Evidence-Guided Drug Repurposing
Investigating BUB1B dysfunction in mosaic variegated aneuploidy through reproducible reanalyses, source-linked evidence and explicit functional validation gates.
No exact-genotype pharmacological rescue is established. Wet-lab validation remains future work. This page is research context, not a clinical diagnostic report or a treatment recommendation.
Two BUB1B variants raise distinct molecular questions: L737* introduces a premature stop (an RNA and translation question), N1002K is a missense change in the kinase region (a protein stability and function question).
4 quantitative reanalyses, 6 evidence audits and 1 synthetic software test, drawn from primary papers and public perturbation datasets, each labeled with its model and limits.
L737* NMD susceptibility is predicted, not measured. N1002K stability and residual function are unresolved. Checkpoint competence and chromosome segregation have not been measured for either variant.
Un recorrido por la evidencia, los candidatos de investigación y el experimento propuesto para BUB1B
Propuesta de investigación. No constituye una recomendación de tratamiento.
Clarification, . The narration (around 01:20 in the automatic transcript) says “12 nearby sequence contexts”. The revision distinguishes 12 measured variant rows representing 8 distinct six-base contexts; they are not independent contexts or biological replicates. The rest of that conclusion stands: no exact L737* measurement was found. The video, its audio and its captions have not been changed, and no full audiovisual review is claimed. Video clarification package
Two variant questions guide the research. Functional rescue is the deciding endpoint.
NMD modulation alone cannot establish a useful protein product. Readthrough needs exact-context and functional validation.
Inspect the RNA gateStability and residual function remain unresolved. Matched protein abundance must be followed by independent functional measurements.
Inspect the function gateAmlexanox remains on hold for nomination until product eligibility is resolved. Montelukast is conditional on useful exact L737* protein function. Gentamicin plus mefloquine remains experimental.
Inspect the candidate decisionsFollow the research trail. The Literature Workspace keeps this reading order as a trail, step by step, with the hypotheses and evidence gaps behind each conclusion. Open the MVA · BUB1B trail
Key areas where additional evidence could inform biology and therapeutic opportunity. Each card opens the matching conceptual viewer or validation plan.
Illustrations explain questions; they do not show experimental results. No exact-genotype rescue is established. Protein shapes are conceptual and are not BUBR1 structures.
Follow the path from a gene to cell division. Choose a research branch to see the mechanism it proposes and the evidence still missing.
Select a branch to highlight its proposed site of action. No biological experiment is running.
Two unresolved mechanisms
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Illustration steps · no experiment running · no response calculatedRNA / readthrough hypothesis
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Illustration steps · no experiment running · no response calculatedNMD-modulation hypothesis
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Illustration steps · no experiment running · no response calculatedExperimental readthrough branch
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Illustration steps · no experiment running · no response calculatedProtein-homeostasis hypothesis
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Illustration steps · no experiment running · no response calculatedCell-state and confounding branch
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Illustration steps · no experiment running · no response calculatedDownstream exploratory branch
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Illustration steps · no experiment running · no response calculatedNo exact-genotype pharmacological rescue is established. Animation illustrates a question; it does not calculate drug efficacy, repair DNA or predict a clinical outcome.
L737* introduces a premature stop; NMD susceptibility is predicted. N1002K raises separate questions about protein stability and residual function.
Measure exact-variant function before assuming that more RNA or more protein would help.
A related 731X construct motivates testing whether L737* retains useful function when NMD is bypassed. The exact L737* experiment has not been performed.
Sources, model and limitations →No exact-N1002K functional experiment was located. I909T/L1012P checkpoint rescue at matched abundance makes an abundance-limited mechanism plausible, but equally expressed B56-binding mutants still failed chromosome-congression rescue and mouse L1012P showed allelic effects beyond total protein level. Stabilization remains conditional; no drug is promoted.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore context-dependent NMD modulation and stop-codon readthrough. The highlighted steps are proposed sites of action, not measured effects in BUB1B.
Can exact-L737*-derived full-length BUBR1 be demonstrated alongside independent checkpoint and segregation improvement?
Functional CFTR evidence supports investigating amlexanox, but negative NEFL rescue with neurite toxicity and context-dependent NMD responses prevent promotion to an established lead. GDAP1 immunofluorescence does not by itself resolve full-length protein. No exact-L737* rescue is established.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore whether modulating RNA surveillance could preserve a stop-containing transcript. More RNA alone cannot establish useful protein function.
Does the exact L737* truncation retain useful function, and does an allele-specific RNA response translate into functional protein?
Montelukast has a published permutation q of 0.021150, but the response is reporter-dependent and confounded by non-NMD isoform changes. No hit establishes functional BUBR1 rescue.
Sources, model and limitations →A related 731X construct motivates testing whether L737* retains useful function when NMD is bypassed. The exact L737* experiment has not been performed.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore bypass of a premature stop during translation. Combination evidence from other genes does not establish this combination's efficacy in BUB1B.
Test the exact L737* context and protein product. Readthrough need not restore native leucine or functional BUBR1.
G418/ELX-02 with or without mefloquine were studied beyond reporters, including endogenous PKD1 protein and withdrawal measurements. This does not establish gentamicin-combination efficacy or BUB1B rescue.
Sources, model and limitations →No exact L737* measurement or exact six-flanking-base match in the 5,837-PTC table. Twelve nearest contexts have a median paired gentamicin increment of 0.0165 percentage points.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore an indirect heat-shock/protein-homeostasis rationale. Direct engagement of BUBR1 and rescue of N1002K have not been established.
N1002K stability and residual function must be measured; increased abundance alone would not establish rescue.
No direct BUBR1 or N1002K rescue evidence was located in the audit. Heat-shock responses are context-dependent; arimoclomol is not promoted to lead candidate.
Sources, model and limitations →No exact-N1002K functional experiment was located. I909T/L1012P checkpoint rescue at matched abundance makes an abundance-limited mechanism plausible, but equally expressed B56-binding mutants still failed chromosome-congression rescue and mouse L1012P showed allelic effects beyond total protein level. Stabilization remains conditional; no drug is promoted.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore how altered cell state could affect the interpretation of a rescue assay. The public fibroblast reanalysis does not support an RNA-abundance-increase rationale in that model.
Separate cytostasis from improved segregation per completed division, including a future transient-exposure/washout comparison.
