ABSTRACT
BACKGROUND: Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients. MATERIALS AND METHODS: This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared. RESULTS: The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05). CONCLUSION: GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment. TRIAL REGISTRATION NUMBER: NCT02635971. DATE OF REGISTRATION: 21/12/2015.
Subject(s)
Adenocarcinoma , Angiography, Digital Subtraction , Antineoplastic Combined Chemotherapy Protocols , Deoxycytidine , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Male , Female , Middle Aged , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Infusions, Intra-Arterial , Adult , Prospective Studies , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Gemcitabine , Infusions, Intravenous , Pancreas/pathology , Pancreas/diagnostic imaging , Organoplatinum CompoundsABSTRACT
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
Subject(s)
Autophagy , Disease Models, Animal , Ferroptosis , Lipid Peroxidation , Pancreatitis , Rats, Sprague-Dawley , Animals , Pancreatitis/metabolism , Pancreatitis/pathology , Rats , Male , Adenine/analogs & derivatives , Adenine/pharmacology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Taurocholic Acid , Cyclohexylamines/pharmacology , Pancreas/pathology , Pancreas/metabolism , Phenylenediamines/pharmacology , Malondialdehyde/metabolism , Reactive Oxygen Species/metabolism , Acute Disease , Glutathione/metabolism , Iron/metabolismABSTRACT
Ras-related Rap1A GTPase is implicated in pancreas ß-cell insulin secretion and is stimulated by the cAMP sensor Epac2, a guanine exchange factor and activator of Rap1 GTPase. In this study, we examined the differential proteomic profiles of pancreata from C57BL/6 Rap1A-deficient (Null) and control wild-type (WT) mice with nanoLC-ESI-MS/MS to assess targets of Rap1A potentially involved in insulin regulation. We identified 77 overlapping identifier proteins in both groups, with 8 distinct identifier proteins in Null versus 56 distinct identifier proteins in WT mice pancreata. Functional enrichment analysis showed four of the eight Null unique proteins, ERO1-like protein ß (Ero1lß), triosephosphate isomerase (TP1), 14-3-3 protein γ, and kallikrein-1, were exclusively involved in insulin biogenesis, with roles in insulin metabolism. Specifically, the mRNA expression of Ero1lß and TP1 was significantly (p < 0.05) increased in Null versus WT pancreata. Rap1A deficiency significantly affected glucose tolerance during the first 15-30 min of glucose challenge but showed no impact on insulin sensitivity. Ex vivo glucose-stimulated insulin secretion (GSIS) studies on isolated Null islets showed significantly impaired GSIS. Furthermore, in GSIS-impaired islets, the cAMP-Epac2-Rap1A pathway was significantly compromised compared to the WT. Altogether, these studies underscore an essential role of Rap1A GTPase in pancreas physiological function.
Subject(s)
Insulin , Mice, Inbred C57BL , Pancreas , Proteomics , Signal Transduction , rap1 GTP-Binding Proteins , Animals , rap1 GTP-Binding Proteins/metabolism , rap1 GTP-Binding Proteins/genetics , Mice , Proteomics/methods , Insulin/metabolism , Pancreas/metabolism , Insulin-Secreting Cells/metabolism , Mice, Knockout , Guanine Nucleotide Exchange Factors/metabolism , Guanine Nucleotide Exchange Factors/genetics , Insulin Secretion , Male , Glucose/metabolismABSTRACT
BACKGROUND/AIMS: Pancreatic steatosis (PS) is a pathology associated with metabolic syndrome (MS), endocrin and exocrine disfunctions of the pancreas, and fatty liver. The data on the frequency of PS are very limited. We aimed to evaluate the frequency of PS detected by transabdominal ultrasonography (TAU) in gastroenterology clinics located in different geographical regions of Turkey and the factors associated with it. MATERIALS AND METHODS: Volunteers were evaluated by TAU for PS and hepatosteatosis (HS), and its degree. Pancreatic stiffness was evaluated by ultrasonographic shear wave elastography (SWE). All demographic, physical, and biochemical parametres were measured. RESULTS: A total of 1700 volunteers from 14 centers throughout Turkey were included in the study. Mean age was 48.03 ± 20.86 years (56.9% female). Prevalance of PS was detected in 68.9%. In the PS group, age, body mass index (BMI), waist circumference, systolic blood pressure, fasting blood glucose (FBG), lipid levels, insulin resistance, diabetes mellitus, hypertension, MS frequency, and pancreatic SWE score were increasing, and fecal elastase level was decreasing in correlation with the degree of PS. The frequency of HS was 55.5%. Hepatosteatosis [odds ratio (OR): 9.472], increased age (OR: 1.02), and BMI (OR: 1.089) were independent risk factors for the occurrence of PS. Lean-PS rate was 11.8%. The lean-PS group was predominantly female and younger than non-lean PS. Also it has lower blood pressure, FBG, liver enzymes, lipid levels, and HS rates. CONCLUSION: The frequency of PS was found 68.9% in Turkey. Its relationship was determined with age, BMI, HS, MS (and its components), pancreatic stiffness, and fecal elastase level.
