ABSTRACT
Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.
Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.
Subject(s)
Humans , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/classification , Biomarkers , Biological Transport/genetics , Biotransformation/genetics , Combined Modality Therapy , Drug Combinations , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Drug Resistance, Neoplasm/genetics , Enzymes/genetics , Ethnicity/genetics , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Fluorouracil/pharmacokinetics , Fluorouracil/therapeutic use , Gastrectomy , Mexico , Molecular Targeted Therapy , Organoplatinum Compounds/pharmacokinetics , Oxonic Acid/pharmacokinetics , Patient Selection , Pharmacogenetics , Precision Medicine , Prodrugs/pharmacokinetics , Stomach Neoplasms/genetics , Stomach Neoplasms/surgery , Tegafur/pharmacokineticsABSTRACT
Variations in somato-genetic patterns in muscle-fibre biology, biochemical metabolic pathways and pulmonary physiology are hypothesized to have been concentrated by natural selection over the centuries in the Afrocentric peoples displaced from West Africa to the New World. These phenotypic and genotypic characteristics are attributed to provide the athletic prowess so well documented in African-Americans. Not the least of coincidence seems to be the influence of the compensatory mechanisms on oxygen transport and its availability to the tissues, in response to the sickle cell gene. The reduced availability coupled with reduced myoglobin in the preponderant fast-twitch muscle fibres which are adapted for rapid energy (ATP) regeneration, all give a NET outcome of muscle anatomical and biochemical advantages which support outstanding performances in athleticism.
Existe la hipótesis de que los patrones somatogenéticos en la biología fibromuscular, las vías meta-bólicas bioquímicas, y la fisiología pulmonar, se han concentrado mediante selección natural a lo largo de siglos, en los pueblos afrocéntricos desplazados desde C1frica Occidental al Nuevo Mundo. A estas características fenotípicas y genotípicas se les atribuye las proezas atléticas, tan bien docu-mentadas en los afroamericanos. Tampoco parece ser coincidencia en lo más mínimo, la influencia de los me-canismos compensatorios de transporte de oxígeno, y su disponibilidad en los tejidos, en respuesta al gene de la célula falciforme. Esta disponibilidad reducida acoplada con la mioglobina reducida en las fibras musculares de contracción rápida preponderantes que están adaptadas para la rápida re-generación de energía (ATP), producen de conjunto un resultado neto en términos de ventajas musculares anatómicas y bioquímicas que constituyen la base de las actuaciones destacadas en el atletismo.
Subject(s)
Humans , Oxygen Consumption/genetics , Sports/physiology , Muscle Fibers, Fast-Twitch/metabolism , Black People/genetics , Sickle Cell Trait/genetics , Biomechanical Phenomena , Phenotype , Muscle Fibers, Fast-Twitch/physiology , Genotype , Muscle, Skeletal/metabolism , Caribbean Region , Biological Transport/genetics , Sickle Cell Trait/metabolism , Africa, Western/ethnologyABSTRACT
We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R²) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001) and CETP (R² = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005) and LCAT/AI (R² = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.
Subject(s)
Animals , Male , Mice , Apolipoprotein A-I/genetics , Atherosclerosis/genetics , Cholesterol Ester Transfer Proteins/genetics , Diet, Atherogenic , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Apolipoprotein A-I/metabolism , Atherosclerosis/metabolism , Biological Transport/genetics , Cholesterol Ester Transfer Proteins/metabolism , Disease Models, Animal , Genotype , Linear Models , Mice, Transgenic , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , Severity of Illness IndexABSTRACT
The complete genome sequence of the free-living bacterium Chromobacterium violaceum has been determined by a consortium of laboratories in Brazil. Almost 500 open reading frames (ORFs) coding for transport-related membrane proteins were identified in C. violaceum, which represents 11 of all genes found. The main class of transporter proteins is the primary active transporters (212 ORFs), followed by electrochemical potential-driven transporters (154 ORFs) and channels/pores (62 ORFs). Other classes (61 ORFs) include group translocators, transport electron carriers, accessory factors, and incompletely characterized systems. Therefore, all major categories of transport-related membrane proteins currently recognized in the Transport Protein Database (http://tcdb.ucsd.edu/tcdb) are present in C. violaceum. The complex apparatus of transporters of C. violaceum is certainly an important factor that makes this bacterium a dominant microorganism in a variety of ecosystems in tropical and subtropical regions. From a biotechnological point of view, the most important finding is the transporters of heavy metals, which could lead to the exploitation of C. violaceum for bioremediation