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INTRODUCTION: Chronic Pancreatitis Prognosis Score (COPPS) was developed to discriminate disease severity and predict risk for future hospitalizations. In this cohort study, we evaluated if COPPS predicts the likelihood of hospitalization(s) in an American cohort. METHODS: The CPDPC consortium provided data and serum from subjects with chronic pancreatitis (N=279). COPPS was calculated with baseline data and stratified by severity (low, moderate, high). Primary endpoints included number and duration of hospitalizations during 12-month follow-up. RESULTS: The mean±SD COPPS was 8.4±1.6. COPPS correlated with all primary outcomes: hospitalizations for any reason (number: r=0.15, p=0.01; duration: r=0.16, p=0.01) and pancreas-related hospitalizations (number: r=0.15, p=0.02; duration: r=0.13, p=0.04). The severity distribution was 13.3% low, 66.0% moderate, and 20.8% high. 37.6% of subjects had ≥1 hospitalization(s) for any reason; 32.2% had ≥1 pancreas-related hospitalization(s). All primary outcomes were significantly different between severity groups: hospitalizations for any reason (number, p=0.004; duration, p=0.007) and pancreas-related hospitalizations (number, p=0.02; duration, p=0.04). The prevalence of continued drinking at follow-up (p=0.04) was higher in the low and moderate groups. The prevalence of anxiety at enrollment (p=0.02) and follow-up (p<0.05) was higher in the moderate and high groups. DISCUSSION: Statistically, COPPS significantly correlated with hospitalization outcomes, but the correlations were weaker than in previous studies, which may be related to the outpatient nature of the PROCEED cohort and lower prevalence of high severity disease. Studies in other prospective cohorts are needed to understand the full utility of COPPS as a potential tool for clinical risk assessment and intervention.
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Introduction: The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that Ehmt2 inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Methods: Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from Ehmt2 conditional knockout animals (Ehmt2 fl/fl ) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48 Cre/+ ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the Ehmt2 fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. Results and discussion: The Ehmt2 fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional Ehmt2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
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Background/Objectives: Perinatal exposure to malnutrition has been hypothesised to influence the development of young-onset cancer (≤50 years of age). This study aimed to determine if perinatal malnutrition in individuals exposed to the Great Famine of China increased their risk of developing young-onset cancer compared to other individuals born prior to the famine. Subjects/Methods: This cross-sectional study involved 7272 participants from the China Health and Nutrition Survey who were classified into four groups based on birth year: participants born between 1953 and 1955 (before the famine) were designated as the pre-famine group (unexposed); the remainder formed perinatal exposure groups comprised of those exposed during the famine (1959-1961), those exposed in the early post-famine period (1962-1964), and those exposed in the late post-famine period (1965-1967). Multivariable adjusted log-binomial regression models were used to calculate the RR and 95% CI of young-onset cancer (including genitourinary cancer) across four groups. Results: Perinatal exposure to early post-famine (RR 2.08; 95%CI 1.04, 4.34; p = 0.043) and the female sex (RR 15.6, 95%CI 4.54, 60.3; p < 0.001) were noted to have a significantly increased risk of young-onset cancer. In addition, the early (RR 13.8; 95%CI 2.68, 253; p = 0.012) and late post-famine (RR 12.3; 95%CI 2.16, 231; p = 0.020) cohorts demonstrated a significantly increased risk of young-onset genitourinary cancer. The latter was accompanied by an increased risk of hypertension (RR 3.30; 95%CI 1.28, 7.87; p = 0.009). Conclusions: Perinatal exposure to famine, especially in females, was associated with a higher risk of young-onset cancer. This was particularly evident for young-onset genitourinary cancers. These findings highlight the potential long-term impact of perinatal malnutrition on young-onset carcinogenesis.
