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We present a strategy to control dynamically the loading and release of molecular ligands from synthetic nucleic acid receptors using in vitro transcription. We demonstrate this by engineering three model synthetic DNA-based receptors: a triplex-forming DNA complex, an ATP-binding aptamer, and a hairpin strand, whose ability to bind their specific ligands can be cotranscriptionally regulated (activated or inhibited) through specific RNA molecules produced by rationally designed synthetic genes. The kinetics of our DNA sensors and their genetically generated inputs can be captured using differential equation models, corroborating the predictability of the approach used. This approach shows that highly programmable nucleic acid receptors can be controlled with molecular instructions provided by dynamic transcriptional systems, illustrating their promise in the context of coupling DNA nanotechnology with biological signaling.
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Aptámeros de Nucleótidos , Ácidos Nucleicos , Genes Sintéticos , ADN/química , Nanotecnología , Ligandos , Aptámeros de Nucleótidos/químicaRESUMEN
Proposed herein is a systematic media design framework that combines multivariate statistical approaches with in silico analysis of a genome-scale metabolic model of Chinese hamster ovary cell. The framework comprises sequential modules including cell culture and metabolite data collection, multivariate data analysis, in silico modeling and flux prediction, and knowledge-based identification of target media components. Two monoclonal antibody-producing cell lines under two different media conditions were used to demonstrate the applicability of the framework. First, the cell culture and metabolite profiles from all conditions were generated, and then statistically and mechanistically analyzed to explore combinatorial effects of cell line and media on intracellular metabolism. As a result, we found a metabolic bottleneck via a redox imbalance in the TCA cycle in the poorest growth condition, plausibly due to inefficient coenzyme q10-q10h2 recycling. Subsequent in silico simulation allowed us to suggest q10 supplementation to debottleneck the imbalance for the enhanced cellular energy state and TCA cycle activity. Finally, experimental validation was successfully conducted by adding q10 in the media, resulting in increased cell growth. Taken together, the proposed framework rationally identified target nutrients for cell line-specific media design and reformulation, which could greatly improve cell culture performance.
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Técnicas de Cultivo de Célula , Modelos Biológicos , Animales , Células CHO , Simulación por Computador , Cricetinae , Cricetulus , Medios de CultivoRESUMEN
A 78-year-old man who had been diagnosed with autosomal dominant polycystic kidney disease (ADPKD) and hypertension presented with chest pain. His family history was positive for ADPKD. Chest computed tomography (CT) revealed a type A aortic dissection with thrombotic occlusion of a false lumen and an ulcer-like projection in the ascending aorta, an aneurysm of the ascending aorta, and pericardial effusion. Abdominal CT showed multiple renal and hepatic cysts. At surgery, aortic dissection with thrombotic occlusion of the false lumen and an intimal tear in the distal ascending aorta were observed. Hemiarch replacement including the intimal tear was performed. The patient is doing well without requiring dialysis and without recurrence of aortic dissection or aneurysm under strict antihypertensive therapy 3 years after the operation. Pathological examination of aortic wall specimens revealed no degenerative abnormality. ADPKD should be kept in mind as one of the causative disorders of aortic dissection.
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Aorta/cirugía , Aneurisma de la Aorta Torácica/etiología , Disección Aórtica/etiología , Implantación de Prótesis Vascular/métodos , Riñón Poliquístico Autosómico Dominante/complicaciones , Anciano , Disección Aórtica/diagnóstico , Disección Aórtica/cirugía , Aorta/diagnóstico por imagen , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/cirugía , Humanos , Masculino , Riñón Poliquístico Autosómico Dominante/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. METHODS: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1-4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters. RESULTS: Hepatic parameters (glutamate-oxaloacetic transaminase [GOT] and glutamic-pyruvic transaminase [GPT]) with CDDP did not change until day 3 and only GOT increased on day 4. Renal parameters (plasma creatinine, blood urea nitrogen) with CDDP continuously increased up to day 4. Alanyl-glutamine infusion significantly elevated blood ammonia level of CDDP rats with the peak on day 3, although the same dose did not change that of control rats. CONCLUSION: These results indicates that CDDP enhances the increase in blood ammonia level by glutamine supplementation without correlating with primary parameters for hepatic/renal dysfunction.
