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Patients with chronic pancreatitis are at risk of developing malabsorption and malnutrition. Exocrine pancreatic insufficiency is accompanied by decreased serum micronutrient levels and low vitamin D levels are a frequent finding in up to 60-80% of patients. The aim of our prospective study was to investigate vitamin D in the blood serum of subjects with chronic pancreatitis with the possibility of influencing the reduced vitamin D levels with supplementation therapy. MATERIAL AND METHODOLOGY: Fifty patients with chronic pancreatitis and 20 subjects in the control group without gastrointestinal tract diseases, including pancreatic disease, were examined. The vitamin D level in blood serum was determined. The results were evaluated according to the age distribution of subjects with pancreatic disease and according to gender. Patients with low vitamin D levels were treated for 24 weeks with a dose of 1.500.000 IU of vitamin D3 per day, and then blood serum vitamin D levels were determined. RESULTS: In people with chronic pancreatitis, vitamin D levels were statistically significantly reduced compared to the control group. There was no statistically significant relationship of vitamin D with gender and age. Supplementation with vitamin D3 achieved an adjustment of vitamin D level to the level of the control group. CONCLUSION: Blood serum vitamin D levels are significantly reduced in people with chronic pancreatitis. Its correction by oral vitamin D supplementation was effective. Whether this adjustment of levels will be effective also in terms of e.g. beneficial effect on fibrogenesis will require further representative studies, because the limitation of the interpretation of the results of our study is the smaller number of subjects with chronic pancreatitis (Tab. 4, Ref. 29).
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Pancreatitis Crónica , Vitamina D , Humanos , Pancreatitis Crónica/sangre , Pancreatitis Crónica/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Vitamina D/sangre , Adulto , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/complicaciones , Estudios Prospectivos , Anciano , Colecalciferol/administración & dosificación , Colecalciferol/sangre , Colecalciferol/uso terapéutico , Suplementos DietéticosRESUMEN
It has been established that gut dysbiosis contributed to the pathogenesis of digestive disorders. We aimed to explore the causal relationships between intestinal microbiota, circulating inflammatory cytokines and chronic pancreatitis (CP). Summary statistics of genome-wide association studies (GWAS) of intestinal microbiome was retrieved from the MiBioGen study and the GWAS data of 91 circulating inflammatory cytokines and CP were obtained from the GWAS catalog. The 2-sample bidirectional Mendelian randomization (MR) analysis was performed between gut microbiota, circulating inflammatory cytokines and CP, in which the inverse variance weighted (IVW) method was regarded as the primary analysis approach. To prove the reliability of the causal estimations, multiple sensitivity analyses were utilized. IVW results revealed that genetically predicted 2 genera, including Sellimonas and Eubacteriumventriosumgroup, and plasm C-C motif chemokine 23 (CCL23) level were positively associated with CP risk, while genus Escherichia Shigella, Eubacteriumruminantiumgroup and Prevotella9, and plasma Caspase 8, Adenosine Deaminase (ADA), and SIR2-like protein 2 (SIRT2) level, demonstrated an ameliorative effect on CP. Leave-one-out analysis confirmed the robustness of the aforementioned causal effects and no significant horizontal pleiotropy or heterogeneity of the instrumental variables was detected. However, no association was found from the identified genera to the CP-related circulating inflammatory cytokines. Besides, the reverse MR analysis demonstrated no causal relationship from CP to the identified genera and circulating inflammatory cytokines. Taken together, our comprehensive analyses offer evidence in favor of the estimated causal connections from the 5 genus-level microbial taxa and 4 circulating inflammatory cytokines to CP risk, which may help to reveal the underlying pathogenesis of CP.
