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Transcription factor GATA3 is essential for the developmental processes of T cells. Recently, the silencer of a cytokine IFNγ gene was identified, the inhibitory activity of which requires GATA3. GATA3 has 2 Zn fingers and the commonly used GATA3 deficient mice lack both fingers (D2). We have established a mouse line that lacks only one Zn finger close to the C terminus (D1). The D1 mice line developed dermatitis, which was not observed in D2 mice. The expression of S100a8/S100a9 was elevated in D1 to a level higher than in D2, suggesting their roles in dermatitis development. CD8 T cells of both D1 and D2 lines expressed inhibitory receptors associated with the exhausted state. In the absence of MHC class II, the skin inflammation was exacerbated in both lines. The gene expression pattern of CD8 T cells became similar to that of effector T cells. Blocking Ab against LAG3 upregulated the expression of the effector molecules of T cells. These results suggest that the disfunction of GATA3 can lead to the spontaneous activation of CD8 T cells that causes skin inflammation, and that suppressive activity of MHC class II ‐ LAG3 interaction ameliorates dermatitis development. [ABSTRACT FROM AUTHOR]

Background: In the world, approximately 1% of the population suffers from chronic spontaneous urticaria (CSU), burdening patients' quality of life and challenging clinicians in terms of treatment. Recent scientific evidence has unveiled the potential role of a family of molecules known as "alarmins" in the pathogenesis of CSU. Methods: Papers focusing on the potential pathogenetic role of alarmins in CSU with diagnostic (as biomarkers) and therapeutic implications, in English and published in PubMed, Scopus, Web of Science, as well as clinical studies registered in ClinicalTrials.gov and the EudraCT Public website, were reviewed. Results: The epithelial-derived alarmins thymic stromal lymphopoietin and IL-33 could be suitable diagnostic and prognostic biomarkers and possible therapeutic targets in CSU. The evidence on the role of non-epithelial-derived alarmins (heat shock proteins, S-100 proteins, eosinophil-derived neurotoxin, β-defensins, and acid uric to high-density lipoproteins ratio) is more heterogeneous and complex. Conclusions: More homogeneous studies on large cohorts, preferably supported by data from international registries, will be able to elucidate the intriguing and complex pathogenetic world of CSU. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, a global health challenge, significantly impacts women worldwide, causing morbidity, disability, and mortality. Objectives: To analyze the role of genes encoding S100 calcium-binding proteins and their relationship with radiation as possible markers in breast carcinogenesis. Methods: The normal MCF-10F cell line was used to study the role of ionizing radiation and estrogen to induce distinct stages of malignancy giving rise to an in vitro experimental breast cancer model. Results: Analysis of an Affymetrix system revealed that the gene expression levels of the S100 calcium-binding protein P (S100P), the S100 calcium-binding protein A14 (S100A14), and the S100 calcium-binding protein A2 (S100A2) were greater in the Tumor2 than the non-tumorigenic Alpha3 or the tumorigenic Alpha5 cell lines; however, the S100 calcium-binding protein A8 (S100A8) and the S100 calcium-binding protein A9 (S100A9) expression levels were higher in A5 than T2 and A3 cell lines. A significant positive association was found between the estrogen receptor alpha gene (ESR1) and S100A14 in Basal and Her2 patients. The association between ESR1 and S100A8 and S100A9 expression levels was positive in Basal patients but negative in Her2, Luminal A, and Luminal B. S100P and S100A14 expression levels were higher in tumor tissues than in normal ones. The estrogen receptor status was positive in patients with high levels of the S10014 gene, but negative in S100A2, S100A8, and S100A9 expression levels. Conclusion: Cell dependence needs to be considered while designing new breast cancer treatments since gene signatures might vary depending on the type of tumor. [ABSTRACT FROM AUTHOR]

Abstract Background The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. Methods The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. Results The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p 0.05). Conclusions The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.