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Amoníaco/sangre , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Dipéptidos/farmacología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Ácido Glutámico/sangre , Glutamina/sangre , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , RatasRESUMEN
We report a case of aortic valve infective endocarditis (IE) in a 24-year-old man with atopic dermatitis (AD). He had a history of balloon valvuloplasty for a stenotic bicuspid aortic valve, and had dental caries but no invasive dental procedure before the onset of IE. On admission, skin lesions of AD with itching and scratches were found on the neck, trunk, and extremities. Echocardiography showed a vegetation on the aortic valve with mild steno-regurgitation, but extension of IE to the annulus was not detected. Magnetic resonance imaging identified fresh cerebral infarction without neurological dysfunction, leading us to suspect an embolism. Blood cultures grew methicillin-sensitive Staphylococcus aureus. During emergency surgery, a vegetation attached to the conjoined cusp was observed, and the aortic valve was replaced with a mechanical valve. The patient recovered uneventfully without any complications such as recurrent IE or mediastinitis. We also review previously reported cases of IE associated with AD.
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Dermatitis Atópica/complicaciones , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/etiología , Endocarditis Bacteriana/terapia , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Although recent studies have revealed the importance of inflammation in the pathogenesis of aortic dissection (AD), little is known about the relationships among inflammatory cells in human AD tissue. METHODS AND RESULTS: We assessed the relationships among various immune cell types, including neutrophils, macrophages (M1 and M2), B cells, and helper T cells (Th1, Th2, Th17, Treg and Tfh ) in human AD tissue. AD tissues displayed abundant infiltration of immune cells. Correlation analysis revealed two groups of highly correlated cell types: a group of neutrophils and M1 and M2 macrophages, and another group consisting of B cells and helper T cells. In one particular case of AD, we were able to analyze the correlations between neutrophils and M1 and M2 macrophages in the entry, border, and intact zones of the AD lesions. Neutrophils showed significant correlations with M1 and M2 macrophages in the border zones. The entry and border zones showed M1-dominant polarization, whereas the intact zone showed M2-dominant polarization. CONCLUSIONS: These findings indicate the existence of cell type-specific and site-specific interactions among immune cell types in human AD tissues.
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OBJECTIVE: Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. MATERIALS AND METHODS: We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. RESULTS: Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. CONCLUSION: Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.
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Benzoxazoles , Butiratos , Modelos Animales de Enfermedad , Miembro Posterior , Isquemia , Neovascularización Fisiológica , Estrés Oxidativo , Especies Reactivas de Oxígeno , Animales , Estrés Oxidativo/efectos de los fármacos , Benzoxazoles/farmacología , Benzoxazoles/uso terapéutico , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Masculino , Miembro Posterior/irrigación sanguínea , Especies Reactivas de Oxígeno/metabolismo , Butiratos/farmacología , Butiratos/uso terapéutico , Ratones , Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , PPAR alfa/metabolismo , Recuperación del Miembro , AngiogénesisRESUMEN
BACKGROUND: Aortoesophageal fistula (AEF) is a rare but potentially life-threatening condition. The best treatment for the AEF due to esophageal carcinoma is still unresolved. Here, we report a rare case of AEF caused by esophageal cancer, that was successfully treated with emergency thoracic endovascular aortic repair (TEVAR), followed by esophagectomy and gastric tube reconstruction. CASE PRESENTATION: A 64-year-old man presented with loss of consciousness and hypotension during chemoradiotherapy for advanced esophageal cancer. Enhanced computed tomography showed extravasation from the descending aorta into the esophagus at the tumor site. We performed emergency TEVAR for the AEF, which stabilized the hemodynamics. We then performed thoracoscopic subtotal esophagectomy on day 4 after TEVAR to prevent graft infection, followed by gastric tube reconstruction on day 30 after TEVAR. At 9 months after the onset of AEF, the patient continues to receive outpatient chemotherapy and leads a normal daily life. CONCLUSION: TEVAR is a useful hemostatic procedure for AEF. If the patient is in good condition and can continue treatment for esophageal cancer, esophagectomy and reconstruction after TEVAR should be performed to prevent graft infection and maintain quality of life.
