Iter-4360dd15-0073-transcript
第 73 轮执行轨迹
→ call search_memory({"limit":10,"query":"4360dd15 PMID 摘要 研究类型 年龄判据 主要终点 候选"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":10,"tag":"4360dd15"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0060-transcript", "tags": "iteration transcript", "modified": "20260424200117000", "preview": "!! 第 60 轮执行轨迹
→"}, {"title": "Iter-4360dd15-0059-transcript", "tags": "iteration transcript", "modified": "20260424195947000", "preview": "!! 第 59 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 NEXT_FOCUS PMID 10 条候选 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0072-reflection", "modified": "20260424202124000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424202124000", "tags": "pinned focus"}, {"title": "先确认研究类型再谈终点", "modified": "20260424202124000", "tags": "lesson audit study-design endpoint"}, {"title": "Iter-4360dd15-0072-transcript", "modified": "20260424202113000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0072-review-exclusion-first-rule", "modified": "20260424202103000", "tags": "4360dd15 knowledge method"}, {"title": "Iter-4360dd15-0071-reflection", "modified": "20260424201859000", "tags": "iteration reflection"}, {"title": "先抽字段再定规则", "modified": "20260424201859000", "tags": "lesson audit endpoint-extraction synonym-mapping"}, {"title": "Iter-4360dd15-0071-transcript", "modified": "20260424201853000", "tags": "iteration transcript"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Iter-4360dd15-0072-review-exclusion-first-rule", "modified": "20260424202103000"}, {"title": "Iter-4360dd15-0071-minimal-audit-rules", "modified": "20260424201843000"}, {"title": "Iter-4360dd15-0069-standardized-audit-table-two-trials", "modified": "20260424201621000"}, {"title": "Iter-4360dd15-0068-abstract-endpoint-extraction", "modified": "20260424201407000"}, {"title": "Iter-4360dd15-0067-abstract-endpoints-aging-criteria", "modified": "20260424201141000"}, {"title": "Iter-4360dd15-0066-TierA-abstracts-and-endpoints-for-aging-criteria", "modified": "20260424200925000"}, {"title": "Iter-4360dd15-0065-minimal-relevance-decision-rules-for-retained-mtor-trials", "modified": "20260424200748000"}, {"title": "Iter-4360dd15-0064-relevance-tiering-10-pmids", "modified": "20260424200602000"}, {"title": "Iter-4360dd15-0063-10-pmid-audit-table", "modified": "20260424200432000"}, {"title": "Iter-4360dd15-0062-pubmed-title-verification-10-pmids", "modified": "20260424200328000"}]}
→ call read_note({"title":"NEXT_FOCUS"})
【tool:read_note】
{"ok": true, "title": "NEXT_FOCUS", "tags": "pinned focus", "text": "!! 下轮焦点（来自 mission `4360dd15` · Iter-0072）\n\n下一轮必须只做一件事：逐个读取剩余候选 PMID 的摘要，抽取研究类型、年龄判据和主要终点，并据此完成保留/排除分类。"}
→ call search_memory({"limit":10,"query":"4360dd15 剩余 候选 PMID 10 条"})
→ call read_note({"title":"Iter-4360dd15-0063-10-pmid-audit-table"})
→ call read_note({"title":"Iter-4360dd15-0064-relevance-tiering-10-pmids"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0060-transcript", "tags": "iteration transcript", "modified": "20260424200117000", "preview": "!! 第 60 轮执行轨迹