Atherosclerosis is a condition that is associated with lipid accumulation in the arterial intima. Consequently, the enlarging lesion, which is also known as an atherosclerotic plaque, may close the blood vessel lumen, thus leading to organ ischaemia. Furthermore, the plaque may rupture and initiate the formation of a thrombus, which can cause acute ischaemia. Atherosclerosis is a background pathological condition that can eventually lead to major cardiovascular diseases such as acute coronary syndrome or ischaemic stroke. The disorder is associated with an altered profile of alarmins, stress response molecules that are secreted due to cell injury or death and that induce inflammatory responses. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33, and heat shock proteins (HSPs) also affect the behaviour of endothelial cells and vascular smooth muscle cells (VSMCs). Thus, alarmins control the inflammatory responses of endothelial cells and proliferation of VSMCs, two important processes implicated in the pathogenesis of atherosclerosis. In this review, we will discuss the role of alarmins in the pathophysiology of atherosclerosis and myocardial infarction.

Background: The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. Methods: The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. Results: The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). Conclusions: The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients. [ABSTRACT FROM AUTHOR]

Alarmins are immune-activating factors released after cellular injury or death. By secreting alarmins, cells can interact with immune cells and induce a variety of inflammatory responses. The broad family of alarmins involves several members, such as high-mobility group box 1, S100 proteins, interleukin-33, and heat shock proteins, among others. Studies have found that the concentrations and expression profiles of alarmins are altered in immune-mediated diseases. Furthermore, they are involved in the pathogenesis of inflammatory conditions. The aim of this narrative review is to present the current evidence on the role of alarmins in rheumatoid arthritis, osteoarthritis, and psoriasis. We discuss their potential involvement in mechanisms underlying the progression of these diseases and whether they could become therapeutic targets. Moreover, we summarize the impact of pharmacological agents used in the treatment of these diseases on the expression of alarmins.

Objective: Rare disease Background: Schwannomas are tumors that arise from Schwann cells that surround and support nerve cells. Most common sites for presentations are head, neck, and extremities. Schwannomas of gastrointestinal tract are rare, slowgrowing tumors, usually benign, arising from gastrointestinal tract's neural plexus. They are histologically distinguishable from conventional schwannomas that arise in soft tissue or the central nervous system. Preoperative diagnosis of gastrointestinal schwannoma is challenging, requiring immunohistological confirmation of the nature of the tumor. Here, we report a case of 57-year-old woman with an incidental finding of an asymptomatic submucosal jejunal schwannoma. Case Report: A 57-year-old woman with a medical history of hematological disorder underwent a contrast abdominal computed tomography as part of medical follow-up. The imaging revealed the presence of a jejunal mass. The patient underwent laparoscopic surgical resection of the lesion, followed by side-to-side jejuno-jejunal anastomosis with 4-cm clear surgical margins. The final pathologic study revealed the presence of jejunal schwannoma, as tested positive for S-100 protein. The patient was discharged home on the fourth postoperative day, having an uneventful recovery. Conclusions: Jejunal schwannoma are usually benign and asymptomatic, and they are often discovered incidentally during diagnostic tests for other conditions; therefore, it should be included in the differential diagnosis of gastrointestinal tumors. Surgical treatment appears to be necessary to achieve a definitive diagnosis through a biopsy of the tumor tissue. Benign jejunal schwannomas have a good prognosis. [ABSTRACT FROM AUTHOR]

Background: In the world, approximately 1% of the population suffers from chronic spontaneous urticaria (CSU), burdening patients’ quality of life and challenging clinicians in terms of treatment. Recent scientific evidence has unveiled the potential role of a family of molecules known as “alarmins” in the pathogenesis of CSU. Methods: Papers focusing on the potential pathogenetic role of alarmins in CSU with diagnostic (as biomarkers) and therapeutic implications, in English and published in PubMed, Scopus, Web of Science, as well as clinical studies registered in ClinicalTrials.gov and the EudraCT Public website, were reviewed. Results: The epithelial-derived alarmins thymic stromal lymphopoietin and IL-33 could be suitable diagnostic and prognostic biomarkers and possible therapeutic targets in CSU. The evidence on the role of non-epithelial-derived alarmins (heat shock proteins, S-100 proteins, eosinophil-derived neurotoxin, β-defensins, and acid uric to high-density lipoproteins ratio) is more heterogeneous and complex. Conclusions: More homogeneous studies on large cohorts, preferably supported by data from international registries, will be able to elucidate the intriguing and complex pathogenetic world of CSU.

