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Efficacy of depatuxizumab mafodotin (ABT-414) in preclinical models of head and neck cancer. 德帕妥珠单抗马福多汀(ABT-414)在头颈癌临床前模型中的疗效。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae014
Lucas Mani, Abdullah Naveed, Ashtyn McAdoo, Eben Rosenthal, Marisa Hom

Epidermal growth factor receptor (EGFR) is highly expressed in 80-90% of head and neck squamous cell carcinomas (HNSCCs), making it an ideal target for antibody-drug conjugates. Depatuxizumab mafodotin (ABT-414), is an EGFR-targeting ADC comprised of the monoclonal antibody ABT-806 conjugated to monomethyl auristatin F, a tubulin polymerization inhibitor. This study assessed the in vivo efficacy of ABT-414 in HNSCC. The effects of ABT-414 on HNSCCs were determined using in vitro cytotoxicity assays and in vivo flank xenograft mouse models. The distribution of ABT-414 was assessed ex vivo via optical imaging methods using a conjugate of ABT-414 to the near-infrared agent IRDye800. In vitro treatment of high EGFR-expressing human HNSCC cell lines (UMSCC47 and FaDu) with ABT-414 (0-3.38 nM) resulted in dose-dependent cell death (IC50 values of 0.213 nM and 0.167 nM, respectively). ABT-414 treatment of the FaDu mouse xenografts displayed antitumor activity (P = 0.023) without a change in body mass (P = 0.1335), whereas treatment of UMSCC47 did not generate a significant response (P = 0.1761). Fluorescence imaging revealed ABT-414-IRDye800 accumulation in the tumors of both FaDu and UMSCC47 cell lines, with a signal-to-background ratio of >10. ABT-414 treatment yielded antitumor activity in FaDu tumors, but not in UMSCC47, highlighting the potential for ABT-414 efficacy in high EGFR-expressing tumors. Although ABT-414-IRDye800 localized tumors in both cell lines, the differing antitumor responses highlight the need for further investigation into the role of the tumor microenvironment in drug delivery.

表皮生长因子受体(EGFR)在80-90%的头颈部鳞状细胞癌(HNSCC)中高度表达,因此成为抗体药物共轭物(ADC)的理想靶点。Depatuxizumab mafodotin(ABT-414)是一种表皮生长因子受体靶向ADC,由单克隆抗体(mAb)ABT-806与单甲基auristatin F(一种微管蛋白聚合抑制剂)结合而成。本研究评估了ABT-414在HNSCC中的体内疗效。ABT-414对HNSCC的影响是通过体外细胞毒性试验和体内侧腹异种移植小鼠模型确定的。利用ABT-414与近红外药剂IRDye800的共轭物,通过光学成像方法评估了ABT-414在体内外的分布情况。用ABT-414(0-3.38 nM)体外处理高表皮生长因子受体表达的人类HNSCC细胞系(UMSCC47和FaDu)会导致剂量依赖性细胞死亡(IC50值分别为0.213 nM和0.167 nM)。ABT-414治疗FaDu小鼠异种移植显示了抗肿瘤活性(p= 0.023),但体重没有变化(p= 0.1335),而治疗UMSCC47则没有产生显著反应(p= 0.1761)。荧光成像显示,ABT-414-IRDye800在FaDu和UMSCC47细胞系的肿瘤中均有积累,信噪比大于10。ABT-414治疗在FaDu肿瘤中产生了抗肿瘤活性,但在UMSCC47中却没有,这凸显了ABT-414在表皮生长因子受体高表达肿瘤中的潜在疗效。虽然ABT-414-IRDye800在两种细胞系中都能定位肿瘤,但不同的抗肿瘤反应突显了进一步研究肿瘤微环境在给药中的作用的必要性。
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引用次数: 0
Long non-coding RNA KB-1460A1.5 promotes ferroptosis by inhibiting mTOR/SREBP-1/SCD1-mediated polyunsaturated fatty acid desaturation in glioma. 长非编码RNA KB-1460A1.5通过抑制胶质瘤中mTOR/SREBP-1/SCD1介导的多不饱和脂肪酸脱饱和来促进铁变态反应。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae016
Lixia Xu, Binli Wen, Qiaoli Wu, Shan Lu, Jianwen Liao, Lidong Mo, Qingguo Li, Xiaoguang Tong, Hua Yan

Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.

