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Gut microbial carcinogen metabolism: another avenue to cancer 肠道微生物致癌物代谢:通往癌症的另一条途径
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s41392-024-02015-8
Florian R. Greten, Melek C. Arkan

A recent study published in Nature by Roje, Zhang and colleagues highlights the emergent role gut microbiota play in processing environmental carcinogens and raises its potential as a target for reducing cancer risk in humans.1 This study fills yet another piece into the giant jigsaw puzzle that illustrates the central role of the dynamic structure and function of the intestinal microbiome in cancer pathogenesis and therapy efficacy.

罗杰(Roje)、张(Zhang)及其同事最近在《自然》(Nature)杂志上发表的一项研究强调了肠道微生物群在处理环境致癌物方面发挥的新作用,并提高了其作为降低人类癌症风险靶点的潜力。
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引用次数: 0
Miniproteins may have a big impact: new therapeutics for autoimmune diseases and beyond 微小蛋白可能产生重大影响:自身免疫疾病及其他疾病的新疗法
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s41392-024-02010-z
Nariaki Asada, Christian F. Krebs, Ulf Panzer

In a landmark study recently published in Cell, Berger et al. demonstrated that computationally designed miniproteins could serve as novel, orally available treatment strategies by specifically targeting cytokine signaling pathways through the potent inhibition of ligand-receptor interactions in the body.1 This breakthrough study unveils the potential for miniprotein-based therapies to revolutionize molecular treatment strategies for autoimmune diseases and cancers.

在最近发表于《细胞》(Cell)杂志的一项具有里程碑意义的研究中,Berger 等人证明,通过计算设计的小蛋白可以通过有效抑制体内配体与受体之间的相互作用,特异性地靶向细胞因子信号通路,从而成为新型的口服治疗策略。
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引用次数: 0
Perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy for resectable non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 2 trial (TD-NeoFOUR trial) 围手术期辛替利马和新辅助安罗替尼加化疗治疗可切除的非小细胞肺癌:一项多中心、开放标签、单臂、2 期试验(TD-NeoFOUR 试验)
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s41392-024-01992-0
Hongtao Duan, Changjian Shao, Zhilin Luo, Tianhu Wang, Liping Tong, Honggang Liu, Xin Yao, Jie Lei, Jinbo Zhao, Yuan Gao, Tao Jiang, Xiaolong Yan

This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1–14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4–6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF+ cells and CD4+Foxp3+ Treg cells, and increased perivascular CD4+ T cells, CD39+CD8+ T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).

这项开放标签、单臂 2 期试验评估了新辅助辛替利单抗联合安罗替尼和化疗治疗可切除 NSCLC 的疗效和安全性,随后进行辛替利单抗辅助治疗。45名患者接受了安罗替尼(10毫克,QD,PO,第1-14天)、辛替利单抗(200毫克,第1天)和铂类化疗,每个化疗周期为三周,共3个周期,随后在4-6周内进行手术。辅助性辛替利马单抗(200 毫克)每 3 周注射一次。主要终点是获得病理完全反应(pCR)。从2021年6月10日到2023年10月10日,45名患者被纳入意向治疗人群。26名患者(57.8%)获得了pCR,30名患者(66.7%)获得了主要病理反应(MPR)。41名患者接受了手术治疗。在按方案治疗组(PP 组)中,63.4% 的患者(26/41)获得了 pCR,73.2% 的患者获得了 MPR。中位无事件生存期未达标(95% CI,25.1-NE)。在新辅助治疗阶段,25 名患者(55.6%)出现了 3 级或 4 级治疗相关不良事件,7 名患者(15.6%)出现了免疫相关不良事件。我们通过 mIHC 检测 NSCLC 组织中相关细胞标记物的表达,评估了血管正常化和免疫相关细胞的浸润情况。在 pCR 患者中观察到了显著的肿瘤微环境变化,包括 VEGF+ 细胞和 CD4+Foxp3+ Treg 细胞减少,血管周围 CD4+ T 细胞、CD39+CD8+ T 细胞和 M1 巨噬细胞增加。总之,围手术期辛替利马和新辅助安罗替尼加化疗可使相当一部分可切除的NSCLC患者获得pCR,并且与肿瘤微环境的深刻变化有关(ClinicalTrials.gov NCT05400070)。
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引用次数: 0
Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials 全身纵向免疫图谱分析发现增殖的Treg细胞是免疫疗法获益的预测因子:来自CONTINUUM和DIPPER三期试验的生物标记物分析
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41392-024-01988-w
Sai-Wei Huang, Wei Jiang, Sha Xu, Yuan Zhang, Juan Du, Ya-Qin Wang, Kun-Yu Yang, Ning Zhang, Fang Liu, Guo-Rong Zou, Feng Jin, Hai-Jun Wu, Yang-Ying Zhou, Xiao-Dong Zhu, Nian-Yong Chen, Cheng Xu, Han Qiao, Na Liu, Ying Sun, Jun Ma, Ye-Lin Liang, Xu Liu

The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.

由于许多研究缺乏对照组,很难区分预后生物标志物和预测性生物标志物,因此免疫疗法预测指标的确定往往受到阻碍。本研究介绍了CONTINUUM三期试验(NCT03700476)的生物标志物分析,该试验首次证明在化放疗(CRT)中加入抗PD-1(aPD1)可改善局部晚期鼻咽癌患者的无事件生存期(EFS)。我们使用质谱仪对12对aPD1-CRT治疗组中匹配的复发和非复发患者的外周血单核细胞样本进行了动态单细胞图谱分析。利用监督表征学习算法,我们确定了一个 Ki67+ 增殖调节性 T 细胞(Tregs)群体,该群体表达高水平的活化和免疫抑制分子,包括 FOXP3、CD38、HLA-DR、CD39 和 PD-1,其丰度与治疗结果相关。与非复发患者相比,复发患者中这些 Ki67+ Tregs 的频率在基线时明显较高,并在治疗过程中有所增加。流式细胞术(n = 120)的进一步验证证实了该Treg亚群的预测价值。多重免疫组化(n = 249)表明,肿瘤中的 Ki67+ Tregs 可预测免疫疗法的疗效,而 aPD1 仅可改善基线 Ki67+ Tregs 水平较低的患者的 EFS。这些发现在NSCLC抗PD-L1免疫疗法的多中心3期DIPPER试验(n = 262,NCT03427827)和3期OAK试验中得到了进一步验证,强调了Ki67+ Treg频率在确定免疫疗法受益者和潜在指导个性化治疗策略方面的预测价值。
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引用次数: 0
Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial Ruxolitinib加类固醇治疗急性移植物抗宿主疾病:一项多中心、随机、3期试验
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41392-024-01987-x
Liping Dou, Yanli Zhao, Jingjing Yang, Lei Deng, Nan Wang, Xiawei Zhang, Qingyang Liu, Yan Yang, Zhijie Wei, Fuxu Wang, Yifan Jiao, Fei Li, Songhua Luan, Liangding Hu, Sujun Gao, Chuanfang Liu, Xiangjun Liu, Jinsong Yan, Xuejun Zhang, Fang Zhou, Peihua Lu, Daihong Liu

Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; P < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; P < 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; P < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% P = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.

新确诊的高危急性移植物抗宿主病(aGVHD)患者往往临床疗效不佳,完全缓解率低。在我们的 I 期研究中,Ruxolitinib 联合皮质类固醇治疗在改善反应和无失败生存期方面显示出良好的疗效。这项研究(ClinicalTrials.gov:NCT04061876)旨在评估Ruxolitinib(RUX,5毫克/天)与皮质类固醇(1毫克/公斤/天甲基强的松龙,RUX/皮质类固醇联合组)联合治疗与单独使用甲基强的松龙(2毫克/公斤/天,仅使用皮质类固醇组)的安全性和有效性。新确诊的中危或高危 aGVHD 患者均被纳入其中,风险等级根据明尼苏达 aGVHD 风险评分或生物标志物评估进行分类。患者按1:1的比例随机分为两组:99名患者接受RUX联合甲基强的松龙治疗,另外99名患者则接受单纯甲基强的松龙作为初始治疗。RUX/类固醇组第28天的总反应率(ORR)(92.9%)明显高于单纯类固醇组(70.7%,Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4-14.0; P < 0.001)。同样,RUX/类固醇组第56天的ORR也更高(85.9% vs. 46.5%;OR = 7.07;95% CI, 3.36-15.75; P <0.001)。此外,与单纯类固醇组(33.3%;危险比=0.46;95% CI,0.31-0.68;P <0.001)相比,RUX/类固醇组的18个月无失败生存率(57.2%)明显更高。两组的不良事件(AEs)发生率相当,但RUX/类固醇组的4级不良事件较少(26.3% vs. 50.5% P = 0.005)。据我们所知,该研究是首个前瞻性随机对照试验,证明在标准甲泼尼龙方案中加入鲁索利替尼可为新诊断的高危急性GVHD患者提供有效、安全的一线治疗。
{"title":"Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial","authors":"Liping Dou, Yanli Zhao, Jingjing Yang, Lei Deng, Nan Wang, Xiawei Zhang, Qingyang Liu, Yan Yang, Zhijie Wei, Fuxu Wang, Yifan Jiao, Fei Li, Songhua Luan, Liangding Hu, Sujun Gao, Chuanfang Liu, Xiangjun Liu, Jinsong Yan, Xuejun Zhang, Fang Zhou, Peihua Lu, Daihong Liu","doi":"10.1038/s41392-024-01987-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01987-x","url":null,"abstract":"<p>Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; <i>P</i> &lt; 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; <i>P</i> &lt; 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; <i>P</i> &lt; 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% <i>P</i> = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
5-Formylcytosine: a new epigenetic player 5-甲酰基胞嘧啶:新的表观遗传参与者
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41392-024-02016-7
Dharmendra Kumar, Iqbal Hyder, Wilfried A. Kues

In a landmark study published in Cell, Parasyraki et al. demonstrated a functional role of 5-formylcytosine (5fC) as an epigenetic mark during zygotic/embryonic genome activation (ZGA) in Xenopus and murine embryos that is spatially associated with RNA polymerase III (Pol III) transcription.1 ZGA (or maternal to embryonic transition) is the unique phase of embryonic development when the maternal genome of the oocyte is reprogrammed to an embryonic gene expression.

Parasyraki 等人在《细胞》(Cell)杂志上发表的一项具有里程碑意义的研究表明,5-醛基胞嘧啶(5fC)在章鱼和小鼠胚胎的子代/胚胎基因组激活(ZGA)过程中起着表观遗传标记的功能作用,它与 RNA 聚合酶 III(Pol III)的转录在空间上相关。
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引用次数: 0
MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB 抑制 MEK 可通过下调 c-Fos 和 JunB 防止 CAR-T 细胞衰竭和分化
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-22 DOI: 10.1038/s41392-024-01986-y
Xiujian Wang, Xiao Tao, Pengjie Chen, Penglei Jiang, Wenxiao Li, Hefeng Chang, Cong Wei, Xinyi Lai, Hao Zhang, Yihan Pan, Lijuan Ding, Zuyu Liang, Jiazhen Cui, Mi Shao, Xinyi Teng, Tianning Gu, Jieping Wei, Delin Kong, Xiaohui Si, Yingli Han, Huarui Fu, Yu Lin, Jian Yu, Xia Li, Dongrui Wang, Yongxian Hu, Pengxu Qian, He Huang

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

临床证据证明,T细胞衰竭和终末分化对嵌合抗原受体-T(CAR-T)细胞的持久性和有效性构成了挑战。MEK1/2抑制剂(MEKIs)因其抑制异常MAPK信号传导的能力而被广泛用于癌症治疗,在与免疫疗法结合使用时显示出潜在的协同效应。然而,MEKIs 对 CAR-T 细胞的影响和机制仍不确定且存在争议。为了解决这个问题,我们进行了一项全面调查,以确定 MEKIs 是否会增强或损害 CAR-T 细胞的疗效。我们的研究结果表明,MEKIs 可减轻补体信号传导和抗原刺激引起的 CAR-T 细胞衰竭和终末分化,从而提高 CAR-T 细胞对血液肿瘤和实体瘤的疗效。值得注意的是,这些效应与CAR中使用的特定scFvs和共刺激结构域无关。从机理上讲,对体细胞和单细胞转录谱的分析表明,MEK抑制的效果与同化代谢的降低以及c-Fos和JunB的下调有关。此外,CAR-T 细胞中 c-Fos 或 JunB 的过表达抵消了 MEK 抑制的效果。此外,我们的剪切-标记检测发现,MEK抑制下调了与衰竭、分化、贫血、糖酵解和凋亡相关的JunB驱动基因谱。总之,我们的研究揭示了 MAPK-c-Fos-JunB 轴在驱动 CAR-T 细胞衰竭和末期分化中的关键作用。这些机制方面的见解大大拓宽了 MEKIs 在提高 CAR-T 疗法有效性方面的潜在应用。
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引用次数: 0
Corynebacterium parakroppenstedtii secretes a novel glycolipid to promote the development of granulomatous lobular mastitis 副猪嗜血杆菌分泌一种新型糖脂,促进肉芽肿性小叶乳腺炎的发展
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 DOI: 10.1038/s41392-024-01984-0
Ran Liu, Zixuan Luo, Chong Dai, Yuchen Wei, Shuqing Yan, Xinwen Kuang, Kuan Qi, Aisi Fu, Yinxin Li, Shuai Fu, Zhengning Ma, Wen Dai, Xiao Xiao, Qing Wu, Haokui Zhou, Yan Rao, Jingping Yuan, Ting Shi, Zixin Deng, Chuang Chen, Tiangang Liu

Granulomatous lobular mastitis (GLM) is a chronic idiopathic granulomatous mastitis of the mammary gland characterized by significant pain and a high propensity for recurrence, the incidence rate has gradually increased, and has become a serious breast disease that should not be ignored. GLM is highly suspected relative to microbial infections, especially those of Corynebacterium species; however, the mechanisms involved are unclear, and prevention and treatment are difficult. In this study, we demonstrated the pathogenicity of Corynebacterium parakroppenstedtii in GLM using Koch’s postulates. Based on the drug sensitization results of C. parakroppenstedtii, and utilizing a retrospective study in conjunction with a comprehensive literature review, we suggested an efficacious, targeted antibiotic treatment strategy for GLM. Subsequently, we identified the pathogenic factor as a new type of glycolipid (named corynekropbactins) secreted by C. parakroppenstedtii. Corynekropbactins may chelate iron, cause the death of mammary cells and other mammary -gland-colonizing bacteria, and increase the levels of inflammatory cytokines. We further analyzed the prevalence of C. parakroppenstedtii infection in patients with GLM. Finally, we suggested that the lipophilicity of C. parakroppenstedtii may be associated with its infection route and proposed a possible model for the development of GLM. This research holds significant implications for the clinical diagnosis and therapeutic management of GLM, offering new insights into targeted treatment approaches.

肉芽肿性小叶性乳腺炎(GLM)是一种慢性特发性乳腺肉芽肿性乳腺炎,以疼痛明显、复发率高为特征,发病率逐渐升高,已成为一种不容忽视的严重乳腺疾病。相对于微生物感染,尤其是棒状杆菌感染,GLM 被高度怀疑;然而,相关机制尚不清楚,预防和治疗也很困难。在本研究中,我们利用科赫推论证明了副猪棒状杆菌在 GLM 中的致病性。根据副猪棒状杆菌的药敏结果,通过回顾性研究和全面的文献综述,我们提出了一种针对 GLM 的有效抗生素治疗策略。随后,我们确定了致病因子是一种由 C. parakroppenstedtii 分泌的新型糖脂(命名为 Corynekropbactins)。Corynekropbactins可螯合铁,导致乳腺细胞和其他乳腺定植细菌死亡,并增加炎症细胞因子的水平。我们进一步分析了 GLM 患者中 Parakroppenstedtii 感染的流行率。最后,我们认为副嗜血杆菌的亲脂性可能与其感染途径有关,并提出了一种可能的 GLM 发病模式。这项研究对GLM的临床诊断和治疗管理具有重要意义,为有针对性的治疗方法提供了新的见解。
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引用次数: 0
Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy 用于结直肠癌治疗中精确细胞内递送和增强降解疗效的序贯响应性纳米 PROTACs
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-18 DOI: 10.1038/s41392-024-01983-1
Liuqing Yang, Ye Yang, Jing Zhang, Minghui Li, Long Yang, Xing Wang, Meifang Chen, Hua Zhang, Bing He, Xueqing Wang, Wenbing Dai, Yiguang Wang, Qiang Zhang

PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.

促溶解嵌合体(PROteolysis TArgeting Chimeras,PROTACs)一直被认为是下一个热门疗法。然而,由于其固有的局限性,PROTACs 的疗效往往因组织穿透力有限,尤其是作用部位的细胞内化不足而受到影响。本文基于超pH敏感和酶敏感纳米技术,按照细胞周期蛋白依赖性激酶4和6(CDK4/6)PROTAC的结构,特意设计了一种聚合物PROTAC共轭和pH/胰蛋白酶B序列响应纳米颗粒(PSRNs)。结肠直肠癌(CRC)是本研究选择的肿瘤模型,它对许多治疗方法甚至免疫检查点阻断剂都几乎没有反应。结果发现,PSRNs 在血液循环中能保持纳米结构(40 nm),并通过增强的渗透和滞留效应在肿瘤中有效积累。然后,它们在酸性肿瘤微环境中解离成单聚体(10 nm),促进肿瘤穿透和细胞内化。重要的是,PSRNs 在体外和体内都能促进靶蛋白的降解。CDK4/6 的降解还通过上调癌细胞中程序性细胞死亡配体 1(PD-L1)的表达和抑制肿瘤微环境中调节性 T 细胞的增殖,增强了免疫检查点阻断的功效。通过与α-PD-1联用,CT26肿瘤模型的抗肿瘤效果得到了很好的增强。总之,我们的研究验证了 PROTACs 细胞内精确递送的意义,并为靶向联合治疗 CRC 引入了一种前景广阔的治疗策略。
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引用次数: 0
Cold and hot tumors: from molecular mechanisms to targeted therapy 冷肿瘤和热肿瘤:从分子机制到靶向治疗
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-18 DOI: 10.1038/s41392-024-01979-x
Bo Wu, Bo Zhang, Bowen Li, Haoqi Wu, Meixi Jiang

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the “hot” (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct “cold” (immune-desert) phenotype, differing from the features of “hot” tumors. Additionally, there is a more nuanced “excluded” immune phenotype, positioned between the “cold” and “hot” categories, known as the immune “excluded” type. Effective differentiation between “cold” and “hot” tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on “hot” tumors, with limited efficacy against “cold” or “altered” tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert “cold” or “altered” tumors into “hot” ones. Therefore, aligning with the traits of “cold” and “hot” tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on “cold” and “hot” tumors to assess clinical efficacy.

免疫疗法在癌症治疗中取得了长足进步,尤其是通过免疫检查点阻断(ICB),在各种肿瘤类型中显示出显著的临床疗效。尽管 ICB 治疗对癌症治疗产生了变革性影响,但只有少数患者对 ICB 治疗产生了积极反应。在实体瘤患者中,对 ICB 治疗反应良好的患者通常表现出活跃的免疫特征,被称为 "热"(免疫炎症)表型。另一方面,无反应的患者可能表现出明显的 "冷"(免疫凋亡)表型,与 "热 "肿瘤的特征不同。此外,还有一种介于 "冷 "和 "热 "两类肿瘤之间的更细微的 "排斥 "免疫表型,即免疫 "排斥 "型。有效区分 "冷 "和 "热 "肿瘤,了解肿瘤内在因素、免疫特征、TME 和外部因素,对于预测肿瘤反应和治疗效果至关重要。目前普遍认为,ICB 疗法对 "热 "肿瘤的疗效更显著,而对 "冷 "或 "改变 "肿瘤的疗效有限,因此需要与其他治疗方式相结合,以增强免疫细胞对肿瘤组织的浸润,将 "冷 "或 "改变 "肿瘤转化为 "热 "肿瘤。因此,本综述根据 "冷 "肿瘤和 "热 "肿瘤的特征,系统阐述了各自的免疫特征、影响因素,并广泛讨论了基于 "冷 "肿瘤和 "热 "肿瘤的各种治疗方法和药物靶点,以评估临床疗效。
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Signal Transduction and Targeted Therapy
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