American Journal of Pathology最新文献_第10页

Hepatocyte-Specific Casein Kinase 1 Epsilon Ablation Ameliorates Metabolic Dysfunction–Associated Steatohepatitis by Up-Regulating Tumor Necrosis Factor Receptor–Associated Factor 3 in Mice 肝细胞特异性酪蛋白激酶 1 epsilon 消融可通过上调 TRAF3 改善小鼠代谢功能障碍相关性脂肪性肝炎。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-22 DOI: 10.1016/j.ajpath.2024.08.003

Mwense Leya , Hyuneui Jeong , Daram Yang , Tien Huyen Ton Nu Bao , Prakash Raj Pandeya , Sang-Ik Oh , Yoon-Seok Roh , Jong-Won Kim , Bumseok Kim

Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, phosphorylates a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction–associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1ε^ΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1ε^fl/fl) and Cre-expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1ε^ΔHEP was associated with a decreased severity of WD- or methionine- and choline-deficient diet–induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1ε^ΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1ε^ΔHEP WD-fed mice showed significantly down-regulated TNF receptor–associated factor (TRAF) 3, phosphorylated (p) transforming growth factor-β–activated kinase 1, p–TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid–induced steatohepatitis in vitro and attenuated WD-induced metabolic profile in vivo. In conclusion, CK1ε up-regulates TNF receptor–associated factor 3, which, in turn, causes transforming growth factor-β–activated kinase 1–dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction–associated steatotic liver disease.

众所周知，酪蛋白激酶 1 epsilon（CK1ε）是丝氨酸/苏氨酸蛋白激酶家族的成员，能使多种底物磷酸化。然而，它在慢性肝病发展过程中的作用仍然难以捉摸。本研究旨在探讨 CK1ε 在代谢功能障碍相关性脂肪性肝炎（MASH）的发生和发展过程中的作用。通过将CK1ε等位基因缺失的小鼠（CK1εfl/fl）与Cre表达的Albumin小鼠杂交，产生肝细胞特异性CK1ε基因敲除（CK1εΔHEP）小鼠。用西式饮食（WD）或蛋氨酸和胆碱缺乏（MCD）喂养小鼠以诱导 MASH。CK1εΔHEP与WD或MCD诱导的MASH严重程度的降低有关，这可以从肝脏病变发生率的降低以及丙氨酸氨基转移酶、天门冬氨酸氨基转移酶和促炎细胞因子TNF-α水平的显著降低得到证实。CK1εΔHEP WD喂养小鼠的总胆固醇、甘油三酯和新生脂质基因均有明显改善，表明CK1ε可影响脂质代谢。CK1εΔHEP WD饲养小鼠的TRAF3、磷酸化（p）TAK1、pTBK1和pAKT水平明显下调，从而影响了下游MAPK信号转导，这表明了所观察到的拯救作用的潜在机制。最后，用 PF670462 对 CK1ε 进行药理抑制可改善 PA 诱导的体外脂肪性肝炎，并减轻 WD 诱导的体内代谢特征。总之，CK1ε会上调TRAF3，进而引起TAK1依赖性信号转导，放大下游MAPK信号转导，改变p-c-Jun水平，加剧炎症，所有这些都是WD诱导MASLD的因素。

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引用次数: 0

Inhibition of the Sterol Regulatory Element Binding Protein SREBF-1 Overcomes Docetaxel Resistance in Advanced Prostate Cancer 抑制固醇调节元件结合蛋白（SREB-P）SREBF-1可克服晚期前列腺癌对多西他赛的耐药性。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-19 DOI: 10.1016/j.ajpath.2024.07.019

Maximilian P. Brandt , Olesya Vakhrusheva , Hubert Hackl , Tamas Daher , Katrin Tagscherer , Wilfried Roth , Igor Tsaur , Florian Handle , Andrea Eigentler , Zoran Culig , Christian Thomas , Holger H.H. Erb , Axel Haferkamp , Eva Jüngel , Martin Puhr

