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The Role of Telomeres and Telomerase in Endocrine Tumors

Incidentally-discovered Adrenal Masses

Abstract: Unanticipated adrenal masses are frequently encountered in modern, high resolution diagnostic imaging. Most often, these masses are benign adrenal adenomas, but when detected they necessitate a clinical evaluation sufficient to exclude subclinical endocrine disease, primary adrenal cancer, and remote metastases to the adrenal glands from other malignancies. These "incidentally-discovered" adrenal masses or so-called "adrenal incidentalomas" can be further evaluated with CT, MRI, and nuclear medicine imaging techniques. A substantial literature supports the use of each of these modalities to non-invasively characterize these neoplasms that have been considered by some as a 'disease' of modern imaging technology. ... Read more

Inactivation of the p53 Tumor Suppressor Gene and Activation of the Ras Oncogene: Cooperative Events in Tumorigenesis

Abstract: Since the discovery of the tumor suppressor p53 and the Ras oncogene, ample data have been accumulated, describing their aberrations in human cancer and their contribution to the multistep process of tumorigenesis. Several studies have also demonstrated that these dysregulated pathways cooperate to promote malignancy. Here we review recent studies on the cooperative molecular mechanisms by which p53 inactivation and oncogenic Ras converge to enhance tumorigenesis. ... Read more

Advances in Medical Therapies for Cushing's Syndrome

Abstract: Cushing's syndrome (CS) is a heterogeneous disorder of diverse etiologies, leading to cortisol excess. Endogenous CS is caused by tumors secreting adrenocorticotropin (ACTH) (either eutopically or ectopically), cortisol, or very rarely corticotropin-releasing hormone (CRH). Definitive therapy of endogenous CS optimally involves tumor resection. Indications for medical therapy include acutely ill patients in preparation for surgery, those for whom surgery is not indicated (such as patients with unknown tumor location or unresectable lesions, and patients unfit for surgery for medical reasons), or patients who remain hypercortisolemic postoperatively. In the current article, the published literature has been reviewed to summarize data on medical therapies used in CS. Several agents are either used "off label" or being studied as potential therapies for CS. Medications suppressing adrenal steroidogenesis currently in use include ketoconazole, metyrapone, mitotane, or etomidate. In addition, the investigational agent LCI699 is under study. Centrally acting agents, which suppress ACTH secretion, include cabergoline, octreotide, as well as the investigational agents pasireotide, bexarotene, and lapatinib, which are being studied in patients with pituitary tumors. Mifepristone, a type 2 glucocorticoid receptor antagonist, was recently approved by the FDA as a new therapy for CS. Although not definitive at present, medical therapies have an important role in the management of CS patients. It is anticipated that understanding the pathogenesis of these tumors at a molecular level may spawn the development of rationally designed, highly efficacious medical therapies for CS in the future. ... Read more

The Nuclear Epidermal Growth Factor Receptor Signaling Network and Its Role in Cancer

Abstract: The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics. ... Read more

The Multidimensional Nature of Epigenetic Information and Its Role in Disease

Abstract: This year marks the 10th anniversary of the publications that reported the initial human genome sequence. In the historic press conference that announced this landmark accomplishment, it was proclaimed that the genome sequence would "revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases." However, subsequent work over the past decade has revealed that "complex diseases" are much more intricate than originally thought. Even with the advent of several new powerful technologies, our understanding of the underlying genetic etiologies of most complex and non-Mendelian diseases is far from complete. These results have raised the possibility that the DNA sequence, i.e., genetic information, may not be the only relevant source of information in order to understand the molecular basis of disease. In this review, we assemble evidence that information encoded beyond the DNA sequence, i.e., epigenetic information, may hold the key to a better understanding of various pathological conditions. Unlike the genetic information encoded within the DNA sequence, epigenetic information can be stored in multiple dimensions, such as in the form of DNA modifications, RNA, or protein. Ideas presented here support the view that to better understand the molecular etiology of diseases, we need to gain a better understanding of both the genetic and epigenetic components of biological information. We hence believe that the fast development of genome-wide technologies will facilitate a better understanding of both genetic and epigenetic dimensions of disease. ... Read more

Drug Profile: Sensipar

Other Names: cinacalcet HCl, AMG 073.

Makers: NPS Pharmaceuticals and Amgen.

Disease Treated: (1) Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis; (2) hypercalcemia in patients with parathyroid carcinoma.

