MOOT (rendered moot by the current 6-channel panel) · 4 LOW · 7 MEDIUM open · 5 HIGH open (O7, O8, O14, O27, O38); O34 (Channel Paradox) reclassified as a design principle. The high-severity open items are the honest limits of a theoretical framework — long-horizon biology (O7, O8), paediatric validation (O14), external-dependency conditioning (O27), and the physical-sensing reframe (O38). O1 — p_i = 0.01 lacks empirical grounding: MEDIUM — the single open empirical (Level-B) variable; it rescales estimates, does not dismantle the structure. O2 — statistical independence undemonstrated: RESOLVED (measured) — independence MEASURED on real scRNA-seq (within-tumour Kendall τ-b < 0.20, N_eff 3.3–4.1/5); a wet-lab ROC would confirm the operating point, not the principle. O3 — population-level selective pressure: MEDIUM — per-patient handled by the Pattern Drift Sensor; population dynamics need a formal distinction and long-horizon data. O4 — T-ε cannot reach p_i = 0.01: MOOT — T-ε recast as a non-core AND-gate/vote candidate (ledger S3), so the core p_i requirement no longer applies. O5 — DQIS-J paediatric procedures: LOW — single-dose threshold-effect architecture. O6 — T-γ* temporal criterion: MOOT — T-γ* dropped (O36/O38, ledger S1). O7 — CHIP clonal drift: HIGH OPEN — managed by conditioning + cfDNA barcoding + selective iC9 reset; long-horizon organoid validation required. O8 — progressive epigenetic transgene silencing: HIGH OPEN — CTCF insulators + AAVS1 + HSC turnover proposed; T-cell-subpopulation wet-lab validation non-negotiable before clinical use. O9 — P_quorum in the TME: RESOLVED — transit model (k-of-N; balanced M/E grouping superseded, ledger S11). O10 — bulk vs single-cell correlations: RESOLVED — ρ_sc ≤ ρ_bulk for inter-group pairs. O11 — Ci-VSP immunogenicity: MOOT — the Ci-VSP construct and T-γ* are dropped (ledger S1). O12 — CDIC dormant cells: MEDIUM — covered structurally by T-δ (CIN, proliferation-independent) + NK/missing-self; the τ threshold is not yet calibrated. O13 — HLA silencing / NK missing-self: LOW — HLA-E in construct; pool self-sustaining at 3.5× threshold. O14 — Penn Medicine data transferability to children: HIGH OPEN — N_ss 5–9× above threshold computationally; preclinical model required before Phase I. O15 — brain reporter gap: RESOLVED — S_tm + hepatic S₂ cascade (blue-urine signal). O16 — T-α self-activation: RESOLVED mathematically — triple-AND-gate (p_i = 0.0003–0.002 from literature). O17 — tonic-signalling exhaustion: RESOLVED mathematically — Pulsed Activity Architecture, ε(10y) = 0.921 (doxycycline + tet-on). O18 — θ for cold tumours: RESOLVED with data — GBM θ = 0.199 (reclassified hot); PDAC θ = 1.214 (confirmed cold, IPS module resolves). O19 — Magenta Therapeutics closure: RESOLVED — replaced by Jasper Therapeutics briquilimab (Phase 1b, 2025). O20 — data-access bottleneck: RESOLVED — datasets downloaded, script validated (May 2026). O21 — normal pancreas intrinsically cold: RESOLVED — pancreatic epithelium co-regulates the presence channels by design; IPS discriminates where θ cannot. O22 — IPS module PDAC detection: RESOLVED — 15.5× penetrance signal, P(false alarm) = 0.0003. O23 — bone-marrow self-attack: RE-SCOPED (LOW) → TASE 2.0 — T-γ* dropped, marrow risk re-evaluated on the current channels (mainly T-α), ledger S15. O24 — Piezo1 Goldilocks (T-β exhaustion): MOOT — T-β recast as a non-core AND-gate/vote candidate (ledger S3), so it is no longer a core-channel risk. O25 — NKG2D-CAR in-vivo toxicity (T-ε): MOOT — T-ε NKG2D sensor is non-core; CDIC coverage now via T-δ (CIN) + NK/missing-self (O12 frame, ledger S3). O26 — B2M-KO + HLA-E industry abandonment: MEDIUM OPEN — external industry dependency; reassess by 2028. O27 — briquilimab still combined with