Notch-1

引言肝窦内皮细胞(LSECs)中的NOTCH信号调节肝纤维化，这是慢性肝脏疾病的病理特征。POFUT1是NOTCH信号的重要调节因子。2024年3月6日，西安交通大学王一东、袁祖贻及吴岳共同通讯在Journal of Hepatology（IF 26）在线发表题为“Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis”的研究论文，该研究表明内皮细胞POFUT1通过抑制纤维蛋白原合成来控制损伤性肝纤维化。POFUT1缺失促进损伤诱导的LSECs毛细血管化和HSC活化，导致肝纤维化加重。RNA-seq分析显示，POFUT1缺乏可上调LSECs中纤维蛋白原的表达。与此一致的是，肝硬化患者的LSECs中纤维蛋白原升高。与对照LSECs上清液相比，用Pofut1缺失小鼠LSECs上清液处理的HSCs表现出激活加剧，这种效应通过敲低纤维蛋白原或通过药理抑制纤维蛋白原受体信号传导而减弱，表明LSECs来源的纤维蛋白原诱导了HSCs的激活。在机制上，POFUT1缺失通过增强NOTCH/HES1/STAT3信号通路来增强纤维蛋白原的表达。总之，内皮细胞POFUT1通过抑制纤维蛋白原的表达来预防损伤性肝纤维化，而纤维蛋白原是激活造血干细胞的促纤维化旁分泌信号。针对POFUT1/NOTCH/HES1/STAT3/纤维蛋白原轴的治疗为预防和治疗纤维化性肝病提供了一种有希望的策略。肝纤维化是一种细胞病理过程，以细胞外基质蛋白(主要包括胶原蛋白)的过度积累为特征，在大多数慢性肝病中均有发生。不受控制的肝纤维化可发展为肝硬化，导致门脉高压和肝衰竭，通常需要肝移植。肝星状细胞是肝脏中产生胶原的肌成纤维细胞的主要细胞来源。在对损伤的反应中，局部的、静止的HSC在一个被称为HSC激活的过程中变得增殖和纤维化，这被认为是肝纤维化的主要驱动因素。静止的HSC被来自肝脏内邻近细胞的旁分泌信号激活，包括免疫细胞、肝细胞、胆道上皮细胞和肝窦内皮细胞(LSECs)。识别这些HSC激活信号可能为治疗纤维化肝疾病提供新的靶点。LSECs是高度特化的内皮细胞，排列在肝的窦状毛细血管上，是最丰富的非实质肝细胞群。与其他器官的一般毛细血管不同，LSECs的膜上有小孔，缺乏有组织的基底膜。这些特征促进了膜的通透性，使肝细胞与动脉和门静脉血流之间的物质直接交换成为可能。LSECs在维持肝脏稳态中发挥多种功能，包括调节血管张力、抗原呈递、抗原清除，调节肝内凝固，以及维持HSC处于静止状态。此外，LSECs产生促再生血管分泌信号，包括WNT2、WNT9和HGF，以支持肝细胞增殖促进肝脏再生。在急性或慢性损伤的反应中，LSECs经历了一种被称为毛细血管化的表型开关，并对邻近细胞产生负面影响，包括肝细胞增殖的衰减和HSC的激活，导致肝纤维化。模式图（Credit: Journal of Hepatology）蛋白O-岩藻糖基转移酶1((POFUT1)是一种酶，负责通过与表皮生长因子-样(EGF-like)重复序列中的丝氨酸或苏氨酸残基的O连锁将焦点添加到蛋白。O键的焦点可以被其他糖进一步修饰，这些修饰对蛋白质功能是必不可少的。大约100种人类蛋白质含有EGF-like重复序列，其一致序列为O-聚焦。其中，NOTCH 受体(NOTCH1-4)比数据库中的其他蛋白含有更多的EGF-Like重复序列。研究表明，在黑胃果蝇和小鼠中，由于在血管发生、心脏发生、躯体发生和神经发生方面存在严重缺陷，POFUT1的缺失会导致胚胎死亡，这些表型与NOTCH基因敲除时所见的表型相似。Pofut1和Notch1突变体之间的这种表型相似性表明Notch1可能是Pofut1的靶点。事实上，NOTCH受体的O-聚焦化对于NOTCH配体的正确结合以及下游NOTCH信号的启动至关重要。该研究使用内皮特异性缺失POFUT1的小鼠系研究了POFUT1在损伤性肝纤维化中的功能。研究结果显示，POFUT1的缺失加重了四氯化碳(CCl4)或胆管结扎(BDL) 手术引起的肝纤维化。在机制上，POFUT1缺失导致NOTCH信号升高，随后STAT3通路激活，进而诱导LSECs中的纤维蛋白原表达。与小鼠研究的观察结果一致，发现肝硬化患者LSECs中纤维蛋白原水平上调。此外，LSECs来源的纤维蛋白原促进HSC活化，从而导致肝纤维化加重。总之，该研究结果确定纤维蛋白原是LSECs产生的一种新的促纤维化旁分泌信号，可以靶向治疗纤维化性肝病。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1016/j.jhep.2024.02.032责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

SAN DIEGO--(BUSINESS WIRE)-- DermTech International (NASDAQ: DMTK) (DermTech or the Company), a leader in precision dermatology enabled by a non-invasive skin genomics technology, today announced the presentation of two research abstracts at the 2024 American Academy of Dermatology (AAD) Annual Meeting, taking place March 8th-12th in San Diego, California. The first research abstract, “Non-invasive gene expression analyses to rule out melanoma in patients with Fitzpatrick skin types IV-VI” will be presented March 9th at 8:45am PT by Maral K. Skelsey, MD, lead author and Clinical Professor of Dermatology at Georgetown University’s Medical School. In this research, the negative predictive value (NPV) for both Fitzpatrick skin type group I-III and Fitzpatrick skin type group IV-VI was greater than 99%, and the 95% confidence interval indicated that there was no significant difference between the skin phototype groups. “This real-world clinical study demonstrates that the DMT can help clinicians improve outcomes for cutaneous melanomas in patients of all skin types,” commented Dr. Skelsey. “This is especially important because ruling out melanoma in individuals with Fitzpatrick IV-VI skin types can be particularly challenging.” The second research abstract titled, “Skin cancer risk is increased by somatic mutations detected noninvasively in healthy-appearing sun-exposed skin” will be presented March 9th at 10:05am PT by lead author John Whitaker, Ph.D., Senior Director of Bioinformatics at DermTech. The research found that somatic mutations in healthy-appearing sun-exposed skin indicate an increased risk for skin cancer. Furthermore, these mutations capture skin cancer risk information that is not accounted for by other risk factors. A complete description of this research has been accepted for publication in the Journal of Investigative Dermatology and will be published on March 19th: ( (24)00176-3/fulltext) This