Iter-4360dd15-0039-transcript
第 39 轮执行轨迹
→ call search_memory({"limit":10,"query":"4360dd15 PMID 38310895 Crossref 75 references human trial rapamycin everolimus sirolimus"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":20,"tag":"4360dd15"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0038-transcript", "tags": "iteration transcript", "modified": "20260424191624000", "preview": "!! 第 38 轮执行轨迹
→ call search_memory({\"limit\":8,\"query\":\"4360dd15 PMID 38310895 reference chain Crossref 75 references human trial rapamycin everolimus sirolimus\"}) → call list_recent({\"n\":8}) → call list_tools({}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0010-transcript\", \"tags\": \"iteration transcript\", \"modified\": \"20260424175830000\", \"preview\": \"!! 第 10"}, {"title": "Iter-4360dd15-0010-transcript", "tags": "iteration transcript", "modified": "20260424175830000", "preview": "!! 第 10 轮执行轨迹 【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0038-reflection", "modified": "20260424191630000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424191630000", "tags": "pinned focus"}, {"title": "先拿引用数组再做精筛", "modified": "20260424191630000", "tags": "lesson evidence-retrieval crossref reference-chain"}, {"title": "Iter-4360dd15-0038-transcript", "modified": "20260424191624000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0038-crossref-human-trial-filter-method", "modified": "20260424191618000", "tags": "knowledge experiment fact 4360dd15"}, {"title": "Iter-4360dd15-0037-reflection", "modified": "20260424191353000", "tags": "iteration reflection"}, {"title": "Iter-4360dd15-0037-transcript", "modified": "20260424191347000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0036-reflection", "modified": "20260424191122000", "tags": "iteration reflection"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Iter-4360dd15-0038-crossref-human-trial-filter-method", "modified": "20260424191618000"}, {"title": "Iter-4360dd15-0030-vu-research-portal-entry-without-direct-pdf-link", "modified": "20260424185400000"}, {"title": "2024 rapamycin systematic review: abstract-level constraints and what remains missing", "modified": "20260424175824000"}, {"title": "Added included ADPKD rapalog trial CRAD001ADE12 and its body-weight endpoint", "modified": "20260424174657000"}, {"title": "Rapamycin human trials: completed studies table from PMC review", "modified": "20260424174352000"}, {"title": "Iter-4360dd15-0004-critique-rapamycin-evidence", "modified": "20260424174226000"}, {"title": "Rapamycin human trials: extracted endpoints and outcomes from the 2024 systematic review review pass 1", "modified": "20260424173529000"}, {"title": "Human longevity interventions evidence maturity matrix 2026-04-25", "modified": "20260424173237000"}]}
→ call read_note({"title":"NEXT_FOCUS"})
→ call read_note({"title":"Iter-4360dd15-0038-crossref-human-trial-filter-method"})
→ call read_note({"title":"2024 rapamycin systematic review: abstract-level constraints and what remains missing"})
【tool:read_note】
{"ok": true, "title": "NEXT_FOCUS", "tags": "pinned focus", "text": "!! 下轮焦点（来自 mission 4360dd15 · Iter-0038）\n\n把该综述 DOI 的 75 条 references 本地解析，并按 human trial / rapamycin / everolimus / sirolimus 精准过滤出剩余 11 项。"}
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0038-crossref-human-trial-filter-method", "tags": "knowledge experiment fact 4360dd15", "text": "!! 本轮进展\n用 Crossref 机器可读 references（DOI 10.1016/S2666-7568(23)00258-1，共 75 条）做了本地过滤，得到一个可复现的“rapalog + human trial-ish”候选集。\n\n!! 可复现方法\n
\nimport requests, re\n\ndoi='10.1016/S2666-7568(23)00258-1'\nmsg=requests.get(f'https://api.crossref.org/works/{doi}', timeout=30,\n headers={'User-Agent':'Mozilla/5.0'}).json()['message']\nrefs=msg['reference']\n\nkw = re.compile(r'rapamycin|sirolimus|everolimus|temsirolimus|rapalog|mtor inhibitor|mammalian target of rapamycin', re.I)\nhuman = re.compile(r'clinical|trial|patients?|subjects?|healthy volunteers?|randomi[sz]ed|placebo|double blind|phase\\s*[1-4]|crossover|human|proof-of-concept|pilot|feasibility|futility', re.I)\n\ntrialish=[]\nfor r in refs:\n txt=' | '.join(str(r.get(k,'')) for k in ['article-title','journal-title','author','DOI','unstructured'])\n if any(t in (r.get('article-title') or r.get('unstructured') or '').lower()\n for t in ['trial','randomized','randomised','placebo','phase','proof-of-concept','feasibility','futility','extension']) \\\n and any(dr in txt.lower() for dr in ['rapamycin','sirolimus','everolimus','temsirolimus']):\n trialish.append(r)\n\nprint('trial_title_count', len(trialish))\ntrial_title_count = 14。\n- 其中 1 条是动物研究：`Mechanisms of life span extension by rapamycin in the fruit 【tool:read_note】