铁氧化是一种新的细胞调节性死亡形式,由磷脂的铁依赖性过氧化引起,与细胞代谢、氧化还原平衡和与癌症相关的各种信号通路有关。长非编码 RNA(lncRNA)KB-1460A1.5 作为抑癌基因调控胶质瘤的肿瘤生长,但其分子网络调控机制尚不清楚。本研究发现,KB-1460A1.5能诱导胶质瘤的铁突变,并提高胶质瘤对铁突变诱导剂RSL3的敏感性。TMT蛋白质组学和非靶向代谢组学表明,KB-1460A1.5会影响多不饱和脂肪酸的代谢过程。基于 GC-MS 的中链和长链脂肪酸靶向代谢组学证实,上调 KB-1460A1.5 会降低胶质瘤细胞中单不饱和脂肪酸 (MUFA)、油酸 (OA) 和棕榈油酸 (PO) 的水平。加入油酸和棕榈油酸后,KB-1460A1.5 诱导的细胞铁变态反应得以恢复。分子方面,KB-1460A1.5 可抑制 mTOR 信号通路,从而抑制下游固醇调节元件结合蛋白 1(SREBP-1)的表达,从而减弱硬脂酰-CoA 去饱和酶-1(SCD1)介导的多不饱和脂肪酸的去饱和作用。最后,皮下胶质瘤动物模型证实,KB-1460A1.5 可抑制肿瘤进展、SREBP1/SCD1 的表达和铁变态反应。总之,提高KB-1460A1.5在胶质瘤中的表达水平可通过SREBP1/SCD1介导的脂肪生成,促进诱导癌细胞的氧化应激和铁变态反应,在临床前模型中显示出治疗潜力。
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引用次数: 0
CYR61 confers chemoresistance by upregulating survivin expression in triple-negative breast cancer. CYR61通过上调三阴性乳腺癌中存活素的表达而产生化疗耐药性。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae013
Hyungjoo Kim, Seogho Son, Yunhyo Ko, Hogeun Lim, Joohyung Lee, Kyung-Min Lee, Incheol Shin

Cysteine-rich angiogenic inducer 61 (CYR61) is a protein from the CCN family of matricellular proteins that play diverse regulatory roles in the extracellular matrix. CYR61 is involved in cell adhesion, migration, proliferation, differentiation, apoptosis, and senescence. Here, we show that CYR61 induces chemoresistance in triple-negative breast cancer (TNBC). We observed that CYR61 is overexpressed in TNBC patients, and CYR61 expression correlates negatively with the survival of patients who receive chemotherapy. CYR61 knockdown reduced cell migration, sphere formation and the cancer stem cell (CSC) population and increased the chemosensitivity of TNBC cells. Mechanistically, CYR61 activated Wnt/β-catenin signaling and increased survivin expression, which are associated with chemoresistance, the epithelial-mesenchymal transition, and CSC-like phenotypes. Altogether, our study demonstrates a novel function of CYR61 in chemotherapy resistance in breast cancer.

富半胱氨酸血管生成诱导剂 61(CYR61)是一种属于 CCN 家族的基质蛋白,在细胞外基质中发挥着多种调节作用。CYR61 参与细胞粘附、迁移、增殖、分化、凋亡和衰老。在这里,我们发现 CYR61 会诱导三阴性乳腺癌(TNBC)的化疗耐药性。我们观察到 CYR61 在 TNBC 患者中过表达,而且 CYR61 的表达与接受化疗的患者的生存率呈负相关。敲除 CYR61 可减少细胞迁移、球体形成和癌症干细胞(CSC)数量,并增加 TNBC 细胞的化疗敏感性。从机理上讲,CYR61激活了Wnt/β-catenin信号转导并增加了survivin的表达,这与化疗耐药性、上皮-间质转化和CSC样表型有关。总之,我们的研究证明了 CYR61 在乳腺癌化疗耐药性中的新功能。
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引用次数: 0
Unfurling the functional association between long intergenic noncoding RNAs (lincRNAs) and HPV16-related cervical cancer pathogenesis through weighted gene co-expression network analysis of differentially expressed lincRNAs and coding genes. 通过对差异表达的长基因间非编码RNA(lincRNA)和编码基因进行加权基因共表达网络分析,揭示长基因间非编码RNA(lincRNA)与HPV16相关宫颈癌发病机制之间的功能性关联。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae019
Abarna Sinha, Sahana Ghosh, Abhisikta Ghosh, Arnab Ghosh, Sonia Mathai, Jaydip Bhaumik, Asima Mukhopadhyay, Arindam Maitra, Nidhan K Biswas, Sharmila Sengupta

