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Developmental Oncology: Principles and Therapy of Cancers of Children and Young Adults.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-17 DOI: 10.1101/cshperspect.a041847
Alex Kentsis, Alejandro Gutierrez

Children and young adults are affected by a number of different cancers. These are developmental in origin and arise, in particular, in susceptible cell types. Recent advances have led to significant progress in our understanding of the underlying causes and the pathogenetic mechanisms involved. This is informing design of therapeutic approaches that offer new hope for patients.

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引用次数: 0
Threats from the Fungal Kingdom.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-17 DOI: 10.1101/cshperspect.a041630
Arturo Casadevall

The fungal kingdom includes a large set of species with pathogenic potential for humans, plants, and wildlife. Whereas threats from the fungal kingdom to agriculture are appreciated, the potential of fungi to threaten humans, animals, ecosystems, and infrastructure is often unappreciated. Fungal disease and mold damage often follow natural disasters. The threats from the fungal kingdom are amplified by the relative paucity of countermeasures, which includes few antifungal drugs and fungicides and an increasing prevalence of resistance to both. Anthropomorphic climate change resulting in global warming is expected to increase the likelihood and potential number of threats from the fungal kingdom. Preparation against fungal threats requires continued investments in basic research to understand the unique aspects of fungal metabolism, development of vaccines, investment in new drugs and fungicides, and a careful mapping of the natural world to identify the existing taxonomic diversity and their potential for harm.

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引用次数: 0
Parallels in Canonical Developmental Signaling Pathways between Normal Development and the Tumor Microenvironment.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-17 DOI: 10.1101/cshperspect.a041609
Julia Segal, James Cronk, Brendan Ball, Greta Forbes, Kailey Jackett, Kathy Li, Alondra Martinez Osorno, Emily San Andres Montalvan, Alice Browne, Jessica Lake, Rosandra N Kaplan

The tumor microenvironment (TME) is comprised of both cellular and stromal elements and plays an essential role in the growth, survival, and dissemination of malignancies. The TME is an organized program that develops with a growing tumor, using many processes involved in normal tissue development. In multiple solid tumors, developmental pathways are used to recruit immunosuppressive cells, including immunosuppressive monocytes and neutrophils, tumor-associated macrophages, and regulatory T cells to block the antitumor immune response. In addition, stromal cells sustain tumor growth via trophic support, angiogenesis, repair mechanisms, and associated immunosuppression, driven, at least in part, by canonical developmental signaling pathways. The microenvironmental ecosystem shapes tumor progression from its earliest inception by modulating important programs that dictate tumor behavior, necessitating further consideration when studying the developmental origins of malignancy. Here, we review the role of developmental pathways in the formation and modulation of the TME in pediatric and adult solid tumors, including Wnt, Notch, Hippo, Hedgehog, TGF-β, BMP, SOX, and OCT.

肿瘤微环境(TME)由细胞和基质两部分组成,在恶性肿瘤的生长、存活和扩散过程中起着至关重要的作用。肿瘤微环境是一个有组织的程序,它随着肿瘤的生长而发展,并利用正常组织发育的许多过程。在多种实体瘤中,发育途径被用来招募免疫抑制细胞,包括免疫抑制单核细胞和中性粒细胞、肿瘤相关巨噬细胞和调节性 T 细胞,以阻断抗肿瘤免疫反应。此外,基质细胞通过营养支持、血管生成、修复机制和相关的免疫抑制来维持肿瘤生长,至少部分是由典型的发育信号通路驱动的。微环境生态系统通过调节决定肿瘤行为的重要程序,从一开始就影响着肿瘤的进展,因此在研究恶性肿瘤的发育起源时有必要进一步加以考虑。在此,我们回顾了发育通路在儿童和成人实体瘤中形成和调节TME中的作用,包括Wnt、Notch、Hippo、Hedgehog、TGF-β、BMP、SOX和OCT。
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引用次数: 0
Imaging of Disease-Related Networks in Parkinson's Disease.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-17 DOI: 10.1101/cshperspect.a041841
Yoshikazu Nakano, Martin Niethammer, David Eidelberg

Functional neuroimaging techniques are increasingly being used to advance the diagnosis and management of Parkinson's disease (PD). Methods such as [18F]-fluorodeoxyglucose positron emission tomography (FDG PET), resting-state functional magnetic resonance imaging (rs-fMRI), arterial spin labeling (ASL) MRI, and single-photon emission computed tomography (SPECT) enable the identification of disease-specific patterns like the PD-related pattern (PDRP) and PD cognition-related pattern (PDCP), which correlate with motor and cognitive symptoms. Network analysis using graph theory further elucidates the alterations in brain connectivity associated with PD, providing insights into disease progression and response to treatment. Moreover, these neuroimaging patterns assist in distinguishing PD from atypical parkinsonian syndromes, enhancing diagnostic accuracy. Understanding the impact of genetic variants like LRRK2 and GBA1 on functional connectivity highlights the potential for precision medicine in PD. As neuroimaging technologies evolve, their integration into clinical practice will be pivotal in the personalized management of PD, offering improved diagnostic precision and targeted therapeutic interventions.

功能神经成像技术越来越多地被用于帕金森病(PD)的诊断和治疗。[18F]-氟脱氧葡萄糖正电子发射断层扫描(FDG PET)、静息态功能磁共振成像(rs-fMRI)、动脉自旋标记磁共振成像(ASL MRI)和单光子发射计算机断层扫描(SPECT)等方法能够识别与运动和认知症状相关的帕金森病相关模式(PDRP)和帕金森病认知相关模式(PDCP)等疾病特异性模式。利用图论进行的网络分析进一步阐明了与帕金森病相关的大脑连通性改变,为了解疾病进展和治疗反应提供了线索。此外,这些神经影像模式有助于区分帕金森病和非典型帕金森综合征,从而提高诊断的准确性。了解 LRRK2 和 GBA1 等基因变异对功能连接性的影响凸显了帕金森病精准医疗的潜力。随着神经成像技术的发展,将其融入临床实践将对帕金森病的个性化管理起到关键作用,从而提高诊断的准确性和有针对性的治疗干预。
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引用次数: 0
Advances in Studying Cancer Immunology in Mice. 研究小鼠癌症免疫学的进展。
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1101/cshperspect.a041682
Marcus Bosenberg

The recent rise in effective immuno-oncology therapies has increased demand for experimental approaches to model anticancer immunity. A variety of mouse models have been developed and used to study cancer immunology. These include mutagen-induced, genetically engineered, syngeneic, and other models of cancer immunology. These models each have the potential to define mechanistic aspects of anticancer immune responses, identify potential therapeutic targets, and serve as preclinical models for further therapeutic development. Specific benefits and liabilities are characteristic of particular cancer immunology modeling approaches. The optimal choice and utilization of models depends on the cancer immunology scientific question being addressed and can serve to increase mechanistic understanding and development of human immuno-oncology therapies.

近年来,有效的免疫肿瘤学疗法不断涌现,对抗癌免疫模型实验方法的需求也随之增加。目前已开发出多种小鼠模型,用于研究癌症免疫学。这些模型包括诱变剂诱导模型、基因工程模型、同种异体模型和其他癌症免疫学模型。这些模型都有可能确定抗癌免疫反应的机理方面,确定潜在的治疗靶点,并作为临床前模型用于进一步的治疗开发。特定的癌症免疫学建模方法具有特定的优点和缺点。对模型的最佳选择和利用取决于所要解决的癌症免疫学科学问题,并有助于加深对人体免疫肿瘤疗法的机理理解和开发。
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引用次数: 0
Toxin-Induced Animal Models of Parkinson's Disease. 毒素诱导的帕金森病动物模型。
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1101/cshperspect.a041643
Kim Tieu, Said S Salehe, Harry J Brown

The debilitating motor symptoms of Parkinson's disease (PD) result primarily from the degenerative nigrostriatal dopaminergic pathway. To elucidate pathogenic mechanisms and evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. Herein, we systematically review the literature over the past decade. Some models no longer serve the purpose of PD models. The primary objectives of this review are: First, to assist new investigators in navigating through available animal models and making appropriate selections based on the objective of the study. Emphasis will be placed on common toxin-induced murine models. And second, to provide an overview of basic technical requirements for assessing the nigrostriatal pathway's pathology, structure, and function.

帕金森病(PD)使人衰弱的运动症状主要源于黑质多巴胺能通路的退化。为了阐明帕金森病的致病机制和评估治疗策略,人们开发了许多动物模型。了解这些模型的优势和局限性会对模型选择、实验设计和数据解读产生重大影响。在此,我们系统回顾了过去十年的文献。一些模型已不再符合 PD 模型的目的。本综述的主要目的是首先,帮助新研究人员浏览现有的动物模型,并根据研究目的做出适当的选择。重点将放在常见的毒素诱导小鼠模型上。其次,概述评估黑质通路病理学、结构和功能的基本技术要求。
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引用次数: 0
Angiogenesis: Biology and Pathology, Second Edition. 血管生成:血管生成:生物学与病理学》,第二版。
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1101/cshperspect.a041779
Diane R Bielenberg, Patricia A D'Amore

During development, the first blood vessels are formed by the de novo assembly of angioblasts, endothelial cell precursors, in a process called vasculogenesis. All subsequent sprouting of blood vessels from pre-existing vessels is termed angiogenesis and is a process that continues throughout our lifespan during physiological processes such as wound healing as well as in number of pathological conditions, such as tumor growth and age-related macular degeneration. The circulatory system pumps blood from the heart out to the organs through arteries and deliveries oxygen and nutrients via capillaries to tissues and cells and returns carbon dioxide and waste products back through veins. Each organ varies in its blood vessel patterning, reflecting specialization to accomplish diverse functions including vascular permeability, filtration, immune trafficking, and hormone regulation. Approximately 90% of the fluid extravasated into the interstitium is recycled back to the circulatory system via the unidirectional lymphatic system. Lymphatic capillaries drain fluid, proteins, and cells from tissues and transport this lymph fluid through collecting lymphatic ducts toward lymph nodes. Eventually lymphatic fluid from the right and left lymphatic ducts joins the subclavian veins and recirculates throughout the circulatory system. These two intricate vascular systems, working in cooperation, help to maintain essential bodily functions such as fluid dynamics, tissue homeostasis, blood pressure, metabolism, and immunity. However, dysfunction of these systems is associated with a host of pathological conditions, including cardiovascular diseases, obesity, retinopathy, hypoxia, necrosis, and vascular malformations.

在发育过程中,血管母细胞(内皮细胞的前体)从头组装形成第一条血管,这一过程被称为血管生成。随后,血管从先前存在的血管中萌发出来的所有过程都被称为血管生成,这一过程贯穿人的一生,既包括伤口愈合等生理过程,也包括肿瘤生长和老年性黄斑变性等病理过程。循环系统通过动脉将血液从心脏泵出到器官,通过毛细血管将氧气和营养物质输送到组织和细胞,并通过静脉将二氧化碳和废物送回。每个器官的血管形态都不尽相同,这反映了器官的专业化,以完成不同的功能,包括血管通透性、过滤、免疫贩运和激素调节。渗入间质的液体约有 90% 通过单向淋巴系统循环回循环系统。淋巴毛细血管从组织中排出液体、蛋白质和细胞,并通过收集淋巴管将淋巴液输送到淋巴结。最终,来自左右淋巴管的淋巴液汇入锁骨下静脉,在整个循环系统中再循环。这两个错综复杂的血管系统相互配合,帮助维持人体的基本功能,如流体动力学、组织平衡、血压、新陈代谢和免疫。然而,这些系统的功能障碍与一系列病理状况有关,包括心血管疾病、肥胖、视网膜病变、缺氧、坏死和血管畸形。
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引用次数: 0
Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer. 癌症中脂肪酸和胆固醇代谢与细胞应激反应途径的相互作用
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1101/cshperspect.a041548
Alina M Winkelkotte, Kamal Al-Shami, Adriano B Chaves-Filho, Felix C E Vogel, Almut Schulze

Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.

脂质作为细胞膜的结构成分、高效储能分子和信号介质的前体,具有重要的功能。癌症中的葡萄糖和氨基酸代谢失调已受到广泛关注,但人们对脂质在癌细胞代谢重塑过程中的作用却不甚了解。然而,自近 70 年前首次描述癌症组织中的新脂肪酸生物合成以来,已有大量研究探讨了癌症中脂质代谢改变的复杂功能。在此,我们将总结致癌信号通路调节脂肪酸和胆固醇代谢以推动癌细胞快速增殖并保护其免受环境压力的机制。综述还讨论了脂肪酸代谢在适应癌症发展过程中不断变化的微环境所需的代谢可塑性中的作用,以及脂肪酸和胆固醇代谢与铁变态反应之间的联系。
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引用次数: 0
Exploring Parkinson's through the Lens of Genomics and Bioinformatics.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-10 DOI: 10.1101/cshperspect.a041621
Vilas Menon

Within the last three decades, revolutions in genomics data generation and bioinformatics analysis techniques have profoundly impacted our understanding of the molecular mechanisms of Parkinson's disease (PD). From the description of the first PD-associated risk gene in 1997 through today, new technologies have revolutionized approaches to identify genetic and molecular mechanisms implicated in human health and disease. Spurred by the dramatically decreasing costs for genotyping, genome sequencing, and transcriptomics approaches, the ability to profile large cohorts of human populations or model organisms has accelerated the understanding of disease susceptibility, pathways, and genes. Thus far, ∼30 genetic loci have been unequivocally linked to the pathogenesis of PD, highlighting essential molecular pathways underlying this common disorder. More recently, the advent of single-cell transcriptomics techniques applied to human brain tissue has implicated cell-type-specific dysregulation and vulnerability (beyond the loss of dopaminergic neurons) in the disease. Herein, we discuss how neurogenomics and bioinformatics are applied to dissect the nature of this complex disease with the overall aim of identifying new targets for therapeutic interventions.

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引用次数: 0
Genetic Predisposition to Hematologic Malignancies.
IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-10 DOI: 10.1101/cshperspect.a041585
Kayla V Hamilton, Akiko Shimamura, Jessica A Pollard

Hematologic malignancies (HMs) have been increasingly recognized in association with an underlying genetic predisposition syndrome (GPS) in individuals of all ages. It is critical for hematology and oncology providers to be aware of the diagnostic findings, physical examination findings, and aspects of family history that raise suspicion for an underlying GPS. Moreover, recognition of how somatic gene panel testing, frequently done at the time of HM diagnosis, may raise suspicion for an underlying germline condition based on the mutation profile reported, is prudent. With knowledge of an underlying germline condition, the chemotherapy used for a given HM may be impacted and the role of hematopoietic stem cell transplant more critically considered. Off-therapy monitoring after HM treatment is completed will also likely be impacted. In this work, we review key features of several GPSs associated with increased risks for HM while also outlining the diagnostic workup to identify GPSs and treatment considerations for affected patients. Armed with this knowledge, treating providers may evaluate the possibility of a GPS in patients with leukemia/lymphoma and modify their treatment plan accordingly.

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引用次数: 0
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Cold Spring Harbor perspectives in medicine
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