RESUMEN
BACKGROUND & AIMS: Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS: We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS: We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS: Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.
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Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Inflamación/complicaciones , Metaplasia/etiología , Metaplasia/patología , Metaplasia/prevención & control , Tristetraprolina/genética , Animales , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Inmunohistoquímica , Inflamación/etiología , Inflamación/metabolismo , Metaplasia/metabolismo , Ratones , Ratones Noqueados , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
OBJECTIVE: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC). METHODS: 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. RESULTS: Consensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori. CONCLUSION: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori. Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.
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Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/prevención & control , Antibacterianos/administración & dosificación , Programas de Optimización del Uso de los Antimicrobianos , Toma de Decisiones Clínicas , Análisis Costo-Beneficio , Técnica Delphi , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Farmacorresistencia Bacteriana , Detección Precoz del Cáncer , Endoscopía Gastrointestinal , Gastritis Atrófica/microbiología , Gastritis Atrófica/prevención & control , Reflujo Gastroesofágico , Microbioma Gastrointestinal , Marcadores Genéticos , Salud Global , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Humanos , Síndrome Metabólico , Metaplasia/microbiología , Metaplasia/prevención & control , Inhibidores de la Bomba de Protones/administración & dosificación , Reinfección , Neoplasias Gástricas/epidemiologíaRESUMEN
As a chronic airway disease, asthma has two characteristics, tissue remodeling and airway inflammation. This research focused on miR-92a to explore how it works in asthma. We revealed that the expressions of miR-92a were decreased in both serum and lung tissues from ovalbumin-induced asthma mouse. Bioinformatics analysis, quantitative polymerase chain reaction (qPCR) and dual luciferase assay revealed that miR-92a targets MUC5AC, which was linked to mucus hypersecretion in the pulmonary tracts. By injecting miR-92a-mimics into the trachea, both the airway hyper-reactivity and airway inflammation can be alleviated in an asthma mouse model which is induced by ovalbumin. Moreover, the goblet cell phenotype of asthmatic mice is significantly reduced by the action of miR-92a. Furthermore, miR-92a blocked interleukin (IL)-13-induced MUC5AC luciferase activity in 16HBE. Together, upregulation of miR-92a expression in asthmatic mice plays a role in blocking goblet cell metaplasia by targeting MUC5AC, and thus in the treatment of chronic airway diseases, miR-92a can prevent epithelial remodeling, which is a reasonable method.
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Asma/complicaciones , Regulación de la Expresión Génica , Células Caliciformes/patología , Metaplasia/prevención & control , MicroARNs/genética , Mucina 5AC/metabolismo , Animales , Asma/inducido químicamente , Asma/patología , Femenino , Células Caliciformes/metabolismo , Metaplasia/etiología , Metaplasia/metabolismo , Metaplasia/patología , Ratones , Ratones Endogámicos C57BL , Mucina 5AC/genética , Ovalbúmina/toxicidadRESUMEN
BACKGROUND & AIMS: The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. METHODS: We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. RESULTS: We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. CONCLUSIONS: In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa.
