Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In children with pancreatic disease, computed tomography (CT) has a primary role in the evaluation of pancreatitis, trauma, and malignancy. At CT, pancreatic abnormalities may manifest as pancreatic enlargement (tumor, acute pancreatitis), pancreatic atrophy (cystic fibrosis, chronic pancreatitis), cystic lesions (pseudocysts, congenital simple cysts, autosomal dominant polycystic kidney disease, von Hippel-Lindau disease, cystic fibrosis, cystic neoplasms), or fatty replacement (cystic fibrosis, Shwachman-Diamond syndrome, history of steroid therapy, Cushing syndrome, Johanson-Blizzard syndrome, obesity). CT is the best modality for evaluation of pancreatitis, allowing detection of pancreatic abnormalities as well as abnormal extrapancreatic fluid collections. In children who have undergone blunt abdominal trauma, CT has been shown to be the best initial imaging study, being more sensitive than ultrasound for detection of pancreatic injury. In neoplastic conditions, CT demonstrates the extent of disease, enables characterization of the tissue components of the tumor, and allows accurate posttreatment follow-up. Although the various diseases of the pancreas may have overlapping appearances at CT, the correct diagnosis can often be made on the basis of the CT findings in combination with the clinical history, laboratory data, and the patient's age.
 ...
PMID:Pancreatic disease in children and young adults: evaluation with CT. 974 14

The development of renal cell carcinoma (RCC) has been associated with both genetic and environmental factors, with somatic and germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and with tobacco smoking, obesity, long term exposure to some nutrients, pollutants, and industrial solvents such as trichloroethylene. Intra and interfamilial variability of expression of germline mutations in the VHL gene and variable susceptibility to carcinogens in the sporadic forms strongly suggest the involvement of conditional modifier genes. In order to identify sub groups of individuals at increased risk because of susceptibility genotypes, we have collected a series of 460 patients who developed an RCC and 79 families with the von Hippel Lindau disease. To collect clinical and mutational data for correlation analysis we have developed a unique tool the Universal Mutation Database. Comparison of the spectrum of germline and somatic mutations in the VHL gene showed that: 1) in sporadic RCC mutations lead more often to truncated proteins (83%), while the remaining mutations (17%), include 3/4 of transversions and 1/4 of transitions. This high proportion of transversions supports the involvement of carcinogens the impact of which is conditioned by the genetic variability of xenobiotic metabolizing enzymes; 2) whereas in familial cases missense mutations are more common; this difference allowed us to define a prognostic factor for the occurrence of RCC in a VHL context. In order to look for genotypes conferring a higher risk we genotyped the RCC patients for 8 different genes (50 genotypes). A significant relationship was observed for several combinations of alleles including CYP1A1 ("variant"), NAT2 and NAT1 (slow) and GSTM1 (null allele). Associations between specific mutational profiles and at risk genotypes at different tumoral stages should allow us to: 1) define more precisely the nature of specific patterns of mutations in relation with the deficiency or overexpression of such or such enzymes in presence of particular carcinogens; 2) demonstrate that certain combinations of genotypes confer a particular risk to develop a specific type of tumor in VHL patients. Thus tracking of potentially carcinogenic substances, through their footprints and through identification of conditionally detrimental genotypes of genes participating in their detoxification should permit a better prevention through an appropriate nutrition adapted to each individual.
 ...
PMID:[Prevention of renal carcinoma: the nutri-genetic approach]. 1110 47

Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.
 ...
PMID:Precancerous lesions in the kidney. 1114 93

Although renal cell carcinoma accounts for only 3% of adult malignancies, it has been increasing in incidence by 2-4% per year since the 1970's. Cigarette smoking, obesity and end-stage renal disease are important risk factors. Genetic syndromes such as von Hippel-Lindau disease are also associated with an increased incidence of renal cell carcinoma. Localized disease should be treated with surgical resection. However, approximately 30% of patients present with metastatic disease. Complete resection of metastases can result in long-term survival in some individuals. Removal of the primary renal tumor in patients with unresectable disseminated disease has also been shown to improve survival in selected good performance status patients receiving systemic immunotherapy. While chemotherapy has been relatively ineffective in the treatment of renal cell carcinoma, biologic therapy with interleukin-2 or interferon does lead to responses in a minority of patients, with occasional long-term survivors. Recently, promising results have been reported with allogeneic stem cell transplantation using a non-myeloablative conditioning regimen. However, therapy for metastatic renal cell carcinoma remains inadequate. Ongoing trials with novel approaches such as anti-angiogenesis agents, cyclin-dependent kinase inhibitors, and tumor vaccines will hopefully lead to improved outcomes in this disease.
 ...
PMID:Renal cell carcinoma: current status and future directions. 1260 28