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Citocinas , Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Pancreatitis Crónica , Humanos , Microbioma Gastrointestinal/genética , Citocinas/sangre , Pancreatitis Crónica/microbiología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/genéticaRESUMEN
OBJECTIVE: Aim: To investigate and analyze homeostatic disorders in patients with a combination of Chronic Pancreatitis(CP) and Arterial Hypertension (AH) and to develop correcting ways of the detected changes. PATIENTS AND METHODS: Materials and Methods: General clinical, laboratory-instrumental examination of 121 patients, who were undergoing inpatient treatment with a diagnosis of Chronic Pancreatitis in combination with Arterial Hypertension of the II stage during 2021-2022. RESULTS: Results: In the majority of cases of patients signs the increasing in IL-1,6 and Cortisol levels were found. A decrease in Ca to the lower limit of the norm was observed (2.18 ± 0.26 mmol/l to the data of control group patients (2.32 ± 0.12 mmol/l, p= 0.01 ), the levels of trace elements Zn and Se were determined within the reference values. The Atherogenic Index was increased 1.8 times and was significantly different from the control group date. During the FE-1 study, a decrease in the level of this indicator was revealed by 151.71±13.91 mg/g of feces, both to the values of reference values and a significant difference to the data of the control group (241.28±29.17 mg/g of feces, p<0 .05). CONCLUSION: Conclusions: Based on the multivariate linear regression analysis of the obtained data, formulas have been developed that can be used to predict the dynamics of the dependent variable (FE-1, IL-1, Selenium level, Glutathione Peroxidase, blood pressure) according to changes in the studied influencing factors.
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Hipertensión , Análisis Multivariante , Pancreatitis Crónica , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico , Pancreatitis Crónica/patología , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/patología , Humanos , Adulto , Persona de Mediana Edad , Enfermedades Gastrointestinales/diagnósticoRESUMEN
BACKGROUND & AIMS: In this study, we assessed serum trace element concentrations in patients with pancreatic cancer and compared the results to those of healthy controls and patients with chronic pancreatitis. We evaluated the association between trace element concentrations during cancer treatment and the risk of cancer progression and mortality in pancreatic cancer patients. METHODS: A retrospective cohort study was conducted at a tertiary center in Korea. Serum trace element concentrations of cobalt (Co), copper (Cu), selenium (Se), and zinc (Zn) were measured at diagnosis using an inductively coupled plasma-mass spectrometry in 124 patients with pancreatic cancer, 50 patients with chronic pancreatitis, and 120 healthy controls. Trace elements were measured after a median of 282.5 (95% confidence interval [CI], 224.0-326.5) days from treatment initiation to assess changes in trace element concentrations during treatment. RESULTS: Serum Co concentrations were significantly higher in patients with chronic pancreatitis and pancreatic cancer compared to healthy controls, while serum Se concentrations were significantly lower. During treatment, serum concentrations of Cu, Se, and Zn significantly decreased in patients with pancreatic cancer. During the follow-up (median 152.5; 95% CI, 142.8-160.0 months), 85.5% of patients experienced progression or relapse, and 84.7% of patients died. Patients with decreased Se and Zn concentrations during treatment had a higher mortality (hazard ratio [HR], 2.10; 95% CI, 1.31-3.38; P = 0.0020 for Se; HR, 1.72; 95% CI, 1.06-2.79; P = 0.0269 for Zn) compared to those with unchanged or increased trace element concentrations during treatment. Patients with a greater reduction in Zn concentrations during treatment had a higher mortality than those with a smaller reduction (HR, 1.59; 95% CI, 1.01-2.52; P = 0.0483). Patients whose Zn status changed from normal to deficient during treatment had an increased mortality (HR, 1.76; 95% CI, 1.16-2.67, P = 0.0084). Patients with multiple (≥2) trace element deficiencies after treatment had poorer outcomes than those with no or single trace element deficiency. CONCLUSIONS: This study revealed that decreases in Se and Zn concentrations during cancer treatment were associated with adverse outcomes in terms of cancer progression and mortality in patients with pancreatic cancer. Further prospective investigations are recommended.
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Neoplasias Pancreáticas , Oligoelementos , Humanos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Oligoelementos/sangre , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Pronóstico , República de Corea/epidemiología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/mortalidad , Selenio/sangre , Zinc/sangre , Progresión de la Enfermedad , Cobre/sangre , Cobalto/sangreRESUMEN
OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.
