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BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.
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Neoplasias Pancreáticas , Masculino , Humanos , Feminino , Estados Unidos/epidemiologia , Idoso , Incidência , Sistema de Registros , Neoplasias Pancreáticas/epidemiologia , Pâncreas , Neoplasias PancreáticasRESUMO
BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.
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Diabetes Mellitus , Pancreatite Crônica , Humanos , Doença Aguda , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/epidemiologia , Progressão da Doença , Dor Abdominal , BiomarcadoresRESUMO
PURPOSE: Risk factors for pancreatic cancer include racial/ethnic disparities and smoking. However, risk trajectories by smoking history and race/ethnicity are unknown. We examined the association of smoking with pancreatic cancer by race/ethnicity to generate age-specific incidence estimates by smoking history. METHODS: We modeled pancreatic cancer incidence by race/ethnicity, age, pack-years, and years-quit using an excess relative risk model for 182,011 Multiethnic Cohort participants. We tested heterogeneity of smoking variables and pancreatic cancer by race/ethnicity and predicted incidence by smoking history. RESULTS: We identified 1,831 incident pancreatic cancer cases over an average 19.3 years of follow-up. Associations of pack-years (p interaction by race/ethnicity = 0.41) and years-quit (p interaction = 0.83) with pancreatic cancer did not differ by race/ethnicity. Fifty pack-years smoked was associated with 91% increased risk (95% CI 54%, 127%) relative to never smokers in the combined sample. Every year quit corresponded to 9% decreased excess risk (95% CI 2%, 15%) from pack-years smoked. Differences in baseline pancreatic cancer risk across racial/ethnic groups (p < 0.001) translated to large differences in risk for smokers at older ages across racial/ethnic groups (65-122 cases per 100,000 at age 70). CONCLUSION: Smoking pack-years were positively associated with elevated pancreatic cancer risk. Predicted risk trajectories showed a high impact of smoking cessation at < 65 years. Although we did not identify significant heterogeneity in the association of pack-years or years quit with pancreatic cancer risk, current smoker risk varied greatly by race/ethnicity in later life due to large differences in baseline risk.
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Neoplasias Pancreáticas , Abandono do Hábito de Fumar , Humanos , Idoso , Estudos de Coortes , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Risco , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/etiologiaRESUMO
OBJECTIVE: To investigate worldwide incidence, deaths, disability-adjusted life years (DALYs) and risk factors for young-onset pancreatic cancer (YOPC) using the Global Burden of Disease Study 2019-20 data. METHODS: We queried the Global Health Data Exchange tool for "pancreatic cancer" and "incidence", "deaths" as the "measure", and "DALYs" as the "cause" for the age group of 15-49 years to determine global, regional, and national trends in the incidence, deaths, and DALYs of YOPC. Sociodemographic index (SDI) was used to evaluate the associations between socioeconomic development and YOPC. Risk factors including smoking, tobacco use, hi2gh body mass index (BMI), and high fasting plasma glucose (FPG) were evaluated, and their attributable burden was estimated. RESULTS: Global incidence, death, and DALY rates of YOPC significantly increased from 1990 to 2019 ((0.30 (p = 0.001), 0.25 (p = 0.001), and 11.18 (p = 0.002), respectively). Regions with the highest and lowest incidence, death, and DALY rates of YOPC were Eastern Europe and Central Sub-Saharan Africa, respectively. Incidence, death, and DALY rates increased with increasing age and SDI. Leading risk factors for YOPC in 2019 were smoking and tobacco use. DALYs attributable to smoking and tobacco use decreased from 1990 to 2019, especially in females, while those attributable to high BMI and FPG increased during the same period. CONCLUSIONS: The global incidence, death and DALY rates of YOPC have significantly increased over 3 decades. Certain regions and nations are witnessing a higher increase in this trend. There is an urgent need for global efforts targeting preventable causes of YOPC.
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Carga Global da Doença , Neoplasias Pancreáticas , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/etiologia , Saúde GlobalRESUMO
OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.