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The concentration of free glutamate (Glu) in rat's milk is â¼10 times higher than that in plasma. Previous work has shown that mammary tissue actively transports circulatory leucine (Leu), which is transaminated to synthesize other amino acids such as Glu and aspartate (Asp). To investigate the molecular basis of Leu transport and its conversion into Glu in the mammary gland, we characterized the expression of Leu transporters and [(3)H]Leu uptake in rat mammary cells. Gene expression analysis indicated that mammary cells express two Leu transporters, LAT1 and LAT2, with LAT1 being more abundant than LAT2. This transport system is sodium independent and transports large neutral amino acids. The Leu transport system in isolated rat mammary cells could be specifically blocked by the LAT1 inhibitors 2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid (BCH) and triiodothyronine (T3). In organ cultures, Glu secretion was markedly inhibited by these LAT1 inhibitors. Furthermore, the profiles of Leu uptake inhibition by amino acids in mammary cells were similar to those reported for LAT1. In vivo, concentrations of free Glu and Asp increased in milk by oral gavage with Leu at 6, 12, and 18 days of lactation. These results indicate that the main Leu transporter in mammary tissue is LAT1 and the transport of Leu is a limiting factor for the synthesis and release of Glu and Asp into milk. Our studies provide the bases for the molecular mechanism of Leu transport in mammary tissue by LAT1 and its active role on free Glu secretion in milk, which confer umami taste in suckling pups.
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Ácido Glutámico/biosíntesis , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Leche/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Aminoácidos/genética , Aminoácidos/metabolismo , Animales , Transporte Biológico , Línea Celular , Femenino , Cadenas Ligeras de la Proteína-1 Reguladora de Fusión/genética , Cadenas Ligeras de la Proteína-1 Reguladora de Fusión/metabolismo , Ácido Glutámico/genética , Ácido Glutámico/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/genética , Leucina/genética , Leucina/metabolismo , Glándulas Mamarias Animales/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Open surgery for the treatment of focal infrarenal aortic stenosis in high-risk patients may result in complications and mortality. Endovascular aortic repair may be used to treat these lesions. Here, we present the case of a 78-year-old woman with severe, highly calcified stenosis of the infrarenal abdominal aorta, which was successfully treated with the GORE VIABAHN VBX (Gore Medical; Flagstaff, AZ) balloon-expandable covered stent. Long-term and randomized controlled studies comparing open surgery with EVAR are necessary to evaluate the usefulness of this novel device.
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Estenosis de la Válvula Aórtica , Implantación de Prótesis Vascular , Femenino , Humanos , Anciano , Prótesis Vascular , Implantación de Prótesis Vascular/efectos adversos , Reparación Endovascular de Aneurismas , Stents , Estenosis de la Válvula Aórtica/etiología , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Isolated aneurysms of the external iliac artery are rare in patients with fibromuscular dysplasia. In this study, we report the case of a 74-year-old man with advanced gastric cancer who was found to have a medium-sized aneurysm of the external iliac artery (35 mm) on preoperative computed tomography angiograms. The patient underwent laparoscopic gastrectomy followed by replacement of the external iliac artery 6 months later. Histological examination of biopsy specimens revealed fibromuscular dysplasia. The 6 month postoperative course was uneventful. Such a case of external iliac artery aneurysm caused by fibromuscular dysplasia is very rare, and open surgery is recommended for its removal.