Long intergenic noncoding RNAs (lincRNAs) do not overlap annotated coding genes and are located in intergenic regions, as opposed to antisense and sense-intronic lncRNAs, located in genic regions. LincRNAs influence gene expression profiles and are thereby key to disease pathogenesis. In this study, we assessed the association between lincRNAs and HPV16-positive cervical cancer (CaCx) pathogenesis using weighted gene co-expression network analysis (WGCNA) with coding genes, comparing differentially expressed lincRNA and coding genes (DElincGs and DEcGs, respectively) in HPV16-positive patients with CaCx (n = 44) with those in HPV-negative healthy individuals (n = 34). Our analysis revealed five DElincG modules, co-expressing and correlating with DEcGs. We validated a substantial number of such module-specific correlations in the HPV16-positive cancer TCGA-CESC dataset. Four such modules, displayed significant correlations with patient traits, such as HPV16 physical status, lymph node involvement and overall survival (OS), highlighting a collaborative effect of all genes within specific modules on traits. Using the DAVID bioinformatics knowledgebase, we identified the underlying biological processes associated with these modules as cancer development and progression-associated pathways. Next, we identified the top 10 DElincGs with the highest connectivity within each functional module. Focusing on the prognostic module hub genes, downregulated CTD-2619J13.13 expression was associated with poor patient OS. This lincRNA gene interacted with 25 coding genes of its module and was associated with such biological processes as keratinization loss and keratinocyte differentiation, reflecting severe disease phenotypes. This study has translational relevance in fighting various cancers with high mortality rates in underdeveloped countries.

长基因间非编码 RNA(lincRNA)与注释的编码基因不重叠,位于基因间区域,而反义和有义内切 lncRNA 则位于基因区域。LincRNA 影响基因表达谱,因此是疾病发病机制的关键。在这项研究中,我们利用加权基因共表达网络分析(WGCNA)评估了LincRNA与HPV16阳性宫颈癌(CaCx)发病机制之间的关联,比较了HPV16阳性宫颈癌患者(44人)与HPV阴性健康人(34人)中差异表达的LincRNA和编码基因(分别为DElincGs和DEcGs)。我们的分析揭示了与 DEcGs 共同表达和相关的五个 DElincG 模块。我们在 HPV16 阳性癌症 TCGA-CESC 数据集中验证了大量此类特定模块的相关性。其中四个模块与患者的特征(如 HPV16 物理状态、淋巴结受累和总生存率(OS))有明显的相关性,突显了特定模块内的所有基因对特征的协同作用。利用 DAVID 生物信息学知识库,我们将与这些模块相关的潜在生物过程确定为癌症发展和进展相关通路。接下来,我们确定了每个功能模块中连接性最高的前 10 个 DElincGs。以预后模块枢纽基因为重点,CTD-2619J13.13表达下调与患者不良的OS有关。该lincRNA基因与其模块中的25个编码基因相互作用,与角质化丧失和角质细胞分化等生物过程相关,反映了严重的疾病表型。这项研究对不发达国家抗击高死亡率的各种癌症具有转化意义。
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引用次数: 0
LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism. LMO3 是基底样/鳞状亚型的抑制因子,通过甘油-3-磷酸代谢降低胰腺癌的侵袭性。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae011
Yuuki Ohara, Amanda J Craig, Huaitian Liu, Shouhui Yang, Paloma Moreno, Tiffany H Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, Stefan Ambs, S Perwez Hussain

