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NeoReviews Jul 2023See Bonus NeoBriefs videos and downloadable teaching slides Gastrointestinal complications of cystic fibrosis (CF) are often the earliest manifestations of disease and... (Review)
Review
See Bonus NeoBriefs videos and downloadable teaching slides Gastrointestinal complications of cystic fibrosis (CF) are often the earliest manifestations of disease and contribute to significant morbidity and mortality. Early diagnosis of CF is paramount, as early intervention has been associated with improved long-term pulmonary and nutritional outcomes. In this review, we describe common gastrointestinal, pancreatic, hepatic, and nutritional manifestations of CF in neonates to aid clinicians in diagnosing and managing the earliest gastrointestinal manifestations of CF. Furthermore, we discuss how the use of CFTR-targeted therapies by pregnant and/or breastfeeding persons may affect CF diagnosis in newborns and their potential impact on halting or reversing CF disease progression.
Topics: Infant, Newborn; Humans; Female; Pregnancy; Cystic Fibrosis; Gastrointestinal Diseases
PubMed: 37391660
DOI: 10.1542/neo.24-6-e414 -
Human Cell Jul 2023The pancreas is an abdominal organ with both endocrine and exocrine functions, and patients with pancreatic diseases suffer tremendously. The regulated cell death of... (Review)
Review
The pancreas is an abdominal organ with both endocrine and exocrine functions, and patients with pancreatic diseases suffer tremendously. The regulated cell death of various cells in the pancreas is thought to play a key role in disease development. As one of the newly discovered regulated cell death modalities, ferroptosis has the potential for therapeutic applications in the study of multiple diseases. Ferroptosis has been observed in several pancreatic diseases, but its role in pancreatic diseases has not been systematically elucidated or reviewed. Understanding the occurrence of ferroptosis in various pancreatic diseases after damage to the different cell types is crucial in determining disease progression, evaluating targeted therapies, and predicting disease prognosis. Herein, we summarize the research progress associated with ferroptosis in four common pancreatic diseases, namely acute pancreatitis, chronic pancreatitis, pancreatic ductal adenocarcinoma, and diabetes mellitus. Furthermore, the elucidation of ferroptosis in rare pancreatic diseases may provide sociological benefits in the future.
Topics: Humans; Pancreatitis; Ferroptosis; Acute Disease; Pancreatic Diseases; Pancreatic Neoplasms
PubMed: 36929283
DOI: 10.1007/s13577-023-00894-7 -
Current Opinion in Gastroenterology Sep 2023Some children with acute recurrent and chronic pancreatitis stand to benefit from therapeutic endoscopic interventions. The purpose of this review is to summarize... (Review)
Review
PURPOSE OF REVIEW
Some children with acute recurrent and chronic pancreatitis stand to benefit from therapeutic endoscopic interventions. The purpose of this review is to summarize specific endoscopic therapies used for these conditions and highlight areas of future research.
RECENT FINDINGS
Multicenter collaboration and consortium efforts have provided more data now than ever on the technical outcomes and safety of therapeutic endoscopic procedures for pancreatitis in children. Indications are growing but more research is needed to help guide patient selection.
SUMMARY
Advanced endoscopic procedures including endoscopic retrograde cholangiopancreatography, endoscopic-ultrasound guided therapies, and single-operator pancreatoscopy may be used in patients with acute recurrent or chronic pancreatitis to manage pancreatic duct obstruction or local complications including pseudocysts and walled-off necrosis. Patient and procedural factors differ between adults and children. Access to these procedures for younger children is growing, and technical outcomes and adverse event rates appear similar between adults and children.
Topics: Adult; Humans; Child; Cholangiopancreatography, Endoscopic Retrograde; Pancreatic Diseases; Pancreatitis, Chronic; Cysts; Treatment Outcome; Multicenter Studies as Topic
PubMed: 37523027
DOI: 10.1097/MOG.0000000000000955 -
Current Opinion in Gastroenterology Sep 2023The diagnosis and management of exocrine pancreatic dysfunction (EPD) can be challenging. EPD classically results from conditions that cause loss of pancreatic acinar... (Review)
Review
PURPOSE OF REVIEW
The diagnosis and management of exocrine pancreatic dysfunction (EPD) can be challenging. EPD classically results from conditions that cause loss of pancreatic acinar cell function and decreased digestive enzyme production. However, several conditions may contribute to signs or symptoms of EPD with otherwise normal pancreatic exocrine function. A thoughtful approach to considering these conditions, along with their specific therapies, can guide a tailored management approach.
RECENT FINDINGS
An EPD severity classification schema has been proposed, which emphasizes a shift towards a more restrictive prescription of pancreas enzyme replacement therapy (PERT) for patients with milder EPD. In contrast, PERT use has been associated with a measurable survival benefit among individuals with EPD and pancreatic cancer, so the prescription of PERT may be more liberal in this population. Recent publications in the cystic fibrosis population offer pearls guiding the titration and optimization of PERT.