Background: Breast cancer, a global health challenge, significantly impacts women worldwide, causing morbidity, disability, and mortality. Objectives: To analyze the role of genes encoding S100 calcium-binding proteins and their relationship with radiation as possible markers in breast carcinogenesis. Methods: The normal MCF-10F cell line was used to study the role of ionizing radiation and estrogen to induce distinct stages of malignancy giving rise to an in vitro experimental breast cancer model. Results: Analysis of an Affymetrix system revealed that the gene expression levels of the S100 calcium-binding protein P (S100P), the S100 calcium-binding protein A14 (S100A14), and the S100 calcium-binding protein A2 (S100A2) were greater in the Tumor2 than the non-tumorigenic Alpha3 or the tumorigenic Alpha5 cell lines; however, the S100 calcium-binding protein A8 (S100A8) and the S100 calcium-binding protein A9 (S100A9) expression levels were higher in A5 than T2 and A3 cell lines. A significant positive association was found between the estrogen receptor alpha gene (ESR1) and S100A14 in Basal and Her2 patients. The association between ESR1 and S100A8 and S100A9 expression levels was positive in Basal patients but negative in Her2, Luminal A, and Luminal B. S100P and S100A14 expression levels were higher in tumor tissues than in normal ones. The estrogen receptor status was positive in patients with high levels of the S10014 gene, but negative in S100A2, S100A8, and S100A9 expression levels. Conclusion: Cell dependence needs to be considered while designing new breast cancer treatments since gene signatures might vary depending on the type of tumor.

S100 proteins are small proteins that are only expressed in vertebrates. They are widely expressed in many different cell types and are involved in the regulation of calcium homeostasis, glucose metabolism, cell proliferation, apoptosis, inflammation and tumorigenesis. As members of the S100 protein subfamily of myeloid‐related proteins, S100A8, S100A9 and S100A12 play a crucial role in resisting microbial infection and maintaining immune homeostasis. These proteins chelate the necessary metal nutrients of pathogens invading the host by means of 'nutritional immunity' and directly inhibit the growth of pathogens in the host. They interact with receptors on the cell surface to initiate inflammatory signal transduction, induce cytokine expression and participate in the inflammatory response and immune regulation. Furthermore, the increased content of these proteins during the pathological process makes them useful as disease markers for screening and detecting related diseases. This article summarizes the structure and function of the proteins S100A8, S100A9 and S100A12 and lays the foundation for further understanding their roles in infection, immunity and inflammation, as well as their potential applications in the prevention and treatment of infectious diseases. [ABSTRACT FROM AUTHOR]

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B. [ABSTRACT FROM AUTHOR]

S100A8, S100A9, and S100A12 proteins are important members of the S100 protein family, act primarily as congenital immunomodulators, and are closely related to the occurrence of infectious diseases. There have been few reports on the functional properties of S100A8, S100A9, and S100A12 proteins in swine, but it is certain that porcine S100A8, S100A9, and S100A12 proteins are highly expressed in diseased swine. To address the current lack of reliable and timely detection tools for these three proteins, we generated monoclonal antibodies specific to the porcine S100A8, S100A9, and S100A12 proteins using hybridoma technology. The results of serum sample testing showed that the above monoclonal antibodies specifically recognize the proteins S100A8, S100A9, and S100A12 in the serum and were able to evaluate the content change of these proteins during the infection process. This provides the basis for the use of porcine S100A8, S100A9, and S100A12 in the surveillance and diagnosis of swine diseases and laid a foundation for further understanding their roles in infection, immunity, and inflammation, as well as their potential applications in preventing or treating gastrointestinal tract or inflammatory diseases in swine. [ABSTRACT FROM AUTHOR]

Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in invasive breast and pancreatic cancer cells. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal shear-stress damaged membrane when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and may even accelerate migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We expect that inhibiting membrane repair will be particularly effective in aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with anti-ANXA2 antibodies, which have been shown to inhibit metastasis of breast and pancreatic cancer cells, or with small molecule drugs. [ABSTRACT FROM AUTHOR]