Subject(s)
Elasticity Imaging Techniques , Fatty Liver , Metabolic Syndrome , Pancreatic Diseases , Humans , Turkey/epidemiology , Female , Middle Aged , Male , Prevalence , Adult , Risk Factors , Metabolic Syndrome/epidemiology , Pancreatic Diseases/epidemiology , Fatty Liver/epidemiology , Body Mass Index , Aged , Pancreas/diagnostic imaging , Pancreatic Elastase/analysis , Waist Circumference , Insulin Resistance , Blood Glucose/analysis , Blood Glucose/metabolismABSTRACT
There is increasing interest in developing in-depth proteomic approaches for mapping tissue heterogeneity in a cell-type-specific manner to better understand and predict the function of complex biological systems such as human organs. Existing spatially resolved proteomics technologies cannot provide deep proteome coverage due to limited sensitivity and poor sample recovery. Herein, we seamlessly combined laser capture microdissection with a low-volume sample processing technology that includes a microfluidic device named microPOTS (microdroplet processing in one pot for trace samples), multiplexed isobaric labeling, and a nanoflow peptide fractionation approach. The integrated workflow allowed us to maximize proteome coverage of laser-isolated tissue samples containing nanogram levels of proteins. We demonstrated that the deep spatial proteomics platform can quantify more than 5000 unique proteins from a small-sized human pancreatic tissue pixel (â¼60,000 µm2) and differentiate unique protein abundance patterns in pancreas. Furthermore, the use of the microPOTS chip eliminated the requirement for advanced microfabrication capabilities and specialized nanoliter liquid handling equipment, making it more accessible to proteomic laboratories.
Subject(s)
Peptides , Proteome , Proteomics , Humans , Proteome/analysis , Proteomics/methods , Peptides/analysis , Peptides/chemistry , Pancreas/metabolism , Pancreas/chemistry , Nanotechnology , Microfluidic Analytical Techniques/instrumentation , Laser Capture Microdissection/methodsABSTRACT
Ectopic pancreas, also known as heterotopic pancreas, is a rare condition in which the pancreatic tissue is found outside its usual location in the gastrointestinal (GI) tract. It is commonly asymptomatic and benign, and is often discovered incidentally during routine imaging, endoscopy, surgery, or autopsy. However, complications can arise, such as inflammation, bleeding, obstruction, or even malignant transformation, necessitating surgical intervention in some cases. Ectopic pancreas at the ampulla of Vater (EPAV) is an extremely rare condition and a diagnostic and therapeutic nightmare. Most cases have been diagnosed through invasive surgery due to concerns for malignancy, which carries significant morbidity and mortality. In our case, endoscopic snare papillectomy (ESP) was employed to establish a diagnosis. Thus far, only one other case has been reported in which ESP was used to diagnose and resect a pancreatic heterotopia at the ampulla.
Subject(s)
Ampulla of Vater , Choristoma , Pancreas , Humans , Ampulla of Vater/surgery , Choristoma/surgery , Choristoma/diagnosis , Choristoma/pathology , Female , Male , Middle Aged , Cholangiopancreatography, Endoscopic RetrogradeABSTRACT
Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects.
