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Cancer Immunology, Immunotherapy : CII Dec 2023This study examined the composition of the immune microenvironment at different sites within resected pancreas specimens from patients with pancreatic ductal...
This study examined the composition of the immune microenvironment at different sites within resected pancreas specimens from patients with pancreatic ductal adenocarcinoma (PDAC). Therefore, single-cell suspensions were made from fresh tumor and non-tumorous tissue. Fourteen patients were included from whom twelve PDAC and five non-tumorous samples were obtained. These samples were analyzed with a nineteen marker panel on the Aurora spectral flow cytometer. Furthermore, slides from formalin-fixed paraffine PDACs of eight additional patients were stained with eight markers and analyzed by multispectral imaging. These corresponded to central tumor, periphery of the tumor, i.e., invasive front and resected lymph node and were divided into tumor and adjacent tissue. In the single-cell suspension, a decreased ratio between lymphoid and myeloid cells and between M1 and M2 macrophages was observed in the tumor tissue compared to non-tumorous tissue. Furthermore, an increase in CD169 + macrophages in patients undergoing neoadjuvant therapy was found. Using immunofluorescence, more macrophages compared to T cells were observed, as well as a lower ratio of CD8 to M2 macrophage, a higher ratio of CD4-CD8 T cells and a higher ratio of immune-suppressive cells to pro-inflammatory cells in the PDAC area compared to the adjacent non-tumorous tissue. Finally, there were more immune-suppressive cells in the central tumor area compared to the invasive front. In conclusion, we show a gradient in the immune-suppressive environment in PDAC from most suppressive in the central tumor to least suppressive in distant non-tumorous tissue.
Topics: Humans; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreas; T-Lymphocytes
PubMed: 37938368
DOI: 10.1007/s00262-023-03573-6 -
Veterinary Research Dec 2023It is well-established that the genetic diversity, regional prevalence, and broad host range of astroviruses significantly impact the poultry industry. In July 2022, a...
It is well-established that the genetic diversity, regional prevalence, and broad host range of astroviruses significantly impact the poultry industry. In July 2022, a small-scale commercial broiler farm in China reported cases of growth retardation and a 3% mortality rate. From chickens displaying proventriculitis and pancreatitis, three chicken astroviruses (CAstV) isolates were obtained and named SDAU2022-1-3. Complete genomic sequencing and analysis revealed the unique characteristics of these isolates from known CAstV strains in ORF1a, ORF1b, and ORF2 genes, characterized by an unusually high variability. Analysis of amino acid mutations in ORF1a, ORF1b, and ORF2 indicated that the accumulation of these mutations played a pivotal role in the emergence of the variant strain. Inoculation experiments demonstrated that affected chickens exhibited liver and kidney enlargement, localized proventricular hemorrhage, and a dark reddish-brown appearance in about two-thirds of the pancreas. Histopathological examination unveiled hepatic lymphocytic infiltration, renal tubular epithelial cell swelling, along with lymphocytic proventriculitis and pancreatitis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis indicated viremia and viral shedding at 3 days post-infection (dpi). The proventriculus displayed the highest viral loads, followed by the liver, kidney, duodenum, and pancreas. Liver parameters (AST and ALT) and kidney parameters (UA and UN) demonstrated mild damage consistent with earlier findings. While the possibility of new mutations in the ORF2 gene of CAstV causing proventriculitis and pancreatitis warrants further investigation, these findings deepen our comprehension of CAstV's pathogenicity in chickens. Additionally, they serve as valuable references for subsequent research endeavors.
Topics: Animals; Avastrovirus; Chickens; Virulence; Astroviridae Infections; Pancreatitis; Poultry Diseases; Phylogeny
PubMed: 38066626
DOI: 10.1186/s13567-023-01250-1 -
Current Opinion in Pharmacology Dec 2018The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is... (Review)
Review
The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is partly because much of the epidemiological evidence derives from studies of neutralising antibody generation in blood samples while less attention has been paid to the pancreatic beta cell as a site of infection. Nevertheless, recent studies have revealed that beta cells express specific enteroviral receptors and that they can sustain a productive enteroviral infection. Importantly, they can also mount antiviral responses which attenuate viral replication and may favour the establishment of a persistent enteroviral infection. Together, these responses combine to create the Trojan horse by which enteroviruses might precipitate islet autoimmunity.
