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Frontiers in Immunology 2024Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness... (Review)
Review
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
Topics: Islets of Langerhans Transplantation; Humans; Animals; Diabetes Mellitus, Type 1; Graft Rejection; Biomedical Engineering; Islets of Langerhans
PubMed: 38650946
DOI: 10.3389/fimmu.2024.1375177 -
Infectious Diseases & Clinical... Sep 2023This study aimed to determine the effect of prophylactic use of carbapenems for acute pancreatitis on clinical outcomes. (Review)
Review
OBJECTIVE
This study aimed to determine the effect of prophylactic use of carbapenems for acute pancreatitis on clinical outcomes.
MATERIALS AND METHODS
It was conducted according to the preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by using the keywords "Pancrea AND carbapenem OR imipenem OR ertapenem OR meropenem OR doripenem." Primer outcomes were mortality, surgical intervention, and pancreatic and non-pancreatic infection. Subgroup analyses were also performed to reduce the risk of bias.
RESULTS
Ten studies with 4038 patients were included in the meta-analyses. While eight of ten were randomized controlled trials, two were observational studies. The prophylactic use of carbapenems had no statistically significant effect on mortality (OR=0.82, 95% CI=0.65-1.04, I²=0%) and surgical intervention. (OR=0.81, 95% CI=0.57-1.17, I²=0%). However, the real impact of prophylaxis on reducing the incidence of mortality and surgical intervention was uncertain due to the insufficient sample size. The prophylactic use of carbapenems was significantly associated with a lower risk of peripancreatic (OR=0.37, 95% CI=0.25-0.55, I²=61%) and non-pancreatic infection risk (OR=0.60, 95% CI=0.46-0.78, I²=65%). The definitions of infection in the articles were not clear, and the diagnostic approach to infection was based on subjective criteria. In addition, there was inadequate collateral damage and safety assessments. In high-quality studies with a low risk of bias, prophylactic carbapenems had no effect on peripancreatic infection (RR=1.54, 95% CI=0.65-3.47, I²=0%) and non-pancreatic infection (RR=0.72, 95% CI=0.48-1.07, I²=0%).
CONCLUSION
Although there is a reduction in the infection risk, routine carbapenem use in acute pancreatitis cases should not be recommended based on current evidence. Cooperation with Infectious Disease specialists and developing diagnostic algorithms are required instead of routine prophylaxis to prevent infection, especially non-pancreatic infection.
PubMed: 38633556
DOI: 10.36519/idcm.2023.239 -
Signal Transduction and Targeted Therapy Apr 2024
Topics: Humans; SARS-CoV-2; Pandemics; COVID-19; Pancreas
PubMed: 38627360
DOI: 10.1038/s41392-024-01807-2 -
Transplant International : Official... 2024A public health emergency such as the COVID-19 pandemic has behavioral, mental and physical implications in patients with type 1 diabetes (T1D). To what extent the... (Clinical Trial)
Clinical Trial Observational Study
A public health emergency such as the COVID-19 pandemic has behavioral, mental and physical implications in patients with type 1 diabetes (T1D). To what extent the presence of a transplant further increases this burden is not known. Therefore, we compared T1D patients with an islet or pancreas transplant (β-cell Tx; = 51) to control T1D patients ( = 272). Fear of coronavirus infection was higher in those with β-cell Tx than without (Visual Analogue Scale 5.0 (3.0-7.0) vs. 3.0 (2.0-5.0), = 0.004) and social isolation behavior was more stringent (45.8% vs. 14.0% reported not leaving the house, < 0.001). A previous β-cell Tx was the most important predictor of at-home isolation. Glycemic control worsened in patients with β-cell Tx, but improved in control patients (ΔHbA1c +1.67 ± 8.74 vs. -1.72 ± 6.15 mmol/mol, = 0.006; ΔTime-In-Range during continuous glucose monitoring -4.5% (-6.0%-1.5%) vs. +3.0% (-2.0%-6.0%), = 0.038). Fewer patients with β-cell Tx reported easier glycemic control during lockdown (10.4% vs. 22.6%, = 0.015). All T1D patients, regardless of transplantation status, experienced stress (33.4%), anxiety (27.9%), decreased physical activity (42.0%), weight gain (40.5%), and increased insulin requirements (29.7%). In conclusion, T1D patients with β-cell Tx are increasingly affected by a viral pandemic lockdown with higher fear of infection, more stringent social isolation behavior and deterioration of glycemic control. This trial has been registered in the clinicaltrials.gov registry under identifying number NCT05977205 (URL: https://clinicaltrials.gov/study/NCT05977205).
Topics: Female; Humans; Male; Anxiety; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Glycemic Control; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Pandemics; Public Health
PubMed: 38601276
DOI: 10.3389/ti.2024.12278 -
The Journal of Molecular Diagnostics :... Jun 2024Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset...
Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.