The primary BUB1B-spanning feature has a Rap/Pro mean ratio of 0.585706 (41.43% lower); reduced-serum/Pro is 0.186191. Three nearly full-span features give the same direction. This does not support an RNA-abundance-increase rationale for sirolimus in this model.
Sources, model and limitations →The synthetic fixture flags fewer raw error-positive divisions without a lower error rate per completed division. It does not measure sirolimus activity.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore a future hypothesis of selectively removing harmful senescent cells. This would not repair BUB1B; tumor control is a different outcome from disease rescue.
Establish a selectively targetable harmful cell population in a relevant BUB1B model while preserving normal tissue function.
Genetic senescent-cell ablation delayed selected phenotypes in BubR1-deficient mice; uPAR CAR T benefits came from other mouse models. HER2 CAR T and nivolumab/ipilimumab show limited antitumor signals in sarcoma, while nivolumab monotherapy lacked solid-tumor responses in ADVL1412. Tumor control does not establish BUB1B rescue. No exact-genotype immunotherapy rescue was located.
Sources, model and limitations →Evidence from the current deployed snapshot. Wet-lab validation remains future work.
Explore what each record examined, what it found and what still needs validation. The illustrations explain the method; the evidence below provides the result.
Conceptual method illustrations. No experiment is running and no new result is calculated.
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Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
Montelukast has a published permutation q of 0.021150, but the response is reporter-dependent and confounded by non-NMD isoform changes. No hit establishes functional BUBR1 rescue.
Published mouse Neuro-2a AS-NMD isoform summaries; three reporter genes, not BUB1B.
Establish L737* residual function first; any NMD candidate then needs allele-specific RNA, protein synthesis, and separate checkpoint/segregation endpoints.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
No exact L737* measurement or exact six-flanking-base match in the 5,837-PTC table. Twelve nearest contexts have a median paired gentamicin increment of 0.0165 percentage points.
Published 144-nt PTC reporters in human cells; nearest-context subset, not endogenous BUB1B.
Use the exact L737* context with matched controls and independently test full-length protein, checkpoint response and segregation fidelity.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
Figure 4B source-data medians are 650 minutes for WT and 60 minutes for D137R. A control for checkpoint competence, not a drug-rescue result.
Published HeLa BUBR1 depletion/replacement with WT or engineered TPR variants under nocodazole challenge.
Require independent checkpoint and chromosome-segregation readouts in future equal-expression assays.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
No exact-N1002K functional experiment was located. I909T/L1012P checkpoint rescue at matched abundance makes an abundance-limited mechanism plausible, but equally expressed B56-binding mutants still failed chromosome-congression rescue and mouse L1012P showed allelic effects beyond total protein level. Stabilization remains conditional; no drug is promoted.
Published human-cell BUBR1 depletion/replacement studies, MVA fibroblast rescue and a mouse L1012P comparator model; none tests N1002K.
At measured matched abundance, compare WT, N1002K and L1012P in one depletion-replacement system; report nocodazole checkpoint arrest separately from chromosome alignment and missegregation per completed division. Wet-lab work is deferred.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
A related 731X construct motivates testing whether L737* retains useful function when NMD is bypassed. The exact L737* experiment has not been performed.
Published 731X/753X BUBR1 constructs and a proposed exact-L737* validation design.
Test WT, clean L737*, 731X and 753X at matched abundance; advance NMD modulation only if the exact truncation retains useful function.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
No direct BUBR1 or N1002K rescue evidence was located in the audit. Heat-shock responses are context-dependent; arimoclomol is not promoted to lead candidate.
Human-cell heat-shock studies and a nominal molar conversion of FDA-label serum concentrations.
Require target engagement at relevant exposure plus exact-variant functional rescue before reconsidering prioritization.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
The synthetic fixture flags fewer raw error-positive divisions without a lower error rate per completed division. It does not measure sirolimus activity.
Invented test counts used only to test code; not an experiment or a biological simulation.
Reuse the denominator checks with prospectively designed real measurements when wet-lab work becomes available.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
The primary BUB1B-spanning feature has a Rap/Pro mean ratio of 0.585706 (41.43% lower); reduced-serum/Pro is 0.186191. Three nearly full-span features give the same direction. This does not support an RNA-abundance-increase rationale for sirolimus in this model.
Normal 2DD fibroblasts: proliferative vehicle, 0.5% serum, or 500 nM rapamycin for five days; two biological replicates per condition.
Keep sirolimus conditional. Proposed: compare full-length BUBR1 protein and segregation errors per completed division after transient exposure and washout at matched cell-cycle distribution. Wet-lab work is deferred.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
G418/ELX-02 with or without mefloquine were studied beyond reporters, including endogenous PKD1 protein and withdrawal measurements. This does not establish gentamicin-combination efficacy or BUB1B rescue.
Published HEK293 PKD1 reporters and WT9-12 cells bearing endogenous PKD1 Q2556X; not BUB1B.
Keep gentamicin plus mefloquine experimental only; add ELX-02 to proposed mechanistic comparators, not the repurposing lead list. Require exact-L737* RNA, full-length protein and checkpoint/segregation outcomes after withdrawal. Wet-lab deferred.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
Functional CFTR evidence supports investigating amlexanox, but negative NEFL rescue with neurite toxicity and context-dependent NMD responses prevent promotion to an established lead. GDAP1 immunofluorescence does not by itself resolve full-length protein. No exact-L737* rescue is established.
Published CFTR cells, GDAP1 neuronal progenitors, NEFL motor neurons and mouse NMD reporters; no exact BUB1B model.
Can exact-L737*-derived full-length BUBR1 be demonstrated at an exposure that also improves checkpoint and segregation independently of cytostasis? Require allele attribution, viability/proliferation controls and separate functional endpoints. Wet-lab validation remains proposed.
Read sources, method and limitations →Drag to rotate · pinch or scroll to zoom. Use arrow keys when focused.
Illustration steps · no experiment running · no response calculatedThe status refers to the recorded analysis, not biological rescue.
Genetic senescent-cell ablation delayed selected phenotypes in BubR1-deficient mice; uPAR CAR T benefits came from other mouse models. HER2 CAR T and nivolumab/ipilimumab show limited antitumor signals in sarcoma, while nivolumab monotherapy lacked solid-tumor responses in ADVL1412. Tumor control does not establish BUB1B rescue. No exact-genotype immunotherapy rescue was located.