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Carcinoma Ductal Pancreático , Colangiocarcinoma , Inmunohistoquímica , Mucina 4 , Neoplasias Pancreáticas , Humanos , Mucina 4/metabolismo , Mucina 4/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangre , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/sangre , Adulto , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/genética , Pancreatitis Crónica/diagnóstico , Pancreatitis Crónica/sangre , Estudios de Casos y Controles , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/patología , Relevancia ClínicaRESUMEN
INTRODUCTION: Diabetes (T3cDM) secondary to chronic pancreatitis (CP) arises due to endocrine dysfunction and metabolic dysregulations. Currently, diagnostic tests are not available to identify patients who may progress from normoglycemia to hyperglycemia in CP. We conducted plasma metabolomic profiling to diagnose glycemic alterations early in the course of disease. METHODS: Liquid chromatography-tandem mass spectrometry was used to generate untargeted, targeted plasma metabolomic profiles in patients with CP, controls (n = 445) following TRIPOD guidelines. Patients were stratified based on glucose tolerance tests following ADA guidelines. Multivariate analysis was performed using partial least squares discriminant analysis to assess discriminatory ability of metabolites among stratified groups. COMBIROC and logistic regression were used to derive biomarker signatures. AI-ML tool (Rapidminer) was used to verify these preliminary results. RESULTS: Ceramide, lysophosphatidylethanolamine, phosphatidylcholine, lysophosphatidic acid (LPA), phosphatidylethanolamine, carnitine, and lysophosphatidylcholine discriminated T3cDM CP patients from healthy controls with AUC 93% (95% CI 0.81-0.98, P < 0.0001), and integration with pancreatic morphology improved AUC to 100% (95% CI 0.93-1.00, P < 0.0001). LPA, phosphatidylinositol, and ceramide discriminated nondiabetic CP with glycemic alterations (pre-diabetic CP); AUC 66% (95% CI 0.55-0.76, P = 0.1), and integration enhanced AUC to 74% (95% CI 0.55-0.88, P = 0.86). T3cDM was distinguished from prediabetic by LPA, phosphatidylinositol, and sphinganine (AUC 70%; 95% CI 0.54-0.83, P = 0.08), and integration improved AUC to 83% (95% CI 0.68-0.93, P = 0.05). CombiROC cutoff identified 75% and 78% prediabetes in validation 1 and 2 cohorts. Random forest algorithm assessed performance of integrated panel demonstrating AUC of 72% in predicting glycemic alterations. DISCUSSION: We report for the first time that a panel of metabolites integrated with pancreatic morphology detects glycemia progression before HbA1c in patients with CP.
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Biomarcadores , Hemoglobina Glucada , Metabolómica , Pancreatitis Crónica , Estado Prediabético , Humanos , Masculino , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico , Estado Prediabético/sangre , Estado Prediabético/diagnóstico , Femenino , Persona de Mediana Edad , Adulto , Biomarcadores/sangre , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Metabolómica/métodos , Progresión de la Enfermedad , Lisofosfolípidos/sangre , Lisofosfolípidos/metabolismo , Carnitina/sangre , Carnitina/análogos & derivados , Espectrometría de Masas en Tándem , Estudios de Casos y Controles , Prueba de Tolerancia a la Glucosa , Ceramidas/sangre , Glucemia/análisis , Glucemia/metabolismo , Anciano , Cromatografía Liquida , Páncreas/patología , Páncreas/metabolismo , Metaboloma , Lisofosfatidilcolinas/sangreRESUMEN
OBJECTIVES: Chronic pancreatitis (CP) is an inflammatory disease affecting the absorption of fat-soluble nutrients. Signaling in pancreatic cells that lead to inflammation may be influenced by fatty acids (FAs) through diet and de novo lipogenesis. Here, we investigated the relationship between plasma FA composition in CP with heterogeneity of etiology and complications of CP. MATERIALS AND METHODS: Blood and clinical parameters were collected from subjects with CP (n = 47) and controls (n = 22). Plasma was analyzed for FA composition using gas chromatography and compared between controls and CP and within CP. RESULTS: Palmitic acid increased, and linoleic acid decreased in CP compared with controls. Correlations between age or body mass index and FAs are altered in CP compared with controls. Diabetes, pancreatic calcifications, and substance usage, but not exocrine pancreatic dysfunction, were associated with differences in oleic acid and linoleic acid relative abundance in CP. De novo lipogenesis index was increased in the plasma of subjects with CP compared with controls and in calcific CP compared with noncalcific CP. CONCLUSIONS: Fatty acids that are markers of de novo lipogenesis and linoleic acid are dysregulated in CP depending on the etiology or complication. These results enhance our understanding of CP and highlight potential pathways targeting FAs for treating CP.
