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TRKing down drug resistance in NTRK fusion-positive cancers† 通过 TRK 降低 NTRK 融合阳性癌症的耐药性†。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-29 DOI: 10.1002/path.6341
Abigail G Parrish, Frank Szulzewsky

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.

在最近一期《病理学杂志》(The Journal of Pathology)上,Chen及其同事建立了新型NTRK融合阳性软组织肉瘤患者衍生体外模型,以研究酪氨酸激酶抑制剂靶向治疗的耐药机制。长期暴露于浓度不断升高的酪氨酸激酶抑制剂entrectinib,最终导致了耐药克隆的出现,这种耐药克隆在NF2基因中携带一种失活突变,而这种突变以前从未在这种情况下被描述过,同时伴随着PI3K/AKT/mTOR和Ras/Raf/MEK/ERK信号的增强。最后,通过抑制剂筛选发现,MEK 和 mTOR 抑制剂是潜在的联合用药。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain 神经生长因子诱导因子(VGF)是乳腺癌向脑部转移的分泌介质。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-29 DOI: 10.1002/path.6319
Rita Carvalho, Liliana Santos, Inês Conde, Ricardo Leitão, Hugo RS Ferreira, Célia Gomes, Ana Paula Silva, Fernando Schmitt, Carina Carvalho-Maia, João Lobo, Carmen Jerónimo, Joana Paredes, Ana Sofia Ribeiro

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells’ secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood–brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.

脑转移是乳腺癌(BC)进展过程中最严重的临床问题之一,与较低的生存率和缺乏有效疗法有关。因此,为了剖析脑转移过程的早期阶段,我们研究了脑器质性BC细胞分泌物对脑转移前生态位(PMN)建立的影响。我们发现,在体外和体内模型中,对大脑有特异性滋养作用的BC细胞会导致血脑屏障(BBB)严重破坏以及小胶质细胞活化。此外,我们还寻找了脑器质性转移特征,以此作为发现脑转移进展中新生物标志物的可能来源。与此相关的是,我们发现 VGF(神经生长因子诱导因子)是这一过程中的关键介质,在体外和体内也会影响 BBB 和小胶质细胞的功能。在一系列人类乳腺肿瘤中,VGF 在癌细胞和邻近基质中均有表达。重要的是,VGF 阳性的肿瘤预后明显较差,并与 HER2(人表皮生长因子受体 2)过表达和三阴性分子特征有关。在转移性 BC 病例的原发肿瘤中进行的进一步临床验证显示,VGF 与脑转移位置有显著关联,对脑转移 BC 患者的预后有明显影响。总之,我们的研究揭示了一种独特的对脑部有趋向性的 BC 分泌组特征,突出了 VGF 在这一过程中的关键介质作用。此外,其作为脑转移 BC 患者不良预后预测因子的特殊影响为靶向 VGF 控制脑转移疾病的进展开辟了新途径。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
The CCL2–CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop through glomerular macrophage and neutrophil infiltration in lupus nephritis CCL2-CCR2轴决定狼疮肾炎患者是通过肾小球巨噬细胞和中性粒细胞浸润形成肾小球内毛细血管高细胞性还是线环病变。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-26 DOI: 10.1002/path.6331
Takeshi Zoshima, Tomohisa Baba, Kimihiko Nakatani, Michio Nagata, Naofumi Mukaida, Mitsuhiro Kawano

The CCL2–CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2–CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2−/−) mice similarly observed in Ccr2−/− mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5−/− mice but not when only glomerular macrophage infiltration was inhibited in Ccr5−/− mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2−/− and Ccr2−/− mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2−/− mice. In conclusion, the CCL2–CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.

