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Understanding the Warburg Effect in Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Zhaoqi Li, Muhammad Bin Munim, Daniel A. Sharygin, Brooke J. Bevis, Matthew G. Vander Heiden
Rapidly proliferating cells, including cancer cells, adapt metabolism to meet the increased energetic and biosynthetic demands of cell growth and division. Many rapidly proliferating cells exhibit increased glucose consumption and fermentation regardless of oxygen availability, a phenotype termed aerobic glycolysis or the Warburg effect in cancer. Several explanations for why cells engage in aerobic
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Autoantigen-Specific Immunotherapies for the Prevention and Treatment of Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Mark Peakman, Pere Santamaria
Type 1 diabetes (T1D) is driven by an immunologically complex, diverse, and self-sustaining immune response directed against tissue autoantigens, leading to loss or dysfunction of β cells. To date, the single approved immune intervention in T1D is based on a strategy that is similar to that used in other related autoimmune diseases, namely, the attenuation of immune cell activation. As a next-generation
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Technologies for Decoding Cancer Metabolism with Spatial Resolution Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Walter W. Chen, Michael E. Pacold, David M. Sabatini, Naama Kanarek
It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of
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Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Ruby Yun-Ju Huang, Jimmy Jin-Che Lin
Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct pathological features, molecular profiles, and biological functions. OCCC has high incidence rates in East Asia compared to the Western hemisphere and Europe and is associated with endometriosis. With its relative resistance to conventional treatment regimens and the worst stage-adjusted prognosis
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The Teplizumab Saga: The Challenge of Not Getting Lost in Clinical Translation Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Lucienne Chatenoud, Kevan C. Herold, Jean-François Bach, Jeffrey A. Bluestone
In November 2022, teplizumab became the first drug approved to delay the course of any autoimmune disease and to change the course of type 1 diabetes (T1D) since the discovery of insulin. The path to its approval took more than 30 years with both successes and failures along the way that would have normally led to its abandonment in other circumstances. Development of the drug was based on studies
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Cancer Metabolism: Aspirations for the Coming Decade Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Ralph J. DeBerardinis, Karen H. Vousden, Navdeep S. Chandel
Fueled by technological and conceptual advancements over the past two decades, research in cancer metabolism has begun to answer questions dating back to the time of Otto Warburg. But, as with most fields, new discoveries lead to new questions. This review outlines the emerging challenges that we predict will drive the next few decades of cancer metabolism research. These include developing a more
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Rebalancing the Immune System to Treat Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-16 Yannick D. Muller, Patrick Ho, Jeffrey A. Bluestone, Qizhi Tang
In type 1 diabetes (T1D), the immune system mistakenly attacks the pancreatic islet β cells resulting in the loss of insulin secretion. Insulin-replacement therapy developed more than a century ago provided means to manage the symptoms of diabetes without addressing the root cause of the disease—the faulty immune system. A healthy immune system has built-in mechanisms to limit unwanted, excessive immune
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Breakdown and Repair of Peripheral Immune Tolerance in Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Gerald T. Nepom
Failures in peripheral immune tolerance mechanisms create a permissive environment for autoimmune diabetes initiation and disease progression. Biomarker analyses provide tools that allow recognition of this loss of tolerance, reflecting a serial acquisition of pathogenic characteristics causally linked to islet β-cell dysfunction and death. Autoimmune effector cell activation and expansion, ineffective
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Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Domitille Rérolle, Hsin-Chieh Wu, Hugues de Thé
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion oncoprotein. Over the years, it has emerged as a model system to understand how this simple (and sometimes sole) genetic alteration can transform hematopoietic progenitors through the acquisition of dominant-negative properties toward both transcriptional control by nuclear receptors
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Immunometabolic Maladaptations to the Tumor Microenvironment Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Emma S. Hathaway, Erin Q. Jennings, Jeffrey C. Rathmell
Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede
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Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Daniel Peled, Ruth Casey, Eyal Gottlieb
With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of “westward expansion,” ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated
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Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Esther W. Lim, Christian M. Metallo