→"}, {"title": "Iter-4360dd15-0059-transcript", "tags": "iteration transcript", "modified": "20260424195947000", "preview": "!! 第 59 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 NEXT_FOCUS PMID 10 条候选 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0063-10-pmid-audit-table", "tags": "4360dd15 knowledge fact clinical-trials audit", "text": "!! 第 63 轮：10 条 PMID 可审计表\n\n本轮把上一轮已经用 PubMed 题名证据核实为“原始临床研究”的 10 条 PMID，整理为逐条可审计表，统一给出 PMID、题名、研究类型、保留/排除和理由。\n\n| PMID | 题名 | 研究类型 | 处理 | 理由 |\n|---:|---|---|---|---|\n| 33977284 | ''Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.'' | phase 2b/3 randomised trial | 保留 | 明确为随机临床试验，属于原始研究 |\n| 22367193 | ''A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults.'' | single-dose controlled study | 保留 | 单次给药对照原始临床研究 |\n| 29408453 | ''A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.'' | randomized controlled trial | 保留 | RCT，直接属于原始临床研究 |\n| 22115710 | ''A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.'' | randomized dose-escalation study | 保留 | 剂量递增的原始临床试验 |\n| 35040506 | ''mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.'' | randomized double-blind placebo-controlled futility trial + longitudinal analysis | 保留 | 主试验为原始临床试验；longitudinal analysis 为附带分析，不构成排除 |\n| 2552
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0064-relevance-tiering-10-pmids", "tags": "4360dd15 knowledge fact critical-review stratification", "text": "!! 第 64 轮：10 条已保留 PMID 的最小相关性分层\n\n本轮不再争论它们是否为原始临床研究，而是按与衰老/长寿主问题的相关性强弱做最小分层。\n\n!! 分层结果\n\n!!! Tier A：直接指向衰老/老年功能表型\n判据：题名直接出现 ''older adults'' / ''biological ageing'' / 年龄相关功能终点（免疫、体能、认知）。\n- PMID 33977284 — ''Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.''\n- PMID 29408453 — ''A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.''\n\n!!! Tier B：年龄相关退行性病变，存在衰老邻近信号\n判据：对象本身是典型 age-related degeneration / neurodegeneration / 退行性表型，但题名未直接以衰老为干预目标。\n- PMID 35040506 — ''mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.''\n- PMID 25525171 — ''Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.''\n\n!!! Tier C：原始临床试验，但与长寿主问题仅间接相关\n判据：主要适应症是安全性、剂量学或非衰老疾病；若要纳入长寿证据链，必须额外证明其反映了可泛化的 aging biology，而不能只靠 mTOR 药物身份。\n- PMID 22367193 — temsirolimus 心电安全性\n- PMID 18037627 — rheumatoid arthritis proof-of-concept\n- PMID 27613521 — tuberous sclerosis 癫痫\n- PMID 29992557 — metastatic breast cancer\n- PMID 24618547 — severe pulmonary hypertension\n- PMID 22115710 — diabetic macu
→ call search_memory({"limit":20,"query":"4360dd15 PMID 候选 研究类型 年龄判据 主要终点 33977284 29408453 35040506 22367193 22115710 25525171 24618547 18037627 27613521 29992557"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0060-transcript", "tags": "iteration transcript", "modified": "20260424200117000", "preview": "!! 第 60 轮执行轨迹
→"}, {"title": "Iter-4360dd15-0059-transcript", "tags": "iteration transcript", "modified": "20260424195947000", "preview": "!! 第 59 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 NEXT_FOCUS PMID 10 条候选 研究类型 保留 排除 理由\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \" → call pubmed_search({"limit":1,"query":"33977284"})
→ call pubmed_search({"limit":1,"query":"29408453"})
→ call pubmed_search({"limit":1,"query":"35040506"})
→ call pubmed_search({"limit":1,"query":"25525171"})
→ call pubmed_search({"limit":1,"query":"22367193"})
→ call pubmed_search({"limit":1,"query":"18037627"})
→ call pubmed_search({"limit":1,"query":"27613521"})
→ call pubmed_search({"limit":1,"query":"29992557"})
→ call pubmed_search({"limit":1,"query":"24618547"})
→ call pubmed_search({"limit":1,"query":"22115710"})
【tool:pubmed_search】
{"ok": true, "query": "33977284", "results": [{"pmid": "33977284", "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.", "source": "Lancet Healthy Longev", "pubdate": "2021 May", "authors": ["Mannick JB", "Teo G", "Bernardo P", "Quinn D", "Russell K", "Klickstein L", "Marshall W", "Shergill S"], "url": "https://pubmed.ncbi.nlm.nih.gov/33977284/"}]}
【tool:pubmed_search】
