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Diseases, Volume 2, Issue 3 (September 2014), Pages 209-295

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Research

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Open AccessArticle TRAIL Deficient Mice Are Protected from Sugen/Hypoxia Induced Pulmonary Arterial Hypertension
Diseases 2014, 2(3), 260-273; doi:10.3390/diseases2030260
Received: 11 March 2014 / Revised: 15 July 2014 / Accepted: 28 July 2014 / Published: 31 July 2014
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Abstract
Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression
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Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression is increased in pulmonary vascular lesions and pulmonary artery smooth muscle cells (PASMC) of patients with idiopathic PAH. The addition of recombinant TRAIL induces the proliferation and migration of PASMCs in vitro. TRAIL is required for hypoxia-induced pulmonary hypertension in mice, and blockade of TRAIL prevents and reduces disease development in other rodent models of PAH. Due to the availability of knockout and transgenic mice, murine models of disease are key to further advances in understanding the complex and heterogeneous pathogenesis of PAH. However, murine models vary in their disease severity, and are often criticized for lacking the proliferative pulmonary vascular lesions characteristic of PAH. The murine Sugen-hypoxic (SuHx) mouse model has recently been reported to have a more severe PAH phenotype consisting advanced pulmonary vascular remodelling. We therefore aimed to determine whether TRAIL was also required for the development of PAH in this model. C57BL/6 and TRAIL−/− mice were exposed to normoxia, Sugen5416 alone, hypoxia or both Sugen5416 and hypoxia (SuHx). We report here that SuHx treated C57BL/6 mice developed more severe PAH than hypoxia alone, and that TRAIL−/− mice were protected from disease development. These data further emphasise the importance of this pathway and support the use of the SuHx mouse model for investigating the importance of potential mediators in PAH pathogenesis. Full article
(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

Review

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Open AccessReview Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma
Diseases 2014, 2(3), 209-225; doi:10.3390/diseases2030209
Received: 16 April 2014 / Revised: 24 June 2014 / Accepted: 25 June 2014 / Published: 1 July 2014
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Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein),
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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein), DDK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) and microRNAs in blood are being tested for early screening of liver cancer. Since 2008, sorafenib has been used as the standard molecular targeting agent for HCC. However, overall outcomes for sorafenib alone or in combination with other tyrosine kinase inhibitors are unsatisfactory. Whether simultaneously or sequentially, addiction switches and compensatory pathway activation in HCC, induced by sorafenib treatment, may induce acquired resistance. Forkhead box M1 (FOXM1) and metadherin (MTDH) have been shown to be master regulators of different aspects of tumorigenesis, including angiogenesis, invasion, metastasis and drug resistance. Elevated expression of both FOXM1 and MTDH is known to be a consequence of both activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN in various types of cancers including HCC. The role of FOXM1 and MTDH as potential prognostic markers as well as therapeutic targets in HCC will be discussed. In addition, microRNAs (miRNAs), endogenous small non-coding RNAs involved in the regulation of gene expression, are involved in HCC and interact with both FOXM1 and MTDH in several ways. Thus, altered expression of miRNAs in HCCs will also be discussed as potential tools for diagnosis, prognosis and therapy in HCC. Full article
(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)
Open AccessReview A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α
Diseases 2014, 2(3), 226-242; doi:10.3390/diseases2030226
Received: 11 April 2014 / Revised: 10 June 2014 / Accepted: 2 July 2014 / Published: 7 July 2014
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Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis due to its high rate of recurrence after the initial curative treatment. Therefore, development of effective therapeutic strategies that can prevent recurrence and secondary tumor formation is required to improve the clinical outcomes
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Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis due to its high rate of recurrence after the initial curative treatment. Therefore, development of effective therapeutic strategies that can prevent recurrence and secondary tumor formation is required to improve the clinical outcomes of HCC patients. Malfunctioning of the retinoid X receptor-s (RXRs) of HCC patient by activation of the Ras- mitogen-activated protein kinase (MAPK) signaling pathway is strongly associated with hepatocarcinogenesis. Acyclic retinoid (ACR), a synthetic retinoid, prevents HCC recurrence by inhibiting Ras-MAPK activation and the subsequent RXRα phosphorylation, thereby improving patient prognosis. Here, we have reviewed the detailed effects of ACR on the prevention of HCC development, with particular references to the results of our previous basic and clinical research. Full article
(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)
Open AccessReview The Significance of Pulmonary Artery Size in Pulmonary Hypertension
Diseases 2014, 2(3), 243-259; doi:10.3390/diseases2030243
Received: 12 June 2014 / Revised: 21 July 2014 / Accepted: 25 July 2014 / Published: 31 July 2014
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Abstract
Pulmonary hypertension (PH) has been found to have significant morbidity and mortality. The treatment of PH has advanced considerably with increasingly more effective and safer options. With an increasing effort to diagnose patients early, non-invasive techniques are often used to screen those patients
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Pulmonary hypertension (PH) has been found to have significant morbidity and mortality. The treatment of PH has advanced considerably with increasingly more effective and safer options. With an increasing effort to diagnose patients early, non-invasive techniques are often used to screen those patients likely to have PH. Computerized tomography (CT) chest scans are increasingly utilized in the evaluation of patients with exertional dyspnea, including those with suspected PH. The main role of the CT scan is to evaluate for any associated underlying diseases. There have been attempts to address the utility of CT to predict the presence of PH. This article reviews previously published investigations to summarize the relationship between pulmonary artery dimensions and PH to determine both the strength of the correlation and its discriminatory ability for use in clinical practice. Full article
(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))
Open AccessReview Right Ventricular Geometry and Function in Pulmonary Hypertension: Non-Invasive Evaluation
Diseases 2014, 2(3), 274-295; doi:10.3390/diseases2030274
Received: 16 May 2014 / Revised: 3 July 2014 / Accepted: 21 July 2014 / Published: 18 September 2014
Cited by 1 | PDF Full-text (481 KB) | HTML Full-text | XML Full-text
Abstract
Pulmonary hypertension (PH) is a rare disease, which still carries a poor prognosis. PH is characterized by a pressure overload on the right ventricle (RV), which develops hypertrophy, followed by a progressive failure. Accordingly, recent evidence showed that RV function has an important
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Pulmonary hypertension (PH) is a rare disease, which still carries a poor prognosis. PH is characterized by a pressure overload on the right ventricle (RV), which develops hypertrophy, followed by a progressive failure. Accordingly, recent evidence showed that RV function has an important prognostic role in patients with PH. Echocardiography, cardiac magnetic resonance (CMR), computed tomography, and nuclear imaging allow a non-invasive evaluation of the RV size and function, but only the first two are routinely used in the clinical arena. Some conventional echocardiographic parameters, such as TAPSE (tricuspid anular plane systolic excursion), have demonstrated prognostic value in patients with PH. Moreover, there are some new advanced echo techniques, which can provide a more detailed assessment of RV function. Three-dimensional (3D) echocardiography allows measurement of RV volumes and ejection fraction, and two-dimensional (2D) speckle tracking (STE), allows assessment of RV myocardial mechanics. CMR provides accurate measurement of RV volumes, ejection fraction, and mass and allows the characterization of the RV wall composition by identifying the presence of fibrosis by late gadolinium enhancement. Although CMR seems to hold promise for both initial assessment and follow-up of patients with PH, its main role has been restricted to diagnostic work-up only. Full article
(This article belongs to the Special Issue Pulmonary Arterial Hypertension (PAH))

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