Subject(s)
COVID-19 , Disease Models, Animal , Hyperglycemia , Liver , SARS-CoV-2 , Animals , Hyperglycemia/immunology , COVID-19/immunology , COVID-19/virology , COVID-19/blood , Chlorocebus aethiops , SARS-CoV-2/immunology , Liver/virology , Liver/metabolism , Liver/immunology , Glycogen/metabolism , Blood Glucose/metabolism , Humans , Male , Pancreas/virology , Pancreas/immunology , Pancreas/pathology , Pancreas/metabolism , Chemokines/metabolism , Chemokines/blood , Female , Virus ReplicationABSTRACT
The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.
Subject(s)
Pancreas, Exocrine , Pancreatic Diseases , Humans , Animals , Pancreatic Diseases/physiopathology , Pancreatic Diseases/pathology , Pancreatic Diseases/metabolism , Pancreas, Exocrine/physiopathology , Pancreas, Exocrine/metabolism , Pancreas, Exocrine/pathology , Pancreas/physiopathology , Pancreas/pathology , Endocrine System/physiopathology , Endocrine System/physiologyABSTRACT
Pancreatitis caused by a fish bone penetrating the posterior wall of the stomach and entering the pancreas is rare. We herein report a case involving a woman in her late 30s with an approximately 1-month history of recurrent upper abdominal pain. Initial evaluation at another hospital failed to identify the cause but raised suspicion of pancreatic cancer. Computed tomography, magnetic resonance imaging, and a detailed consultation led us to suspect that the patient's pain had been caused by inadvertent ingestion of a fish bone. We used three-dimensional visualization technology to determine the location of the fish bone and informed the patient of the lesion and surgical plan through a simulated surgical demonstration. During surgery, we applied augmented reality navigation technology to remove the fish bone by a minimally invasive approach. The patient was discharged on postoperative day 3. She was followed up by telephone 24 hours after discharge. Outpatient follow-up was performed 1 week after discharge and on day 30. The patient recovered well and developed no complications. This case shows that digital medical technology can be applied in patients undergoing surgical removal of a pancreatic foreign body. Such technology assists with preoperative evaluation, patient education, and intraoperative trauma reduction.
Subject(s)
Foreign Bodies , Minimally Invasive Surgical Procedures , Pancreas , Humans , Female , Pancreas/surgery , Pancreas/diagnostic imaging , Adult , Foreign Bodies/surgery , Foreign Bodies/diagnostic imaging , Minimally Invasive Surgical Procedures/methods , Tomography, X-Ray Computed , Imaging, Three-Dimensional , Magnetic Resonance ImagingABSTRACT
Heterotopic pancreas is a rare congenital abnormality. The most common location is the stomach, duodenum and proximal jejunum. Rare locations are represented by the ampulla of Vater, esophagus, ileum, Meckel diverticulum, biliary tract, mesentery and spleen. We present the case of a 49 year old patient investigated for obstructive jaundice and diagnosed with an ampullar heterotopy of pancreas parenchyma, initially considered to be a malignant tumor. A Whipple pancreatoduodenectomy was performed with good postoperative evolution, the serum levels of bilirubin being normal after the first postoperative week.
Subject(s)
Ampulla of Vater , Choristoma , Jaundice, Obstructive , Pancreas , Pancreaticoduodenectomy , Humans , Ampulla of Vater/surgery , Jaundice, Obstructive/etiology , Jaundice, Obstructive/surgery , Jaundice, Obstructive/diagnosis , Choristoma/complications , Choristoma/surgery , Choristoma/diagnosis , Pancreaticoduodenectomy/methods , Middle Aged , Treatment Outcome , Diagnosis, Differential , Male , Common Bile Duct Diseases/surgery , Common Bile Duct Diseases/diagnosis , Common Bile Duct Diseases/complicationsABSTRACT
Researchers are increasingly interested in discovering new pancreatic lipase inhibitors as anti-obesity ingredients. Medicine-and-food homology plants contain a diverse set of natural bioactive compounds with promising development potential. This study screened and identified potent pancreatic lipase inhibitors from 20 commonly consumed medicine-and-food homology plants using affinity ultrafiltration combined with spectroscopy and docking simulations. The results showed that turmeric exhibited the highest pancreatic lipase-inhibitory activity, and curcumin, demethoxycurcumin, and bisdemethoxycurcumin were discovered to be potent pancreatic lipase inhibitors within the turmeric extract, with IC50 values of 0.52 ± 0.04, 1.12 ± 0.05, and 3.30 ± 0.08 mg/mL, respectively. In addition, the enzymatic kinetics analyses demonstrated that the inhibition type of the three curcuminoids was the reversible competitive model, and curcumin exhibited a higher binding affinity and greater impact on the secondary structure of pancreatic lipase than found with demethoxycurcumin or bisdemethoxycurcumin, as observed through fluorescence spectroscopy and circular dichroism. Furthermore, docking simulations supported the above experimental findings, and revealed that the three curcuminoids might interact with amino acid residues in the binding pocket of pancreatic lipase through non-covalent actions, such as hydrogen bonding and π-π stacking, thereby inhibiting the pancreatic lipase. Collectively, these findings suggest that the bioactive compounds of turmeric, in particular curcumin, can be promising dietary pancreatic lipase inhibitors for the prevention and management of obesity.
