There is a group of diseases characterized by inflammatory nodules which generally located on the lower leg. They have certain clinical appearances in common, which often makes a differential diagnosis difficult or impossible on clinical grounds alone. There is a great variation in histopathologic appearance, which depends on the duration of the lesions and sites from specimens are obtained for biopsy. Therefore, separating and subclassifying inflammatory nodule lesions of the legs, based on the subtle clinical and histological variation, is not easy. Despite all these difficulties, a specific diagnosis can be made with an adequate clinic-pathologic correlation.
Inflammatory nodules; Lower leg
Keratoacanthoma (KA) is a benign epidermal tumor, characterized by rapid and abundant growth, a tendency toward spontaneous regression and histopathologic similarity to squamous cell carcinoma (SCC). Because KA can be easily misdiagnosed as SCC, surgery is considered the treatment of choice. Recently, regression of KAs following application of 5% imiquimod cream (Aldara®) has been reported. We present 4 cases of KA treated with topical imiquimod, applied 3 to 4 times a week. Obvious improvement was observed after 4 to 6 weeks of application and the lesions were almost cleared leaving scars after 9 to 11 weeks. These results show that topical imiquimod can be an effective option for the conservative management of KA as previously reported. We also suggest that lesions treated with imiquimod cream should be considered for biopsy to judge histopathological remission after 5 to 8 weeks of application to shorten the duration of the treatment.
Despite numerous treatments available for deteriorated cutaneous wound healing such as a diabetic foot, there is still the need for more effective therapy. Adipose-derived stem cells (ASCs) are mesenchymal stem cells, which are self-renewing and multipotent. Mesenchymal stem cells have the potential for tissue repair and regeneration.
To investigate the effects of human ASCs on the healing of cutaneous wounds in nude mice.
15-mm round full-thickness skin defects were generated on the back of BALB/c nude mice. The mice were divided into three groups for wound coverage: (i) human ASCs-populated collagen gel, (ii) human dermal fibroblasts-populated collagen gel, and (iii) collagen gel alone. Wound contraction was prevented with a splint method. Wound size was measured 10 days after injury. At 28 days histological analysis was performed.
Both ASCs and dermal fibroblasts accelerated wound closure, but dermal fibroblasts were more effective than ASCs. At 28 days, the dermal portion of ASCs or dermal fibroblasts wound scars were thicker than collagen gel wound scars.
ASCs and dermal fibroblasts stimulate cutaneous wound healing and improve scar thickness.
Adipose tissue; Fibroblast; Mesenchymal stem cell; Mouse; Wound healing
Melanocytic nevi are subject to change with age in both clinical and histopathologic findings. In 1991, Cho et al. first reported three cases of lobulated intradermal nevi and suggested their cases represented an unusual form of regressing melanocytic nevus. Herein we report four cases of lobulated intradermal nevus and review previous literature.
Lobulated intradermal nevus
Primary cutaneous CD4 positive small/medium T cell lymphoma (PCSM-TCL) is a provisional entity in the new WHO-EORTC classification for cutaneous lymphoma, and it is a rare disease with a favorable clinical course. PCSM-TCL may present with different clinical and pathologic features associated with the biologic behavior of the disease. Herein we report on a 63-year-old woman with multiple, multifocal, erythematous to violaceous papules and plaques that progressed despite local radiotherapy.
CD4; Cutaneous T cell lymphoma; Small/medium
Clear cell acanthoma (CCA) is a rare benign epidermal tumor. It usually presents as a flat nodule or dome-shaped plaque and is often localized on the legs of the elderly. We observed an unusual case of polypoid CCA on the nipple of a 14-year-old girl. At present, a few cases of CCA on the nipple area have been reported in the literature. However, CCA presented as a polypoid tumor on the nipple area has been reported very rarely. We herein report the very rare case of polypoid CCA on the nipple and suggest that CCA should be included in the clinical differential diagnosis of polypoid lesions on the nipple.
Clear cell acanthoma; Nipple
Imiquimod is a new immunomodulating agent with antitumor and antiviral properties that has been shown to be clinically effective in various kinds of skin diseases, including precancerous dermatoses. Erythroplasia of Queyrat is a carcinoma in situ that mainly occurs on the glans penis. There are several non-invasive treatment options for erythroplasia of Queyrat such as photodynamic therapy, cryosurgery and applying various kinds of topical agents. We now report a case of typical erythroplasia of Queyrat on glans penis associated with human papillomavirus type 16 infection that was treated by imiquimod 5% cream and the subsequent excision of an imiquimod-resistant penile lesion.
