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Frontiers in Genetics 2024The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the...
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 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. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from conditional knockout animals ( ) targeted to the exocrine pancreatic epithelial cells ( and ), 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 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 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 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.
PubMed: 38948355
DOI: 10.3389/fgene.2024.1412767 -
World Journal of Transplantation Jun 2024The number of solid organ transplantations performed annually is increasing and are increasing in the following order: Kidney, liver, heart, lung, pancreas, small bowel,...
The number of solid organ transplantations performed annually is increasing and are increasing in the following order: Kidney, liver, heart, lung, pancreas, small bowel, and uterine transplants. However, the outcomes of transplants are improving (organ survival > 90% after the 1 year). Therefore, there is a high probability that a general surgeon will be faced with the management of a transplant patient with acute abdomen. Surgical problems in immunocompromised patients may not only include graft-related problems but also nongraft-related problems. The perioperative regulation of immunosuppression, the treatment of accompanying problems of immunosuppression, the administration of cortisol and, above all, the realization of a rapidly deteriorating situation and the accurate evaluation and interpretation of clinical manifestations are particularly important in these patients. The perioperative assessment and preparation includes evaluation of the patient's cardiovascular system and determining if the patient has hypertension or suppression of the hypothalamic-pituitary-adrenal axis, or if the patient has had any coagulation mechanism abnormalities or thromboembolic episodes. Immunosuppression in transplant patients is associated with the use of calcineurin inhibitors, corticosteroids, and antiproliferation agents. Many times, the clinical picture is atypical, resulting in delays in diagnosis and treatment and leading to increased morbidity and mortality. Multidetector computed tomography is of utmost importance for early diagnosis and management. Transplant recipients are prone to infections, especially specific infections caused by cytomegalovirus and , and they are predisposed to intraoperative or postoperative complications that require great care and vigilance. It is necessary to follow evidence-based therapeutic protocols. Thus, it is required that the clinician choose the correct therapeutic plan for the patient (conservative, emergency open surgery or minimally invasive surgery, including laparoscopic or even robotic surgery).
PubMed: 38947966
DOI: 10.5500/wjt.v14.i2.93944 -
Kidney Medicine Jul 2024The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist...
RATIONALE & OBJECTIVE
The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist candidates. Despite excellent reported outcomes, center uptake has remained low across the United States. Here, we examined the effect of implementing an A2/A2B protocol using a cutoff titer of ≤1:8 for IgG and ≤1:16 for IgM on blood group B kidney transplant recipients at a single center.
STUDY DESIGN
Retrospective observational study.
SETTING & PARTICIPANTS
Blood group B recipients of deceased donor kidney transplants at a single center from January 1, 2019, to December 2022.
EXPOSURE
Recipients of deceased donor kidney transplants were analyzed based on donor blood type with comparisons of A2/A2B versus blood group compatible.
OUTCOMES
One-year patient survival, death-censored allograft function, primary nonfunction, delayed graft function, allograft function as measured using serum creatinine levels and estimated glomerular filtration rate at 1 year, biopsy-proven rejection, and need for plasmapheresis.
ANALYTICAL APPROACH
Comparison between the A2/A2B and compatible groups were performed using the Fisher test or the χ test for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables.
RESULTS
A total of 104 blood type B patients received a deceased donor kidney transplant at our center during the study period, 49 (47.1%) of whom received an A2/A2B transplant. Waiting time was lower in A2/A2B recipients compared with blood group compatible recipients (57.9 months vs 74.7 months, = 0.01). A2/A2B recipients were more likely to receive a donor after cardiac death (24.5% vs 1.8%, < 0.05) and experience delayed graft function (65.3% vs 41.8%). There were no observed differences in the average serum creatinine level or estimated glomerular filtration rate at 1 month, 3 months, and 1 year post kidney transplantation, acute rejection, or primary nonfunction.
LIMITATIONS
Single-center study. Small cohort size limiting outcome analysis.
