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Phosphoenolpyruvate carboxykinase-2 (PCK2) is a therapeutic target in triple-negative breast cancer. 磷酸烯醇丙酮酸羧激酶-2(PCK2)是三阴性乳腺癌的治疗靶点。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-23 DOI: 10.1007/s10549-024-07462-z
Vignesh Gunasekharan, Hao-Kuen Lin, Michal Marczyk, Alejandro Rios-Hoyo, Gerson Espinoza Campos, Naing Lin Shan, Mostafa Ahmed, Sheila Umlauf, Peter Gareiss, Raaisa Raaisa, Richard Williams, Rebecca Cardone, Stephan Siebel, Richard Kibbey, Yulia V Surovtseva, Lajos Pusztai

Purpose: Metabolic rewiring in malignant transformation is often accompanied by altered expression of metabolic isozymes. Phosphoenolpyruvate carboxykinase-2 (PCK2) catalyzes the rate-limiting step of gluconeogenesis and is the dominant isoform in many cancers including triple-negative breast cancer (TNBC). Our goal was to identify small molecule inhibitors of PCK2 enzyme activity.

Methods: We assessed the impact of PCK2 down regulation with shRNA on TNBC cell growth in vitro and used AtomNet® deep convolutional neural network software to identify potential small molecule inhibitors of PCK2-based structure. We iteratively tested candidate compounds in an in vitro PCK-2 enzyme assay. The impact of the top hit on metabolic flux and cell viability was also assessed.

Results: PCK2 downregulation decreased growth of BT-549 and MDA-MB-231 cells and reduced metabolic flux through pyruvate carboxylase. The first AtomNet® in silico structural screen of 7 million compounds yielded 86 structures that were tested in PCK2 enzyme assay in vitro. The top hit (IC50 = 2.4 µM) was used to refine a second round of in silico screen that yielded 82 candidates to be tested in vitro, which resulted in 45 molecules with inhibition > 20%. In the second in vitro screen we also included 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate, previously suggested to be PCK2 inhibitor based on structure, which emerged as the top hit. The specificity of this compound was tested in PCK1 and PCK2 enzymatic assays and showed IC50 of 500 nM and 3.5-27 nM for PCK1 and PCK2, respectively.

Conclusion: 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate is a high affinity PCK2 enzyme inhibitor that also has significant growth inhibitory activity in breast cell lines in vitro and represents a potential therapeutic lead compound.

目的:恶性转化过程中的代谢重构往往伴随着代谢同工酶表达的改变。磷酸烯醇丙酮酸羧激酶-2(PCK2)催化葡萄糖生成的限速步骤,是包括三阴性乳腺癌(TNBC)在内的许多癌症中的主要同工酶。我们的目标是鉴定 PCK2 酶活性的小分子抑制剂:我们评估了用 shRNA 下调 PCK2 对 TNBC 细胞体外生长的影响,并使用 AtomNet® 深度卷积神经网络软件鉴定了基于 PCK2 结构的潜在小分子抑制剂。我们在体外 PCK-2 酶测定中对候选化合物进行了反复测试。我们还评估了热门化合物对代谢通量和细胞活力的影响:结果:PCK2 下调会降低 BT-549 和 MDA-MB-231 细胞的生长,并减少通过丙酮酸羧化酶的代谢通量。AtomNet® 首次对 700 万种化合物进行了结构筛选,得出了 86 种结构,并在体外 PCK2 酶试验中进行了测试。第一轮筛选结果(IC50 = 2.4 µM)被用于第二轮硅学筛选,共筛选出 82 个候选化合物进行体外测试,其中 45 个分子的抑制率大于 20%。在第二轮体外筛选中,我们还加入了 3-(3,4-二羟基苯基)-2-羟基丙酸酯,这是之前根据结构被认为是 PCK2 抑制剂的一种化合物。结论:3-(3,4-二羟基苯基)-2-羟基丙酸酯是一种高亲和力的 PCK2 酶抑制剂,在体外对乳腺细胞株也有显著的生长抑制活性,是一种潜在的治疗先导化合物。
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引用次数: 0
Fragmentation of care in breast cancer: greater than the sum of its parts. 乳腺癌治疗的分散性:大于各部分的总和。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-03 DOI: 10.1007/s10549-024-07442-3
Hadley D Freeman, Linnea C Burke, Ja'Neil G Humphrey, Ashley J Wilbers, Halley Vora, Rhami Khorfan, Naveenraj L Solomon, Jukes P Namm, Liang Ji, Sharon S Lum

Introduction: Fragmentation of care (FC, the receipt of care at > 1 institution) has been shown to negatively impact cancer outcomes. Given the multimodal nature of breast cancer treatment, we sought to identify factors associated with FC and its effects on survival of breast cancer patients.

Methods: A retrospective analysis was performed of surgically treated, stage I-III breast cancer patients in the 2004-2020 National Cancer Database, excluding neoadjuvant therapy recipients. Patients were stratified into two groups: FC or non-FC care. Treatment delay was defined as definitive surgery > 60 days after diagnosis. Multivariable logistic regression was performed to identify factors predictive of FC, and survival was compared using Kaplan-Meier and multivariable Cox proportional hazards methods.