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Ácidos Grasos , Ácido Linoleico , Pancreatitis Crónica , Humanos , Proyectos Piloto , Pancreatitis Crónica/sangre , Pancreatitis Crónica/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Adulto , Ácidos Grasos/sangre , Ácido Linoleico/sangre , Estudios de Casos y Controles , Lipogénesis , Anciano , Ácido Palmítico/sangre , Ácido Oléico/sangre , Biomarcadores/sangreRESUMEN
INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.
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Biomarcadores , Lipocalina 2 , Pancreatitis Crónica , Humanos , Masculino , Femenino , Lipocalina 2/sangre , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico , Persona de Mediana Edad , Biomarcadores/sangre , Adulto , Estudios Transversales , Leucocitos Mononucleares/metabolismo , Anciano , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Ácido Linoleico/sangre , Estudios de Casos y ControlesRESUMEN
The objective of this study was to analyze the value of artificial intelligence algorithm-based computerized tomography (CT) image combined with serum tumor markers for diagnoses of pancreatic cancer. In the study, 68 hospitalized patients with pancreatic cancer were selected as the experimental group, and 68 hospitalized patients with chronic pancreatitis were selected as the control group, all underwent CT imaging. An image segmentation algorithm on account of two-dimensional (2D)-three-dimensional (3D) convolution neural network (CNN) was proposed. It also introduced full convolutional network (FCN) and UNet network algorithm. The diagnostic performance of CT, serum carbohydrate antigen-50 (CA-50), serum carbohydrate antigen-199 (CA-199), serum carbohydrate antigen-242 (CA-242), combined detection of tumor markers, and CT-combined tumor marker testing (CT-STUM) for pancreatic cancer were compared and analyzed. The results showed that the average Dice coefficient of 2D-3D training was 84.27%, which was higher than that of 2D and 3D CNNs. During the test, the maximum and average Dice coefficient of the 2D-3D CNN algorithm was 90.75% and 84.32%, respectively, which were higher than the other two algorithms, and the differences were statistically significant (P < 0.05). The penetration ratio of pancreatic duct in the experimental group was lower than that in the control group, the rest were higher than that in the control group, and the differences were statistically significant (P < 0.05). CA-50, CA-199, and CA-242 in the experimental group were 141.72 U/mL, 1548.24 U/mL, and 83.65 U/mL, respectively, which were higher than those in the control group, and the differences were statistically significant (P < 0.05). The sensitivity, specificity, positive predictive value, and authenticity of combined detection of serum tumor markers were higher than those of CA-50, CA-199, and CA-242, and the differences were statistically significant (P < 0.05). The results showed that the proposed algorithm 2D-3D CNN had good stability and image segmentation performance. CT-STUM had high sensitivity and specificity in diagnoses of pancreatic cancer.