Resistance to antiandrogens and chemotherapy (Cx) limits therapeutic options for patients with metastatic hormone-sensitive (mHSPC) and metastatic castration-resistant (mCRPC) prostate cancer. In this context, up-regulation of the glucocorticoid receptor is identified as a potential bypass mechanism in mCRPC. A combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of the glucocorticoid receptor, re-sensitizes docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing was performed in docetaxel-resistant prostate cancer cell models after Doc + RU-486 treatment with consecutive functional assays. Expression of selected proteins was verified in prostatic tissue from prostate cancer patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability, and RNA sequencing revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly down-regulated target. Functional assays confirmed that SREBF-1 down-regulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacologic sterol regulatory element binding protein inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced prostate cancer tissues, showing its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represents a potential additive future therapeutic option to improve mCRPC therapy.

对抗雄激素和化疗（Cx）的抵抗限制了激素敏感性前列腺癌（mHSPC）和激素抵抗性前列腺癌（mCRPC）患者的治疗选择。在这种情况下，糖皮质激素受体（GR）的上调被认为是mCRPC的一种潜在旁路机制，多西他赛和GR抑制剂米非司酮（Doc + RU-486）的组合能使多西他赛耐药细胞模型对Cx重新敏感。本研究旨在阐明造成这种现象的分子机制。在多西他赛+RU-486治疗后，对多西他赛耐药的PCa细胞模型进行了RNA测序（RNA-seq），并进行了连续的功能测试。在疾病进展期前列腺癌（PCa）患者的前列腺组织中验证了所选蛋白质的表达。RNA-Seq发现，胆固醇和脂质生物合成的转录因子--固醇结合转录因子1（SREBF-1）是一个显著下调的靶点。功能测定证实，SREBF-1 的下调是造成这一观察结果的部分原因。同时，SREBF-1敲除和药理 SREBP 抑制以及胆固醇途径中的其他关键酶也显示出相似的结果。此外，SREBF-1 在晚期 PCa 组织中的表达明显升高，表明它可能参与了肿瘤的进展和新出现的耐药性。因此，对胆固醇和脂质生物合成的特异性抑制也可能针对Cx耐药的癌细胞，是未来改善mCRPC治疗的一种潜在附加治疗方案。

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引用次数: 0

Medulloblastomas Initiated by Homologous Recombination Defects in Mice 小鼠同源重组缺陷引发的髓母细胞瘤

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-19 DOI: 10.1016/j.ajpath.2024.07.018

Huimei Lu , Yuan Wang , Shipra Chaudhary , Varshita Balaga , Hua Ke , Fuqian Shi , Jingmei Liu , Yanying Huo , Peter J. Romanienko , Bing Xia , Subhajyoti De , Chang S. Chan , Zhiyuan Shen

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1^– and Bccip^– producing the worst defects. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip^– mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1^–, Palb2^–, and Brca2^– mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.

同源重组（HR）基因的种系突变是导致髓母细胞瘤的主要因素之一。相当一部分人类髓母细胞瘤表现出HR缺陷的基因组特征。我们的问题是，在小鼠大脑中消减Brca2、Palb2以及与之相关的Brca1和Bccip基因是否会以不同方式诱发髓母细胞瘤。我们建立了这些HR基因的条件性基因敲除小鼠模型，以及Bccip的条件性基因敲除（shBccip-KD）模型。任何一个基因的缺失都会导致小头畸形和神经系统缺陷，其中以Brca1和Bccip的缺失最为严重。Trp53共缺失能显著缓解Brca1、Palb2和Brca2缺失导致的小头畸形，但对Bccip-小鼠的影响有限。研究首次发现，用Trp53使Brca1或Palb2失活可诱发髓母细胞瘤。尽管shBccip-CKD具有高度穿透性，但Bccip/Trp53缺失不能诱发髓母细胞瘤。这些肿瘤显示出不同的免疫组化特征和染色体拷贝数变异。虽然细胞增殖通路广泛上调，但大多数肿瘤都表达了Sonic Hedgehog亚群的生物标志物。Brca1-、Palb2-和Brca2-小鼠的MB对PARP抑制剂高度敏感，而shBccip-CKD小鼠的MB则不敏感。我们的模型再现了髓母细胞瘤的自发发展过程，具有高穿透性和较窄的时间窗口，为测试治疗药物提供了理想的平台，这些药物能够区分HR缺陷和熟练的肿瘤。