BubR1 H/H INK-ATTAC mice; separate aging/metabolic CAR T mouse models; early human sarcoma studies. No exact BUB1B variant model.
Retain immune senolysis as future exploratory research, not the immediate BUB1B rescue lead. Does a relevant BUB1B model contain harmful senescent cells with a selectively targetable surface antigen while preserving normal/progenitor cells and tissue function? Wet-lab validation remains proposed.
Read sources, method and limitations →Separate assays, separate scales. No clinical probabilities or efficacy scores. Every chart names its model, unit, exact values and limitations.
NMD / non-NMD normalized RNA ratio · zero-based scale
Model / scopePublished mouse Neuro-2a AS-NMD isoform summaries; three reporter genes, not BUB1B.
Dashed line: reference ratio 1.
| Condition | Ptbp2 | Hnrnpl | Tra2b | Context |
|---|---|---|---|---|
| Montelukast sodium | 1.3153820850896314 | 3.406494677098417 | 1.7654686351224798 | Published permutation q = 0.02115; not a BUBR1 endpoint. |
| Artesunate | 1.718112969537028 | 1.0078988102818638 | 4.2875477079256585 | Published permutation q = 0.010071; not a BUBR1 endpoint. |
| Cladribine | 2.126124275101715 | 2.0820411294900216 | 1.6377191943091594 | Published permutation q = 0.010071; not a BUBR1 endpoint. |
| Albendazole | 1.5634627380948676 | 1.701726223666598 | 3.2992143735876955 | Published permutation q = 0.015667; not a BUBR1 endpoint. |
| Topotecan hydrochloride | 3.9533398228039465 | 2.3994174963086077 | 0.6542839291174242 | Published permutation q = 0.0 (finite-sampling zero, not zero uncertainty); not a BUBR1 endpoint. |
| Homoharringtonine | 5.0039366160196295 | 24.97590928901173 | 11.672927661494484 | Published permutation q = 0.0 (finite-sampling zero, not zero uncertainty); not a BUBR1 endpoint. |
| Mefloquine hydrochloride | 1.181600971576268 | 1.3075083215610865 | 1.5102164979716604 | Published permutation q = 0.061224; not a BUBR1 endpoint. |
| Nicotinic acid | 1.1859031685137231 | 1.4152893426077033 | 0.9171679519898492 | Published permutation q = 0.08225; not a BUBR1 endpoint. |
Median reporter readthrough (%) · zero-based scale
Model / scopePublished 144-nt PTC reporters in human cells; nearest-context subset, not endogenous BUB1B.
| Condition | Median | Context |
|---|---|---|
| Untreated | 0.1745 | 12 nearest measured six-base contexts; exact L737* context absent. |
| Gentamicin | 0.1985 | Same 12 contexts, not BUB1B efficacy or a patient prediction. |
Median NEBD-to-exit time (minutes) · zero-based scale
Model / scopePublished HeLa BUBR1 depletion/replacement with WT or engineered TPR variants under nocodazole challenge.
| Condition | Median | Context |
|---|---|---|
| Wild type | 650 | 27 cells; representative replicate, not independent biological replicates. |
| D137R | 60 | 39 cells; representative replicate, not independent biological replicates. |
RPKM as deposited; genomic-span RNA feature · zero-based scale
Model / scopeNormal 2DD fibroblasts: proliferative vehicle, 0.5% serum, or 500 nM rapamycin for five days; two biological replicates per condition.
| Condition | Biological replicate 1 | Biological replicate 2 | Context |
|---|---|---|---|
| Proliferative vehicle | 6.227185 | 5.570779 | 10% FBS; DMSO vehicle. |
| Reduced serum | 1.2674783 | 0.9291951 | 0.5% FBS for five days; not matched for cell-cycle distribution. |
| Rapamycin 500 nM | 3.7114706 | 3.198672 | 500 nM for five days; 10% FBS. Mean is 0.585706 times proliferative control. |
Recorded analyses, their limits, and the next experiment that could change the decision.
Research, not a treatment recommendation. Public literature, computational reanalyses and explicitly labeled synthetic software checks only. Wet-lab validation is deferred. No private genomic data are included. The GSE65145 summary and N1002K equal-expression audit were checked by the research assistant for source support, privacy and scientific limits; neither has received independent human scientific review. The readthrough-transfer audit is assistant-reviewed, not independently human-reviewed. The immunotherapy audit is assistant-reviewed, not independently human-reviewed, and distinguishes tumor control from BUB1B disease rescue. “Completed” describes the recorded computational or review work, not biological validation. No exact-genotype pharmacologic rescue is established in this snapshot.
Filter the recorded work, then open a record for its sources, method and limitations.
11 records. Expand a record to inspect evidence and provenance.