Topics: Animals; Antiviral Agents; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Drug Design; Enterovirus; Enterovirus Infections; Host-Pathogen Interactions; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Risk Factors
PubMed: 30064099
DOI: 10.1016/j.coph.2018.07.006 -
Nefrologia 2023Graft outcomes in pancreas transplantation have improved in recent decades, but data are mainly derived from registries or prospective single-centre studies. This large...
INTRODUCTION AND OBJECTIVES
Graft outcomes in pancreas transplantation have improved in recent decades, but data are mainly derived from registries or prospective single-centre studies. This large epidemiological study was undertaken to investigate the impact of clinical and demographic factors on graft and patient survival in pancreas transplant recipients in Spain, and to provide robust, country-wide, practice-based data to complement registry findings.
PATIENTS AND METHODS
We conducted a retrospective, longitudinal, epidemiological study to assess risk factors impacting patient and graft survival in pancreas transplant recipients in eight centres in Spain. All patients transplanted between 1 January 2008 and 31 December 2012 were included; data were collected until 31 December 2015. The Kaplan-Meier method was used for all time-to-event analyses, including patient survival, graft survival, acute rejection, and BPAR. For graft survival analysis, in cases of death with functioning graft, patients were censored without any event on the date of death. For acute rejection and BPAR, patients were censored without any event on the date of death or graft loss. Univariable and multivariable analyses (Cox proportional hazards model) were conducted to assess the association between baseline clinical and demographic characteristics and patient/graft survival.
RESULTS
Data were included for 241 (80.1%) simultaneous pancreas-kidney transplants, 56 (18.6%) pancreas-after-kidney transplants and 4 (1.3%) pancreas transplants alone. Mean±standard deviation time from diagnosis until transplantation was 26.1±7.5 years. Nineteen patients died, mainly due to infections (n=10); the remaining 282 patients (93.7%) survived from transplantation until the end of the study. Among 55 patients (18.3%) with pancreas graft loss, the main reasons were vascular thrombosis (n=19), chronic rejection (n=10), acute rejection (n=6) and death with a functioning graft (n=5). The overall rate of vascular-related death was 1.3% at 5 years post transplant. Univariable analysis showed that patient age and weight, donor age, previous kidney transplantation, previous cardiovascular events and need for insulin more than 48h post transplantation were significantly associated with pancreas graft survival. Of these, in multivariable analyses pancreas graft survival was inferior in patients who had received a previous kidney transplant prior to pancreas transplantation (log-rank test, p=0.0002). Glucose metabolism, renal function and cardiovascular risk factors were generally stable following transplantation.
CONCLUSIONS
The results of this multicentre study highlight the excellent patient and graft outcomes following pancreas transplantation, with a notably low incidence of cardiovascular events.
Topics: Humans; Graft Survival; Pancreas Transplantation; Retrospective Studies; Prospective Studies; Pancreas; Cardiovascular Diseases
PubMed: 36494288
DOI: 10.1016/j.nefroe.2022.11.019 -
Frontiers in Cellular and Infection... 2022The intestinal microenvironment is composed of normal gut microbiota and the environment in which it lives. The largest microecosystem in the human body is the gut... (Review)
Review
The intestinal microenvironment is composed of normal gut microbiota and the environment in which it lives. The largest microecosystem in the human body is the gut microbiota, which is closely related to various diseases of the human body. Pancreatic cancer (PC) is a common malignancy of the digestive system worldwide, and it has a 5-year survival rate of only 5%. Early diagnosis of pancreatic cancer is difficult, so most patients have missed their best opportunity for surgery at the time of diagnosis. However, the etiology is not entirely clear, but there are certain associations between PC and diet, lifestyle, obesity, diabetes and chronic pancreatitis. Many studies have shown that the translocation of the gut microbiota, microbiota dysbiosis, imbalance of the oral microbiota, the interference of normal metabolism function and toxic metabolite products are closely associated with the incidence of PC and influence its prognosis. Therefore, understanding the correlation between the gut microbiota and PC could aid the diagnosis and treatment of PC. Here, we review the correlation between the gut microbiota and PC and the research progresses for the gut microbiota in the diagnosis and treatment of PC.