The discovery and characterization of the von Hippel Lindau (VHL) syndrome has brought about tremendous advances in understanding the molecular mechanisms of renal cell carcinoma. VHL mutations are known to act through hypoxia inducible factor, which has a physiologic role in detecting hypoxia. Recent investigations into other hereditary forms of kidney cancer with mutations in genes involving energy metabolism and oxidative changes, such as fumarate hydratase, suggest that metabolic changes related to hypoxia detection may be a common mechanism of tumorigenesis. This implicates aberrations in the kidney's physiologic role in detection of hypoxia in tumor formation. Germline mutations of genes involved in energy metabolism and oxidative perturbations lead to tumors in other tissues that detect hypoxia, such as head and neck paragangliomas that occur in the area of the carotid body. Therefore, aberrations in physiologic detection of hypoxia that predispose to tumor formation may not be a mechanism unique to the kidney. Furthermore, inducers of hypoxic perturbations other than germline mutations in metabolic genes may predispose to cancers in organs that have a physiologic role in detecting hypoxia. Conditions that effectively lead to tissue hypoxia in hypoxia detecting tissues is one such mechanism. We propose that some of the common molecular and physiologic mechanisms in heritable forms of kidney cancer, namely detection of hypoxia, may play a role in the genesis of sporadic kidney cancer. We survey evidence suggesting that the mechanism of some recognized risk factors of kidney cancer, such as smoking and obesity, may be due in part to tissue hypoxia, reflecting physiologic detection of hypoxia gone awry.
 ...
PMID:Perturbations in hypoxia detection: a shared link between hereditary and sporadic tumor formation? 1636 63

We have recently proposed lipid peroxidation as a unifying mechanistic pathway by which several seemingly unrelated risk/protective factors (obesity, hypertension, diabetes, smoking, oophorectomy/hysterectomy, parity, antioxidants) affect renal cell carcinoma development. In experimental studies, increased lipid peroxidation is a principal mechanistic pathway in renal carcinogenesis induced by different chemicals. In this communication, we provide additional lines of evidence that further support a role for lipid peroxidation on renal cell cancer development. (1) Lipid peroxidation may explain the role of other risk (analgesic use, pre-eclampsia) or protective (alcohol intake, oral contraceptives) factors for renal cell carcinoma. (2) Additional experimental evidence supports lipid peroxidation as an important mechanism in renal carcinogenesis, and (3) Existing evidence support a cross-talk between the lipid peroxidation pathway and other pathways that are relevant to renal carcinogenesis, such as apoptosis, VHL, and possibly other pathways.
 ...
PMID:Lipid peroxidation and renal cell carcinoma: further supportive evidence and new mechanistic insights. 1645 3

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.
 ...
PMID:The mTOR pathway and its role in human genetic diseases. 1859 80

The mammalian target of rapamycin (mTOR) is part of two distinct complexes, mTORC1, containing raptor and mLST8, and mTORC2, containing rictor, mLST8 and sin1. Although great endeavors have already been made to elucidate the function and regulation of mTOR, the cytoplasmic nuclear distribution of the mTOR complexes is unknown. Upon establishment of the proper experimental conditions, we found mTOR, mLST8, rictor and sin1 to be less abundant in the nucleus than in the cytoplasm of non-transformed, non-immortalized, diploid human primary fibroblasts. Although raptor is also high abundant in the nucleus, the mTOR/raptor complex is predominantly cytoplasmic, whereas the mTOR/rictor complex is abundant in both compartments. Rapamycin negatively regulates the formation of both mTOR complexes, but the molecular mechanism of its effects on mTORC2 remained elusive. We describe that in primary cells short-term treatment with rapamycin triggers dephosphorylation of rictor and sin1 exclusively in the cytoplasm, but does not affect mTORC2 assembly. Prolonged drug treatment leads to complete dephosphorylation and cytoplasmic translocation of nuclear rictor and sin1 accompanied by inhibition of mTORC2 assembly. The distinct cytoplasmic and nuclear upstream and downstream effectors of mTOR are involved in many cancers and human genetic diseases, such as tuberous sclerosis, Peutz-Jeghers syndrome, von Hippel-Lindau disease, neurofibromatosis type 1, polycystic kidney disease, Alzheimer's disease, cardiac hypertrophy, obesity and diabetes. Accordingly, analogs of rapamycin are currently tested in many different clinical trials. Our data allow new insights into the molecular consequences of mTOR dysregulation under pathophysiological conditions and should help to optimize rapamycin treatment of human diseases.
 ...
PMID:Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. 1861 46

We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle.
 ...
PMID:Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome. 2352 18

An association between obesity and development of clear cell renal cell carcinoma (ccRCC) has been established in the literature; however, there are limited data regarding the molecular mechanisms that underlie this association. Therefore, we used a multistage design to identify and validate genes that are associated with obesity-related ccRCC. We conducted a microarray study and compared gene expression between obese and non-obese subjects in ccRCC tumors and patient-matched normal kidney tissues. Analyses were stratified by smoking status and subsequently performed on the combined cohort. The primary objective was to identify genes where the fold change of ccRCC tumor expression between obese and non-obese subjects was different than the fold change in the patient-matched normal kidney tissue. Thus, we utilized a mixed model and evaluated the tissue type-by-obesity status interaction term. Targeted validation was performed using reverse transcription-polymerase chain reaction (RT-PCR) on an independent cohort. ENRAGE was identified in the microarray study and subsequently validated using RT-PCR to have a statistically significant tissue type-by-obesity status interaction. Specifically, although ENRAGE is similarly expressed across obese and non-obese subjects in normal tissue, it is upregulated in the patient-matched ccRCC tumor tissue. Additionally, ENRAGE is upregulated in tumors that are wild-type for the von Hippel Lindau gene and in tumors for subjects with poorer overall survival. In summary, we provide evidence that overexpression of ENRAGE in ccRCC tumor tissue is an obesity-associated somatic alteration. Upregulation of ENRAGE could lead to local, autocrine stimulation of the RAGE receptor and thus support cancer progression.
...
PMID:Somatic expression of ENRAGE is associated with obesity status among patients with clear cell renal cell carcinoma. 2437 25


1 2 Next >>