Erythroplasia of Queyrat; Imiquimod
Hydroa vacciniforme (HV) is a photosensitivity disorder characterized by recurrent necrotic vesiculopapules on sun-exposed areas, which heal spontaneously during adolescence. Recently, an association has been reported between latent Epstein-Barr virus (EBV) infection and atypical HV-like eruption and malignant potential. However, latent EBV infection has also been reported in the setting of typical HV. An 11-year-old girl presented with recurrent, scattered, discrete vesicular eruptions with scarring on the face and the extensor surfaces of both forearms. In-situ hybridization was carried out to detect latent EBV infection. Based on the clinical and histopathological findings, typical EBV-associated HV was suspected.
Epstein-Barr virus; Hydroa vacciniforme
The brain requires task-dependent interregional coherence of information flow in the anatomically connected neural network. However, it is still unclear how a neuronal group can flexibly select its communication target. In this study, we revealed a hidden routing mechanism on the basis of recurrent connections. Our simulation results based on the spike response model show that recurrent connections between excitatory and inhibitory neurons modulate the resonant frequency of a local neuronal group, and that this modulation enables a neuronal group to receive selective information by filtering a preferred frequency component. We also found that the recurrent connection facilitates the successful routing of any necessary information flow between neuronal groups through frequency-dependent resonance of synchronized oscillations. Taken together, these results suggest that recurrent connections act as a phase-locking neuronal tuner which determines the resonant frequency of a local group and thereby controls the preferential routing of incoming signals.
Phosphoinositide 3-kinases (PI3Ks) and Ras and Rho family small GTPases are key regulators of cell polarization, motility, and chemotaxis.They influence each other's activities by direct and indirect feedback processes that are only partially understood. Here, we show that 21 small GTPase homologs activate PI3K. Using a microscopy-based binding assay, we show that K-Ras, H-Ras, and five homologous Ras family small GTPases function upstream of PI3K by directly binding the PI3K catalytic subunit, p110. In contrast, several Rho family small GTPases activated PI3K by an indirect cooperative positive feedback that required a combination of Rac, CDC42, and RhoG small GTPase activities. Thus, a distributed network of Ras and Rho family small GTPases induces and reinforces PI3K activity, explaining past challenges to elucidate the specific relevance of different small GTPases in regulating PI3K and controlling cell polarization and chemotaxis.
Cellular behavior is determined not by a single molecule but by many molecules that interact strongly with one another and form a complex network. It is unclear whether cellular behavior can be controlled by regulating certain molecular components in the network. By analyzing a variety of biomolecular regulatory networks, we discovered that only a small fraction of the network components need to be regulated to govern the network dynamics and control cellular behavior. We defined a minimal set of network components that must be regulated to make the cell reach a desired stable state as the control kernel and developed a general algorithm for identifying it. We found that the size of the control kernel was related to both the topological and logical characteristics of a network. Intriguingly, the control kernel of the human signaling network included many drug targets and chemical-binding interactions, suggesting therapeutic application of the control kernel.
Treatment for patent ductus arteriosus (PDA) in premature infants can consist of medical or surgical approaches. The appropriate therapeutic regimen remains contentious. This study evaluated the role of surgery in improving the survival of premature neonates weighing less than 1,500 g with PDA.
Materials and Methods
From January 2008 to June 2011, 68 patients weighing less than 1,500 g with PDA were enrolled. The patients were divided into three groups: a group managed only by medical treatment (group I), a group requiring surgery after medical treatment (group II), and a group requiring primary surgical treatment (group III).
The rate of conversion to surgical methods due to failed medical treatment was 67.6% (25/37) in the patients with large PDA (≥2 mm in diameter). The number of patients who could be managed with medical treatment was nine which was only 20.5% (9/44) of the patients with large PDA. There was no surgery-related mortality. Group III displayed a statistically significantly low rate of development of bronchopulmonary dysplasia (BPD) (p=0.008). The mechanical ventilation time was significantly longer in group II (p=0.002).