One-carbon (1C) metabolism is a network of biochemical reactions distributed across organelles that delivers folate-activated 1C units to support macromolecule synthesis, methylation, and reductive homeostasis. Fluxes through these pathways are up-regulated in highly proliferative cancer cells, and anti-folates, which target enzymes within the 1C pathway, have long been used in the treatment of cancer
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Imaging Approaches in Cancer Biology Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Nirakar Rajbhandari, Emily Diaz, Marcie Kritzik, Tannishtha Reya
A majority of cancer research is focused on defining the cellular and molecular basis of cancer cells and the signals that control oncogenic transformation; as a consequence, we know very little about the dynamic behavior of cancer cells in vivo. To begin to view and understand the mechanisms and interactions that control cancer initiation, growth, and metastatic progression and how these processes
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History of Finding Genes and Mutations Causing Inherited Retinal Diseases Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-09-01 Stephen P. Daiger, Lori S. Sullivan, Elizabeth L. Cadena, Sara J. Bowne
This is a brief history of the work by many investigators throughout the world to find genes and mutations causing inherited retinal diseases (IRDs). It largely covers 40 years, from the late-1980s through today. Perhaps the best reason to study history is to better understand the present. The “present” for IRDs is exceptionally complex. Mutations in hundreds of genes are known to cause IRDs; tens
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The Human Pancreas in Type 1 Diabetes: Lessons Learned from the Network of Pancreatic Organ Donors with Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-12 Irina Kusmartseva, Amanda Posgai, Mingder Yang, Richard Oram, Mark Atkinson, Alberto Pugliese, Carmella Evans-Molina
The Network for Pancreatic Organ Donors with Diabetes (nPOD) has helped shape the contemporary understanding of type 1 diabetes (T1D) pathogenesis in humans through the procurement, distribution to scientists, and collaborative study of human pancreata and disease-related tissues from organ donors with T1D and islet autoantibody positivity. Since its inception in 2007, nPOD has collected tissues from
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The Pathogenesis of Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-12 Kevan C. Herold, Jeffrey P. Krischer
Type 1 diabetes (T1D) is a chronic autoimmune disease with a metabolic outcome. Studies over the past decades, have identified the contributions of genetics, environmental factors, and disorders of innate and adaptive immunity that collectively cause β-cell killing. The risk for T1D can be genetically identified but genotypes alone do not identify factors that lead to disease progression. The incidence
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Genetics and Epigenetics of Type 1 Diabetes Self-Reactive T Cells Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-12 Tae Gun Kang, Benjamin Youngblood
Type 1 diabetes (T1D) serves as an exemplar of chronic autoimmune disease characterized by insulin deficiency due to pancreatic β-cell destruction, leading to hyperglycemia and progressive organ failure. Until recently, therapeutic efforts to mitigate the root cause of disease have been limited by the challenges in studying mechanisms involved in immune tolerance in humans. The current clinical advances
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The Role of B Lymphocytes in Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-12 Mia J. Smith, Joanne Boldison, F. Susan Wong
While autoreactive T cells are known to induce β-cell death in type 1 diabetes (T1D), self-reactive B cells also play an important role in the pathogenesis of T1D. Studies have shown that individuals living with T1D have an increased frequency of self-reactive B cells that escape from the bone marrow and populate peripheral organs, become activated, and participate in disease. These failed tolerance
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Genetics of Parkinson's Disease: From Causes to Treatment Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-12 Ana Westenberger, Norbert Brüggemann, Christine Klein
The genetic architecture of Parkinson's disease (PD) comprises five autosomal dominantly inherited forms with a clinical picture overall resembling idiopathic disease (PARK-SNCA, PARK-LRRK2, PARK-VPS35, PARK-CHCHD2, and PARK-RAB32) and three recessive types (PARK-PRKN, PARK-PINK1, and PARK-PARK7), several monogenic forms causing atypical parkinsonism, as well as a plethora of known genetic risk factors
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Optogenetic Vision Restoration Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 Volker Busskamp, Botond Roska, Jose-Alain Sahel
Optogenetics has emerged over the past 20 years as a powerful tool to investigate the various circuits underlying numerous functions, especially in neuroscience. The ability to control by light the activity of neurons has enabled the development of therapeutic strategies aimed at restoring some level of vision in blinding retinal conditions. Promising preclinical and initial clinical data support such
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Mouse Models of Metastasis and Dormancy Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 Ahmed Mahmoud, Karuna Ganesh
Metastasis is the ultimate and often lethal stage of cancer. Metastasis occurs in three phases that may vary across individuals: First, dissemination from the primary tumor. Second, tumor dormancy at the metastatic site where micrometastatic cancer cells remain quiescent or, in dynamic cycles of proliferation and elimination, remaining clinically undetectable. Finally, cancer cells are able to overcome
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Germline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 Siddhartha Yadav, Fergus J. Couch, Susan M. Domchek