research study used non-invasively sampled DNA from healthy-appearing skin, in a reference cohort of 1,038 individuals, to measure the occurrence of somatic mutations at skin cancer-associated hotspots located within TP53 and NOTCH1. The number of detected mutations was combined with clinical variables known to be associated with skin cancer risk to create a skin cancer risk model (DNA-Skin Cancer Assessment of Risk, DNA-SCAR). DNA-SCAR’s risk calculation was validated by comparison to the U.S. population and was trained to predict personal history of skin cancer from age, family history, skin tone and mutation count. About DermTech DermTech is a leading genomics company in dermatology and is creating a new category of medicine, precision dermatology, enabled by its non-invasive skin genomics technology. DermTech’s mission is to improve the lives of millions by providing non-invasive precision dermatology solutions that enable individualized care. DermTech provides genomic analysis of skin samples collected using its Smart StickersTM. DermTech develops and markets products that facilitate the assessment of melanoma. For additional information, please visit DermTech. Forward-Looking Statements This press release includes “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. The expectations, estimates, and projections of DermTech may differ from its actual results and consequently, you should not rely on these forward-looking statements as predictions of future events. 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These forward-looking statements include, without limitation, expectations and evaluations with respect to: the performance, patient benefits, cost- effectiveness, commercialization and adoption of DermTech’s products and the market opportunity for these products; expectations regarding DermTech’s potential growth, scale, patient reach, financial outlook, including its cash runway and future financial performance DermTech’s ability to increase its test volume, revenue and the proportion of reimbursed billable tests and control or reduce cost, expenses and cash burn, including as a result of DermTech’s recent restructuring actions; and expectations regarding agreements with or reimbursement or cash collection patterns from government payers (including Medicare) or commercial payers and related billing practices or number of covered lives. These forward-looking statements involve significant risks and uncertainties that could cause the actual results to differ materially from the expected results. Most of these factors are outside of the control of DermTech and are difficult to predict. Factors that may cause such differences include, but are not limited to: (1) the outcome of any legal proceedings that may be instituted against DermTech; (2) DermTech’s ability to obtain additional capital when and as needed or on acceptable terms; (3) the existence of favorable or unfavorable clinical guidelines for DermTech’s tests; (4) the reimbursement of DermTech’s tests by government payers (including Medicare) and commercial payers; (5) the ability of patients or healthcare providers to obtain coverage of or sufficient reimbursement for DermTech’s products; (6) DermTech’s ability to grow, manage growth and retain its key employees and maintain or improve its operating efficiency and reduce operating expenses; (7) changes in applicable laws or regulations; (8) the market adoption and demand for DermTech’s products and services together with the possibility that DermTech may be adversely affected by other economic, business, and/or competitive factors; (9) DermTech’s ability to continue as a going concern and (10) other risks and uncertainties included in the “Risk Factors” section of the most recent Annual Report on Form 10-K filed by DermTech with the Securities and Exchange Commission (the “SEC”), and other documents filed or to be filed by DermTech with the SEC, including subsequently filed reports. DermTech cautions that the foregoing list of factors is not exclusive. You should not place undue reliance upon any forward- looking statements, which speak only as of the date made. DermTech does not undertake or accept any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements to reflect any change in its expectations or any change in events, conditions, or circumstances on which any such statement is based.

Researchers used various sequencing technologies to explore the molecular characteristics of myeloid/natural killer cell precursor acute leukemia (MNKPL). They observed activation of the NOTCH1 and RUNX3 genes, with lower expression of the BCL11B gene. MNKPL cells were also highly sensitive to a drug called L-asparaginase. Collectively, these qualities make MNKPL distinct from other leukemia types. These insights will assist with more accurate clinical diagnoses and therapeutic development for MNKPL. Leukemia is a common term used to refer to a form of blood cancer. However, there are different types of leukemia depending on the cell type involved. One unique form is myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL). Because of its rarity, there is no consensus on the specific characteristics needed to clinically identify this disease. In a recent article published in Science Advances, a team led by researchers at Tokyo Medical and Dental University (TMDU) used various approaches to better assess the molecular pro drug sensitivity characteristics of MNKPL. MNKPL was only first proposed as a leukemia subtype in 1997. Extramedullary involvement is one of the hallmarks of MNKPL. It is prevalent in East Asian countries. Although the immunological phenotype of MNKPL was explored previously, a full genetic characterization of this cancer type had not been performed. These details would help support more accurate diagnoses for patients, which would lead to more appropriate therapeutic decisions. Therefore, the TMDU group aimed to investigate MNKPL on a single-cell level. "A single-cell exploration of MNKPL would not only help us better understand its clinical and genomic features, but also clarify the specific cellular origin of this disease," says Dr. Akira Nishimura, lead author of the study. The team first used what is known as a multiomics approach to investigate MNKPL patient samples. They used various sequencing technologies to determine if there were any relevant mutations in specific genes, look for expression differences in certain signaling pathways at the RNA level, and examine any unique DNA methylation patterns. "Our results demonstrate that MNKPL has molecular qualities that are distinct from other similar cancers, such as acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia," explains Dr. Masatoshi Takagi, senior author. "Specific hallmarks of MNKPL include activation of the NOTCH1 and RUNX3, as well as lower expression of the BCL11B." Further work at the single-cell level in MNKPL cells showed that NK cells and myeloid cells come from a common progenitor cell type. The researchers also conducted in vitro drug sensitivity assays where they measured MNKPL cell responses to 79 individual anti-cancer drugs. "We observed that MNKPL cells were highly sensitive to a drug called L-asparaginase, which has already shown clinical effectiveness for this disease," says Dr. Nishimura. "Mechanistically, we found that this was from low expression of asparagine synthetase, a quality that was distinct from other similar types of leukemia." Overall, the robust and comprehensive analysis performed in this study provides crucial molecular details for characterizing MNKPL. This work will undoubtedly help clinicians more effectively diagnose MNKPL and choice of therapeutic option. Additionally, this work provides data that will assist with novel therapeutic target identification and drug development in this leukemia.