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《Actas urologicas espa?olas》2014,38(3):192-199
Context and objectiveTo analyze the influence of different alterations in human leukocyte antigen class I molecules (HLA I) in renal cell carcinoma, as well as in bladder and prostate cancer. We also study the correlation between HLA I expression and the progression of the disease and the response after immunotherapy protocols.Evidences acquisitionIt has been shown, experimentally, that the immune system can recognize and kill neoplastic cells. By analyzing the expression of HLA I molecules on the surface of cancer cells, we were able to study the tumor escape mechanisms against the immune system.Evidences synthesisAlteration or irreversible damage in HLA I molecules is used by the neoplastic cells to escape the immune system. The function of these molecules is to recognize endogenous peptides and present them to T cells of the immune system. There is a clear relationship between HLA I reversible alterations and success of therapy. Irreversible lesions also imply a lack of response to treatment. The immune system activation can reverse HLA I molecules expression in tumors with reversible lesions, whereas tumors with irreversible ones do not respond to such activation. Determine the type of altered HLA I molecules in tumors is of paramount importance when choosing the type of treatment to keep looking for therapeutic success. Those tumors with reversible lesions can be treated with traditional immunotherapy; however, tumour with irreversible alterations should follow alternative protocols, such as the use of viral vectors carrying the HLA genes to achieve damaged re-expression of the protein.ConclusionFrom studies in urologic tumors, we can conclude that the HLA I molecules play a key role in these tumors escape to the immune system. 相似文献
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Severe asthma affects fewer than 10% of patients with asthma, is associated with a severe risk of death and disability, has a great impact on health and quality of life, and represents a huge cost to patients and society. Given the poor response to treatment and the side effects associated with medications for severe asthma, more efficient, cost-effective, and phenotype-specific medications are needed. Considering severe asthma as an orphan disease could encourage the pharmaceutical industry to stratify studies based on a more detailed characterization of study subjects at baseline, resulting in the development of novel therapeutic approaches. 相似文献
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Alam I Robling AG Weissing S Carr LG Lumeng L Turner CH 《Alcoholism, clinical and experimental research》2005,29(10):1769-1776
BACKGROUND: The association between moderate alcohol intake and elevated bone mineral density observed in several epidemiologic studies might result from common genetic pathway regulating both phenotypes. In this study, we determined whether there is a relationship between alcohol preference and high bone mass or strength and whether bone mass-regulating genes segregate during selective breeding of alcohol preferring rats. METHODS: Six different lines of male rats with high or low preference for alcohol consumption were used in this study. The high alcohol preference lines are alcohol-preferring (P), high-alcohol-drinking 1 (HAD1), and high-alcohol-drinking 2 (HAD2), and their corresponding low alcohol preference lines are alcohol-nonpreferring (NP), low-alcohol-drinking 1 (LAD1), and low-alcohol-drinking 2 (LAD2). Bone mass phenotypes were determined using dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and biomechanics in long bones and lumbar vertebrae from rats at 3 and 6 months of age. RESULTS: P rats had significantly higher bone mass and strength compared with NP rats, mainly due to higher cortical bone in long bones and lumbar vertebrae. HAD2 rats also had significantly higher bone mass compared with LAD2 rats, but mostly due to increased trabecular bone leading to increased strength only in lumbar vertebra. Conversely, HAD1 rats had significantly lower bone mass and strength compared with LAD1 rats in long bones. The vertebral bone mass and strength did not differ between HAD1 and LAD1 rats. CONCLUSIONS: This study demonstrated that preference for alcohol consumption had no consistent relationship with high bone mass or strength, as each alcohol-preferring rat line had their unique bone mass phenotypes. However, genes regulating bone mass and strength appear to segregate with alcohol preference genes in P and HAD rat lines, suggesting that alcohol preferring rat lines may be useful for identifying genes that regulate bone mass and structure. 相似文献
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X. Y. Song S. Y. Lee R. C. W. Ma W. Y. So J. H. Cai C. Tam V. Lam W. Ying M. C. Y. Ng J. C. N. Chan 《Diabetologia》2009,52(8):1543-1553
Aims/hypothesis Cardiovascular and renal diseases share common risk factors. We used structural equation modelling (SEM) to evaluate the independent
and combined effects of phenotypes and genotypes implicated in cardiovascular diseases on renal function in type 2 diabetes.
Methods 1,188 type 2 diabetic patients were stratified into high-risk and low-risk groups according to bimodal distributions of the
logarithmically transformed (loge) urinary albumin:creatinine ratio and plasma creatinine levels. Models for these groups, comprising continuous and non-ranking
categorical data, were developed separately to evaluate the inter-relationships among measured variables and latent factors
using non-linear SEMs, Bayesian estimation and model selection as assessed by a goodness-of-fit statistic.
Results Inter-correlated measured variables (obesity, glycaemia, lipid, blood pressure) and variants of the genes encoding endothelial
nitric oxide synthase (NOS), β-adrenergic receptor (ADRB), components of the renin–angiotensin system (RAS) and lipid metabolism
were loaded onto their respective latent factors of phenotypes and genotypes. In addition to direct and indirect effects,
latent factors of obesity, lipid and BP interacted with latent factors of ADRB and RAS genotypes to influence renal function.
Together with variants of the genes encoding peroxisome proliferator-activated receptor γ, atrial natriuretic peptide, adducin,
G protein β3 subunit, epithelial sodium channel α subunit and matrix metallopeptidase 3, these parameters explained 39–80% of the variance
in renal function in the high-risk and low-risk models.
Conclusions/interpretation SEM is a useful tool for confirming and quantifying multiple interactions of biological pathways with genetic determinants.
The combined and interactive effects of blood pressure, lipid and obesity on renal function may have therapeutic implications,
especially in type 2 diabetic individuals with genetic risk factors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
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There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs. 相似文献