Topics: Carcinogenesis; Dysbiosis; Gastrointestinal Microbiome; Humans; Pancreas; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 35463649
DOI: 10.3389/fcimb.2022.872019 -
Applied and Environmental Microbiology Mar 2022Pathogenic bacteria, such as enteropathogenic Escherichia coli (EPEC) and enterotoxigenic E. coli (ETEC), cause diarrhea in mammals. In particular, E. coli colonizes and...
Pathogenic bacteria, such as enteropathogenic Escherichia coli (EPEC) and enterotoxigenic E. coli (ETEC), cause diarrhea in mammals. In particular, E. coli colonizes and infects the gastrointestinal tract via type 1 fimbriae (T1F). Here, the major zymogen granule membrane glycoprotein 2 (GP2) acts as a host cell receptor. GP2 is also secreted by the pancreas and various mucous glands, interacting with luminal type 1 fimbriae-positive E. coli. It is unknown whether GP2 isoforms demonstrate specific E. coli pathotype binding. In this study, we investigated interactions of human, porcine, and bovine EPEC and ETEC, as well as commensal E. coli isolates with human, porcine, and bovine GP2. We first defined pathotype- and host-associated FimH variants. Second, we could prove that GP2 isoforms bound to FimH variants to various degrees. However, the GP2-FimH interactions did not seem to be influenced by the host specificity of E. coli. In contrast, soluble GP2 affected ETEC infection and phagocytosis rates of macrophages. Preincubation of the ETEC pathotype with GP2 reduced the infection of cell lines. Furthermore, preincubation of E. coli with GP2 improved the phagocytosis rate of macrophages. Our findings suggest that GP2 plays a role in the defense against E. coli infection and in the corresponding host immune response. Infection by pathogenic bacteria, such as certain Escherichia coli pathotypes, results in diarrhea in mammals. Pathogens, including zoonotic agents, can infect different hosts or show host specificity. There are Escherichia coli strains which are frequently transmitted between humans and animals, whereas other Escherichia coli strains tend to colonize only one host. This host specificity is still not fully understood. We show that glycoprotein 2 is a selective receptor for particular Escherichia coli strains or variants of the adhesin FimH but not a selector for a species-specific Escherichia coli group. We demonstrate that GP2 is involved in the regulation of colonization and infection and thus represents a molecule of interest for the prevention or treatment of disease.
Topics: Animals; Cattle; Diarrhea; Enteropathogenic Escherichia coli; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Fimbriae, Bacterial; Mammals; Membrane Glycoproteins; Secretory Vesicles; Swine
PubMed: 35020452
DOI: 10.1128/aem.02279-21 -
The Cochrane Database of Systematic... Jun 2018The use of surgical drains has been considered mandatory after pancreatic surgery. The role of prophylactic abdominal drainage to reduce postoperative complications... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The use of surgical drains has been considered mandatory after pancreatic surgery. The role of prophylactic abdominal drainage to reduce postoperative complications after pancreatic surgery is controversial.
OBJECTIVES
To assess the benefits and harms of routine abdominal drainage after pancreatic surgery, compare the effects of different types of surgical drains, and evaluate the optimal time for drain removal.
SEARCH METHODS
For the last version of this review, we searched CENTRAL (2016, Issue 8), and MEDLINE, Embase, Science Citation Index Expanded, and Chinese Biomedical Literature Database (CBM) to 28 August 2016). For this updated review, we searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and CBM from 2016 to 15 November 2017.
SELECTION CRITERIA
We included all randomized controlled trials that compared abdominal drainage versus no drainage in people undergoing pancreatic surgery. We also included randomized controlled studies that compared different types of drains and different schedules for drain removal in people undergoing pancreatic surgery.
DATA COLLECTION AND ANALYSIS
We identified six studies (1384 participants). Two review authors independently identified the studies for inclusion, collected the data, and assessed the risk of bias. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). For all analyses, we used the random-effects model.
MAIN RESULTS
Drain use versus no drain useWe included four studies with 1110 participants, who were randomized to the drainage group (N = 560) and the no drainage group (N = 550) after pancreatic surgery. There was little or no difference in mortality at 30 days between groups (1.5% with drains versus 2.3% with no drains; RR 0.78, 95% CI 0.31 to 1.99; four studies, 1055 participants; moderate-quality evidence). Drain use probably slightly reduced mortality at 90 days (0.8% versus 4.2%; RR 0.23, 95% CI 0.06 to 0.90; two studies, 478 participants; moderate-quality evidence). We were uncertain whether drain use reduced intra-abdominal infection (7.9% versus 8.2%; RR 0.97, 95% CI 0.52 to 1.80; four studies, 1055 participants; very low-quality evidence), or additional radiological interventions for postoperative complications (10.9% versus 12.1%; RR 0.87, 95% CI 0.79 to 2.23; three studies, 660 participants; very low-quality evidence). Drain use may lead to similar amount of wound infection (9.8% versus 9.9%; RR 0.98 , 95% CI 0.68 to 1.41; four studies, 1055 participants; low-quality evidence), and additional open procedures for postoperative complications (9.4% versus 7.1%; RR 1.33, 95% CI 0.79 to 2.23; four studies, 1055 participants; low-quality evidence) when compared with no drain use. There was little or no difference in morbidity (61.7% versus 59.7%; RR 1.03, 95% CI 0.94 to 1.13; four studies, 1055 participants; moderate-quality evidence), or length of hospital stay (MD -0.66 days, 95% CI -1.60 to 0.29; three studies, 711 participants; moderate-quality evidence) between groups. There was one drain-related complication in the drainage group (0.2%). Health-related quality of life was measured with the pancreas-specific quality-of-life questionnaire (FACT-PA; a scale of 0 to 144 with higher values indicating a better quality of life). Drain use may lead to similar quality of life scores, measured at 30 days after pancreatic surgery, when compared with no drain use (105 points versus 104 points; one study, 399 participants; low-quality evidence). Hospital costs and pain were not reported in any of the studies.Type of drainWe included one trial involving 160 participants, who were randomized to the active drain group (N = 82) and the passive drain group (N = 78) after pancreatic surgery. An active drain may lead to similar mortality at 30 days (1.2% with active drain versus 0% with passive drain; low-quality evidence), and morbidity (22.0% versus 32.1%; RR 0.68, 95% CI 0.41 to 1.15; low-quality evidence) when compared with a passive drain. We were uncertain whether an active drain decreased intra-abdominal infection (0% versus 2.6%; very low-quality evidence), wound infection (6.1% versus 9.0%; RR 0.68, 95% CI 0.23 to 2.05; very low-quality evidence), or the number of additional open procedures for postoperative complications (1.2% versus 7.7%; RR 0.16, 95% CI 0.02 to 1.29; very low-quality evidence). Active drain may reduce length of hospital stay slightly (MD -1.90 days, 95% CI -3.67 to -0.13; one study; low-quality evidence; 14.1% decrease of an 'average' length of hospital stay). Additional radiological interventions, pain, and quality of life were not reported in the study.Early versus late drain removalWe included one trial involving 114 participants with a low risk of postoperative pancreatic fistula, who were randomized to the early drain removal group (N = 57) and the late drain removal group (N = 57) after pancreatic surgery. There was no mortality in either group. Early drain removal may slightly reduce morbidity (38.6% with early drain removal versus 61.4% with late drain removal; RR 0.63, 95% CI 0.43 to 0.93; low-quality evidence), length of hospital stay (MD -2.10 days, 95% CI -4.17 to -0.03; low-quality evidence; 21.5% decrease of an 'average' length of hospital stay), and hospital costs (MD -EUR 2069.00, 95% CI -3872.26 to -265.74; low-quality evidence; 17.0% decrease of 'average' hospital costs). We were uncertain whether early drain removal reduced additional open procedures for postoperative complications (0% versus 1.8%; RR 0.33, 95% CI 0.01 to 8.01; one study; very low-quality evidence). Intra-abdominal infection, wound infection, additional radiological interventions, pain, and quality of life were not reported in the study.