{"ok": true, "query": "29408453", "results": [{"pmid": "29408453", "title": "A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.", "source": "Exp Gerontol", "pubdate": "2018 May", "authors": ["Kraig E", "Linehan LA", "Liang H", "Romo TQ", "Liu Q", "Wu Y", "Benavides AD", "Curiel TJ"], "url": "https://pubmed.ncbi.nlm.nih.gov/29408453/"}]}
【tool:pubmed_search】
{"ok": true, "query": "35040506", "results": [{"pmid": "35040506", "title": "mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.", "source": "Mov Disord", "pubdate": "2022 Apr", "authors": ["Palma JA", "Martinez J", "Millar Vernetti P", "Ma T", "Perez MA", "Zhong J", "Qian Y", "Dutta S"], "url": "https://pubmed.ncbi.nlm.nih.gov/35040506/"}]}
【tool:pubmed_search】
{"ok": true, "query": "25525171", "results": [{"pmid": "25525171", "title": "Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.", "source": "Invest Ophthalmol Vis Sci", "pubdate": "2014 Dec 18", "authors": ["Petrou PA", "Cunningham D", "Shimel K", "Harrington M", "Hammel K", "Cukras CA", "Ferris FL", "Chew EY"], "url": "https://pubmed.ncbi.nlm.nih.gov/25525171/"}]}
【tool:pubmed_search】
{"ok": true, "query": "22367193", "results": [{"pmid": "22367193", "title": "A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults.", "source": "Cancer Chemother Pharmacol", "pubdate": "2012 Jun", "authors": ["Boni JP", "Leister C", "Hug B", "Burns J", "Sonnichsen D"], "url": "https://pubmed.ncbi.nlm.nih.gov/22367193/"}]}
【tool:pubmed_search】
{"ok": true, "query": "18037627", "results": [{"pmid": "18037627", "title": "Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.", "source": "Ann Rheum Dis", "pubdate": "2008 Aug", "authors": ["Bruyn GA", "Tate G", "Caeiro F", "Maldonado-Cocco J", "Westhovens R", "Tannenbaum H", "Bell M", "Forre O"], "url": "https://pubmed.ncbi.nlm.nih.gov/18037627/"}]}
【tool:pubmed_search】
{"ok": true, "query": "27613521", "results": [{"pmid": "27613521", "title": "Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study.", "source": "Lancet", "pubdate": "2016 Oct 29", "authors": ["French JA", "Lawson JA", "Yapici Z", "Ikeda H", "Polster T", "Nabbout R", "Curatolo P", "de Vries PJ"], "url": "https://pubmed.ncbi.nlm.nih.gov/27613521/"}]}
【tool:pubmed_search】
{"ok": true, "query": "29992557", "results": [{"pmid": "29992557", "title": "Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial.", "source": "Int J Cancer", "pubdate": "2019 Feb 15", "authors": ["Tesch H", "Stoetzer O", "Decker T", "Kurbacher CM", "Marmé F", "Schneeweiss A", "Mundhenke C", "Distelrath A"], "url": "https://pubmed.ncbi.nlm.nih.gov/29992557/"}]}
【tool:pubmed_search】
{"ok": true, "query": "24618547", "results": [{"pmid": "24618547", "title": "Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial.", "source": "Pulm Circ", "pubdate": "2013 Sep", "authors": ["Seyfarth HJ", "Hammerschmidt S", "Halank M", "Neuhaus P", "Wirtz HR"], "url": "https://pubmed.ncbi.nlm.nih.gov/24618547/"}]}
【tool:pubmed_search】
{"ok": true, "query": "22115710", "results": [{"pmid": "22115710", "title": "A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.", "source": "Ophthalmology", "pubdate": "2012 Jan", "authors": ["Dugel PU", "Blumenkranz MS", "Haller JA", "Williams GA", "Solley WA", "Kleinman DM", "Naor J"], "url": "https://pubmed.ncbi.nlm.nih.gov/22115710/"}]}
→ call web_fetch({"max_chars":6000,"url":"https://pubmed.ncbi.nlm.nih.gov/33977284/"})
【tool:web_fetch】
{"ok": false, "error": "Client error '403 Forbidden' for url 'https://pubmed.ncbi.nlm.nih.gov/33977284/'\nFor more information check: https://developer.mozilla.org/en-US/docs/Web/HTTP/Status/403"}
→ call web_fetch({"max_chars":4000,"url":"https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=33977284&retmode=xml"})
