bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2026–01–25
eleven papers selected by
Grigor Varuzhanyan, UCLA
  1. EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy.
  2. c-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors.
  3. Extracellular vesicle-associated lncRNA LYPLAL1-DT mediates endothelial-cancer cell communication, promoting small cell lung cancer progression.
  4. A screening strategy based on machine learning for diagnostic biomarkers in small cell lung cancer.
  5. Primary cutaneous non neuroendocrine small cell carcinoma POU2F3 subtype: morphologic, immunohistochemical, transcriptomic and methylation analysis of two cases.
  6. POU2F3-positive neuroendocrine carcinoma of the urinary bladder showing basaloid morphology: expanding the morphologic spectrum of tuft cell-like carcinoma.
  7. The role of neuroendocrine differentiation in treatment resistance of prostate cancer and intervention strategies.
  8. Metformin Suppresses MEN1-Associated Pancreatic and Pituitary Neuroendocrine Tumors: Evidence from Mouse Models and Clinical Data.
  9. Targeting STAT3 by SH-4-54 suppresses the occurrence and inactivates oxidative phosphorylation in small-cell lung cancer via the SRC signaling.
  10. Evaluation of prognostic factors using nutritional indicators in extensive-stage small cell lung cancer.
  11. Evaluation of ICAM and VCAM as biomarkers in serum and bronchoscopic lavage samples of lung cancer patients.
  1. JCI Insight. 2026 Jan 23. pii: e197008. [Epub ahead of print]11(2):
    EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy.
    Atsuko Ogino, Amir Vajdi, Xinmeng Jasmine Mu, Navin R Mahadevan, Kenneth Ngo, Matthew A Booker, Paloma Cejas, Jeffrey J Okoro, Man Xu, Benjamin F Springer, Benjamin K Eschle, Cameron M Messier, Stephen Wang, Sudeepa Syamala, Rubii M Tamen, Anika E Adeni, Emily S Chambers, Israel Canadas, Tran Thai, Camilla L Christensen, Chunxiao Xu, Patrick H Lizotte, Geoffrey R Oxnard, Hideo Watanabe, Henry W Long, Prafulla C Gokhale, Cloud P Paweletz, Lynette M Sholl, Matthew G Oser, David A Barbie, Michael Y Tolstorukov, Pasi A Jänne.
      Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.
    Keywords:  Cell biology; Drug therapy; Lung cancer; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.197008
  2. Cell Rep Med. 2026 Jan 20. pii: S2666-3791(25)00622-6. [Epub ahead of print]7(1): 102549
    c-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors.
    Hyatt Balke-Want, Vimal Keerthi, Maria Del Carmen Arenas, Yiyun Chen, Meena Malipatlolla, Dorota D Klysz, Peng Xu, Katie Ho, Kyle Asano, David Stahl, Jing Huang, Aidan Retherford, Sunny Patel, Carley Fowler, Lukas Maas, Nikolaos Gkitsas-Long, Qiaoshi Jiang, Xikun Liu, Roland Ullrich, Julie George, Sabine Heitzeneder, Ramya Tunuguntla, Julien Sage, Elena Sotillo, Crystal L Mackall, Steven A Feldman.
      Small cell lung cancer (SCLC), a highly lethal disease, limits T cell responses by downregulating major histocompatibility (MHC) class I molecules. Because chimeric antigen receptor (CAR) T cells are not MHC restricted, they may provide a powerful strategy against SCLC. However, few CAR targets for SCLC are known. Here, we show that B7-H3/CD276 is expressed in SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs) that can clinicopathologically mimic SCLC. Thoracic SMARCA4-deficient UTs limit killing by B7-H3 CAR T cells via secretion of transforming growth factor β1 (TGF-β1). To overcome tumor-driven CAR T cell suppression, we knock in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells utilizing CRISPR-Cas9. Non-viral c-JUN+B7-H3 CAR T cells show enhanced killing of both SCLC cells with low antigen density and thoracic SMARCA4-deficient UTs, providing a platform to address these highly aggressive entities. We also provide evidence that good manufacturing practice (GMP) clinical-scale manufacturing is feasible for c-JUN+B7-H3 CAR T cells.