AUTHORS' CONCLUSIONS
It was unclear whether routine abdominal drainage had any effect on the reduction of mortality at 30 days, or postoperative complications after pancreatic surgery. Moderate-quality evidence suggested that routine abdominal drainage probably slightly reduced mortality at 90 days. Low-quality evidence suggested that use of an active drain compared to the use of a passive drain may slightly reduce the length of hospital stay after pancreatic surgery, and early removal may be superior to late removal for people with low risk of postoperative pancreatic fistula.
Topics: Abdomen; Device Removal; Drainage; Humans; Length of Stay; Pancreas; Postoperative Complications; Randomized Controlled Trials as Topic; Time Factors
PubMed: 29928755
DOI: 10.1002/14651858.CD010583.pub4 -
Biochimica Et Biophysica Acta Jun 2016In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by...
In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.
Topics: Acinar Cells; Animals; Cell Death; Enzyme Activation; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Signal Transduction; p21-Activated Kinases
PubMed: 26912410
DOI: 10.1016/j.bbadis.2016.02.008 -
Frontiers in Immunology 2023Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that... (Review)
Review
Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.
Topics: Humans; Diabetes Mellitus, Type 1; Pancreas; Enterovirus Infections; Virus Diseases; Coronavirus Infections; COVID-19
PubMed: 38239343
DOI: 10.3389/fimmu.2023.1326711 -
Journal of Infection in Developing... Jun 2023Stenotrophomonas maltophilia is a Gram-negative, opportunistic pathogen associated with a high morbidity and mortality rate. We report our clinical experience in...
INTRODUCTION
Stenotrophomonas maltophilia is a Gram-negative, opportunistic pathogen associated with a high morbidity and mortality rate. We report our clinical experience in treating a patient with infected pancreatic necrosis caused by multidrug-resistant (MDR) S. maltophilia with a novel drug combination.
CASE REPORT
A 65-year-old male with history of type II diabetes was admitted with acute pancreatitis, voluminous ascites, and signs of sepsis after undergoing an echo-endoscopy procedure with pancreas biopsy to investigate a Wirsung duct dilatation. Retroperitoneal fluid culture revealed S. maltophilia resistant to colistin and with intermediate susceptibility to trimethoprim-sulfamethoxazole and levofloxacin. The synergy between aztreonam (ATM) and ceftazidime/avibactam (CZA) was demonstrated using the combined disk pre-diffusion test.
CONCLUSIONS
There are sparse data providing guidance on the optimal regimen against MDR S. maltophilia infections. Although in this case a surgical excision was essential, combination of ATM and CZA provided effective synergistic antimicrobial treatment with clinical cure of severe acute pancreatitis infected with S. maltophilia. The combined disk pre-diffusion test with ATM and CZA requires no special equipment and can be routinely performed in clinical microbiology labs. Combination of ATM with CZA should be considered for cases of MDR S. maltophilia infections with limited treatment options.
Topics: Male; Humans; Aged; Aztreonam; Ceftazidime; Anti-Bacterial Agents; Stenotrophomonas maltophilia; Diabetes Mellitus, Type 2; Acute Disease; Pancreatitis; Drug Combinations; Microbial Sensitivity Tests; Gram-Negative Bacterial Infections
PubMed: 37406060
DOI: 10.3855/jidc.17290