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BACKGROUND & AIMS: Reports of a rise in childhood cancer incidence in Australia and globally prompted the investigation of cancer incidence and survival in South Australia (SA) and the Northern Territory (NT) over a 28-year period, with emphasis on Indigenous peoples. METHODS: This cross-sectional analysis of two prospective longitudinal databases, the SA and NT Cancer Registries (1990-2017), included all reported cases of childhood cancers. Poisson regression provided estimates of incidence rate ratios and survival was modelled using Cox proportional hazard models for children aged <5 and ≥5 years. RESULTS: A total of 895 patients across SA (N = 753) and the NT (N = 142) were ascertained. Overall and in the NT, childhood cancer incidence was higher in males compared with females (IRR 1.19 [1.04-1.35] and 1.43 [1.02-2.01], respectively). Lymphocytic leukemia was the most reported cancer type across all locations. With reference to the 1990-1999 era (181.67/100,000), cancer incidence remained unchanged across subsequent eras in the combined cohort (SA and NT) (2000-2009: 190.55/100,000; 1.06 [0.91-1.25]; 2010-2017: 210.00/100,000; 1.15 [0.98-1.35]); similar outcomes were reflected in SA and NT cohorts. Cancer incidence amongst non-Indigenous children significantly decreased from the 1990-1999 era (278.32/100,000) to the 2000-2009 era (162.92/100,000; 0.58 [0.35-0.97]). Amongst 39 Indigenous children in the NT, incidence rates remained unchanged across eras (p > 0.05). With reference to the 1990-1999 era, overall survival improved in subsequent eras in SA (2000-2009: HR 0.53 [0.38-0.73]; 2010-2017: 0.44 [0.28-0.68]); however, remained unchanged in the NT (2000-2009: 0.78 [0.40-1.51]; 2010-2017: 0.50 [0.24-1.05]). In the NT, overall survival of Indigenous patients was significantly lower compared with the non-Indigenous cohort (3.42 [1.92-6.10]). While the survival of Indigenous children with cancer significantly improved in the last two eras (p < 0.05), compared to the 1990-1999 era, no change was noted amongst non-Indigenous children in the NT (p > 0.05). CONCLUSIONS: The incidence of childhood cancers has remained unchanged over 28-years in SA and the NT. Encouragingly, improved survival rates over time were observed in SA and amongst Indigenous children of the NT. Nevertheless, survival rates in Indigenous children remain lower than non-Indigenous children.
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OBJECTIVES: Acute pancreatitis (AP) is a complex disease representing a significant portion of gastrointestinal-related hospitalizations in the U.S. Understanding risk factors of AP might provide attractive therapeutic targets. We evaluated hypophosphatemia a prognostic marker in AP. METHODS: We performed a retrospective review of electronic health records of patients with AP from 01/ 01/2012-12/31/2021 at Cedars-Sinai Medical Center with serum phosphate measured within 48 hours of admission. Multivariable logistic regression modeling was used to evaluate associations with ICU admission and AP severity. Multivariable log-linear modeling was employed to examine associations with length of stay (LOS). RESULTS: Of 1526 patients admitted for AP, 33% (499) had a serum phosphate level measured within 48 hours. Patients with hypophosphatemia were more likely to have ICU admission (adjusted odds ratio (AOR) = 4.57; 95% confidence interval (CI): 2.75-7.62; P < 0.001), have a longer hospital stay (log-LOS = 0.34; SE; 0.09; 95% CI: 0.17-0.52; P < 0.001), and have moderate or severe AP (AOR = 1.80; 95% CI: 1.16-2.80; P < 0.001) compared with those without hypophosphatemia. CONCLUSION: Serum phosphate is infrequently measured in patients with AP and shows promise as an early prognostic marker for outcomes of AP.
Subject(s)
Biomarkers , Hypophosphatemia , Length of Stay , Pancreatitis , Humans , Hypophosphatemia/blood , Hypophosphatemia/diagnosis , Female , Male , Retrospective Studies , Pancreatitis/blood , Pancreatitis/diagnosis , Middle Aged , Prognosis , Length of Stay/statistics & numerical data , Biomarkers/blood , Adult , Aged , Acute Disease , Severity of Illness Index , Phosphates/blood , Risk Factors , Intensive Care Units/statistics & numerical data , Logistic ModelsABSTRACT
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.
