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Feed: JOURNAL OF CLINICAL INVESTIGATION -- CURRENT ISSUE
Journal of Clinical Investigation RSS feed -- Current issue
In This Issue
By:
Plus ça change, plus c’est la même chose
By:
Laurence A. Turka
Sean Morrison and the Texas brain gain
By:
Kathryn Claiborn
Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma
By:
Uma M. Sachdeva, Joan M. O’Brien
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.
Synergy of understanding dermatologic disease and epidermal biology
By:
John R. Stanley
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.
Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases
By:
Akiharu Kubo, Keisuke Nagao, Masayuki Amagai
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.
Dissecting the bulge in hair regeneration
By:
Peggy Myung, Mayumi Ito
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.
Basal cell carcinoma — molecular biology and potential new therapies
By:
Maria Kasper, Viljar Jaks, Daniel Hohl, Rune Toftgård
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.
From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma
By:
Vladimir Ratushny, Michael D. Gober, Ryan Hick, Todd W. Ridky, John T. Seykora
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.
Skin care in the aging female: myths and truths
By:
Ushma S. Neill
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.”
Teaching an old dog new tricks: potential antiatherothrombotic use for statins
By:
Roy L. Silverstein
Thrombotic complications represent a highly significant component of morbidity and mortality associated with hypercholesterolemia and atherosclerosis. In this issue of the JCI, Owens et al. report possible mechanisms underlying the prothrombotic, proinflammatory state accompanying hypercholesterolemia. Using rodent, monkey, and human subjects, they show that circulating oxidized LDL and circulating monocyte-derived tissue factor are important instigating factors driving the thrombotic, inflammatory phenotype and, surprisingly, that statin therapy ameliorated the phenotype even in the absence of lowering cholesterol levels. The studies raise the intriguing possibility that therapies directed at pathways generating oxidant stress or pathways involved in transmitting oxidized LDL–mediated signals in circulating platelets and monocytes could have antiatherothrombotic potential, probably with minimal anticoagulant and hemorrhagic potential.
Plasmacytoid dendritic cells lead the charge against tumors
By:
Sonia Jiménez-Baranda, Inês Pires Silva, Nina Bhardwaj
Imiquimod is a TLR agonist that is used as an antitumor agent, mainly against skin tumors. Its clinical benefits are well described in several studies; however, the mechanisms behind its antitumor effects are not completely understood. In this issue of the JCI, Drobits and colleagues demonstrate that topical application of imiquimod suppresses cutaneous melanoma by TLR7-dependent recruitment and transformation of plasmacytoid dendritic cells into killer cells; this occurs independently of conventional adaptive immune mechanisms.
Genetic instability in neural stem cells: an inconvenient truth?
By:
Neil J. Harrison
The evolutionary struggles from which mutants arise have been documented in almost every living system. In this issue of the JCI, Varela and colleagues extend this list of systems to include neural derivatives of human embryonic stem cells, which they show exhibit a repeated gain of material from chromosome 1q. Although this raises safety issues for therapeutic use of such cells, the frequent observation of a particular change may direct screening strategies for detection and removal of these unwanted cellular variants.
Yes, even human brown fat is on fire!
By:
Barbara Cannon, Jan Nedergaard
That adult humans possess brown fat is now accepted — but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity — provided that brown fat becomes activated not only by cold but also through food-related stimuli.
MicroRNAs, fibrotic remodeling, and aortic aneurysms
By:
Dianna M. Milewicz
Aortic aneurysms are a common clinical condition that can cause death due to aortic dissection or rupture. The association between aortic aneurysm pathogenesis and altered TGF-β signaling has been the subject of numerous investigations. Recently, a TGF-β–responsive microRNA (miR), miR-29, has been identified to play a role in cellular phenotypic modulation during aortic development and aging. In this issue of JCI, Maegdefessel and colleagues demonstrate that decreasing the levels of miR-29b in the aortic wall can attenuate aortic aneurysm progression in two different mouse models of abdominal aortic aneurysms. This study highlights the relevance of miR-29b in aortic disease but also raises questions about its specific role.
Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine
By:
Joel M. Weinberg, Manjeri A. Venkatachalam
Several adenosine receptor subtypes on endothelial, epithelial, mesangial, and inflammatory cells have been implicated in ischemic acute kidney injury, a life-threatening condition that frequently complicates the care of hospitalized patients. In this issue of the JCI, Grenz and coworkers provide novel insight into how preservation of postischemic renal perfusion by endothelial cell adenosine A2B receptors is antagonized by adenosine reuptake into proximal tubule cells by equilibrative nucleotide transporter 1, which can be inhibited by dipyridamole. The work suggests that adenosine A2B receptor agonists and inhibition of equilibrative nucleoside transporters by dipyridamole may have therapeutic potential in ischemic acute kidney injury, a condition for which there are currently no specific therapeutic interventions.
Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development
By:
Lars Maegdefessel, Junya Azuma, Ryuji Toh, Denis R. Merk, Alicia Deng, Jocelyn T. Chin, Uwe Raaz, Anke M. Schoelmerich, Azad Raiesdana, Nicholas J. Leeper, Michael V. McConnell, Ronald L. Dalman, Joshua M. Spin, Philip S. Tsao
MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe–/– mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti–miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia
By:
Hsien-yang Lee, Junko Nakayama, Ying Xu, Xueliang Fan, Maha Karouani, Yiguo Shen, Emmanuel N. Pothos, Ellen J. Hess, Ying-Hui Fu, Robert H. Edwards, Louis J. Ptácek
Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33–q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for c-fos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neurotransmitter release in response to stress and other precipitating factors.
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
By:
Evita van de Steeg, Viktor Stránecký, Hana Hartmannová, Lenka Nosková, Martin Hřebíček, Els Wagenaar, Anita van Esch, Dirk R. de Waart, Ronald P.J. Oude Elferink, Kathryn E. Kenworthy, Eva Sticová, Mohammad al-Edreesi, A.S. Knisely, Stanislav Kmoch, Milan Jirsa, Alfred H. Schinkel
Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
IFN-{alpha} inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome
By:
Laura Belloni, Lena Allweiss, Francesca Guerrieri, Natalia Pediconi, Tassilo Volz, Teresa Pollicino, Joerg Petersen, Giovanni Raimondo, Maura Dandri, Massimo Levrero
HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and in vivo, and pegylated IFN-α is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-α suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-α inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-α resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-α treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-α was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-α treatment. Our results identify a molecular mechanism whereby IFN-α mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics.
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