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BACKGROUND AND AIM: The measurement of esophageal acid exposure time (AET) using combined multichannel intraluminal impedance-pH (MII-pH) tests is the gold standard for diagnosing gastroesophageal reflux disease (GERD). However, this catheter-based 24-h test can cause considerable patient discomfort. Our aim is to identify factors affecting AET and to develop a scoring model for predicting AET abnormalities before conducting the MII-pH test. METHODS: Of the 366 patients who underwent MII-pH test at two facilities in Japan and Vietnam, 255 patients who also had esophagogastroduodenoscopy and high-resolution manometry were included in this study. Logistic regression analysis was conducted using risk factors for AET > 6% identified from a derivation cohort (n = 109). A scoring system predicting AET > 6% was then constructed and externally validated with a separate cohort (n = 146). RESULTS: Three variables were derived from the prediction model: male gender, Hill grades III-IV, and weak mean distal contractile integrals. Based on these scores, patients were classified into low (0 point), intermediate (1-3 points), and high (4 points) risk groups. The probabilities of having an AET > 6% were 6%, 34%, and 100% for these groups, respectively. A score of < 1 excluded patients with abnormal AET, with a negative predictive value of 93.8% in the derivation cohort and 80.0% in the validation cohort. CONCLUSIONS: We derived and externally validated a prediction model for abnormal AET. This system could assist in guiding the appropriate treatment strategies for GERD.
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Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV+ CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV+ CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV+ CTCs nor MycN amplification. Of note, the low number of CSV+ CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV+ CTCs (every 6 mL) are present in the blood samples compared to >3 CSV+ CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV+ CTC data in any study in a long-term longitudinal manner.
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Recurrencia Local de Neoplasia/diagnóstico , Células Neoplásicas Circulantes/metabolismo , Neuroblastoma/diagnóstico , Vimentina/metabolismo , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Ensayos Clínicos Fase II como Asunto , Detección Precoz del Cáncer , Eflornitina/uso terapéutico , Transición Epitelial-Mesenquimal , Femenino , Humanos , Estudios Longitudinales , Masculino , Recurrencia Local de Neoplasia/metabolismo , Neuroblastoma/metabolismo , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERα and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose-response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERα expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region.
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Dietilhexil Ftalato/toxicidad , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipotálamo/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal , Animales , Aromatasa/genética , Disruptores Endocrinos , Receptor alfa de Estrógeno/genética , Femenino , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Masculino , Exposición Materna , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/fisiología , Embarazo , Resultado del Embarazo , Próstata/efectos de los fármacos , Próstata/fisiología , Ratas Sprague-DawleyRESUMEN
Tumors of the central nervous system (CNS) are the most common and lethal childhood malignancy. Detection of residual disease and longitudinal monitoring of treatment response in patients are challenging and rely on serial imaging. This current standard of care fails to detect microscopic disease or provide molecular characteristics of residual tumors. As such, there is dire need for minimally invasive liquid biopsy techniques. We have previously shown the high specificity of using cell surface vimentin (CSV) to identify circulating tumor cells (CTCs) from patients bearing various types of cancers. Here, we describe the first report of CTCs captured from peripheral blood samples in 58 pediatric CNS tumor patients. In this study, we used a CSV-coated cell capture chip, the Abnova CytoQuest automated CTC isolation system, to boost the CTC capture from pediatric patients with CNS tumors. We successfully isolated CTCs in six glioma patients using immunostaining of histone H3 lysine27-to-methionine (H3K27M) mutations which are highly expressed by this tumor. We show that CSV is a viable marker for CNS CTC isolation and that this is a feasible method for detecting microscopic disease. Larger-scale studies focusing on CTCs in pediatric CNS tumors to explore their diagnostic and prognostic value are warranted.
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Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)-specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8+ TRM cells may have promising implications for the prevention of brain tumor recurrence.