CCL2-CCR2轴参与了狼疮肾炎,但其在肾小球免疫复合物沉积后形成不同病理病变的机制中的确切作用仍然难以捉摸。此前,我们曾证实,在小鼠狼疮肾炎中,遗传性 CCR2 抑制诱导了组织学上从肾小球内毛细血管高细胞性到线环病变的转变。本研究旨在阐明 CCL2-CCR2 轴介导的细胞机制在这些不同病理病变的形成过程中的作用。我们将 MRL/lpr 小鼠衍生的单克隆 IgG3 抗体杂交瘤 2B11.3 或 B1 注入野生型(WT)小鼠体内,选择性地诱导肾小球毛细血管内皮细胞增生或线环病变。我们使用 RT 定量 PCR 和/或免疫荧光分析了趋化因子和趋化因子受体的表达。我们发现,2B11.3会导致WT小鼠肾小球内毛细血管过度细胞化,肾小球内会浸润大量表达CCR2的巨噬细胞和吞噬免疫复合物的中性粒细胞,而B1则会诱发线环病变。在肾小球内毛细血管细胞过多的情况下,CCL2 被确定为参与 CCR2 阳性细胞浸润的配体;它由肾小球内皮细胞和巨噬细胞表达。值得注意的是,在 CCL2 缺乏(Ccl2-/-)的小鼠中,2B11.3 诱导的肾小球毛细血管内皮细胞增生转变为线环状病变,肾小球巨噬细胞和中性粒细胞浸润减少,这与在 Ccr2-/-小鼠中观察到的情况类似。此外,当抗Ly6G抗体处理的Ccr5-/-小鼠的肾小球巨噬细胞和中性粒细胞浸润均受到抑制时,也能观察到这种组织学转换,但当Ccr5-/-小鼠的肾小球巨噬细胞浸润仅受到抑制或抗Ly6G抗体处理的WT小鼠的肾小球中性粒细胞浸润仅受到抑制时,则不能观察到这种组织学转换。相反,注射 B1 会导致 Ccl2-/- 和 Ccr2-/- 小鼠出现线环病变,这与在 WT 小鼠中观察到的结果相同。此外,在向 Ccr2-/-小鼠注射 B1 时,2B11.3 比 B1 更能诱导肾小球内皮细胞产生 CCL2。总之,CCL2-CCR2 轴通过调节肾小球吞噬细胞(巨噬细胞和中性粒细胞)的浸润,决定肾小球内毛细血管高细胞性或线环病变的发生。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation 对含有神经母细胞成分的合并梅克尔细胞癌的分析表明,梅克尔细胞癌中 T 抗原表达的缺失可能会导致细胞周期停滞和神经母细胞的转分化。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-25 DOI: 10.1002/path.6304
Thibault Kervarrec, Silke Appenzeller, Susanne Gramlich, Etienne Coyaud, Kamel Bachiri, Romain Appay, Nicolas Macagno, Anne Tallet, Christine Bonenfant, Yannick Lecorre, Jean Kapfer, Sami Kettani, Nalini Srinivas, Kuan Cheok Lei, Anja Lange, Jürgen C Becker, Eva Maria Sarosi, Hervé Sartelet, Andreas von Deimling, Antoine Touzé, Serge Guyétant, Mahtab Samimi, David Schrama, Roland Houben

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

梅克尔细胞癌(MCC)是一种侵袭性皮肤癌,常由梅克尔细胞多瘤病毒(MCPyV)基因组整合引起。MCPyV 阴性病例通常表现为合并 MCC,这是一个独特的肿瘤亚群,其特点是 MCC 与第二种肿瘤成分(主要是鳞状细胞癌)相关联。迄今为止,只有特殊病例报道过合并神经细胞分化的 MCC。在本文中,我们描述了另外两例伴有神经母细胞分化的合并 MCC,并对这些肿瘤进行了全面的形态学、免疫组织化学、转录组学、遗传学和表观遗传学特征描述,这两例肿瘤均发生于老年男性,表现为孤立的腹股沟腺病。显微镜检查发现,肿瘤呈双相,既有分化不良的高级别癌,也有分化不良的神经母细胞成分,但缺乏增殖迹象。免疫组化检查显示,MCC部分有角蛋白20和MCPyV T抗原(TA),而两个病例中的另一部分则被证实为神经母细胞分化。通过全外显子组分析,在两个合并肿瘤中分别发现了20个和14个共同的获得性点突变,由此可以推断这两个部分存在克隆关系。空间转录组学显示,神经母细胞部分的干细胞标志基因(如SOX2和MCM2)表达较低。有趣的是,虽然神经母细胞部分缺乏TA表达,但在两个肿瘤部分都观察到了相同的基因组MCPyV整合和相同的大T截断突变。鉴于有报道称 MCC 细胞系在 TA 受抑制时会发生神经元转分化,这两种 MCC/neuroblastic 合并肿瘤最有可能的情况是,神经母细胞转分化是由于 MCC 细胞中的一个亚群失去了 TA 的表达。事实上,DNA甲基化分析表明,MCC/神经母细胞瘤的合并细胞起源于MCC典型细胞。© 2024 作者。病理学杂志》由约翰威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
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引用次数: 0
TP53 mutations in urothelial carcinoma: not all one and the same† 尿路上皮癌中的 TP53 基因突变:不尽相同†。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-24 DOI: 10.1002/path.6335
Alexis R Barr, Amy Burley, Anna Wilkins

Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, et al reports that disruptive versus non-disruptive TP53 mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive TP53 tumour mutations had poor overall survival versus those with non-disruptive TP53 mutations or wild type TP53 but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8+ T-cell infiltration was seen in tumours with disruptive mutations. The impact of different TP53 mutations on prognosis and therapy choices appears to be tumour- and therapy-type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of TP53 mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of TP53 mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of TP53 mutations on other clinically important aspects of the tumour microenvironment, including cancer-associated fibroblasts. Furthermore, the impact of gain-of-function mutations in TP53 and other related genes signalling upstream or downstream of TP53 is of wide interest. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

近年来,尿路上皮癌的全身治疗方案不断扩大,免疫疗法和细胞毒性化疗都已广泛应用。然而,我们缺乏生物标志物来选择哪种药物对患者的疗效最好。金、徐、苏等人在本刊上发表的一篇新文章指出,TP53突变的破坏性与非破坏性可指导这些个性化疗法的选择。耐人寻味的是,与非破坏性TP53突变或野生型TP53相比,破坏性TP53肿瘤突变患者的总生存率较低,但对免疫疗法的反应特别好。与此相关的是,在具有破坏性突变的肿瘤中,肿瘤突变负荷增加,效应CD8+ T细胞浸润增加。不同的TP53突变对预后和治疗选择的影响似乎与肿瘤和治疗类型有关,对于突变类型导致的整体肿瘤表型还没有明确的共识。尽管如此,利用靶向测序或免疫组化技术分析特定类型的 TP53 突变在临床上越来越可行。目前迫切需要对尿路癌进行更多的研究,以明确如何最好地将肿瘤中出现的 TP53 突变类型用作预测性生物标记物。其他尚存的重要问题包括 TP53 突变对肿瘤微环境(包括癌症相关成纤维细胞)的其他临床重要方面的影响。此外,TP53和TP53上游或下游信号传递的其他相关基因的功能增益突变的影响也引起了广泛关注。© 2024 作者。病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。
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引用次数: 0
Histone demethylase PHF8 promotes prostate cancer metastasis via the E2F1–SNAI1 axis 组蛋白去甲基化酶PHF8通过E2F1-SNAI1轴促进前列腺癌转移
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-18 DOI: 10.1002/path.6325
Ze Wang, Peng Tang, Haiyang Xiao, Song Peng, Jian Chen, Yapeng Wang, Jing Xu, Qian Yan, Junying Zhang, Jie Deng, Qiang Ma, Hailin Zhu, Weiming Luo, Dianzheng Zhang, Luofu Wang, Jun Qin, Weihua Lan, Jun Jiang, Qiuli Liu

Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. © 2024 The Pathological Society of Great Britain and Ireland.

转移是导致包括前列腺癌在内的多种癌症死亡的罪魁祸首。尽管取得了很大进展,但前列腺癌转移的确切机制还远未完全阐明。通过使用Phf8基因敲除和未敲除的转基因小鼠前列腺癌模型(TRAMP),我们发现了PHF8在前列腺癌转移中的关键作用。通过与 E2F1 复合物,PHF8 以去甲基化依赖的方式转录上调 SNAI1。上调的 SNAI1 随后会促进上皮细胞向间质转化(EMT)和转移。鉴于异常激活的 PHF8/E2F1-SNAI1 轴在前列腺癌转移和不良预后中的作用,PHF8 的水平或该轴的活性可作为前列腺癌转移的生物标志物。此外,以该轴为靶点可能成为治疗前列腺癌的一种潜在策略。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease 肝脏腐胺水平升高是与代谢功能障碍相关性脂肪性肝病进展有关的一个新的潜在因素。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-18 DOI: 10.1002/path.6330
María Ángeles Núñez-Sánchez, María Antonia Martínez-Sánchez, Marta Sierra-Cruz, Ana Lambertos, Sara Rico-Chazarra, Alba Oliva-Bolarín, Andrés Balaguer-Román, José Enrique Yuste, Carlos Manuel Martínez, Adriana Mika, María Dolores Frutos, Camilo J Llamoza-Torres, José Córdoba-Chacón, Bruno Ramos-Molina