Aim: To report a case of non-neural granular cell tumor (NN-GCT), an uncommon neoplasm, with only six studies worldwide describing cases involving the oral cavity. Methods: A 26-year-old male patient with an erythematous, firm, polypoid nodule in the floor of the mouth that exhibited areas of ulceration and mild bleeding to the touch. A biopsy was performed to aid in the diagnosis. Results: Based on the histopathological and immunohistochemical results (vimentin +, CD68 +, S100 -), the diagnosis was compatible with S100-negative (primitive polypoid non-neural) granular cell tumor. No recurrence was observed over two years of follow-up. Conclusion: The diagnosis of NN-GCT is extremely challenging because this tumor shares histological and immunophenotypic features with many benign and malignant tumors. Although oral NN-GCT may exhibit unusual and atypical histological features, it has an indolent behavior. Thus, until more cases of oral involvement are reported, complete resection and close follow-up are recommended. [ABSTRACT FROM AUTHOR]

The outer layer of the epidermis composes the skin barrier, a sophisticated filter constituted by layers of corneocytes in a lipid matrix. The matrix lipids, especially the ceramide-generated sphingosine 1-phosphate, are the messengers that the skin barrier uses to communicate with the basal layer of the epidermis where replicating keratinocytes are located. Sphingosine 1-phosphate is a bioactive sphingolipid mediator involved in various cellular functions through S1PR1‒5, expressed by keratinocytes. We discovered that the S1pr2 absence is linked to an impairment in the skin barrier function. Although S1pr2-/- mouse skin has no difference in its phenotype and barrier function compared with that of wild-type mouse, after tape stripping, S1pr2-/- mouse showed significantly higher transepidermal water loss and required another 24 hours to normalize their transepidermal water loss levels. Moreover, after epicutaneous Staphylococcus aureus application, impaired S1pr2-/- mouse epidermal barrier function allowed deeper bacterial penetration and denser neutrophil infiltration in the dermis. Microarray and RNA sequence of S1pr2-/- mouse epidermis linked the barrier dysfunction with a decrease in FLG2 and tight junction components. In conclusion, S1pr2-/- mice have compromised skin barrier function and increased bacteria permeability, making them a suitable model for diseases that present similar characteristics, such as atopic dermatitis.

Introduction: Traumatic brain injury (TBI) represents a significant global health burden. This systematic review delves into the comparison of S100B and Neuron-Specific Enolase (NSE) regarding their diagnostic and prognostic accuracy in TBI within the adult population. Methods: Conducted on October 21, 2023, the search identified 24 studies encompassing 6454 adult patients. QUADAS-2 and QUAPAS tools were employed to assess the risk of bias. The analyses aimed to evaluate the diagnostic and prognostic performance of S100B and NSE based on sensitivity, specificity, and area under the curve (AUC). The outcomes were detecting intracranial injury, mortality, and unfavorable outcome. Results: Pooled data analysis tended towards favoring S100B for diagnostic and prognostic purposes. S100B exhibited a diagnostic AUC of 0.74 (95% confidence interval (CI): 0.70-0.78), sensitivity of 80% (95% CI: 63%-90%), and specificity of 59% (95% CI: 45%-72%), outperforming NSE with an AUC of 0.66 (95% CI: 0.61–0.70), sensitivity of 74% (95% CI: 53%-88%), and specificity of 46% (95% CI: 24%-69%). Notably, both biomarkers demonstrated enhanced diagnostic value when blood samples were collected within 12 hours post-injury. The analyses also revealed the excellent diagnostic ability of S100B with a sensitivity of 99% (95% CI: 4%-100%) and a specificity of 76% (95% CI: 51%-91%) in mild TBI patients (AUC = 0.89 [0.86–0.91]). In predicting mortality, S100B showed a sensitivity of 90% (95% CI: 65%-98%) and specificity of 61% (95% CI: 39%-79%), slightly surpassing NSE's performance with a sensitivity of 88% (95% CI: 76%-95%) and specificity of 56% (95% CI: 47%-65%). For predicting unfavorable outcomes, S100B exhibited a sensitivity of 83% (95% CI: 74%-90%) and specificity of 51% (95% CI: 30%-72%), while NSE had a sensitivity of 80% (95% CI: 64%-90%) and specificity of 59% (95% CI: 46%-71%). Conclusion: Although neither biomarker has shown promising diagnostic performance in detecting abnormal computed tomography (CT) findings, they have displayed acceptable outcome prediction capabilities, particularly with regard to mortality.