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

胰腺导管腺癌(PDAC)包含多种分子亚型,包括经典/原发亚型和基底样/鳞状亚型,每种亚型都表现出不同的特征,其中基底样/鳞状亚型以其侵袭性著称。我们采用了一种结合转录组和代谢组分析的综合方法,以确定导致基底样/鳞状亚型分化的潜在基因。将这种方法应用于我们的 NCI-UMD-German 和一个验证队列,我们发现 LIM Domain Only 3(LMO3)(一种转录辅助因子)是基底样/鳞状亚型的候选抑制因子。LMO3 表达的降低与病理分级升高、疾病分期晚期、基底样/鳞状亚型的诱导以及 PDAC 患者生存率的降低有显著相关性。体外实验表明,LMO3转基因表达抑制了PDAC细胞的增殖和迁移/侵袭,同时下调了基底样/鳞状细胞基因特征。对患者肿瘤和 PDAC 细胞的代谢组分析表明,代谢程序与 LMO3 的升高和经典/原癌基因亚型有关,其特点是脂肪生成增强和氨基酸代谢受抑制。值得注意的是,甘油-3-磷酸(G3P)水平与LMO3的表达呈正相关,并与患者生存率的提高有关。此外,甘油-3-磷酸脱氢酶1(GPD1)是合成G3P的关键酶,在LMO3高表达和经典/原发PDAC中显示出上调,表明其在减轻疾病侵袭性方面的潜在作用。总之,我们的研究结果表明,LMO3表达的增加降低了转录组和代谢组的特征,表明基底样/鳞状肿瘤的特征,降低了PDAC患者疾病的侵袭性。这些观察结果表明,LMO3 是 PDAC 诊断和治疗的候选靶点。
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引用次数: 0
Long noncoding RNA XIST: a novel independent prognostic biomarker for patients with ABC-DLBCL receiving R-CHOP treatment. 长非编码 RNA XIST:接受R-CHOP治疗的ABC-DLBCL患者的一种新的独立预后生物标志物。
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-07-08 DOI: 10.1093/carcin/bgae017
Han-Bing Li, Di Wang, Yue Zhang, Di Shen, Yi-Qun Che

Approximately one-third of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cases were unresponsive to standard first-line therapy; thus, identifying biomarkers to evaluate therapeutic efficacy and assessing the emergence of drug resistance is crucial. Through early-stage screening, long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) was found to be correlated with the R-CHOP treatment response. This study aimed to clarify the characteristics of XIST in ABC-DLBCL. The expression level of XIST in 161 patients with ABC-DLBCL receiving R-CHOP therapy was examined via RNA in situ hybridization, and the association between XIST expression and clinicopathological features, treatment response and prognosis was analyzed in the study cohort and validated in the Gene Expression Omnibus cohort. Cell biological experiments and bioinformatics analyses were conducted to reveal aberrant signaling. The proportion of complete response in patients with high XIST expression was lower than that in patients with low XIST expression (53.8% versus 77.1%) (P = 0.002). High XIST expression was remarkably associated with the characteristics of tumor progression and was an independent prognostic element for overall survival (P = 0.039) and progression-free survival (P = 0.027) in ABC-DLBCL. XIST was proven to be involved in m6A-related methylation and ATF6-associated autophagy. XIST knockdown repressed ABC-DLBCL cellular proliferation by regulating Raf/MEK/ERK signaling. High XIST expression was associated with ABC-DLBCL tumorigenesis and development and contributed to R-CHOP treatment resistance. XIST may be a promising signal to predict ABC-DLBCL prognosis.

大约三分之一的活化B细胞样弥漫大B细胞淋巴瘤(ABC-DLBCL)病例对标准一线疗法无反应;因此,确定生物标志物以评估疗效和耐药性的出现至关重要。通过早期筛选,发现长非编码RNA(lncRNA)X-非活性特异性转录本(XIST)与R-CHOP治疗反应相关。本研究旨在明确XIST在ABC-DLBCL中的特征。通过RNA原位杂交检测了161名接受R-CHOP治疗的ABC-DLBCL患者的XIST表达水平,分析了XIST表达与临床病理特征、治疗反应和预后之间的关联,并在基因表达总库队列中进行了验证。研究还进行了细胞生物学实验和生物信息学分析,以揭示异常信号转导。XIST高表达患者的完全应答比例低于XIST低表达患者(53.8%对77.1%)(P = 0.002)。在ABC-DLBCL中,XIST高表达与肿瘤进展特征显著相关,是总生存期(P = 0.039)和无进展生存期(P = 0.027)的独立预后要素。XIST被证明参与了m6A相关甲基化和ATF6相关自噬。通过调节Raf/MEK/ERK信号传导,敲除XIST抑制了ABC-DLBCL细胞增殖。XIST的高表达与ABC-DLBCL的肿瘤发生和发展有关,并导致R-CHOP治疗耐药。XIST可能是预测ABC-DLBCL预后的一个有希望的信号。
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引用次数: 0
Genomic and transcriptomic significance of multiple primary lung cancers detected by next-generation sequencing in clinical settings. 临床环境中通过新一代测序检测到的多发性原发性肺癌的基因组和转录组意义。
IF 4.7 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-10 DOI: 10.1093/carcin/bgae026
Meihong Yao, Hu Chen, Zui Chen, Yingying Wang, Dongliang Shi, Dan Wu, Wen Li, Jianping Huang, Guizhen Chen, Qiaoling Zheng, Zhengtao Ye, Chenxin Zheng, Yinghong Yang

Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., P < 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., P < 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (P < 0.0001). Additionally, NECTIN4 (P < 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.

