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# Research Synthesis: Rapamycin Cancer Effects — full paper ## Abstract This paper synthesizes evidence on rapamycin cancer effects across 19 accepted source papers and 980 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct clinical evidence, 13 adjacent clinical sources, and 2 mechanistic or model-system sources, with 12 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, safety and comorbidity outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that rapamycin cancer effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## Methods ### Review type and protocol This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-rapamycin_cancer_effects-v06-DAILY-2026-06-15T12-04-02Z`. ### Information sources Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-15. ### Search strategy The following topic-anchored queries were executed against the information sources listed above: - `rapamycin cancer effects aging` - `rapamycin cancer effects older adults` - `rapamycin cancer effects randomized controlled trial` - `rapamycin aging` - `rapamycin older adults` - `rapamycin randomized controlled trial` - `cancer aging` - `cancer older adults` - `cancer randomized controlled trial` ### Eligibility criteria - Sources whose primary content addresses rapamycin cancer effects. - Sources with extractable quantitative or qualitative findings. - Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable. - Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle). ### Selection of sources of evidence The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 1120 records in the receipt-candidate union, 367 were classified as source candidates and 19 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission. ### source admission funnel | Admission bucket | n | |---|---:| | Receipt candidate union | 1120 | | Classified source candidates | 367 | | No extractable claims | 263 | | None-only claim binding | 84 | | Mixed partial-or-none claim-binding candidates | 277 | | Partial-only claim-binding candidates | 94 | | Strict high-confidence sources | 35 | | Admitted final sources | 19 | ### Exclusion reasons - No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus. ### Data items The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text. ### Risk-of-bias appraisal Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`. ### Synthesis approach Evidence-tension synthesis: claims grouped by outcome class (contextual adjacent evidence, immune and inflammation, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates. ### AI-use disclosure Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified. ### Accountability Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review. ## Results **Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim. | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=15; claims=457 | no extracted directional signal in 11/15 sources | 12 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class | | Safety and Comorbidity | n=2; claims=138 | positive signal in 1/2 sources | 1 mechanistic; 1 review | limited corpus depth in this outcome class | | Immune and Inflammation | n=1; claims=41 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | Safety | n=1; claims=344 | mixed signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating | This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 15 included sources were assigned to this outcome class. Directional coding: negative=1, null=11, unclear=3. Directness coding: indirect=12, mechanistic=1, review=2. ### Safety Comorbidity Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=1, review=1. ### Immune Inflammation Outcomes 1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: indirect=1. ### Safety Outcomes 1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: review=1. ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. The curated corpus on Rapamycin Cancer Effects contains no long-term mortality or cancer-incidence randomized trial in non-diabetic, cancer-free adults, and the absence of such a trial is the single largest boundary on the headline conclusions. This means that claims linking rapamycin to cancer prevention in healthy aging populations rest on indirect chains of inference rather than direct trial evidence. Several clinically relevant outcomes in this synthesis are supported by only one source and therefore cannot be internally replicated within the corpus. The enrolled populations in the available sources are almost entirely adults with established cancer or undergoing cytotoxic