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Citocinas , Pancreatite Crônica , Humanos , Projetos Piloto , Doença Aguda , Estudos Transversais , Quimiocinas , Interleucina-6RESUMO
BACKGROUND AND AIMS: Although pancreatic endotherapy (PET) is commonly used for treating adverse events of chronic pancreatitis, data on the frequency and factors associated with the use of PET are limited. Our aim was to define the use of and factors predictive for receiving PET in a well-characterized chronic pancreatitis cohort. METHODS: This is a cross-sectional analysis of data from PROCEED, a multicenter U.S. cohort study of chronic pancreatitis. PET modalities primarily consisted of ERCP. A treatment course was defined as the number of sessions performed for a specific indication. A repeat course was defined as PET >1 year after completion of the last course. Multivariable logistic regression identified predictive factors for receiving PET, and proportional rates model assessed risk factors for repeat PET. RESULTS: Of 681 subjects, 238 (34.9%) received PET. Factors associated with receiving PET included female sex (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.03-1.53), lower education (OR, 1.30; 95% CI, 1.04-1.62), income ≤$50,000 per year (OR, 1.35; 95% CI, 1.07-1.71), and prior acute pancreatitis (OR, 1.74; 95% CI, 1.31-2.32). Of 238 subjects, 103 (43.3%) underwent repeat PET at a median duration of 2 years, with 23.1% receiving 2 courses, 9.7% receiving 3 courses, and 10.4% receiving ≥4 courses. CONCLUSIONS: Nearly half of patients with chronic pancreatitis who undergo PET received 1 or more repeat courses within 2 to 3 years. In addition to a prior history of acute pancreatitis, demographic and socioeconomic factors were associated with receiving PET.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatite Crônica , Humanos , Pancreatite Crônica/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Estados Unidos , Estudos Transversais , Adulto , Fatores Sexuais , Estudos de Coortes , Idoso , Modelos Logísticos , Escolaridade , Renda , Fatores de Risco , Retratamento/estatística & dados numéricos , Análise MultivariadaRESUMO
Prostate cancer (PC), particularly its metastatic castration-resistant form (mCRPC), is a leading cause of cancer-related deaths among men in the Western world. Traditional systemic treatments, including hormonal therapy and chemotherapy, offer limited effectiveness due to tumors' inherent resistance to these therapies. Moreover, they often come with significant side effects. We have developed a delivery method using a tumor-cell-specific heptamethine carbocyanine dye (DZ) designed to transport therapeutic agents directly to tumor cells. This research evaluated simvastatin (SIM) as the antitumor payload because of its demonstrated chemopreventive effects on human cancers and its well-documented safety profile. We designed and synthesized a DZ-SIM conjugate for tumor cell targeting. PC cell lines and xenograft tumor models were used to assess tumor-cell targeting specificity and killing activity and to investigate the corresponding mechanisms. DZ-SIM treatment effectively killed PC cells regardless of their androgen receptor status or inherent therapeutic resistance. The conjugate targeted and suppressed xenograft tumor formation without harming normal cells of the host. In cancer cells, DZ-SIM was enriched in subcellular organelles, including mitochondria, where the conjugate formed adducts with multiple proteins and caused the loss of transmembrane potential, promoting cell death. The DZ-SIM specifically targets PC cells and their mitochondria, resulting in a loss of mitochondrial function and cell death. With a unique subcellular targeting strategy, the conjugate holds the potential to outperform existing chemotherapeutic drugs. It presents a novel strategy to circumvent therapeutic resistance, offering a more potent treatment for mCRPC.
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Neoplasias de Próstata Resistentes à Castração , Sinvastatina , Masculino , Humanos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Próstata/metabolismo , Carbocianinas , Linhagem Celular TumoralRESUMO
BACKGROUND AND AIMS: Pain is a cardinal symptom of chronic pancreatitis (CP). Using Patient-Reported Outcomes Measurement Information System (PROMIS) measures, we characterized physical and mental health and symptom profiles of a well-defined cohort of individuals with CP and compared them with control subjects. Among patients with CP, we also examined associations between pain (intensity, temporal nature) and PROMIS symptom profiles and the prevalence of clinically significant psychological comorbidities. METHODS: We analyzed baseline data in 488 CP patients and 254 control subjects enrolled in PROCEED (Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies), an ongoing longitudinal cohort study. Participants completed the PROMIS-Global Health, which captures global physical and mental health, and the PROMIS-29 profile, which captures 7 symptom domains. Self-reported pain was categorized by severity (none, mild-moderate, severe) and temporal nature (none, intermittent, constant). Demographic and clinical data were obtained from the PROCEED database. RESULTS: Pain was significantly associated with impairments in physical and mental health. Compared with participants with no pain, CP participants with severe pain (but not mild-moderate pain) had more decrements in each PROMIS domain in multivariable models (effect sizes, 2.54-7.03) and had a higher prevalence of clinically significant depression, anxiety, sleep disturbance, and physical disability (odds ratios, 2.11-4.74). Similar results were noted for constant pain (but not intermittent pain) for PROMIS domains (effect sizes, 4.08-10.37) and clinically significant depression, anxiety, sleep disturbance and physical disability (odds ratios, 2.80-5.38). CONCLUSIONS: Severe and constant pain are major drivers for poor psychological and physical health in CP. Systematic evaluation and management of psychiatric comorbidities and sleep disturbance should be incorporated into routine management of patients with CP. (ClinicalTrials.gov, Number: NCT03099850).