有效诊断和了解多发性原发性肺癌(MPLC)肺内转移(IM)的机制有助于临床治疗。然而,临床上实际使用的检测面板各不相同。目前对多发性肺癌和肺内转移的肿瘤微环境(TME)研究尚不充分。因此,对这两种疾病的鉴别诊断和肿瘤微环境差异进行更多调查至关重要。研究人员招募了 214 名患有多种肿瘤的非小细胞肺癌患者,并对 507 份样本进行了 DNA 测序(NGS 10)。然后,对 32 名患者的标本进行了 DNA 和 RNA 测序(master panel),比较了每位患者肿瘤之间和不同患者肿瘤之间的 TME 图谱以及差异表达基因。4 名患者根据 NGS 10 结果重新分组。主小组解决了 6 例未确定患者的分类问题。MPLC的TME表现出自然杀伤(NK)细胞、CD56dim NK细胞、内皮细胞等的高度浸润,P<0.05。相反,B 细胞、活化的 B 细胞、调节细胞、未成熟树突状细胞等(P < 0.001)在 IM 中大量浸润。NECTIN4和LILRB4 mRNA在MPLC中下调(P<0.0001)。此外,NECTIN4(P<0.05)和LILRB4与MPLC无病生存率的提高有关。总之,IM 可通过病理联合 NGS 10 次检测从 MPLC 中筛选出来,然后对无法区分的患者进行大样本 NGS 检测。MPLC的优越预后可能与免疫激活的TME以及作为潜在药物治疗靶点的NECTIN4和LILRB4的下调有关。
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引用次数: 0
The BET inhibitor GNE-987 effectively induces anti-cancer effects in T-cell acute lymphoblastic leukemia by targeting enhancer regulated genes. BET 抑制剂 GNE-987 通过靶向增强子调控基因,有效诱导 T 细胞急性淋巴细胞白血病的抗癌作用。
IF 4.7 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-10 DOI: 10.1093/carcin/bgae006
Juanjuan Yu, Yang Yang, Rongfang Zhou, Yanfang Tao, Frank Zhu, Wanyan Jiao, Zimu Zhang, Tongting Ji, Tiandan Li, Fang Fang, Yi Xie, Di Wu, Ran Zhuo, Xiaolu Li, Yanling Chen, Hongli Yin, Jianwei Wang, Jian Pan

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy originating from T progenitor cells. It accounts for 15% of childhood and 25% of adult ALL cases. GNE-987 is a novel chimeric molecule developed using proteolysis-targeting chimeras (PROTAC) technology for targeted therapy. It consists of a potent inhibitor of the bromodomain and extraterminal (BET) protein, as well as the E3 ubiquitin ligase Von Hippel-Lindau (VHL), which enables the effective induction of proteasomal degradation of BRD4. Although GNE-987 has shown persistent inhibition of cell proliferation and apoptosis, its specific antitumor activity in T-ALL remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antitumor effect of GNE-987 in T-ALL. To achieve this, we employed technologies including RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and CUT&Tag. The degradation of BET proteins, specifically BRD4, by GNE-987 has a profound impact on T-ALL cell. In in vivo experiments, sh-BRD4 lentivirus reduced T-ALL cell proliferation and invasion, extending the survival time of mice. The RNA-seq and CUT&Tag analyses provided further insights into the mechanism of action of GNE-987 in T-ALL. These analyses revealed that GNE-987 possesses the ability to suppress the expression of various genes associated with super-enhancers (SEs), including lymphoblastic leukemia 1 (LCK). By targeting these SE-associated genes, GNE-987 effectively inhibits the progression of T-ALL. Importantly, SE-related oncogenes like LCK were identified as critical targets of GNE-987. Based on these findings, GNE-987 holds promise as a potential novel candidate drug for the treatment of T-ALL.