SUMMARY
Among individuals with severe EPD, PERT is an effective therapy. Among individuals with milder EPD, although PERT is effective, there may be opportunities to provide additional and potentially more effective therapies.
Topics: Humans; Exocrine Pancreatic Insufficiency; Pancreas; Pancreatic Neoplasms; Gastrointestinal Agents
PubMed: 37530731
DOI: 10.1097/MOG.0000000000000951 -
Molecular Cancer Dec 2023Circular RNAs (circRNAs) play important roles in the occurrence and development of cancer and chemoresistance. DNA damage repair contributes to the proliferation of...
hsa_circ_0007919 induces LIG1 transcription by binding to FOXA1/TET1 to enhance the DNA damage response and promote gemcitabine resistance in pancreatic ductal adenocarcinoma.
BACKGROUND
Circular RNAs (circRNAs) play important roles in the occurrence and development of cancer and chemoresistance. DNA damage repair contributes to the proliferation of cancer cells and resistance to chemotherapy-induced apoptosis. However, the role of circRNAs in the regulation of DNA damage repair needs clarification.
METHODS
RNA sequencing analysis was applied to identify the differentially expressed circRNAs. qRT-PCR was conducted to confirm the expression of hsa_circ_0007919, and CCK-8, FCM, single-cell gel electrophoresis and IF assays were used to analyze the proliferation, apoptosis and gemcitabine (GEM) resistance of pancreatic ductal adenocarcinoma (PDAC) cells. Xenograft model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor growth and DNA damage in vivo. RNA sequencing and GSEA were applied to confirm the downstream genes and pathways of hsa_circ_0007919. FISH and nuclear-cytoplasmic RNA fractionation experiments were conducted to identify the cellular localization of hsa_circ_0007919. ChIRP, RIP, Co-IP, ChIP, MS-PCR and luciferase reporter assays were conducted to confirm the interaction among hsa_circ_0007919, FOXA1, TET1 and the LIG1 promoter.
RESULTS
We identified a highly expressed circRNA, hsa_circ_0007919, in GEM-resistant PDAC tissues and cells. High expression of hsa_circ_0007919 correlates with poor overall survival (OS) and disease-free survival (DFS) of PDAC patients. Hsa_circ_0007919 inhibits the DNA damage, accumulation of DNA breaks and apoptosis induced by GEM in a LIG1-dependent manner to maintain cell survival. Mechanistically, hsa_circ_0007919 recruits FOXA1 and TET1 to decrease the methylation of the LIG1 promoter and increase its transcription, further promoting base excision repair, mismatch repair and nucleotide excision repair. At last, we found that GEM enhanced the binding of QKI to the introns of hsa_circ_0007919 pre-mRNA and the splicing and circularization of this pre-mRNA to generate hsa_circ_0007919.
CONCLUSIONS
Hsa_circ_0007919 promotes GEM resistance by enhancing DNA damage repair in a LIG1-dependent manner to maintain cell survival. Targeting hsa_circ_0007919 and DNA damage repair pathways could be a therapeutic strategy for PDAC.
Topics: Humans; Gemcitabine; RNA, Circular; RNA Precursors; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; DNA Damage; MicroRNAs; Cell Proliferation; Cell Line, Tumor; Mixed Function Oxygenases; Proto-Oncogene Proteins; Hepatocyte Nuclear Factor 3-alpha
PubMed: 38044421
DOI: 10.1186/s12943-023-01887-8 -
Gastrointestinal Endoscopy Clinics of... Jul 2024Per-oral pancreatoscopy (POP) is a pancreas-preserving modality that allows for targeted pancreatic duct interventions, particularly in cases where standard techniques... (Review)
Review
Per-oral pancreatoscopy (POP) is a pancreas-preserving modality that allows for targeted pancreatic duct interventions, particularly in cases where standard techniques fail. POP specifically has an emerging role in the diagnosis, risk stratification, and disease extent determination of main duct intraductal papillary mucinous neoplasms (IPMNs). It has also been successfully used for laser ablation of IPMNs in poor surgical candidates, lithotripsy for complex stone disease, and laser stricturoplasty. As experience with POP increases beyond select referral center practices, further studies validating POP efficacy with long-term follow-up will help clarify when POP-guided intervention is most beneficial in relation to surgical intervention.
Topics: Humans; Pancreatic Diseases; Endoscopy, Digestive System; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatic Intraductal Neoplasms
PubMed: 38796290
DOI: 10.1016/j.giec.2024.02.007 -
Radiographics : a Review Publication of... Aug 2023
Topics: Humans; Ascariasis; Pancreas; Pancreatitis; Biliary Tract Diseases
PubMed: 37471244
DOI: 10.1148/rg.230049 -
Cancer Discovery Jan 2024Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that...