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引用次数: 0

TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction–Associated Steatotic Liver Disease TRIM24 上调 ORM2，缓解阻塞性睡眠呼吸暂停综合征和代谢功能障碍相关脂肪肝小鼠的脂质代谢异常、炎症和氧化应激。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-19 DOI: 10.1016/j.ajpath.2024.07.020

Hui Zhang , Si Lei , Hui Zhuo , Yan Xu , Yun Ye , Yingquan Luo

Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). Tripartite motif containing 24 (TRIM24) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid–induced mouse liver cells served as an in vitro model. TRIM24 and HIF1A were up-regulated under the IH condition. HIF1A enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 up-regulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to ORM2 promoter. The cell rescue model was used to verify that ORM2 mediated the hepatoprotective effects of TRIM24. The current study reveals the important role of TRIM24 as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.

阻塞性睡眠呼吸暂停综合征（OSAS）与代谢功能障碍相关性脂肪性肝病（MASLD）的发生和发展有关。据报道，含三方基质 24（TRIM24）缺乏会导致肝脏脂质蓄积和肝炎。然而，TRIM24在OSAS和MASLD中的表达、功能和机制仍不清楚。通过间歇性缺氧（IH）和高脂饮食建立了 OSAS & MASLD 小鼠模型。IH和1%游离脂肪酸诱导的小鼠肝细胞作为体外模型。TRIM24和HIF-1α在IH条件下上调。HIF-1α增强了TRIM24的转录活性。在 OSAS 和 MASLD 小鼠中，过表达 TRIM24 可减少肝脏脂质积累，降低血清 TC、TG 和 LDL-C 水平，增加血清 HDL-C 水平。此外，TRIM24 的过表达还能缓解炎症、氧化应激和调节异常脂质代谢。在机制上，TRIM24通过与H3K27ac结合并招募RAR-α至ORM2启动子，上调了ORM2的表达，ORM2是肝脏脂肪生成的关键调节因子。细胞拯救模型验证了 ORM2 介导了 TRIM24 的保肝作用。我们的证据揭示了TRIM24作为转录的表观遗传共调控因子在OSAS和MASLD中的重要作用，为了解OSAS和MASLD的发病机制和预防其发展提供了新的视角。

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引用次数: 0

Immunoregulatory Properties of Immune Cells that Associate with the Lens Capsule Surface during Acute and Resolution Phases of Experimental Autoimmune Uveitis 实验性自身免疫性葡萄膜炎急性期和缓解期与晶状体囊表面结合的免疫细胞的免疫调节特性

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-17 DOI: 10.1016/j.ajpath.2024.07.021

Phuong M. Le , Mary J. Mattapallil , Rachel R. Caspi , Mary Ann Stepp , A. Sue Menko

Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)⁺CD4⁺] and M2 macrophages (CD68⁺ arginase 1⁺IL-10⁺), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule–associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.

眼部炎症受到严格调控，以防止视力受损和不可逆转的失明。新的证据表明，免疫细胞会在自身免疫性葡萄膜炎时被特异性地招募到晶状体囊，但它们在调节这种炎症性疾病中的潜在作用仍未得到探索。在这里，我们使用免疫定位方法结合高分辨率共聚焦显微镜，研究了在患有实验性自身免疫性葡萄膜炎（EAU）的C57BL/6J小鼠眼中，与晶状体囊稳定关联的免疫细胞是否具有免疫调节表型。这些研究发现，在葡萄膜炎的急性期，即诱发疾病后的第18天，特异性招募到晶状体囊的免疫细胞包括那些具有抗炎和促进溶解作用的免疫细胞，如调节性T细胞（FoxP3+CD4+）和M2巨噬细胞（CD68+Arg1+IL10+）。这些晶状体囊相关免疫调节表型的出现频率在诱导后第 35 天即 EAU 炎症消退阶段有所增加。在炎症消退的后期阶段，大多数巨噬细胞除了表达 Arg1 和 IL10 外，还表达负责清除炎症分子的甘露糖受体 CD206。我们的研究结果表明，晶状体是免疫细胞招募的场所，其作用是抑制炎症、促进缓解和维持EAU的缓解，而晶状体的这一作用此前尚不为人知。