    Keywords:  B7-H3; CRISPR knock-in; cell therapy scaling; non-viral CAR T-cells; small cell lung cancer; thoracic SMARCA4-deficient undifferentiated tumor; transforming growth factor-beta 1
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102549
  3. Extracell Vesicles Circ Nucl Acids. 2025 ;6(4): 1015-1033
    Extracellular vesicle-associated lncRNA LYPLAL1-DT mediates endothelial-cancer cell communication, promoting small cell lung cancer progression.
    Xing Zhang, Caijiao Hu, Zhihui Li, Jing Lu, Xueyun Huo, Lixue Cao, Meng Guo, Changlong Li, Xin Liu, Zhenwen Chen, Jianyi Lv, Xiaoyan Du.
      Aim: Representing about 15% of lung cancers, small cell lung cancer (SCLC) is an extremely aggressive disease characterized by rapid growth and early spread, leading to dismal clinical outcomes. In this study, we aimed to investigate the dual roles of exosomal long non-coding RNA (lncRNA) LYPLAL1-DT (LYPLAL1 divergent transcript) in both tumor cells and vascular endothelial cells. Methods: The circulating levels of LYPLAL1-DT were measured using real-time polymerase chain reaction in 13 SCLC patients and 21 normal controls. Exosomes from the supernatant of cell culture medium or serum were extracted through ultracentrifugation and dyed with PKH67 green fluorescent cell linker to identify internalization. Migration and invasion assay, colony formation, Cell Counting Kit-8 (CCK-8), and tube formation assays were used to assess the malignant effects of extracellular RNAs (exRNAs) LYPLAL1-DT in exosomes. Results: Exosomal LYPLAL1-DT is upregulated in SCLC patients and plays a dual role in promoting tumor cell aggressiveness and enhancing pro-angiogenic behavior in endothelial cells, thereby accelerating SCLC progression. Mechanistically, LYPLAL1-DT functions as a competing endogenous RNA, exerting its effects through the miR-204-5p/profilin-2, miR-204-5p/B-cell lymphoma 2 and miR-204-5p/sirtuin 1 regulatory axes. These pathways underscore the pleiotropic effects of exosomal LYPLAL1-DT and underscore its value as a promising therapeutic target. Conclusion: In the current study, we investigated the bidirectional communication mediated by exRNA LYPLAL1-DT between SCLC and endothelial cells, while also exploring its potential regulatory targets. This research provides a potential circulating biomarker for the diagnosis, prognosis, and treatment of SCLC.
    Keywords:  BCL2; LYPLAL1-DT; PFN2; SCLC; SIRT1; endothelial cells; exosome
    DOI:  https://doi.org/10.20517/evcna.2025.119
  4. PLoS One. 2026 ;21(1): e0339195
    A screening strategy based on machine learning for diagnostic biomarkers in small cell lung cancer.
    Yifeng Pan, Xuansheng Ding, Wenyun Duan, Liangbiao Wang, Yong Dai, Rongrong Han, Shubei Wang, Mingquan Guo.
