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BACKGROUND: The homeobox (HOX) family consists of 39 genes whose expressions are tightly controlled and coordinated within the family, during development. We performed a comprehensive analysis of this gene family in cancer settings. METHODS: Gene correlation analysis was performed using breast cancer data available in The Cancer Genome Atlas (TCGA) and data from the patients admitted to our hospital. We also analyzed the data of normal breast tissue (GSE20437). We next collected gene expression and prognosis data of breast cancer patients (GSE11121, GSE7390, GSE3494, and GSE2990) and performed unsupervised hierarchal clustering by the HOX gene expression pattern and compared prognosis. We additionally performed this analysis to leukemia (available in TCGA) and sarcoma (GSE20196) data. RESULTS: Gene correlation analysis showed that the proximal HOX genes exhibit strong interactions and are expressed together in breast cancer, similar to the expression observed during development. However, in normal breast tissue, less interactions were observed. Breast cancer microarray meta-data classified by the HOX gene expression pattern predicted the prognosis of luminal B breast cancer patients (p = 0.016). Leukemia (p = 0.00016) and sarcoma (p = 0.018) presented similar results. The Wnt signaling pathway, one of the major upstream signals of HOX genes in development, was activated in the poor prognostic group. Interestingly, poor prognostic cancer presented stronger correlation in the gene family compared to favorable prognostic cancer. CONCLUSION: Comprehensive analysis of the HOX family demonstrated their similar roles in cancer and development, and indicated that the strong interaction of HOX genes might be specific to malignancies, especially in the case of poor prognostic cancer.
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Neoplasias da Mama , Leucemia , Neoplasias da Mama/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Homeobox/genética , HumanosRESUMO
Invasive lobular carcinoma (ILC) has a different treatment response from invasive ductal carcinoma (IDC). We assessed whether perioperative chemotherapy was associated with improved prognosis in patients with ILC. Retrospective data of women who underwent surgery for ILC were extracted from the SEER database. Subjects were divided into non-chemotherapy and chemotherapy groups. Overall, 10 537 patients were included, and 2107 patients were stratified into each group after propensity score matching. Perioperative chemotherapy significantly improved 10-year survival rates for ILC, particularly in patients with large tumor size and lymph node metastases. Perioperative chemotherapy is effective for ILC patients with proper selection.
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Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Terapia Neoadjuvante , Pontuação de Propensão , Estudos RetrospectivosRESUMO
PURPOSE: In adjuvant settings of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, anthracycline-based chemotherapy followed by taxane and trastuzumab is a standard regimen. Recent studies have reported the use of anthracycline-free adjuvant chemotherapy in selected HER2-positive breast cancer patients. We conducted a single-center retrospective study to identify the characteristics of HER2-positive breast cancer patients for whom anthracyclines can be safely omitted. METHODS: A total of 238 women were diagnosed with HER2-positive breast cancer and treated with neoadjuvant and/or adjuvant chemotherapy between January 1, 2008 and December 31, 2015 at Keio University Hospital. They were divided in two cohorts: an "anthracycline" cohort of 112 anthracycline-treated women and a "no anthracycline" cohort of 126 anthracycline-untreated women. Survival outcomes were estimated by Kaplan-Meier method. RESULTS: The 3-year disease-free survival rates in the no-anthracycline and anthracycline cohorts were 91.3% and 93.1%, respectively (P = 0.692). After using a statistical method with inverse probability of treatment weighting to minimize the selection bias, no significant differences were observed between the two cohorts (adjusted hazard ratio for disease-free survival: 1.042; P = 0.909). Stratified by tumor size, no significant differences were observed between the two cohorts in the cT1N0 and cT2N0 subsets (P = 0.516 and P = 0.579, respectively). The recurrence rate was low among patients who achieved pathological complete response after receiving neoadjuvant chemotherapy with or without anthracyclines. CONCLUSION: Our study suggests that anthracyclines can be safely omitted in selected patients with HER2-positive breast cancer, who have cT1N0 or cT2N0 and achieved pathological complete response after receiving neoadjuvant chemotherapy.
