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Scientific Reports May 2024Evaluating the quality of isolated human islets before transplantation is crucial for predicting the success in treating Type 1 diabetes. The current gold standard...
Evaluating the quality of isolated human islets before transplantation is crucial for predicting the success in treating Type 1 diabetes. The current gold standard involves time-intensive in vivo transplantation into diabetic immunodeficient mice. Given the susceptibility of isolated islets to hypoxia, we hypothesized that hypoxia present in islets before transplantation could indicate compromised islet quality, potentially leading to unfavorable outcomes. To test this hypothesis, we analyzed expression of 39 hypoxia-related genes in human islets from 85 deceased donors. We correlated gene expression profiles with transplantation outcomes in 327 diabetic mice, each receiving 1200 islet equivalents grafted into the kidney capsule. Transplantation outcome was post-transplant glycemic control based on area under the curve of blood glucose over 4 weeks. In linear regression analysis, DDIT4 (R = 0.4971, P < 0.0001), SLC2A8 (R = 0.3531, P = 0.0009) and HK1 (R = 0.3444, P = 0.0012) had the highest correlation with transplantation outcome. A multiple regression model of 11 genes increased the correlation (R = 0.6117, P < 0.0001). We conclude that assessing pre-transplant hypoxia in human islets via gene expression analysis is a rapid, viable alternative to conventional in vivo assessments. This approach also underscores the importance of mitigating pre-transplant hypoxia in isolated islets to improve the success rate of islet transplantation.
Topics: Humans; Animals; Islets of Langerhans Transplantation; Mice; Islets of Langerhans; Diabetes Mellitus, Experimental; Male; Diabetes Mellitus, Type 1; Hypoxia; Female; Cell Hypoxia; Middle Aged; Blood Glucose
PubMed: 38811610
DOI: 10.1038/s41598-024-61604-3 -
Internal Medicine (Tokyo, Japan) May 2024We herein report an unusual case of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, and emphasize its unique presentation and diagnostic...
We herein report an unusual case of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, and emphasize its unique presentation and diagnostic challenges. Our patient exhibited uncommon symptoms and significant organ involvement, particularly pancreatic enlargement that is not typically associated with ECD. Contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) and EUS-fine needle aspiration (EUS-FNA) play crucial roles in the comprehensive assessment of the disease, demonstrating their superiority in identifying and characterizing elusive ECD lesions. This is the first report to document pancreatic lesions in patients with ECD evaluated using CEH-EUS. EUS-FNA is valuable for diagnosing rare diseases, including ECD, with diffuse pancreatic enlargement.
PubMed: 38811216
DOI: 10.2169/internalmedicine.3864-24 -
Asian Pacific Journal of Cancer... May 2024Disease reactivation/refractory remains a major challenge in managing Langerhans cell histiocytosis (LCH). Outcomes and late sequelae should be explored.
BACKGROUND
Disease reactivation/refractory remains a major challenge in managing Langerhans cell histiocytosis (LCH). Outcomes and late sequelae should be explored.
METHODS
A multi-institutional retrospective study was conducted to describe clinical characteristics, predictive factors, outcomes and late sequelae of pediatric reactivation/refractory LCH in Thailand.
RESULTS
In all, 47 patients were studied, 25 (53.2%) patients had disease reactivation and 22 (46.8%) patients had refractory LCH. The median reactivation and refractory time were 1.59 and 0.33 years from diagnosis, respectively (p <0.001). The most common site of reactivation/refractory was the bone (n = 26, 55%), and 20 (42.6%) patients developed late sequelae. The 5-year overall survival (OS) was 76.1%. Patients with reactivation and refractory LCH performed similarly in 5-year OS (88% vs. 63%, p = 0.055). Prognostic factors associated with mortality were liver, spleen, hematopoietic system and lung reactivation (p <0.05). Lung reactivation was the only independent risk factor associated with the survival outcome (p = 0.002).
CONCLUSIONS
The outcomes of pediatric patients between reactivation and refractory LCH in Thailand were similarly desirable and mortality was minimal although late sequelae may evolve. Pulmonary reactivation/refractory was an independent risk factor associated with survival.
