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Nuclear PD-L1 compartmentalization suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance in mice via histone macroH2A1. 核PD-L1分区通过组蛋白宏H2A1抑制小鼠的肿瘤发生并克服免疫检查点疗法的耐药性。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI181314
Yong Liu, Zhi Yang, Shuanglian Wang, Rui Miao, Chiung-Wen Mary Chang, Jingyu Zhang, Xin Zhang, Mien-Chie Hung, Junwei Hou

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

PD-L1 通常是细胞表面的抑制性免疫检查点。最近的研究观察到 PD-L1 在癌细胞的细胞核中表达。但是核PD-L1(nPD-L1)在肿瘤生长和抗肿瘤免疫中的生物学功能尚不清楚。在这里,我们强化了 nPD-L1 的表达并建立了稳定的细胞。nPD-L1 在体外和体内都抑制了肿瘤的发生和侵袭性。与 PD-L1 基因缺失相比,nPD-L1 的表达能更明显地抑制肿瘤生长并提高免疫功能正常小鼠的存活率。磷酸化的AMPKα(p-AMPKα)促进了PD-L1的核分区,然后与其合作直接磷酸化组蛋白变体macroH2A1(mH2A1)的S146,从而表观遗传地激活细胞衰老、JAK/STAT和Hippo信号通路基因的表达。诱导核PD-L1转位的硫辛酸(LA)可抑制肿瘤发生并增强抗肿瘤免疫力。重要的是,硫辛酸治疗与PD-1抗体协同作用,克服了免疫检查点阻断(ICB)的耐药性,这可能是由于nPD-L1增加了MHC-I的表达和肿瘤细胞对干扰素-γ的敏感性。这些发现为 PD-L1 的功能提供了概念上的进步,并建议将 LA 作为克服 ICB 抗性的一种有前途的治疗选择。
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引用次数: 0
The lung is a megakaryocyte outpost that can defend against thrombocytopenic attack. 肺是巨核细胞的前哨,可以抵御血小板减少症的侵袭。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI186111
Anthony K Yeung, George J Murphy

Lung megakaryocytes (Mks) are a unique subset of Mks that are distinct from their bone marrow counterparts. Recent evidence suggests that lung Mks favor an immune phenotype, but have unclear contributions to the total platelet mass. In this issue of the JCI, Livada et al. used an array of complementary in vivo labeling and tracing models in mice to investigate a longstanding question of where lung Mks are derived. By combining these models with stressed conditions, the authors assessed the contribution of lung Mks to total platelet counts in a homeostatic and thrombocytopenic state. Mks were minor contributors to the circulating pool of platelets during homeostasis but increased output during thrombocytopenia. These findings add critical understanding to the development of lung Mks and demonstrate the dynamic potential of these specialized cells to respond to thrombocytopenia.

肺巨核细胞(Mks)是一种独特的巨核细胞亚群,有别于骨髓巨核细胞。最近的证据表明,肺巨核细胞倾向于免疫表型,但对血小板总量的贡献尚不清楚。在本期 JCI 杂志上,Livada 等人利用一系列互补的小鼠体内标记和追踪模型来研究一个长期存在的问题,即肺 Mks 从何而来。通过将这些模型与受压条件相结合,作者评估了肺Mks在平衡和血小板减少状态下对血小板总数的贡献。在平衡状态下,Mks 对循环血小板池的贡献较小,但在血小板减少状态下,Mks 的输出量会增加。这些发现使人们对肺Mks的发展有了更重要的了解,并证明了这些特化细胞对血小板减少做出反应的动态潜力。
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引用次数: 0
Genetics of hemostasis: from bedside to bench and back again. 止血遗传学:从床边到工作台,再从工作台到床边。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI183500
David Ginsburg
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引用次数: 0
Super chickens, givers, and collective intelligence: the importance of collaboration, teamwork, and mentorship in science. 超级鸡、奉献者和集体智慧:科学中合作、团队和导师的重要性。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI187403
Benjamin D Humphreys
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引用次数: 0
Parkin paves the path to antitumor immunity: Expanding Parkin's role as a tumor suppressor. Parkin为抗肿瘤免疫铺平了道路:拓展Parkin作为肿瘤抑制因子的作用
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI185838
Hyungsoo Kim, Ze'ev A Ronai

Parkin, a ring-between-ring-type E3 ubiquitin ligase, first shown to play a critical role in autosomal recessive juvenile Parkinsonism, has recently emerged as a key player in cancer biology. Parkin is now known to serve as a tumor suppressor, and its deregulation frequently promotes tumorigenesis. In this issue of the JCI, Perego et al. expand that role by showing that Parkin expression stimulated an interferon (IFN) response to modulate CD8+ T cell activity. These findings suggest that, in addition to directly inhibiting tumor progression, Parkin enhances antitumor immune responses, highlighting it as a promising therapeutic target for cancer treatment.

Parkin是一种环间型E3泛素连接酶,最初被证明在常染色体隐性幼年帕金森病中发挥关键作用,最近又成为癌症生物学中的一个关键角色。目前已知Parkin是一种肿瘤抑制因子,它的失调经常会促进肿瘤的发生。在本期 JCI 杂志上,Perego 等人通过研究发现,Parkin 的表达会刺激干扰素 (IFN) 的反应,从而调节 CD8+ T 细胞的活性,从而扩大了这种作用。这些研究结果表明,除了直接抑制肿瘤进展外,Parkin 还能增强抗肿瘤免疫反应,使其成为治疗癌症的一个很有前景的靶点。
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引用次数: 0
Cell-cycle machinery is critical in regulating uterine steroid hormone for embryo implantation and development. 细胞周期机制是调节子宫类固醇激素以促进胚胎植入和发育的关键。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI186194
Francesco J DeMayo

Proper embryo implantation is necessary for a successful pregnancy. In this issue of the JCI, Aljubran et al. identified the cell cycle regulatory protein cyclin A2 (CCNA2) as a factor in supporting embryo implantation and embryo development. Endometrial stromal cells showed higher levels of CCNA2 in patients undergoing assisted reproductive technology who had successful pregnancies. CCNA2 expression correlated with stromal cell proliferation and the expression of steroid hormone receptors for estrogen (ESR1, also known as ERα) and progesterone (PGR). Notably, loss of Ccna2 in mouse models resulted in infertility. The uteri of these mice were hypoplastic with reduced estrogen sensitivity, resulting in the disruption of stroma cell decidualization and loss of embryo viability after implantation. These findings demonstrate the importance of stroma cell proliferation in preparing the uterus for embryo implantation. They also identify CCNA2 as a coregulator of steroid hormone receptor signaling and suggest that impaired uterine stroma can underly early pregnancy loss.

正确的胚胎植入是成功怀孕的必要条件。在本期 JCI 杂志上,Aljubran 等人发现细胞周期调控蛋白细胞周期蛋白 A2 (CCNA2) 是支持胚胎着床和胚胎发育的一个因素。在接受辅助生殖技术并成功怀孕的患者中,子宫内膜基质细胞的CCNA2水平较高。CCNA2的表达与基质细胞的增殖以及雌激素(ESR1,又称ERα)和孕酮(PGR)等类固醇激素受体的表达相关。值得注意的是,在小鼠模型中缺失 Ccna2 会导致不孕。这些小鼠的子宫发育不良,对雌激素的敏感性降低,导致基质细胞蜕膜化中断,胚胎植入后丧失存活能力。这些研究结果表明了基质细胞增殖在子宫为胚胎植入做准备过程中的重要性。他们还发现 CCNA2 是类固醇激素受体信号转导的核心调节因子,并提示子宫基质受损可能是早孕妊娠损失的原因。
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引用次数: 0
Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles. 减数分裂 I 的缺陷是雄激素性水滴形痣的成因之一。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI170669
Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A Fisher, Michael J Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo, Rima Slim

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.

为了找出导致复发性水滴形痣(HMs)的新基因,我们对已知基因突变呈阴性的 75 名无关患者进行了外显子组测序。我们在雄激素遗传性水滴形痣患者中发现了 6 个基因(FOXL2、MAJIN、KASH5、SYCP2、MEIOB 和 HFM1)的双偶缺失变异,其中包括一个由 3 名患者组成的家族病例。其中五个基因是减数分裂 I 的必需基因,缺乏这些基因会导致卵巢早衰。高龄产妇是偶发性雄激素性 HM 的最大风险因素,每 600 例妊娠中就有 1 例罹患该病。我们对Hfm1-/-雌性小鼠进行了研究,发现这些小鼠在青春期前失去了所有卵母细胞,但在较年轻时保留了一些。Hfm1-/-小鼠的卵母细胞开始减数分裂成熟,并在培养过程中挤出第一个极体;然而,它们的减数分裂纺锤体在端期I时的位置往往与卵原膜平行,而不是垂直,有些卵母细胞在分裂后期II时将整个纺锤体连同所有染色体挤出极体,这是我们之前在Mei1-/-卵母细胞中报道的一种机制。在两种小鼠模型中出现的共同机制证明了人类雄激素性 HM 形成的起源是合理的。
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引用次数: 0
MGA loss-of-function variants cause premature ovarian insufficiency. MGA 功能缺失变体会导致卵巢早衰。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI183758
Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/- female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.

卵巢早衰(POI)是导致女性不孕和不育的常见原因之一,虽然它具有公认的遗传因素,但目前与 POI 有关的遗传因素只占病例的有限比例。在此,我们对由1027例POI病例和2733名来自中国的种族匹配女性对照组成的发现队列进行了基于基因的全外显子组病例对照分析,发现MAX二聚化蛋白(MGA)的杂合子功能缺失(LoF)变异在发现队列中明显富集,占POI病例的2.6%,而在匹配对照女性中未发现MGA LoF变异。我们在另外 4 个 POI 队列(2 个来自中国,2 个来自美国)中进行了进一步的外显子组筛查,以进行复制研究,结果发现分别有 1.0%、1.4%、1.0% 和 1.0% 的 POI 病例存在杂合 MGA LoF 变异。总之,在 38 个 POI 病例中总共发现了 37 个不同的杂合 MGA LoF 变异,约占本研究分析的 1,910 个 POI 病例的 2.0%。因此,与 WT 小鼠相比,Mga+/- 雌性小鼠生育力低下,生殖寿命缩短,卵泡数量减少,与人类观察到的表型相似。我们的研究结果突显了MGA缺乏对雌性生殖能力受损的重要作用。
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引用次数: 0
Xylazine induces dopamine release and augments the effects of fentanyl. 赛拉嗪可诱导多巴胺释放,并增强芬太尼的作用。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI183354
Joseph R Trinko, Ethan Foscue, Edward M Kong, Aakash Basu, Anouk M Corstens, Summer L Thompson, Alfred P Kaye, Jane R Taylor, Ralph J DiLeone
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引用次数: 0
It takes a village. 这需要一个村庄。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-15 DOI: 10.1172/JCI188177
Alex D Waldman
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引用次数: 0
期刊
Journal of Clinical Investigation
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