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Algoritmos , Biomarcadores de Tumor/sangre , Tomografía Computarizada Multidetector/estadística & datos numéricos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/diagnóstico por imagen , Adulto , Anciano , Antígenos de Carbohidratos Asociados a Tumores/sangre , Inteligencia Artificial , Estudios de Casos y Controles , Biología Computacional , Femenino , Humanos , Imagenología Tridimensional/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico por imagen , Sensibilidad y EspecificidadRESUMEN
BACKGROUND AND OBJECTIVE: Living organisms respond to physical, chemical, and biological threats with a potent inflammatory response which alters organ cell signaling and leads to dysfunction. We evaluated the therapeutic effect of bone marrow-based mesenchymal stromal cell (BM-MSC) transplanted in rats to preserve tissue integrity and to restore homeostasis and function in the pancreatitis experimental pattern. METHODS: This study involved 40 adult male Wister rats. Repeated L-arginine injections caused chronic pancreatitis (CP), leading to the development of pancreatic damage and shifting the intracellular signaling pathways. Rats were then infused with BM-MSC labeled with PKH26 fluorescent linker dye for 12 weeks. RESULTS: Cell-surface indicators of BM-MSCs such as CD 90 and CD29 were expressed with the lack of CD34 expression. BM-MSC treatment considerably improved the alterations induced in a series of inflammatory markers, including IL-18, TNF-α, CRP, PGE2, and MCP-1. Furthermore, improvement was found in digestive enzymes and lipid profile with amelioration in myeloperoxidase activity. BM-MSC treatment also regulated the (TGF-/p-38MPAK/SMAD2/3) signaling factors that enhances repair of damaged pancreatic tissue, confirmed by reversed alteration of histopathological examination. CONCLUSION: our results further bring to light the promise of cell transplant therapy for chronic pancreatitis.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Pancreatitis Crónica/terapia , Amilasas/metabolismo , Animales , Arginina , Proteína C-Reactiva/análisis , Citocinas , Dinoprostona/sangre , Lipasa/metabolismo , Metabolismo de los Lípidos , Masculino , Páncreas/enzimología , Páncreas/patología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/inducido químicamente , Pancreatitis Crónica/metabolismo , Ratas Wistar , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20-100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004-2015 during a median 9 years of follow-up (range 0-15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48-67) and the median plasma pancreatic amylase 32 U/L (26-40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st-60th percentiles, those with extreme low (1st-2.5th percentiles) and extreme high (97.5th-100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6-3.6) and 2.2 (1.4-3.7) for pancreatic cancer, of 1.8 (1.1-3.3) and 3.2 (1.8-5.6) for chronic pancreatitis, and of 1.1 (0.6-1.8) and 1.5 (0.8-2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2-threefold higher risk of both pancreatic cancer and chronic pancreatitis.
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Amilasas/sangre , alfa-Amilasas Pancreáticas/sangre , Pancreatitis/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/patología , Pancreatitis/diagnóstico , Pancreatitis/etiología , Pancreatitis/patología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/etiología , Pancreatitis Crónica/patología , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
Plasma-derived extracellular vesicles (EV) can serve as markers of cell damage/disease but can also have therapeutic utility depending on the nature of their cargo, such as miRNA. Currently, there are challenges and lack of innovations regarding early diagnosis and therapeutic options within different aspects of management of patients suffering from chronic pancreatitis (CP). Use of EV as biomarkers for pancreatic health and/or as adjuvant therapy would make a difference in management of these patients. The aim of this study was to characterize the miRNA cargo of EV purified from the plasma of CP patients and compared to those of healthy participants. EVs were isolated from plasma of 15 CP patients and 10 healthy controls. Nanoparticle tracking analysis was used to determine frequency and size, while NanoString technology was used to characterize the miRNA cargo. Relevant clinical parameters were correlated with EV miRNA cargo. ~ 30 miRNA species were identified to have significantly (p < 0.05) different expression in EV from individuals with CP compared to healthy individuals; ~ 40 miRNA were differentially expressed in EV from pre-diabetic versus non-diabetic CP patients. miR-579-3p, while exhibiting significantly lower (~ 16-fold) expression in CP compared to healthy and lower (~ 24-fold) in CP narcotic users compared to the non-users, is actually enriched (~ 32-fold) within EV in pre-diabetic CP patients compared to non-diabetic CP patients. A unique pattern was identified in female CP patients. These data support the prospect of using a plasma-derived EV cargo to assess pancreatic health and its therapeutic potential in CP patients.