T 细胞急性淋巴细胞白血病(T-ALL)是一种高度侵袭性的血液恶性肿瘤,起源于 T 祖细胞。它占儿童 ALL 病例的 15%,占成人 ALL 病例的 25%。GNE-987 是一种新型嵌合分子,采用蛋白水解靶向嵌合体 (PROTAC) 技术开发,用于靶向治疗。它是一种强效的溴化多聚酶域和外膜(BET)蛋白抑制剂,同时也是E3泛素连接酶Von Hippel-Lindau(VHL)的抑制剂,能有效诱导蛋白酶体降解BRD4。虽然GNE-987对细胞增殖和凋亡有持续抑制作用,但其在T-ALL中的特异性抗肿瘤活性仍不明确。本研究旨在探讨 GNE-987 在 T-ALL 中抗肿瘤作用的分子机制。为此,我们采用了RNA测序(RNA-seq)、染色质免疫沉淀测序(ChIP-seq)和CUT&Tag等技术。GNE-987对BET蛋白(尤其是BRD4)的降解对T-ALL细胞产生了深远的影响。在体内实验中,sh-BRD4慢病毒减少了T-ALL细胞的增殖和侵袭,延长了小鼠的存活时间。RNA-seq和CUT&Tag分析进一步揭示了GNE-987在T-ALL中的作用机制。这些分析表明,GNE-987能够抑制与超增强子(SE)相关的各种基因的表达,包括淋巴细胞白血病1(LCK)。通过靶向这些SE相关基因,GNE-987能有效抑制T-ALL的进展。重要的是,LCK 等 SE 相关致癌基因被确定为 GNE-987 的关键靶点。基于这些发现,GNE-987有望成为治疗T-ALL的新型候选药物。
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引用次数: 0
Dietary phytoestrogen intake and ovarian cancer risk: a prospective study in the prostate, lung, colorectal and ovarian (PLCO) cohort. 膳食植物雌激素摄入量与卵巢癌风险:前列腺、肺、结直肠和卵巢 (PLCO) 队列的前瞻性研究。
IF 4.7 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-10 DOI: 10.1093/carcin/bgae015
Yizuo Song, Huijun Huang, Mingmin Jin, Binwei Cheng, Shanshan Wang, Xinjun Yang, Xiaoli Hu

Estrogen plays a crucial role in ovarian tumorigenesis. Phytoestrogens (PEs) are a type of daily dietary nutrient for humans and possess a mild estrogenic characteristic. This study aimed to assess the correlation of the consumption of dietary PEs with ovarian cancer risk using data in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Participants were enrolled in PLCO from 1993 to 2001. Hazard ratios (HR) and 95% confidence intervals (CI) were utilized to determine the association between the intake of PEs and ovarian cancer occurrence, which were calculated by the Cox proportional hazards regression analysis. In total, 24 875 participants were identified upon completion of the initial dietary questionnaire (DQX). Furthermore, the analysis also included a total of 45 472 women who filled out the diet history questionnaire (DHQ). Overall, after adjustment for confounders, the dietary intake of total PEs was significantly associated with the risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.69, 95% CI: 0.50-0.95; P for trend = 0.066). Especially, individuals who consumed the highest quartile of isoflavones were found to have a decreased risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.68, 95% CI: 0.50-0.94; P for trend = 0.032). However, no such significant associations were observed for the DQX group. In summary, this study suggests that increased dietary intake of total PEs especially isoflavones was linked with a lower risk for developing ovarian cancer. More research is necessary to validate the findings and explore the potential mechanisms.

雌激素在卵巢肿瘤发生中起着至关重要的作用。植物雌激素(PE)是人类日常膳食营养素的一种,具有轻微的雌激素特性。本研究旨在利用前列腺癌、肺癌、结肠直肠癌和卵巢癌筛查试验(PLCO)的数据,评估膳食中雌激素摄入量与卵巢癌风险的相关性。参与者于 1993 年至 2001 年期间参加了 PLCO。通过 Cox 比例危险度回归分析,利用危险度比(HRs)和 95% 置信区间(CIs)来确定 PE 摄入量与卵巢癌发生率之间的关系。共有 24,875 名参与者完成了最初的饮食调查问卷(DQX)。此外,该分析还包括填写饮食史问卷(DHQ)的 45,472 名妇女。总体而言,在对混杂因素进行调整后,在 DHQ 组中,总 PEs 的膳食摄入量与卵巢癌的发病风险显著相关(HRQ4vsQ1 = 0.69,95% CI:0.50-0.95;趋势 P = 0.066)。特别是,在 DHQ 组中,异黄酮摄入量最高四分位数的人患卵巢癌的风险降低(HRQ4vsQ1 = 0.68,95% CI:0.50-0.94;趋势 P = 0.032)。然而,在 DQX 组中没有观察到这种明显的关联。总之,这项研究表明,从膳食中摄入更多的总 PEs(尤其是异黄酮)与患卵巢癌的风险较低有关。有必要开展更多的研究,以验证研究结果并探索其潜在机制。
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引用次数: 0
Growth modulatory effects of fenretinide encompass keratinocyte terminal differentiation: a favorable outcome for oral squamous cell carcinoma chemoprevention. 芬瑞替尼的生长调节作用包括角质形成细胞的终末分化:口腔鳞状细胞癌化学预防的有利结果
IF 3.3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-06-10 DOI: 10.1093/carcin/bgae022
Daren Wang, Ping Pei, Fortune Shea, Richard Spinney, Albert Chang, Joerg Lahann, Susan R Mallery

