Open AccessFeature PaperReview
TGF-β Signaling in Gastrointestinal Cancers: Progress in Basic and Clinical Research
J. Clin. Med. 2017, 6(1), 11; doi:10.3390/jcm6010011 (registering DOI) -
Abstract
Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several
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Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several cancers. Similarly, TGF-β-induced protein (TGFBI)—a downstream component of the TGF-β signaling pathway—has been shown to promote and/or inhibit cancer. Here, we review the state of basic and clinical research on the roles of TGF-β and TGFBI in gastrointestinal cancers. Full article
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Open AccessFeature PaperArticle
Integrated Treatment of PTSD and Substance Use Disorders: The Mediating Role of PTSD Improvement in the Reduction of Depression
J. Clin. Med. 2017, 6(1), 9; doi:10.3390/jcm6010009 -
Abstract
Posttraumatic stress disorder (PTSD) represents one of the most common mental health disorders, particularly among veterans, and is associated with significant distress and impairment. This highly debilitating disorder is further complicated by common comorbid psychiatric disorders, such as substance use disorders (SUD). Individuals
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Posttraumatic stress disorder (PTSD) represents one of the most common mental health disorders, particularly among veterans, and is associated with significant distress and impairment. This highly debilitating disorder is further complicated by common comorbid psychiatric disorders, such as substance use disorders (SUD). Individuals with PTSD and co-occurring SUD also commonly present with secondary symptoms, such as elevated depression. Little is known, however, about how these secondary symptoms are related to treatment outcome. The aim of the present study, therefore, was to examine (1) the effects of treatment of comorbid PTSD/SUD on depressive symptoms; and (2) whether this effect was mediated by changes in PTSD severity or changes in SUD severity. Participants were 81 U.S. military veterans (90.1% male) with PTSD and SUD enrolled in a randomized controlled trial examining the efficacy of an integrated, exposure-based treatment (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; n = 54) versus relapse prevention (n = 27). Results revealed significantly lower depressive symptoms at post-treatment in the COPE group, as compared to the relapse prevention group. Examination of the mechanisms associated with change in depression revealed that reduction in PTSD severity, but not substance use severity, mediated the association between the treatment group and post-treatment depression. The findings underscore the importance of treating PTSD symptoms in order to help reduce co-occurring symptoms of depression in individuals with PTSD/SUD. Clinical implications and avenues for future research are discussed. Full article
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Open AccessReview
Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox
J. Clin. Med. 2017, 6(1), 10; doi:10.3390/jcm6010010 -
Abstract
Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in
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Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-β function. This article reviews facets of mammary gland involution that are TGF-β regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-β blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression. Full article
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Open AccessEditorial
Acknowledgement to Reviewers of Journal of Clinical Medicine in 2016
J. Clin. Med. 2017, 6(1), 8; doi:10.3390/jcm6010008 -
Open AccessFeature PaperReview
Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy and Long-Term Pulmonary Outcomes
J. Clin. Med. 2017, 6(1), 4; doi:10.3390/jcm6010004 -
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been
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Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been made in reducing rates of BPD. Lack of progress may in part be attributed to the limited therapeutic options available for prevention and treatment of BPD. Several lung-protective strategies have been shown to reduce risks, including use of non-invasive support, as well as early extubation and volume ventilation when intubation is required. These approaches, along with optimal nutrition and medical therapy, decrease risk of BPD; however, impacts on long-term outcomes are poorly defined. Characterization of late outcomes remain a challenge as rapid advances in medical management result in current adult BPD survivors representing outdated neonatal care. While pulmonary disease improves with growth, long-term follow-up studies raise concerns for persistent pulmonary dysfunction; asthma-like symptoms and exercise intolerance in young adults after BPD. Abnormal ventilatory responses and pulmonary hypertension can further complicate disease. These pulmonary morbidities, combined with environmental and infectious exposures, may result in significant long-term pulmonary sequalae and represent a growing burden on health systems. Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease. Full article
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Open AccessFeature PaperReview
Stromal Modulators of TGF-β in Cancer
J. Clin. Med. 2017, 6(1), 7; doi:10.3390/jcm6010007 -
Abstract
Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of