Topics: Humans; Histiocytosis, Langerhans-Cell; Male; Female; Retrospective Studies; Child; Prognosis; Child, Preschool; Thailand; Survival Rate; Infant; Follow-Up Studies; Adolescent; Risk Factors
PubMed: 38809656
DOI: 10.31557/APJCP.2024.25.5.1831 -
Endocrinology, Diabetes & Metabolism... Apr 2024RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented...
SUMMARY
RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.
LEARNING POINTS
Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
PubMed: 38804700
DOI: 10.1530/EDM-23-0079 -
Journal of Diabetes Research 2024Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients...
Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1 (SDF-1)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.
Topics: Animals; Islets of Langerhans Transplantation; Diabetes Mellitus, Experimental; Myoblasts, Skeletal; Mice; Male; Insulin; Neovascularization, Physiologic; Hepatocyte Growth Factor; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A; Islets of Langerhans; Chemokine CXCL12; Blood Glucose; Diabetes Mellitus, Type 1; Signal Transduction; Insulin Secretion; Cell Differentiation
PubMed: 38800586
DOI: 10.1155/2024/5574968 -
International Journal of Surgery Case... May 2024LCH in adults is rarely encountered, with the preference in children and axial skeleton as predilection site. Limited understanding of adult LCH causes frequent...
INTRODUCTION AND IMPORTANCE
LCH in adults is rarely encountered, with the preference in children and axial skeleton as predilection site. Limited understanding of adult LCH causes frequent misdiagnosis, as our experience in an adult case of LCH threw off our differential diagnosis.
CASE PRESENTATION
A 21-year-old male was referred to our hospital due to pain in his right shoulder. Plain radiograph and MRI showed a solitary well-marginated lytic lesion on the distal third of the clavicle. Together with a clear history and physical exam, the benign bone cyst was suspected and we performed an open biopsy simultaneously with curettage followed by internal fixation using a bone graft. Pathology and immunohistochemistry dismissed our suspicion and confirmed LCH as the main diagnosis. At six months post-surgery, no signs of recurrence were seen on the fixated site nor complained by the patient.
DISCUSSION
Diagnosing LCH involves considering imaging appearances and patient demographics as initial clues. However, confirming the diagnosis requires a biopsy with proven CD1 expression. Currently, the majority of studies recommend confirming the diagnosis before initiating therapy. This precaution is necessary due to the unclear pathophysiology of LCH, which complicates the implementation of specific therapies. Based on benign features of skeletal lesions found from imaging, invasive treatment before biopsy confirmation still gave a satisfactory outcome despite not being in line with the current recommendation.
CONCLUSION
Excisional biopsy and curettage in solitary LCH yield satisfactory outcomes. However, further studies are needed with larger sample sizes and interventional designs.
PubMed: 38796936
DOI: 10.1016/j.ijscr.2024.109801 -
Viruses May 2024Dengue virus (DENV) is a continuing global threat that puts half of the world's population at risk for infection. This mosquito-transmitted virus is endemic in over 100... (Review)
Review
Dengue virus (DENV) is a continuing global threat that puts half of the world's population at risk for infection. This mosquito-transmitted virus is endemic in over 100 countries. When a mosquito takes a bloodmeal, virus is deposited into the epidermal and dermal layers of human skin, infecting a variety of permissive cells, including keratinocytes, Langerhans cells, macrophages, dermal dendritic cells, fibroblasts, and mast cells. In response to infection, the skin deploys an array of defense mechanisms to inhibit viral replication and prevent dissemination. Antimicrobial peptides, pattern recognition receptors, and cytokines induce a signaling cascade to increase transcription and translation of pro-inflammatory and antiviral genes. Paradoxically, this inflammatory environment recruits skin-resident mononuclear cells that become infected and migrate out of the skin, spreading virus throughout the host. The details of the viral-host interactions in the cutaneous microenvironment remain unclear, partly due to the limited body of research focusing on DENV in human skin. This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector, and the models used to study DENV interactions in the cutaneous environment.