      Small cell lung cancer (SCLC) is the most aggressive subtype with high mortality rates due to the lack of specific diagnostic biomarkers to delay the optimal opportunity for treatment. Traditional biomarkers, such as neuron-specific enolase (NSE) or pro-gastrin-releasing peptide (ProGRP), have insufficient specificity and sensitivity to meet the demands of clinical diagnosis. Exosome and its contents have become burgeoning cancer biomarkers due to their diverse molecular cargo to achieve intercellular communication. Herein, a novel machine learning strategy was reported for rapid, efficient screening of biomarkers and identified an optimal exosome RNA combination as diagnostic biomarker of SCLC. Firstly, RNA sequencing data from 111 SCLC patients and 362 healthy controls were obtained from the exoRBase 2.0 and 3.0 databases. The machine learning methods were employed to select specific RNA by using 20 iterations with 10-fold nested cross-validation for SCLC diagnosis. Then, an optimal combination of three exosome RNAs (LINC00989, CXCL5, and MAP3K7CL) was confirmed and achieved excellent diagnostic performance (area under the curve (AUC) of 0.950, sensitivity of 0.936, and specificity of 0.892). Finally, an independent validation cohort containing tissue-based RNA expression data for two biomarkers (CXCL5 and MAP3K7CL) from 79 SCLC patients and 7 standard controls was used to evaluate the diagnostic performance of the selected RNAs. The results demonstrated modest diagnostic performance in tissue samples (AUC = 0.718) with two biomarkers, indicating potential cross-tissue applicability despite the limitations of incomplete biomarker coverage. In addition, a specificity analysis of exosome RNA data, including gastric cancer, hepatocellular carcinoma, and breast cancer, demonstrated significant specificity for SCLC. Therefore, the novel biomarker screening strategy integrating nested cross-validation with multiple machine learning algorithms successfully established to offer a potentially valuable protocol for early SCLC diagnosis and other cancers.
    DOI:  https://doi.org/10.1371/journal.pone.0339195
  5. Virchows Arch. 2026 Jan 22.
    Primary cutaneous non neuroendocrine small cell carcinoma POU2F3 subtype: morphologic, immunohistochemical, transcriptomic and methylation analysis of two cases.
    Kerman Zyani, Daniel Pissaloux, Charly Liddell, Mahtab Samimi, Franck Tirode, Andreas von Deimling, Serge Guyétant, Sylvie Lantuejoul, Thibault Kervarrec.
      Up to 10% of small cell lung carcinomas do not express any neuroendocrine markers and are characterized by an expression of the transcription factor POU2F3. Recently, few cases of poorly differentiated carcinomas harboring POU2F3 expression have been described in the breast, cervix, and bladder. Herein, we report the morphological, immunohistochemical, and molecular characterization of two primary cutaneous POU2F3-expressing small cell carcinomas. The cases arose in the temple and on the occipital region in a 92-year-old woman and a 78-year-old man respectively. Microscopic examination revealed in both cases a large and ulcerated poorly differentiated neoplasm infiltrating the full thickness of the dermis with extension into the subcutaneous tissues in case #1. The tumors harbored solid and trabecular growth patterns and were composed of poorly differentiated highly mitotic cells. Immunohistochemical investigation revealed diffuse pancytokeratin positivity while no expression of cytokeratin 20, chromogranin A, synaptophysin, CD56, or INSM1 was detected. Diffuse nuclear expression of POU2F3 was observed. Transcriptomic analysis revealed a SBS7 mutation signature related to UV-induced DNA damages in one case and evidenced an expression profile similar to the one observed in POU2F3-expressing small cell lung cancers in both. Methylation analysis confirmed the proximity of the two cases with other skin cancers. To conclude, we report herein the first description of primary cutaneous small cell carcinoma POU2F3 subtype.
    Keywords:  Carcinoma; Neuroendocrine differentiation; POU2F3 subtype
    DOI:  https://doi.org/10.1007/s00428-026-04406-4
  6. Virchows Arch. 2026 Jan 19.
    POU2F3-positive neuroendocrine carcinoma of the urinary bladder showing basaloid morphology: expanding the morphologic spectrum of tuft cell-like carcinoma.
    Ayaka Fukui, Naoki Nakajima, Yuki Teramoto, Shinsuke Shibuya, Yosuke Yamada, Kai Mizoguchi, Hironori Haga.