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Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of TGF-β in malignant development and progression requires a better understanding of the molecular mechanisms involved in its tumor suppressor to tumor promoter switch. One important aspect of TGF-β function is its interaction with proteins within the tumor microenvironment. Several stromal proteins have the natural ability to interact and modulate TGF-β function. Understanding the complex interplay between the TGF-β signaling network and these stromal proteins may provide greater insight into the development of novel therapeutic strategies that target the TGF-β axis. The present review highlights our present understanding of how stroma modulates TGF-β activity in human cancers. Full article
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Open AccessReview
The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance
J. Clin. Med. 2017, 6(1), 5; doi:10.3390/jcm6010005 -
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age,
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β) signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target. Full article
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Open AccessArticle
Combined Effects of Androgen and Growth Hormone on Osteoblast Marker Expression in Mouse C2C12 and MC3T3-E1 Cells Induced by Bone Morphogenetic Protein
J. Clin. Med. 2017, 6(1), 6; doi:10.3390/jcm6010006 -
Abstract
Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we
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Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling. Full article
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Open AccessReview
Liquid Biopsies for Cancer: Coming to a Patient near You
J. Clin. Med. 2017, 6(1), 3; doi:10.3390/jcm6010003 -
Abstract
The use of circulating tumor DNA (ctDNA) as a novel and non-invasive test for the diagnosis and surveillance of cancer is a rapidly growing area of interest, with sequencing of ctDNA acting as a potential surrogate for tissue biopsy. Circulating tumor DNA has
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The use of circulating tumor DNA (ctDNA) as a novel and non-invasive test for the diagnosis and surveillance of cancer is a rapidly growing area of interest, with sequencing of ctDNA acting as a potential surrogate for tissue biopsy. Circulating tumor DNA has been detected incidentally during noninvasive prenatal testing and additionally in more than 75% of known cancer patients participating in ctDNA studies evaluating its sensitivity. In the setting of mutation-based targeted tumor therapy, it shows a concordance rate >80% when compared with gold-standard tissue biopsies. Through ctDNA detection and sequencing, a simple blood test becomes a liquid biopsy for cancer, surveying a patient’s entire circulation with the goal of early detection, prognostic information, personalized therapy options, and tracking for recurrence or resistance, all with fewer or no tissue biopsies. Given the recent first-ever FDA approval of a liquid biopsy, it is important for clinicians to be aware of the rapid advancements likely to bring these tests into our practices soon. Here we review the biology, clinical implications, and recent advances in circulating tumor DNA analysis. Full article
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Open AccessReview
A Systematic Review of the Role of Dysfunctional Wound Healing in the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis
J. Clin. Med. 2017, 6(1), 2; doi:10.3390/jcm6010002 -
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disorder showcasing an interaction between genetic predisposition and environmental risks. This usually involves the coaction of a mixture of cell types associated with abnormal wound healing, leading to structural distortion and loss of
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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disorder showcasing an interaction between genetic predisposition and environmental risks. This usually involves the coaction of a mixture of cell types associated with abnormal wound healing, leading to structural distortion and loss of gas exchange function. IPF bears fatal prognosis due to respiratory failure, revealing a median survival of approximately 2 to 3 years. This review showcases the ongoing progress in understanding the complex pathophysiology of IPF and it highlights the latest potential clinical treatments. In IPF, various components of the immune system, particularly clotting cascade and shortened telomeres, are highly involved in disease pathobiology and progression. This review also illustrates two US Food and Drug Administration (FDA)-approved drugs, nintedanib (OFEV, Boehringer Ingelheim, Ingelheim am Rhein, Germany) and pirfenidone (Esbriet, Roche, Basel, Switzerland), that slow IPF progression, but unfortunately neither drug can reverse the course of the disease. Although the mechanisms underlying IPF remain poorly understood, this review unveils the past and current advances that encourage the detection of new IPF pathogenic pathways and the development of effective treatment methods for the near future. Full article
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Open AccessArticle
The Effects of Ascorbate, N-Acetylcysteine, and Resveratrol on Fibroblasts from Patients with Mitochondrial Disorders
J. Clin. Med. 2017, 6(1), 1; doi:10.3390/jcm6010001 -
Abstract
Reactive oxygen species (ROS) are assumed to be implicated in the pathogenesis of inborn mitochondrial diseases affecting oxidative phosphorylation (OXPHOS). In the current study, we characterized the effects of three small molecules with antioxidant properties (N-acetylcysteine, ascorbate, and resveratrol) on ROS
