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The Journal of Allergy and Clinical... May 2024The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates... (Review)
Review
The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at one year of biologic treatment. However, psoriasis may recur following drug withdrawal, and so patients tend to remain on costly treatment indefinitely. Here, we review research into the 'inflammatory memory' in resolved psoriasis skin and the potential mechanisms leading to psoriasis recurrence following drug withdrawal. Research has implicated immune cells such as tissue-resident memory T cells, Langerhans cells and dermal dendritic cells, and there is growing interest in keratinocytes and fibroblasts. A better understanding of the interactions between these cell populations, enabled by single-cell technologies, will help to elucidate the events underpinning the shift from remission to recurrence. This may inform the development of personalised strategies for sustaining remission while reducing long-term drug burden.
PubMed: 38761994
DOI: 10.1016/j.jaci.2024.05.008 -
Cell Transplantation 2024Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously revealed that a gelatin...
Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously revealed that a gelatin hydrogel nonwoven fabric (GHNF) markedly improved subcutaneous islet engraftment. We herein investigated whether the addition of adipose tissue-derived stem cells (ADSCs) to GHNF affected the outcome. A silicone spacer sandwiched between two GHNFs with (AG group) or without (GHNF group) ADSCs, or a silicone spacer alone (Silicone group) was implanted into the subcutaneous space of healthy mice at 6 weeks before transplantation, then diabetes was induced 7 days before transplantation. Syngeneic islets were transplanted into the pretreated space. Intraportal transplantation (IPO group) was also performed to compare the transplant efficiency. Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, and inflammatory mediators were evaluated. The results in the subcutaneous transplantation were compared using the Silicone group as a control. The results of the IPO group were also compared with those of the AG group. The AG group showed significantly better blood glucose changes than the Silicone and the IPO groups. The cure rate of AG group (72.7%) was the highest among the groups (GHNF; 40.0%, IPO; 40.0%, Silicone; 0%). The number of vWF-positive vessels in the subcutaneous space of the AG group was significantly higher than that in other groups before transplantation ( < 0.01). Lectin angiography also showed that the same results ( < 0.05). According to the results of the ADSCs tracing, ADSCs did not exist at the transplant site (6 weeks after implantation). The positive rates for laminin and collagen III constructed around the transplanted islets did not differ among groups. Inflammatory mediators were higher in the Silicone group, followed by the AG and GHNF groups. Pretreatment using bioabsorbable scaffolds combined with ADSCs enhanced neovascularization in subcutaneous space, and subcutaneous islet transplantation using GHNF with ADSCs was superior to intraportal islet transplantation.
Topics: Animals; Islets of Langerhans Transplantation; Adipose Tissue; Gelatin; Mice; Hydrogels; Male; Diabetes Mellitus, Experimental; Stem Cells; Islets of Langerhans; Blood Glucose; Mice, Inbred C57BL
PubMed: 38756050
DOI: 10.1177/09636897241251621 -
Pulmonology May 2024
PubMed: 38755092
DOI: 10.1016/j.pulmoe.2024.04.002 -
Archives of Pathology & Laboratory... May 2024Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.
CONTEXT.—
Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children.
OBJECTIVE.—
To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH.
DESIGN.—
We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients.
RESULTS.—
A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor.
CONCLUSIONS.—
Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.
PubMed: 38749502
DOI: 10.5858/arpa.2023-0236-OA -
The Journal of Clinical Investigation May 2024
Topics: Animals; Ghrelin; Mice; Islets of Langerhans; Mice, Knockout; Gene Deletion; Organ Size
PubMed: 38747294
DOI: 10.1172/JCI182168 -
Frontiers in Endocrinology 2024The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor...
INTRODUCTION
The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome.
METHODS
Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas.
RESULTS
Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon.
DISCUSSION
This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.
Topics: Animals; Tacrolimus; Metabolic Syndrome; Obesity; Rats; Rats, Sprague-Dawley; Male; Disease Models, Animal; Immunosuppressive Agents; Insulin-Secreting Cells; Phenotype; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Insulin Resistance; Diet, High-Fat
PubMed: 38745946
DOI: 10.3389/fendo.2024.1388361 -
Cell Transplantation 2024Pancreatic islet transplantation is one of the clinical options for certain types of diabetes. However, difficulty in maintaining islets prior to transplantation limits...
Pancreatic islet transplantation is one of the clinical options for certain types of diabetes. However, difficulty in maintaining islets prior to transplantation limits the clinical expansion of islet transplantations. Our study introduces a dynamic culture platform developed specifically for primary human islets by mimicking the physiological microenvironment, including tissue fluidics and extracellular matrix support. We engineered the dynamic culture system by incorporating our distinctive microwell-patterned porous collagen scaffolds for loading isolated human islets, enabling vertical medium flow through the scaffolds. The dynamic culture system featured four 12 mm diameter islet culture chambers, each capable of accommodating 500 islet equivalents (IEQ) per chamber. This configuration calculates > five-fold higher seeding density than the conventional islet culture in flasks prior to the clinical transplantations (442 vs 86 IEQ/cm). We tested our culture platform with three separate batches of human islets isolated from deceased donors for an extended period of 2 weeks, exceeding the limits of conventional culture methods for preserving islet quality. Static cultures served as controls. The computational simulation revealed that the dynamic culture reduced the islet volume exposed to the lethal hypoxia (< 10 mmHg) to ~1/3 of the static culture. Dynamic culture ameliorated the morphological islet degradation in long-term culture and maintained islet viability, with reduced expressions of hypoxia markers. Furthermore, dynamic culture maintained the islet metabolism and insulin-secreting function over static culture in a long-term culture. Collectively, the physiological microenvironment-mimetic culture platform supported the viability and quality of isolated human islets at high-seeding density. Such a platform has a high potential for broad applications in cell therapies and tissue engineering, including extended islet culture prior to clinical islet transplantations and extended culture of stem cell-derived islets for maturation.
Topics: Humans; Islets of Langerhans; Tissue Scaffolds; Collagen; Porosity; Cell Culture Techniques; Islets of Langerhans Transplantation
PubMed: 38742734
DOI: 10.1177/09636897241249556 -
Brain Tumor Research and Treatment Apr 2024Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is...
Eosinophilic granuloma (EG), a subtype of Langerhans cell histiocytosis (LCH), the monostotic form, is a rare condition characterized by a solitary bone lesion. It is even more unusual for this condition to be accompanied by an epidural hematoma (EDH). This case is unique in that it is the first to involve delayed EDH following a seizure. We describe a remarkable example of EG accompanied by an EDH and consider the rarity of this comorbidity. A 32-month-old boy developed a rapidly growing skull mass following a minor head injury. During surgical preparation for a biopsy, the patient experienced a single convulsion. Imaging following the seizure revealed an EDH in the vicinity of the mass. The mass was excised and confirmed to be an EG, but with positive margins. The patient underwent chemotherapy after systemic skeletal evaluation, in accordance with the LCH III protocol established by the Histiocytosis Society. EG is a rare neoplasm that typically presents as a painless growth on the skull that gradually enlarges over time. The correlation between EG and EDH is exceedingly uncommon, with only a few documented cases. This case study underscores the significance of considering EG in the differential diagnosis of an expanding cranium mass, even when associated with EDH. Prompt diagnosis and treatment can prevent serious complications and improve patient outcomes.
PubMed: 38742265
DOI: 10.14791/btrt.2024.0018 -
Brain Tumor Research and Treatment Apr 2024Langerhans cell histiocytosis (LCH) is a rare condition in adults, especially when it is limited to a single area of the skull, known as solitary calvarial involvement....
Langerhans cell histiocytosis (LCH) is a rare condition in adults, especially when it is limited to a single area of the skull, known as solitary calvarial involvement. In this case report, we present a unique instance of LCH affecting the parietal bone with a pus-draining fistula. This is a rare and unusual presentation at this location, which has been scarcely reported in medical literature. A 30-year-old woman with no prior comorbidity presented with complaints of headache that persisted for a year. She also had swelling on her scalp and a yellowish discharge for 3 weeks, but no neurological problems were observed. Radiology revealed thinning of the calvaria, with ragged margins along the inner table, multiple focal erosions, and involvement of overlying soft tissue and bony sequestrum. The patient underwent biparietal craniotomy and excision of the lesion. The histopathology report showed LCH. After 8 months of follow-up, there was no recurrence. The management of solitary calvarial involvement by LCH with masquerading presentation as a scalp infection can be achieved through complete excision of the lesions, resulting in a favorable outcome.
PubMed: 38742259
DOI: 10.14791/btrt.2023.0043 -
PLoS Computational Biology May 2024Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and...
Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disruptions in this coordination are implicated in irregular insulin secretion, a hallmark of diabetes. Recently, innovative approaches, such as integrating multicellular calcium imaging with network analysis, have emerged for a quantitative assessment of the cellular activity in islets. However, different groups use distinct experimental preparations, microscopic techniques, apply different methods to process the measured signals and use various methods to derive functional connectivity patterns. This makes comparisons between findings and their integration into a bigger picture difficult and has led to disputes in functional connectivity interpretations. To address these issues, we present here a systematic analysis of how different approaches influence the network representation of islet activity. Our findings show that the choice of methods used to construct networks is not crucial, although care is needed when combining data from different islets. Conversely, the conclusions drawn from network analysis can be heavily affected by the pre-processing of the time series, the type of the oscillatory component in the signals, and by the experimental preparation. Our tutorial-like investigation aims to resolve interpretational issues, reconcile conflicting views, advance functional implications, and encourage researchers to adopt connectivity analysis. As we conclude, we outline challenges for future research, emphasizing the broader applicability of our conclusions to other tissues exhibiting complex multicellular dynamics.
PubMed: 38739680
DOI: 10.1371/journal.pcbi.1012130