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Linfocitos T CD8-positivos , Glioblastoma , Animales , Ratones , Encéfalo , Glioblastoma/terapia , Memoria Inmunológica , Células T de Memoria , Recurrencia Local de Neoplasia , Linfocitos T/inmunologíaRESUMEN
Purpose: Esophageal mucosal admittance (MA) is a promising diagnostic method for gastroesophageal reflux disease (GERD). We conducted a study to describe the esophageal MA in patients with reflux symptoms and determine its diagnostic accuracy. Patients and Methods: We recruited 92 patients with ambulatory pH-impedance monitoring, upper gastrointestinal endoscopy, and MA measured by the tissue conductance meter. MA was measured during endoscopy at 5cm (distal esophagus) and 15cm above the Z line (middle esophagus), repeated at least five times at each position, and median MA was obtained. Afterwards, two biopsies were taken 5cm above the Z line for histopathological evaluation using the Esohisto criteria. Patients were classified as GERD or non-GERD according to the 2018 Lyon consensus. Results: The mean age was 43.2 years, and 42 patients were males. The most common symptoms were regurgitation (75.0%), belching (65.2%), and heartburn (46.7%). Twenty-three (32.3%) were diagnosed with GERD using the Lyon consensus, and 24 (26.1%) had esophagitis on histopathology. The median MA at the distal and middle esophagus was moderately correlated. The median MA at both positions was higher in the GERD group but only statistically significant in the middle esophagus. MA was not associated with pH-impedance parameters and esophagitis on histopathology. The diagnostic model developed using the logistic regression did not have good accuracy. Conclusion: MA was not different between GERD and non-GERD patients.
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Background and Aim: We aimed to evaluate the application of Peptest, a novel technique to detect pepsin in the saliva, and identify its threshold level for the diagnosis of gastroesophageal reflux disease (GERD) with extraesophageal symptoms. Methods: A cross-sectional study was conducted in two groups: patients with extraesophageal GERD symptoms (symptomatic group divided into GERD and non-GERD groups according to 24-h esophageal pH-impedance monitoring [pH-I] results) and healthy controls. For the symptomatic group, endoscopy, pH 24 h, high-resolution manometry (HRM), and salivary Peptest were performed. For the healthy control group, only Peptest was done. The accuracy of Peptest was compared with that of pH-I by the Lyon consensus criteria. Results: Chronic laryngitis was the most frequent extraesophageal symptom. On saliva testing, the GERD group had a higher prevalence of positive samples and pepsin concentration than the control group. Between GERD and non-GERD groups, the optimal threshold level was 31.2 ng/mL, with a sensitivity of 86.7% and specificity of 27.5%. The optimal threshold level was 31.4 ng/mL to differentiate GERD from healthy controls, with a sensitivity of 86.7% and specificity of 66.0%. Age, number of total refluxes, DeMeester score, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedence (MNBI) were associated with pepsin concentration. Regarding HRM metrics, there was no significant difference of pepsin concentration between low/normal upper esophageal sphincter (UES) resting pressure, low/normal lower esophageal sphincter (LES) resting pressure, low/normal 4-s integrated relaxation pressure (IRP4s), and hypomotility/normal motility. Conclusion: Patients with extraesophageal symptoms had a higher prevalence of positive Peptest. The optimum threshold level of 31.4 ng/mL had high sensitivity and moderate specificity to differentiate between patients with GERD and healthy controls.
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Background: We established a diquat-induced human kidney-2 cells (HK-2 cells) apoptosis model in this study to identify differentially expressed microRNAs (miRNAs) and signaling pathways involved in diquat poisoning via gene sequencing and bioinformatics analysis and explored the related therapeutic benefits. Methods: The effects of diquat on the viability and apoptosis of HK-2 cells were explored using the CCK-8 and Annexin V-FITC/PI double staining methods. Total RNAs were extracted using the TRizol method and detected by Illumina HiSeq 2500. Bioinformatics analysis was performed to explore differentially expressed (DE) miRNAs, their enriched biological processes, pathways, and potential target genes. The RT-qPCR method was used to verify the reliability of the results. Results: Diquat led to HK-2 cell injury and apoptosis played an important role, hence an HK-2 cell apoptosis model in diquat poisoning was established. Thirty-six DE miRNAs were screened in diquat-treated HK-2 cells. The enriched biological process terms were mainly cell growth, regulation of apoptotic signaling pathway, extrinsic apoptotic signaling pathway, and Ras protein signal transduction. The enriched cellular components were mainly cell-cell junction, cell-substrate junction, ubiquitin ligase complex, and protein kinase complex. The enriched molecular functions were mainly Ras GTPase binding, ubiquitin-like protein transferase activity, DNA-binding transcription factor binding, ubiquitin-protein transferase activity, nucleoside-triphosphatase regulator activity, transcription coactivator activity, and ubiquitin-like protein ligase binding. Signaling pathways such as MAPK, FoxO, Ras, PIK3-Akt, and Wnt were also enriched. Conclusion: These findings aid in understanding the mechanisms of diquat poisoning and the related pathways, where DE miRNAs serve as targets for gene therapy.