Subject(s)
Curcuma , Curcumin , Diarylheptanoids , Enzyme Inhibitors , Lipase , Molecular Docking Simulation , Pancreas , Lipase/antagonists & inhibitors , Curcumin/pharmacology , Curcumin/analogs & derivatives , Curcumin/chemistry , Curcuma/chemistry , Diarylheptanoids/pharmacology , Pancreas/enzymology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Humans , Plants, Medicinal/chemistryABSTRACT
Pancreatic lesions can be solid or cystic and comprise a wide range of benign, premalignant, and malignant entities. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the current primary sampling method for the preoperative diagnosis of pancreatic lesions. Optimal handling of cytology/small tissue specimens is critical to ensure that the often-scant diagnostic material is appropriately utilized for ancillary and/or molecular studies when appropriate. Ultimately, evaluation of EUS-FNA cytology and small biopsy material can provide accurate and timely diagnoses to guide patient management and triage them to surveillance or surgical intervention.
Subject(s)
Endoscopic Ultrasound-Guided Fine Needle Aspiration , Pancreas , Pancreatic Neoplasms , Humans , Endoscopic Ultrasound-Guided Fine Needle Aspiration/methods , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/diagnosis , Pancreas/pathology , Biopsy, Fine-Needle/methods , Pancreatic Diseases/pathology , Pancreatic Diseases/diagnosisABSTRACT
BACKGROUND: Isolated pancreatic injury after blunt abdominal trauma is rare but unreliably excludable based on clinical symptoms. A CT-abdomen is the golden standard in diagnosing. Undiagnosed pancreatic injury can result in severe complications as abscesses and fistulas. CASE DESCRIPTION: A sixteen-year old patient was brought to the Emergency Department (ED) with epigastric pain, two days after a low-energy scooter accident. No (abdominal) alarming symptoms were objectified during direct assessment by the general practitioner. However, a complete pancreatic transection was diagnosed after assessment at the ED, eventually resulting in a distal pancreatectomy with postoperative associated complications. CONCLUSION: In all traumas, the mechanism of injury should be judged critically for the possibility of abdominal injury (as pancreatic damage) and thus the need for imaging. An initially harmless clinical condition can mask extensive injury. This case illustrates the importance of thoughtful expectant policies with return instructions or demarcated follow-up when no CT-scan is performed.
Subject(s)
Abdominal Injuries , Pancreas , Pancreatectomy , Wounds, Nonpenetrating , Humans , Wounds, Nonpenetrating/complications , Wounds, Nonpenetrating/diagnosis , Abdominal Injuries/complications , Pancreas/injuries , Male , Adolescent , Accidents, Traffic , Tomography, X-Ray ComputedABSTRACT
Robotic surgery has been increasingly adopted in various surgical fields, but the cost-effectiveness of this technology remains controversial due to its high cost and limited improvements in clinical outcomes. This study aims to explore the health economic implications of robotic pancreatic surgery, to investigate its impact on hospitalization costs and consumption of various medical resources. Data of patients who underwent pancreatic surgery at our institution were collected and divided into robotic and traditional groups. Statistical analyses of hospitalization costs, length of stay, costs across different service categories, and subgroup cost analyses based on age, BMI class, and procedure received were performed using t tests and linear regression. Although the total hospitalization cost for the robotic group was significantly higher than that for the traditional group, there was a notable reduction in the cost of medical consumables. The reduction was more prominent among elderly patients, obese patients, and those undergoing pancreaticoduodenectomy, which could be attributed to the technological advantages of the robotic surgery platform that largely facilitate blood control, tissue protection, and suturing. The study concluded that despite higher overall costs, robotic pancreatic surgery offers significant savings in medical consumables, particularly benefiting certain patient subgroups. The findings provide valuable insights into the economic viability of robotic surgery, supporting its adoption from a health economics perspective.