UNLABELLED
Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC.
SIGNIFICANCE
The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models. This article is featured in Selected Articles from This Issue, p. 5.
Topics: Humans; Vitamin B 6; Tumor Microenvironment; Killer Cells, Natural; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Carbon
PubMed: 37931287
DOI: 10.1158/2159-8290.CD-23-0334 -
JAMA Network Open Aug 2023Accurate risk prediction models using routinely measured biomarkers-eg, carbohydrate antigen 19-9 (CA19-9) and bilirubin serum levels-for pancreatic cancer could...
IMPORTANCE
Accurate risk prediction models using routinely measured biomarkers-eg, carbohydrate antigen 19-9 (CA19-9) and bilirubin serum levels-for pancreatic cancer could facilitate early detection of pancreatic cancer and prevent potentially unnecessary diagnostic tests for patients at low risk. An externally validated model using CA19-9 and bilirubin serum levels in a larger cohort of patients with pancreatic cancer or benign periampullary diseases is needed.
OBJECTIVE
To assess the discrimination, calibration, and clinical utility of a prediction model using readily available blood biomarkers (carbohydrate antigen 19-9 [CA19-9] and bilirubin) to distinguish early-stage pancreatic cancer from benign periampullary diseases.
DESIGN, SETTING, AND PARTICIPANTS
This diagnostic study used data from 4 academic hospitals in Italy, the Netherlands, and the UK on adult patients with pancreatic cancer or benign periampullary disease treated from 2014 to 2022. Analyses were conducted from September 2022 to February 2023.
EXPOSURES
Serum levels of CA19-9 and bilirubin from samples collected at diagnosis and before start of any medical intervention.
MAIN OUTCOMES AND MEASURES
Discrimination (measured by the area under the curve [AUC]), calibration, and clinical utility of the prediction model and the biomarkers, separately.
RESULTS
The study sample comprised 249 patients in the development cohort (mean [SD] age at diagnosis, 67 [11] years; 112 [45%] female individuals), and 296 patients in the validation cohort (mean [SD] age at diagnosis, 68 [12] years; 157 [53%] female individuals). At external validation, the prediction model showed an AUC of 0.89 (95% CI, 0.84-0.93) for early-stage pancreatic cancer vs benign periampullary diseases, and outperformed CA19-9 (difference in AUC [ΔAUC], 0.10; 95% CI, 0.06-0.14; P < .001) and bilirubin (∆AUC, 0.07; 95% CI, 0.02-0.12; P = .004). In the subset of patients without elevated tumor marker levels (CA19-9 <37 U/mL), the model showed an AUC of 0.84 (95% CI, 0.77-0.92). At a risk threshold of 30%, decision curve analysis indicated that performing biopsies based on the prediction model was equivalent to reducing the biopsy procedure rate by 6% (95% CI, 1%-11%), without missing early-stage pancreatic cancer in patients.
CONCLUSIONS AND RELEVANCE
In this diagnostic study of patients with pancreatic cancer or benign periampullary diseases, an easily applicable risk score showed high accuracy for distinguishing early-stage pancreatic cancer from benign periampullary diseases. This model could be used to assess the added diagnostic and clinical value of novel biomarkers and prevent potentially unnecessary invasive diagnostic procedures for patients at low risk.
Topics: Adult; Humans; Female; Child; Male; CA-19-9 Antigen; Pancreatic Neoplasms; Bilirubin; Carbohydrates
PubMed: 37639271
DOI: 10.1001/jamanetworkopen.2023.31197 -
Clinical & Experimental Metastasis Jun 2024Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of... (Review)
Review
Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of diseases including cancer. They play a complex role in cancers, having both tumour suppressor and promoter properties. In addition, a single miRNA can be involved in regulating several mRNAs or many miRNAs can regulate a single mRNA, therefore assessing these roles is essential to a better understanding in cancer initiation and development. Pancreatic cancer is a leading cause of cancer death worldwide, in part due to the lack of diagnostic tools and limited treatment options. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by major genetic mutations that drive cancer initiation and progression. The regulation or interaction of miRNAs with these cancer driving mutations suggests a strong link between the two. Understanding this link between miRNA and PDAC progression may give rise to novel treatments or diagnostic tools. This review summarises the role of miRNAs in PDAC, the downstream signalling pathways that they play a role in, how these are being used and studied as therapeutic targets as well as prognostic/diagnostic tools to improve the clinical outcome of PDAC.
Topics: Humans; MicroRNAs; Pancreatic Neoplasms; Disease Progression; Carcinoma, Pancreatic Ductal; Gene Expression Regulation, Neoplastic; Neoplasm Metastasis; Signal Transduction; Animals
PubMed: 38240887
DOI: 10.1007/s10585-023-10256-0