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AIMS: To determine the effectiveness of a mobile application (app) in improving the quality of bowel preparation for colonoscopy. METHOD: An endoscopist-blinded randomised controlled trial enrolled patients who were undergoing a colonoscopy on the same day of bowel preparation. The intervention used a Vietnamese mobile app that provides instructions on bowel preparation while patients in the comparison group received conventional instructions. Outcomes included the Boston Bowel Preparation Scale (BBPS) to assess the quality of bowel preparation and the polyp detection rate (PDR) and adenoma detection rate (ADR). RESULTS: The study recruited 515 patients (256 in the intervention group). The median age was 42 years, 50.9% were females, 69.1% high school graduates and higher, and 45.2% from urban area. Patients in the intervention group had higher adherence to instructions (60.9% vs 52.4%, p=0.05) and longer length of taking laxatives (mean difference 0.17 hours, 95% CI 0.06 to 0.27). The intervention did not reduce the risk of poor bowel cleansing (total BBPS<6) in both overall (7.4% vs 7.7%; risk ratio 0.96, 95% CI 0.53 to 1.76) and subgroup analysis. PDR and ADR were similar between the two groups. CONCLUSIONS: The mobile app providing instructions on proper bowel preparation improved the practice during bowel preparation but did not improve the quality of bowel cleansing or PDR.
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Adenoma , Aplicaciones Móviles , Femenino , Humanos , Adulto , Masculino , Catárticos/uso terapéutico , Estudios Prospectivos , Educación del Paciente como Asunto , Colonoscopía , Adenoma/diagnósticoRESUMEN
BACKGROUND: Bean pod mottle virus (BPMV) is a wide-spread and destructive virus that causes huge economic losses in many countries every year. A sensitive, reliable and specific method for rapid surveillance is urgently needed to prevent further spread of BPMV. METHODS: A degenerate reverse-transcription loop-mediated isothermal amplification (RT-LAMP) primer set was designed on the conserved region of BPMV CP gene. The reaction conditions of RT-LAMP were optimized and the feasibility, specificity and sensitivity of this method to detect BPMV were evaluated using the crude RNA rapidly extracted from soybean seeds. RESULTS: The optimized RT-LAMP parameters including 6 mM MgCl2, 0.8 M betaine and temperature at 62.5-65°C could successfully amplify the ladder-like bands from BPMV infected soybean seeds. The amplification was very specific to BPMV that no cross-reaction was observed with other soybean viruses. Inclusion of a fluorescent dye makes it easily be detected in-tube by naked eye. The sensitivity of RT-LAMP assay is higher than the conventional RT-PCR under the conditions tested, and the conventional RT-PCR couldn't be used for detection of BPMV using crude RNA extract from soybean seeds. CONCLUSION: A highly efficient and practical method was developed for the detection of BPMV in soybean seeds by the combination of rapid RNA extraction and RT-LAMP. This RT-LAMP method has great potential for rapid BPMV surveillance and will assist in preventing further spread of this devastating virus.
