Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully ...understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.
While the bone marrow attracts tumor cells in many solid cancers leading to poor outcome in affected patients, comprehensive analyses of bone marrow metastases have not been performed on a ...single-cell level. We here set out to capture tumor heterogeneity and unravel microenvironmental changes in neuroblastoma, a solid cancer with bone marrow involvement. To this end, we employed a multi-omics data mining approach to define a multiplex imaging panel and developed DeepFLEX, a pipeline for subsequent multiplex image analysis, whereby we constructed a single-cell atlas of over 35,000 disseminated tumor cells (DTCs) and cells of their microenvironment in the metastatic bone marrow niche. Further, we independently profiled the transcriptome of a cohort of 38 patients with and without bone marrow metastasis. Our results revealed vast diversity among DTCs and suggest that FAIM2 can act as a complementary marker to capture DTC heterogeneity. Importantly, we demonstrate that malignant bone marrow infiltration is associated with an inflammatory response and at the same time the presence of immuno-suppressive cell types, most prominently an immature neutrophil/granulocytic myeloid-derived suppressor-like cell type. The presented findings indicate that metastatic tumor cells shape the bone marrow microenvironment, warranting deeper investigations of spatio-temporal dynamics at the single-cell level and their clinical relevance.
Summary
Background and objectives
Pyoderma gangrenosum is an ulcerative autoinflammatory disease, lacking distinct histopathological characteristics to differentiate from other ulcerating conditions, ...like venous leg ulcers. The objective of this study was therefore to find histopathological characteristics of pyoderma gangrenosum in a head‐to‐head comparison to venous leg ulcers.
Patients and methods
Eight tissue samples of pyoderma gangrenosum, twelve samples of venous leg ulcers and six samples of healthy skin were stained using an immunohistological multi antigen staining technology. The immune infiltrate and its spatial distribution were analyzed with contextual tissue cytometry software using fluorescence images.
Results
The dense epidermal presence of CD45RO+ memory T cells and the rarefication of CD1a+ Langerhans cells in the epidermis were defining markers for pyoderma gangrenosum, implicating an epidermal immune reaction. In addition, high numbers of CD11c+CD68+ pro‐inflammatory M1 macrophages were detected in the dermis, significantly extending the numbers seen in venous leg ulcers.
Conclusions
The histopathological differences found between pyoderma gangrenosum and venous leg ulcer can be used to distinguish between the two diseases and thus provide an important aid for the rapid initiation of adequate therapy. In addition, our data hint at an antigen‐driven process in the epidermis, possibly involving CD1a+ Langerhans cells.
Zusammenfassung
Hintergrund und Ziele
Pyoderma gangraenosum ist eine ulzerierende, autoinflammatorische Erkrankung. Es gibt keine eindeutigen histopathologischen Merkmale zur Differenzierung von ...anderen Ursachen chronischer Wunden wie dem Ulcus cruris venosum. Ziel dieser Studie war es, histopathologische Merkmale von Pyoderma gangraenosum und Unterschiede zu venösen Ulzerationen zu detektieren.
Patienten und Methodik
Acht Gewebeproben von Pyoderma gangraenosum, zwölf Proben von Ulcus cruris venosum und sechs Proben von gesunder Haut wurden einer immunhistologischen Multi‐Antigen‐Analyse unterzogen. Das Immuninfiltrat und seine räumliche Verteilung wurden anhand von Fluoreszenzbildern mit einer Gewebezytometriesoftware analysiert.
Ergebnisse
Die dichte epidermale Präsenz von CD45RO+‐T‐Gedächtnis‐Zellen und die Rarefizierung von CD1a+‐Langerhans‐Zellen in der Epidermis waren Marker für Pyoderma gangraenosum, welche auch auf eine epidermale Immunreaktion schließen lassen. Darüber hinaus konnte dermal eine hohe Anzahl CD11c+CD68+ pro‐inflammatorischer M1‐Makrophagen nachgewiesen werden. Diese überstieg die Anzahl der in venösen Ulzerationen beobachteten Makrophagen deutlich.
Schlussfolgerungen
Die histopathologischen Unterschiede zwischen Pyoderma gangraenosum und Ulcus cruris venosum können zur Unterscheidung der beiden Erkrankungen herangezogen werden und somit eine wichtige Hilfe zur schnellen Einleitung einer adäquaten Therapie sein. Darüber hinaus deuten unsere Daten auf einen antigengesteuerten Prozess in der Epidermis hin, möglicherweise unter Beteiligung von CD1a+ Langerhans‐Zellen.
Zusammenfassung
Hintergrund und Ziele
Pyoderma gangraenosum ist eine ulzerierende, autoinflammatorische Erkrankung. Es gibt keine eindeutigen histopathologischen Merkmale zur Differenzierung von ...anderen Ursachen chronischer Wunden wie dem Ulcus cruris venosum. Ziel dieser Studie war es, histopathologische Merkmale von Pyoderma gangraenosum und Unterschiede zu venösen Ulzerationen zu detektieren.
Patienten und Methodik
Acht Gewebeproben von Pyoderma gangraenosum, zwölf Proben von Ulcus cruris venosum und sechs Proben von gesunder Haut wurden einer immunhistologischen Multi‐Antigen‐Analyse unterzogen. Das Immuninfiltrat und seine räumliche Verteilung wurden anhand von Fluoreszenzbildern mit einer Gewebezytometriesoftware analysiert.
Ergebnisse
Die dichte epidermale Präsenz von CD45RO
+
‐T‐Gedächtnis‐Zellen und die Rarefizierung von CD1a
+
‐Langerhans‐Zellen in der Epidermis waren Marker für Pyoderma gangraenosum, welche auch auf eine epidermale Immunreaktion schließen lassen. Darüber hinaus konnte dermal eine hohe Anzahl CD11c
+
CD68
+
pro‐inflammatorischer M1‐Makrophagen nachgewiesen werden. Diese überstieg die Anzahl der in venösen Ulzerationen beobachteten Makrophagen deutlich.
Schlussfolgerungen
Die histopathologischen Unterschiede zwischen Pyoderma gangraenosum und Ulcus cruris venosum können zur Unterscheidung der beiden Erkrankungen herangezogen werden und somit eine wichtige Hilfe zur schnellen Einleitung einer adäquaten Therapie sein. Darüber hinaus deuten unsere Daten auf einen antigengesteuerten Prozess in der Epidermis hin, möglicherweise unter Beteiligung von CD1a
+
Langerhans‐Zellen.
Consider a linear autonomous Hamiltonian system with a time periodic bound
state solution. In this paper we study the structural instability of this bound
state ^M relative to time almost periodic ...perturbations which are small,
localized and Hamiltonian.
This class of perturbations includes those whose time dependence is periodic,
but encompasses a large class of those with finite (quasiperiodic) or
infinitely many non-commensurate frequencies. Problems of the type considered
arise in many areas of application including ionization physics and the
propagation of light in optical fibers in the presence of defects.
The mechanism of instability is radiation damping due to resonant coupling of
the bound state to the continuum modes by the time-dependent perturbation. This
results in a transfer of energy from the discrete modes to the continuum. The
rate of decay of solutions is slow and hence the decaying bound states can be
viewed as metastable. These results generalize those of A. Soffer and M.I.
Weinstein, who treated localized time-periodic perturbations of a particular
form. In the present work, new analytical issues need to be addressed in view
of (i) the presence of infinitely many frequencies which may resonate with the
continuum as well as (ii) the possible accumulation of such resonances in the
continuous spectrum. The theory is applied to a general class of Schr\"odinger
operators.
Consider a linear autonomous Hamiltonian system with a time periodic bound state solution. In this paper we study the structural instability of this bound state ^M relative to time almost periodic ...perturbations which are small, localized and Hamiltonian. This class of perturbations includes those whose time dependence is periodic, but encompasses a large class of those with finite (quasiperiodic) or infinitely many non-commensurate frequencies. Problems of the type considered arise in many areas of application including ionization physics and the propagation of light in optical fibers in the presence of defects. The mechanism of instability is radiation damping due to resonant coupling of the bound state to the continuum modes by the time-dependent perturbation. This results in a transfer of energy from the discrete modes to the continuum. The rate of decay of solutions is slow and hence the decaying bound states can be viewed as metastable. These results generalize those of A. Soffer and M.I. Weinstein, who treated localized time-periodic perturbations of a particular form. In the present work, new analytical issues need to be addressed in view of (i) the presence of infinitely many frequencies which may resonate with the continuum as well as (ii) the possible accumulation of such resonances in the continuous spectrum. The theory is applied to a general class of Schr\"odinger operators.
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