      POU2F3 defines tuft cell-like carcinomas, yet POU2F3-driven neuroendocrine neoplasia in the urinary bladder remains incompletely characterized and can morphologically mimic basaloid carcinomas. We report a case of an octogenarian woman with a diverticular bladder tumor composed of conventional high-grade urothelial carcinoma juxtaposed with a sharply demarcated basaloid component. Although the basaloid component lacked classical small-cell morphology and showed scant conventional neuroendocrine marker expression, it was diffusely POU2F3-positive, underscoring a potential diagnostic pitfall with human papillomavirus (HPV)-associated basaloid squamous cell carcinoma. Both components showed concordant aberrant tumor-suppressor immunoprofiles (p53 overexpression and Rb loss), and high-risk HPV RNA in situ hybridization (RNAscope) was negative. This case expands the recognized morphologic spectrum of bladder neuroendocrine carcinoma to include POU2F3-defined non-small cell neuroendocrine carcinoma with basaloid architecture, supporting the practical value of incorporating POU2F3 into immunohistochemical panels for poorly differentiated basaloid bladder tumors.
    Keywords:  Bladder diverticulum; Neuroendocrine tumors; POU domain factors; Tuft cells; Urinary bladder neoplasms; Urothelial carcinoma
    DOI:  https://doi.org/10.1007/s00428-026-04407-3
  7. Front Oncol. 2025 ;15 1743689
    The role of neuroendocrine differentiation in treatment resistance of prostate cancer and intervention strategies.
    Baozhen Wang, Yanyun Zhang, Wenbo Zhang.
      Prostate cancer is one of the most common malignancies in men, and resistance to conventional treatments is frequently encountered in clinical practice. Among the mechanisms contributing to this resistance, neuroendocrine differentiation (NED) is particularly significant. NED does not only change the basic biological characteristics of cancer cells but also is capable of inducing resistance to endocrine therapy and chemotherapy, which impact the overall prognosis negatively. While NED drives prostate cancer progression and treatment resistance, its pathophysiology and the mechanisms underlying its development are still poorly understood, which restricts the availability of effective clinical interventions. Hence, a detailed study on the molecular pathways that cause NED and the role of this phenomenon in therapy resistance will be needed to improve treatment outcomes in prostate cancer. This review delineates the role of NED in mediating therapy resistance in prostate cancer and evaluates current therapeutic interventions, with the aim of informing the development of new treatment strategies for this malignancy.
    Keywords:  CRPC; NEPC; neuroendocrine differentiation; prostate cancer; resistance
    DOI:  https://doi.org/10.3389/fonc.2025.1743689
  8. Endocr Relat Cancer. 2026 Jan 22. pii: ERC-25-0518. [Epub ahead of print]
    Metformin Suppresses MEN1-Associated Pancreatic and Pituitary Neuroendocrine Tumors: Evidence from Mouse Models and Clinical Data.
    Airi Nakano, Yao Huang, Yuri Mistui, Ryunosuke Shirai, Yu Chen, Tomoko Tajima, Yukiko Sakaguchi, Tomoka Moro, Chihiro Hoshino, Kosuke Terada, Naoaki Sakata, Akihiko Yokoyama, Susumu Hijioka, Masamichi Ishiai, Hidetoshi Kassai, Yuko Tabata, Rieko Ohki.
      Pancreatic neuroendocrine tumors (PanNETs) represent a rare subset of pancreatic cancers, comprising approximately 1-2% of all cases. Non-functioning PanNETs (NF-PanNETs), which account for the majority of PanNETs, can be difficult to treat as they show no hormone-related symptoms and are often not diagnosed until the more advanced stages. Current therapeutic agents have limited efficacy, highlighting the need for novel treatment strategies. Multiple endocrine neoplasia type 1 is a hereditary syndrome strongly associated with PanNETs and pituitary neuroendocrine tumors (PitNETs), caused by germline mutations in the MEN1 gene. Using Men1f/f-RipCre+ mice, which develop both NF-PanNETs and PitNETs, we investigated whether long-term administration of metformin, a first-line anti-diabetic drug, could suppress tumor development and progression. Metformin significantly inhibited the elevation of blood glucose in Men1f/f-RipCre+ mice, and longer-term treatment attenuated PanNETs and restored normal insulin secretion. Metformin suppressed the proliferative pathways including the PI3K/Akt/mTOR signaling pathway. In addition to its effects on PanNETs, metformin also attenuated PitNET development, elevated antiproliferative pathways and suppressed angiogenic pathways. Furthermore, clinical data revealed that NF-PanNET patients with prior metformin use exhibited improved prognosis. These findings demonstrate that blood glucose control through metformin represents a promising preventive and therapeutic strategy for NF-PanNETs and MEN1-associated neuroendocrine tumors.