Results: Of the 531,644 patients identified, 340,297 (64.0%) received FC. After adjustment, FC (OR 1.27, 95% CI 1.25-1.29) was independently associated with treatment delay. Factors predictive of FC included Hispanic ethnicity (OR 1.04, 95% CI: 1.01-1.07), treatment at comprehensive community cancer programs (OR 1.06, 95% CI: 1.03-1.08) and integrated network cancer programs (OR 1.55, 95% CI: 1.51-1.59), AJCC stage II (OR 1.06, 95% CI 1.05-1.07) and stage III tumors (OR 1.06, 95% CI: 1.02-1.10), and HR + /HER2 + tumors (OR 1.05, 95% CI: 1.02-1.07). Treatment delay was independently associated with increased risk of mortality (HR 1.23, 95% CI 1.20-1.26), whereas FC (HR 0.87, 95% CI 0.86-0.88) showed survival benefit.

Conclusions: While treatment delay negatively impacts survival in breast cancer patients, our findings suggest FC could be a marker for multispecialty care that may mitigate some of these effects.

简介:医疗分散(FC,在一家以上的医疗机构接受治疗)已被证明会对癌症治疗效果产生负面影响。鉴于乳腺癌治疗的多模式性质,我们试图找出与FC相关的因素及其对乳腺癌患者生存的影响:我们对 2004-2020 年国家癌症数据库中接受过手术治疗的 I-III 期乳腺癌患者(不包括接受新辅助治疗的患者)进行了回顾性分析。患者被分为两组:FC 或非 FC 治疗组。治疗延迟的定义是确诊后大于 60 天的明确手术。通过多变量逻辑回归确定了预测 FC 的因素,并使用 Kaplan-Meier 和多变量 Cox 比例危险度法比较了生存率:在已确认的 531,644 例患者中,340,297 例(64.0%)接受了 FC 治疗。经调整后,FC(OR 1.27,95% CI 1.25-1.29)与治疗延迟有独立关联。预测 FC 的因素包括西班牙裔(OR 1.04,95% CI:1.01-1.07)、在综合社区癌症项目(OR 1.06,95% CI:1.03-1.08)和综合网络癌症项目(OR 1.55,95% CI:1.51-1.59)、AJCC II 期(OR 1.06,95% CI 1.05-1.07)和 III 期肿瘤(OR 1.06,95% CI:1.02-1.10)以及 HR + /HER2 + 肿瘤(OR 1.05,95% CI:1.02-1.07)。治疗延迟与死亡风险增加(HR 1.23,95% CI 1.20-1.26)独立相关,而FC(HR 0.87,95% CI 0.86-0.88)则显示出生存获益:尽管治疗延迟会对乳腺癌患者的生存产生负面影响,但我们的研究结果表明,FC可以作为多专科护理的标志,从而减轻其中的一些影响。
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引用次数: 0
Cytokine levels in breast cancer are highly dependent on cytomegalovirus (CMV) status. 乳腺癌中的细胞因子水平与巨细胞病毒(CMV)状态密切相关。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-22 DOI: 10.1007/s10549-024-07459-8
Juliet V Spencer, Jianfang Liu, Brenda Deyarmin, Hai Hu, Craig D Shriver, Stella Somiari

Purpose: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer.

Methods: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN-; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37).

Results: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.043). The results were quite different in CMV- patients where cIL-10 levels were highest in Inv/LN- compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046).

Conclusion: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer.

目的:在美国,乳腺癌占所有女性癌症的 30%。巨细胞病毒(CMV)是一种可造成终身感染的疱疹病毒,可能与乳腺癌有关。CMV 并非致癌病毒,但在乳腺肿瘤中检测到了病毒 DNA 和蛋白质,这表明 CMV 可能对肿瘤的发展起了作用。CMV编码cmvIL-10,它是人类细胞IL-10(cIL-10)的同源物,具有强大的免疫抑制活性。我们研究了 CMV 感染、细胞因子和乳腺癌之间的关系:我们评估了患有良性乳腺疾病(38 人)、原位癌(41 人)、浸润性癌、无淋巴结受累(Inv/LN-;41 人)和浸润性淋巴结受累(Inv/LN+;37 人)的女性血浆中的 CMV 血清状态和细胞因子水平:结果:50%的患者样本(79 例)CMV 血清阳性。CMV状态与诊断之间没有相关性(P = 0.75)。对于CMV+患者,侵袭性疾病的CMV IgG水平有升高趋势(p = 0.172)。与Inv/LN-组和Inv/LN+组相比,CMV+原位患者的CmvIL-10水平更高(p = 0.020)。同样,与 Inv/LN- 组和 Inv/LN+ 组相比,CMV+原位患者的 cIL-10 水平更高(p = 0.043)。CMV-患者的结果则截然不同,与良性、原位或Inv/LN+相比,Inv/LN-患者的cIL-10水平最高(p = 0.019)。非裔美国人患者与CMV+状态明显相关(p = 0.001),其cmvIL-10水平低于白种人患者(p = 0.046):结论:CMV IgG 与诊断之间没有关联,但 CMV 感染会影响细胞因子的产生,并导致乳腺癌细胞因子谱的改变。
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引用次数: 0
A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer. 一项随机试验,比较了早期乳腺癌患者 6 个月一次唑来膦酸盐辅助治疗与一次性单剂量治疗的效果。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-07-31 DOI: 10.1007/s10549-024-07443-2
Arif Ali Awan, Carol Stober, Gregory R Pond, Igor Machado, Lucas Clemons, Henry Conter, Demetrios Simos, Sukhbinder Dhesy-Thind, Mihaela Mates, Vikaash Kumar, John Hilton, Marie-France Savard, Dean Fergusson, Lisa Vandermeer, Mark Clemons