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Background. A large thrombus entrapped in the patent foramen ovale (PFO) is an extremely rare condition. Moreover, it is considered even rarer after temporary inferior vena cava filter (TIVCF) placement for the prevention of fatal pulmonary embolism due to venous thromboembolism (VTE). Case Report. A 58-year-old man presented with syncope following chest pain and dyspnea due to PE exacerbation during TIVCF protection, which then led to cardiogenic shock. Echocardiography revealed a large thrombus entrapped in the PFO, and computed tomography (CT) showed a bilateral pulmonary artery embolism. The patient was treated with open surgical embolectomy for a pulmonary artery thrombus and PFO thrombus with simultaneous closure of the PFO. The patient's postoperative course was uneventful. Results and Conclusion. Surgical embolectomy was useful with respect to the feasibility of resection of both intracardiac thrombus and pulmonary artery thrombus performed simultaneously, contributing to the prevention of systemic embolisms, and echocardiography plays an important role for early diagnosis.
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We reviewed the effect of monosodium glutamate (MSG) on the development and healing of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal lesions in rats. Loxoprofen (60 mg/kg, p.o.) induced lesions in the small intestine within 24 h, accompanied by a decrease of Muc2 expression and an increase in enterobacterial invasion and inducible nitric oxide synthase (iNOS) expression. These lesions were prevented when MSG was given as a mixture of powdered food for 5 days before the loxoprofen treatment. This effect of MSG was accompanied by an increase in Muc2 expression / mucus secretion as well as the suppression of bacterial invasion and iNOS expression. These intestinal lesions healed spontaneously within 6 days, but the process was impaired by the repeated administration of low-dose loxoprofen (30 mg/kg) for 5 days after the ulceration, with the decrease of vascular endothelial derived growth factor (VEGF) expression and angiogenesis. The healing-impairing effect of loxoprofen was prevented by feeding 5% MSG for 5 days after the ulceration. These results suggest that MSG not only prevents loxoprofen-induced small intestinal damage but also promotes a healing of these lesions; the former is functionally associated with the increase in Muc2 expression / mucus secretion and the suppression of bacterial invasion and iNOS expression, while the latter is associated with the stimulation of VEGF expression/angiogenesis.
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Antiinflamatorios no Esteroideos/toxicidad , Enfermedades Intestinales/tratamiento farmacológico , Fenilpropionatos/toxicidad , Glutamato de Sodio/farmacología , Animales , Modelos Animales de Enfermedad , Aditivos Alimentarios/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Mucina 2/genética , Óxido Nítrico Sintasa de Tipo II/genética , Ratas , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Chemosensing of nutrients in the gastrointestinal tract plays physiologically important roles in the regulation of food intake behaviors, including digestion, absorption, metabolism and other subsequently occurring body functions via brain activation. Free amino acids, liberated from ingested foods, are of course essential nutrients which compose the body proteins and sometimes determine the taste of the food. Glutamate, one of the most abundant amino acids in the foods and the liberated free form, critically contributes to the 'umami' taste perception. Recently, it has been revealed that dietary glutamate has many beneficial functions in the gastrointestinal tract. However, the precise mechanism of glutamate sensing still remains unclear. Using primary rat gastric mucosal cell cultures, we demonstrated that somatostatin-secreting D cells are candidate cells for glutamate sensing in the stomach through inhibition of somatostatin release. Considering that somatostatin is one of the major negative regulators of gastric functions, it is suggested that some parts of glutamate's beneficial effects could be explained by suppression of the inhibitory somatostatin effects, i.e. stimulation, by glutamate.