Medical treatment has a high failure rate in infants weighing less than 1,500 g with PDA exceeding 2.0 mm. Surgical closure following medical treatment requires a longer mechanical ventilation time and increases the incidence of BPD. Primary surgical closure of PDA exceeding 2.0 mm in the infants weighing less than 1,500 g should be considered to reduce mortality and long-term morbidity events including BPD.
Patent ductus arteriosus; Premature; Neonate
Synovial sarcoma is a malignant soft tissue tumor that most commonly occurs in the extremities of young and middle-aged adults, in the vicinity of large joints. Although synovial sarcoma is frequently associated with joints, it may arise in unexpected sites, such as the mediastinum, heart, lung, pleura, or chest wall. Primary synovial sarcoma of the pleura is rare. To date, nearly 36 cases of primary synovial sarcoma of the pleura have been reported since Gaertner et al. published the first case in 1996. The oncologic characteristics, treatment, and prognosis for pleural synovial sarcomas are not well defined because of a paucity of data. However, a multimodal approach, including surgical resection, chemotherapy, and radiotherapy, has generally been suggested. We report the outcome of one patient with primary pleural synovial sarcoma treated with radical resection and adjuvant treatment.
Primary synovial sarcoma; Pleura; Synovial sarcoma
Cell cycle process of budding yeast (Saccharomyces cerevisiae) consists of four phases: G1, S, G2 and M. Initiated by stimulation of the G1 phase, cell cycle returns to the G1 stationary phase through a sequence of the S, G2 and M phases. During the cell cycle, a cell verifies whether necessary conditions are satisfied at the end of each phase (i.e., checkpoint) since damages of any phase can cause severe cell cycle defect. The cell cycle can proceed to the next phase properly only if checkpoint conditions are met. Over the last decade, there have been several studies to construct Boolean models that capture checkpoint conditions. However, they mostly focused on robustness to network perturbations, and the timing robustness has not been much addressed. Only recently, some studies suggested extension of such models towards timing-robust models, but they have not considered checkpoint conditions.
To construct a timing-robust Boolean model that preserves checkpoint conditions of the budding yeast cell cycle, we used a model verification technique, ‘model checking’. By utilizing automatic and exhaustive verification of model checking, we found that previous models cannot properly capture essential checkpoint conditions in the presence of timing variations. In particular, such models violate the M phase checkpoint condition so that it allows a division of a budding yeast cell into two before the completion of its full DNA replication and synthesis. In this paper, we present a timing-robust model that preserves all the essential checkpoint conditions properly against timing variations. Our simulation results show that the proposed timing-robust model is more robust even against network perturbations and can better represent the nature of cell cycle than previous models.
To our knowledge this is the first work that rigorously examined the timing robustness of the cell cycle process of budding yeast with respect to checkpoint conditions using Boolean models. The proposed timing-robust model is the complete state-of-the-art model that guarantees no violation in terms of checkpoints known to date.
Timing robustness; Yeast cell cycle regulatory network; Model checking; Asynchronous Boolean networks
Apoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems.
Here, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose- and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level.
Using this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis.
Apoptotic pathways; Cisplatin; Mathematical model
The co-regulation of transcription factors (TFs) has been widely observed in various species. Why is such a co-regulation mechanism needed for transcriptional regulation? To answer this question, the following experiments and analyses were performed. First, examination of the human gene regulatory network (GRN) indicated that co-regulation was significantly enriched in the human GRN. Second, mathematical simulation of an artificial regulatory network showed that the co-regulation mechanism was related to the biphasic dose–response patterns of TFs. Third, the relationship between the co-regulation mechanism and the biphasic dose–response pattern was confirmed using microarray experiments examining different time points and different doses of the toxicant tetrachlorodibenzodioxin. Finally, two mathematical models were constructed to mimic highly co-regulated networks (HCNs) and little co-regulated networks (LCNs), and we found that HCNs were more robust to parameter perturbation than LCNs, whereas LCNs were faster in adaptation to environmental changes than HCNs.
How does a cell respond to numerous external stresses with a limited number of internal molecular components? It has been observed that there are some common responses of yeast to various stresses, but most observations were based on gene-expression profiles and only some part of the common responses were intensively investigated. So far there has been no system-level analysis to identify commonly responsive or regulated genes against various stresses. In this study, we identified a core regulation module (CRM), a commonly involved regulation structure in the regulatory networks of yeast, which cells reuse in response to an array of environmental stresses. We found that regulators in the CRM constitute a hierarchical backbone of the yeast regulatory network and that the CRM is evolutionarily well conserved, stable against genetic variations and crucial for cell growth. All these findings were consistently held up to considerable noise levels that we introduced to address experimental noise and the resulting false positives of regulatory interactions. We conclude that the CRM of yeast might be an evolutionarily conserved information processing unit that endows a cell with enhanced robustness and efficiency in dealing with numerous environmental stresses with a limited number of internal elements.
Bullous systemic lupus erythematosus (SLE) is a kind of LE-non-specific bullous skin disease that is rarely induced by a medication. We describe the first case of bullous SLE to develop after administration of methimazole. A 31-yr-old woman presented with generalized erythematous patches, multiple bullae, arthralgia, fever, conjunctivitis, and hemolytic anemia. Biopsy of her bulla showed linear deposition of lgG, lgA, C3, fibrinogen, and C1q at dermo-epidermal junction. She was diagnosed as bullous SLE and treated with prednisolone, dapsone, hydroxychloroquine, and methotrexate. Our experience suggests that SLE should be considered as a differential diagnosis when bullous skin lesions develop in patients being treated for hyperthyroidism.
Bullous Systemic Lupus Erythematosus; Drug-Induced Lupus Erythematosus; Methimazole; Graves Disease
Adipose-derived stem cells (ASCs) are mesenchymal stem cells that have recently been applied to tissue repair and regeneration. Keratinocytes and dermal fibroblasts play key roles in cutaneous wound healing.
We investigated the paracrine effects of ASCs on HaCaT cells (i.e., immortalized human keratinocytes) and human dermal fibroblasts to explore the mechanism of the effects of ASCs on cutaneous wound healing.
HaCaT cells and primary cultured human dermal fibroblasts were treated with 50% conditioned medium of ASCs (ASC-CM). Viability, in vitro wound healing, and fibroblast-populated collagen lattice contraction assays were conducted, and reverse transcription-polymerase chain reaction (RT-PCR) for the type I procollagen α1 chain gene was performed.
The proliferation of HaCaT cells and fibroblasts was increased by ASC-CM in the viability assay. ASC-CM promoted in vitro wound healing of HaCaT cells and increased the contraction of the fibroblast-populated collagen lattice. RT-PCR showed that the transcription of the type I procollagen α1 chain gene in fibroblasts was upregulated by ASC-CM.
The stimulatory effect of ASC on cutaneous wound healing may be partially mediated by paracrine effects of ASCs on other skin cells. Application of ASCs or ASC-derived molecules could be an innovative therapeutic approach in the treatment of chronic wounds and other conditions.
Adipose tissue; Fibroblasts; Keratinocytes; Mesenchymal stem cells; Wound healing
Network motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a “spatiotemporal network motif,” a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts.
On the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns.
Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks.
Synchronized bursting activity (SBA) is a remarkable dynamical behavior in both ex vivo and in vivo neural networks. Investigations of the underlying structural characteristics associated with SBA are crucial to understanding the system-level regulatory mechanism of neural network behaviors.
In this study, artificial pulsed neural networks were established using spike response models to capture fundamental dynamics of large scale ex vivo cortical networks. Network simulations with synaptic parameter perturbations showed the following two findings. (i) In a network with an excitatory ratio (ER) of 80-90%, its connective ratio (CR) was within a range of 10-30% when the occurrence of SBA reached the highest expectation. This result was consistent with the experimental observation in ex vivo neuronal networks, which were reported to possess a matured inhibitory synaptic ratio of 10-20% and a CR of 10-30%. (ii) No SBA occurred when a network does not contain any all-positive-interaction feedback loop (APFL) motif. In a neural network containing APFLs, the number of APFLs presented an optimal range corresponding to the maximal occurrence of SBA, which was very similar to the optimal CR.
In a neural network, the evolutionarily selected CR (10-30%) optimizes the occurrence of SBA, and APFL serves a pivotal network motif required to maximize the occurrence of SBA.