Subject(s)
Pancreatectomy , Robotic Surgical Procedures , Tertiary Care Centers , Robotic Surgical Procedures/economics , Robotic Surgical Procedures/statistics & numerical data , Robotic Surgical Procedures/methods , Humans , China , Tertiary Care Centers/economics , Middle Aged , Female , Male , Aged , Pancreatectomy/economics , Pancreatectomy/methods , Pancreaticoduodenectomy/economics , Pancreaticoduodenectomy/methods , Pancreaticoduodenectomy/statistics & numerical data , Length of Stay/economics , Length of Stay/statistics & numerical data , Cost-Benefit Analysis , Adult , Costs and Cost Analysis , Pancreas/surgery , Hospitalization/economics , Hospitalization/statistics & numerical data , Hospital Costs/statistics & numerical dataABSTRACT
BACKGROUND: Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. METHODS: Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. RESULTS: Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR-/- pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR-/- animals at 80- and 120-days gestation, as are stellate cells at term. CONCLUSION: The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.
Subject(s)
Biomarkers , Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Disease Models, Animal , Pancreatic Stellate Cells , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis/pathology , Animals , Pancreatic Stellate Cells/metabolism , Pancreatic Stellate Cells/pathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Female , Sheep , Pancreas/metabolism , Pancreas/pathology , Pregnancy , Pancreatic Diseases/genetics , Pancreatic Diseases/metabolism , Pancreatic Diseases/pathology , Transcriptome , Humans , Gene Expression ProfilingABSTRACT
Null.
Subject(s)
Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/diagnosis , Pancreas/pathology , Male , Female , Sarcoma/pathologyABSTRACT
We demonstrate robot-assisted treatment of a patient with benign pancreatic insulinoma. A 31-year-old patient suffered from attacks of weakness, numbness of the fingertips and «turbidity of consciousness¼ for 2 years. These symptoms occurred on an empty stomach and regressed after eating. We found pancreatic insulinoma. The patient underwent robotic enucleation of pancreatic tumor. Surgery time was 145 min. Postoperative period proceeded without complications. Hyperglycemia up to 10.5 mmol/l on the first postoperative day was followed by normalization after 4 days. The patient was discharged in 6 days after surgery. Minimally invasive robotic enucleation of insulinoma minimizes surgical trauma and provides precise resection of tumor. The key aspect of safe enucleation is localization of tumor at a distance of at least 2 mm from the pancreatic duct.
Subject(s)
Insulinoma , Pancreatectomy , Pancreatic Neoplasms , Robotic Surgical Procedures , Humans , Insulinoma/surgery , Insulinoma/diagnosis , Adult , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/diagnosis , Robotic Surgical Procedures/methods , Pancreatectomy/methods , Male , Treatment Outcome , Pancreas/surgeryABSTRACT
A variety of therapeutic possibilities have emerged for skillfully regulating protein function or conformation through intermolecular interaction modulation to rectify abnormal biochemical reactions in diseases. Herein, a devised strategy of enzyme coordinators has been employed to alleviate postoperative pancreatic fistula (POPF), which is characterized by the leakage of digestive enzymes including trypsin, chymotrypsin, and lipase. The development of a dextrorotary (D)-peptide supramolecular gel (CP-CNDS) under this notion showcases its propensity for forming gels driven by intermolecular interaction. Upon POPF, CP-CNDS not only captures enzymes from solution into hydrogel, but also effectively entraps them within the internal gel, preventing their exchange with counterparts in the external milieu. As a result, CP-CNDS completely suppresses the activity of digestive enzymes, effectively alleviating POPF. Remarkably, rats with POPF treated with CP-CNDS not only survived but also made a recovery within a mere 3-day period, while mock-treated POPF rats had a survival rate of less than 5 days when experiencing postoperative pancreatic fistula, leak or abscess. Collectively, the reported CP-CNDS provides promising avenues for preventing and treating POPF, while exemplifying precision medicine-guided regulation of protein activity that effectively targets specific pathogenic molecules across multiple diseases.