| Record / question | Work & execution | Finding | Decision | Recorded on |
|---|---|---|---|---|
| MVA-NMD-003704-drug NMD screen: reporter specificity | ReanalysisCompleted · COMPUTATIONAL / PATHWAY EVIDENCE | Read the recorded findingMontelukast has a published permutation q of 0.021150, but the response is reporter-dependent and confounded by non-NMD isoform changes. No hit establishes functional BUBR1 rescue. |
Conditional | |
| MVA-RT-002L737* readthrough: exact versus nearby contexts | ReanalysisCompleted · COMPUTATIONAL / PATHWAY EVIDENCE | Read the recorded findingNo exact L737* measurement or exact six-flanking-base match in the 5,837-PTC table. Twelve nearest contexts have a median paired gentamicin increment of 0.0165 percentage points. |
Deprioritized | |
| MVA-CTRL-006BUBR1 functional controls: arrest duration | ReanalysisCompleted · COMPUTATIONAL / DIRECT-BUBR1 | Read the recorded findingFigure 4B source-data medians are 650 minutes for WT and 60 minutes for D137R. A control for checkpoint competence, not a drug-rescue result. |
Control only | |
| MVA-N1002K-GATE-002N1002K stabilization: equal-expression gate | Evidence auditCompleted · DIRECT-BUBR1 COMPARATORS / RELATED-VARIANT IN VIVO / TARGETED AUDIT | Read the recorded findingNo exact-N1002K functional experiment was located. I909T/L1012P checkpoint rescue at matched abundance makes an abundance-limited mechanism plausible, but equally expressed B56-binding mutants still failed chromosome-congression rescue and mouse L1012P showed allelic effects beyond total protein level. Stabilization remains conditional; no drug is promoted. |
Conditional | |
| MVA-L737-NMD-FIRST-001L737* NMD-first: test truncated-protein function | Evidence auditCompleted · DIRECT-BUBR1 COMPARATOR / OUR INFERENCE | Read the recorded findingA related 731X construct motivates testing whether L737* retains useful function when NMD is bypassed. The exact L737* experiment has not been performed. |
Conditional | |
| MVA-ARI-007Arimoclomol: target engagement and exposure gap | Evidence auditCompleted · PATHWAY EVIDENCE / COMPUTATIONAL / OUR INFERENCE | Read the recorded findingNo direct BUBR1 or N1002K rescue evidence was located in the audit. Heat-shock responses are context-dependent; arimoclomol is not promoted to lead candidate. |
Deprioritized | |
| MVA-FUNC-005Cytostasis confounding: denominator unit test | Software testCompleted · SYNTHETIC SOFTWARE FIXTURE | Read the recorded findingThe synthetic fixture flags fewer raw error-positive divisions without a lower error rate per completed division. It does not measure sirolimus activity. |
Control only | |
| MVA-RAP-GSE65145-001Rapamycin in human fibroblasts: BUB1B locus RNA signal | ReanalysisCompleted · Public human perturbation data; descriptive locus-level RNA reanalysis, not functional rescue. | Read the recorded findingThe primary BUB1B-spanning feature has a Rap/Pro mean ratio of 0.585706 (41.43% lower); reduced-serum/Pro is 0.186191. Three nearly full-span features give the same direction. This does not support an RNA-abundance-increase rationale for sirolimus in this model. |
Conditional | |
| MVA-RT-TRANSFER-009Readthrough combinations: endogenous-protein transfer gap | Evidence auditCompleted · OTHER-GENE HUMAN-CELL EVIDENCE / OUR INFERENCE | Read the recorded findingG418/ELX-02 with or without mefloquine were studied beyond reporters, including endogenous PKD1 protein and withdrawal measurements. This does not establish gentamicin-combination efficacy or BUB1B rescue. |
Conditional | |
| MVA-AMLEXANOX-010Amlexanox: context-dependent readthrough evidence | Evidence auditCompleted · OTHER-GENE HUMAN-CELL / PATHWAY / OUR INFERENCE | Read the recorded findingFunctional CFTR evidence supports investigating amlexanox, but negative NEFL rescue with neurite toxicity and context-dependent NMD responses prevent promotion to an established lead. GDAP1 immunofluorescence does not by itself resolve full-length protein. No exact-L737* rescue is established. |
Conditional | |
| MVA-IMMUNE-011Immunotherapy: disease rescue versus tumor control | Evidence auditCompleted · DIRECT-BUBR1 MOUSE ABLATION / OTHER-MODEL CAR T / CLINICAL ONCOLOGY / OUR INFERENCE | Read the recorded findingGenetic senescent-cell ablation delayed selected phenotypes in BubR1-deficient mice; uPAR CAR T benefits came from other mouse models. HER2 CAR T and nivolumab/ipilimumab show limited antitumor signals in sarcoma, while nivolumab monotherapy lacked solid-tumor responses in ADVL1412. Tumor control does not establish BUB1B rescue. No exact-genotype immunotherapy rescue was located. |
Deprioritized |
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Sources describe published experiments. Proposed validation below has not been performed by this project.
MVA-NMD-003704-drug NMD screen: reporter specificityReanalysisMouse Neuro-2a; three AS-NMD isoform reporters · Tables S1/S2/S4; Figures 2–5 and 7
nmd_reanalysis_20261009/results/selected_candidates.csvad7fa784e6caf2f126c9730e4edaf7dc75f0ea2ad54208661de75555ede6ab9cArtifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-RT-002L737* readthrough: exact versus nearby contextsReanalysisHuman HEK293T landing-pad reporters; not endogenous BUB1B · Supplementary Table 3; Extended Data Figure 4
HEK293 COL4A5 cDNA reporters; different gene and context · Figure 6: gentamicin plus mefloquine
l737_readthrough_gate_2026-10-09/results/results.json8d1f7ca32b05f9e85cedc5d025ea04efee60b581ae4effea8fd389e6f4afbcb9Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-CTRL-006BUBR1 functional controls: arrest durationReanalysisHeLa endogenous BUBR1 RNAi and RNAi-resistant YFP replacement · Figure 4B; supplementary source-data workbook, Sheet1
bubr1_checkpoint_kinetics_2026-10-09/results.jsond6be3833115ac368fffe185dfea0e42439e4c80e723b88c626ecb9b874073e6cArtifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-N1002K-GATE-002N1002K stabilization: equal-expression gateEvidence auditU2OS/HeLa BUBR1 depletion and replacement · Figures 4D and 5; comparator variants, not N1002K