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

代谢功能障碍相关性脂肪性肝病(MASLD)是一种慢性肝病,通常会发展到晚期,如代谢功能障碍相关性脂肪性肝炎(MASH)。除肝脏脂肪变性外,MASH 还以炎症和肝细胞气球化为特征。尽管 MASH 在人群中的发病率相对较高,而且对人类健康有潜在的不利影响,但从病理生理学的角度来看,人们对这种肝病的了解仍不全面。在神经退行性疾病、炎症和癌症等各种病理情况中都发现了多胺水平的失调。然而,多胺通路在慢性肝脏疾病(如 MASLD)中的作用尚未得到探讨。在这项研究中,我们测定了肝脏鸟氨酸脱羧酶(ODC1)的表达(ODC1是负责产生腐胺的限速酶)以及肝脏中腐胺的水平。我们的研究结果表明,与对照组小鼠和非 MASH 患者相比,饮食诱导的 MASH 小鼠和活检证实的 MASH 患者的肝组织中,ODC1 的表达和腐胺酸的水平都有所升高,但亚精胺和精胺的水平却没有升高。此外,我们还发现腐胺酸水平与血清中较高的天冬氨酸氨基转移酶浓度和 SAF 评分(脂肪变性、活动性、纤维化)的增加呈正相关。此外,在使用人 HepG2 细胞进行的体外试验中,我们证明腐胺水平升高会加剧细胞对棕榈酸的反应,导致细胞活力下降和 CK-18 释放增加。我们的研究结果支持 ODC1 的表达与 MASLD 的进展之间存在关联,这可能对理解这种疾病的发病具有转化意义。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
Functional ex vivo DNA fibre assay to measure replication dynamics in breast cancer tissue 用于测量乳腺癌组织复制动态的功能性体内外 DNA 纤维测定。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-18 DOI: 10.1002/path.6328
Mengting Chen, Nathalie van den Tempel, Arkajyoti Bhattacharya, Shibo Yu, Bea Rutgers, Rudolf SN Fehrmann, Sander de Haas, Bert van der Vegt, Marcel ATM van Vugt

Replication stress (RS) is a key trait of cancer cells, and a potential actionable target in cancer treatment. Accurate methods to measure RS in tumour samples are currently lacking. DNA fibre analysis has been used as a common technique to measure RS in cell lines. Here, we investigated DNA fibre analysis on fresh breast cancer specimens and correlated DNA replication kinetics to known RS markers and genomic alterations. Fresh, treatment-naïve primary breast cancer samples (n = 74) were subjected to ex vivo DNA fibre analysis to measure DNA replication kinetics. Tumour cell proliferation was confirmed by EdU incorporation and cytokeratin AE1/AE3 (CK) staining. The RS markers phospho-S33-RPA and γH2AX and the RS-inducing proto-oncogenes Cyclin E1 and c-Myc were analysed by immunohistochemistry. Copy number variations (CNVs) were assessed from genome-wide single nucleotide polymorphism (SNP) arrays. We found that the majority of proliferating (EdU-positive) cells in each sample were CK-positive and therefore considered to be tumour cells. DNA fibre lengths varied largely in most tumour samples. The median DNA fibre length showed a significant inverse correlation with pRPA expression (r = −0.29, p = 0.033) but was not correlated with Cyclin E1 or c-Myc expression and global CNVs in this study. Nuclear Cyclin E1 expression showed a positive correlation with pRPA levels (r = 0.481, p < 0.0001), while cytoplasmic Cyclin E1 expression exhibited an inverse association with pRPA expression (r = −0.353, p = 0.002) and a positive association with global CNVs (r = 0.318, p = 0.016). In conclusion, DNA fibre analysis performed with fresh primary breast cancer samples is feasible. Fibre lengths were associated with pRPA expression. Cyclin E1 expression was associated with pRPA and the percentage of CNVs. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