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Enfermedades Autoinmunes/tratamiento farmacológico , Mucosa Gástrica/patología , Gastritis/tratamiento farmacológico , Interleucinas/administración & dosificación , Lesiones Precancerosas/prevención & control , Animales , Atrofia/inmunología , Atrofia/patología , Atrofia/prevención & control , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Enfermedad Crónica/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Gastritis/diagnóstico , Gastritis/inmunología , Gastritis/patología , Humanos , Masculino , Metaplasia/inmunología , Metaplasia/patología , Metaplasia/prevención & control , Ratones , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Receptores de Citocinas/genética , Proteínas Recombinantes/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumour with an extremely poor prognosis due to its insidious initiation and a lack of therapeutic strategies. Resveratrol suppresses pancreatic cancer progression and attenuates pancreatitis by modulating multiple targets, including nuclear factor kappa B (NFκB) signalling pathways. However, the effect of resveratrol on pancreatic cancer initiation and its mechanisms remain unclear. In this study, we utilised the LSL-KrasG12D/+; Pdx1-Cre (KC) spontaneous pancreatic precancerous lesion mouse model to explore the anti-tumourigenesis mechanisms of resveratrol in vivo. In vitro acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasias (PanINs) formation assays were performed by pancreatic acinar cell 3-dimensional (3D) culture. Histopathological analysis was used to examine the pathological morphology of pancreatic tissues. Resveratrol prevented the progression of pancreatic precancerous lesions and inhibited the activation of NFκB signalling pathway-related molecules in KC mouse pancreatic tissues. In addition, resveratrol reduced the severity of cerulein-induced pancreatitis and the formation of ADM/PanINs in vivo and in vitro, which may be related to its effect on NFκB inactivation. Furthermore, pancreatic acinar 3D culture demonstrated that activation of the NFκB signalling pathway promoted the formation of ADM/PanINs in vitro, and this initiating effect of NFκB was blocked by resveratrol. Resveratrol slowed the tumourigenesis of pancreatic cancer by inhibiting NFκB activation.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Carcinoma Ductal Pancreático/prevención & control , FN-kappa B/metabolismo , Resveratrol/farmacología , Animales , Carcinoma Ductal Pancreático/metabolismo , Células Cultivadas , Ceruletida/farmacología , Proteínas de Homeodominio/genética , Metaplasia/prevención & control , Ratones , Ratones Transgénicos , Pancreatitis/patología , Pancreatitis/prevención & control , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/efectos de los fármacos , Transactivadores/genéticaRESUMEN
BACKGROUND AND AIM: Few studies have evaluated the change in serum pepsinogen (sPG) levels after the eradication of Helicobacter pylori. The aim of this study was to evaluate the effect of H. pylori eradication on sPG levels in patients with gastric cancer/dysplasia in comparison to a control group. METHODS: We prospectively enrolled 368 patients with gastric cancer/dysplasia and 610 control subjects. H. pylori status and sPG levels were measured before and after eradication. The follow-up time points were classified as < 12, 12-23, 24-35, and ≥ 36 months. RESULTS: In 179 H. pylori-eradicated patients with gastric cancer/dysplasia and 168 control group subjects, sPG I significantly decreased, and the sPG I/II ratio significantly increased after eradication compared to baseline, and this improvement in sPG values was maintained during all follow-up time points. Significant differences in sPG I and the sPG I/II ratio were observed between the gastric cancer/dysplasia group and the control group < 24 months after eradication. However, these differences in sPG values disappeared after ≥ 24 months of follow up. Moreover, significant differences in the intestinal metaplasia grade were observed between these two groups before eradication until < 24 months after eradication. However, these differences in the intestinal metaplasia grade disappeared after ≥ 24 months of follow up in the corpus. CONCLUSION: The sPG values and intestinal metaplasia grade (corpus) in the gastric cancer/dysplasia group became similar to those in the control group at long-term follow up after H. pylori eradication. It might be related with the reduction of metachronous gastric neoplasm.
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Gastritis/tratamiento farmacológico , Gastritis/microbiología , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/prevención & control , Pepsinógenos/sangre , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/prevención & control , Estómago/patología , Biomarcadores/sangre , Estudios de Seguimiento , Gastritis/complicaciones , Humanos , Metaplasia/diagnóstico , Metaplasia/etiología , Metaplasia/prevención & control , Neoplasias Primarias Secundarias/etiología , Neoplasias Gástricas/etiología , Factores de TiempoRESUMEN
Gastric cancer is one of the most common causes of cancer-related mortality worldwide. The objective of this article is to review the epidemiology and biology of gastric cancer risk. This literature review explores the biological, clinical, and environmental factors that influence the rates of this disease and discuss the different intervention methods that may not only increase the awareness of gastric cancer but also increase screening in efforts to reduce the risk of gastric cancer. Helicobacter pylori infection is the primary risk factor for gastric cancer. Additional risk factors include geographical location, age, sex, smoking, socioeconomic status, dietary intake, and genetics. Primary and secondary prevention strategies such as dietary modifications and screenings are important measures for reducing the risk of gastric cancer. Interventions, such as H. pylori eradication through chemoprevention trials, have shown some potential as a preventative strategy. Although knowledge about gastric cancer risk has greatly increased, future research is warranted on the differentiation of gastric cancer epidemiology by subsite and exploring the interactions between H. pylori infection, genetics, and environmental factors. Better understanding of these relationships can help researchers determine the most effective intervention strategies for reducing the risk of this disease.