HeLa BUBR1 depletion/reconstitution and BUB1B-mutated MVA fibroblast rescue · Figures 2 and 4; equally expressed B56-binding mutants are functional counterexamples
Mouse BubR1 L1002P ortholog model of human L1012P with hypomorphic or truncating alleles · Abstract and Figures 1-3; related variant, not N1002K
n1002k_equal_expression_audit_2026-10-10/audit.json30a149370a4bd736fbe39618c2e0ed549008066ea004bd24a5e699308657c73dArtifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-L737-NMD-FIRST-001L737* NMD-first: test truncated-protein functionEvidence auditU2OS/HeLa BUBR1 depletion and replacement · Figures 4D and 5; comparator variants, not N1002K
l737_nmd_first_gate_2026-10-09/experiment.json68b890531733aec6fc1f4a6cace8ce8e85bdcccf63bb61900688b831aa383a69Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-ARI-007Arimoclomol: target engagement and exposure gapEvidence auditDifferentiated human SH-SY5Y cells; arimoclomol plus celastrol · Figures 2–5; not a BUBR1 study
Human HSF-responsive reporter and endogenous target systems · Table 1 and Figure 4: negative arimoclomol response in this system
Regulatory label; human serum pharmacokinetics, different indication · Clinical pharmacology; historical label used by the 2026-10-09 audit
arimoclomol_n1002k_gate_2026-10-09/results.json6ce51099f036cd0082358c22176f9f58e3065fc545a32781d40014c020233764Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-FUNC-005Cytostasis confounding: denominator unit testSoftware testmitosis_adjudicator_2026-10-08/examples/cytostasis_results.jsondfb5fa29aa719fc59d206cf34a8d33b1ce59bda41d5665f685a219c6770a753bArtifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-RAP-GSE65145-001Rapamycin in human fibroblasts: BUB1B locus RNA signalReanalysis2DD normal human foreskin fibroblasts; two biological replicates per condition · GSE65145 processed tracks; Figures 1 and 3; Figure S2; Cell culture and RNA-seq methods
MVA_GSE65145_BUB1B_2026-10-10.zip/gse65145_bub1b_results.jsone71199b4f23c6315f02febfd18aac8b9bcd7e7f8bb05a7a7b624ad874d54d3b6Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-RT-TRANSFER-009Readthrough combinations: endogenous-protein transfer gapEvidence auditHuman HEK293 PKD1 reporters and WT9-12 cells; other-gene evidence · Figures 1H-I, 4, 5 and 6; published 2025-11-22
MVA_READTHROUGH_TRANSFER_AUDIT_2026-10-11.json7dc7dc6fedfd923ab7c7fcaff2bf8fb5cada27fa9bb3a3830ddc477af8175d27Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-AMLEXANOX-010Amlexanox: context-dependent readthrough evidenceEvidence auditHuman 6CFSMEo- CFTR nonsense cells · Figure 6
Human iPSC-derived neuronal progenitors with GDAP1 p.Ser194* (UGA) · Figures 2-4
Human iPSC-derived NEFL nonsense motor neurons · Figure 6; Treatments
Mouse Neuro-2a; three AS-NMD isoform reporters · Tables S1/S2/S4; Figures 2–5 and 7
Historical FDA Aphthasol 5% oral-paste label · Pharmacokinetics and Metabolism, page 1
MVA_AMLEXANOX_AUDIT_2026-10-17.json947129103dd93e1ba722f4301b86e158ad705c2376fca6b07fb1fb4066e47394Artifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
MVA-IMMUNE-011Immunotherapy: disease rescue versus tumor controlEvidence auditBubR1 H/H hypomorphic progeroid mice carrying INK-ATTAC. · Abstract; Figures 2-4 public captions.
Naturally aged C57BL/6 mice and high-fat-diet mice. · Figures 3-5 (clearance, safety assessments and metabolic endpoints); Figures 6-7 (persistence/prevention and high-fat diet).
People with progressive HER2-positive sarcoma, including rhabdomyosarcoma. · Abstract; Table 1 and response results / Figure 4 located through indexed primary-article text.
Pediatric and young-adult relapsed/refractory malignancies; phase 1-2. · Abstract, findings and interpretation; no figure-level extraction.
Children and young adults with recurrent/refractory solid tumors. · Abstract reproduced by the investigators at Children's Oncology Group; Figure 3A located in indexed primary text.
MVA_IMMUNOTHERAPY_AUDIT_2026-10-17.json05ae8ff5ec7a7a11a7ca831e3fd20fc2888c6140e508f08a285b362672f4cf2cArtifact names and hashes identify the imported analysis package; they are not links to patient data or a claim that unpublished artifacts exist in the public research repository.
A dated, post-hoc exploratory computational audit of two earlier observations, and the candidate decision matrix it leaves unchanged.
The Track 2 report as originally submitted. Frozen and unchanged by the revision.
11 records: 4 reanalyses, 6 evidence audits and 1 synthetic software test, with 4 charts. Unchanged: the new sensitivity diagnostics are not added to it.
Scientific update prepared and published in the research repository. It is not an officially resubmitted report or PDF. Published at commit bc39224.
Post-hoc exploratory, not a prospective preregistration. The protocol was recorded after the original results were known and amended before these sensitivities were executed. The run used manifest-verified cached public inputs in the current, non-isolated environment, not a fresh download or a clean environment. It adds no statistical test, p-value, confidence interval, causal correction, biological experiment or clinical efficacy.
Exhaustive, deterministic leave-out and feature-selection diagnostics over two published processed datasets: 12 measured readthrough rows selected from 5,837 populated table rows, and GSE65145 RNA tracks with 2 samples per condition. The four original reanalyses were replayed and matched their archived hashes (replay check ).
The readthrough values come from HEK293T landing-pad reporters, not endogenous BUB1B. The RNA feature comes from one normal fibroblast line without the MVA genotype. Neither is an exact L737* or N1002K measurement.
Exact L737* product and N1002K function, BUBR1 protein, checkpoint response and segregation errors per completed division: proposed, not performed (section 06).
No exact six-base context measurement for L737*; no exact-span RNA feature; proliferation confounding unresolved; the 149,122 deposited rows versus 149,135 probes stated in the paper remain an unresolved source discrepancy.
