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Science in Medicine

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New insights into the mechanisms of venous thrombosis
Nigel Mackman
Nigel Mackman
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(7):2331-2336. https://doi.org/10.1172/JCI60229.
View: Text | PDF | Corrigendum

New insights into the mechanisms of venous thrombosis

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Abstract

Venous thrombosis is a leading cause of morbidity and mortality in industrialized countries, especially in the elderly. Many risk factors have been identified for venous thrombosis that alter blood flow, activate the endothelium, and increase blood coagulation. However, the precise mechanisms that trigger clotting in large veins have not been fully elucidated. The most common site for initiation of the thrombus appears to be the valve pocket sinus, due to its tendency to become hypoxic. Activation of endothelial cells by hypoxia or possibly inflammatory stimuli would lead to surface expression of adhesion receptors that facilitate the binding of circulating leukocytes and microvesicles. Subsequent activation of the leukocytes induces expression of the potent procoagulant protein tissue factor that triggers thrombosis. Understanding the mechanisms of venous thrombosis may lead to the development of new treatments.

Authors

Nigel Mackman

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Hooked! Modeling human disease in zebrafish
Cristina Santoriello, Leonard I. Zon
Cristina Santoriello, Leonard I. Zon
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(7):2337-2343. https://doi.org/10.1172/JCI60434.
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Hooked! Modeling human disease in zebrafish

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Abstract

Zebrafish have been widely used as a model system for studying developmental processes, but in the last decade, they have also emerged as a valuable system for modeling human disease. The development and function of zebrafish organs are strikingly similar to those of humans, and the ease of creating mutant or transgenic fish has facilitated the generation of disease models. Here, we highlight the use of zebrafish for defining disease pathways and for discovering new therapies.

Authors

Cristina Santoriello, Leonard I. Zon

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The molecular pathogenesis of head and neck squamous cell carcinoma
S. Michael Rothenberg, Leif W. Ellisen
S. Michael Rothenberg, Leif W. Ellisen
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(6):1951-1957. https://doi.org/10.1172/JCI59889.
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The molecular pathogenesis of head and neck squamous cell carcinoma

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Abstract

Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the molecular pathogenesis of this disease. Overall, while somatic activating mutations within classical oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead genetic data point to a contribution of multiple tumor suppressor pathways, including p53, Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies, should promote novel therapeutic approaches and improved disease outcomes.

Authors

S. Michael Rothenberg, Leif W. Ellisen

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Uncovering the role of genomic “dark matter” in human disease
Lance Martin, Howard Y. Chang
Lance Martin, Howard Y. Chang
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(5):1589-1595. https://doi.org/10.1172/JCI60020.
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Uncovering the role of genomic “dark matter” in human disease

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Abstract

The human genome encodes thousands of long noncoding RNAs (lncRNAs). Although most remain functionally uncharacterized biological “dark matter,” lncRNAs have garnered considerable attention for their diverse roles in human biology, including developmental programs and tumor suppressor gene networks. As the number of lncRNAs associated with human disease grows, ongoing research efforts are focusing on their regulatory mechanisms. New technologies that enable enumeration of lncRNA interaction partners and determination of lncRNA structure are well positioned to drive deeper understanding of their functions and involvement in pathogenesis. In turn, lncRNAs may become targets for therapeutic intervention or new tools for biotechnology.

Authors

Lance Martin, Howard Y. Chang

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Chromosomal instability and cancer: a complex relationship with therapeutic potential
Samuel F. Bakhoum, Duane A. Compton
Samuel F. Bakhoum, Duane A. Compton
Published April 2, 2012
Citation Information: J Clin Invest. 2012;122(4):1138-1143. https://doi.org/10.1172/JCI59954.
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Chromosomal instability and cancer: a complex relationship with therapeutic potential

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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

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Macrophage plasticity and polarization: in vivo veritas
Antonio Sica, Alberto Mantovani
Antonio Sica, Alberto Mantovani
Published March 1, 2012
Citation Information: J Clin Invest. 2012;122(3):787-795. https://doi.org/10.1172/JCI59643.
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Macrophage plasticity and polarization: in vivo veritas

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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

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Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma
Uma M. Sachdeva, Joan M. O’Brien
Uma M. Sachdeva, Joan M. O’Brien
Published February 1, 2012
Citation Information: J Clin Invest. 2012;122(2):425-434. https://doi.org/10.1172/JCI57114.
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Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma

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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

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Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover
Roger H. Unger, Alan D. Cherrington
Roger H. Unger, Alan D. Cherrington
Published January 3, 2012
Citation Information: J Clin Invest. 2012;122(1):4-12. https://doi.org/10.1172/JCI60016.
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Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

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Abstract

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor–null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.

Authors

Roger H. Unger, Alan D. Cherrington

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Pancreatic ductal cells in development, regeneration, and neoplasia
Maximilian Reichert, Anil K. Rustgi
Maximilian Reichert, Anil K. Rustgi
Published December 1, 2011
Citation Information: J Clin Invest. 2011;121(12):4572-4578. https://doi.org/10.1172/JCI57131.
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Pancreatic ductal cells in development, regeneration, and neoplasia

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Abstract

The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

Authors

Maximilian Reichert, Anil K. Rustgi

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Cellular pathophysiology of ischemic acute kidney injury
Joseph V. Bonventre, Li Yang
Joseph V. Bonventre, Li Yang
Published November 1, 2011
Citation Information: J Clin Invest. 2011;121(11):4210-4221. https://doi.org/10.1172/JCI45161.
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Cellular pathophysiology of ischemic acute kidney injury

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Abstract

Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease. Better understanding of the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive kidney disease.

Authors

Joseph V. Bonventre, Li Yang

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