Subject(s)
Hydrogels , Pancreatic Fistula , Peptides , Pancreatic Fistula/prevention & control , Animals , Rats , Hydrogels/chemistry , Male , Peptides/pharmacology , Peptides/chemistry , Peptides/metabolism , Chymotrypsin/metabolism , Postoperative Complications/prevention & control , Trypsin/metabolism , Trypsin/chemistry , Lipase/metabolism , Humans , Rats, Sprague-Dawley , Disease Models, Animal , Pancreas/enzymology , Pancreas/pathologyABSTRACT
Pancreatic bioengineering is a potential therapeutic alternative for type 1 diabetes (T1D) in which the pancreas is decellularized, generating an acellular extracellular matrix (ECM) scaffold, which may be reconstituted by recellularization with several cell types to generate a bioartificial pancreas. No consensus for an ideal pancreatic decellularization protocol exists. Therefore, we aimed to determine the best-suited detergent by comparing sodium dodecyl sulfate (SDS), sodium deoxycholate (SDC), and Triton X-100 at different concentrations. Murine (n=12) and human pancreatic tissue from adult brain-dead donors (n=06) was harvested in accordance with Institutional Ethical Committee of the University of São Paulo Medical School (CEP-FMUSP) and decellularized under different detergent conditions. DNA content, histological analysis, and transmission and scanning electron microscopy were assessed. The most adequate condition for pancreatic decellularization was found to be 4% SDC, displaying: a) effective cell removal; b) maintenance of extracellular matrix architecture; c) proteoglycans, glycosaminoglycans (GAGs), and collagen fibers preservation. This protocol was extrapolated and successfully applied to human pancreas decellularization. The acellular ECM scaffold generated was recelullarized using human pancreatic islets primary clusters. 3D clusters were generated using 0.5×104 cells and then placed on top of acellular pancreatic slices (25 and 50 µm thickness). These clusters tended to connect to the acellular matrix, with visible cells located in the periphery of the clusters interacting with the ECM network of the bioscaffold slices and continued to produce insulin. This study provided evidence on how to improve and accelerate the pancreas decellularization process, while maintaining its architecture and extracellular structure, aiming at pancreatic bioengineering.
Subject(s)
Deoxycholic Acid , Detergents , Pancreas , Sodium Dodecyl Sulfate , Tissue Engineering , Tissue Scaffolds , Animals , Detergents/chemistry , Detergents/pharmacology , Humans , Pancreas/cytology , Mice , Sodium Dodecyl Sulfate/pharmacology , Deoxycholic Acid/pharmacology , Deoxycholic Acid/chemistry , Tissue Scaffolds/chemistry , Tissue Engineering/methods , Octoxynol/chemistry , Extracellular Matrix , Diabetes Mellitus, Type 1 , Microscopy, Electron, Scanning , Decellularized Extracellular Matrix/chemistryABSTRACT
The development of the pancreatic head originates from the fusion of the ventral and dorsal pancreatic primordia during embryonic development. Theoretically, the origin of pancreatic head cancer also exists from the ventral pancreas and the dorsal pancreas. Among 49 patients with pancreatic head cancer, pancreatic head cancer was divided into pancreatic head cancer originating from the ventral (PHCv) or dorsal pancreas (PHCd) through imaging and pathological classification. The clinical data was collected and compared between the PHCv group and the PHCd group. The results showed that the patients from the PHCd group had worse long-term survival than those from the PHCv group (10 months vs 14.5 months). Similarly, the progression-free survival (PFS) results also indicate that patients from the PHCd group had a shorter time than those from the PHCv group (5 months vs 9.5 months). Further stratified analysis of potentially related factors showed that microvascular invasion is related to poor prognosis, and patients with pancreatic head cancer derived from the dorsal pancreas are more likely to develop microvascular invasion.