| Check | Executed result | Reading | What it means |
|---|---|---|---|
| Readthrough near L737* (published PTC reporter table)Primary source: Toledano et al., genome-scale PTC readthrough (Nature Genetics), Supplementary Table 3 ↗ | |||
| Readthrough denominator | 12 measured variant rows representing 8 unique six-base contexts. Exact six-base matches with L737*: 0. Minimum Hamming distance: 1. | Changes | Not 12 independent contexts and not 12 biological replicates. The earlier wording “12 nearby sequence contexts” is corrected. |
| Median paired increment, full nearest set | +0.0165 percentage points; 11 positive and 1 negative individual paired differences (RP1_S542X, −0.0030 percentage points). | Holds | Small source-table median in reporter sequences; not “0.0165% rescue” and not BUB1B efficacy. |
| Leave one measured row out | 12 deletions; median paired increment +0.0140 to +0.0190 percentage points. | Holds | All retained-set medians stay positive. A finite diagnostic range, not a confidence interval. |
| Leave one whole context group out | 8 deletions; median paired increment +0.0135 to +0.0285 percentage points. | Holds | Direction retained after removing repeated contexts; the magnitude changes. Not a confidence interval. |
| Equal weight per context | Median of 8 within-context medians: +0.0160 percentage points. | Changes | A separate descriptive estimand, not an independent replication. |
| Difference between marginal medians | Gentamicin 0.1985% minus untreated 0.1745%: +0.0240 percentage points. | Changes | A different quantity. It does not replace the median paired increment (+0.0165 percentage points). |
| Rapamycin and the BUB1B-spanning RNA feature (GSE65145)Primary sources: GSE65145 processed tracks (NCBI GEO) ↗ · Gillespie et al., rapamycin and normal human fibroblast transcription ↗ | |||
| Feature selection, reciprocal overlap | 95%, 97.5%, 99% and 99.5% select the same 3 highly redundant features; Rap/Pro ≈ 0.585706. | Holds | Technical selection stability. The features are redundant locus views and do not increase the biological n. |
| Exact-span threshold | 100% reciprocal overlap: no eligible feature. | Insufficient | Insufficient, not zero expression; no silent fallback to another feature. |
| Primary feature, condition means | Arithmetic Rap/Pro 0.585706 (41.43% lower); geometric 0.584998. | Holds | Direction unchanged under the second estimator. An RNA feature, not BUBR1 protein or rescue. |
| Leave one sample out | 6 deletions; Rap/Pro 0.542241 to 0.629171. | Holds | All remain below 1. The condition that loses a sample keeps one. Not a precision interval. |
| Unpaired cross-condition ratios | 4 Rap/Pro sample ratios: 0.513663 to 0.666239. | Holds | A sample-dependence diagnostic, not 4 biological replicates. |
| Proliferation state | Qui/Pro 0.186191; Rap/Qui 3.145731. | Insufficient | Descriptive comparisons without adjustment. Reduced serum is not a cell-cycle-matched control: proliferation confounding is not resolved and no BUB1B-specific effect is shown. |
| Both analyses | |||
| Exact-genotype function | No exact L737* context measurement, BUBR1 protein, exact-genotype functional rescue or clinical efficacy was tested. | Insufficient | Not tested by this audit; it remains future wet-lab work. |
4062d0d4d50a2d0e6ef43904727e7f50487ae10de9dd16affc00c1ca2129c2e1, verified when this page loads it.No exact-genotype pharmacological rescue is established. Priorities are experimental branches, not an efficacy ranking or a treatment plan, and the rows keep the document's order. The product findings were already public at commit 0cb71c4; they are not new results of this revision. Competition eligibility remains a separate determination.
| Candidate | Verified product status | Exact versus other-model evidence | Exposure limit | Functional uncertainty | Current gate | Decisive experiment |
|---|---|---|---|---|---|---|
| AmlexanoxEligibility HOLD | HOLD for nomination. US 5% dental paste NDA020511/001 and 2 mg topical patch NDA021727/001: Discontinued. Current eligible systemic product unresolved. | No exact L737* rescue. CFTR functional signal; contrary NEFL findings with neurite toxicity. GDAP1 staining does not establish full-length protein. | Paste-associated total serum ~0.402 µM is not systemic-tablet PK. Other-gene culture conditions 0.2-25 µM and 100 µM differ by model. Adequate systemic unbound bridge absent. | RNA increase or staining may not yield useful BUBR1. Readthrough can insert a non-native residue. | Resolve product, formulation and jurisdiction before nomination. Require useful identified protein and functional gain at defensible exposure; reject toxicity or cytostasis-only signal. | In splice-preserving exact L737* cells, verify allele-specific RNA and both protein termini, then checkpoint and errors per completed division. Measure unbound exposure and viability. |
| MontelukastConditional NMD hypothesis | US Rising/Teva 10 mg-base oral tablets ANDA209012/001 and ANDA078605/001: Prescription. This is not organizer eligibility certification. | No exact BUB1B rescue. Mouse Neuro-2a endogenous AS-NMD reporter-isoform response, not BUB1B target engagement. | 5 µM for 5 h in reporter study versus historical mean Cmax ~0.720 µM total plasma; >99% plasma binding. These are not matched free exposures. | Exact L737* truncated-protein function is unknown. NMD modulation preserves the stop codon. The related 731X frameshift is not an exact surrogate. | Conditional mechanism branch only. First require useful exact-truncation function. RNA-only response cannot pass; stop if truncation is inactive or harmful. | Express exact L737* under controlled abundance; test checkpoint and segregation. Only if useful, test endogenous allele-specific stabilization and functional benefit under credible exposure. |
| Gentamicin + mefloquineExperimental branch | US gentamicin injection ANDA062366/001-002 and mefloquine oral tablet ANDA076392/001: Prescription. Combination unapproved for MVA. | No exact BUB1B rescue. Omachi Figure 6B/D: HEK293 COL4A5-R1563X/G5X NanoLuc reporters, 2/4 mM gentamicin + 20 µM mefloquine, 24 h. G418 panels are separate. | Nominal culture concentrations; no justified simultaneous unbound human exposure. Mefloquine total-plasma comparison is not a safety margin. No gentamicin mixture mass conversion. | Reporter luminescence does not establish functional BUBR1 or synergy. Full-length readthrough may be non-native. | Experimental only. Require identified full-length product and gain over the relevant single agent. Stop for unsupported co-exposure, toxicity or absent functional gain. | Compare both monotherapies, combination, vehicle and corrected controls in exact splice-preserving context. Separate protein identity, checkpoint, segregation and viability endpoints. |
| SirolimusMechanistic comparator | Mechanistic comparator, not current rescue lead. Product-level re-nomination and eligibility not established in this matrix. | No exact-genotype rescue. Normal-fibroblast RNA feature decreased 41.43% with rapamycin versus proliferative vehicle. Earlier mTOR/SASP evidence is pathway/model dependent. | 500 nM continuously for 5 days in GSE65145. No MVA target-tissue PK or functional exposure bridge established. | Deposited RNA feature is not mature-isoform abundance, BUBR1 protein or rescue. Proliferation confounding remains. | Do not advance an RNA-increase rationale. A downstream branch needs a demonstrated pathway abnormality and separate tissue endpoint with mitotic safety. | In genotype-relevant cells, establish the pathway abnormality and test the chosen endpoint with matched proliferation, lineage/viability tracking and errors per division. |
Shared GO rule: predefine independent biological units, primary functional endpoint, meaningful effect, precision and toxicity/exposure bounds. Inconclusive is not GO. Checkpoint-only benefit is not segregation rescue. No candidate passes these gates yet.
Sources: product and exposure fiche (references P1-P16) · source evidence appendix · revised report, sections 4 and 6 · Omachi et al. (2022), COL4A5 readthrough reporters, Figure 6B/D ↗ · Organizer combination guidance ↗. The human-exposure anchors are historical and formulation-specific; prescription status is not local stock, pediatric safety or efficacy.