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引用次数: 0

The Circadian Clock of Müller Glia Is Necessary for Retinal Homeostasis and Neuronal Survival Müller胶质细胞的昼夜节律对视网膜平衡和神经元存活至关重要

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-13 DOI: 10.1016/j.ajpath.2024.07.017

Lauren Pickel , Soo Jin Kim , Sabiha Hacibekiroglu , Andras Nagy , Junyeop Lee , Hoon-Ki Sung

Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. The current study indicated an age-dependent decline in circadian clock gene and protein expression in the human retina. An animal model of targeted Bmal1 deficiency was used to identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.

通过调节局部昼夜节律钟，全身的生物过程在时间上协调一致。视网膜是新陈代谢最活跃的组织之一，其需求在很大程度上取决于光/暗周期。已知啮齿类动物视网膜内的大多数细胞类型都能表达昼夜节律时钟，但人类视网膜时钟的表达以前尚未定位。此外，局部昼夜节律时钟功能障碍对视网膜稳态的影响尚不完全清楚。我们证明了人类视网膜中昼夜节律钟基因和蛋白质表达的下降与年龄有关。利用靶向 Bmal1 缺乏的动物模型，我们发现视网膜 Müller 胶质体的昼夜节律钟对神经元存活、血管完整性和视网膜功能至关重要。这些结果表明，视网膜 Müller 胶质中的局部昼夜节律钟在与年龄相关的视网膜疾病和视网膜退化中可能扮演着重要角色。

引用次数: 0

Intestinal Dysbacteriosis Contributes to Persistent Cognitive Impairment after Resolution of Acute Liver Failure 肠道菌群失调是急性肝衰竭缓解后认知功能持续受损的原因之一。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-13 DOI: 10.1016/j.ajpath.2024.07.014

Zhen Li , Tianning Sun , Zhigang He , Zhixiao Li , Jun Xiong , Hongbing Xiang

Regulating the gut microbiota alleviates hepatic encephalopathy (HE). Whether it is imperative to withhold treatment for microbial imbalance after liver functional recovery remains unclear. The aim of this work was to elucidate the alterations in cognitive behavior, liver function, synaptic transmission, and brain metabolites in acute liver failure (ALF) mice before and after hepatic function recovery. Towards this end, thioacetamide was injected intraperitoneally to establish an ALF mouse model, which induced HE. Hierarchical clustering analysis indicated that while the liver functions normalized, cognitive dysfunction and intestinal dysbacteriosis occurred in the ALF mice 14 days after thioacetamide injection. In addition, fecal microbiota transplantation from the ALF mice with liver function recovery induced liver injury and cognitive impairment. Alterations in synaptic transmission were found in the ALF mice with liver function improvement, and the correlations between the gut bacteria and synaptic transmission in the cortex were significant. Finally, apparent alterations in the brain metabolic profiles of the ALF mice were detected after liver function improvement by performing ¹H nuclear magnetic resonance spectroscopy, suggesting a risk of HE. These results showed that intestinal dysbacteriosis in ALF mice with liver function recovery is sufficient to induce liver injury and cognitive impairment. This indicates that continuous care may be necessary for monitoring microbial imbalance even in patients with ALF-induced HE whose liver function has recovered significantly.

