Review

Abstract

Sickle cell disease (SCD) is a monogenic disorder characterized by recurrent episodes of severe bone pain, multi-organ failure, and early mortality. Although medical progress over the past several decades has improved clinical outcomes and offered cures for many affected individuals living in high-income countries, most SCD patients still experience substantial morbidity and premature death. Emerging technologies to manipulate somatic cell genomes and insights into the mechanisms of developmental globin gene regulation are generating potentially transformative approaches to cure SCD by autologous hematopoietic stem cell (HSC) transplantation. Key components of current approaches include ethical informed consent, isolation of patient HSCs, in vitro genetic modification of HSCs to correct the SCD mutation or circumvent its damaging effects, and reinfusion of the modified HSCs following myelotoxic bone marrow conditioning. Successful integration of these components into effective therapies requires interdisciplinary collaborations between laboratory researchers, clinical caregivers, and patients. Here we summarize current knowledge and research challenges for each key component, emphasizing that the best approaches have yet to be developed.

Authors

Phillip A. Doerfler, Akshay Sharma, Jerlym S. Porter, Yan Zheng, John F. Tisdale, Mitchell J. Weiss

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Abstract

Scientific progress and discovery of preventions and cures for life-threatening diseases depend on the vitality of the biomedical research workforce. We analyzed the workforce of cancer researchers applying for and receiving R01 awards from the National Cancer Institute (NCI) from fiscal years 1990 to 2016, the last year prior to implementation of the Next Generation Researchers Initiative. Here we report that the NCI R01 Principal Investigator (PI) workforce expanded 1.4-fold and aged over this time frame. We tracked 9 age groups and found that the number of PIs in the 3 oldest groups increased dramatically, in contrast with the younger groups. Sustained increases in the number of funded older PIs stemmed from increases in the number of older PIs submitting applications, rather than higher funding rates for older PIs. The decline in the number of funded younger PIs was driven in part by (a) a marked increase in time from PhD degree to first R01 application and award, as well as (b) a decrease in retention of PIs in the funded R01 workforce beyond their first R01 award. The NCI is using these and other analyses to inform strategies and policies for attracting, supporting, and retaining meritorious early-career researchers.

Authors

Melissa D. Antman, Roman Gorelik, Amy Kennedy, Grace F. Liou, Eddie N. Billingslea, James G. Corrigan, L. Michelle Bennett

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Abstract

As part of the centennial celebration of insulin’s discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the β cells in the pancreatic islet and requires life-long insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regards to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This review highlights knowledge gaps and opportunities to improve the understanding of T1D pathogenesis and outlines emerging therapies to treat or prevent T1D and reduce the burden of T1D.

Authors

Alvin C. Powers

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Abstract

The tumor microenvironment profoundly influences the behavior of recruited leukocytes and tissue-resident immune cells. These immune cells, which inherently have environmentally driven plasticity necessary for their roles in tissue homeostasis, dynamically interact with tumor cells and the tumor stroma and play critical roles in determining the course of disease. Among these immune cells, neutrophils were once considered much more static within the tumor microenvironment; however, some of these earlier assumptions were the product of the notorious difficulty in manipulating neutrophils in vitro. Technological advances that allow us to study neutrophils in context are now revealing the true roles of neutrophils in the tumor microenvironment. Here we discuss recent data generated by some of these tools and how these data might be synthesized into more elegant ways of targeting these powerful and abundant effector immune cells in the clinic.

Authors

Amanda J. McFarlane, Frédéric Fercoq, Seth B. Coffelt, Leo M. Carlin

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Abstract

Treatment resistance leads to cancer patient mortality. Therapeutic approaches that employ synthetic lethality to target mutational vulnerabilities in key tumor cell signaling pathways have proven effective in overcoming therapeutic resistance in some cancers. Yet, tumors are organs composed of malignant cells residing within a cellular and noncellular stroma. Tumor evolution and resistance to anticancer treatment are mediated through a dynamic and reciprocal dialogue with the tumor microenvironment (TME). Accordingly, expanding tumor cell synthetic lethality to encompass contextual synthetic lethality has the potential to eradicate tumors by targeting critical TME circuits that promote tumor progression and therapeutic resistance. In this Review, we summarize current knowledge about the TME and discuss its role in treatment. We outline the concept of tumor cell–specific synthetic lethality and describe therapeutic approaches to expand this paradigm to leverage TME synthetic lethality to improve cancer therapy.

Authors

Kevin J. Metcalf, Alaa Alazzeh, Zena Werb, Valerie M. Weaver

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Abstract

Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth’s surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as “photoaging.” We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.

Authors

Asurayya Worrede, Stephen M. Douglass, Ashani T. Weeraratna

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Abstract

Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.

Authors

Aaron M. Muscarella, Sergio Aguirre, Xiaoxin Hao, Sarah M. Waldvogel, Xiang H.-F. Zhang

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Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Authors

Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis

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Abstract

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.

Authors

Alvaro A. Ordonez, Elizabeth W. Tucker, Carolyn J. Anderson, Claire L. Carter, Shashank Ganatra, Deepak Kaushal, Igor Kramnik, Philana L. Lin, Cressida A. Madigan, Susana Mendez, Jianghong Rao, Rada M. Savic, David M. Tobin, Gerhard Walzl, Robert J. Wilkinson, Karen A. Lacourciere, Laura E. Via, Sanjay K. Jain

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Abstract

With the growing number of transgender and gender-nonbinary individuals who are becoming visible, it is clear that there is a need to develop a rigorous evidence base to inform care practice. Transgender health research is often limited to HIV/AIDS or mental health research and is typically subsumed in larger studies with general LGBTQ focus. Although the number of knowledgeable health care providers remains modest, the model for the medical approach to transgender health is shifting owing to growing social awareness and an appreciation of a biological component. Gender-affirming medicine facilitates aligning the body of the transgender person with the gender identity; typical treatment regimens include hormone therapy and/or surgical interventions. While broadly safe, hormone treatments require some monitoring for safety. Exogenous estrogens are associated with a dose-dependent increase in venous thromboembolic risk, and androgens stimulate erythropoiesis. The degree to which progressing gender-affirming hormone treatment changes cancer risk, cardiac heart disease risk, and/or bone health remains unknown. Guidelines referencing the potential exacerbation of cancer, heart disease, or other disease risk often rely on physiology models, because conclusive clinical data do not exist. Dedicated research infrastructure and funding are needed to address the knowledge gap in the field.

Authors

Joshua D. Safer

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