Rolling neutrophils form tethers with submicron diameters. Here, we report that these tethers detach, forming elongated neutrophil-derived structures (ENDS) in the vessel lumen. We studied ENDS formation in mice and humans in vitro and in vivo. ENDS do not contain mitochondria, endoplasmic reticulum, or DNA, but are enriched for S100A8, S100A9, and 57 other proteins. Within hours of formation, ENDS round up, and some of them begin to present phosphatidylserine on their surface (detected by annexin-5 binding) and release S100A8-S100A9 complex, a damage-associated molecular pattern protein that is a known biomarker of neutrophilic inflammation. ENDS appear in blood plasma of mice upon induction of septic shock. Compared with healthy donors, ENDS are 10-100-fold elevated in blood plasma of septic patients. Unlike neutrophil-derived extracellular vesicles, most ENDS are negative for the tetraspanins CD9, CD63, and CD81. We conclude that ENDS are a new class of bloodborne submicron particles with a formation mechanism linked to neutrophil rolling on the vessel wall.

The skin, the outermost layer of the human body, is exposed to various external stimuli that cause inflammatory skin reactions. These external stimulants trigger external epithelial cell damage and the release of intracellular substances. Following cellular damage or death, intracellular molecules are released that enhance tissue inflammation. As an important substance released from damaged cells, the S100 protein is a low-molecular-weight acidic protein with two calcium-binding sites and EF-hand motif domains. S100 proteins are widely present in systemic organs and interact with other proteins. Recent studies revealed the involvement of S100 in cutaneous inflammatory disorders, psoriasis, and atopic dermatitis. This review provides detailed information on the interactions among various S100 proteins in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Recent research shows that introgression between closely-related species is an important source of adaptive alleles for a wide range of taxa. Typically, detection of adaptive introgression from genomic data relies on comparative analyses that require sequence data from both the recipient and the donor species. However, in many cases, the donor is unknown or the data is not currently available. Here, we introduce a genome-scan method-VolcanoFinder-to detect recent events of adaptive introgression using polymorphism data from the recipient species only. VolcanoFinder detects adaptive introgression sweeps from the pattern of excess intermediate-frequency polymorphism they produce in the flanking region of the genome, a pattern which appears as a volcano-shape in pairwise genetic diversity. Using coalescent theory, we derive analytical predictions for these patterns. Based on these results, we develop a composite-likelihood test to detect signatures of adaptive introgression relative to the genomic background. Simulation results show that VolcanoFinder has high statistical power to detect these signatures, even for older sweeps and for soft sweeps initiated by multiple migrant haplotypes. Finally, we implement VolcanoFinder to detect archaic introgression in European and sub-Saharan African human populations, and uncovered interesting candidates in both populations, such as TSHR in Europeans and TCHH-RPTN in Africans. We discuss their biological implications and provide guidelines for identifying and circumventing artifactual signals during empirical applications of VolcanoFinder.

Abstract Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.

The most common tumor affecting the head and neck is head and neck squamous cell carcinoma (HNSCC). The characteristics of HNSCC include a rapid onset, a lack of early diagnosis, drug resistance, relapse and systemic adverse effects, leading to inadequate prevention, diagnosis and treatment. Notably, previous research suggests that there is an association between S100 proteins and HNSCC. S100A8, S100A9 and S100A14 interfere with tumor cell proliferation by blocking the cell cycle. The present review discusses this association. S100A4 enhances cancer stem cell properties, and interacts with actin and tropomyosin to promote tumor cell migration. S100A1, S100A8, S100A9, S100A10, S100A14 and S100P are involved in the initiation and progression of HNSCC via Hippo, nuclear factor κB, phosphatidylinositol kinase/protein kinase B/mammalian target of rapamycin and other signaling pathways. In addition, certain long non-coding RNAs and microRNAs are involved in regulating the expression of S100 proteins in HNSCC. Reducing the expression of certain members of the S100 protein family may enhance the chemosensitivity of HNSCC. Collectively, it is suggested that S100 proteins may function as markers and targets for the prevention, diagnosis and treatment of HNSCC. [ABSTRACT FROM AUTHOR]