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Vesículas Extracelulares/genética , MicroARNs/genética , Pancreatitis Crónica/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , MicroARNs/sangre , Pancreatitis Crónica/sangre , Pancreatitis Crónica/patologíaRESUMEN
BACKGROUNDS: Due to difficulty in early diagnosis of chronic pancreatitis (CP), it is urgent to find novel biomarkers to detect CP. Exosomal microRNAs (Exo-miRNAs) located in the serum may be potential diagnostic and therapeutic targets for CP. OBJECTIVE: To identify differentially expressed Exo-miRNAs (DE-Exo-miRNAs) in the serum of CP patients, we performed a bioinformatics analysis. METHODS: The dataset GSE128508 was downloaded from the Gene Expression Omnibus (GEO) database. The analysis was carried out using BRB-ArrayTools and significance analysis of microarrays (SAM). The target genes of DE-S-Exo-miRNAs were predicted by miRWalk databases. Further gene ontology (GO) term and Kyoto Encyclopedia of Genomes (KEGG) pathway analyses were performed with plug-in ClueGO in Cytoscape software 3.7.0. Subsequently, the interaction regulatory network between encoded proteins of target genes was performed with the Search Tool for the Retrieval of Interacting Genes (STRING) database and analyzed using plug-in Molecular Complex Detection (MCODE) and cytoHubba in Cytoscape software 3.7.0. RESULTS: We identified 227 DE-Exo-miRNAs in the serum. Further analysis using the miRWalk database identified 5164 target genes of these miRNAs. The protein-protein interaction (PPI) regulatory network of 1912 potential target genes for hub 10 up-regulated miRNAs with high degrees and one down-regulated miRNAs were constructed using the STRING database and Cytoscape software. The functional analysis using Cytoscape software tool highlighted that target genes involved in pancreatic cancer. Acinar-ductal metaplasia (ADM) in the inflammatory environment of CP is a precursor of pancreatic cancer. Subsequently, we constructed a network of target genes associated with ADM and their miRNAs. CONCLUSIONS: Exo-miRNAs in the serum as well as their target genes may be promising targets for the early diagnosis and treatment of CP. In addition, we identified potential Exo-miRNAs involved in ADM that is a precursor of pancreatic cancer associated with CP.
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MicroARNs/sangre , Páncreas/patología , Neoplasias Pancreáticas/genética , Pancreatitis Crónica/patología , Lesiones Precancerosas/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biología Computacional , Conjuntos de Datos como Asunto , Exosomas/metabolismo , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Metaplasia , MicroARNs/metabolismo , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/inmunología , Lesiones Precancerosas/sangre , Lesiones Precancerosas/genética , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas/genéticaRESUMEN
Pancreatic cancer (PC) has been the fourth cancer-related death worldwide, diagnosed at an unresectable stage due to its rapid progression and few symptoms of this disease at early stages. The aim of this study was to determine the association between the diversity of T-cell receptor (TCR) repertoire and clinicopathological characteristics of patients with PC and other benign pancreatic diseases. In order to make a comprehensive analysis the TCR repertoire, high-throughput sequencing was used to differentiate complementarity determining region 3 (CDR3) of the TCR ß chain in peripheral blood samples from 3 PC, 3 chronic pancreatitis, 3 pancreatic cystic lesions and 3 pancreatic neuroendocrine tumour patients. We found that there were significant differences related to TCR repertoire between PC and other pancreatic diseases, and PC is a relatively immunosuppressive tumour. Changes of peripheral TCR repertoire may be used to predict the progression of PC and the response to immunotherapy. And there may exist novel-specific antigens in PC patients which could be used to design targeting immunotherapy in the nearly future.