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Reactive oxygen species (ROS) are assumed to be implicated in the pathogenesis of inborn mitochondrial diseases affecting oxidative phosphorylation (OXPHOS). In the current study, we characterized the effects of three small molecules with antioxidant properties (N-acetylcysteine, ascorbate, and resveratrol) on ROS production and several OXPHOS parameters (growth in glucose free medium, ATP production, mitochondrial content and membrane potential (MMP)), in primary fibroblasts derived from seven patients with different molecularly defined and undefined mitochondrial diseases. N-acetylcysteine appeared to be the most beneficial compound, reducing ROS while increasing growth and ATP production in some patients’ cells. Ascorbate showed a variable positive or negative effect on ROS, ATP production, and mitochondrial content, while incubation with resveratrol disclosed either no effect or detrimental effect on ATP production and MMP in some cells. The individual responses highlight the importance of investigating multiple parameters in addition to ROS to obtain a more balanced view of the overall effect on OXPHOS when evaluating antioxidant treatment options for mitochondrial diseases. Full article
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Open AccessReview
The Dual Role of Neutrophils in Inflammatory Bowel Diseases
J. Clin. Med. 2016, 5(12), 118; doi:10.3390/jcm5120118 -
Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of
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Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn’s disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD. Full article
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Open AccessArticle
Treatment of Post-Traumatic Stress Disorder Nightmares at a Veterans Affairs Medical Center
J. Clin. Med. 2016, 5(12), 117; doi:10.3390/jcm5120117 -
Abstract
The effectiveness of medications for PTSD in general has been well studied, but the effectiveness of medicatio.ns prescribed specifically for post-traumatic stress disorder (PTSD) nightmares is less well known. This retrospective chart review examined the efficacy of various medications used in actual treatment
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The effectiveness of medications for PTSD in general has been well studied, but the effectiveness of medicatio.ns prescribed specifically for post-traumatic stress disorder (PTSD) nightmares is less well known. This retrospective chart review examined the efficacy of various medications used in actual treatment of PTSD nightmares at one Veteran Affairs Hospital. Records at the Salem, VA Veterans Affairs Medical Center (VAMC) were examined from 2009 to 2013 to check for the efficacy of actual treatments used in comparis.on with treatments suggested in three main review articles. The final sample consisted of 327 patients and 478 separate medication trials involving 21 individual medications plus 13 different medication combinations. The three most frequently utilized medications were prazosin (107 trials), risperidone (81 trials), and quetiapine (72 trials). Five medications had 20 or more trials with successful results (partial to full nightmare cessation) in >50% of trials: risperidone (77%, 1.0–6.0 mg), clonidine (63%, 0.1–2.0 mg), quetiapine (50%, 12.5–800.0 mg), mirtazapine (50%; 7.5–30.0 mg), and terazosin (64%, 50.0–300.0 mg). Notably, olanzapine (2.5–10.0) was successful (full remission) in all five prescription trials in five separate patients. Based on the clinical results, the use of risperidone, clonidine, terazosin, and olanzapine warrants additional investigation in clinically controlled trials as medications prescribed specifically for PTSD nightmares. Full article
Open AccessReview
Technical Developments and Clinical Use of Telemedicine in Sleep Medicine
J. Clin. Med. 2016, 5(12), 116; doi:10.3390/jcm5120116 -
Abstract
The use of assistive technology and telemedicine is likely to continue to shape our medical practice in the future, notably in the field of sleep medicine, especially within developed countries. Currently, the number of people suffering from obstructive sleep apnea syndrome (OSAS) is
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The use of assistive technology and telemedicine is likely to continue to shape our medical practice in the future, notably in the field of sleep medicine, especially within developed countries. Currently, the number of people suffering from obstructive sleep apnea syndrome (OSAS) is increasing. Telemedicine (TM) can be used in a variety of ways in sleep medicine: telediagnostics, teleconsultation, teletherapy and telemonitoring of patients being treated with positive pressure devices. In this review, we aim to summarize the recent scientific progresses of these techniques and their potential clinical applications and give consideration to the remaining problems related to TM application. Full article
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Open AccessReview
Bronchiectasis in the Last Five Years: New Developments
J. Clin. Med. 2016, 5(12), 115; doi:10.3390/jcm5120115 -
Abstract
Bronchiectasis, a chronic lung disease characterised by cough and purulent sputum, recurrent infections, and airway damage, is associated with considerable morbidity and mortality. To date, treatment options have been limited to physiotherapy to clear sputum and antibiotics to treat acute infections. Over the
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Bronchiectasis, a chronic lung disease characterised by cough and purulent sputum, recurrent infections, and airway damage, is associated with considerable morbidity and mortality. To date, treatment options have been limited to physiotherapy to clear sputum and antibiotics to treat acute infections. Over the last decade, there has been significant progress in understanding the epidemiology, pathophysiology, and microbiology of this disorder. Over the last five years, methods of assessing severity have been developed, the role of macrolide antibiotic therapy in reducing exacerbations cemented, and inhaled antibiotic therapies show promise in the treatment of chronic Pseudomonas aeruginosa infection. Novel therapies are currently undergoing Phase 1 and 2 trials. This review aims to address the major developments within the field of bronchiectasis over this time. Full article
Open AccessReview
A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy
J. Clin. Med. 2016, 5(12), 114; doi:10.3390/jcm5120114 -
Abstract
Significant advances in the understanding of the pathophysiology of pulmonary arterial hypertension over the past two decades have led to the development of targeted therapies and improved patient outcomes. Currently, a broad armamentarium of pulmonary arterial hypertension-specific drugs exists to assist in the
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Significant advances in the understanding of the pathophysiology of pulmonary arterial hypertension over the past two decades have led to the development of targeted therapies and improved patient outcomes. Currently, a broad armamentarium of pulmonary arterial hypertension-specific drugs exists to assist in the treatment of this complex disease state. In this manuscript, we provide a comprehensive review of the current Food and Drug Administration (FDA)-approved pulmonary arterial hypertension-specific therapies, and their supporting evidence for adults, targeting the nitric oxide, soluble guanylate cyclase, endothelin, and prostacyclin pathways. Full article
Open AccessReview
Diaphragm Dysfunction: Diagnostic Approaches and Management Strategies
J. Clin. Med. 2016, 5(12), 113; doi:10.3390/jcm5120113 -
Abstract
The diaphragm is the main inspiratory muscle, and its dysfunction can lead to significant adverse clinical consequences. The aim of this review is to provide clinicians with an overview of the main causes of uni- and bi-lateral diaphragm dysfunction, explore the clinical and
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The diaphragm is the main inspiratory muscle, and its dysfunction can lead to significant adverse clinical consequences. The aim of this review is to provide clinicians with an overview of the main causes of uni- and bi-lateral diaphragm dysfunction, explore the clinical and physiological consequences of the disease on lung function, exercise physiology and sleep and review the available diagnostic tools used in the evaluation of diaphragm function. A particular emphasis is placed on the clinical significance of diaphragm weakness in the intensive care unit setting and the use of ultrasound to evaluate diaphragmatic action. Full article
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Open AccessReview
Switching Roles of TGF-β in Cancer Development: Implications for Therapeutic Target and Biomarker Studies
J. Clin. Med. 2016, 5(12), 109; doi:10.3390/jcm5120109 -
Abstract
TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes
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TGF-β induces complicated and even opposite responses in numerous biological processes, e.g., tumor suppression in pre-malignant cells and metastasis promotion in cancer cells. However, the cellular contextual determinants of these different TGF-β roles remain elusive, and the driver genes triggering the determinants’ changes have not been identified. Recently, however, several findings have provided new insights on the contextual determinants of Smads in TGF-β’s biological processes. These novel switches and their effectors may serve as prognostic biomarkers and therapeutic targets of TGF-β-mediated cancer progression. Full article
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Open AccessReview
Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer
J. Clin. Med. 2016, 5(12), 111; doi:10.3390/jcm5120111 -
Abstract
TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous
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TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia. Full article
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Open AccessCase Report
Burkholderia contaminans Colonization from Contaminated Liquid Docusate (Colace) in a Immunocompetent Adult with Legionnaire’s Disease: Infection Control Implications and the Potential Role of Candida pellucosa
J. Clin. Med. 2016, 5(12), 110; doi:10.3390/jcm5120110 -
Abstract
Objective:B. contaminans was cultured from respiratory secretions and liquid docusate (Colace) in a Neurosurgical Intensive Care Unit (NICU) patient with community-acquired Legionnaire’s disease but not from another bottle given to the patient. Unexpectedly, C. pelliculosa was cultured from two bottles, but not
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Objective:B. contaminans was cultured from respiratory secretions and liquid docusate (Colace) in a Neurosurgical Intensive Care Unit (NICU) patient with community-acquired Legionnaire’s disease but not from another bottle given to the patient. Unexpectedly, C. pelliculosa was cultured from two bottles, but not the B. contaminans bottle or respiratory secretions. Methods:B. cepacia, later identified as B. contaminans, was cultured from a bottle of liquid docusate (Colace) dispensed to a non-cystic fibrosis patient. His respiratory secretions were colonized with B. contaminans. Results: Eradication of B. contaminans colonization in the patient’s respiratory secretions was attempted. With levofloxacin, B. contaminans developed multidrug resistance (MDR). Subsequent TMP-SMX therapy did not result in further MDR. Nine other ICU patients were given docusate from the same lot, but there were no other B. contaminans isolates. Conclusion:B. contaminans colonization of respiratory secretion may be difficult to eliminate. The significance of C. pelliculosa cultured from liquid docusate (Colace) remains to be elucidated. In this case, it appeared that B. contaminans may have inhibited the growth of C. pelliculosa in the same bottle. Others should be alerted to the possibility that C. pelliculosa may be present in B. contaminans–contaminated lots of liquid docusate (Colace). Full article