BackgroundThe Human Epidermal Growth Factor Receptor (EGFR/HER1) can be activated by several ligands including Transforming Growth Factor alpha (TGF-α) and Epidermal Growth Factor (EGF). Following ligand binding, EGFR heterodimerizes with other HER family members, such as HER2 (human epidermal growth factor receptor-2). Previously, we showed that the EGFR is upregulated in trastuzumab resistant HER2 positive (HER2+) breast cancer cells. This study is aimed to determine the downstream effects on transcription following EGFR upregulation in HER2+ breast cancer cells.MethodsRNA-sequence and ChIP-sequence for H3K18ac and H3K27ac (Histone H3 lysine K18 and K27 acetylation) were conducted following an Epidermal Growth Factor (EGF) treatment time course in HER2+ breast cancer cells, SKBR3. The levels of several proteins of interest were confirmed by western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis.ResultsOver the course of 24 h, EGFR stimulation resulted in the modulation of over 4000 transcripts. Moreover, our data demonstrates that EGFR/HER2 signaling regulates the epigenome, with global H3K18ac and H3K27ac oscillating as a function of time following EGF treatment. RNA-sequence data demonstrates the activation of immediate early genes (IEGs) and delayed early genes (DEGs) within 1 h of EGF treatment. More importantly, we have identified members of the S100 (S100 Calcium Binding Protein) gene family as likely direct targets of EGFR signaling as H3K18ac, H3K27ac and pol2 (RNA polymerase II) increase near the transcription start sites of some of these genes.ConclusionsOur data suggests that S100 proteins, which act as Ca2+ sensors, could play a role in EGF induced tumor cell growth and metastasis, contribute to trastuzumab resistance and cell migration and that they are likely drug targets in HER2+ breast cancer.

Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC. SIGNIFICANCE: These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.

We have generated an induced pluripotent stem cell (iPSC) line KCLi002-A (iOP107) from a female donor, heterozygous for the loss-of-function mutation p.R2447X in the filaggrin gene (FLG). Epidermal keratinocytes were reprogrammed using non-integrating Sendai virus vectors. The entire process of derivation and expansion of iPSCs were performed under xeno-free culture conditions. Characterization of KCLi002-A line included molecular karyotyping, mutation screening using restriction enzyme digestion Sanger sequencing and next generation sequencing (NGS), whereas pluripotency and differentiation potential were confirmed by expression of associated markers in vitro and in vivo teratoma assay.

Psoriasis is a chronic inflammatory skin disease. The histopathologicl features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis. [ABSTRACT FROM AUTHOR]

Cell interactions represent an important mechanism involved in the pathogenesis of chronic inflammation. The key S100 proteins A8 and A9 have been studied in several models of chronic inflammatory diseases with highly heterogeneous conclusions. In this context, the aim of this study was to determine the role of cell interactions on S100 protein production and their effect on cytokine production during cell interactions, between immune and stromal cells from synovium or skin. Peripheral blood mononuclear cells (PBMC) were cultured alone or with synoviocytes or skin fibroblasts, with or without phytohemagglutinin, exogenous A8, A9, A8/A9 proteins or anti-A8/A9 antibody. Production of IL-6, IL-1β, IL-17, TNF, A8, A9, and A8/A9 was measured by ELISA. Cell interactions with synoviocytes had no effect on A8, A9, or A8/A9 secretion, while cell interactions with skin fibroblasts decreased A8 production. This highlights the importance of stromal cell origin. The addition of S100 proteins in co-cultures with synoviocytes did not increase the production of IL-6, IL-17, or IL-1β, except for an increase of IL-6 secretion with A8. The presence of anti-S100A8/A9 antibody did not show obvious effects. Low concentration or absence of serum in the culture medium decreased the production of IL-17, IL-6, and IL-1β but despite these conditions, the addition of S100 proteins did not increase cytokine secretion. In conclusion, the role of A8/A9 in cell interactions during chronic inflammation appears complex and heterogeneous, depending on multiple factors, notably the origin of stromal cells that can affect their secretion. Effects of S100 proteins on cytokine production during interactions between PBMC and synoviocytes. [ABSTRACT FROM AUTHOR]