    Keywords:  MEN1; PI3K/Akt/mTOR pathway; Pancreatic neuroendocrine tumor; glucose control; metformin; pituitary NET
    DOI:  https://doi.org/10.1530/ERC-25-0518
  9. Naunyn Schmiedebergs Arch Pharmacol. 2026 Jan 21.
    Targeting STAT3 by SH-4-54 suppresses the occurrence and inactivates oxidative phosphorylation in small-cell lung cancer via the SRC signaling.
    Chen Chen, Hang Hu, Zhongxiang Liu, Yongqian Jiang, Minhua Shi.
      Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are the two main types of lung cancer. Signal transducer and activator of transcription 3 (STAT3) plays an oncogenic role in various malignancies, including lung cancer, and targeting STAT3 is currently being considered as a potential therapeutic approach. The expression of p-STAT3, STAT3, p-SRC, SRC, and apoptosis- and mitochondrial fission-related proteins was assessed through western blot analysis. The cellular events including cell proliferation, apoptosis and cell cycle, and cisplatin resistance were assessed via CCK8, colony formation assays, and flow cytometry. Mitochondrial oxidative stress was measured by DCFH-DA, JC-1, and oxygen consumption rate (OCR) kits. Network pharmacology combined with molecular docking was used to investigate the molecular targets of STAT3 inhibitor SH-4-54 in the treatment of SCLC. Xenograft mouse models were constructed to verify the in vivo impacts of SH-4-54, and related biochemical parameters were analyzed. STAT3 phosphorylation was upregulated in SCLC. The STAT3 inhibitor SH-4-54 inhibited cell proliferation, promoted cell apoptosis, induced cell cycle arrest, decreased cisplatin resistance, and reduced oxidative phosphorylation in mitochondria of SCLC cells. Additionally, it inhibited tumor growth in tumor-bearing mice. SRC functioned as a core target of SH-4-54, and its phosphorylation level was decreased by SH-4-54. YEEI peptide, an SRC activator, could reverse the in vitro impacts of SH-4-54 on ROS production, cell proliferation, apoptosis, and cell cycle. Our findings demonstrate that the STAT3 inhibitor SH-4-54 can target SRC to suppress the tumorigenesis and oxidative phosphorylation in SCLC.
    Keywords:  Cisplatin resistance; SH-4–54; SRC; Small-cell lung cancer
    DOI:  https://doi.org/10.1007/s00210-025-04893-3
  10. J Rural Med. 2026 Jan;21(1): 20-26
    Evaluation of prognostic factors using nutritional indicators in extensive-stage small cell lung cancer.
    Mamiko Kuriyama, Makoto Nakao, Ryohei Gomyo, Mariko Hasegawa, Syuntaro Hayashi, Norihisa Takeda, Hideki Muramatsu.
       Objective: The Glasgow Prognostic Score (GPS), Prognostic Nutritional Index (PNI), and Neutrophil-to-Lymphocyte Ratio (NLR) have been shown to predict the prognosis of various cancer types. However, the prognostic roles of GPS, PNI, and NLR in patients with extensive-stage small cell lung cancer (ES-SCLC) remain controversial. This study aimed to assess the prognostic value of these three immunonutritional indicators in patients with ES-SCLC.
