The 10 most-cited articles in Journal of Clinical Medicine, 2016

Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the vast heterogeneity in its exact definition, methodology of assessment, and patient stratification need to be resolved before it can be routinely used as a standardized prognostic feature. Here, we discuss the heterogeneity in defining and assessing tumor budding, its clinical significance across multiple cancer types, and its prospective implementation in clinical practice. Next, we review the emerging evidence about partial, rather than complete, epithelial-mesenchymal phenotype at the tumor bud level, and its connection with tumor proliferation, quiescence, and stemness. Finally, based on recent literature, indicating a co-expression of epithelial and mesenchymal markers in many tumor buds, we posit tumor budding to be a manifestation of this hybrid epithelial/mesenchymal…

Epithelial-mesenchymal transition (EMT) is a complex molecular program that regulates changes in cell morphology and function during embryogenesis and tissue development. EMT also contributes to tumor progression and metastasis. Cells undergoing EMT expand out of and degrade the surrounding microenvironment to subsequently migrate from the primary site. The mesenchymal phenotype observed in fibroblasts is specifically important based on the expression of smooth muscle actin (α-SMA), fibroblast growth factor (FGF), fibroblast-specific protein-1 (FSP1), and collagen to enhance EMT. Although EMT is not completely dependent on EMT regulators such as Snail, Twist, and Zeb-1/-2, analysis of upstream signaling (i.e., TGF-β, EGF, Wnt) is necessary to understand tumor EMT more comprehensively. Tumor epithelial-fibroblast interactions that regulate tumor progression have been identified during prostate cancer. The cellular crosstalk is significant because these events influence therapy response and patient outcome. This review addresses how canonical EMT signals originating from prostate…

Despite the advancement in medicine, management of heart failure (HF), which usually presents as a disease syndrome, has been a challenge to healthcare providers. This is reflected by the relatively higher rate of readmissions along with increased mortality and morbidity associated with HF. In this review article, we first provide a general overview of types of HF pathogenesis and diagnostic features of HF including the crucial role of exercise in determining the severity of heart failure, the efficacy of therapeutic strategies and the morbidity/mortality of HF. We then discuss the quality control measures to prevent the growing readmission rates for HF. We also attempt to elucidate published and ongoing clinical trials for HF in an effort to evaluate the standard and novel therapeutic approaches, including stem cell and gene therapies, to reduce the morbidity and mortality. Finally, we discuss the appropriate utilization/documentation and medical coding based on the severity of the HF alone and with minor and major co-morbidities. We consider that this review provides an extensive…

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogenic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies.

Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery.

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…

Cancer is a major disease worldwide. Despite progress in cancer therapy, conventional cytotoxic therapies lead to unsatisfactory long-term survival, mainly related to development of drug resistance by tumor cells and toxicity towards normal cells. n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can exert anti-neoplastic activity by inducing apoptotic cell death in human cancer cells either alone or in combination with conventional therapies. Indeed, n-3 PUFAs potentially increase the sensitivity of tumor cells to conventional therapies, possibly improving their efficacy especially against cancers resistant to treatment. Moreover, in contrast to traditional therapies, n-3 PUFAs appear to cause selective cytotoxicity towards cancer cells with little or no toxicity on normal cells. This review focuses on studies investigating the cytotoxic activity of n-3 PUFAs against cancer cells via apoptosis, analyzing the molecular mechanisms underlying this effective and selective activity. Here, we highlight the multiple molecules potentially…

Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG₄-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and…

Transitory phenotypic changes such as the epithelial-mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor β (TGFβ), prominently induces EMT via a group of specific transcription factors. The potency of TGFβ is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGFβ signaling or act as cooperating partners of this pathway are…

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.