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Aminoácidos/farmacología , Mucosa Gástrica/citología , Mucosa Gástrica/metabolismo , Receptores Sensibles al Calcio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Células Secretoras de Somatostatina/efectos de los fármacos , Animales , Células Cultivadas , Ratas , Ratas Sprague-Dawley , Somatostatina/metabolismoRESUMEN
BACKGROUND & AIMS: The gut-brain axis, which transmits nutrient information from the gastrointestinal tract to the brain, is important for the detection of dietary nutrients. We used functional magnetic resonance imaging of the rat forebrain to investigate how this pathway conveys nutrient information from the gastrointestinal tract to the brain. METHODS: We investigated the contribution of the vagus nerve by comparing changes of blood oxygenation level-dependent signals between 24 control rats and 22 rats that had undergone subdiaphragmatic vagotomy. Functional data were collected under alpha-chloralose anesthesia continuously 30 minutes before and 60 minutes after the start of intragastric infusion of L-glutamate or glucose. Plasma insulin, L-glutamate, and blood glucose levels were measured and compared with blood oxygenation level-dependent signals. RESULTS: Intragastric administration of L-glutamate or glucose induced activation in distinct forebrain regions, including the cortex, hypothalamus, and limbic areas, at different time points. Vagotomy strongly suppressed L-glutamate-induced activation in most parts of the forebrain. In contrast, vagotomy did not significantly affect brain activation induced by glucose. Instead, blood oxygenation level-dependent signals in the nucleus accumbens and amygdala, in response to gastrointestinal glucose, varied along with fluctuations of plasma insulin levels. CONCLUSIONS: These results indicate that the vagus nerve and insulin are important for signaling the presence of gastrointestinal nutrients to the rat forebrain. These signal pathways depend on the ingested nutrients.
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Sistema Nervioso Entérico/metabolismo , Tracto Gastrointestinal/inervación , Glucosa/metabolismo , Prosencéfalo/metabolismo , Transducción de Señal , Glutamato de Sodio/metabolismo , Nervio Vago/metabolismo , Administración Oral , Animales , Glucemia/metabolismo , Mapeo Encefálico/métodos , Vaciamiento Gástrico , Tracto Gastrointestinal/metabolismo , Glucosa/administración & dosificación , Insulina/sangre , Imagen por Resonancia Magnética , Masculino , Prosencéfalo/anatomía & histología , Ratas , Ratas Sprague-Dawley , Glutamato de Sodio/administración & dosificación , Glutamato de Sodio/sangre , Factores de Tiempo , Vagotomía , Nervio Vago/cirugíaRESUMEN
Dietary free glutamate is known to elicit umami, one of the five basic tastes perceived via the specific taste sensor cells on the tongue. Recent studies suggest the specific glutamate sensors exist in the gastric mucosa and contribute to the regulation of gastrointestinal functions, yet the precise mechanism remains still unknown. We established the method to enrich various cell fractions from the isolated rat gastric mucosa and characterized the expression of putative glutamate sensors using such cell fractions. The gastric mucosal cell fractions such as surface mucous, parietal, chief, and endocrine cells were successfully prepared by mucosal protease digestion, elutriation, and gradient centrifugation. The characteristics of these cells were confirmed by real-time RT-PCR using the respective cell-specific markers. Parietal cell fraction exclusively expressed putative umami receptor molecules such as T1R1 and mGluR1 compared to other fractions, although the degree of expression was low. In contrast, the representative taste cell specific markers such as PLCbeta2 and TRPM5 were specifically expressed in the smaller endocrine cell fraction. Both parietal and smaller endocrine cell fractions also positively expressed some mGluR subtypes. The chief-cell fraction less expressed T1R1 and mGluR1. These results suggest that multiple glutamate sensors, probably different mechanisms from taste buds, contribute to the glutamate sensing in the gastric mucosa.