Topics: Animals; Humans; Cytokines; Dengue; Dengue Virus; Host-Pathogen Interactions; Immunity, Innate; Skin; Virus Replication; Arthropods
PubMed: 38793609
DOI: 10.3390/v16050727 -
Cancers May 2024Langerhans cells (LCs) are professional Dendritic Cells (DCs) involved in immunoregulatory functions. At the skin level, LCs are immature. In response to tissue... (Review)
Review
BACKGROUND
Langerhans cells (LCs) are professional Dendritic Cells (DCs) involved in immunoregulatory functions. At the skin level, LCs are immature. In response to tissue injuries, they migrate to regional Lymph Nodes (LNs), reaching a full maturation state. Then, they become effective antigen-presenting cells (APCs) that induce anti-cancer responses. Notably, melanoma patients present several DC alterations in the Sentinel Lymph Node (SLN), where primary antitumoral immunity is generated. LCs are the most represented DCs subset in melanoma SLNs and are expected to play a key role in the anti-melanoma response. With this paper, we aim to review the current knowledge and future perspectives regarding LCs and melanoma.
METHODS
A systematic review was carried out according to the PRISMA statement using the PubMed (MEDLINE) library from January 2004 to January 2024, searching for original studies discussing LC in melanoma.
RESULTS
The final synthesis included 15 articles. Several papers revealed significant LCs-melanoma interactions.
CONCLUSIONS
Melanoma immune escape mechanisms include SLN LC alterations, favoring LN metastasis arrival/homing and melanoma proliferation. The SLN LCs of melanoma patients are defective but not irreversibly, and their function may be restored by appropriate stimuli. Thus, LCs represent a promising target for future immunotherapeutic strategies and cancer vaccines.
PubMed: 38791968
DOI: 10.3390/cancers16101890 -
International Journal of Molecular... May 2024Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal... (Review)
Review
Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to their ability to constantly shift their phenotype and adapt to the current microenvironment. Consequently, both macrophage populations play dual roles in psoriasis. In some circumstances, pro-inflammatory activated macrophages and Langerhans cells trigger psoriatic inflammation, while in other cases their anti-inflammatory stimulation results in amelioration of the disease. These features make macrophages interesting candidates for modern therapeutic strategies. Owing to the significant progress in knowledge, our review article summarizes current achievements and indicates future research directions to better understand the function of macrophages in psoriasis.
Topics: Psoriasis; Animals; Macrophages; Disease Models, Animal; Mice; Humans; Langerhans Cells; Immunity, Innate; Skin
PubMed: 38791342
DOI: 10.3390/ijms25105306 -
Cells May 2024Allogeneic islet transplantation has become a standard therapy for unstable type 1 diabetes. However, considering the large number of type 1 diabetic patients, the... (Review)
Review
Allogeneic islet transplantation has become a standard therapy for unstable type 1 diabetes. However, considering the large number of type 1 diabetic patients, the shortage of donors is a serious issue. To address this issue, clinical islet xenotransplantation is conducted. The first clinical islet xenotransplantation was performed by a Swedish team using fetal pancreatic tissue. Thereafter, clinical trials of islet xenotransplantation were conducted in New Zealand, Russia, Mexico, Argentina, and China using neonatal pig islets. In clinical trials, fetal or neonatal pancreata are used because of the established reliable islet isolation methods. These trials demonstrate the method's safety and efficacy. Currently, the limited number of source animal facilities is a problem in terms of promoting islet xenotransplantation. This limitation is due to the high cost of source animal facilities and the uncertain future of xenotransplantation. In the United States, the first xenogeneic heart transplantation has been performed, which could promote xenotransplantation. In Japan, to enhance xenotransplantation, the 'Medical Porcine Development Association' has been established. We hope that xenogeneic transplantation will become a clinical reality, serving to address the shortage of donors.
Topics: Islets of Langerhans Transplantation; Transplantation, Heterologous; Animals; Humans; Graft Rejection; Swine; Treatment Outcome; Diabetes Mellitus, Type 1; Clinical Trials as Topic; Islets of Langerhans
PubMed: 38786050
DOI: 10.3390/cells13100828