Current clinical opinion on CFTR dysfunction and patient risk of pancreatitis: diagnostic and therapeutic considerations

Phadke, Madhura Y.; Sellers, Zachary M.

doi:10.1080/17474124.2022.2084072

Cited by 5 publications

(3 citation statements)

References 79 publications

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“…This is a key link in the transportation of nutrients and trace elements. It has been demonstrated that CFTR dysfunction significantly increases the risk of CP ( Berke et al, 2022 ; Phadke and Sellers, 2022 ). Meanwhile, mutations in CFTR are associated with a modest increase in risk for PDAC ( McWilliams et al, 2010 ; Hennig et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics

et al. 2023

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Background: Pancreatic ductal adenocarcinoma (PDAC) develops rapidly and has a poor prognosis. It has been demonstrated that pancreatic ductal adenocarcinoma and chronic pancreatitis (CP) have a close connection. However, the underlying mechanisms for chronic pancreatitis transforming into pancreatic ductal adenocarcinoma are still unclear. The purpose of this study was to identify real hub genes in the development of chronic pancreatitis and pancreatic ductal adenocarcinoma.Methods: RNA-seq data of chronic pancreatitis and pancreatic ductal adenocarcinoma were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between chronic pancreatitis and pancreatic ductal adenocarcinoma. GEO2R and a Venn diagram were used to identify differentially expressed genes. Then visualized networks were constructed with ClueGO, and modules of PPI network were calculated by MCODE plugin. Further validation of the results was carried out in two additional cohorts. Analyses of CEL-coexpressed genes and regulators including miRNAs and transcription factors were performed by using the corresponding online web tool. Finally, the influence of CEL in the tumor immune microenvironment (TIME) was assessed by immune contextual analysis.Results: With the help of WGCNA and GEO2R, four co-expression modules and six hub genes were identified, respectively. ClueGO enrichment analysis and MCODE cluster analysis revealed that the dysfunctional transport of nutrients and trace elements might contribute to chronic pancreatitis and pancreatic ductal adenocarcinoma development. The real hub gene CEL was identified with a markedly low expression in pancreatic ductal adenocarcinoma in external validation sets. According to the miRNA-gene network construction, hsa-miR-198 may be the key miRNA. A strong correlation exists between CEL and TIME after an evaluation of the influence of CEL in TIME.Conclusion: Our study revealed the dysfunctional transport of nutrients and trace elements may be common pathogenesis of pancreatic ductal adenocarcinoma and chronic pancreatitis. Examination on these common pathways and real hub genes may shed light on the underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics

et al. 2023

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“…Glucagon‐like peptide (GLP‐1) receptor agonists have gained popularity for their efficacy in weight loss for adults with obesity 124 . Aside from a case report, the use of GLP‐1 receptor agonists for the treatment of obesity in CF has not yet been examined systematically, and given the known risk of pancreatitis with both HEMT and GLP‐1 receptor agonists, special consideration of this comorbidity is essential 63,125 . While not examined for treatment of obesity in CF, GLP‐1 receptor agonists have been shown to augment glucose‐dependent insulin secretion in PI‐CF, supporting the possibility that GLP‐1 receptor agonists may have therapeutic benefits in CF‐related diabetes 126,127 .…”

Section: Treatments For Overnutrition Overweight and Obesitymentioning

confidence: 99%

“…124 Aside from a case report, the use of GLP-1 receptor agonists for the treatment of obesity in CF has not yet been examined systematically, and given the known risk of pancreatitis with both HEMT and GLP-1 receptor agonists, special consideration of this comorbidity is essential. 63,125 While not examined for treatment of obesity in CF, GLP-1 receptor agonists have been shown to augment glucose-dependent insulin secretion in PI-CF, supporting the possibility that GLP-1 receptor agonists may have therapeutic benefits in CF-related diabetes. 126,127 In a population of 12 individuals with PI-CF and CFRD randomized to sitagliptin (GLP-1 and glucose-dependent insulinotropic polypeptide agonist), main side effects were rash and mild hypoglycemia.…”

Section: Treatments For Overnutrition Overweight and Obesitymentioning

confidence: 99%

Nutritional status in the era of highly effective CFTR modulators

Bass,

Alvarez

2024

Pediatric Pulmonology

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Advances in cystic fibrosis (CF) diagnostics and therapeutics have led to improved health and longevity, including increased body weight and decreased malnutrition in people with CF. Highly effective CFTR modulator therapies (HEMT) are associated with increased weight through a variety of mechanisms, accelerating trends of overweight and obesity in the CF population. Higher body mass index (BMI) is associated with improved pulmonary function in CF, yet the incremental improvement at overweight and obese BMIs is not clear. Improvements in pulmonary health with increasing BMI are largely driven by increases in fat‐free mass (FFM), and impact of HEMT on FFM is uncertain. While trends toward higher weight and BMI are generally seen as favorable in CF, the increased prevalence of overweight and obesity has raised concern for potential risk of traditional age‐ and obesity‐related comorbidities. Such comorbidities, including impaired glucose tolerance, hypertension, cardiac disease, hyperlipidemia, fatty liver, colon cancer, and obstructive sleep apnea, may occur on top of pre‐existing CF‐related comorbidities. CF nutrition recommendations are evolving in the post‐modulator era to more individualized approaches, in contrast to prior blanket high‐fat, high‐calorie prescriptions for all. Ultimately, it will be essential to redefine goals for optimal weight and nutritional status to allow for holistic health and aging in people with CF.

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Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

Osorio-Vasquez,

Lumibao,

Peck

et al. 2024

Preprint

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Background and Aims: Chronic pancreatitis (CP) affects more than 200,000 Americans and 1 million individuals world wide, but treatment generally focuses on supportive care like pain management. 28-80% of CP cases are idiopathic and 10-15% are hereditary with mutations in PRSS1, SPINK1, and CFTR. The etiology of the disease has little impact on the therapeutic approach used to treat these patients. Developing human models of pancreatitis to understand the drivers of the disease and targeting key players in this disease will provide novel therapeutic approaches for these patients who have limited options. Methods: Utilizing patient samples from surgical resections or TPIAT procedures we have generated a first-of-its-kind human CP patient derived organoid (PDO) biobank. This biobank is representative of hereditary mutations found across patients, contains idiopathic cases, and histologically recapitulates features of this disease. Genetic concordance was determine between PDO and primary specimens using whole genome sequencing. RNAseq and cytokine analysis was conducted on PDO to determine inflammatory features of this model. Forskolin induced swelling assays were conducted to determine the function of CFTR in PDO models. Results: There is a 98% concordance between PDO and primary tissue specimens showing the recapitulation of patient genotypes in our model. RNAseq revealed that CP organoids are transcriptionally distinct from normal pancreas organoids and three distinct subtypes of CP that are driven by transcriptional features. Utilizing the PDO model we can restore CFTR function using a combination of correctors and potentiators. Conclusions: There are three subtypes of CP that require further study to employ targeted therapeutics against these drivers. hCP PDO are a model that can be used to assess CFTR function and correction providing evidence for these drugs to be used in CP patients. Keywords: chronic pancreatitis, patient derived organoids, CFTR

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Current clinical opinion on CFTR dysfunction and patient risk of pancreatitis: diagnostic and therapeutic considerations

Cited by 5 publications

References 79 publications

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics

Nutritional status in the era of highly effective CFTR modulators

Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

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