co-therapy, which limits external validity to the broader anti-aging use case. Healthy, cancer-free older adults — the population of greatest interest for a geroprotective indication — are not represented in the sources reviewed here. The endpoint scope of the corpus is narrow and skewed toward pharmacodynamic and immunologic surrogates rather than patient-important outcomes. Directness flags show the bulk of sources are indirect (mechanistic cell-line, animal, or review-level), and the only trial-coded source (Withers 2025, NCT00803569) reports vaccine-induced memory T-cell frequencies, not survival, progression-free survival, or cancer incidence. Because the Ioannidis 2005 caution that surrogate endpoint associations do not guarantee hard-outcome validity is a general methodological principle rather than a corpus finding, it must be invoked as background context: the rapamycin-cancer effect estimates in this synthesis are predominantly surrogate-endpoint estimates, and the hard-outcome side of the ledger is empty within the available sources. A mechanism-to-clinic gap is the dominant structural feature of the safety comorbidity class. The cross-study disagreements in the cross-study disagreement map, including the partial conflict between Zhou 2024 (positive on safety comorbidity in mice) and Shao 2024 (null on safety comorbidity in humans), show that mechanistic safety plausibility does not translate cleanly to clinical safety. Because human RCT evidence in the targeted population is absent, the magnitude of clinical safety benefit — and its boundary conditions by cancer type, combination agent, and dosing schedule — cannot be specified from this corpus, and any quantitative generalization beyond the murine and in-vitro sources is unsupported. ## Conclusion For rapamycin cancer effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging. ## What This Synthesis Adds This synthesis maps 19 included sources on Rapamycin Cancer Effects across 4 outcome classes and 12 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit. Across 19 curated reference papers, the evidence base for Rapamycin Cancer Effects shows a context-dependent profile. Positive signals appear in: safety comorbidity. Negative signals appear in: contextual other. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Rapamycin Cancer Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the null vs positive between Shao 2024 and Zhou 2024 on safety and comorbidity (severity 4/5), which defines the boundary condition future studies must test rather than smooth over. Prior reviews in the corpus (Lin 2022, Kim 2026) emphasize convergent signals on Rapamycin Cancer Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary. ### Boundary-Condition Matrix | Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary | |---|---:|---:|---|---| | safety | 0 | 1 | mixed | direct interventional hard-endpoint gap | | contextual adjacent evidence | 0 | 15 | negative, null, unclear | conflict-resolution gap | | safety and comorbidity | 0 | 2 | null, positive | conflict-resolution gap | | immune and inflammation | 0 | 1 | unclear | direct interventional hard-endpoint gap | ### Evidence-Gap Priority | Priority | Gap | Rationale | |---|---|---| | P1 | safety: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: mixed | | P2 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 15 indirect sources; direction profile: negative, null, unclear | | P3 | safety and comorbidity: conflict-resolution gap | 0 direct and 2 indirect sources; direction profile: null, positive | | P4 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear | ### Next-Study Design Recommendation The next high-yield study for Rapamycin Cancer Effects should target the **safety** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating. ## Evidence Snapshot The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement. ### Load-Bearing Included Studies - Lin 2022; tier=B1; directness=review; endpoint=safety; direction=mixed; representative statistic=P < 0.001. - Kim 2026; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=negative; representative statistic=P = 0.001. - Jhaveri 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001. - Dhakal 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=p≤0.001. - RuizMalagon 2024; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null. - Singh 2009; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.04. - Jeong 2021; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001. - Withers 2025; tier=B2; directness=indirect; endpoint=immune