fludarabine + TBI in all current trials: HIGH OPEN — no standalone non-genotoxic conditioning demonstrated; the single most important gating constraint and critical path for Phase 1 in healthy subjects; monitor anti-CD117 trials 2026–2030. O28 — solid-tumour CAR-T regulatory failure (Marsico 2025, Small): MEDIUM-HIGH — afami-cel and lifileucel (FDA 2024) partially falsify the impossibility claim; the framework redistributes the four challenges via the multi-channel quorum + DMI + PDS + IPS + PAA (~5,000–30,000× on hot tumours); Phase 0 PoC is the only empirical rebuttal. O29 — T-γ* false-positive tissue map: MOOT — T-γ* dropped (O36/O38, ledger S1); Ki-67 gating survives only as a general proliferation AND-gate (ledger S13). O30 — T-ε ex-vivo fratricide: LOW — resolved by architecture (separate GMP sub-pool expansion, combined only at pooling). O31 — DMI flag degradation in desmoplastic TME: MEDIUM OPEN — poly-cationic 4×KKKK extension restores t½ = 28h; PDAC uses the IPS module as primary. O32 — Sequential Verification ordered quorum: MOOT — was the false-positive patch for T-γ*; with T-γ* dropped it is obsolete (ledger S12), the quorum is plain k-of-N over independent channels. O33 — inter-channel T-α/T-δ correlation (ACLY link): RESOLVED via the T-δ CIN redesign — the θ_ME = 0.40 figure was never a within-tumour measurement (real τ-b ≈ 0.02–0.10, ledger S4); T-δ as a CIN sensor is mechanistically orthogonal to metabolism. O34 — Channel Paradox: RECLASSIFIED to a design principle — not a quantitative risk on the measured panel (ρ ≈ 0.08); retained as the rationale of the θ < 0.20 independence gate (ledger S6). O35 — T-δ v2.0 extracellular detection mechanism: MEDIUM OPEN — two literature-validated paths (STING ectodomain receptor for extracellular cGAMP via LRRC8A/VRAC, Lahey 2020 / Wang 2024, primary; MICA/MICB via the DDR pathway, alternative); key experiment ≈ €20–40k, 8–12 weeks. O36 — T-γ* trans-cellular Vm transduction not specified: ACTED ON — no trans-cellular Vm correlate exists, so T-γ* is dropped; generalised by O38 (ledger S1/S17). O37 — Adaptive k=1/N + Gate_G dissolves the quorum: MOOT — the current quorum is plain k-of-N (operative k=2), neither k=1/N + Gate_G nor balanced M/E (ledger S11/S13); the tissue-specificity concern survives only for any future single-channel AND-gate. O38 — passive sensing of internal state is physically closed: STRUCTURAL — ADDRESSED via reframe — channels recast as readers of surface/secreted proxies, security expressed as a measured ROC, with a two-level (Early/Established) DQIS. O39 — immunoediting / antigen escape in the early window: STRUCTURAL — ADDRESSED (co-resistance measured) — evolutionary escape P ∝ μ^h (h = N−k+1 = 5 for k=2 of 6); the 10⁴–10⁹-cell interception window is the safe operating regime, "silencing all six channels" is ≈0% except near lethal mass, and three essential channels give an ~10⁹× brake. Co-resistance was tested twice on real escape — two Merkel-cell-carcinoma relapses (soft) and a genetically-defined CD19+/CD19− B-ALL escape (GSE153697): channels do not co-fall, independence holds (N_eff ≈ 4.65/6); to be extended (n=1 leukaemia). Every load-bearing citation in this register was checked by direct PubMed/PMC fetch. Read alongside the DQIS Consolidated Framework v36 and Addendum I v20. This is not a peer-reviewed publication — a prior-art deposit released under CC BY 4.0. Contact: [email protected] documents (current versions): DQIS Consolidated Framework v36; Addendum I — Temporal Stratification of Tail Dependence Risk v20. Contact: [email protected] documents: - DQIS Consolidated Framework (main document): https://zenodo.org/records/21128521- Addendum I — Temporal Stratification of Tail Dependence Risk: https://zenodo.org/records/21128894