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Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxoides/administração & dosagem , Trastuzumab/administração & dosagemRESUMO
AIMS: To investigate the effect of the phosphodiesterase 5 (PDE5) inhibitor Tadalafil on bladder blood flow and bladder function in a rat model of partial bladder outlet obstruction (BOO). METHODS: Female 14-15-week-old Sprague-Dawley rats were divided into three groups. BOO was surgically induced in rats by placing a rubber ring around the urethra. BOO rats were administered daily oral Tadalafil (BOO-Tadalafil) or vehicle (BOO-Vehicle), while sham-operated animals were treated with vehicle (Sham). On the 14th day after surgery, micturition behavior was recorded for 24 hr by using a metabolic cage. On the 15th day after surgery, bladder blood flow and bladder weight were measured. The expression of PDE5 mRNA in the vesical and iliac arteries of intact rats was measured by reverse transcriptase-polymerase chain reaction. RESULTS: BOO led to a significant decrease in bladder blood flow and a significant increase in bladder weight. These changes were partially suppressed by Tadalafil treatment. The number of micturitions in the BOO group was significantly increased and the average micturition volume was significantly decreased, without affecting the total micturition volume. Repeated Tadalafil treatment markedly inhibited the increase in micturition frequency and the decrease in average micturition volume. PDE5 mRNA was expressed in the vesical and iliac arteries. CONCLUSION: Tadalafil suppressed the reduction in bladder blood flow caused by BOO in rats and improved urinary function. This action of Tadalafil may contribute to its amelioration of bladder function. Neurourol. Urodynam. 35:444-449, 2016. © 2015 Wiley Periodicals, Inc.
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Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Feminino , Contração Muscular/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tadalafila/uso terapêutico , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacosRESUMO
Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. SIGNIFICANCE: PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.
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Fosfoglicerato Desidrogenase , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Resistencia a Medicamentos Antineoplásicos , Serina/metabolismo , Palmitatos , Ácidos Graxos , Linhagem Celular Tumoral , Proteína-Arginina N-Metiltransferases/genética , Proteínas RepressorasRESUMO
Whole-genome sequencing of non-H(2)S-producing Salmonella enterica serovar Typhimurium and S. enterica serovar Infantis isolates from poultry meat revealed a nonsense mutation in the phsA thiosulfate reductase gene and carriage of a CMY-2 ß-lactamase. The lack of production of H(2)S might lead to the incorrect identification of S. enterica isolates carrying antimicrobial resistance genes.
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Doenças das Aves Domésticas/microbiologia , Salmonelose Animal/microbiologia , Salmonella enterica/genética , Animais , Genoma Bacteriano , Sulfeto de Hidrogênio/metabolismo , Japão , Salmonella enterica/enzimologia , Salmonella enterica/isolamento & purificação , Salmonella enterica/metabolismo , Análise de Sequência de DNA , Sulfurtransferases/genética , beta-Lactamases/genéticaRESUMO
Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis, and thereby contributes to the control of whole-body energy expenditure (EE) and body fat content. BAT activity can be assessed by fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in human subjects. Grains of paradise (GP, Aframomum melegueta), a species of the ginger family, contain pungent, aromatic ketones such as 6-paradol, 6-gingerol and 6-shogaol. An alcohol extract of GP seeds and 6-paradol are known to activate BAT thermogenesis in small rodents. The present study aimed to examine the effects of the GP extract on whole-body EE and to analyse its relation to BAT activity in men. A total of nineteen healthy male volunteers aged 20-32 years underwent FDG-PET after 2 h of exposure to cold at 19°C with light clothing. A total of twelve subjects showed marked FDG uptake into the adipose tissue of the supraclavicular and paraspinal regions (BAT positive). The remaining seven showed no detectable uptake (BAT negative). Within 4 weeks after the FDG-PET examination, whole-body EE was measured at 27°C before and after oral ingestion of GP extract (40 mg) in a single-blind, randomised, placebo-controlled, crossover design. The resting EE of the BAT-positive group did not differ from that of the BAT-negative group. After GP extract ingestion, the EE of the BAT-positive group increased within 2 h to a significantly greater (P<0·01) level than that of the BAT-negative group. Placebo ingestion produced no significant change in EE. These results suggest that oral ingestion of GP extract increases whole-body EE through the activation of BAT in human subjects.