调节肠道微生物群可缓解肝性脑病（HE）。目前仍不清楚肝功能恢复后是否必须暂停治疗微生物失衡。本研究旨在阐明急性肝衰竭（ALF）小鼠在肝功能恢复前后认知行为、肝功能、突触传递和脑代谢物的改变。本文通过腹腔注射硫代乙酰胺来建立ALF小鼠模型，从而诱导HE。通过分层聚类分析，我们发现注射硫代乙酰胺14天后，ALF小鼠的肝功能恢复正常，但出现认知功能障碍和肠道菌群失调。此外，肝功能恢复的 ALF 小鼠的粪便微生物群移植可诱发肝损伤和认知障碍。此外，我们还发现肝功能改善的ALF小鼠的突触传递发生了改变，而且肠道细菌与大脑皮层的突触传递之间存在显著的相关性。最后，我们通过1H核磁共振波谱检测发现，肝功能改善后的ALF小鼠大脑代谢谱发生了明显改变，这表明小鼠有患高血压的风险。这些结果表明，肝功能恢复后的 ALF 小鼠肠道菌群失调足以诱发肝损伤和认知障碍。这些结果表明，即使是肝功能已明显恢复的ALF诱导的肝损伤患者，也可能需要持续护理以监测微生物失衡。

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引用次数: 0

Differential Abundance of DNA Damage Sensors and Innate Immune Signaling Proteins in Inositol Polyphosphate 4-Phosphatase Type II–Negative Triple-Negative Breast Cancer Classified by Immunotype 按免疫类型分类的 INPP4B 阴性 TNBC 中 DNA 损伤传感器和先天免疫信号蛋白的丰度差异。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-13 DOI: 10.1016/j.ajpath.2024.07.015

F. Scott Heinemann , Paul D. Gershon

The influence of neoplastic cells on the tumor microenvironment is poorly understood. In this study, eight patient samples representing two immunotypes of triple-negative breast cancer (TNBC), defined by quantitative histologic criteria as T-cell desert and T-cell infiltrated (TCI), were compared via label-free quantitative protein mass spectrometry of material extracted directly from targeted regions of formalin-fixed, paraffin-embedded tissue sections. Of 2934 proteins quantitated, 439 were significantly differentially abundant, among which 361 were overabundant in TCI-TNBC. The 361-protein group included proteins involved in major histocompatibility complex-I antigen processing and presentation, viral defense, DNA damage response, and innate immune signaling. Immunohistochemical validation of selected proteins showed good positive correlation between neoplastic cell histoscores and label-free quantitation. Extension of immunohistochemical analysis to a total of 58 inositol polyphosphate 4-phosphatase type II–negative TNBC confirmed elevated levels of the DNA damage sensor interferon-γ–inducible protein 16, inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and pore-forming protein gasdermin D in TCI-TNBC neoplastic cells. By contrast, cGMP-AMP synthase inhibitor barrier to autointegration factor (BAF) was elevated in the neoplastic cells of T-cell desert TNBC. These findings demonstrate a previously unknown correlation between the degree of T-cell infiltration in inositol polyphosphate 4-phosphatase type II–negative TNBC and the levels, in cognate neoplastic cells, of proteins that modulate innate immune signaling in response to DNA damage.

人们对肿瘤细胞对肿瘤微环境的影响知之甚少。在这项研究中，通过对直接从福尔马林固定石蜡包埋组织切片的目标区域提取的材料进行无标记定量（LFQ）蛋白质质谱分析，比较了代表三阴性乳腺癌（TNBC）两种免疫类型的八个患者样本，这两种免疫类型被定量组织学标准定义为T细胞荒漠（TCD）和T细胞浸润（TCI）。在定量分析的 2,934 个蛋白质中，439 个蛋白质的含量存在显著差异，其中 361 个蛋白质在 TCI-TNBC 中含量过高。这361种蛋白质包括参与MHC-I抗原处理和呈递、病毒防御、DNA损伤反应和先天性免疫信号转导的蛋白质。对所选蛋白质进行的免疫组化（IHC）验证显示，肿瘤细胞组织评分与 LFQ 之间存在良好的正相关性。将 IHC 分析扩展到总共 58 个肌醇多磷酸酶 II 型（INPP4B）阴性 TNBC，证实了 TCI-TNBC 肿瘤细胞中 DNA 损伤传感器 IFI16、炎性体适配体 ASC 和孔形成蛋白 GSDMD 水平的升高。相比之下，TCD-TNBC 肿瘤细胞中的环 GMP-AMP 合成酶（cGAS）抑制剂 BAF 水平升高。这些发现表明，在 INPP4B 阴性 TNBC 中，T 细胞浸润程度与同种肿瘤细胞中调节先天性免疫信号以应对 DNA 损伤的蛋白质水平之间存在着一种以前未知的相关性。