Proposed work. These biological experiments have not been performed by this project.
Published sources behind the records, the scope of this snapshot, and the historical Track 1 context that motivated the case.
Public literature, computational reanalyses and explicitly labeled synthetic software checks only. Wet-lab validation is deferred. No private genomic data are included. The GSE65145 summary and N1002K equal-expression audit were checked by the research assistant for source support, privacy and scientific limits; neither has received independent human scientific review. The readthrough-transfer audit is assistant-reviewed, not independently human-reviewed. The immunotherapy audit is assistant-reviewed, not independently human-reviewed, and distinguishes tumor control from BUB1B disease rescue.
Snapshot mva-results-2026-10-17-immunotherapy-audit-v1 · data as of . Each record states its evidence class, model, limitations and the next proposed validation.
Mouse Neuro-2a; three AS-NMD isoform reporters · Tables S1/S2/S4; Figures 2–5 and 7
Human HEK293T landing-pad reporters; not endogenous BUB1B · Supplementary Table 3; Extended Data Figure 4
HEK293 COL4A5 cDNA reporters; different gene and context · Figure 6: gentamicin plus mefloquine
U2OS/HeLa BUBR1 depletion and replacement · Figures 4D and 5; comparator variants, not N1002K
HeLa BUBR1 depletion/reconstitution and BUB1B-mutated MVA fibroblast rescue · Figures 2 and 4; equally expressed B56-binding mutants are functional counterexamples
Mouse BubR1 L1002P ortholog model of human L1012P with hypomorphic or truncating alleles · Abstract and Figures 1-3; related variant, not N1002K
HeLa endogenous BUBR1 RNAi and RNAi-resistant YFP replacement · Figure 4B; supplementary source-data workbook, Sheet1
Differentiated human SH-SY5Y cells; arimoclomol plus celastrol · Figures 2–5; not a BUBR1 study
Human HSF-responsive reporter and endogenous target systems · Table 1 and Figure 4: negative arimoclomol response in this system
Regulatory label; human serum pharmacokinetics, different indication · Clinical pharmacology; historical label used by the 2026-10-09 audit
2DD normal human foreskin fibroblasts; two biological replicates per condition · GSE65145 processed tracks; Figures 1 and 3; Figure S2; Cell culture and RNA-seq methods
Human HEK293 PKD1 reporters and WT9-12 cells; other-gene evidence · Figures 1H-I, 4, 5 and 6; published 2025-11-22
Human 6CFSMEo- CFTR nonsense cells · Figure 6
Human iPSC-derived neuronal progenitors with GDAP1 p.Ser194* (UGA) · Figures 2-4
Human iPSC-derived NEFL nonsense motor neurons · Figure 6; Treatments
Historical FDA Aphthasol 5% oral-paste label · Pharmacokinetics and Metabolism, page 1
BubR1 H/H hypomorphic progeroid mice carrying INK-ATTAC. · Abstract; Figures 2-4 public captions.
Naturally aged C57BL/6 mice and high-fat-diet mice. · Figures 3-5 (clearance, safety assessments and metabolic endpoints); Figures 6-7 (persistence/prevention and high-fat diet).
People with progressive HER2-positive sarcoma, including rhabdomyosarcoma. · Abstract; Table 1 and response results / Figure 4 located through indexed primary-article text.
Pediatric and young-adult relapsed/refractory malignancies; phase 1-2. · Abstract, findings and interpretation; no figure-level extraction.
Children and young adults with recurrent/refractory solid tumors. · Abstract reproduced by the investigators at Children's Oncology Group; Figure 3A located in indexed primary text.
Behind the data is a real child with mosaic variegated aneuploidy (MVA), a rare disorder of chromosome segregation that combines a predisposition to childhood cancer with severe growth restriction.
Given the patient's genome, which variants explain the disease?
BUB1B encodes BubR1, a core component of the spindle assembly checkpoint. The pair includes a premature stop and a missense substitution in the C-terminal region. Molecular phase, residual function and pharmacologic rescue remain unresolved.
c.2210T>GIntroduces a stop codon at residue 737 before the C-terminal kinase/pseudokinase region. The transcript is predicted to be NMD-sensitive; its abundance and any residual truncated-protein function have not been measured for this case. ClinVar annotations associate this variant with MVA syndrome type 1.
c.3006T>GUltra-rare: observed once among ~1.46 million alleles in gnomAD v4.1, with no homozygotes. Asparagine to lysine at residue 1002, inside the BubR1 kinase domain.
The VCF carried no phase information and there was no parental segregation data. We could not independently show that the two alleles are in trans, one inherited from each parent.
We left it in the report as an open limitation, together with the validation path that would resolve it. A genomic result that does not state what it did not prove is not a result; it is a claim.
p.Leu737Ter and p.Asn1002Lys motivate a reduced-functional-BubR1 hypothesis; residual function is unmeasured.
The spindle checkpoint no longer holds anaphase until every chromosome is attached.
Division goes ahead anyway and a chromosome is left behind.
Daughters inherit n+1 and n−1. Repeated through development, this yields a mosaic body.
This simplified disease model motivates research into future segregation errors. It is not evidence that an intervention can reverse established aneuploidy, developmental abnormalities or cancer.
bcftools view -H "${VCF}" | wc -l
bcftools view -f PASS
bcftools view -r 15:40161069-40221123
bcftools view -i 'GT="het"'
VEP --offline, MANE transcript
ClinVar · gnomAD · SIFT · PolyPhen · CADD · domain
Driven by the disease mechanism rather than brute force: prioritise the gene, extract and QC the locus, map to the MANE transcript, and require every candidate to survive converging evidence.
The public Track 1 repository documents containerized commands. Controlled inputs and separate Track 2 analysis artifacts are not bundled with that repository.
make build # Ubuntu 24.04 ARM64 + bcftools, samtools, bedtools make check # every tool answers before touching data make qc # quality control of the full VCF make bub1b # targeted extraction of the locus make bub1b-phase # phase review of the candidates # Functional annotation, offline against a local cache vep --cache --offline --dir_cache /vep_data \ --species homo_sapiens --assembly GRCh38 \ --symbol --canonical --mane --sift b --polyphen b \ --af --af_gnomade --af_gnomadg --max_af --clin_sig # Last step: audit before the repository goes public bash scripts/prepublish_audit.sh
The whole analysis ran locally in a reproducible container. --offline guarantees no patient coordinate leaves the machine to be resolved by an external service.