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Dor Crônica , Pancreatite Crônica , Humanos , Estudos Longitudinais , Dor Crônica/epidemiologia , Pancreatite Crônica/complicações , Pancreatite Crônica/epidemiologia , Saúde Mental , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
BACKGROUND & AIMS: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. METHODS: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. RESULTS: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. CONCLUSIONS: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Neoplasias Pancreáticas/patologia , Adenocarcinoma/patologia , Hialuronoglucosaminidase/farmacologia , Hialuronoglucosaminidase/uso terapêutico , Ácido Hialurônico , Carcinoma Ductal Pancreático/genética , Neoplasias Hepáticas/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal , Citocinas/farmacologia , Morte Celular , Polietilenoglicóis/uso terapêutico , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.
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Pâncreas Exócrino , Pancreatite Crônica , Células Acinares/patologia , Animais , Estrogênios/metabolismo , Humanos , Camundongos , Camundongos Knockout , Pâncreas/patologia , Pâncreas Exócrino/metabolismo , Pancreatite Crônica/patologiaRESUMO
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect. METHODS: We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity. RESULTS: DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells' subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death. CONCLUSIONS: Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Animais , Camundongos , Carcinoma de Células Renais/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias Renais/patologia , Apoptose , Morte Celular , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
BACKGROUND/OBJECTIVE: Alcohol consumption is increasing in women, who more frequently report abdominal symptoms compared to men. We aimed to examine differences in presentation of acute pancreatitis [AP] in male and female patients hospitalized with alcohol-associated AP. METHODS: We analyzed 138 patients enrolled in an ongoing case-crossover study of alcohol-associated AP conducted across 5 medical centers in the U.S. Patients meeting the Revised Atlanta Classification of AP and who scored 3 or higher on the AUDIT-C instrument were invited to participate in the study and were interviewed while hospitalized with AP. Sex differences in the timing and type of pancreas-associated pain, alcohol consumption, clinical presentation, and quality of life were examined by Chi-squared tests, Wilcoxon rank sum tests and t-tests. RESULTS: Female patients reported significantly longer interval from onset of pain to deciding to seek medical attention (median 40 h, interquartile range [IQR] 14, 74) as compared to males (14 h, IQR 4, 50; p = 0.005). While male patients were more likely to have been admitted to the intensive care unit [ICU] (21%) as compared to female patients (7%; p = 0.04), the incidence of SIRS or severe AP did not differ by sex. Quality of life measures as reported through the PROMIS-29 instrument were equally suboptimal in both sexes. Anxiety disorders were diagnosed more frequently among females (61%) than in males (41%, p = 0.009). CONCLUSION: In a large case series of alcohol-associated AP, we found that female patients delayed seeking medical care compared to males. However, there were no differences in the type, location and intensity of abdominal pain.
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Pancreatite , Humanos , Feminino , Masculino , Pancreatite/epidemiologia , Pancreatite/etiologia , Pancreatite/terapia , Doença Aguda , Qualidade de Vida , Estudos Cross-Over , Dor Abdominal/etiologia , Dor Abdominal/terapia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP. DESIGN: We performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort. RESULTS: Deep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay. CONCLUSION: Single-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.
