Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The frequency, symptoms, and complication rate of PUD seem to decrease during pregnancy. Yet clinicians often have to treat dyspepsia or pyrosis of undetermined origin during pregnancy because the frequency of pyrosis significantly increases during pregnancy, and clinicians reluctantly perform EGD during pregnancy for pyrosis to differentiate reliably between GERD and PUD. Dyspepsia or pyrosis during pregnancy is initially treated with dietary and lifestyle modifications. If the symptoms do not remit with these modifications, sucralfate or antacids, preferably magnesium-containing or aluminum-containing antacids, should be administered. Histamine2 receptor antagonists are recommended when symptoms are refractory to antacid or sucralfate therapy. Ranitidine seems to be a relatively safe H2 receptor antagonist. If symptoms continue despite H2 receptor antagonist therapy, the patient should be evaluated for possible EGD or PPI therapy. Pregnant women with hemodynamically significant upper gastrointestinal bleeding or other worrisome clinical findings should undergo EGD. Indications for surgery include ulcer perforation, ongoing active bleeding from an ulcer requiring transfusion of six or more units of packed erythrocytes, gastric outlet obstruction refractory to intense medical therapy, and a malignant gastric ulcer without evident metastases.
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PMID:Gastric and duodenal ulcers during pregnancy. 1263 19

Metastatic cancer is a complex positive feedback loop system. Such as system has a tendency to acquire extreme robustness. Signaling pathways controlling that robustness can fail completely if an essential element from the signaling is removed. That element is a locus of fragility. Targeting that locus represents the best way to target the cancer robustness. This prospect presents another locus of fragility in signaling complex system network, controlling the cell cycle progression through the PI3K/AKT/mTOR/RAN pathway and cell migration and angiogenesis through the VEGF/PI3K/AKT/NO/ICAM-1 pathway. The locus of fragility of these pathways is AKT, which is regulated by a balance of catalase/H2O2 or by AKT inhibitor. Tiny and trivial perturbations such as change in redox state in the cells by antioxidant enzyme catalase, scavenging H2O2 signaling molecule, regulates robust signaling molecule AKT, abolishing its phosporilation and inducing cascading failure of robust signaling pathways for cell growth, proliferation, migration, and angiogenesis. An anticancer effect of the antioxidant is achieved through the AKT locus, by abolishing signals from growth factors VEGF, HGF, HIF-1alpha and H2O2. Previously reported locus of fragility nitric oxide (NO) and locus AKT are close in the complex signaling interactome network, but they regulate distinct signaling modules. Simultaneously targeted loci represents new principles in cancer robustness chemotherapy by blocking cell proliferation, migration, angiogenesis and inducing rather slow then fast apoptosis leading to slow eradication of cancer.
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PMID:AKT as locus of fragility in robust cancer system. 1842 70

Mammary tumors are a major health threat to women and female dogs. In both, metastasis of the primary tumor to distant organs is the most common cause of tumor-related death. Nevertheless, the molecular mechanisms of tumor metastasis are far from being understood, and it is still unknown why some human and canine carcinomas metastasize and others do not. Using 2D-DIGE and MALDI-TOF-MS we identified 21 proteins with significant changes (fold change >1.5; p < 0.05) in protein expression between metastasizing (n = 6) and nonmetastasizing (n = 6) canine mammary carcinomas. Quantitative RT-PCR was used to identify transcriptional or post-transcriptional regulation of protein expression. Up-regulated proteins in metastatic carcinomas included proliferating cell nuclear antigen, ferritin light chain, bomapin, tropomyosin 3, thioredoxin-containing domain C5, adenosin, ornithine aminotransferase, coronin 1A, RAN-binding protein 1,3-phosphoglycerate dehydrogenase, and eukaryotic translation elongation factor 1. Down-regulated proteins in metastatic carcinomas included calretinin, myosin, light chain 2, peroxiredoxin 6, maspin, ibrinogen beta chain, vinculin, isocitrate dehydrogenase 1, tropomyosin 1, annexin A5, and Rho GTPase activating protein 1. Interestingly, 19 of these 21 proteins have been described with a malignancy-associated expression in human breast cancer and other human cancer types before. Further investigations are now necessary to test whether these markers are of prognostic value for canine mammary carcinomas and whether their expression is directly involved in canine mammary carcinogenesis or represent solely a secondary reactive phenotype.
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PMID:Proteome of metastatic canine mammary carcinomas: similarities to and differences from human breast cancer. 2093 60

Development of multiple drug resistance mechanisms in melanomas necessitates the identification of new drug targets, which when inhibited could impact multiple cellular pathways, thus circumventing potential resistance. By performing complementary DNA microarray analysis, we identified four key components of the nucleocytoplasmic transport machinery-CRM1, RAN (RAN-GTPase), RANGAP1, and RANBP1-to be overexpressed in human melanoma metastases. Chromosome region maintenance 1 (CRM1) inhibition induced a marked depletion of prosurvival/cytoplasmic extracellular signal-regulated kinase 1/2 (Erk1/2) and p90 ribosomal S6 kinase1 and elicited persistent Erk-signaling hyperactivation. Consistently, CRM1 inhibition inflicted extensive apoptosis in melanoma cells while sparing nontransformed melanocytes and primary lung fibroblasts. Apoptosis required both the intrinsic and extrinsic apoptotic pathways and was associated with a nuclear entrapment and downregulation of the antiapoptotic CRM1 target protein, Survivin. Apoptosis was preceded by a G1 cell-cycle arrest, and even though CRM1 inhibition mediated marked p53 and p21 induction in wild-type p53 melanoma cells, the latter's silencing or inactivation failed to alleviate apoptosis. Notably, CRM1 inhibition induced cell line-specific, G1 to S progression-retarding changes in the expression of multiple cell-cycle regulatory proteins, thus potentially explaining p53 dispensability. We propose CRM1 as a potential therapeutic target in human melanoma, whose inhibition induces loss of prosurvival/cytoplasmic Erk1/2, mediates persistent Erk hyperactivation, and initiates a multitude of cell context-dependent molecular events to trigger G1 arrest followed by massive apoptosis.
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PMID:Inhibition of CRM1-mediated nucleocytoplasmic transport: triggering human melanoma cell apoptosis by perturbing multiple cellular pathways. 2283 92

Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, decreases self-renewal and migration. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and self-renewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7i and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B. Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.
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PMID:LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase. 3233 49