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Tecido Adiposo Marrom/metabolismo , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Extratos Vegetais/farmacologia , Zingiberaceae/química , Tecido Adiposo , Tecido Adiposo Marrom/efeitos dos fármacos , Adulto , Antropometria , Calorimetria Indireta , Estudos Cross-Over , Dieta , Fluordesoxiglucose F18 , Guaiacol/análogos & derivados , Guaiacol/metabolismo , Humanos , Cetonas/química , Cetonas/metabolismo , Masculino , Tomografia por Emissão de Pósitrons , Sementes/metabolismo , Método Simples-Cego , Temperatura , Fatores de Tempo , Adulto JovemRESUMO
AIMS: (±)-Tramadol hydrochloride (tramadol) is a widely used analgesic that stimulates the µ-opioid receptor and inhibits the reuptake of serotonin and noradrenalin. Although tramadol is also known to inhibit the micturition reflex in rats, its effects on urethral continence function have not been reported. We therefore examined whether intravenous tramadol (1, 3, and 10 mg/kg) affects intraurethral pressure, bladder leak point pressure, and leak volume in urethane-anesthetized female rats. METHODS: (1) The intraurethral pressure was recorded with a microtip pressure transducer placed at the maximum pressure zone of the intrinsic urethral sphincter. (2) Gentle pressure was directly applied to the saline-filled bladder with a cotton bud until leakage occurred, and the bladder pressure at the moment of leakage was taken as the bladder leak point pressure. (3) The leak volume was measured as the amount of fluid leakage from the urethral orifice after electrical stimulation of abdominal muscles. RESULTS: Tramadol significantly increased the intraurethral pressure. Both tramadol and morphine increased the bladder leak point pressure and decreased the leak volume. These changes were reversed by subcutaneous pretreatment with naloxone. CONCLUSIONS: Tramadol improved urethral function and inhibited urinary incontinence through µ-opioid receptors.
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Analgésicos Opioides/uso terapêutico , Receptores Opioides mu/agonistas , Tramadol/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Incontinência Urinária por Estresse/tratamento farmacológico , Analgésicos Opioides/farmacologia , Animais , Feminino , Morfina/farmacologia , Morfina/uso terapêutico , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Tramadol/farmacologia , Urodinâmica/efeitos dos fármacosRESUMO
AIMS: Ischemia-reperfusion injury is an important factor in the development of lower urinary tract symptoms (LUTS) that is partly mediated by the generation of free radicals. We investigate the effect of the phytotherapeutic agent Eviprostat, a treatment for benign prostatic hyperplasia (BPH) that has antioxidant and anti-inflammatory activity, on urinary bladder blood flow (BBF), and function in a rat model of bladder overdistension and emptying (OE). METHODS: For 8 days before surgery, OE rats received daily oral Eviprostat (36 mg/kg/day) or vehicle, while sham-operated animals received vehicle. The bladder was distended by infusion of saline over a period of 2 hr (overdistension) and then emptied. After 24 hr, BBF was measured with a laser speckle blood flow imager. The oxidative-stress marker malondialdehyde (MDA), proinflammatory cytokines, and myeloperoxidase were determined in the isolated bladder, and histological analysis was performed. Functional contractile responses of bladder strips to electrical field stimulation, carbachol, and KCl were measured. RESULTS: Twenty-four hours after bladder OE, a significant decrease in BBF and significant increases in bladder weight, malondialdehyde, proinflammatory cytokines, and myeloperoxidase were observed. Eviprostat almost completely prevented these changes. Histological analysis of the bladder of OE rats showed hemorrhage, accumulation of leukocytes, desquamation of epithelium, and edema, and Eviprostat suppressed these changes. The reduction in functional contractile forces in the bladder of OE rats was also prevented by Eviprostat. CONCLUSION: Eviprostat-mediated suppression of increased bladder oxidative stress and inflammation caused by bladder OE may contribute to the improvement of BBF and bladder function by Eviprostat.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Etamsilato/farmacologia , Extratos Vegetais/farmacologia , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Velocidade do Fluxo Sanguíneo , Citocinas/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Mediadores da Inflamação/metabolismo , Fluxometria por Laser-Doppler , Malondialdeído/metabolismo , Contração Muscular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Fitoterapia , Plantas Medicinais , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Fatores de Tempo , Bexiga Urinária/irrigação sanguínea , Bexiga Urinária/inervação , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/patologia , Obstrução do Colo da Bexiga Urinária/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: We evaluated an alternative procedure for sentinel lymph node biopsy (SLNB) for breast