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Pancreatite Crônica , Receptores CCR6 , Imunidade Adaptativa , Linfócitos T CD8-Positivos , Quimiocina CCL20/metabolismo , Citometria de Fluxo , Humanos , Pancreatite Crônica/genética , Receptores CCR6/genética , Receptores CCR6/metabolismoRESUMO
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are intestinal complications characterized by chronic inflammation, autophagy abnormality, and lysosomal stress, which are derived from genetic predisposition and environmental risk factors. It is generally precepted that dietary green vegetable is beneficial for physiological homeostasis. In this study, we found that dextran sulfate sodium (DSS)-induced colitis and altered intestinal epithelia in mice were attenuated by oral administration of chlorophyllin (CHL), a water-soluble derivate of chlorophyll. In DSS-treated mice, autophagy was persistently activated in intestinal tissues and associated with bowel disorders. Conversely, supplement of CHL in diet or gavage suppressed intestinal inflammation, downregulated autophagy flux in intestinal tissue, and relieved endoplasmic reticulum stress. In vitro studies show that CHL could activate Akt and mTOR pathways, leading to downregulation of autophagic and lysosomal flux. Thus, consumption of green vegetables and chlorophyllin may be beneficial for IBD recovery in part through alleviation of inflammation and autolysosomal flux.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal disease, while the etiology remains poorly understood. Dietary composition and lifestyle are crucial for pathogenesis and progression of IBD. In this study, we observed that autophagy in the intestinal tissue was persistently activated in IBD mice. Chlorophyllin (CHL), a water-soluble derivate of chlorophyll, can attenuate colitis by regulating autophagy and inflammation. Thus, consumption of green vegetables and chlorophyllin may be beneficial for IBD recovery.
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Clorofilídeos , Colite , Doenças Inflamatórias Intestinais , Animais , Autofagia , Clorofilídeos/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana , Inflamação , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Endogâmicos C57BL , ÁguaRESUMO
BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS: We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS: Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-ß, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.
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Imunidade Inata , Macrófagos/imunologia , Monócitos/imunologia , Pâncreas/imunologia , Pancreatite/imunologia , Animais , Biomarcadores/sangue , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Monócitos/metabolismo , Pâncreas/metabolismo , Pancreatite/sangue , Pancreatite/diagnóstico , Fenótipo , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Pathophysiology of transformation of inflammatory lesions in chronic pancreatitis (CP) to pancreatic ductal adenocarcinoma (PDAC) is not clear. METHODS: We conducted a systematic review, meta-analysis of circulating metabolites, integrated this data with transcriptome analysis of human pancreatic tissues and validated using immunohistochemistry. Our aim was to establish biomarker signatures for early malignant transformation in patients with underlying CP and identify therapeutic targets. RESULTS: Analysis of 19 studies revealed AUC of 0.86 (95% CI 0.81-0.91, P < 0.0001) for all the altered metabolites (n = 88). Among them, lipids showed higher differentiating efficacy between PDAC and CP; P-value (< 0.0001). Pathway enrichment analysis identified sphingomyelin metabolism (impact value-0.29, FDR of 0.45) and TCA cycle (impact value-0.18, FDR of 0.06) to be prominent pathways in differentiating PDAC from CP. Mapping circulating metabolites to corresponding genes revealed 517 altered genes. Integration of these genes with transcriptome data of CP and PDAC with a background of CP (PDAC-CP) identified three upregulated genes; PIGC, PPIB, PKM and three downregulated genes; AZGP1, EGLN1, GNMT. Comparison of CP to PDAC-CP and PDAC-CP to PDAC identified upregulation of SPHK1, a known oncogene. CONCLUSIONS: Our analysis suggests plausible role for SPHK1 in development of pancreatic adenocarcinoma in long standing CP patients. SPHK1 could be further explored as diagnostic and potential therapeutic target.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite Crônica , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/genética , Transcriptoma , Neoplasias PancreáticasRESUMO
Acute pancreatitis is characterized by necrosis of its parenchymal cells and influx and activation of inflammatory cells that further promote injury and necrosis. This review is intended to discuss the central role of disorders of calcium metabolism and mitochondrial dysfunction in the mechanism of pancreatitis development. The disorders are placed in context of calcium and mitochondria in physiologic function of the pancreas. Moreover, we discuss potential therapeutics for preventing pathologic calcium signals that injure mitochondria and interventions that promote the removal of injured mitochondria and regenerate new and heathy populations of mitochondria.