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Mucosa Gástrica/patología , Infecciones por Helicobacter/epidemiología , Helicobacter pylori/patogenicidad , Fumar/epidemiología , Neoplasias Gástricas/epidemiología , Factores de Edad , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Antibacterianos/uso terapéutico , Quimioprevención/métodos , Conducta Alimentaria/fisiología , Mucosa Gástrica/microbiología , Predisposición Genética a la Enfermedad , Geografía , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Humanos , Metaplasia/epidemiología , Metaplasia/microbiología , Metaplasia/patología , Metaplasia/prevención & control , Inhibidores de la Bomba de Protones/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversos , Clase Social , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & control , Resultado del TratamientoAsunto(s)
Acrilonitrilo/análogos & derivados , Compuestos de Anilina/administración & dosificación , Bencimidazoles/administración & dosificación , Mucosa Gástrica/patología , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/patología , Acrilonitrilo/administración & dosificación , Animales , Biopsia con Aguja , Modelos Animales de Enfermedad , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Gerbillinae , Helicobacter pylori/efectos de los fármacos , Inmunohistoquímica , Masculino , Metaplasia/tratamiento farmacológico , Metaplasia/prevención & control , Distribución Aleatoria , Valores de Referencia , Resultado del TratamientoRESUMEN
The development of intestinal-type gastric cancer is preceded by the emergence of metaplastic cell lineages in the gastric mucosa. In particular, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) have been associated with the pathological progression to intestinal-type gastric cancer. The development of SPEM represents a physiological response to damage that recruits reparative cells to sites of mucosal injury. Metaplastic cell lineages are characterized by mucus secretion, adding a protective barrier to the epithelium. Increasing evidence indicates that the influence of alarmins and cytokines is required to initiate the process of metaplasia development. In particular, IL-33 derived from epithelial cells stimulates IL-13 production by specialized innate immune cells to induce chief cell transdifferentiation into SPEM following the loss of parietal cells from the corpus of the stomach. While SPEM represents a physiological healing response to acute injury, persistent injury and chronic inflammation can perpetuate a recurring pattern of reprogramming and metaplasia that is a risk factor for gastric cancer development. The transdifferentiation of zymogen secreting cells into mucous cell metaplasia may represent both a general repair mechanism in response to mucosal injury in many epithelia as well as a common pre-neoplastic pathway associated with chronic injury and inflammation.