Our understanding of hereditary breast and ovarian cancer has significantly improved over the past two decades. In addition to BRCA1/2, pathogenic variants in several other DNA-repair genes have been shown to increase the risks of breast and ovarian cancer. The magnitude of cancer risk is impacted not only by the gene involved, but also by family history of cancer, polygenic risk scores, and, in certain
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Resistance and Resilience to Alzheimer's Disease Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 Caitlin S. Latimer, Katherine E. Prater, Nadia Postupna, C. Dirk Keene
Dementia is a significant public health crisis; the most common underlying cause of age-related cognitive decline and dementia is Alzheimer's disease neuropathologic change (ADNC). As such, there is an urgent need to identify novel therapeutic targets for the treatment and prevention of the underlying pathologic processes that contribute to the development of AD dementia. Although age is the top risk
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Breast Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 Jane E. Visvader, Jeffrey M. Rosen, Samuel Aparicio
Breast cancer kills hundreds of thousands of people every year. Rapid progress over the past two decades has increased our understanding of the genetic and environmental risk factors for disease. It has also shed light on drivers of tumor progression and the molecular landscape underpinning tumor heterogeneity, as well as the role of the microenvironment and the immune system. These strides forward
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Geroscience and Its Promise Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-08-01 S. Jay Olshansky, James L. Kirkland
Why we age and whether our lifespan can be extended have intrigued scientists for centuries. Meanwhile public health advances mean humanity is having to confront the realities of an aging and increasingly frail population. The nascent field of geroscience offers hope that healthspan not just lifespan can be extended. It has spawned a vibrant scientific community that includes researchers studying fundamental
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Angiogenesis: Biology and Pathology, Second Edition Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-29 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
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Advances in Islet Transplantation and the Future of Stem Cell–Derived Islets to Treat Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-29 Timothy J. Kieffer, Corinne A. Hoesli, A.M. James Shapiro
β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and
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Innate Immunity in Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-29 Léo Bertrand, Alexander V. Chervonsky, Agnès Lehuen
Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance
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Corrigendum: Modeling Parkinson's Disease in Primates. Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-25 Erwan Bezard,Margaux Teil,Marie-Laure Arotcarena,Gregory Porras,Qin Li,Benjamin Dehay
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Checkpoint Inhibitor-Induced Autoimmune Diabetes: An Autoinflammatory Disease Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-22 Zoe Quandt, Ana Perdigoto, Mark S. Anderson, Kevan C. Herold
Immunomodulatory agents targeting immune checkpoints are now the state-of-the-art for the treatment of many cancers, but at the same time have led to autoimmune side effects, including autoimmune diabetes: immune checkpoint inhibitor-induced diabetes (CPI-DM). Emerging research shows the importance of preexisting autoimmune disease risk that has been identified through genetics, and autoantibodies
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Inflammatory β-Cell Stress and Immune Surveillance in Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-22 Anil Bhushan, Peter J. Thompson
Recent years have seen increased recognition for the role of β-cell stress as a contributing factor to the autoimmune destruction process that ultimately results in symptomatic type 1 diabetes (T1D). Preclinical studies have discovered a variety of stress responses in the β-cell that occur at presymptomatic stages and contribute to disease progression, but unifying explanations of how these mechanisms
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Cross Talk between β Cells and Immune Cells: What We Know, What We Think We Know, and What We Should Learn Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-22 Fatoumata Samassa, Capucine Holtzmann, Roberto Mallone
Type 1 diabetes (T1D) is a disease whose pathogenesis is driven by both immune dysregulation and β-cell dysfunction. While the specialized structure and function of β cells make them vulnerable to autoimmunity, several surface receptor/ligand pairs underlie the cross talk engaged with T lymphocytes and other immune subsets. The expression of these ligands on β cells is coordinately up-regulated by
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Immunotherapies for Childhood Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-15 Jeong A. Park, Nai-Kong V. Cheung
Children are surviving cancer in greater numbers than ever. Over the last 50 years, substantial advancements in pediatric cancer treatment have resulted in an 85% 5-year survival rate. Nonetheless, a notable 10%–15% of patients encounter relapse or develop refractory disease, leading to significantly lower survival. Recent attempts to further intensify cytotoxic chemotherapy have failed due to either
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Targeting Hyperactive Ras Signaling in Pediatric Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-15 Anya Levinson, Kevin Shannon, Benjamin J. Huang