→ call web_fetch({"max_chars":4000,"url":"https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=29408453&retmode=xml"})
→ call web_fetch({"max_chars":4000,"url":"https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=35040506&retmode=xml"})
→ call web_fetch({"max_chars":4000,"url":"https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=25525171&retmode=xml"})
→ call web_fetch({"max_chars":4000,"url":"https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=22367193&retmode=xml"})
【tool:web_fetch】
{"ok": true, "url": "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=33977284&retmode=xml", "status": 200, "content_type": "text/xml; charset=UTF-8", "text": "33977284 2022 08 30 2025 11 12 2666-7568 2 5 2021 May The lancet. Healthy longevity Lancet Healthy Longev Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. e250 e262 e250-e262 10.1016/S2666-7568(21)00062-3 The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season. We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had
【tool:web_fetch】
{"ok": true, "url": "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=29408453&retmode=xml", "status": 200, "content_type": "text/xml; charset=UTF-8", "text": "29408453 2019 04 23 2021 12 04 1873-6815 105 2018 May Experimental gerontology Exp Gerontol A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. 53 69 53-69 10.1016/j.exger.2017.12.026 S0531-5565(17)30913-0 Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAP
【tool:web_fetch】
{"ok": true, "url": "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=35040506&retmode=xml", "status": 200, "content_type": "text/xml; charset=UTF-8", "text": "35040506 2022 04 19 2023 04 02 1531-8257 37 4 2022 Apr Movement disorders : official journal of the Movement Disorder Society Mov Disord mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis. 778 789 778-789 10.1002/mds.28923 Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants. Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976). The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants wer
【tool:web_fetch】
{"ok": true, "url": "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=25525171&retmode=xml", "status": 200, "content_type": "text/xml; charset=UTF-8", "text": "25525171 2015 03 03 2022 04 09 1552-5783 56 1 2014 Dec 18 Investigative ophthalmology & visual science Invest Ophthalmol Vis Sci Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. 330 338 330-8 10.1167/iovs.14-15877 To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with
【tool:web_fetch】
{"ok": true, "url": "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=22367193&retmode=xml", "status": 200, "content_type": "text/xml; charset=UTF-8", "text": "22367193 2012 08 03 2018 12 11 1432-0843 69 6 2012 Jun Cancer chemotherapy and pharmacology Cancer Chemother Pharmacol A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults. 1433 1442 1433-42 10.1007/s00280-012-1845-7 Temsirolimus, a selective inhibitor of mammalian target of rapamycin, is an approved treatment for patients with advanced renal cell carcinoma (RCC). This study assessed the effect of intravenous (i.v.) temsirolimus 25 mg, the recommended dose for patients with RCC, on the corrected QT (QTc) interval. This 3-period crossover study enrolled healthy subjects. In periods 1 and 2, subjects received i.v. placebo either alone or with open-label oral moxifloxacin. In period 3, subjects received a single dose of temsirolimus 25 mg. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QT