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Inflamación/complicaciones , Péptidos y Proteínas de Señalización Intercelular/efectos adversos , Interleucina-13/metabolismo , Intestinos/inmunología , Metaplasia/patología , Células Parietales Gástricas/inmunología , Estómago/inmunología , Animales , Humanos , Inflamación/metabolismo , Intestinos/patología , Metaplasia/etiología , Metaplasia/metabolismo , Metaplasia/prevención & control , Células Parietales Gástricas/metabolismo , Células Parietales Gástricas/patología , Estómago/patologíaRESUMEN
Luteolin, a flavone, has been demonstrated to have anticancer properties. In the current study, the effects of luteolin on certain carcinogenesisassociated changes induced by pancreatitis, which are significant risk factors for pancreatic cancer, were investigated. Male sixweekold C57BL6 mice used in the current study were divided into three groups; the control group, acute pancreatitis group and luteolin group. Intraperitoneal injection of cearulein was performed in the acute pancreatitis group and luteolin group to induce acute pancreatitis whereas the luteolin group received intraperitoneal injection of luteolin. The control group received intraperitoneal injection of normal saline. Then, the expression of SOX9, phosphorylated (p) STAT3, pEGFR, cytokeratin19, Ki67 and Ncadherin were determined by immunohistochemistry. Morphological changes of acinar cells were determined by hematoxylin and eosin staining. The mRNA expression of the epithelialmesenchymal transition markers CDH1, CDH2, Slug, Zeb1, EpCAM, ZO1, Vimentin, Snail and Twist was determined by reverse transcriptionquantitative polymerase chain reaction. It was identified that luteolin inhibits the formation of tubular complexes and ectopic expression of cytokeratin19 and luteolin also decreased proteins of SOX9, pSTAT3 and pEGFR. In addition, luteolin inhibits proliferation and epithelialmesenchymal transition of acinar cells induced by acute pancreatitis. As tubular complex formation and ectopic expression of cytokeratin19 were two prominent characters of acinarductal metaplasia, it was concluded that luteolin inhibits acinarductal metaplasia induced by pancreatitis and also inhibits pancreatitisinduced proliferation and epithelialmesenchymal transition of acinar cells. Acinarductal metaplasia and proliferation have close associations with pancreatic carcinogenesis. It is suggested that luteolin has potential antipancreatic carcinogenesis effects and merits further investigation.
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Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Luteolina/farmacología , Células Acinares/citología , Células Acinares/metabolismo , Enfermedad Aguda , Animales , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inmunohistoquímica , Queratina-19/genética , Queratina-19/metabolismo , Luteolina/uso terapéutico , Masculino , Metaplasia/prevención & control , Ratones , Ratones Endogámicos C57BL , Páncreas/patología , Pancreatitis/patología , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Helicobacter pylori (H. pylori) is a Gram negative spiraliform bacterium that is commonly found in the stomach. H. pylori infection is still one of the world's most frequent infections, present in the stomachs of approximately one-half of the world's people. H. pylori infection is etiologically linked to histologic chronic active gastritis, peptic ulcer disease, and primary B-cell gastric lymphoma (gastric MALT lymphoma) and represents the major risk factor for the development of sporadic non-cardia gastric cancer (GC) of both intestinal and diffuse type. Studies that have examined the impact of GC prevention through H. pylori eradication have shown mixed results, but recent data suggest that prevention is only efficacious in patients without intestinal metaplasia or dysplasia. This indicates that, like in Barrett's esophagus, we need better clinical risk markers to indicate which patients are at greatest risk of developing cancer to guide clinical strategies. Furthermore, recent epidemiological data have suggested a possible contribution of H. pylori in modifying the risk of developing other gastrointestinal malignancies (including esophageal, pancreatic, hepatocellular, and colorectal cancer), although mechanistically these associations remain unexplained. We review clinically relevant aspects of H. pylori infection in the context of GC development as well as studies that have examined the impact of eradication on GC development and, lastly, discuss these recent epidemiological studies connecting H. pylori infection to extragastric gastrointestinal malignancies.