Subject(s)
Cholangiopancreatography, Endoscopic Retrograde , Pancreatitis, Chronic , Humans , Pancreatitis, Chronic/therapy , Female , Male , Middle Aged , United States , Cross-Sectional Studies , Adult , Sex Factors , Cohort Studies , Aged , Logistic Models , Educational Status , Income , Risk Factors , Retreatment/statistics & numerical data , Multivariate AnalysisABSTRACT
Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFß, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar-ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial-mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.
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The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that EHMT2 inactivation alters growth and immune gene expression networks, antagonizing KRAS-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of EHMT2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from EHMT2 conditional knockout animals ( EHMT2 fl/fl ) targeted to the exocrine pancreatic epithelial cells ( Pdx1-Cre and P48 Cre/+ ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the EHMT2 fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The EHMT2 fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional EHMT2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific EHMT2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the EHMT2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
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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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Cytokines , Pancreatitis, Chronic , Humans , Pilot Projects , Acute Disease , Cross-Sectional Studies , Chemokines , Interleukin-6ABSTRACT
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. METHODS: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. RESULTS: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. CONCLUSIONS: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.
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Network Meta-Analysis , Non-alcoholic Fatty Liver Disease , Randomized Controlled Trials as Topic , Non-alcoholic Fatty Liver Disease/drug therapy , Humans , Treatment Outcome , Fibroblast Growth Factors , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/therapeutic useABSTRACT
Pancreatic fibrosis (PF) is primarily characterized by aberrant production and degradation modes of extracellular matrix (ECM) components, resulting from the activation of pancreatic stellate cells (PSCs) and the pathological cross-linking of ECM mediated by lysyl oxidase (LOX) family members. The excessively deposited ECM increases matrix stiffness, and the over-accumulated reactive oxygen species (ROS) induces oxidative stress, which further stimulates the continuous activation of PSCs and advancing PF; challenging the strategy toward normalizing ECM homeostasis for the regression of PF. Herein, ROS-responsive and Vitamin A (VA) decorated micelles (named LR-SSVA) to reverse the imbalanced ECM homeostasis for ameliorating PF are designed and synthesized. Specifically, LR-SSVA selectively targets PSCs via VA, thereby effectively delivering siLOXL1 and resveratrol (RES) into the pancreas. The ROS-responsive released RES inhibits the overproduction of ECM by eliminating ROS and inactivating PSCs, meanwhile, the decreased expression of LOXL1 ameliorates the cross-linked collagen for easier degradation by collagenase which jointly normalizes ECM homeostasis and alleviates PF. This research shows that LR-SSVA is a safe and efficient ROS-response and PSC-targeted drug-delivery system for ECM normalization, which will propose an innovative and ideal platform for the reversal of PF.
Subject(s)
Extracellular Matrix , Fibrosis , Nanoparticles , Reactive Oxygen Species , Reactive Oxygen Species/metabolism , Extracellular Matrix/metabolism , Animals , Fibrosis/metabolism , Resveratrol/pharmacology , Humans , Pancreatic Stellate Cells/metabolism , Pancreatic Stellate Cells/drug effects , Pancreas/metabolism , Pancreas/pathology , Pancreatic Diseases/metabolism , Disease Models, Animal , Oxidative Stress/drug effects , Vitamin A/metabolism , Mice , Rats , Drug Delivery Systems/methodsABSTRACT
Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor-bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor-bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer-stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity.
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In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = -0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC (p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC.
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Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management.