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Comovirus/clasificación , Comovirus/aislamiento & purificación , Glycine max/virología , Técnicas de Amplificación de Ácido Nucleico/métodos , Semillas/virología , Secuencia de Bases , ARN Viral/genética , Sensibilidad y Especificidad , Temperatura , Factores de TiempoRESUMEN
Receptor-ligand binding has been analyzed at the protein level using isothermal titration calorimetry and surface plasmon resonance and at the cellular level using interaction-associated downstream gene induction/suppression. However, no currently available technique can characterize this interaction directly through visualization. In addition, all available assays require a large pool of cells; no assay capable of analyzing receptor-ligand interactions at the single-cell level is publicly available. Here, we describe a new microfluidic chip-based technique for analyzing and visualizing these interactions at the single-cell level. First, a protein is immobilized on a glass slide and a low-flow-rate pump is used to isolate cells that express receptors that bind to the immobilized ligand. Specifically, we demonstrate the efficacy of this technique by immobilizing biotin-conjugated FGL2 on an avidin-coated slide chip and passing a mixture of GFP-labeled wild-type T cells and RFP-labeled FcγRIIB-knockout T cells through the chip. Using automated scanning and counting, we found a large number of GFP+ T cells with binding activity but significantly fewer RFP+ FcγRIIB-knockout T cells. We further isolated T cells expressing a membrane-anchored, tumor-targeted IL-12 based on the receptor's affinity to vimentin to confirm the versatility of our technique. This protocol allows researchers to isolate receptor-expressing cells in about 4 hours for further downstream processing.
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Avidina , Biotina , Biotina/metabolismo , Interleucina-12 , Ligandos , Microfluídica , VimentinaRESUMEN
PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges. EXPERIMENTAL DESIGN: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells. RESULTS: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. Mechanistically, attIL12-PBMC treatment resulted in tumor-restricted antitumor cytokine release and accumulation of attIL12-PBMCs in tumors. It also induced terminal differentiation of osteosarcoma cells into bone-like cells to impede tumor growth. CONCLUSIONS: In summary, attIL12-PBMC therapy is safe and effective against osteosarcoma. Our goal is to move this treatment into a clinical trial. Owing to the convenience of the attIL12-PBMC production process, we believe it will be feasible.
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Neoplasias Óseas , Osteosarcoma , Neoplasias Óseas/terapia , Línea Celular Tumoral , Humanos , Inmunoterapia Adoptiva/métodos , Interleucina-12 , Leucocitos Mononucleares , Osteosarcoma/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has disrupted the practice of gastrointestinal (GI) endoscopy units and may increase the risk of digestive disorders. We described the situational changes in GI endoscopy and peptic ulcer disease (PUD) proportion during COVID-19 in Vietnam and examined the associated factors. METHODS: A retrospective ecological study was conducted on data of Hanoi Medical University Hospital, Vietnam. The number of upper GI endoscopy and the proportion of GI emergency endoscopy and PUD were compared between 2019 and 2020 by month (January to June). Log-binomial regression was used to explore associated factors of GI emergency endoscopy and PUD. RESULTS: The number of endoscopies decreased remarkably during the nationwide social distancing in April 2020. Compared to April 2019, the proportion in April 2020 of both GI emergency endoscopy [4.1 vs. 9.8%, proportion ratio (PR) 2.39, 95% CI 2, 2.87], and PUD [13.9 vs. 15.8%; PR, 1.14; 95% CI, 1.01, 1.29] was significantly higher. In log-binomial models, the proportion of GI emergency endoscopy was higher in April 2020 compared to April 2019 (adjusted PR, 2.41; 95% CI, 2.01, 2.88). Male sex and age of ≥50 years were associated with an increased PUD and GI emergency conditions. CONCLUSION: The proportion of both GI emergency endoscopy and PUD was significantly higher during the time of the state of emergency due to the ongoing COVID-19 pandemic in 2020 when compared to 2019 at the same health facility in Vietnam. The findings suggest that healthcare delivery reforms during the era of an emerging pandemic are required to reduce digestive disorders, in particular, and chronic diseases in general.