Topics: Humans; Hepatocyte Nuclear Factor 1-beta; Diabetes Mellitus, Type 2; Female; Male; Adult; Precision Medicine; Mutation; Adolescent; Middle Aged; Young Adult
PubMed: 38575066
DOI: 10.1016/j.jmoldx.2024.03.006 -
Cureus Mar 2024Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and... (Review)
Review
Acute pancreatitis, marked by sudden inflammation of the pancreas, presents a complex spectrum of causative factors including gallstone obstruction, alcohol abuse, and viral infections. Recent studies have illuminated the emergence of vaccine-induced acute pancreatitis, notably associated with COVID-19 vaccinations, presenting diverse mechanisms ranging from direct viral-mediated injury to autoimmune reactions. Understanding this link is pivotal for public health, yet challenges persist in identifying and managing cases post-vaccination. Comprehensive literature reviews employing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement outline the potential pathways and mechanisms leading to vaccine-induced pancreatitis, emphasizing the need for deeper investigations into underlying health conditions and modifications to vaccine components. Notably, the rare occurrences of vaccine-induced pancreatitis extend beyond COVID-19 vaccines, with reports also documenting associations with measles, mumps, and rubella (MMR), human papillomavirus (HPV), and other viral vaccinations. Mechanistically, hypotheses such as molecular mimicry and immunologic injury have been proposed, necessitating ongoing vigilance and exploration. Regulatory agencies play a crucial role in monitoring and communicating vaccine safety concerns, emphasizing transparency to address potential risks and maintain public trust. Understanding and communicating these rare adverse events with transparency remain integral for informed vaccination policies and to allay concerns surrounding vaccine safety.
PubMed: 38571842
DOI: 10.7759/cureus.55426 -
Surgical Case Reports Apr 2024Pancreatic adenosquamous cell carcinoma (PASC) is a relatively rare histological type of pancreatic malignancy, and preoperative diagnosis is difficult because of its...
BACKGROUND
Pancreatic adenosquamous cell carcinoma (PASC) is a relatively rare histological type of pancreatic malignancy, and preoperative diagnosis is difficult because of its rarity. PASC accounts for 1-4% of all pancreatic cancers, and even after curative surgery, its prognosis is poorer than that of ordinary pancreatic adenocarcinoma. Pathologically, it shows glandular and squamous differentiation of cells. Complete resection is the only method to achieve a good long-term prognosis, and an increasing doubling time of PASC is considered to indicate early recurrence after surgery. Here, we report a rare case of PASC with an infected pancreatic cyst that was difficult to treat, along with a review of the literature.
CASE PRESENTATION
A woman in her 80s with a history of breast cancer presented with pericardial pain. Computed tomography revealed a 20-mm hypovascular tumor in the body of the pancreas and a 27-mm pseudocyst. Endoscopic retrograde cholangiopancreatography showed a severe main pancreatic duct stenosis in the body of the pancreas that made cannulation impossible, and contrast media extravasation was due to pancreatic duct disruption in the pancreatic tail. Endoscopic fine-needle aspiration revealed that the tumor was a PASC. Because the patient had an infected pancreatic cyst, central intravenous nutrition and antibiotics were administered, which stabilized her general condition. She was diagnosed with resectable PASC and underwent distal pancreatectomy with lymphadenectomy. The postoperative course was uneventful. Immunohistochemical analysis of the resected specimen confirmed T2N0M0 stage IB. Systemic adjuvant chemotherapy with S-1 is ongoing.
CONCLUSION
Appropriate preoperative management and preoperative accurate staging (T2N0M0 stage IB) of PASC with curative surgery can ensure predictable outcomes.
PubMed: 38557796
DOI: 10.1186/s40792-024-01868-z -
The Journal of Clinical Investigation Apr 2024Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at...
Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.
Topics: Mice; Animals; Calcium Channels; Calcium; Pancreas; Exocytosis; Secretory Vesicles
PubMed: 38557489
DOI: 10.1172/JCI169428 -
Vaccines Mar 2024Group B coxsackieviruses (CVBs) cause a wide range of diseases in humans, but no vaccines are currently available to prevent these infections. Previously, we had...
Group B coxsackieviruses (CVBs) cause a wide range of diseases in humans, but no vaccines are currently available to prevent these infections. Previously, we had demonstrated that a live attenuated CVB3 vaccine virus, Mutant 10 (Mt10), offers protection against multiple CVB serotypes as evaluated in various inbred mouse strains; however, the applicability of these findings to the outbred human population remains uncertain. To address this issue, we used Diversity Outbred (DO) mice, whose genome is derived from eight inbred mouse strains that may capture the level of genetic diversity of the outbred human population. To determine the efficacy of the Mt10 vaccine, we established the CVB3 infection model in the DO mice. We noted that CVB3 infection resulted mainly in pancreatitis, although viral RNA was detected in both the pancreas and heart. Histologically, the pancreatic lesions comprised of necrosis, post-necrotic atrophy, and lymphocyte infiltration. In evaluating the efficacy of the Mt10 vaccine, both male and female DO mice were completely protected in challenge studies with CVB3, and viral RNA was not detected in the heart or pancreas. Likewise, vaccine recipients of both sexes showed significant levels of virus-neutralizing antibodies. Furthermore, by using the CVB3 viral protein 1, virus-reactive antibodies were found to be diverse in the order of IgG2c, followed by IgG2a, IgG2b/IgG3, and IgG1. Together, the data suggest that the Mt10 vaccine virus can offer protection against CVB infections that may have translational significance.
PubMed: 38543901
DOI: 10.3390/vaccines12030266