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1.  Lymphangiogenic factors, mechanisms, and applications 
Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.
doi:10.1172/JCI71603
PMCID: PMC3934166  PMID: 24590272
2.  Lymphatic transport of high-density lipoproteins and chylomicrons 
The life cycles of VLDLs and most LDLs occur within plasma. By contrast, the role of HDLs in cholesterol transport from cells requires that they readily gain access to and function within interstitial fluid. Studies of lymph derived from skin, connective tissue, and adipose tissue have demonstrated that particles as large as HDLs require transport through lymphatics to return to the bloodstream during reverse cholesterol transport. Targeting HDL for therapeutic purposes will require understanding its biology in the extravascular compartment, within the interstitium and lymph, in health and disease, and we herein review the processes that mediate the transport of HDLs and chylomicrons through the lymphatic vasculature.
doi:10.1172/JCI71610
PMCID: PMC3934183  PMID: 24590278
3.  Lymphatic vessels and tertiary lymphoid organs 
Tertiary lymphoid organs (TLOs) are accumulations of lymphoid cells in chronic inflammation that resemble LNs in their cellular content and organization, high endothelial venules, and lymphatic vessels (LVs). Although acute inflammation can result in defective LVs, TLO LVs appear to function normally in that they drain fluid and transport cells that respond to chemokines and sphingosine-1-phosphate (S1P) gradients. Molecular regulation of TLO LVs differs from lymphangiogenesis in ontogeny with a dependence on cytokines and hematopoietic cells. Ongoing work to elucidate the function and molecular regulation of LVs in TLOs is providing insight into therapies for conditions as diverse as lymphedema, autoimmunity, and cancer.
doi:10.1172/JCI71611
PMCID: PMC3934190  PMID: 24590281
4.  Insulin, osteoblasts, and energy metabolism: why bone counts calories 
The Journal of Clinical Investigation  2014;124(4):1465-1467.
Recent studies have demonstrated that insulin stimulates bone cells to produce and activate osteocalcin, an endocrine hormone that increases the efficiency of glucose metabolism through its actions on the pancreas and other peripheral tissues. In this issue of the JCI, Wei and colleagues directly explore the contribution of insulin signaling in osteoblasts to the disturbances in whole-body glucose metabolism associated with a high-fat diet. In mice fed a high-fat diet, increased uptake of saturated fatty acids by the osteoblast accelerates the ubiquitination and degradation of the insulin receptor. In this setting, impairments in osteoblast insulin signaling reduce serum levels of undercarboxylated osteocalcin, which in turn exacerbate insulin resistance in muscle and white adipose tissue. These findings underscore the importance of insulin-responsive skeletal cells as components of a newly appreciated endocrine network critical for regulating global energy homeostasis.
doi:10.1172/JCI75554
PMCID: PMC3973079  PMID: 24642463
5.  Recent developments in the treatment of age-related macular degeneration 
The Journal of Clinical Investigation  2014;124(4):1430-1438.
Age-related macular degeneration (AMD) is a common cause of visual loss in the elderly, with increasing prevalence due to increasing life expectancy. While the introduction of anti-VEGF therapy has improved outcomes, there are still major unmet needs and gaps in the understanding of underlying biological processes. These include early, intermediate, and atrophic disease stages. Recent studies have assessed therapeutic approaches addressing various disease-associated pathways, including complement inhibitors. Drug-delivery aspects are also relevant, as many agents have to be administered repeatedly. Herein, relevant pathogenetic factors and underlying mechanisms as well as recent and potential therapeutic approaches are reviewed.
doi:10.1172/JCI71029
PMCID: PMC3973093  PMID: 24691477
6.  Harnessing FOXP3+ regulatory T cells for transplantation tolerance  
The Journal of Clinical Investigation  2014;124(4):1439-1445.
Early demonstrations that mice could be tolerized to transplanted tissues with short courses of immunosuppressive therapy and that with regard to tolerance to self, CD4+FOXP3+ regulatory T cells (Tregs) appeared to play a critical role, have catalyzed strategies to harness FOXP3-dependent processes to control rejection in human transplantation. This review seeks to examine the scientific underpinning for this new approach to finesse immunosuppression.
doi:10.1172/JCI67226
PMCID: PMC3973097  PMID: 24691478
7.  Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity 
The Journal of Clinical Investigation  2014;124(4):1454-1457.