cancer after approval of the study by the Ethics Committee of Tokyo Medical University Hospital in 2004. We examined the efficacy and safety of SLNB using the photosensitizer talaporfin sodium (Laserphyrin®, Meiji Seika Pharma, Tokoyo, Japan), compared with current methods. STUDY DESIGN/PATIENTS AND METHODS: The study included 21 breast cancer patients (Japanese women; median age, 54 years; range, 35-75). All patients received a breast cancer operation combined with SLNB between June 2004 and May 2005. Three milliliters of talaporfin solution was locally injected into the subareolar region just before the operation. We attempted to identify a sentinel lymph node (SLN) that exhibited fluorescence and was consistent with a radioisotope (RI) localization technique. Our purpose was to verify the accuracy and validity of the talaporfin fluorescence imaging method after 8 years of application. RESULTS: There was no consistent correlation between fluorescence and pathological SLN metastasis, although all four cases of pathological SLN metastasis revealed positive fluorescence. In some cases in which we could not identify SLNs by the RI technique, we could identify SLNs using talaporfin. The method using talaporfin did not adversely affect the patients after the operation, even the chronic renal failure patient. After 8 years, all patients are alive, and none had lymph node recurrence. Side effects were not observed. CONCLUSION: SLNB using the photosensitizer talaporfin sodium in breast cancer patients is considered to be useful as complementary to other current methods. We could evaluate the accuracy and validity of this method 8 years after all of the procedures were performed. In the future, a large-scale clinical study with statistical analyses should be conducted.
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Neoplasias da Mama/patologia , Carcinoma/patologia , Imagem Óptica/métodos , Fármacos Fotossensibilizantes , Porfirinas , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Imagem Óptica/instrumentação , Biópsia de Linfonodo Sentinela/instrumentaçãoRESUMO
Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.
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PURPOSE: To evaluate the sensitivity of diffusion tensor imaging (DTI) in assessing peripheral nerve regeneration in vivo. We assessed the changes in the DTI parameters and histological analyses after nerve injury to examine degeneration and regeneration in the rat sciatic nerves. MATERIALS AND METHODS: For magnetic resonance imaging (MRI), 16 rats were randomly divided into two groups: group P (permanently crushed; n = 7) and group T (temporally crushed; n = 9). Serial MRI of the right leg was performed before the operation, and then performed at the timepoints of 1, 2, 3, and 4 weeks after the crush injury. The changes in fractional anisotropy (FA), axial diffusivity (λ(â¥)), and radial diffusivity (λ(⟂)) were quantified. For histological analyses, the number of axons and the myelinated axon areas were quantified. RESULTS: Decreased FA and increased λ(⟂) were observed in the degenerative phase, and increased FA and decreased λ(⟂) were observed in the regenerative phase. The changes in FA and λ(⟂) were strongly correlated with histological changes, including axonal and myelin regeneration. CONCLUSION: DTI parameters, especially λ(⟂) , can be good indicators for peripheral nerve regeneration and can be applied as noninvasive diagnostic tools for a variety of neurological diseases.
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Imagem de Tensor de Difusão/métodos , Regeneração Nervosa , Sistema Nervoso Periférico/patologia , Nervo Isquiático/patologia , Animais , Anisotropia , Axônios/patologia , Difusão , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Modelos Estatísticos , Bainha de Mielina/química , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
In this paper, we report a single-step trypsin inhibitor assay on a microchannel array device immobilizing enzymes and substrates by inkjet printing. The microdevice is composed of a poly(dimethylsiloxane) (PDMS) microchannel array that immobilizes trypsin and fluorescent substrates as reactive reagents at the two bottom corners of a microchannel. Inkjet printers allow simple, accurate, and position-selective immobilization of reagents as nanoliter spots. Therefore, plural reactive reagents, such as enzymes and substrates, can be separately immobilized at different positions in the same microchannel without mixing, and thus allowing for single-step operation by simply introducing a sample solution through capillary action. Furthermore, reproducible fabrication and mass production of the device could be expected. In this study, the efficiency of an acidic solution as a spotting agent for protease immobilization to prevent decrease in the fluorescence intensity was confirmed. Additionally, single-step trypsin inhibitor screening was performed using three inhibitors. Finally, we investigated the storage stability of the device and confirmed that it remained stable for at least 10 days.
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Bioensaio , Inibidores da Tripsina , TripsinaRESUMO
Reactive astrogliosis occurs after diverse central nervous system (CNS) insults. While astrogliosis provides protection against inflammation, it is also obstructive in the progress of neuranagenesis after CNS insults. Thus, a method that enables in vivo visualization and tissue characterization for gliosis would be invaluable for studies of CNS insults and corresponding treatments. Manganese has proven to be a useful MRI contrast agent that enters cells via Ca(2+) channels and has been applied to manganese-enhanced MRI (MEMRI) for neuronal functional mapping. This study investigated whether MEMRI can detect astrogliosis after focal ischemia in vivo. Rats were divided into groups according to the number of days after either transient middle cerebral artery occlusion or a sham. Ring- or crescent-shaped enhancement of MEMRI corresponded to the GFAP-positive astroglia observed in the peripheral region of the ischemic core 11 days after middle cerebral artery occlusion. This indicates that MEMRI enhancement predominantly reflects reactive astrogliosis after stroke.
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Encefalopatias/patologia , Encéfalo/patologia , Cloretos , Gliose/patologia , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês , Animais , Meios de Contraste , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Immediate and certain determination of the treatable area is important for choosing risky treatments such as thrombolysis for brain ischemia, especially in the super-acute phase. Although it has been suggested that the mismatch between regions displaying 'large abnormal perfusion' and 'small abnormal diffusion' indicates a treatable area on an MRI, it has also been reported that the mismatch region is an imperfect approximation of the treatable region named the 'penumbra'. Manganese accumulation reflecting calcium influx into cells was reported previously in a middle cerebral artery occlusion (MCAO) model using activity-induced manganese-enhanced (AIM) MRI. However, in the super-acute phase, there have been no reports about mismatches between areas showing changes to the apparent diffusion coefficient (ADC) and regions that are enhanced in AIM MRI. It is expected that the AIM signal can be enhanced immediately after cerebral ischemia in the necrotic core region due to calcium influx. In this study, a remote embolic rat model, created using titanium-oxide macrospheres, was used to observe necrotic neural responses in the super-acute phase after ischemia. In addition, images were evaluated by comparison between ADC, AIM MRI, and histology. The signal enhancement in AIM MRI was detected at 2 min after the cerebral infarction using a remote embolic method. The enhanced area on the AIM MRI was significantly smaller than that on the ADC map. The tissue degeneration highlighted by histological analysis corresponded more closely to the enhanced area on the AIM MRI than that on the ADC map. Thus, the manganese-enhanced region in brain ischemia might indicate 'necrotic' irreversible tissue that underwent calcium influx.
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Isquemia Encefálica/diagnóstico , Isquemia Encefálica/patologia , Mapeamento Encefálico , Imageamento por Ressonância Magnética/métodos , Manganês , Neurônios/patologia , Animais , Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Masculino , Necrose , Ratos , Ratos Wistar , Fatores de TempoRESUMO
In this study, we report an inkjet printing-based method for the immobilization of different reactive analytical reagents on a single microchannel for a single-step and homogeneous solution-based competitive immunoassay. The immunoassay microdevice is composed of a poly(dimethylsiloxane) microchannel that is patterned using inkjet printing by two types of reactive reagents as dissolvable spots, namely, antibody-immobilized graphene oxide and a fluorescently labeled antigen. Since nanoliter-sized droplets of the reagents could be accurately and position-selectively spotted on the microchannel, different reactive reagents were simultaneously immobilized onto the same microchannel, which was difficult to achieve in previously reported capillary-based single-step bioassay devices. In the present study, the positions of the reagent spots and amount of reagent matrix were investigated to demonstrate the stable and reproducible immobilization and a uniform dissolution. Finally, a preliminary application to a single-step immunoassay of C-reactive protein was demonstrated as a proof of concept.
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First identified as a developmental gene, HOXB9 is also known to be involved in tumor biological processes, and its aberrant expression correlates with poor prognosis of various cancers. In this study, we isolated a homeodomain-less, novel HOXB9 variant (HOXB9v) from human breast cancer cell line-derived mRNA. We confirmed that the novel variant was produced from variationless HOXB9 genomic DNA. RT-PCR of mRNA isolated from clinical samples and reanalysis of publicly available RNA-seq data proved that the new transcript is frequently expressed in human breast cancer. Exogenous HOXB9v expression significantly enhanced the proliferation of breast cancer cells, and gene ontology analysis indicated that apoptotic signaling was suppressed in these cells. Considering that HOXB9v lacks key domains of homeobox proteins, its behavior could be completely different from that of the previously described variationless HOXB9. Because none of the previous studies on HOXB9 have considered the presence of HOXB9v, further research analyzing the two transcripts individually is warranted to re-evaluate the true role of HOXB9 in cancer.
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BACKGROUND: Low-dose aspirin is used for secondary prevention of ischemic heart disease and ischemic cerebrovascular disease. Currently, the frequency of gastrointestinal disorder among users of low-dose aspirin is unknown. AIMS: To investigate through endoscopic examination the frequency of gastroduodenal disorder associated with buffered and enteric-coated aspirin (ECA). METHODS: Screening upper endoscopic examinations were prospectively performed on 236 patients with ischemic heart disease. Endoscopic findings including ulcers and flat erosions were assessed as mucosal defects. RESULTS: Mucosal defects were found in 92 of 190 (48.4%) users of low-dose aspirin and 6 of 46 (13.0%) nonusers. There were significantly more mucosal defects among users of low-dose aspirin than among those using no aspirin (P<0.0001). Mucosal defects were found in 54 of 98 (60.7%) users of buffered aspirin (BA), whereas 38 of 101 (37.6%) users of ECA had mucosal defects. Users of ECA had significantly fewer erosions than did those of BA (P=0.0015). The frequency of ulcer is similar between BA users and ECA users. CONCLUSIONS: As endoscopy frequently reveals gastroduodenal disorder among low-dose aspirin users, both administration of BA and of enteric-coated aspirin warrant concern for gastroduodenal ulcer.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Duodeno , Mucosa Gástrica , Mucosa Intestinal , Isquemia Miocárdica/tratamento farmacológico , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Soluções Tampão , Esquema de Medicação , Duodeno/efeitos dos fármacos , Duodeno/patologia , Endoscopia Gastrointestinal , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/patologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Comprimidos com Revestimento EntéricoRESUMO
P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Apoptose , Colesterol/metabolismo , Citocinas/metabolismo , Humanos , Fosfolipídeos/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Polimorfismo Genético , Esfingomielinas/metabolismoRESUMO
BACKGROUND AND AIM: Low-dose aspirin is effective for the prevention of cardiovascular and cerebrovascular events, but the frequency of gastrointestinal injuries among users of low-dose aspirin in Japan is currently unknown. In the present study endoscopic examination was performed to investigate the frequency of gastroduodenal injuries associated with low-dose aspirin in patients with ischemic heart disease (IHD). METHODS: Screening upper endoscopic examinations were prospectively performed on 131 patients with IHD who were not receiving antiulcer treatment. Endoscopic findings such as ulcers and flat erosions were assessed as mucosal injuries. RESULTS: Mucosal injuries were found in 62 of 101 (61.4%) low-dose aspirin users and three of 30 (10%) nonaspirin users. There were significantly more mucosal injuries among low-dose aspirin users than among the non-users (P<0.0001). Gastroduodenal ulcers were found in 19 of 101 (18.8%) low-dose aspirin users compared with one of 30 (3.3%) nonaspirin users. The frequency of mucosal injuries was not associated with the duration of aspirin treatment. CONCLUSION: Endoscopy frequently reveals low-dose aspirin-induced gastroduodenal injuries in patients with IHD.