    Patients and Methods: We retrospectively analyzed 102 ES-SCLC patients who received first-line platinum-doublet chemotherapy. The GPS, PNI, and NLR were assessed before the initiation of first-line chemotherapy. Based on previous reports, the optimal cut-off levels were 40 for PNI and 3 for NLR. The Kaplan-Meier method and Cox proportional hazards models were used to evaluate progression-free survival (PFS) and overall survival (OS).
    Results: Of the total participants, 102 had ES-SCLC. Patients with a GPS of 0/1 showed significantly longer PFS than those with a GPS of 2 (133 vs. 63 days, P<0.001), and a high PNI was also associated with longer PFS (133 vs. 80 days, P=0.007). No significant difference in PFS was observed between the low and high NLR groups (P=0.471). Similarly, OS was significantly longer in patients with a GPS of 0/1 than in those with a GPS of 2 (300 vs. 117 days, P<0.001) and in those with a high PNI than in those with a low PNI (296 vs. 136 days, P<0.001). The OS did not differ significantly in the NLR group (P=0.303). Multivariate analyses revealed that the GPS and PNI were independently associated with worse PFS and OS.
    Conclusion: Our study demonstrated that both the GPS and PNI were significantly associated with PFS and OS in patients with ES-SCLC. The GPS may be a simple and reliable immunonutritional marker for predicting outcomes in patients with ES-SCLC treated with platinum doublet chemotherapy.
    Keywords:  Glasgow prognostic score; neutrophil-to-lymphocyte ratio; prognostic nutritional index; small-cell lung cancer
    DOI:  https://doi.org/10.2185/jrm.2025-043
  11. Clin Transl Oncol. 2026 Jan 20.
    Evaluation of ICAM and VCAM as biomarkers in serum and bronchoscopic lavage samples of lung cancer patients.
    Burcu Nur Gülbahar, Alperen Aksakal, Buğra Kerget, Nurinnisa Öztürk, Ömer Araz, Elif Yılmazel Uçar, Leyla Sağlam.
       BACKGROUND: This study aimed to assess the diagnostic and prognostic potential of adhesion molecules ICAM-1, ICAM-2, and VCAM-1 by analyzing their levels in serum and bronchoalveolar lavage (BAL) samples from patients with lung cancer.
    METHODS: This prospective, single-center, cross-sectional study was conducted at the chest diseases clinic of Atatürk University Faculty of Medicine from March 2024 to May 2025. Patients diagnosed with malignant or benign lung disease by bronchoscopy, along with a control group of healthy volunteers, were included in the study. Serum samples were collected from all participants, and BAL samples were obtained from the patient groups. ICAM-1, ICAM-2, and VCAM-1 levels were measured by ELISA. Statistical analyses were performed using the SPSS 20.0 software package. Diagnostic accuracy was evaluated with ROC analysis, and 1-year survival was assessed using Kaplan-Meier curves.
    RESULTS: In the lung cancer group, ICAM-1, ICAM-2, and VCAM-1 levels in serum and BAL samples were significantly higher compared to the benign and control groups (p < 0.001 for all). BAL ICAM-2 level showed the highest diagnostic performance (AUC: 0.990; sensitivity and specificity: 96.4%). Serum ICAM-2 and ICAM-1 also showed high diagnostic performance. BAL ICAM-1 levels were significantly higher in non-small cell lung cancer (NSCLC) than in small cell lung cancer (SCLC) (p = 0.036). High serum ICAM-1 and BAL ICAM-2 levels were associated with mortality (p = 0.048 and p = 0.015, respectively).
    CONCLUSIONS: Serum and BAL levels of ICAM-1, ICAM-2, and VCAM-1 show promise as potential diagnostic biomarkers for lung cancer. Among these, BAL ICAM-2 levels are especially notable due to their high diagnostic accuracy and link to survival.
    Keywords:  Biomarker; Bronchoalveolar lavage; Diagnosis; ICAM-1; ICAM-2; Lung cancer; Prognosis; VCAM-1
    DOI:  https://doi.org/10.1007/s12094-025-04199-z
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