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引用次数: 0

Growth Differentiation Factor 11 Evokes Lung Injury, Inflammation, and Fibrosis in Mice through the Activin A Receptor Type II-Like Kinase, 53kDa–Smad2/3 Signaling Pathway GDF11 通过 ALK5-Smad2/3 信号通路诱发小鼠肺损伤、炎症和纤维化。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-13 DOI: 10.1016/j.ajpath.2024.07.016

Qian Li, Hanchao Li, Li Zhu, Lijuan Zhang, Xiaoyan Zheng, Zhiming Hao

Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor beta superfamily and participates in various pathophysiological processes. Initially, GDF11 was suggested to act as a rejuvenator by improving age-related phenotypes of the heart, brain, and skeletal muscle in aged mice. Recent studies demonstrate that GDF11 also serves as an adverse risk factor for human frailty and diseases. However, the role of GDF11 in pulmonary fibrosis (PF) remains unclear. This study explored the role and signaling mechanisms of GDF11 in PF. GDF11 expression was markedly up-regulated in fibrotic lung tissues of both humans and mice. Intratracheal administration of commercial recombinant GDF11 caused lung injury, inflammation, and fibrogenesis in mice. Furthermore, adenovirus-mediated secretory expression of mature GDF11 was exacerbated, whereas full-length GDF11 or the GDF11 propeptide (GDF11_1-298) alleviated bleomycin-induced PF in mice. In in vitro experiments, GDF11 suppressed the growth of alveolar and bronchial epithelial cells (A549 and BEAS-2B) and human pulmonary microvascular endothelial cells, promoted fibroblast activation, and induced epithelial/endothelial-mesenchymal transition. These effects corresponded to the phosphorylation of Smad2/3, and blocking activin A receptor type II-like kinase, 53kDa (ALK5)-Smad2/3 signaling abolished the in vivo and in vitro effects of GDF11. In conclusion, these findings provide evidence that GDF11 acts as a potent injurious, proinflammatory, and profibrotic factor in the lungs via the ALK5-Smad2/3 pathway.

生长分化因子 11（GDF11）属于转化生长因子-β（TGF-β）超家族，参与各种病理生理过程。最初，GDF11 被认为能改善老年小鼠心脏、大脑和骨骼肌与年龄相关的表型，从而起到返老还童的作用。然而，最近的研究表明，GDF11 也是导致人类虚弱和疾病的不利风险因素。然而，GDF11在肺纤维化（PF）中的作用仍不清楚。本研究探讨了 GDF11 在肺纤维化中的作用和信号转导机制。我们发现，在人和小鼠的纤维化肺组织中，GDF11的表达均明显上调。气管内注射商品化重组 GDF11 会导致小鼠肺损伤、炎症和纤维化。此外，腺病毒介导的成熟 GDF11 的分泌表达会加剧小鼠的肺损伤，而全长 GDF11 或 GDF11 多肽（GDF111-298）则能缓解博莱霉素诱导的小鼠肺纤维化。体外实验表明，GDF11能抑制肺泡和支气管上皮细胞（A549和BEAS-2B）以及肺微血管内皮细胞（HPMVEC）的生长，促进成纤维细胞活化，并诱导上皮/内皮-间充质转化（EMT/EndoMT）。这些效应与 Smad2/3 的磷酸化相对应，阻断 ALK5-Smad2/3 信号转导可消除 GDF11 在体内和体外的效应。总之，我们的研究结果提供了证据，证明GDF11通过ALK5-Smad2/3通路在肺部起着强烈的损伤、促炎和促纤维化作用。

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引用次数: 0

The Impact of Generative Artificial Intelligence on the External Review of Scientific Manuscripts and Editorial Peer Review Processes 生成式人工智能对科学手稿外部评审和编辑同行评审流程的影响。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-10 DOI: 10.1016/j.ajpath.2024.08.002

Chhavi Chauhan , George Currie

引用次数: 0