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Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Intestinos/microbiología , Neoplasias Gástricas/microbiología , Antibacterianos/uso terapéutico , Gastritis/microbiología , Gastritis/patología , Gastritis/prevención & control , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/prevención & control , Helicobacter pylori/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Intestinos/patología , Linfoma no Hodgkin/microbiología , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/prevención & control , Metaplasia/prevención & control , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & controlRESUMEN
BACKGROUND: Changes in CDX1/CDX2 in gastric mucosae following Helicobacter pylori eradication have not been clarified yet. AIMS: To evaluate the changes in CDX1/CDX2 expression after H. pylori eradication, in relation to the reversibility of intestinal metaplasia (IM). METHODS: Time course of CDX1/CDX2 expressions was investigated in 176 subjects with various gastroduodenal disorders. Among them, 132 patients were H. pylori positives; H. pylori were eradicated in 107 of them; 13 failed to eradicate; and 12 did not receive H. pylori eradication therapy. Forty-four subjects were H. pylori negatives. Expression levels in CDX1 and CDX2 from noncancerous gastric mucosae of the corpus, as well as the histologic findings of gastric mucosae, were evaluated during the follow-up. RESULTS: Average follow-up duration was 33.7 months (range 2-97 months). Expression levels in both CDX1 and CDX2 mRNAs were correlated with IM grade in the corpus (ρ = 0.633 and 0.554, respectively, all P < 0.001). Changes in CDX1/CDX2 mRNA expressions following H. pylori eradication showed only insignificant results; IM grade at the antrum and corpus showed a tendency to decrease after H. pylori eradication without statistical significance (P > 0.05). However, histologic improvement of IM at the corpus was associated with a decrease in CDX2 mRNA expression during the follow-up (linear mixed model, P for slope = 0.015). CONCLUSIONS: In this study, eradication of H. pylori did not show any beneficial effects on aberrant CDX1/CDX2 expressions or IM. Reversibility of IM may be associated with a decrease in CDX2 mRNA expression.
Asunto(s)
Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/metabolismo , Proteínas de Homeodominio/metabolismo , Anciano , Factor de Transcripción CDX2 , Carcinoma/etiología , Carcinoma/metabolismo , Carcinoma/prevención & control , Femenino , Estudios de Seguimiento , Mucosa Gástrica/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Masculino , Metaplasia/etiología , Metaplasia/metabolismo , Metaplasia/prevención & control , Persona de Mediana Edad , ARN Mensajero/metabolismo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/prevención & controlRESUMEN
PURPOSE: Inflammation and squamous metaplasia is a common pathological process that occurs in many ocular surface diseases such as dry eye, Stevens-Johnson syndrome, mucous membrane pemphigoid, and chemical/thermal burns. At present, there is no ideal medicinal treatment for this abnormality. We report herein on an ex vivo conjunctival inflammation and squamous metaplasia model by culturing human conjunctival tissues at an air-liquid interface for up to 8 days to study the effects of minocycline on inflammation and squamous metaplasia. METHODS: The levels of inflammatory mediators including interleukin-1ß, tumor necrosis factor-α, and metalloproteinase-9 in the cultured human conjunctival tissues were determined by enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction. The total and phosphorylated nuclear factor-κB were detected by western blot. Differentiation markers K10, MUC5AC, and Pax6 and proliferation markers Ki67, p63, and K14 were determined by immunofluorescence or immunohistochemical staining. RESULTS: The results indicated that minocycline inhibited inflammation, decreased the expression of interleukin-1ß, tumor necrosis factor-α, and metalloproteinase -9, and squamous metaplasia features such as hyperproliferation and abnormal epidermal differentiation of conjunctival epithelium. CONCLUSIONS: These findings highlight the possibility that minocycline could be used to treat dry eye and other ocular surface diseases exhibiting epithelial cell inflammation and squamous metaplasia.