CONCLUSIONS
Implementation of an A2/A2B protocol increased transplant volumes of blood group B waitlisted patients by 83.6% and decreased the waiting time for transplantation by 22.5% with similar transplant outcomes.
PubMed: 38947773
DOI: 10.1016/j.xkme.2024.100843 -
Frontiers in Immunology 2024Anti-Thymocyte Globulin (ATG) is a cornerstone in immune suppression for solid organ transplantation. The treatment is a delicate balance between complications arising...
INTRODUCTION
Anti-Thymocyte Globulin (ATG) is a cornerstone in immune suppression for solid organ transplantation. The treatment is a delicate balance between complications arising from over-immunosuppression such as infections and cancer versus rejection stemming from under-immunosuppression. CD3 T-lymphocyte measurements are frequently employed for treatment monitoring. However, this analysis is costly and not always accessible. The aim of this study was to investigate whether the total count of lymphocytes could replace CD3 T-lymphocyte measurements based on data from our transplantation center combined with a review of the literature. The hypothesis was that the total lymphocyte count could serve as a diagnostic surrogate marker for CD3 T-lymphocytes.
METHODS
A retrospective cohort study was conducted, including patients who underwent kidney and/or a pancreas transplantation and received ATG as induction therapy or for rejection treatment. The inclusion criterium was that the total lymphocyte count and CD3 T-lymphocyte measurements were measured simultaneously on the same day. Additionally, PubMed and Embase were searched up to 18/10/2023 for published studies on solid organ transplantation, ATG, T-lymphocytes, lymphocyte count, and monitoring. In the retrospective cohort study, a total of 91 patients transplanted between 2016 and 2023, with 487 samples, were included.
RESULTS
Total lymphocyte counts below 0.3 x 10/L had a high sensitivity (86%) as a surrogate marker of CD3 T-lymphocytes below 0.05 x 10/L, but the specificity was low (52%) for total lymphocyte counts above 0.3 x 10/L as a surrogate marker for CD3 T-lymphocytes above 0.05 x 10/L. A review of the literature identified seven studies comparing total lymphocyte counts and CD3 T-lymphocytes in ATG monitoring. These studies supported the use of a low total lymphocyte count as a surrogate marker for CD3 T-lymphocytes and an indicator to omit ATG treatment. However, there was no consensus regarding high total lymphocyte counts as an indicator for continued treatment.
DISCUSSION
Results supports that the total lymphocyte count can be used to omit ATG treatment when below 0.3 x 10/L whereas the CD3 T-lymphocyte analysis should be reserved for higher total lymphocyte counts to avoid ATG overtreatment.
Topics: Humans; Antilymphocyte Serum; Lymphocyte Count; Retrospective Studies; Male; Female; Middle Aged; Adult; Graft Rejection; Immunosuppressive Agents; T-Lymphocytes; Kidney Transplantation; Aged; Pancreas Transplantation; CD3 Complex; Organ Transplantation
PubMed: 38933271
DOI: 10.3389/fimmu.2024.1419726 -
Simultaneous Pancreas and Kidney Transplantation from Donors after Circulatory Death in Switzerland.Journal of Clinical Medicine Jun 2024Simultaneous pancreas and kidney transplantation (SPK) remains the only curative treatment for type I diabetics with end-stage kidney disease. SPK using donors after...
Simultaneous pancreas and kidney transplantation (SPK) remains the only curative treatment for type I diabetics with end-stage kidney disease. SPK using donors after circulatory death (DCD) is one important measure to expand the organ pool for pancreas transplantation (PT). After initial doubts due to higher complications, DCD SPK is now considered safe and equivalent to donation after brain death in terms of survival and graft function. We assessed pancreas and kidney graft function, as well as complications of the first three patients who underwent a DCD SPK in Switzerland. Two transplantations were after rapid procurement, one following normothermic regional perfusion (NRP). Intra- and postoperative courses were uneventful and without major complications in all patients. In the two SPK after rapid procurement, pancreas graft function was excellent, with 100% insulin-free survival, and hemoglobin A1C dropped from 7.9 and 7.5 before SPK and to 5.1 and 4.3 after three years, respectively. Kidney graft function was excellent in the first year, followed by a gradual decline due to recurrent infections. The patient, after NRP SPK, experienced short-term delayed pancreatic graft function requiring low-dose insulin treatment for 5 days post-transplant, most likely due to increased peripheral insulin resistance in obesity. During follow-up, there was persistent euglycemia and excellent kidney function. We report on the first series of DCD SPK ever performed in Switzerland. Results were promising, with low complication rates and sustained graft survival. With almost half of all donors in Switzerland currently being DCD, we see great potential for the expansion of DCD PT.