Nearly two decades ago, we evaluated ten patients with obstructive sleep apnea (OSA). We determined that alarming nocturnal oscillations in arterial pressure and sympathetic nerve activity (SNA) were caused by regulatory coupling and neural interactions among SNA, apnea, and ventilation. Patients with OSA exhibited high levels of SNA when awake, during normal ventilation, and during normoxia, which contributed to hypertension and organ damage. Additionally, we achieved a beneficial and potentially lifesaving reduction in SNA through the application of continuous positive airway pressure (CPAP), which remains a primary therapeutic approach for patients with OSA. With these results in hindsight, we herein discuss three concepts with functional and therapeutic relevance to the integrative neurobiology of autonomic cardiovascular control and to the mechanisms involved in excessive sympathoexcitation in OSA.
doi:10.1172/JCI70420
PMCID: PMC3973099  PMID: 24691480
8.  Nav-igating through a complex landscape: SCN10A and cardiac conduction  
The Journal of Clinical Investigation  2014;124(4):1460-1462.
Genome-wide association studies (GWAS) have implicated SCN10A, which encodes a nociceptor-associated voltage-gated sodium channel subunit, as a modulator of cardiac conduction; however, this role has traditionally been ascribed to SCN5A, which is highly expressed in cardiac muscle. SCN10A is believed to affect cardiac conduction either directly through cardiomyocytes or indirectly via intracardiac neurons. In this issue of the JCI, van den Boogaard and colleagues introduce a third possibility: that the SCN10A locus acts as an enhancer of SCN5A gene expression. The authors demonstrate that SCN10A expression is negligible within human and murine hearts, and that a T-box enhancer within the SCN10A locus drives SCN5A expression within cardiomyocytes. This work reasserts SCN5A as the key determinant of cardiac conduction and highlights the importance of deciphering the functionality of coding versus noncoding regions when interpreting GWAS data.
doi:10.1172/JCI75240
PMCID: PMC3973102  PMID: 24642462
9.  Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch 
The Journal of Clinical Investigation  2014;124(4):1458-1460.
The metastatic spread of tumor epithelial cells accounts for over 90% of cancer-specific mortality; however, the molecular mechanisms that govern tumor spread and distant recolonization remain unclear. In this issue of JCI, Rokavec and colleagues shine light on this murky aspect of tumor biology by focusing through the lens of microenvironmental contributions, namely inflammation, as driving signals that set off a delicate, intracellular feedback loop among cytokine receptors, transcription factors and miRNAs. This study provides in vivo evidence and identifies molecular players behind the elusive switch that drives the epithelial-to-mesenchymal transition and the mesenchymal-to-epithelial transition.
doi:10.1172/JCI75239
PMCID: PMC3973103  PMID: 24642461
10.  A conversation with Bonnie Bassler 
The Journal of Clinical Investigation  2014;124(4):1421-1422.
doi:10.1172/JCI75027
PMCID: PMC3973108  PMID: 24691474
11.  Multifocal epithelial tumors and field cancerization: stroma as a primary determinant 
The Journal of Clinical Investigation  2014;124(4):1446-1453.
It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ “fields.”
doi:10.1172/JCI72589
PMCID: PMC3973113  PMID: 24691479
12.  Beth Levine receives the 2014 ASCI/Stanley J. Korsmeyer Award 
The Journal of Clinical Investigation  2014;124(4):1423-1424.
doi:10.1172/JCI75543
PMCID: PMC3973115  PMID: 24691475
13.  Not simply misshapen red cells: multimolecular and cellular events in sickle vaso-occlusion 
The Journal of Clinical Investigation  2014;124(4):1462-1465.
Thromboinflammatory diseases result from the interactions of vascular endothelial cells, inflammatory cells, and platelets with cellular adhesion molecules, plasma proteins, and lipids. Tipping the balance toward a prothrombotic, proinflammatory phenotype results from multicellular activation signals. In this issue of the JCI, Li et al. explore the regulation of heterotypic neutrophil-platelet contacts in response to TNF-α–induced venular inflammation with relevance to sickle cell disease (SCD).
doi:10.1172/JCI75238
PMCID: PMC3973116  PMID: 24642460
14.  The inextricable role of the kidney in hypertension 
The Journal of Clinical Investigation  2014;124(6):2341-2347.
An essential link between the kidney and blood pressure control has long been known. Here, we review evidence supporting the premise that an impaired capacity of the kidney to excrete sodium in response to elevated blood pressure is a major contributor to hypertension, irrespective of the initiating cause. In this regard, recent work suggests that novel pathways controlling key sodium transporters in kidney epithelia have a critical impact on hypertension pathogenesis, supporting a model in which impaired renal sodium excretion is a final common pathway through which vascular, neural, and inflammatory responses raise blood pressure. We also address recent findings calling into question long-standing notions regarding the relationship between sodium intake and changes in body fluid volume. Expanded understanding of the role of the kidney as both a cause and target of hypertension highlights key aspects of pathophysiology and may lead to identification of new strategies for prevention and treatment.
doi:10.1172/JCI72274
PMCID: PMC4092877  PMID: 24892708
15.  Aging and epigenetic drift: a vicious cycle 
The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome — a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.
doi:10.1172/JCI69735
PMCID: PMC3871228  PMID: 24382386
16.  Harnessing the potential of epigenetic therapy to target solid tumors 
Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer.
doi:10.1172/JCI69736
PMCID: PMC3871229  PMID: 24382390
17.  Predicting response to epigenetic therapy 
Drugs targeting the epigenome are new promising cancer treatment modalities; however, not all patients receive the same benefit from these drugs. In contrast to conventional chemotherapy, responses may take several months after the initiation of treatment to occur. Accordingly, identification of good pretreatment predictors of response is of great value. Many clinical parameters and molecular targets have been tested in preclinical and clinical studies with varying results, leaving room for optimization. Here we provide an overview of markers that may predict the efficacy of FDA- and EMA-approved epigenetic drugs.
doi:10.1172/JCI69737
PMCID: PMC3871230  PMID: 24382389
18.  New and emerging HDAC inhibitors for cancer treatment 
Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.
doi:10.1172/JCI69738
PMCID: PMC3871231  PMID: 24382387
19.  Clinical development of demethylating agents in hematology 
The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.
doi:10.1172/JCI69739
PMCID: PMC3871232  PMID: 24382388
20.  Characterizing DNA methylation alterations from The Cancer Genome Atlas 
The Cancer Genome Atlas (TCGA) Research Network is an ambitious multi-institutional consortium effort aimed at characterizing sequence, copy number, gene (mRNA) expression, microRNA expression, and DNA methylation alterations in 30 cancer types. TCGA data have become an extraordinary resource for basic, translational, and clinical researchers and have the potential to shape cancer diagnostic and treatment strategies. DNA methylation changes are integral to all aspects of cancer genomics and have been shown to have important associations with gene expression, sequence, and copy number changes. This Review highlights the knowledge gained from DNA methylation alterations in human cancers from TCGA.
doi:10.1172/JCI69740
PMCID: PMC3871233  PMID: 24382385
21.  Emerging therapies targeting the ubiquitin proteasome system in cancer 
The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics.
doi:10.1172/JCI71602
PMCID: PMC3871250  PMID: 24382383
22.  Cancer epigenetics drug discovery and development: the challenge of hitting the mark 
Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved “first generation” of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area.
doi:10.1172/JCI71605
PMCID: PMC3871251  PMID: 24382391
23.  A conversation with Marc Feldmann 
doi:10.1172/JCI71860
PMCID: PMC3871253  PMID: 24382381
24.  More than skin deep: connecting melanocyte pigmentation and angiogenic diseases 
Epidemiological studies have identified racial differences in susceptibility to numerous diseases, including several ocular and skin diseases characterized by increased vascular growth. In most cases, the specific mechanisms and genetic variants responsible for these differences have remained elusive. In this issue of the JCI, Adini et al. explore a direct connection between skin pigmentation and susceptibility to angiogenic diseases and identify an extracellular matrix protein that is regulated by melanogenesis and potently modulates angiogenesis.
doi:10.1172/JCI73559
PMCID: PMC3871256  PMID: 24355914
25.  Toward postnatal reversal of ocular congenital malformations 
Aniridia is a panocular disorder that severely affects vision in early life. Most cases are caused by dominantly inherited mutations or deletions of the PAX6 gene, which encodes a transcription factor that is essential for the development of the eye and the central nervous system. In this issue of the JCI, Gregory-Evans and colleagues demonstrate that early postnatal topical administration of an ataluren-based formulation reverses congenital malformations in the postnatal mouse eye, providing evidence that manipulation of PAX6 after birth may lead to corrective tissue remodeling. These findings offer hope that ataluren administration could be a therapeutic paradigm applicable to some major congenital eye defects.
doi:10.1172/JCI73560
PMCID: PMC3871257  PMID: 24355915

Results 1-25 (3827)