Somatic RAS mutations are among the most frequent drivers in pediatric and adult cancers. Somatic KRAS, NRAS, and HRAS mutations exhibit distinct tissue-specific predilections. Germline NF1 and RAS mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased
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Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-15 Katie A. Greenzang, Stephen E. Sallan
Over the last 75 years, pediatric cancer has gone from nearly universally fatal, to having a >80% chance of long-term survival. Below we share highlights in this 75-year history, beginning with the “birth” of chemotherapy in treating childhood leukemia, through the development of multiagent chemotherapy, risk-stratified therapy, the use of molecular strategies in diagnosis and treatment, and adapting
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Metabolic Reprogramming in Human Cancer Patients and Patient-Derived Models Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-15 Teresa W.-M. Fan, Richard M. Higashi, Andrew N. Lane
Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the “benchmark” for cancer models to recapitulate. It is particularly difficult to model patients’ tumor microenvironment (TME) with its complex cell–cell/cell–matrix interactions, which shapes metabolic reprogramming crucial to cancer
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Imaging Tumor Metabolism Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-15 Thomas Ruan, Kayvan R. Keshari
Molecular imaging—the mapping of molecular and cellular processes in vivo—has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic
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The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Maria Skjøtt Hansen, Pravil Pokharel, Jon Piganelli, Lori Sussel
In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves
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Toxin-Induced Animal Models of Parkinson's Disease Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 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
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Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 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
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Organoid Cultures for the Study of Mammary Biology and Breast Cancer: The Promise and Challenges Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Senthil K. Muthuswamy, Joan S. Brugge
During the last decade, biomedical research has experienced a resurgence in the use of three-dimensional culture models for studies of normal and cancer biology. This resurgence has been driven by the development of models in which primary cells are grown in tissue-mimicking media and extracellular matrices to create organoid or organotypic cultures that more faithfully replicate the complex architecture
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Integrating Omics into Functional Biomarkers of Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 S. Alice Long, Peter S. Linsley
Biomarkers are critical to the staging and diagnosis of type 1 diabetes (T1D). Functional biomarkers offer insights into T1D immunopathogenesis and are often revealed using “omics” approaches that integrate multiple measures to identify involved pathways and functions. Application of the omics biomarker discovery may enable personalized medicine approaches to circumvent the more recently appreciated
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Role of Tumor Cell Intrinsic and Host Autophagy in Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Jessie Yanxiang Guo, Eileen White
Macroautophagy (autophagy hereafter) is an intracellular nutrient scavenging pathway induced by starvation and other stressors whereby cellular components such as organelles are captured in double-membrane vesicles (autophagosomes), whereupon their contents are degraded through fusion with lysosomes. Two main purposes of autophagy are to recycle the intracellular breakdown products to sustain metabolism
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Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Kathleen M. McAndrews, Krishnan K. Mahadevan, Raghu Kalluri
The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components
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Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Emiliano Cocco, Elisa de Stanchina
The use of patient-derived xenografts (PDXs) has dramatically improved drug development programs. PDXs (1) reproduce the pathological features and the genomic profile of the parental tumors more precisely than other preclinical models, and (2) more faithfully predict therapy response. However, PDXs have limitations. These include the inability to completely capture tumor heterogeneity and the role
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Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-07-01 Boris Rosin, Eyal Banin, Jose-Alain Sahel
With the rapid expansion of methods encompassed by the term gene therapy, new trials exploring the safety and efficacy of these methods are initiated more frequently. As a result, important questions arise pertaining the design of these trials and patient participation. One of the most important aspects of any clinical trial is the ability to measure the trial's outcome in a manner that will reflect
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Advancing Animal Models of Human Type 1 Diabetes Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-17 David V. Serreze, Jennifer R. Dwyer, Jeremy J. Racine
Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the
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Lessons Learned from Cancer Metabolism for Physiology and Disease Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-10 Sydney L. Campbell, Heather R. Christofk
Tumor cells divide rapidly and dramatically alter their metabolism to meet biosynthetic and bioenergetic needs. Through studying the aberrant metabolism of cancer cells, other contexts in which metabolism drives cell state transitions become apparent. In this work, we will discuss how principles established by the field of cancer metabolism have led to discoveries in the contexts of physiology and
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Historical Perspectives of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-10 Christopher G. Goetz
Although components of possible Parkinson's disease can be found in earlier documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated the clinical spectrum of Parkinson's
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Metabolic Signaling in Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-10 Laura V. Pinheiro, Pedro Costa-Pinheiro, Kathryn E. Wellen
Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis
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Modeling Parkinson's Disease in Primates Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-10 Erwan Bezard, Margaux Teil, Marie-Laure Arotcarena, Gregory Porras, Qin Li, Benjamin Dehay
Decades of research have identified the pathological and pathophysiological hallmarks of Parkinson's disease (PD): profound deficit in brain dopamine and other monoamines, pathological α-synuclein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, altered energy homeostasis, inflammation, and neuronal cell death. The purpose of this contribution is to present the phenocopy
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The Extraordinary Phenotypic and Genetic Variability of Retinal and Macular Degenerations: The Relevance to Therapeutic Developments Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-01 Isabelle Audo, Marco Nassisi, Christina Zeitz, José-Alain Sahel
Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of rare conditions leading to various degrees of visual handicap and to progressive blindness in more severe cases. Besides visual rehabilitation, educational, and socio-professional support, there are currently limited therapeutic options, but the approval of the first gene therapy product for RPE65-related IRDs
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Breast Cancer Histopathology in the Age of Molecular Oncology Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-01 Zuzana Kos, Torsten O. Nielsen, Anne-Vibeke Laenkholm
For more than a century, microscopic histology has been the cornerstone for cancer diagnosis, and breast carcinoma is no exception. In recent years, clinical biomarkers, gene expression profiles, and other molecular tests have shown increasing utility for identifying the key biological features that guide prognosis and treatment of breast cancer. Indeed, the most common histologic pattern—invasive
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Cellular Origins and Lineage Plasticity in Cancer Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-01 Jason R. Pitarresi, Ben Z. Stanger
All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those “cells-of-origin” has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide
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Next-Generation Modeling of Cancer Using Organoids Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-01 Jillian R. Love, Wouter R. Karthaus
In the last decade, organoid technology has become a cornerstone in cancer research. Organoids are long-term primary cell cultures, usually of epithelial origin, grown in a three-dimensional (3D) protein matrix and a fully defined medium. Organoids can be derived from many organs and cancer types and sites, encompassing both murine and human tissues. Importantly, they can be established from various
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Aging and Inflammation Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-06-01 Amit Singh, Shepherd H. Schurman, Arsun Bektas, Mary Kaileh, Roshni Roy, David M. Wilson III, Ranjan Sen, Luigi Ferrucci
Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed
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Lineage-Selective Dependencies in Pediatric Cancers Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-05-28 K. Elaine Ritter, Adam D. Durbin
The quest for effective cancer therapeutics has traditionally centered on targeting mutated or overexpressed oncogenic proteins. However, challenges arise in cancers with low mutational burden or when the mutated oncogene is not conventionally targetable, which are common situations in childhood cancers. This obstacle has sparked large-scale unbiased screens to identify collateral genetic dependencies
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Advances in Studying Cancer Immunology in Mice Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-05-21 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
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The Gut–Brain Axis in Parkinson's Disease Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-05-21 Virginia Gao, Carl V. Crawford, Jacqueline Burré
Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps
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The Evolution of Mouse Models of Cancer: Past, Present, and Future Cold Spring Harbor Perspect. Med. (IF 7.8) Pub Date : 2024-05-21 Cory Abate-Shen, Katerina Politi
In the nearly 50 years since the original models of cancer first hit the stage, mouse models have become a major contributor to virtually all aspects of cancer research, and these have evolved well beyond simple transgenic or xenograft models to encompass a wide range of more complex models. As the sophistication of mouse models has increased, an explosion of new technologies has expanded the potential