PubMed: 38930054
DOI: 10.3390/jcm13123525 -
Medicina (Kaunas, Lithuania) May 2024: The pancreatic solid pseudopapillary neoplasm (SPN), a rare tumor predominantly affecting young women, has seen an increased incidence due to improved imaging and...
: The pancreatic solid pseudopapillary neoplasm (SPN), a rare tumor predominantly affecting young women, has seen an increased incidence due to improved imaging and epidemiological knowledge. This study aimed to understand the outcomes of different interventions, possible complications, and associated risk factors. : This study retrospectively analyzed 24 patients who underwent pancreatic surgery for SPNs between September 1998 and July 2020. : Surgical intervention, typically required for symptomatic cases or pathological confirmation, yielded favorable outcomes with a 5-year survival rate of up to 97%. Despite challenges in standardizing preoperative evaluation and follow-up protocols, aggressive complete resection showed promising long-term survival and good oncological outcomes. Notably, no significant differences were found between conventional and minimally invasive (MI) surgery in perioperative outcomes. Histopathological correlations were lacking in prognosis and locations. Among the patients, one developed diffuse liver metastases 41 months postoperatively but responded well to chemotherapy and transcatheter arterial chemoembolization, with disease stability observed at 159 postoperative months. Another patient developed nonalcoholic steatohepatitis after surgery and underwent liver transplantation, succumbing to poor medication adherence 115 months after surgery. : These findings underscore the importance of surgical intervention in managing SPNs and suggest the MI approach as a viable option with comparable outcomes to conventional surgery.
Topics: Humans; Female; Pancreatic Neoplasms; Adult; Retrospective Studies; Male; Middle Aged; Treatment Outcome; Pancreatectomy; Young Adult; Carcinoma, Papillary; Adolescent; Aged
PubMed: 38929506
DOI: 10.3390/medicina60060889 -
Antioxidants (Basel, Switzerland) May 2024Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular... (Review)
Review
The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect.
Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson-Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions.
PubMed: 38929116
DOI: 10.3390/antiox13060678 -
Antioxidants (Basel, Switzerland) May 2024The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative... (Review)
Review
The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included ( = 41 MP; = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.
PubMed: 38929081
DOI: 10.3390/antiox13060642 -
BMC Cancer Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are areas at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression.
METHODS
We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.
RESULTS
In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68 macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm and 1812 ± 1008 µm for the SARIFA-negative and -positive cases, respectively (p < 0.001).
CONCLUSIONS
SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
Topics: Humans; Carcinoma, Pancreatic Ductal; Female; Male; Biomarkers, Tumor; Prognosis; Pancreatic Neoplasms; Aged; Middle Aged; Fatty Acid-Binding Proteins; Neoplasm Invasiveness; Tumor Microenvironment; Lipid Metabolism; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Stromal Cells; CD36 Antigens; Adipocytes; Adult; Aged, 80 and over; CD68 Molecule
PubMed: 38926671
DOI: 10.1186/s12885-024-12519-9 -
Surgery Jun 2024
Corrigendum to "The 2016 update of the International Study Group (ISGPF) definition and grading of postoperative pancreatic fistula: eleven years after." Surgery 2017. Mar; 161 (3):584-591. Epub Dec 28, 2016.
PubMed: 38926000
DOI: 10.1016/j.surg.2024.05.043