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Antibacterianos/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Conjuntiva/patología , Células Epiteliales/patología , Inflamación/prevención & control , Minociclina/farmacología , Biomarcadores/metabolismo , Western Blotting , Técnicas de Cultivo de Célula , Conjuntiva/metabolismo , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Inflamación/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Metaplasia/metabolismo , Metaplasia/prevención & control , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Mucosa Gástrica/patología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Vigilancia de la Población , Lesiones Precancerosas/prevención & control , Neoplasias Gástricas/prevención & control , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Infecciones por Helicobacter/complicaciones , Humanos , Metaplasia/microbiología , Metaplasia/patología , Metaplasia/prevención & control , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Factores de Riesgo , Prevención Secundaria , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND/AIMS: With the enormous increase in the amount of data, the concept of big data has emerged and this allows us to gain new insights and appreciate its value. However, analysis related to gastrointestinal diseases in the viewpoint of the big data has not been performed yet in Korea. This study analyzed the data of the blog's visitors as a set of big data to investigate questions they did not mention in the clinical situation. METHODS: We analyzed the blog of a professor whose subspecialty is gastroenterology at Gangnam Severance Hospital. We assessed the changes in the number of visitors, access path of visitors, and the queries from January 2011 to December 2013. RESULTS: A total of 50,084 visitors gained accessed to the blog. An average of 1,535.3 people visited the blog per month and 49.5 people per day. The number of visitors and the cumulative number of registered posts showed a positive correlation. The most utilized access path of visitors to the website was blog.iseverance.com (42.2%), followed by Google (32.8%) and Daum (6.6%). The most searched term by the visitors in the blog was intestinal metaplasia (16.6%), followed by dizziness (8.3%) and gastric submucosal tumor (7.0%). CONCLUSIONS: Personal blog can function as a communication route for patients with digestive diseases. The most frequently searched word necessitating explanation and education was 'intestinal metaplasia'. Identifying and analyzing even unstructured data as a set of big data is expected to provide meaningful information.
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Blogging/estadística & datos numéricos , Enfermedades Gastrointestinales/prevención & control , Bases de Datos Factuales , Mareo/prevención & control , Humanos , Internet , Metaplasia/prevención & control , Neoplasias Gástricas/prevención & control , Interfaz Usuario-ComputadorRESUMEN
BACKGROUND: Intestinal metaplasia (IM), a premalignant lesion, is associated with an increased risk of gastric cancer. Although estrogen exposure, including tamoxifen, has been studied in correlation with gastric cancer, little has been investigated about its effects on IM. AIMS: Therefore, we investigated whether chronic tamoxifen use was associated with the risk of IM in human stomach. METHODS: We evaluated 512 gastric biopsies from 433 female breast cancer patients that underwent endoscopic gastroduodenoscopy (EGD) ≥6 months after breast surgery. Histopathological findings were scored according to the updated Sydney classification. Demographic and clinical characteristics were also included to identify predictive factors for IM. RESULTS: In a multivariate logistic regression analysis, age at EGD (odds ratio [OR], 1.04; P = 0.002), biopsies from antrum (OR 2.08; P < 0.001), and Helicobacter pylori positivity (OR 1.68; P = 0.016) were significantly associated with an increased risk of IM, whereas chronic tamoxifen use (≥3 months) was associated with a decreased risk of IM (OR 0.59; P = 0.025). After stratifying by biopsy site, association between tamoxifen use and IM persisted for corpus (OR 0.42; P = 0.026) but not for antrum (OR 0.74; P = 0.327). In analysis limited to patients with follow-up EGD, chronic tamoxifen use also correlated with improved IM score compared to no tamoxifen use (improved, 77.8 vs. 22.2%; no change, 65.4 vs. 34.6%; worsened, 30.0 vs. 70.0%; P = 0.019). CONCLUSIONS: This study suggests that chronic tamoxifen use can decrease the risk of IM in human stomach. The effect of tamoxifen is predominantly observed in the corpus.
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Epitelio/efectos de los fármacos , Metaplasia/prevención & control , Estómago/efectos de los fármacos , Tamoxifeno/administración & dosificación , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Esquema de Medicación , Epitelio/patología , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Análisis de Regresión , Factores de Riesgo , Estómago/patología , Adulto JovenRESUMEN
Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its persistent resistance to chemotherapy. The currently limited treatment options for pancreatic cancer underscore the need for more efficient agents. Because activating Kras mutations initiate and maintain pancreatic cancer, inhibition of this pathway should have a major therapeutic impact. We synthesized phospho-farnesylthiosalicylic acid (PFTS; MDC-1016) and evaluated its efficacy, safety, and metabolism in preclinical models of pancreatic cancer. PFTS inhibited the growth of human pancreatic cancer cells in culture in a concentration- and time-dependent manner. In an MIA PaCa-2 xenograft mouse model, PFTS at a dose of 50 and 100 mg/kg significantly reduced tumor growth by 62% and 65% (P < .05 vs vehicle control). Furthermore, PFTS prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. PFTS appeared to be safe, with the animals showing no signs of toxicity during treatment. Following oral administration, PFTS was rapidly absorbed, metabolized to FTS and FTS glucuronide, and distributed through the blood to body organs. Mechanistically, PFTS inhibited Ras-GTP, the active form of Ras, both in vitro and in vivo, leading to the inhibition of downstream effector pathways c-RAF/mitogen-activated protein-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK1/2 kinase and phosphatidylinositol 3-kinase/AKT. In addition, PFTS proved to be a strong combination partner with phospho-valproic acid, a novel signal transducer and activator of transcription 3 (STAT3) inhibitor, displaying synergy in the inhibition of pancreatic cancer growth. In conclusion, PFTS, a direct Ras inhibitor, is an efficacious agent for the treatment of pancreatic cancer in preclinical models, deserving further evaluation.