Approval Status: Approved by the U.S. FDA on March 8, 2004 for the treatment of secondary HPT in patients with CKD on dialysis and the treatment of hypercalcemia in patients with parathyroid carcinoma.

Chemical/Biological Nature: SENSIPAR is a calcimimetic small molecule agent that has a molecular formula of C22H22F3N.HCl and a molecular weight of 393.9 g/mol.

Administration: For secondary HPT in patients with CKD on dialysis: ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Degradation of the Transcription Factor Twist, an Oncoprotein that Promotes Cancer Metastasis

Abstract: Basic helix-loop-helix (bHLH) transcription factor Twist is one of the key inducers of epithelial to mesenchymal transition (EMT) that is a transdifferentiation program associated with embryo development and tumor metastasis. High level of Twist expression is shown to be correlated with cancer malignancy. Although Twist has been reported to be degraded by F-box and leucine-rich repeat protein 14 (FBXL14), the molecular mechanisms by which Twist levels are regulated have not been fully elucidated. In the present study, we identified Twist to be a ubiquitin substrate of β-transducin repeat-containing protein (β-TRCP), the adaptor subunit of SCFβ-TRCP (Skp1-Cul1-F-box protein) E3 ligase complex. We observed that depletion of β-TRCP leads to an accumulation of Twist protein, which could enhance tumor cell motility and cancer metastasis. Moreover, phosphorylation of Twist by inhibitor of KappaB kinase β (IKKβ) at multiple sites triggers its cytoplasmic translocation and the destruction by SCFβ-TRCP. Thus, our results provide the potential molecular mechanism of how the mesenchymal marker Twist is degraded, thereby shedding lights into regulation of the EMT, and providing the rationale for development of new therapeutic intervention to achieve better treatment outcomes in human cancer. ... Read more

The Interplay of Autoimmunity and Insulin Resistance in Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is a common chronic disease characterized by selective autoimmune destruction of the pancreatic islet beta cells and subsequent dependence on exogenous insulin. Certain alleles including the high-risk HLA genotype, HLA-DR3-DQ2/DR4-DQ8, place individuals at increased risk of developing T1D. Autoantibodies to beta cell antigens are used in the diagnosis of T1D, and studies have shown that they can be used to predict risk of developing T1D in first degree relatives of probands. The annual global incidence of T1D is increasing by 3-5% per year. Many environmental factors have been implicated in the rising incidence of T1D. Proponents of the accelerator hypothesis argue that T1D and type 2 diabetes (T2D) are the same disorder of insulin resistance, although with different genetic backgrounds. While insulin resistance is a recognized hallmark of T2D, it also appears to play a significant role in the pathogenesis of T1D and its vascular complications. In this article, we will review: 1) immunogenetics of T1D, 2) risk factors for the development of islet autoimmunity and T1D, 3) mechanisms of insulin resistance in T1D, and 4) links between insulin resistance and complications in T1D. Further studies are needed to define environmental factors causing T1D as well as the role of insulin resistance in the pathogenesis of T1D and its complications. ... Read more

Hedgehog Pathway and GLI1 Isoforms in Human Cancer

Abstract: The Hedgehog signaling pathway regulates normal cell growth and differentiation. When deregulated, the Hedgehog pathway leads to tumorigenesis and supports more aggressive phenotypes of human cancers, such as progression, metastasis, and therapeutic resistance. The glioma-associated oncogene homolog 1 (GLI1) family of zinc finger transcription factors is the nuclear mediator of the Hedgehog pathway that regulates genes essential for various stages of tumor development and progression. Consequently, several components of the Hedgehog pathway are major targets of cancer therapy, including GLI1 and smoothened. Although the GLI1 gene was initially identified as an amplified gene in glioblastoma, its amplification was found to be relatively rare. No somatic mutations have been reported in the GLI1 gene. Notably, two decades after the discovery of the GLI1 gene, the GLI1 transcript was recently found to undergo alternative splicing forming two shorter isoforms, an N-terminal deletion variant (GLI1ΔN) and a truncated GLI1 (tGLI1). These variants appear to have different patterns of tissue expression and functions. Most notably, the tGLI1 isoform behaves as a gain-of-function GLI1 that can induce expression of genes not regulated by GLI1 and promotes more aggressive cancer phenotypes. Therefore, this review will focus on the structural and functional differences between these isoforms, and also on their contributions to important cancer cell characteristics, including proliferation, motility, invasion, and angiogenesis. ... Read more

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