Angiogenesis: state of the art.

Considerable progress has been made recently in understanding the molecular mechanisms of angiogenesis, the formation of new blood vessels by a process of sprouting from preexisting vessels. Angiogenesis is fundamental to a number of physiological processes, including embryonic development, the normal menstrual cycle, and tissue or organ regeneration in which growth of new capillaries is tightly controlled by a finely tuned balance between positive and negative mediators of endothelial cell growth. When blood vessels grow unabated or out of control, angiogenesis becomes pathologic and plays a key role in the development of many neoplastic and non-neoplastic diseases. Presently, abundant results from laboratory experiments and clinical trials have greatly improved our understanding of the molecular basis underlying angiogenic events and paved a new way to the diagnosis and treatment of diseases that depend on angiogenesis. This review focuses on the current advances in the regulation and clinical application of angiogenesis.     

Raman fingerprints as promising markers of cellular senescence and aging

GeroScience - Due to our aging population, understanding of the underlying molecular mechanisms constantly gains more and more importance. Senescent cells, defined by being irreversibly growth...     

T-lymphocyte interactions in cardiac transplant rejection

Transplant rejection is a complex cascade of cellular and molecular inflammatory events triggered by the recognition of donor antigens by the recipient immune system. The interaction between T-cell receptors on "helper" T cells and donor antigen confers specificity of the response, whereas accessory cell interactions and growth factor (lymphokine) secretion regulate the variety of cellular responses. An understanding of these cellular and molecular interactions may promote new therapeutic strategies.     

Molecular mechanisms of cholangiocarcinoma

Cholangiocarcinoma (CC), the malignant tumor of the epithelial cells lining the biliary ducts, has undergone a worldwide increase in incidence and mortality. The malignant transformation of the biliary cells originates from a multistep process evolving through chronic inflammation of the biliary tract to CC. In the last few years several advances have been towards understanding and clarifying the molecular mechanisms implicated in the cholangiocarcinogenesis process. However, many pathophysiologic aspects governing the growth of CC are still undefined. The poor prognosis of this tumor underlines the urgent need to codify the underlying molecular mechanisms involved in the growth and progression of CC in order to design effective preventive measures and valid treatment regimens. This review reports on progresses made in the last few years in clarifying the molecular pathways involved in the process of cholangiocarcinogenesis.     

History of discovery: platelet-derived growth factor

A growth-promoting activity released from activated platelets, the platelet-derived growth factor, was discovered and characterized while the cellular and molecular mechanisms underlying the formation of the lesions of atherosclerosis were being investigated. This review provides a personal account of the different challenges we faced 3 decades ago in this undertaking and describes how our path was influenced by our focus on a disease process and by the evolving general understanding of the molecular effectors of cell proliferation.     

InN Nanowires: Growth and Optoelectronic Properties

An overview on InN nanowires, fabricated using either a catalyst-free molecular beam epitaxy method or a catalyst assisted chemical vapor deposition process, is provided. Differences and similarities of the nanowires prepared using the two techniques are presented. The present understanding of the growth and of the basic optical and transport properties is discussed.     

Liver development: lessons from knockout mice and mutant fish

The liver is an organ with vital functions, including the processing and storage of nutrients, maintenance of serum composition, detoxification and bile production. Over the last 10 years, there have been major advances in our understanding of the molecular and cellular mechanisms underlying liver development. These advances have been achieved through the use of knockout mice as well as through forward-genetics studies employing mutant fish. The examination of many such murine and piscine mutants with defects in liver formation and/or function have pinpointed numerous factors crucial for hepatic cell differentiation and growth. In addition, these studies have permitted the identification of several important liver-specific markers that allow the contributions of variouscell types to hepatogenesis to be monitored. This review summarizes our current state of knowledge of the shared molecular mechanisms that underlie liver development in species as diverse as fish and mice. A better molecular understanding of liver formation may provide new insights into both normal liver biology and liver disease.     

The molecular pathogenesis of cholangiocarcinoma

Cholangiocarcinoma is rising in clinical importance because of increasing incidence, poor prognosis, and suboptimal response to therapy. Recent investigations into the underlying molecular mechanisms involved in cholangiocarcinogenesis and tumor growth have contributed greatly to our understanding of this disease. To review this topic, we discuss the molecular mechanisms in sections reflecting the unique features that allow cancer cells to develop and maintain a growth advantage. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic, and preventative strategies may be developed and hopefully improve the outcome of this devastating disease.     

Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine?

The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlie the diversity of growth patterns of this malignancy remain a clinical concern. Tumours of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome–wide tumour heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behaviour. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies.     

PRV-1 mRNA expression and other molecular markers in polycythemia rubra vera

During the past 4 years, the first molecular markers for polycythemia vera (PV) have been described. These markers include decreased expression of the thrombopoietin receptor c-Mpl, increased expression of the surface receptor polycythemia rubra vera-I, and insulin-like growth factor-I hypersensitivity. Characterization of these abnormalities has allowed the development of the first molecular diagnostic tools for PV. However, despite these advances, the molecular mechanisms leading to the development of PV remain poorly understood. This review summarizes and evaluates recent advances in our understanding of molecular aberrations in PV.     

Genetic control of growth

The application of the powerful tool molecular biology has made it possible to ask questions not only about hormone production and action but also to characterize many of the receptor molecules that initiate responses to the hormones. We are beginning to understand how cells may regulate the expression of genes and how hormones intervene in regulatory processes to adjust the expression of individual genes. In addition, great strides have been made in understanding how individual cells talk to each other through locally released factors to coordinate growth, differentiation, secretion, and other responses within a tissue. In this review I (1) focus on developmental aspects of the pituitary gland, (2) focus on the different components of the growth hormone axis and (3) examine the different altered genes and their related growth factors and/or regulatory systems that play an important physiological and pathophysiological role in growth. Further, as we have already entered the 'post-genomic' area, in which not only a defect at the molecular level becomes important but also its functional impact at the cellular level, I concentrate in the last part on some of the most important aspects of cell biology and secretion.     

Mechanisms and consequences of fibrosis in systemic sclerosis

Systemic sclerosis (SSc), also known as scleroderma, is a complex connective tissue disease that is associated with a high mortality and is challenging to treat because of its clinical heterogeneity and a lack of effective antifibrotic therapies. SSc has vascular, immunologic and fibrotic components that are pathologically interconnected. A growing understanding of the molecular and cellular mechanisms that underlie SSc pathogenesis provides logical and novel approaches to treatment. At present most therapies are organ-based. Vascular and inflammatory components of the disease can also be treated, but effective antifibrotic therapies are lacking. A number of key molecular mediators have the potential to alter immune-cell, vascular and fibrotic processes and these mediators, which include transforming growth factor-beta isoforms, endothelin-1, connective-tissue growth factor, chemokines and members of the interleukin family, are attractive targets for therapeutic modulation. Key mediators can be blocked using antibodies, soluble receptors, endogenous inhibitors or small-molecule antagonists of ligands, receptors or signaling intermediates. Overall, this is an exciting time for new therapies in SSc and advances are being made in synchrony with an improved understanding of the molecular and biochemical basis of the disease.     

Individualized therapy for patients with non-small cell lung cancer: emerging trends and challenges

Non-small cell lung cancer is the leading cause of cancer death in the United States. Efforts to improve outcomes have led to a greater understanding of the predictive and prognostic value of histologic and molecular characteristics of individual tumors. In standard practice, biopsy specimens are examined first on a histologic level, then on a molecular level with the recognition that both histologic subtype and gene expression profile can guide treatment decisions and have a profound effect on clinical outcomes. Epidermal growth factor activation mutations were among the first biomarkers shown to have therapeutic implications, and levels of gene expression for an array of other biomarkers are being evaluated in clinical trials. Ongoing studies underscore the need to implement molecular and histologic screening as part of routine clinical practice. To achieve an integration of clinical, histologic, and molecular parameters when making treatment decisions, collaboration between oncologists and pathologists is essential.     

Thyroid hormone and the growth plate

Thyroid hormone was first identified as a potent regulator of skeletal maturation at the growth plate more than forty years ago. Since that time, many in vitro and in vivo studies have confirmed that thyroid hormone regulates the critical transition between cell proliferation and terminal differentiation in the growth plate, specifically the maturation of growth plate chondrocytes into hypertrophic cells. However these studies have neither identified the molecular mechanisms involved in the regulation of skeletal maturation by thyroid hormone, nor demonstrated how the systemic actions of thyroid hormone interface with the local regulatory milieu of the growth plate. This article will review our current understanding of the role of thryoid hormone in regulating the process of endochondral ossification at the growth plate, as well as what is currently known about the molecular mechanisms involved in this regulation.     

Angiogenesis and hematological malignancies

Since the initial hypotheses on the importance of angiogenesis in the pathogenesis of cancer approximately 30 years ago, there have been major advances in the understanding of the cellular and molecular mechanisms involved in the regulation of this complex process of new vessel formation. Among the multitude of factors, vascular endothelial growth factor (VEGF) has emerged as one of the most potent angiogenic factors, being implicated in the initiation of signal transduction responsible for cell proliferation, survival, migration and adhesion. Inhibition of VEGF and its signaling pathway offers a potential new molecular target in cancer therapy. This article reviews the role of angiogenesis and its mediators, particularly vascular endothelial growth factors, in hematological malignancies, as well as the potential use of anti-angiogenic therapies in the management of these conditions.     

Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan-glycan

Activin and inhibin research has provided important insight into reproductive physiology as well as many areas involving regulation of cell growth, differentiation and function. Progress in understanding the roles of these hormones in various cell and tissue types has been complimented by novel discoveries at the molecular level that have shed light on ligand/receptor interactions, signaling mechanisms and regulation. While the receptors and signaling pathway for activin are now well characterized, the molecular basis for inhibin action has remained relatively unclear. Here we summarize recent advances in understanding inhibin's mode of action focusing on our recent identification of betaglycan-glycan as an inhibin co-receptor capable of mediating inhibin action.     

Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives

Retinal neovascularization and macular edema are central features of diabetic retinopathy, the major cause of blindness in the developed world. Current treatments are limited in their efficacy and are associated with significant adverse effects. Characterization of the molecular and cellular processes involved in vascular growth and permeability has led to the recognition that the angiogenic growth factor and vascular permeability factor vascular endothelial growth factor (VEGF) plays a pivotal role in the retinal microvascular complications of diabetes. Therefore, VEGF represents an exciting target for therapeutic intervention in diabetic retinopathy. This review highlights the current understanding of the mechanisms that regulate VEGF gene expression and mediate its biological effects and how these processes may become altered during diabetes. The cellular and molecular alterations that characterize experimental models of diabetes are considered in relation to the influence of high glucose-mediated oxidative stress on VEGF expression and on the mechanisms of VEGF's actions under hyperglycemic induction. Finally, potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological effects in the diabetic retina are considered.     

Mechanisms of biliary carcinogenesis and growth

Cholangiocarcinoma is a rare cancer originating from the neoplastic transformation of the epithelial cells （i.e. cholangiocytes） that line the biliary tract. The prognosis for patients with cholangiocarcinoma is grim due to lack of viable treatment options. The increase in world-wide incidence and mortality from cholangiocarcinoma highlights the importance of understanding the intracellular mechanisms that trigger the neoplastic transformation of cholangiocytes and the growth of biliary cancers. The purpose of the following review is to address what has been learned over the past decade concerning the molecular basis of cholangiocarcinogenesis. The material presented is divided into two sections：（1） mechanisms regulating neoplastic transformation of cholangiocytes; and （2） factors regulating cholangiocarcinoma growth. An understanding of the growth regulatory mechanisms of cholangiocarcinoma will lead to the identification of therapeutic targets for this devastating cancer.     

Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan

Activin and inhibin research has provided important insight into reproductive physiology as well as many areas involving regulation of cell growth, differentiation and function. Progress in understanding the roles of these hormones in various cell and tissue types has been complimented by novel discoveries at the molecular level that have shed light on ligand/receptor interactions, signaling mechanisms and regulation. While the receptors and signaling pathway for activin are now well characterized, the molecular basis for inhibin action has remained relatively unclear. Here we summarize recent advances in understanding inhibin's mode of action focusing on our recent identification of betaglycan as an inhibin co-receptor capable of mediating inhibin action.     

Role of molecular charge and hydrophilicity in regulating the kinetics of crystal growth

The composition of biologic molecules isolated from biominerals suggests that control of mineral growth is linked to biochemical features. Here, we define a systematic relationship between the ability of biomolecules in solution to promote the growth of calcite (CaCO3) and their net negative molecular charge and hydrophilicity. The degree of enhancement depends on peptide composition, but not on peptide sequence. Data analysis shows that this rate enhancement arises from an increase in the kinetic coefficient. We interpret the mechanism of growth enhancement to be a catalytic process whereby biomolecules reduce the magnitude of the diffusive barrier, Ek, by perturbations that displace water molecules. The result is a decrease in the energy barrier for attachment of solutes to the solid phase. This previously unrecognized relationship also rationalizes recently reported data showing acceleration of calcite growth rates over rates measured in the pure system by nanomolar levels of abalone nacre proteins. These findings show that the growth-modifying properties of small model peptides may be scaled up to analyze mineralization processes that are mediated by more complex proteins. We suggest that enhancement of calcite growth may now be estimated a priori from the composition of peptide sequences and the calculated values of hydrophilicity and net molecular charge. This insight may contribute to an improved understanding of diverse systems of biomineralization and design of new synthetic growth modulators.