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Antineoplásicos/uso terapéutico , Benzoatos/uso terapéutico , Organofosfatos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas ras/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Xenoinjertos , Humanos , Metaplasia/etiología , Metaplasia/prevención & control , Ratones Endogámicos BALB C , Ratones Desnudos , Organofosfatos/farmacocinética , Organofosfatos/farmacología , Neoplasias Pancreáticas/patología , Pancreatitis/complicaciones , Pancreatitis/tratamiento farmacológico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal/fisiología , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacología , Proteínas ras/metabolismoRESUMEN
OBJECTIVE: To evaluate the benefit of mass eradication of Helicobacter pylori infection in reducing premalignant gastric lesions. DESIGN: Mass eradication of H pylori infection was started from 2004 for a Taiwanese population with prevalent H pylori infection, who were >30 years of age. Participants positive for the (13)C-urea breath test underwent endoscopic screening and 1-week clarithromycin-based triple therapy. For subjects whose initial treatment failed, 10-day levofloxacin-based triple therapy was administered. The main outcome measures were changes in the prevalence of H pylori infection and premalignant gastric lesions, and changes in the incidence of premalignant gastric lesions and gastric cancer before (1995-2003) and after (2004-2008) chemoprevention using various comparators. RESULTS: The reduction in H pylori infection was 78.7% (95% CI 76.8% to 80.7%), and the estimated incidence of re-infection/recrudescence was 1% (95% CI 0.6% to 1.4%) per person-year. The effectiveness of reducing the incidence of gastric atrophy resulting from chemoprevention was significant at 77.2% (95% CI 72.3% to 81.2%), while the reduction in intestinal metaplasia was not significant. Compared with the 5-year period before chemoprevention and in the absence of endoscopic screening, the effectiveness in reducing gastric cancer incidence during the chemoprevention period was 25% (rate ratio 0.753, 95% CI 0.372 to 1.524). The reduction in peptic ulcer disease was 67.4% (95% CI 52.2% to 77.8%), while the incidence of oesophagitis was 6% (95% CI 5.1% to 6.9%) after treatment. CONCLUSIONS: Population-based eradication of H pylori infection has led to a significant reduction in gastric atrophy at the expense of increased oesophagitis. The ultimate benefit in reducing gastric cancer incidence and its mortality should be validated by a further long-term follow-up.
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Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/prevención & control , Adulto , Algoritmos , Antibacterianos/uso terapéutico , Antiulcerosos/uso terapéutico , Pruebas Respiratorias , Claritromicina/uso terapéutico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/epidemiología , Helicobacter pylori/efectos de los fármacos , Humanos , Incidencia , Masculino , Metaplasia/microbiología , Metaplasia/prevención & control , Persona de Mediana Edad , Tamizaje Multifásico , Oportunidad Relativa , Úlcera Péptica/microbiología , Úlcera Péptica/prevención & control , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/prevención & control , Prevalencia , Recurrencia , Factores de Riesgo , Taiwán/epidemiología , Resultado del TratamientoRESUMEN
Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis.