L7: SAFETY · EVIDENCE LEDGER V6.2.9

Source_Of_Truth

Receipt: pubmed_multimodal_query.json

Multi-Modal Matrix

POSITIVE

NEGATIVE

CONF / MIXED

CRISPR

Screen

Expr

In Vivo

Clin

PubMed

Calibration Bar: Any axis claiming "validated SL" must approach Cytidine baseline: Isogenic functional data + PDX + Patient.

SL Calibration Rigor

GOLD STD VS PARP

Requirement	Cytidine	PARP Inhibitors
Isogenic cell line (KO/WT/rescue)
IC50 / dose-response shift
PDX in vivo efficacy
Patient response documented
Mechanism validated

ConclusionPARP MEETS 1 OF 5 CRITERIA

Explicit concordance check between genetic dependency and pharmacologic screens prevents false promotion.

PARP DISCORDANCE ALERT

CRISPR (Δ=+0.03)FLAT

GDSC2 (ΔZ=-0.02)FLAT

RESULT: BOTH NEGATIVE. PARP1 EXPR IS A BIOMARKER, NOT A THERAPEUTIC LEVER.

PubMed Receipts

36323843CHABOT T '22

MBD4 KO → CYTIDINE-ANALOG SL (ISOGENIC+PDX)CYTIDINE

35863105SAINT-GHISLAIN '22

MBD4 DEFICIENCY PREDICTS ICB RESPONSE IN OMICB

38619111FRÖHLICH LM '24

PARP1 EXPRESSION PREDICTS PARPI SENSITIVITYPARP1

38658754FERRETTI S '24

HRO761 WRN INHIBITOR — MSI-SPECIFIC SLWRN-MSI

38060262VILLY MC '24

GERMLINE MBD4 → MULTI-TUMOR PREDISPOSITIONCLINICAL

STRUCTURAL RECEIPT (AF3)AF3_v2_pLDDT_94.2

PROT: MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN...