Review
Abstract
While immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. Factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. We will review this complex field from the perspective of neurons, extra-neuronal brain cells, and the systemic environment and highlight the possibility that cell intrinsic innate immune molecules in neurons may function in neurodegenerative processes.
Authors
Eva Czirr, Tony Wyss-Coray
Abstract
Chromosomal instability (CIN) is a hallmark of human neoplasms. Despite its widespread prevalence, knowledge of the mechanisms and contributions of CIN in cancer has been elusive. It is now evident that the role of CIN in tumor initiation and growth is more complex than previously thought. Furthermore, distinguishing CIN, which consists of elevated rates of chromosome missegregation, from aneuploidy, which is a state of abnormal chromosome number, is crucial to understanding their respective contributions in cancer. Collectively, experimental evidence suggests that CIN enables tumor adaptation by allowing tumors to constantly sample the aneuploid fitness landscape. This complex relationship, together with the potential to pharmacologically influence chromosome missegregation frequencies in cancer cells, offers previously unrecognized means to limit tumor growth and its response to therapy.
Authors
Samuel F. Bakhoum, Duane A. Compton
Abstract
Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
Authors
Antonio Sica, Alberto Mantovani
Abstract
Retinoblastoma is a pediatric retinal tumor initiated by biallelic inactivation of the retinoblastoma gene (RB1). RB1 was the first identified tumor suppressor gene and has defined roles in the regulation of cell cycle progression, DNA replication, and terminal differentiation. However, despite the abundance of work demonstrating the molecular function and identifying binding partners of pRb, the challenge facing molecular biologists and clinical oncologists is how to integrate this vast body of molecular knowledge into the development of targeted therapies for treatment of retinoblastoma. We propose that a more thorough genetic understanding of retinoblastoma would inform targeted treatment decisions and could improve outcomes and quality of life in children affected by this disease.
Authors
Uma M. Sachdeva, Joan M. O’Brien
Abstract
Dermatologic disease, although seldom life threatening, can be extremely disfiguring and interfere with the quality of life. In addition, as opposed to other organs, just the aging of skin and its adnexal structure the hair follicle can result in cosmetic concerns that affect most of us. The articles in this dermatology Review Series demonstrate recent progress in understanding the cell biology and molecular pathophysiology of the epidermis and hair follicles, which harbor keratinocyte and melanocyte stem cells. They reveal a dynamic relationship between research and clinical care: knowledge of dermatologic disease has facilitated the understanding of the biology of the epidermis and, in turn, progress in basic science has informed our understanding of disease. This type of synergy is a profound strength of clinical research of the type that the JCI is dedicated to publishing.
Authors
John R. Stanley
Abstract
I recently had the opportunity to visit a very relaxing and beautiful day spa during the middle-of-the-day break from the sessions at a Keystone meeting. I was having a very tranquil and restorative day, when I went in for my final treatment — a facial. The very chipper and cheerful esthetician began examining my skin and applying various creams, when I then heard her say something that nearly ruined my experience: she claimed that the topical treatment she was about to apply would, in her words, “cleanse my liver.”
Authors
Ushma S. Neill
Abstract
Basal cell carcinoma (BCC) of the skin, the most common malignancy in individuals of mixed European descent, is increasing in incidence due to an aging population and sun exposure habits. The realization that aberrant activation of Hedgehog signaling is a pathognomonic feature of BCC development has opened the way for exciting progress toward understanding BCC biology and translation of this knowledge to the clinic. Genetic mouse models closely mimicking human BCCs have provided answers about the tumor cell of origin, and inhibition of Hedgehog signaling is emerging as a potentially useful targeted therapy for patients with advanced or multiple BCCs that have hitherto lacked effective treatment.
Authors
Maria Kasper, Viljar Jaks, Daniel Hohl, Rune Toftgård
Abstract
The adult hair follicle houses stem cells that govern the cyclical growth and differentiation of multiple cell types that collectively produce a pigmented hair. Recent studies have revealed that hair follicle stem cells are heterogeneous and dynamic throughout the hair cycle. Moreover, interactions between heterologous stem cells, including both epithelial and melanocyte stem cells, within the hair follicle are just now being explored. This review will describe how recent findings have expanded our understanding of the development, organization, and regeneration of hair follicle stem cells. At a basic level, this review is intended to help construct a reference point to integrate the surge of studies on the molecular mechanisms that regulate these cells.
Authors
Peggy Myung, Mayumi Ito
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. In this Review we discuss clinical and molecular parameters used to define this range of cutaneous neoplasia and integrate these with the multiple experimental approaches used to study this disease. Insights gained from modeling cSCCs have suggested innovative therapeutic targets for treating these lesions.
Authors
Vladimir Ratushny, Michael D. Gober, Ryan Hick, Todd W. Ridky, John T. Seykora
Abstract
Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators’ attention on epidermal barrier dysfunction as a causative mechanism. The skin’s barrier function has three elements: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases.
Authors
Akiharu Kubo, Keisuke Nagao, Masayuki Amagai
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ISSN: 0021-9738 (print), 1558-8238 (online)