inflammation; direction=unclear; representative statistic=P = 0.005. - Huang 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P < 0.001. - Wang 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - The effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review: outcome=safety; directness=review; tier=B1; direction=mixed; claims=344. - Physical Activity and Hepatocellular Carcinoma Outcomes: a Narrative Review of Pre-clinical, Observational, and Interventional Evidence: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=negative; claims=33. - DESTINY-Breast08: A Phase Ib Study of Trastuzumab Deruxtecan in Combination with Other Anticancer Therapies in Patients with HER2-Low Metastatic Breast Cancer: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=66. - Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=61. - Systematic review: The gut microbiota as a link between colorectal cancer and obesity: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=55. - Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=49. - TCTP protein degradation by targeting mTORC1 and signaling through S6K, Akt, and Plk1 sensitizes lung cancer cells to DNA-damaging drugs: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=41. - mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors: outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=41. - KNSTRN knockdown impairs autophagy flux to inhibit bladder cancer progression: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=21. - The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16. - Zanidatamab, a Dual HER2-Targeted Bispecific Antibody, in Patients with Unresectable Locally Advanced or Metastatic HER2-Positive Salivary Gland Cancer: A Combined Analysis of Early-Phase Studies: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=15. - Targeted Delivery of Rapamycin via Epidermal Growth Factor Receptors in Pancreatic Cancer Cells Inhibits Cell Proliferation and Induces Apoptosis: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=15. - A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer: outcome=safety comorbidity; directness=review; tier=B2; direction=null; claims=11. - Rapamycin Antagonizes BCRP-Mediated Drug Resistance Through the PI3K/Akt/mTOR Signaling Pathway in mPRα-Positive Breast Cancer: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7. - Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6. - BEX2 regulates autophagy by inhibiting PIK3CA-p85 interaction in non-small-cell lung cancer cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6. - Human recombinant arginase I [HuArgI (Co)-PEG5000]-induced arginine depletion inhibits ovarian cancer cell adhesion and migration through autophagy-mediated inhibition of RhoA: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4. - Safety Evaluations of Rapamycin Perfluorocarbon Nanoparticles in Ovarian Tumor-Bearing Mice: outcome=safety comorbidity; directness=mechanistic; tier=C1; direction=positive; claims=127. - Anti-Mullerian hormone attenuates both cyclophosphamide-induced damage and PI3K signalling activation, while rapamycin attenuates only PI3K signalling activation, in human ovarian cortex in vitro: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=62. ### Classification Criteria - **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices. - **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately. - **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else. - **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen. ### Load-Bearing Tensions - Additional corpus sources included animal/preclinical evidence; severity 4 null vs positive: Shao 2024 vs Zhou 2024; Zhou 2024 (positive on safety comorbidity) vs Shao 2024 (null on safety comorbidity) — partial conflict - Severity 4 null vs positive: Rosario 2023 vs Kim 2026; Kim 2026 (negative on contextual other) vs Rosario 2023 (null on contextual other) — partial conflict - Severity 4 null vs positive: Dhakal 2025 vs Kim 2026; Kim 2026 (negative on contextual other) vs Dhakal 2025 (null on contextual other) — partial conflict - Severity 4 null vs positive: RuizMalagon 2024 vs Kim 2026; Kim 2026 (negative on contextual other) vs RuizMalagon 2024 (null on contextual other) — partial conflict - Severity 4 null vs positive: Oluremi 2025 vs Kim 2026; Kim 2026 (negative on contextual other) vs Oluremi 2025 (null on contextual other) — partial conflict - Severity 4 null vs positive: Wang 2025 vs Kim 2026; Kim 2026 (negative on contextual other) vs Wang 2025 (null on contextual other) — partial conflict - Severity 4 null vs positive: Wang 2026 vs Kim 2026; Kim 2026 (negative on contextual other) vs Wang 2026 (null on contextual other) — partial conflict - Severity 4 null vs positive: Kim 2026 vs Jhaveri 2026; Kim 2026 (negative on contextual other) vs Jhaveri 2026 (null on contextual other) — partial conflict Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Lee 2026, Zhang 2021, Niu 2011, El-Mais 2021. ## References - **Lin 2022.