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BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is frequently associated with an unfavorable prognosis for affected individuals. Unfortunately, there has been insufficient exploration in search for a reliable prognosis signature and predictive indicators to forecast outcomes for KIRP patients. AIM: The aim of this study is to employ a comprehensive analysis of data for the identification of prognosis genes, leading to the development of a nomogram with strong predictive capabilities. The objective is to provide a valuable statistical tool that, when implemented in a clinical setting, can offer patients an early opportunity for treatment and enhance their chances of ultimate recovery from this life-threatening disease. METHODS: Different packages in R were used to analyze RNA-seq data from the TCGA data portal. Multivariate Cox regression analysis and Kaplan-Meier analysis were also used to investigate the prognostic values of immune-related genes and construct the predictive model and nomogram. A p-value < 0.05 was considered to be significant. RESULTS: A total of 368 immune-related genes and 60 TFs were identified as differentially expressed in KIRP tissues compared with normal tissues. Of the 368, 23 were found to be related to overall survival. GO and KEGG analysis suggested that these prognostic immune-related genes mainly participated in the ERK1 and ERK2 cascades, Rap1 signaling pathway, and the PI3K-Akt signaling pathway. 9 genes were identified from Cox regression to be statistically significant prognostic-related genes. Survival analysis showed that a model based on these 9 prognostic-related genes has high predictive performance. Immunohistochemistry results show that APOH, BIRC5, CCL19, and GRN were significantly increased in kidney cancer. B cells and CD4 + T cells were positively correlated with risk score model. CONCLUSION: A prognostic model was successfully created based on 9 immune-related genes correlated with overall survival in KIRP. This work aims to provide some insight into therapeutic approaches and prognostic predictors of KIRP.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Prognosis , Nomograms , Phosphatidylinositol 3-Kinases , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , KidneyABSTRACT
CONTEXT: Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. OBJECTIVE: Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). METHODS: Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. RESULTS: Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. CONCLUSION: Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C.
Subject(s)
Ghrelin , Pancreatitis , Humans , Male , Female , Middle Aged , Adult , Ghrelin/blood , Diagnosis, Differential , Pancreatitis/diagnosis , Pancreatitis/blood , Pancreatitis/etiology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/metabolism , Gastrointestinal Hormones/blood , Insulin/blood , Peptide YY/blood , C-Peptide/blood , Glucagon/blood , Blood Glucose/analysis , Blood Glucose/metabolism , Postprandial Period , Gastric Inhibitory Polypeptide/blood , Glucagon-Like Peptide 1/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/metabolism , Case-Control Studies , Diabetes Mellitus/diagnosis , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Pancreatic Hormones/blood , Pancreatic Hormones/metabolism , Insulin ResistanceABSTRACT
Transcription factor EB (TFEB), a master lysosomal biogenesis and autophagy regulator, is crucial for cellular homeostasis, and its abnormality is related to diverse inflammatory diseases. Genetic variations in autophagic genes are associated with susceptibility to inflammatory bowel disease (IBD); however, little is known about the role and mechanism of TFEB in disease pathogenesis. In this study, we found that the genetic deletion of TFEB in mouse intestinal epithelial cells (IEC) caused intestinal barrier dysfunction, leading to increased susceptibility to experimental colitis. Mechanistically, TFEB functionally protected IEC in part through peroxisome proliferator-activated receptor gamma coactivator 1alpha (TFEB-PGC1α axis) induction, which consequently suppressed reactive oxygen species. TFEB can directly regulate PGC-1α transcription to control antioxidation level. Notably, TFEB expression is impaired and downregulated in the colon tissues of IBD patients. Collectively, our results indicate that intestinal TFEB participates in oxidative stress regulation and attenuates IBD progression.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Homeostasis , Inflammatory Bowel Diseases , Intestinal Mucosa , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Reactive Oxygen Species , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Animals , Reactive Oxygen Species/metabolism , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/genetics , Mice , Humans , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Oxidative Stress , Epithelial Cells/metabolism , Epithelial Cells/pathology , Mice, Inbred C57BL , Mice, Knockout , Male , Colitis/metabolism , Colitis/pathology , Colitis/chemically induced , Colitis/geneticsABSTRACT
Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine pancreatic function. The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma. This review summarizes the latest evidence on the diagnosis and management of chronic pancreatitis and its manifestations. In particular, this review discusses advances in understanding of the role of genetic disorders in the mechanisms of the disease and surgical options for patients refractory to medical therapy. Furthermore, clinical trials are under way to develop medical therapeutics.