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Biomarcadores/metabolismo , Carcinoma Neuroendocrino/patología , Regulación de la Expresión Génica , Quiste Pancreático/patología , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/patología , Receptores de Antígenos de Linfocitos T/metabolismo , Adulto , Anciano , Carcinoma Neuroendocrino/sangre , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quiste Pancreático/sangre , Quiste Pancreático/genética , Quiste Pancreático/metabolismo , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pancreatitis Crónica/sangre , Pancreatitis Crónica/genética , Pancreatitis Crónica/metabolismo , Pronóstico , Receptores de Antígenos de Linfocitos T/genética , Estudios RetrospectivosRESUMEN
Early-stage diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to non-specific symptoms. Circulating miRNAs in body fluids have been emerging as potential non-invasive biomarkers for diagnosis of many cancers. Thus, this study aimed to assess a panel of miRNAs for their ability to differentiate PDAC from chronic pancreatitis (CP), a benign inflammatory condition of the pancreas. Next-generation sequencing was performed to identify miRNAs present in 60 FFPE tissue samples (27 PDAC, 23 CP and 10 normal pancreatic tissues). Four up-regulated miRNAs (miR-215-5p, miR-122-5p, miR-192-5p, and miR-181a-2-3p) and four down-regulated miRNAs (miR-30b-5p, miR-216b-5p, miR-320b, and miR-214-5p) in PDAC compared to CP were selected based on next-generation sequencing results. The levels of these 8 differentially expressed miRNAs were measured by qRT-PCR in 125 serum samples (50 PDAC, 50 CP, and 25 healthy controls (HC)). The results showed significant upregulation of miR-215-5p, miR-122-5p, and miR-192-5p in PDAC serum samples. In contrast, levels of miR-30b-5p and miR-320b were significantly lower in PDAC as compared to CP and HC. ROC analysis showed that these 5 miRNAs can distinguish PDAC from both CP and HC. Hence, this panel can serve as a non-invasive biomarker for the early detection of PDAC.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/diagnóstico , MicroARN Circulante/sangre , Neoplasias Pancreáticas/diagnóstico , Pancreatitis Crónica/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/genética , Estudios de Casos y Controles , MicroARN Circulante/metabolismo , Diagnóstico Diferencial , Regulación hacia Abajo , Estudios de Factibilidad , Femenino , Regulación Neoplásica de la Expresión Génica , Voluntarios Sanos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Biopsia Líquida/métodos , Masculino , Persona de Mediana Edad , Páncreas/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/genética , Pancreatitis Crónica/patología , Curva ROC , Regulación hacia Arriba , Adulto JovenRESUMEN
OBJECTIVE: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. DESIGN: We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. RESULTS: A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). CONCLUSIONS: This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.
Asunto(s)
Metabolómica , Pancreatitis Crónica/sangre , Plasma , Teorema de Bayes , Biomarcadores/sangre , Estudios de Casos y Controles , Cromatografía de Gases , Cromatografía Liquida , Femenino , Humanos , Masculino , Espectrometría de Masas , Valor Predictivo de las Pruebas , Pronóstico , Prueba de Estudio ConceptualRESUMEN
BACKGROUND: Chronic pancreatitis (CP) does not have diagnostic or prognostic biomarkers. CP is the end stage of a progressive inflammatory syndrome that is diagnosed at late stages by morphologic features. To diagnose earlier stages of the disease, a new mechanistic definition was established based on identifying underlying pathogenic processes and biomarker evidence of disease activity and stage. Although multiple risk factors are known, the corresponding biomarkers needed to make a highly accurate diagnosis of earlier disease stages have not been established. The goal of this study is to systematically analyze the literature to identify the most likely candidates for development into biomarkers of CP. METHODS: We conducted a systematic review of candidate analytes from easily accessible biological fluids and identified 67 studies that compared CP to nonpancreatic-disease controls. We then ranked candidate biomarkers for sensitivity and specificity by area under the receiver operator curves (AUROCs). RESULTS: Five biomarkers had a large effect size (an AUROC > 0.96), whereas 30 biomarkers had a moderate effect size (an AUROC between 0.96 and 0.83) for distinguishing CP cases from controls or other diseases. However, the studies reviewed had marked variability in design, enrollment criteria, and biospecimen sample handling and collection. CONCLUSIONS: Several biomarkers have the potential for evaluation in prospective cohort studies and should be correlated with risk factors, clinical features, imaging studies and outcomes. The Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreas Cancer provides recommendations for avoiding design biases and heterogeneity in sample collection and handling in future studies.