Assuntos
Pancreatite , Humanos , Pancreatite/patologia , Cálcio/metabolismo , Doença Aguda , Autofagia , Mitocôndrias/metabolismo , Necrose/patologiaRESUMO
BACKGROUND: To evaluate if altered brain metabolites are connected to pain, depression and affective responses in CP. METHODS: In this prospective study we evaluated pain characteristics, QOL (EORTC QLQc30+PAN28), depression (Beck depression inventory [BDI] II) in 558 patients with CP and 67 healthy controls. Brain metabolites were evaluated using magnetic resonance spectroscopy (MRS) in 49 patients and 5 healthy controls. We measured plasma metabolites using gas chromatography-mass spectrometry (GC-MS/MS). Relationship between metabolomic alterations, pain, depression and QOL components were assessed using statistical/bioinformatics methods. Benjamini-Hochberg FDR correction was applied for multiple testing. RESULTS: 261 (46.8%) patients had depression compared to 5 (7.5%) among healthy controls [n = 67](p < 0.0001). Risk [OR (95% CI) of developing depression in the presence of pain was 1.9 (1.33-1.68); p = 0.0004. The depression scores correlated negatively with functional components and positively with symptom components of EORTC QLQ30. Significant negative correlation, though based on a small sample size, was observed between N-acetyl aspartate in the left hippocampus and choline in the left prefrontal cortex with emotional and cognitive functions. PLS-DA modelling revealed significant alteration in the plasma metabolomic profile among patients with CP who had depression. Six metabolites were significantly different between CP with depression and healthy controls, of which glycine contributed most significantly to the PLS-DA model (VIP score of 3.5). CONCLUSIONS: A significant proportion of patients with CP develops depression that correlate with poor QOL functions. Pain, depression, and emotional components of QOL in patients with CP correlated with N-acetyl aspartate and choline in the left hippocampus and left prefrontal cortex of the brain.
Assuntos
Pancreatite Crônica , Qualidade de Vida , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Colina/metabolismo , Depressão , Humanos , Dor , Pancreatite Crônica/complicações , Pancreatite Crônica/metabolismo , Estudos Prospectivos , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: Early prediction of persistent organ failure (POF) is crucial for patients with acute pancreatitis (AP). Growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1), is associated with inflammatory responses. We investigated changes in plasma GDF15 and assessed its predictive value in AP. METHODS: The study included 290 consecutive patients with AP admitted within 36 h after symptoms onset. Clinical data obtained during hospitalization were collected. Plasma GDF15 levels were determined using enzyme-linked immunosorbent assays. The predictive value of GDF15 for POF was analyzed. RESULTS: There were 105 mild, 111 moderately severe, and 74 severe AP patients. Plasma GDF15 peak level were measured on admission, and significantly declined on the 3rd and 7th day. Admission GDF15 predicted POF and mortality with areas under the curve (AUC) of 0.847 (95% confidence interval [CI] 0.798-0.895) and 0.934 (95% CI 0.887-0.980), respectively. Admission GDF15, Bedside Index of Severity in Acute Pancreatitis, and hematocrit were independent factors for POF by univariate and multivariate logistic regression, and the nomogram built on these variables showed good performance (optimism-corrected c-statistic = 0.921). The combined predictive model increased the POF accuracy with an AUC 0.925 (95% CI 0.894-0.956), a net reclassification improvement of 0.3024 (95% CI: 0.1482-0.4565, P < 0.001), and an integrated discrimination index of 0.11 (95% CI 0.0497-0.1703; P < 0.001). CONCLUSIONS: Plasma GDF15 measured within 48 h of symptom onset could help predict POF and mortality in AP patients.
Assuntos
Fator 15 de Diferenciação de Crescimento , Insuficiência de Múltiplos Órgãos , Pancreatite , Doença Aguda , Biomarcadores/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Pancreatite/sangue , Pancreatite/mortalidade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Around 20% of patients with acute pancreatitis (AP) will develop acute recurrent pancreatitis (ARP) and 10% will progress to chronic pancreatitis. While interventions to avoid recurrences exist for the two most common causes - abstinence for alcoholic and cholecystectomy for biliary pancreatitis - the are no known preventive measures in idiopathic ARP. Though it is not included in any of the guidelines, a low-fat diet is often recommended. Our aim is to test dietary fat reduction's effect on AP recurrence in a randomized controlled setting, in order to provide high-quality evidence for the validity of such an intervention. METHODS, DESIGN: Participants with at least 2 episodes of AP in the preceding 2 years of which the last episode was idiopathic will be randomized to one of two diets with different fat contents: a 'reduced fat diet' (15% fat, 65% carbohydrate, 20% protein) and a 'standard healthy diet' (30% fat, 50% carbohydrate, 20% protein; based on WHO recommendations). Participants will be followed-up for 2 years (visits will be scheduled for months 3, 6, 12, 18 and 24) during which they will receive a repeated session of nutritional guidance, complete food frequency questionnaires and data on relapse, mortality, BMI, cardiovascular parameters and serum lipid values will be collected. DISCUSSION: This study will determine the effect of modifying the dietary fat content on AP recurrence, mortality, serum lipids and weight loss in idiopathic cases.