{"ok": true, "title": "2024 rapamycin systematic review: abstract-level constraints and what remains missing", "tags": "lesson fact 4360dd15 evidence retrieval", "text": "!! What I could verify this round\nI could not yet recover the remaining 11 included-study names from the 2024 systematic review, but I did verify the paper’s abstract via PubMed XML and extracted a few important constraints.\n\n!! Verified bibliographic identity\n- PMID: 38310895\n- Title: ''Targeting ageing with rapamycin and its derivatives in humans: a systematic review.''\n- Journal: Lancet Healthy Longev 2024 Feb; 5(2):e152-e162\n- DOI: 10.1016/S2666-7568(23)00258-1\n\n!! Abstract-level findings worth retaining\nThe abstract states that:\n# 18,400 unique articles were screened\n# 19 studies were included\n# benefits were observed in the immune, cardiovascular, and integumentary systems\n# no significant effects were found in the endocrine, muscular, or neurological systems\n# respiratory, digestive, renal, and reproductive systems were not assessed\n# no serious adverse events attributed to rapamycin/derivatives were reported in healthy individuals\n# in individuals with ageing-related diseases, infections and lipid increases were reported\n\n!! Why this matters\nThis is stronger than a generic \"rapamycin is anti-aging\" claim, but still weaker than a study-level map. The review’s abstract already tells us the evidence is:\n- multi-system but fragmented\n- partly positive in healthy or ageing-
→ call run_python({"code":"import requests, re, json, textwrap, itertools, pandas as pd\n\ndoi='10.1016/S2666-7568(23)00258-1'\nmsg=requests.get(f'https://api.crossref.org/works/{doi}', timeout=30, headers={'User-Agent':'Mozilla/5.0'}).json()['message']\nrefs=msg['reference']\n\n# collect candidate refs with trial-ish/title markers and rapalog markers\nmarkers = ['rapamycin','sirolimus','everolimus','temsirolimus'])
【tool:run_python】
{"ok": true, "stdout": "e treatment of geographic atrophy: results of a phase I/II clinical trial\nJOURNAL: Invest Ophthalmol Vis Sci YEAR: 2014 DOI: 10.1167/iovs.14-15877\n---\nTITLE: Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial\nJOURNAL: Pulm Circ YEAR: 2013 DOI: 10.1086/674311\n---\nTITLE: Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study\nJOURNAL: Ann Rheum Dis YEAR: 2008 DOI: 10.1136/ard.2007.078808\n---\nTITLE: Low-dose sirolimus immunoregulation therapy in patients with active rheumatoid arthritis: a 24-week follow-up of the randomized, open-label, parallel-controlled trial\nJOURNAL: J Immunol Res YEAR: 2019 DOI: 10.1155/2019/7684352\n---\nTITLE: Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations\nJOURNAL: Semin Oncol YEAR: 2009 DOI: 10.1053/j.seminoncol.2009.10.009\n---\nTITLE: Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease\nJOURNAL: Exp Neurol YEAR: 2019 DOI: 10.1016/j.expneurol.2018.09.011\n---\nTITLE: Rapamycin reduces degeneration of neurons by inhibiting Akt/mTOR/p70S6K pathway and restoring autophagy in EAE mice\nJOURNAL: Int J Clin Exp Med YEAR: 2018 DOI: None\n---\nTITLE: Late-life rapamycin treatment reverses age-related heart dysfunction\nJOURNAL: Aging Cell YEAR: 2013 D
→ call web_search({"limit":8,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" included studies everolimus sirolimus rapamycin 19 studies"})
→ call web_search({"limit":8,"query":"\"10.1016/S2666-7568(23)00258-1\" rapamycin included studies trial names"})
→ call web_search({"limit":8,"query":"\"Targeting ageing with rapamycin and its derivatives in humans\" table 1 included studies"})
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\" included studies everolimus sirolimus rapamycin 19 studies", "results": [{"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext", "snippet": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies . Rapamycin and its derivatives improved ..."}, {"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.sciencedirect.com/science/article/pii/S2666756823002581", "snippet": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies ."}, {"title": "Targeting ageing with rapamycin and its derivatives in humans: a ...", "url": "https://www.researchgate.net/publication/377976071_Targeting_ageing_with_rapamycin_and_its_derivatives_in_humans_a_systematic_review", "snip