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COVID-19 , Úlcera Péptica , COVID-19/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Úlcera Péptica/epidemiología , Estudios Retrospectivos , SARS-CoV-2 , Vietnam/epidemiologíaRESUMEN
Absent contractility is a rare esophageal motility disorder defined by high-resolution manometry which remains poorly understood in pathogenesis and management. We investigated the clinical symptoms, upper gastrointestinal endoscopy findings, and lower esophageal sphincter (LES) characteristics in adult patients diagnosed with absent contractility on high resolution manometry and factors associated with erosive esophagitis that were found on endoscopy in these patients. A cross-sectional study was conducted in patients with absent contractility who were examined at the Institute of Gastroenterology and Hepatology, Vietnam between March 2018 and December 2020. Clinical symptoms, endoscopic findings, and LES metrics were collected and compared between individuals with and without erosive esophagitis. Logistic regression analysis was used to examine a variety of factors associated with erosive esophagitis. Among 7519 patients who underwent high resolution manometry, 204 (2.7%) were diagnosed with absent contractility. The mean age of the study sample was 45.9 years, 65.7% were women, and none had systemic sclerosis. The most common symptoms were regurgitation, belching, epigastric pain, and bloating. On endoscopy, 50% had erosive esophagitis, mostly Los Angeles grade A (42.9%). On manometry, 44.6% of the patients had LES hypotension and 68.1% had low integrated relaxation pressure in 4 seconds (IRP4s). Male sex (adjusted odds ratioâ =â 2.01, 95% confidence interval: 1.04-3.89) and an IRP4sâ <â 5 mm Hg (adjusted odds ratioâ =â 2.21, 95% confidence interval: 1.12-4.37) were significantly associated with erosive esophagitis. Absent contractility was present in many patients without known systemic diseases. Erosive esophagitis was common and associated with male sex and low IRP4s.
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Esofagitis , Reflujo Gastroesofágico , Úlcera Péptica , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Esfínter Esofágico Inferior , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/complicaciones , Estudios Transversales , Manometría , Esofagitis/complicaciones , Úlcera Péptica/complicaciones , Endoscopía GastrointestinalRESUMEN
Background: A new classification criterion for diagnosing ineffective esophageal motility (IEM) was proposed at the 2018 Stanford symposium, but limited data exists about the utility of this criterion. Methods: We conducted a cross-sectional study among 3826 patients treated at the Institute of Gastroenterology and Hepatology, Hanoi, Vietnam, between March 2018 and May 2020. Patients were classified as having normal motility, mild IEM, severe IEM, or absent contractility based on the Chicago classification version 3.0 and the new IEM criterion (severe IEM was defined as having >70% ineffective swallows). We examined the association between these 4 motility subgroups and the presence of erosive esophagitis and Barrett's esophagus, using multivariate logistic regression analysis. Results: The mean age of the study sample was 44.7 years and 66.3% were women. The prevalence of symptoms, hiatal hernia, and Helicobacter pylori-positive patients was similar in the 4 study groups. The 4-second integrated relaxation pressures and lower esophageal sphincter resting pressures were lower in patients with severe IEM and absent contractility. Severe IEM and absent contractility, but not mild IEM, were significantly associated with Los Angeles (LA) grade B-D esophagitis (relative risk ratio [RRR] for severe IEM 1.81, 95% confidence interval [CI] 1.17-2.80; and RRR for absent contractility 2.37, 95%CI 1.12-5.04). None of the hypomotility subgroups were associated with LA grade A esophagitis and Barrett's esophagus. Conclusions: Patients with severe IEM have a high prevalence of severe erosive esophagitis. These findings suggest the need for a more meaningful classification criterion for IEM.
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In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.