The public repository holds the Dockerfile, scripts, pipeline and documentation, and no patient genomic data: no raw VCFs, genotype-level tables or downloaded references.
An audit script runs before the repository is made public. Checking by hand is not a control; a script that fails is.
Inputs. The reanalysis inputs are public processed sources, cited with each table above. The small causal finding (the BUB1B L737*/N1002K pair) and the permitted phenotype summary come from the gated challenge dataset through Track 1, so the project is not presented as a discovery independent of the case. In the words of the revised report:
Track 2 computations use public references and the participant-provided small causal finding. The causal finding originates from the gated challenge dataset through Track 1, so this is not described as an entirely case-independent public-data discovery. No commercial proprietary drug database or additional private patient-scale dataset was used here.
Use of AI. The declaration of the revised report, unchanged:
OpenAI ChatGPT Work/Codex supported literature discovery, code execution, evidence synthesis and English drafting; the participant reports the ChatGPT plan as “Premium” (name as reported, not relabeled Pro or Business). Anthropic Claude Max was used to generate the web laboratory. On October 24, 2026, the participant confirmed that use of conversations to improve the models was disabled in both ChatGPT and Claude during the project. These plan and setting statements are participant attestations, not an independent account audit; they do not establish zero retention.
The participant also stated that no patient data were shared with AI services. The source methods nevertheless document the challenge-derived small variant pair and permitted phenotype summary, so this statement is not treated as evidence that no case-derived information entered the workflow. The source Track 2 report states that its workspace did not upload or read patient-scale genomic files; no broader claim about earlier local Track 1 analysis or all account activity is inferred. Exact historical model identifiers and the scope of earlier Claude analysis assistance remain unverified.
Source: revised report, section 9 and Appendix A
, commit bc39224.
This work was made possible through the Hackathon, organized by Sage Bionetworks in partnership with the MVA Society, Hugging Face, and BEACON (The Benchmarking, Evaluation, and Assessment Consortium for Science), with prize sponsorship from AWS and Anthropic. We are deeply grateful to the child and their family who generously contributed their data and their story to advance research into this rare disease. We acknowledge their trust in making this Hackathon possible.
This project organizes public evidence to prioritize testable drug-repurposing hypotheses for BUB1B dysfunction in mosaic variegated aneuploidy. It combines literature audits and reproducible reanalyses with an explicit record of what remains uncertain. It does not establish a treatment.
BUB1B encodes BUBR1, a protein involved in the spindle assembly checkpoint and accurate chromosome segregation. A meaningful rescue needs functional measurements: more RNA or more protein alone is insufficient.
Evidence in this snapshot
L737* introduces a premature stop, with predicted but unmeasured NMD susceptibility. N1002K has unresolved protein stability and residual function. These are different questions. Molecular phase and exact-variant function remain unresolved; neither mechanism should be treated as measured for this case.
Evidence in this snapshot
The research register uses published primary papers, their source tables and public perturbation datasets. These include human-cell data and comparator evidence from other models or genes, each labeled in its record. The separate synthetic software fixture tests analysis logic. The website does not run patient experiments or contain patient genome-scale data.
Evidence in this snapshot
No exact-genotype pharmacological rescue is established. Completed means the recorded analysis or evidence audit was completed, not that a drug rescued BUB1B. Biological validation is future work. Neither the charts nor the animation are clinical response probabilities.
Evidence in this snapshot
Amlexanox is on hold for nomination until product eligibility is resolved. Montelukast is a conditional hypothesis that depends on useful exact L737* protein function. Gentamicin plus mefloquine remains experimental only, and sirolimus is a mechanistic comparator. None is a proven treatment or a clinical recommendation; the candidate decision matrix in section 05 lists each gate.
Evidence in this snapshot
Arimoclomol lacks direct BUBR1/N1002K rescue evidence in the audit. The rapamycin fibroblast reanalysis does not support increasing BUB1B RNA in that model; cell-cycle changes can confound interpretation. Immunotherapy tumor responses and senescent-cell removal are distinct from restoring BUB1B function.
Evidence in this snapshot
First establish exact-variant function: test whether the L737* truncation retains useful activity and whether N1002K functions at matched protein abundance. Then measure checkpoint competence and chromosome segregation independently, with viability, proliferation and completed-division controls. These experiments are proposed; wet-lab work is deferred.
Evidence in this snapshot
It calculates no biological response. It highlights a proposed site of action in a conceptual gene-to-function diagram. It does not repair DNA, test a drug, predict efficacy or display live experiments. The scientific results below remain a versioned snapshot.
BioLab is the biomedical research area of Stackfire Labs: research cases built around open evidence, reproducible reanalyses and an explicit record of what remains unresolved. It organizes evidence and proposes experiments; it does not run patient experiments or recommend treatments.
Where to look
Two germline BUB1B variants in mosaic variegated aneuploidy raise separate questions: L737* is an RNA and translation question, N1002K a protein stability and function question. The case records reanalyses and evidence audits, an October 24, 2026 robustness audit and a candidate decision matrix. No exact-genotype pharmacological rescue is established; wet-lab validation remains future work.
Where to look
A shared research library of publications kept as references, not copies. Every entry links to its original source and records which public bibliographic services supplied its metadata and when. Reading states and collections are bibliographic organization, never scientific validation.
Where to look
The graph connects a case to its variants, processes, evidence records, publications and hypotheses. Solid lines are documented connections; dashed lines are hypotheses under review. A connection says that a source or record links two items: it is not evidence of causation or efficacy. Every view also has a list alternative.
Where to look
A research trail is an ordered reading of the evidence, step by step. Hypotheses are statements under research with the evidence that informs or limits them; none is marked validated. Evidence gaps name what has not been measured or located. All of them link to existing records and publications instead of copying them.
Where to look
The auditable record of the MVA reanalyses with their execution records and downloads, and a Protein Structure Explorer of the predicted BUBR1 model. Tools marked Planned are not built yet. Reanalyses of public processed data and predicted structures are not biological experiments.
Where to look
No. BioLab is research context, not a clinical diagnostic report or a treatment recommendation. Drug candidates are research hypotheses with explicit gates, not proven treatments. Questions about a person’s care belong with their clinical team.