【tool:web_search】
{"ok": true, "query": "\"10.1016/S2666-7568(23)00258-1\" rapamycin included studies trial names", "results": []}
【tool:web_search】
{"ok": true, "query": "\"Targeting ageing with rapamycin and its derivatives in humans\" table 1 included studies", "results": []}
→ call web_fetch({"max_chars":7000,"url":"https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call run_python({"code":"import re, json\n\ncands = [\n('phase I/II geographic atrophy','10.1167/iovs.14-15877'),\n('Everolimus in severe pulmonary hypertension: safety and efficacy pilot trial','10.1086/674311'),\n('Everolimus + methotrexate RA proof-of-concept','10.1136/ard.2007.078808'),\n('Low-dose sirolimus immunoregulation therapy in active RA: 24-week follow-up','10.1155/2019/7684352'),\n('Intravenous tems)
【tool:run_python】
{"ok": true, "stdout": "geographic_atrophy 1 ['phase I/II geographic atrophy']\npulm_hypertension 1 ['Everolimus in severe pulmonary hypertension: safety and efficacy pilot trial']\nra_everolimus 0 []\nra_sirolimus_followup 1 ['Low-dose sirolimus immunoregulation therapy in active RA: 24-week follow-up']\ncancer_temsirolimus 1 ['Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations']\nheart_rapamycin 1 ['Late-life rapamycin treatment reverses age-related heart dysfunction']\nhealthspan_observational 1 ['Evaluation of off-label rapamycin use to promote healthspan in 333 adults']\nexist3_core 2 ['Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3)', 'Adjunctive everolimus therapy for TSC-associated refractory seizures: postextension phase of EXIST-3']\nexist3_extension 1 ['Everolimus for treatment-refractory seizures in TSC: extension of a randomized controlled trial']\nexist3_postextension 1 ['Adjunctive everolimus therapy for TSC-associated refractory seizures: postextension phase of EXIST-3']\nbreast_cancer_4ever 1 ['Efficacy and safety of everolimus plus exemestane ... 4EVER trial']\nbolero2 1 ['Safety and efficacy of everolimus with exemestane vs exemestane alone in elderly patients ... BOLERO-2']\nfamily_count 10\narticle_count 12\n", "stderr": "", "returncode": 0}
→ call write_note({"tags":["lesson","critique","4360dd15","evidence retrieval"],"text":"!! 本轮批判性结论\n仅靠 Crossref 参考文献数组里的标题关键词过滤，**会系统性高估**“人类试验数”，因为它把以下几类东西混进来了：\n# 疾病治疗试验（例如肿瘤、TSC、类风湿）\n# 观察性/用药回顾（例如 off-label healthspan 333 adults）\n# 后续/extension/postextension 文章\n# 与长寿目标几乎无关的 rapalog 临床文章（例如药代/剂量讨论）\n\n!! 这轮实际暴露出的风险\n在我手工复核到的 rapalog 候选里，**文章数**并不等于**独立 study family 数**：\n- 仅从当前可见的候选文章看，至少能分出 10 个 family，而不是 12)
【tool:write_note】
{"ok": true, "path": "C:\\Users\\yh599\\Documents\\GitHub\\LLM-yh\\Sisyphus\\wiki\\tiddlers\\Critique_of_Crossref_trialish_filtering_for_PMID_38310895_reference_chain.tid", "title": "Critique of Crossref trialish filtering for PMID 38310895 reference chain"}
→ call write_note({"tags":["fact","4360dd15","crossref","rapalog","human trial"],"text":"!! 第 39 轮：对 Crossref trial-ish 过滤的严格复核\n\n本轮从 PMID 38310895 对应综述的 Crossref reference 数组中，进一步核对了“trial-ish”候选的性质。\n\n!! 复核方法\n
\nimport requests, re\n\ndoi='10.1016/S2666-7568(23)00258-1'\nmsg=requests.get(f'https://api.crossref.org/works/{doi}', timeout=30,\n headers={'User-Agent':'Mozilla/5.0'}).json()[)【tool:write_note】
{"ok": true, "path": "C:\\Users\\yh599\\Documents\\GitHub\\LLM-yh\\Sisyphus\\wiki\\tiddlers\\Iter-4360dd15-0039-crossref-candidate-family-critique.tid", "title": "Iter-4360dd15-0039-crossref-candidate-family-critique"}
【assistant】
本轮我做了严格复核，结论很不客气：**仅靠 Crossref 参考题名关键词过滤，不能可靠恢复综述的 19 项纳入研究清单**。
我从 DOI `10.1016/S2666-7568(23)00258-1` 的 reference 数组里筛出了一批 rapalog 相关人体候选，再人工看了一遍，发现：
- 观察到的候选文章数是 12
- 但按 study family 去重后，至少只有 10 个 family
- EXIST-3 这类 extension / postextension 文章会把“文章数”虚高
- 还有一些条目本身就是药代/剂量、疾病治疗、观察性 healthspan 回顾，和“ageing-related physiological changes in adults”的综述目标并不一致
所以，当前路线的最大问题不是“找不到文献”，而是**召回太粗、精确度太差**，会把很多假阳性混进来。这个批判性结果我已经沉淀成笔记了。
【下轮焦点】从这批 rapalog 候选里做“排除式家族归并”，先剔除明显不属 ageing 综述范围的条目，再逼近真实的 19 included studies 家族清单。
<NEXT_FOCUS>从这批 rapalog 候选里做“排除式家族归并”，先剔除明显不属 ageing 综述范围的条目，再逼近真实的 19 included studies 家族清单。</NEXT_FOCUS>