Asunto(s)
Pancreatitis Crónica/sangre , Pancreatitis Crónica/metabolismo , Biomarcadores/sangre , Humanos , Pancreatitis Crónica/diagnóstico , Pancreatitis Crónica/patologíaRESUMEN
BACKGROUND & AIMS: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. METHODS: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. RESULTS: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. CONCLUSION: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.
Asunto(s)
Antígeno CA-19-9/sangre , Detección Precoz del Cáncer/métodos , Tamizaje Masivo/métodos , Neoplasias Pancreáticas/diagnóstico , Anciano , Diagnóstico Diferencial , Estudios de Factibilidad , Femenino , Voluntarios Sanos , Humanos , Biopsia Líquida/métodos , Masculino , Persona de Mediana Edad , Quiste Pancreático/sangre , Quiste Pancreático/diagnóstico , Neoplasias Pancreáticas/sangre , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico , Sensibilidad y Especificidad , Estados UnidosRESUMEN
BACKGROUND: Interleukin profiles can be used as biochemical markers regarding the early diagnosis of pancreatic cancer. AIMS: To assess CRP, CA 19-9, CEA levels, and interleukin-6, -10, and -17 profiles in pancreatic ductal adenocarcinoma, chronic pancreatitis was compared with a control group, and the correlation with pancreatic cancer survival. METHODS: A total of 87 patients were prospective divided in pancreatic cancer (n = 53), chronic pancreatitis (n = 22) ,and control group (n = 12). The diagnosis of PDAC was made histologically. The diagnosis of chronic pancreatitis was based on medical history, imaging methods, and endoscopic ultrasound. Systemic concentrations of interleukins were measured using ELISA kits. The patients were followed at 1, 3, and 6 months. RESULTS: CRP, CA 19-9, and CEA were higher in the pancreatic cancer group (p < 0.001). Interleukin-10 was significantly higher in the pancreatic cancer and chronic pancreatitis groups (p < 0.001). Interleukin-17 was statistically higher in the pancreatic cancer group (p < 0.0001). The cut-off of interleukin-17 of 0.273 had a sensitivity of 90.9 and a specificity of 80.9 with a curve under ROC of 0.80 in order to differentiate between pancreatic cancer and chronic pancreatitis. The serum levels of interleukins are not correlated with the stage of the disease. CRP, CA 19-9, CEA, and interleukin-6, -10, and -17 were lower in patients with survival more than 6 months. CONCLUSIONS: We detected high levels of interleukin-6, -10, and -17 in chronic pancreatitis and pancreatic cancer. Serum interleukin-17 levels can discriminate between pancreatic cancer and chronic pancreatitis. The prognostic role of interleukins needs to be established.
Asunto(s)
Adenocarcinoma/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatitis Crónica/metabolismo , Adenocarcinoma/sangre , Adenocarcinoma/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Antígeno CA-19-9/genética , Antígeno CA-19-9/metabolismo , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/metabolismo , Interleucina-10/genética , Interleucina-17/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/diagnóstico , Pancreatitis Crónica/sangre , Pancreatitis Crónica/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Children undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis require intensive insulin therapy early after TPIAT with narrow glycemic targets, which can a present significant care burden. Outpatient use of continuous glucose monitoring (CGM) systems by children and caregivers early after TPIAT is inadequately studied. METHODS: In this open-label study, we randomized 14 children and adolescents (mean age 15.4 years) after hospital discharge for TPIAT to Dexcom G6 CGM (n = 7) or standard care with a glucometer (n = 7) to assess acceptability and glycemic control with use of CGM versus usual care (glucometer). Participants in the control arm also wore a blinded CGM for 1 week. RESULT: Children randomized to real-time CGM had lower mean sensor glucose values compared with controls (p = 0.002), and high overall satisfaction with CGM. CONCLUSIONS: Our data indicate that CGM is a useful adjunct to diabetes management for children who have recently undergone TPIAT.