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Cobre , Melanoma , Apoptosis , Cobre/metabolismo , Cobre/farmacología , Humanos , Ionóforos/farmacología , Lisosomas/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Piranos , TionasRESUMEN
BACKGROUND: Adoptive T-cell transfer has become an attractive therapeutic approach for hematological malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) exhibits potent antitumor efficacy against solid tumors, but its clinical application has been stalled because of toxicity. Here, we aimed to develop a safe approach to IL-12 T-cell therapy for eliminating large solid tumors. METHODS: We generated a cell membrane-anchored IL-12 (aIL12), a tumor-targeted IL-12 (ttIL12), and a cell membrane-anchored and ttIL-12 (attIL12) and a cell membrane-anchored and tumor-targeted ttIL-12 (attIL12) armed T cells, chimeric antigen receptor-T cells, and T cell receptor-T (TCR-T) cells with each. We compared the safety and efficacy of these armed T cells in treating osteosarcoma patient-derived xenograft tumors and mouse melanoma tumors after intravenous infusions of the armed T cells. RESULTS: attIL12-T cell infusion showed remarkable antitumor efficacy in human and mouse large solid tumor models. Mechanistically, attIL12-T cells targeted tumor cells expressing cell-surface vimentin, enriching effector T cell and interferon γ production in tumors, which in turn stimulates dendritic cell maturation for activating secondary T-cell responses and tumor antigen spreading. Both attIL12- and aIL12-T-cell transfer eliminated peripheral cytokine release and the associated toxic effects. CONCLUSIONS: This novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Inmunoterapia/métodos , Interleucina-12/inmunología , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
Helicobacter pylori (H. pylori) infection is prevalent and has a rapidly increasing antibiotic resistance rate in Vietnam. Reinfection is quite common, and gastric carcinoma remains one of the most common malignancies, which is not uncommon to develop after successful eradication. The purpose of this consensus is to provide updated recommendations on the management of H. pylori infection in the country. The consensus panel consisted of 32 experts from 14 major universities and institutions in Vietnam who were invited to review the evidence and develop the statements using the Delphi method. The process followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The consensus level was defined as ≥80% for agreement on the proposed statements. Due to the limited availability of high-quality local evidence, this consensus was also based on high-quality evidence from international studies, especially those conducted in other populations in the Asia-Pacific region. The panel finally reached a consensus on 27 statements after two voting rounds, which consisted of four sections (1) indications for testing and selection of diagnostic tests (2), treatment regimens, (3) post-treatment confirmation of H. pylori status, and (4) reinfection prevention methods and follow-up after eradication. Important issues that require further evidence include studies on third-line regimens, strategies to prevent H. pylori reinfection, and post-eradication follow-up for precancerous gastric lesions. We hope this consensus will help guide the current clinical practice in Vietnam and promote multicenter studies in the country and international collaborations.
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MicroRNAs (miRNAs), a group of small noncoding RNAs, may serve as a class of post-transcriptional regulators in plant immune systems. Nevertheless, little is known about their roles in plant immune response to the oomycete pathogens. To identify miRNAs involved in the response of soybean to Phytophthora sojae, we examined expressional patterns of miRNAs upon infection by P. sojae by microarray analysis in three soybean cultivars: Williams (susceptible), Conrad (quantitative resistance), and Williams 82 (qualitative resistance). Expression of a number of miRNAs was significantly altered upon infection and (or) in the different genotypes. qRT-PCR data with some miRNAs further confirmed the microarray results. Comparative analysis of the selected miRNAs and their targeted gene expression datasets uncovered many reciprocally expressed miRNA-target pairs, which could proposed a feedback circuit between miRNA(s) and protein-coding genes. These results may serve as a basis for further in-depth studies of miRNAs involved in soybean resistance to P. sojae.
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Resistencia a la Enfermedad , Glycine max/inmunología , MicroARNs/genética , Phytophthora/patogenicidad , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Genotipo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Phytophthora/inmunología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Glycine max/genética , Glycine max/microbiologíaRESUMEN
OBJECTIVE: Familial transmission can possibly influence the infection and treatment of Helicobacter pylori. This study aimed to describe the prevalence of H. pylori infection and outcomes of eradication treatment among Vietnamese patients who live in the same households. METHODS: We conducted a prospective cohort study of Vietnamese household members with upper gastrointestinal complaints. Participants received esophagogastroduodenoscopy and H. pylori testing. The H. pylori-positive patients were treated and asked to return for follow-up within 4 months. To explore factors associated with H. pylori infection at baseline, we performed multilevel logistic regression to account for the clustering effect of living in the same households. To explore factors associated with eradication failure, we used Poisson regression with robust variance estimation to estimate the risk ratio. RESULTS: The prevalence of H. pylori infection was 83.5% and highest among children <12 years old (92.2%) in 1,272 patients from 482 households. There were variations in H. pylori infection across households (intraclass correlation = 0.14, 95% confidence interval (CI) 0.05, 0.33). Children aged <12 years had higher odds of H. pylori infection (odds ratio = 3.41, 95%CI 2.11, 5.50). At follow-up, H. pylori was eradicated in 264 of 341 patients (77.4%). The risk of eradication failure was lower for the sequential regimen with tetracycline. CONCLUSION: H. pylori infection was common among people living in the same households. Eradication success for H. pylori was higher for the tetracycline sequential regimen. More research should be focused on how family factors influence H. pylori infection and on eradication treatment.