Purpose: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial.

Methods: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS).

Results: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS.

Conclusion: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.

目的:虽然早期乳腺癌(EBC)辅助使用双膦酸盐可改善乳腺癌特异性预后,但最佳的双膦酸盐类型、剂量和时间安排仍存在问题。我们在一项前瞻性随机试验中对单次唑来膦酸盐输注进行了评估:绝经后 EBC 患者被随机分配接受一次唑来膦酸盐输注(4 毫克静脉注射)或 6 个月一次的治疗,为期 3 年。测量结果包括:生活质量(QoL;EQ-5D-5L)、双膦酸盐相关毒性(包括急性期反应(APR))、无复发生存率(RFS)、无骨转移生存率(BMFS)和总生存率(OS)。经过3年的随访,两组患者在生活质量和大多数毒性终点方面无明显差异。81%的患者(171/211)在接受唑来膦酸钠治疗后出现APR(单次输注组为77.6%,6个月治疗组为84.6%)。虽然在 6 个月组中,APR 的发生率在 3 年内有所下降,但仍很常见。在 6 个月治疗组中,34/104(32.7%)名患者提前停用唑来膦酸钠,其中最常见的原因是 APR(16/34,47%)。在3年的随访中,各组在RFS、BMFS或OS方面没有差异:结论:单次输注唑来膦酸钠可为患者提供更多便利,减少毒性,降低治疗中断率。尽管临床上普遍认为APR会随着时间的推移而降低,但在对患者进行专门询问时并未发现这一现象。虽然该研究没有进行非劣效性研究,但目前正在进行长期随访,以确认RFS和OS率。
{"title":"A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.","authors":"Arif Ali Awan, Carol Stober, Gregory R Pond, Igor Machado, Lucas Clemons, Henry Conter, Demetrios Simos, Sukhbinder Dhesy-Thind, Mihaela Mates, Vikaash Kumar, John Hilton, Marie-France Savard, Dean Fergusson, Lisa Vandermeer, Mark Clemons","doi":"10.1007/s10549-024-07443-2","DOIUrl":"10.1007/s10549-024-07443-2","url":null,"abstract":"<p><strong>Purpose: </strong>While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial.</p><p><strong>Methods: </strong>Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS).</p><p><strong>Results: </strong>211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS.</p><p><strong>Conclusion: </strong>A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical and sociodemographic determinants of older breast cancer survivors' reports of receiving advice about exercise. 老年乳腺癌幸存者报告接受运动建议的临床和社会人口决定因素。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI: 10.1007/s10549-024-07460-1
Kaitlyn M Wojcik, Oliver W A Wilson, Dalya Kamil, Padma Sheila Rajagopal, Mara A Schonberg, Jinani Jayasekera

Purpose: Exercise offers various clinical benefits to older breast cancer survivors. However, studies report that healthcare providers may not regularly discuss exercise with their patients. We evaluated clinical and sociodemographic determinants of receiving advice about exercise from healthcare providers among older breast cancer survivors (aged ≥65 years).

Methods: We used data from the Surveillance, Epidemiology, and End Results cancer registries linked to the Medicare Health Outcomes Survey (MHOS) from 2008 to 2015. We included female breast cancer survivors, aged ≥65 years, who completed the MHOS survey ≥2 years after a breast cancer diagnosis in a modified Poisson regression to identify clinical and sociodemographic determinants of reportedly receiving advice about exercise from healthcare providers.

Results: The sample included 1,836 breast cancer survivors. The median age of the sample was 76 years (range: 72-81). Overall, 10.7% of the survivors were non-Hispanic Black, 10.1% were Hispanic, and 69.3% were non-Hispanic White. Only 52.3% reported receiving advice about exercise from a healthcare provider. Higher body mass index (BMI) and comorbid medical history that included diabetes, cardiovascular, or musculoskeletal disease were each associated with a higher likelihood of receiving exercise advice. Lower education levels, lower BMI, and never having been married were each associated with a lower likelihood of receiving exercise advice.

Conclusions: Nearly half of breast cancer survivors aged ≥65 years did not report receiving exercise advice from a healthcare provider, suggesting interventions are needed to improve exercise counseling between providers and survivors, especially with women with lower educational attainment who have never been married.

目的:运动可为老年乳腺癌幸存者带来各种临床益处。然而,有研究报告称,医疗服务提供者可能不会定期与患者讨论运动问题。我们评估了老年乳腺癌幸存者(年龄≥65 岁)从医疗保健提供者那里获得运动建议的临床和社会人口决定因素:我们使用了 2008 年至 2015 年与医疗保险健康结果调查 (MHOS) 相关联的监测、流行病学和最终结果癌症登记处的数据。我们在改良泊松回归中纳入了乳腺癌确诊后≥2 年完成 MHOS 调查的年龄≥65 岁的女性乳腺癌幸存者,以确定临床和社会人口学方面的决定因素,这些因素据说是接受医疗保健提供者提供的运动建议的决定因素:样本包括 1,836 名乳腺癌幸存者。样本年龄中位数为 76 岁(范围:72-81 岁)。总体而言,10.7% 的幸存者为非西班牙裔黑人,10.1% 为西班牙裔,69.3% 为非西班牙裔白人。只有 52.3% 的幸存者表示接受过医疗保健提供者的运动建议。体重指数(BMI)越高,合并糖尿病、心血管疾病或肌肉骨骼疾病的病史越长,接受运动建议的可能性就越大。教育水平较低、体重指数较低和从未结过婚的人接受运动建议的可能性较低:结论:年龄≥65 岁的乳腺癌幸存者中,近一半未接受过医疗保健提供者的运动建议,这表明需要采取干预措施来改善医疗保健提供者与幸存者之间的运动咨询,尤其是对教育程度较低且从未结过婚的女性。
{"title":"Clinical and sociodemographic determinants of older breast cancer survivors' reports of receiving advice about exercise.","authors":"Kaitlyn M Wojcik, Oliver W A Wilson, Dalya Kamil, Padma Sheila Rajagopal, Mara A Schonberg, Jinani Jayasekera","doi":"10.1007/s10549-024-07460-1","DOIUrl":"10.1007/s10549-024-07460-1","url":null,"abstract":"<p><strong>Purpose: </strong>Exercise offers various clinical benefits to older breast cancer survivors. However, studies report that healthcare providers may not regularly discuss exercise with their patients. We evaluated clinical and sociodemographic determinants of receiving advice about exercise from healthcare providers among older breast cancer survivors (aged ≥65 years).</p><p><strong>Methods: </strong>We used data from the Surveillance, Epidemiology, and End Results cancer registries linked to the Medicare Health Outcomes Survey (MHOS) from 2008 to 2015. We included female breast cancer survivors, aged ≥65 years, who completed the MHOS survey ≥2 years after a breast cancer diagnosis in a modified Poisson regression to identify clinical and sociodemographic determinants of reportedly receiving advice about exercise from healthcare providers.</p><p><strong>Results: </strong>The sample included 1,836 breast cancer survivors. The median age of the sample was 76 years (range: 72-81). Overall, 10.7% of the survivors were non-Hispanic Black, 10.1% were Hispanic, and 69.3% were non-Hispanic White. Only 52.3% reported receiving advice about exercise from a healthcare provider. Higher body mass index (BMI) and comorbid medical history that included diabetes, cardiovascular, or musculoskeletal disease were each associated with a higher likelihood of receiving exercise advice. Lower education levels, lower BMI, and never having been married were each associated with a lower likelihood of receiving exercise advice.</p><p><strong>Conclusions: </strong>Nearly half of breast cancer survivors aged ≥65 years did not report receiving exercise advice from a healthcare provider, suggesting interventions are needed to improve exercise counseling between providers and survivors, especially with women with lower educational attainment who have never been married.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
FBLN2 is associated with basal cell markers Krt14 and ITGB1 in mouse mammary epithelial cells and has a preferential expression in molecular subtypes of human breast cancer. 在小鼠乳腺上皮细胞中,FBLN2 与基底细胞标志物 Krt14 和 ITGB1 相关,并在人类乳腺癌分子亚型中优先表达。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-07 DOI: 10.1007/s10549-024-07447-y
Amr Ahmed WalyEldeen, Salwa Sabet, Shady E Anis, Torsten Stein, Ayman M Ibrahim

Background: Fibulin-2 (FBLN2) is a secreted extracellular matrix (ECM) glycoprotein and has been identified in the mouse mammary gland, in cap cells of terminal end buds (TEBs) during puberty, and around myoepithelial cells during early pregnancy. It is required for basement membrane (BM) integrity in mammary epithelium, and its loss has been associated with human breast cancer invasion. Herein, we attempted to confirm the relevance of FBLN2 to myoepithelial phenotype in mammary epithelium and to assess its expression in molecular subtypes of human breast cancer.

Methods: The relationship between FBLN2 expression and epithelial markers was investigated in pubertal mouse mammary glands and the EpH4 mouse mammary epithelial cell line using immunohistochemistry, immunocytochemistry, and immunoblotting. Human breast cancer mRNA data from the METABRIC and TCGA datasets from Bioportal were analyzed to assess the association of Fbln2 expression with epithelial markers, and with molecular subtypes. Survival curves were generated using data from the METABRIC dataset and the KM databases.

Results: FBLN2 knockdown in mouse mammary epithelial cells was associated with a reduction in KRT14 and an increase in KRT18. Further, TGFβ3 treatment resulted in the upregulation of FBLN2 in vitro. Meta-analyses of human breast cancer datasets from Bioportal showed a higher expression of Fbln2 mRNA in claudin-low, LumA, and normal-like breast cancers compared to LumB, Her2 +, and Basal-like subgroups. Fbln2 mRNA levels were positively associated with mesenchymal markers, myoepithelial markers, and markers of epithelial-mesenchymal transition. Higher expression of Fbln2 mRNA was associated with better prognosis in less advanced breast cancer and this pattern was reversed in more advanced lesions.

Conclusion: With further validation, these observations may offer a molecular prognostic tool for human breast cancer for more personalized therapeutic approaches.

背景:Fibulin-2(FBLN2)是一种分泌型细胞外基质(ECM)糖蛋白,已在小鼠乳腺、青春期终末芽(TEB)的帽细胞和妊娠早期肌上皮细胞周围被发现。乳腺上皮基底膜(BM)的完整性需要它,它的缺失与人类乳腺癌的侵袭有关。在此,我们试图证实FBLN2与乳腺上皮细胞肌上皮表型的相关性,并评估其在人类乳腺癌分子亚型中的表达情况:方法:采用免疫组织化学、免疫细胞化学和免疫印迹法研究了青春期小鼠乳腺和EpH4小鼠乳腺上皮细胞系中FBLN2的表达与上皮标记物之间的关系。分析了来自生物门户网站 METABRIC 和 TCGA 数据集的人类乳腺癌 mRNA 数据,以评估 Fbln2 表达与上皮标志物以及分子亚型的关联。利用METABRIC数据集和KM数据库的数据生成了生存曲线:结果:在小鼠乳腺上皮细胞中敲除 FBLN2 与 KRT14 的减少和 KRT18 的增加有关。此外,TGFβ3处理导致体外FBLN2上调。对来自Bioportal的人类乳腺癌数据集进行的元分析表明,与LumB、Her2 +和基底样亚组相比,低Claudin、LumA和正常样乳腺癌中Fbln2 mRNA的表达量更高。Fbln2 mRNA水平与间质标志物、肌上皮标志物以及上皮-间质转化标志物呈正相关。在晚期乳腺癌中,Fbln2 mRNA的高表达与较好的预后有关,而在晚期病变中,这种模式发生了逆转:结论:随着进一步的验证,这些观察结果可能会为人类乳腺癌的分子预后提供一种工具,从而为更个性化的治疗方法提供依据。
{"title":"FBLN2 is associated with basal cell markers Krt14 and ITGB1 in mouse mammary epithelial cells and has a preferential expression in molecular subtypes of human breast cancer.","authors":"Amr Ahmed WalyEldeen, Salwa Sabet, Shady E Anis, Torsten Stein, Ayman M Ibrahim","doi":"10.1007/s10549-024-07447-y","DOIUrl":"10.1007/s10549-024-07447-y","url":null,"abstract":"<p><strong>Background: </strong>Fibulin-2 (FBLN2) is a secreted extracellular matrix (ECM) glycoprotein and has been identified in the mouse mammary gland, in cap cells of terminal end buds (TEBs) during puberty, and around myoepithelial cells during early pregnancy. It is required for basement membrane (BM) integrity in mammary epithelium, and its loss has been associated with human breast cancer invasion. Herein, we attempted to confirm the relevance of FBLN2 to myoepithelial phenotype in mammary epithelium and to assess its expression in molecular subtypes of human breast cancer.</p><p><strong>Methods: </strong>The relationship between FBLN2 expression and epithelial markers was investigated in pubertal mouse mammary glands and the EpH4 mouse mammary epithelial cell line using immunohistochemistry, immunocytochemistry, and immunoblotting. Human breast cancer mRNA data from the METABRIC and TCGA datasets from Bioportal were analyzed to assess the association of Fbln2 expression with epithelial markers, and with molecular subtypes. Survival curves were generated using data from the METABRIC dataset and the KM databases.</p><p><strong>Results: </strong>FBLN2 knockdown in mouse mammary epithelial cells was associated with a reduction in KRT14 and an increase in KRT18. Further, TGFβ3 treatment resulted in the upregulation of FBLN2 in vitro. Meta-analyses of human breast cancer datasets from Bioportal showed a higher expression of Fbln2 mRNA in claudin-low, LumA, and normal-like breast cancers compared to LumB, Her2 +, and Basal-like subgroups. Fbln2 mRNA levels were positively associated with mesenchymal markers, myoepithelial markers, and markers of epithelial-mesenchymal transition. Higher expression of Fbln2 mRNA was associated with better prognosis in less advanced breast cancer and this pattern was reversed in more advanced lesions.</p><p><strong>Conclusion: </strong>With further validation, these observations may offer a molecular prognostic tool for human breast cancer for more personalized therapeutic approaches.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endocrine therapy initiation among women diagnosed with ductal carcinoma in situ from 2001 to 2018. 2001年至2018年被诊断为导管原位癌的妇女开始接受内分泌治疗的情况。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-16 DOI: 10.1007/s10549-024-07453-0
Erin J Aiello Bowles, Cody Ramin, Jacqueline B Vo, Heather Spencer Feigelson, Jennifer C Gander, Lene H S Veiga, Clara Bodelon, Rochelle E Curtis, Carolyn Brandt, Amy Berrington de Gonzalez, Gretchen L Gierach

Purpose: Trials demonstrating benefits of tamoxifen for women with ductal carcinoma in situ (DCIS) were published > 20 years ago; yet subsequent uptake of endocrine therapy was low. We estimated endocrine therapy initiation in women with DCIS between 2001 and 2018 in a community setting, reflecting more recent years of diagnosis than previous studies.

Methods: This retrospective cohort included adult females ≥ 20 years diagnosed with first primary DCIS between 2001 and 2018, followed through 2019, and enrolled in one of three U.S. integrated healthcare systems. We collected data on endocrine therapy dispensings (tamoxifen, aromatase inhibitors [AIs]) from electronic pharmacy records within 12 months after DCIS diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated endocrine therapy initiation rates over time and by patient, tumor (including estrogen receptor [ER] status), and treatment characteristics.

Results: Among 2020 women with DCIS, 587 (29%) initiated endocrine therapy within 12 months after diagnosis (36% among 1208 women with ER-positive DCIS). Among women who used endocrine therapy, 506 (86%) initiated tamoxifen and 81 (14%) initiated AIs. Age-adjusted endocrine therapy initiation declined from 34 to 21% between 2001 and 2017; between 2015 and 2018, AI use increased from 8 to 35%. Women less likely to initiate endocrine therapy were ER-negative or had borderline/unknown or no ER test results, ≥ 65 years at diagnosis, Black, and received no radiotherapy.

Conclusion: One-third of women diagnosed with DCIS initiated endocrine therapy, and use decreased over time. Understanding why women eligible for endocrine therapy do not initiate is important to maximizing disease-free survival following DCIS diagnosis.

目的:20多年前发表的试验表明,他莫昔芬对患有乳腺导管原位癌(DCIS)的妇女有益;但随后内分泌治疗的接受率很低。我们估算了 2001 年至 2018 年期间在社区环境中患有 DCIS 的妇女开始接受内分泌治疗的情况,这反映了比以往研究更近的诊断年份:该回顾性队列包括 2001 年至 2018 年间确诊为首次原发性 DCIS 且年龄≥ 20 岁的成年女性,随访至 2019 年,并在美国三个综合医疗保健系统之一登记。我们从电子药房记录中收集了 DCIS 诊断后 12 个月内的内分泌治疗配药(他莫昔芬、芳香化酶抑制剂 [AIs])数据。我们使用具有对数链接和泊松分布的广义线性模型,估算了不同时期以及不同患者、肿瘤(包括雌激素受体[ER]状态)和治疗特征的内分泌治疗启动率:在2020名DCIS女性患者中,有587人(29%)在确诊后12个月内开始接受内分泌治疗(在1208名ER阳性DCIS女性患者中,这一比例为36%)。在使用内分泌治疗的女性中,506人(86%)开始使用他莫昔芬,81人(14%)开始使用人工合成药物。2001年至2017年间,年龄调整后的内分泌治疗启动率从34%降至21%;2015年至2018年间,人工智能的使用率从8%增至35%。不太可能启动内分泌治疗的女性为ER阴性或ER检测结果为边缘/未知或无ER检测结果、诊断时年龄≥65岁、黑人、未接受放疗:结论:三分之一确诊为DCIS的女性开始接受内分泌治疗,随着时间的推移,内分泌治疗的使用率有所下降。了解符合内分泌治疗条件的妇女为何不开始内分泌治疗,对于最大限度地提高DCIS确诊后的无病生存率非常重要。
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引用次数: 0
Polycystic ovary syndrome and risk of breast cancer in premenopausal and postmenopausal women: a nationwide population-based cohort study. 多囊卵巢综合征与绝经前和绝经后妇女罹患乳腺癌的风险:一项全国性人群队列研究。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-21 DOI: 10.1007/s10549-024-07467-8
Clarissa L B Frandsen, Bugge Nøhr, Mathilde Gottschau, Jakob H Viuff, Thomas Maltesen, Susanne K Kjær, Pernille F Svendsen, Allan Jensen

Purpose: Although some reproductive and metabolic characteristics of polycystic ovary syndrome (PCOS) are known risk factors for breast cancer, the evidence regarding a potential association between PCOS and breast cancer is scarce. In this population-based cohort study including all 1,719,452 women born in Denmark between 1940 and 1993, we investigated the association between PCOS and breast cancer.

Methods: PCOS diagnoses, cancer diagnoses, covariates, migrations, and vital status were all obtained from national population and health registers. Hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer overall and for histological subtypes separately were calculated based on adjusted cox proportional hazards models.

Results: During a median follow-up of 26 years, 63,078 women were diagnosed with breast cancer. We found an increased risk of breast cancer overall among women with PCOS compared with women without PCOS (HR: 1.21, 95% CI 1.02-1.44). In analyses stratified for menopausal status, the increased risk was restricted to postmenopausal women (HR: 1.63, 95% CI 1.23-2.15). The results for ductal and lobular histological subtypes analyses separately resembled those observed for breast cancer overall.

Conclusion: This is the first study to report an increased risk of breast cancer among women with a history of PCOS. The increased risk was seemingly confined to postmenopausal women. Our results therefore contribute to an increased knowledge of the etiology of breast cancer, but our findings should be further confirmed in other large cohort studies with an appropriately long follow-up period.

目的:虽然多囊卵巢综合征(PCOS)的一些生殖和代谢特征是乳腺癌的已知风险因素,但有关 PCOS 与乳腺癌之间潜在联系的证据却很少。在这项基于人群的队列研究中,我们调查了多囊卵巢综合征与乳腺癌之间的关系:PCOS 诊断、癌症诊断、协变量、迁移和生命状态均来自全国人口和健康登记。结果:在 26 年的中位随访期间,PCOS 与乳腺癌的关系发生了显著变化:在 26 年的中位随访期间,共有 63078 名妇女被诊断出患有乳腺癌。我们发现,与未患多囊卵巢综合征的女性相比,患有多囊卵巢综合征的女性罹患乳腺癌的风险总体上有所增加(HR:1.21,95% CI 1.02-1.44)。在根据绝经状况进行的分层分析中,风险增加仅限于绝经后妇女(HR:1.63,95% CI 1.23-2.15)。对导管和小叶组织学亚型的单独分析结果与对乳腺癌总体情况的分析结果相似:这是首个报告有多囊卵巢综合症病史的女性罹患乳腺癌风险增加的研究。结论:这是第一份关于有多囊卵巢综合症病史的女性患乳腺癌风险增加的研究报告,增加的风险似乎仅限于绝经后女性。因此,我们的研究结果有助于增加人们对乳腺癌病因的了解,但我们的研究结果应在其他大型队列研究中得到进一步证实,并进行适当的长期随访。
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引用次数: 0
Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study. 细胞周期蛋白依赖性激酶抑制剂后依维莫司加激素治疗的疗效;现实生活中的经验,一项TOG研究。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-08-09 DOI: 10.1007/s10549-024-07456-x
İsmail Beypınar, Hacer Demir, Şendağ Yaslıkaya, Tolga Köşeci, Bilgin Demir, Gökhan Çolak, Ahmet Burak Ağaoğlu, Mustafa Şahbazlar, Pervin Can Şancı, Devrim Çabuk, Ulaş Işık, Elif Şahin, Alper Coşkun, Burcu Caner, Talat Aykut, Mehmet Artaç, Mustafa Emre Duygulu, Nadiye Sever, Sıla Öksüz, Nedim Turan, Musa Barış Aykan, Esmanur Kaplan Tüzün, Mükremin Uysal, İrem Uğurlu, Abdullah Sakin, Caner Acar, Duygu Özaşkın, Teoman Şakalar, Merve Keskinkılıç, Tuğba Yavuzşen, Naziyet Köse, İsmail Ertürk, Nilgün Yıldırım, Onur Yazdan Balçık, Ali Alkan, Oğuzhan Selvi, Eda Erçin, Olçun Ümit Ünal, Cengiz Karaçin

Purpose: In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences.

Method: The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series.

Results: One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40 years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival.

Conclusion: This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment.

目的:对于晚期乳腺癌患者,如果没有内脏危机,内分泌治疗是首选。细胞周期蛋白依赖性激酶抑制剂(CDKi)是金标准。CDKi 治疗后后续治疗方法的选择仍存在争议,依维莫司(EVE)联合疗法的疗效尚不清楚。在这项研究中,我们旨在根据实际经验调查 CDKi 治疗后依维莫司(EVE)的疗效:研究收集了来自 26 个癌症中心的 208 名患者的数据。记录了患者的人口学和组织学特征、诊断、病情进展、最后就诊日期和毒性反应。本研究是一项回顾性病例系列研究:107 名患者接受了帕博西尼(palbociclib)治疗,101 名患者接受了作为 CDKi 的利博西尼(ribociclib)治疗。EVE组合的总体反应率和疾病控制率分别为60%和88%。在单变量分析中,无肝转移、年龄大于40岁、较好的反应类型以及CDKi后立即治疗与无进展生存期的延长有关。肝转移和反应类型与总生存期显著相关。在多变量分析中,反应对无进展生存期仍有重要影响,而反应类型、肝转移性疾病和血液毒性对总生存期有预后作用:结论:本研究为 CDKi 治疗后 EVE 联合用药的益处提供了证据。EVE联合疗法可能更适用于非肝转移患者,首次治疗反应显示了治疗的益处。此外,CDKi治疗后立即治疗比后期治疗更有益。
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引用次数: 0
Microcalcifications in benign breast biopsies: association with lesion type and risk. 良性乳腺活组织检查中的微钙化:与病变类型和风险的关系。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-04 DOI: 10.1007/s10549-024-07448-x
Sarah Schrup, Heather Hardway, Robert A Vierkant, Stacey J Winham, Matthew R Jensen, Bryan McCauley, Tanya Hoskin, Lisa Seymour, Denice Gehling, Jessica Fischer, Celine M Vachon, Santo Maimone, Laura Pacheco-Spann, Derek C Radisky, Jodi M Carter, Amy C Degnim, Mark E Sherman