Oral squamous cell carcinoma (OSCC) is worldwide health problem associated with high morbidity and mortality. From both the patient and socioeconomic perspectives, prevention of progression of premalignant oral intraepithelial neoplasia (OIN) to OSCC is clearly the preferable outcome. Optimal OSCC chemopreventives possess a variety of attributes including high tolerability, bioavailability, efficacy and preservation of an intact surface epithelium. Terminal differentiation, which directs oral keratinocytes leave the proliferative pool to form protective cornified envelopes, preserves the protective epithelial barrier while concurrently eliminating growth-aberrant keratinocytes. This study employed human premalignant oral keratinocytes and an OSCC cell line to evaluate the differentiation-inducing capacity of the synthetic retinoid, fenretinide (4HPR). Full-thickness oral mucosal explants were evaluated for proof of concept differentiation studies. Results of this study characterize the ability of 4HPR to fulfill all requisite components for keratinocyte differentiation, i.e. nuclear import via binding to cellular RA binding protein-II (molecular modeling), binding to and subsequent activation of retinoic acid nuclear receptors (receptor activation assays), increased expression and translation of genes associated with keratinocyte differentiation [Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting] upregulation of a transglutaminase enzyme essential for cornified envelope formation (transglutaminase 3, functional assay) and augmentation of terminal differentiation in human oral epithelial explants (image-analyses quantified corneocyte desquamation). These data build upon the chemoprevention repertoire of 4HPR that includes function as a small molecule kinase inhibitor and inhibition of essential mechanisms necessary for basement membrane invasion. An upcoming clinical trial, which will assess whether a 4HPR-releasing mucoadhesive patch induces histologic, clinical and molecular regression in OIN lesions, will provide essential clinical insights.

口腔鳞状细胞癌(OSCC)是一个世界性的健康问题,发病率和死亡率都很高。从患者和社会经济角度来看,预防恶性前口腔上皮内瘤变(OIN)发展为 OSCC 显然是最理想的结果。最佳的 OSCC 化学预防药物具有多种特性,包括耐受性高、生物利用度高、疗效好以及能保留完整的表面上皮。末端分化可引导口腔角质细胞离开增殖池,形成保护性粟粒状包膜,从而在消除生长异常的角质细胞的同时保留保护性上皮屏障。本研究采用人类恶性前口腔角质形成细胞和 OSCC 细胞系来评估合成维甲酸芬瑞替尼 (4HPR) 的分化诱导能力。在概念验证分化研究中,对全厚口腔黏膜外植体进行了评估。研究结果表明,4HPR 能够满足角质形成细胞分化的所有必要条件,即通过与 CRABP-II 结合进行核导入(分子建模)、与视黄酸核受体结合并随后激活(受体激活试验)、增加与角质形成细胞分化相关的基因的表达和翻译(RT-PCR、免疫印迹)、上调对角质包膜形成至关重要的转谷氨酰胺酶(TGM3,功能试验)以及增强人类口腔上皮外植体的末端分化(图像分析量化角质形成细胞脱落)。这些数据建立在 4HPR 的化学预防功能基础之上,其中包括作为小分子激酶抑制剂的功能和抑制基底膜侵袭所必需的重要机制。即将进行的临床试验将评估释放 4HPR 的粘液贴片是否能诱导 OIN 病变的组织学、临床和分子消退,这将为临床提供重要的见解。
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引用次数: 0
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Carcinogenesis
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