复制压力(RS)是癌细胞的一个关键特征,也是癌症治疗的一个潜在可操作目标。目前还缺乏精确测量肿瘤样本中 RS 的方法。DNA 纤维分析是测量细胞系中 RS 的常用技术。在这里,我们研究了新鲜乳腺癌标本的 DNA 纤维分析,并将 DNA 复制动力学与已知的 RS 标记和基因组改变相关联。对未经治疗的新鲜原发性乳腺癌样本(n = 74)进行体外 DNA 纤维分析,以测量 DNA 复制动力学。通过EdU掺入和细胞角蛋白AE1/AE3(CK)染色确认肿瘤细胞的增殖。免疫组化分析了RS标记物phospho-S33-RPA和γH2AX以及RS诱导的原癌基因Cyclin E1和c-Myc。通过全基因组单核苷酸多态性(SNP)阵列评估了拷贝数变异(CNV)。我们发现,每个样本中大多数增殖(EdU 阳性)细胞都是 CK 阳性的,因此被认为是肿瘤细胞。大多数肿瘤样本的 DNA 纤维长度差异很大。DNA 纤维长度中位数与 pRPA 表达呈显著的反相关关系(r = -0.29,p = 0.033),但与细胞周期蛋白 E1 或 c-Myc 表达以及本研究中的全局 CNV 无关。核细胞周期蛋白 E1 表达与 pRPA 水平呈正相关(r = 0.481,p = 0.033)。
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引用次数: 0
Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma 多区域外显子组测序表明食管纺锤形细胞鳞状细胞癌起源于单克隆。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-18 DOI: 10.1002/path.6324
Yulu Wang, Qian Zhu, Yaqing Wu, Boyi Li, Xiaoxing Su, Chan Xiang, Yuchen Han

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK–RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

食管纺锤形细胞鳞状细胞癌(ESS)是一种罕见的双相肿瘤,由癌变成分(CaC)和肉瘤成分(SaC)组成。然而,ESS 的基因组起源和基因特征仍不清楚。通过对激光捕获显微切割(LCM)肿瘤样本进行全外显子组测序,我们确定CaC和SaC显示出高度的突变共性,具有相同的顶级高频突变基因、突变特征和肿瘤突变负荷;配对样本共享中位25.5%的突变位点。在染色体3q29、5p15.33和11q13.3上发现了灶性增益。改变的基因主要集中在RTK-RAS信号通路。系统发生树显示ESS起源于单克隆。主干中最常突变的癌基因是TP53,其次是NFE2L2、KMT2D和MUC16。CDC27、LRP2、APC和SNAPC4与预后相关。我们的数据突显了ESS的单克隆起源,TP53是一个强大的驱动癌基因,这表明新的靶向疗法和免疫疗法是治疗的选择。© 2024 大不列颠及爱尔兰病理学会。
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引用次数: 0
Disorganisation of basement membrane zone architecture impairs melanocyte residence in vitiligo 基底膜区结构的紊乱会影响白癜风中黑色素细胞的驻留。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2024-07-11 DOI: 10.1002/path.6321
Fei Yang, Lingli Yang, Yasutaka Kuroda, Sylvia Lai, Yoshito Takahashi, Tetsuya Sayo, Takeshi Namiki, Kimiko Nakajima, Shigetoshi Sano, Shintaro Inoue, Daisuke Tsuruta, Ichiro Katayama

The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

基底膜区是表皮和真皮之间的界面,它在多种皮肤病中受到破坏。在此,我们报告了对白癜风基底膜区的结构和分子因素进行全面研究的结果,白癜风是一种以皮肤色素脱失斑为特征的皮肤病。通过电子显微镜和免疫荧光染色,我们证实了人类白癜风皮肤基底膜区形态异常和基底膜区结构紊乱。此外,我们还发现人真皮成纤维细胞中基质金属蛋白酶 2 (MMP2) 的表达升高是导致基底膜区基质降解的关键因素。在我们的体外和体内模型中,成纤维细胞过量表达 MMP2 会导致基底膜区破坏和黑色素细胞消失。重要的是,我们发现白癜风中黑色素细胞的消失主要与它们对基底膜的粘附力减弱有关,这种粘附力是通过整合素β1和层粘连蛋白以及盘状蛋白结构域受体1和胶原蛋白IV之间的结合来介导的。最后,抑制基质金属蛋白酶 2 的表达可逆转小鼠白癜风模型中的脱色。总之,我们的研究显示了基底膜区完整性对黑色素细胞驻留的重要性,并为治疗干预提供了新的途径,以解决这一具有挑战性的皮肤问题。© 2024 作者。病理学杂志》由约翰威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
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引用次数: 0
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