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Mucosa Gástrica/citología , Mucosa Gástrica/metabolismo , Ácido Glutámico/metabolismo , Animales , Fraccionamiento Celular/métodos , Fraccionamiento Celular/tendencias , Mucosa Gástrica/efectos de los fármacos , Ácido Glutámico/farmacología , Células Parietales Gástricas/citología , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato/biosíntesisRESUMEN
Ammonia is one of the important toxins produced by Helicobacter pylori (H. pylori), the major cause of peptic ulcer diseases. We examined whether glutamine or marzulene (a gastroprotective drug containing 1% sodium azulene and 99% glutamine) protects the gastric mucosa against H. pylori in vivo and investigated the mechanism underlying glutamine-induced mucosal protection against ammonia in gastric epithelial cells in vitro. Mongolian gerbils were fed for 3 months with a diet containing glutamine (2%-20%) or marzulene (20%) starting from 2 weeks or 2 years after H. pylori infection. Then, gastric mucosal changes were evaluated both macro- and microscopically. Cultured gastric epithelial cells were incubated in the presence of ammonia, with or without glutamine; and cell viability, ammonia accumulation, and chemokine production were determined. Gerbils exhibited edema, congestion, and erosion after 3-month infection; and after 2-year infection, they showed cancer-like changes in the gastric mucosa. Glutamine and marzulene significantly suppressed these pathological changes caused in the gastric mucosa by H. pylori infection. Ammonia was accumulated in the cells, resulting in an increase in chemokine production and a decrease in cell viability. These pathological responses were prevented by glutamine. In addition, glutamine decreased chemokine production and cell death through inhibition of cellular accumulation of ammonia, resulting in the prevention of H. pylori-induced gastric diseases in vivo. These results suggest that glutamine/marzulene would be useful for prophylactic treatment of H. pylori-induced gastric diseases in patients.
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Glutamina/administración & dosificación , Infecciones por Helicobacter/prevención & control , Helicobacter pylori/efectos de los fármacos , Gastropatías/prevención & control , Animales , Azulenos/administración & dosificación , Línea Celular Tumoral , Células Cultivadas , Combinación de Medicamentos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gerbillinae , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/fisiología , Humanos , Masculino , Ratas , Gastropatías/microbiología , Gastropatías/patologíaRESUMEN
Lung cancer, the leading cause of cancer death worldwide, is most frequently detected through imaging tests. In this study, we investigated serum microRNAs (miRNAs) as a possible early screening tool for resectable lung cancer. First, we used serum samples from participants with and without lung cancer to comprehensively create 2588 miRNAs profiles; next, we established a diagnostic model based on the combined expression levels of two miRNAs (miR-1268b and miR-6075) in the discovery set (208 lung cancer patients and 208 non-cancer participants). The model displayed a sensitivity of 99% and specificity of 99% in the validation set (1358 patients and 1970 non-cancer participants) and exhibited high sensitivity regardless of histological type and pathological TNM stage of the cancer. Moreover, the diagnostic index markedly decreased after lung cancer resection. Thus, the model we developed has the potential to markedly improve screening for resectable lung cancer.
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Biomarcadores de Tumor/genética , MicroARN Circulante/genética , Detección Precoz del Cáncer , Perfilación de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Transcriptoma , Anciano , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , MicroARN Circulante/sangre , Toma de Decisiones Clínicas , Bases de Datos Genéticas , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Estadificación de Neoplasias , Neumonectomía , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: During this recent decade, microarray-based single nucleotide polymorphism (SNP) data are becoming more widely used as markers for linkage analysis in the identification of loci for disease-associated genes. Although microarray-based SNP analyses have markedly reduced genotyping time and cost compared with microsatellite-based analyses, applying these enormous data to linkage analysis programs is a time-consuming step, thus, necessitating a high-throughput platform. RESULTS: We have developed SNP HiTLink (SNP High Throughput Linkage analysis system). In this system, SNP chip data of the Affymetrix Mapping 100 k/500 k array set and Genome-Wide Human SNP array 5.0/6.0 can be directly imported and passed to parametric or model-free linkage analysis programs; MLINK, Superlink, Merlin and Allegro. Various marker-selecting functions are implemented to avoid the effect of typing-error data, markers in linkage equilibrium or to select informative data. CONCLUSION: The results using the 100 k SNP dataset were comparable or even superior to those obtained from analyses using microsatellite markers in terms of LOD scores obtained. General personal computers are sufficient to execute the process, as runtime for whole-genome analysis was less than a few hours. This system can be widely applied to linkage analysis using microarray-based SNP data and with which one can expect high-throughput and reliable linkage analysis.