** _The effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review._ Aging Clinical and Experimental Research, 2022. DOI: 10.1007/s40520-022-02190-0. PMID: 35861940. - **Zhou 2024.** _Safety Evaluations of Rapamycin Perfluorocarbon Nanoparticles in Ovarian Tumor-Bearing Mice._ Nanomaterials, 2024. DOI: 10.3390/nano14211752. PMID: 39513832. - **Jhaveri 2026.** _DESTINY-Breast08: A Phase Ib Study of Trastuzumab Deruxtecan in Combination with Other Anticancer Therapies in Patients with HER2-Low Metastatic Breast Cancer._ Clinical Cancer Research, 2026. DOI: 10.1158/1078-0432.CCR-25-0874. PMID: 41504632. - **Rosario 2023.** _Anti-Mullerian hormone attenuates both cyclophosphamide-induced damage and PI3K signalling activation, while rapamycin attenuates only PI3K signalling activation, in human ovarian cortex in vitro._ Human Reproduction (Oxford, England), 2023. DOI: 10.1093/humrep/dead255. PMID: 38070496. - **Dhakal 2025.** _Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma._ Journal for Immunotherapy of Cancer, 2025. DOI: 10.1136/jitc-2024-010649. PMID: 39875173. - **RuizMalagon 2024.** _Systematic review: The gut microbiota as a link between colorectal cancer and obesity._ Obesity Reviews, 2024. DOI: 10.1111/obr.13872. PMID: 39614602. - **Singh 2009.** _Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs._ Molecular Cancer, 2009. DOI: 10.1186/1476-4598-8-57. PMID: 19646263. - **Withers 2025.** _mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors._ Journal for Immunotherapy of Cancer, 2025. DOI: 10.1136/jitc-2024-010408. PMID: 40132910. - **Jeong 2021.** _TCTP protein degradation by targeting mTORC1 and signaling through S6K, Akt, and Plk1 sensitizes lung cancer cells to DNA-damaging drugs._ Scientific Reports, 2021. DOI: 10.1038/s41598-021-00247-0. PMID: 34675258. - **Kim 2026.** _Physical Activity and Hepatocellular Carcinoma Outcomes: a Narrative Review of Pre-clinical, Observational, and Interventional Evidence._ Journal of Gastrointestinal Cancer, 2026. DOI: 10.1007/s12029-026-01420-2. PMID: 41781806. - **Huang 2026.** _KNSTRN knockdown impairs autophagy flux to inhibit bladder cancer progression._ iScience, 2026. DOI: 10.1016/j.isci.2026.114734. PMID: 41704764. - **Wang 2026.** _The novel tertiary amine LSD1 inhibitor 596 inhibits endometrial cancer through the mTOR signal transduction pathway._ Translational Oncology, 2026. DOI: 10.1016/j.tranon.2026.102688. PMID: 41671780. - **Oluremi 2025.** _Targeted Delivery of Rapamycin via Epidermal Growth Factor Receptors in Pancreatic Cancer Cells Inhibits Cell Proliferation and Induces Apoptosis._ ACS Omega, 2025. DOI: 10.1021/acsomega.5c02820. PMID: 40757331. - **Lee 2026.** _Zanidatamab, a Dual HER2-Targeted Bispecific Antibody, in Patients with Unresectable Locally Advanced or Metastatic HER2-Positive Salivary Gland Cancer: A Combined Analysis of Early-Phase Studies._ Clinical Cancer Research, 2026. DOI: 10.1158/1078-0432.CCR-25-4158. PMID: 41870284. - **Shao 2024.** _A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer._ BMC Medicine, 2024. DOI: 10.1186/s12916-023-03238-2. PMID: 38212842. - **Zhang 2021.** _Rapamycin Antagonizes BCRP-Mediated Drug Resistance Through the PI3K/Akt/mTOR Signaling Pathway in mPRα-Positive Breast Cancer._ Frontiers in Oncology, 2021. DOI: 10.3389/fonc.2021.608570. PMID: 33912444. - **Wang 2025.** _BEX2 regulates autophagy by inhibiting PIK3CA-p85 interaction in non-small-cell lung cancer cells._ Cell Communication and Signaling : CCS, 2025. DOI: 10.1186/s12964-025-02385-8. PMID: 41398291. - **Niu 2011.** _Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells._ Journal of Experimental & Clinical Cancer Research : CR, 2011. DOI: 10.1186/1756-9966-30-28. PMID: 21392382. - **El-Mais 2021.** _Human recombinant arginase I [HuArgI (Co)-PEG5000]-induced arginine depletion inhibits ovarian cancer cell adhesion and migration through autophagy-mediated inhibition of RhoA._ Journal of Ovarian Research, 2021. DOI: 10.1186/s13048-021-00767-3. PMID: 33423701. ### Background References *Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).* - **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.
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