Purpose: To characterize associations of microcalcifications (calcs) with benign breast disease lesion subtypes and assess whether tissue calcs affect risks of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC).

Methods: We analyzed detailed histopathologic data for 4,819 BBD biopsies from a single institution cohort (2002-2013) followed for DCIS or IBC for a median of 7.4 years for cases (N = 338) and 11.2 years for controls. Natural language processing was used to identify biopsies containing calcs based on pathology reports. Univariable and multivariable regression models were applied to assess associations with BBD lesion type and age-adjusted Cox proportional hazard regressions were performed to model risk of IBC or DCIS stratified by the presence or absence of calcs.

Results: Calcs were identified in 2063 (42.8%) biopsies. Calcs were associated with older age at BBD diagnosis (56.2 versus 49.0 years; P < 0.001). Overall, the risk of developing IBC or DCIS did not differ significantly between patients with calcs (HR 1.13, 95% CI 0.90, 1.41) as compared to patients without calcs. Stratification by BBD severity or subtype, age at BBD biopsy, outcomes of IBC versus DCIS, and mammography technique (screen-film versus full-field digital mammography) did not significantly alter association between calcs and risk.

Conclusion: Our analysis of calcs in BBD biopsies did not find a significant association between calcs and risk of breast cancer.

目的:描述微钙化(calcifications)与良性乳腺疾病病变亚型的关系,并评估组织钙化是否会影响导管原位癌(DCIS)和浸润性乳腺癌(IBC)的风险:我们分析了来自单个机构队列(2002-2013年)的4819例BBD活检的详细组织病理学数据,病例(N = 338)的DCIS或IBC随访中位数为7.4年,对照组为11.2年。根据病理报告,采用自然语言处理技术识别含有钙化物的活检样本。应用单变量和多变量回归模型评估与BBD病变类型的相关性,并进行年龄调整后的Cox比例危险回归,以根据是否存在钙化物对IBC或DCIS的风险进行分层建模:结果:在2063例(42.8%)活检中发现了钙化。钙化与BBD诊断年龄较大有关(56.2岁对49.0岁;P 结论:我们对BBD中的钙化进行了分析:我们对 BBD 活检组织中的钙化组织进行的分析并未发现钙化组织与乳腺癌风险之间存在显著关联。
{"title":"Microcalcifications in benign breast biopsies: association with lesion type and risk.","authors":"Sarah Schrup, Heather Hardway, Robert A Vierkant, Stacey J Winham, Matthew R Jensen, Bryan McCauley, Tanya Hoskin, Lisa Seymour, Denice Gehling, Jessica Fischer, Celine M Vachon, Santo Maimone, Laura Pacheco-Spann, Derek C Radisky, Jodi M Carter, Amy C Degnim, Mark E Sherman","doi":"10.1007/s10549-024-07448-x","DOIUrl":"10.1007/s10549-024-07448-x","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize associations of microcalcifications (calcs) with benign breast disease lesion subtypes and assess whether tissue calcs affect risks of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC).</p><p><strong>Methods: </strong>We analyzed detailed histopathologic data for 4,819 BBD biopsies from a single institution cohort (2002-2013) followed for DCIS or IBC for a median of 7.4 years for cases (N = 338) and 11.2 years for controls. Natural language processing was used to identify biopsies containing calcs based on pathology reports. Univariable and multivariable regression models were applied to assess associations with BBD lesion type and age-adjusted Cox proportional hazard regressions were performed to model risk of IBC or DCIS stratified by the presence or absence of calcs.</p><p><strong>Results: </strong>Calcs were identified in 2063 (42.8%) biopsies. Calcs were associated with older age at BBD diagnosis (56.2 versus 49.0 years; P < 0.001). Overall, the risk of developing IBC or DCIS did not differ significantly between patients with calcs (HR 1.13, 95% CI 0.90, 1.41) as compared to patients without calcs. Stratification by BBD severity or subtype, age at BBD biopsy, outcomes of IBC versus DCIS, and mammography technique (screen-film versus full-field digital mammography) did not significantly alter association between calcs and risk.</p><p><strong>Conclusion: </strong>Our analysis of calcs in BBD biopsies did not find a significant association between calcs and risk of breast cancer.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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