Abstract Emerging evidence has revealed a cross-talk in the etiopathogenesis of burning mouth syndrome (BMS) related to peripheral nerve fibers (NF) and neuropeptides secreted by mast cells. Here, we investigated the S-100+ density and PGP 9.5+ integrity of peripheral NF and the tryptase+ mast cell density in the oral mucosa of BMS patients and healthy individuals. A total of 23 oral mucosa specimens (12 BMS and 11 controls) were evaluated. The clinical diagnosis of BMS was based on a careful examination, excluding other local and systemic causes. Samples were taken from an incisional biopsy of the tongue mucosa of individuals with symptomatic BMS, while the margins of the non-neoplastic tongue biopsy served as controls of healthy individuals. Immunohistochemistry was performed to determine the density/mm2 of S-100+, PGP 9.5+ peripheral NF, and tryptase+ mast cells. Similar densities of S-100+, PGP 9.5+ peripheral NF, and tryptase+ mast cells were found in cases of BMS, with a median value of 3.70, 0.70, and 29.24/mm2, respectively, and in the control group, with a median value of 2.60, 0.80, and 26.01/mm2, respectively (p > 0.05). Moreover, the relationship between S100+ and PGP 9.5+ peripheral NF was the same in both groups (p = 0.70). This study demonstrated that there were no alterations in the density and integrity of peripheral NF in the tongue of symptomatic BMS patients. However, the sensitization of peripheral NF in this disease may not depend on mast cell density.

BackgroundIn the peripheral nerve, pro-inflammatory matrix metalloproteinase (MMP)-9 performs essential functions in the acute response to injury. Whether MMP-9 activity contributes to late-phase injury or whether MMP-9 expression or activity after nerve injury is sexually dimorphic remains unknown.MethodsPatterns of MMP-9 expression, activity and excretion were assessed in a model of painful peripheral neuropathy, sciatic nerve chronic constriction injury (CCI), in female and male rats. Real-time Taqman RT-PCR for MMP-9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) of nerve samples over a 2-month time course of CCI was followed by gelatin zymography of crude nerve extracts and purified MMP-9 from the extracts using gelatin Sepharose-beads. MMP excretion was determined using protease activity assay of urine in female and male rats with CCI.ResultsThe initial upsurge in nerve MMP-9 expression at day 1 post-CCI was superseded more than 100-fold at day 28 post-CCI. The high level of MMP-9 expression in late-phase nerve injury was accompanied by the reduction in TIMP-1 level. The absence of MMP-9 in the normal nerve and the presence of multiple MMP-9 species (the proenzyme, mature enzyme, homodimers, and heterodimers) was observed at day 1 and day 28 post-CCI. The MMP-9 proenzyme and mature enzyme species dominated in the early- and late-phase nerve injury, consistent with the high and low level of TIMP-1 expression, respectively. The elevated nerve MMP-9 levels corresponded to the elevated urinary MMP excretion post-CCI. All of these findings were comparable in female and male rodents.ConclusionThe present study offers the first evidence for the excessive, uninhibited proteolytic MMP-9 activity during late-phase painful peripheral neuropathy and suggests that the pattern of MMP-9 expression, activity, and excretion after peripheral nerve injury is universal in both sexes.

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.

Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that is still not well understood in terms of its pathogenesis and presents diagnostic and therapeutic challenges. Monocytes are key players in initiating and maintaining inflammation through the production of pro-inflammatory cytokines and S100 proteins in RA. This study aimed to test a specific DNA methylation inhibitor (RG108) and activator (budesonide) in the regulation of pro-inflammatory mediators—especially the S100 proteins. We also searched for new biomarkers of high disease activity in RA patients. RNA sequencing analysis of healthy controls (HCs) and RA monocytes was performed. Genes such as the S100 family, TNF, and IL-8 were validated by qRT-PCR following DNA-methylation-targeted drug treatment in a monocytic THP-1 cell line. The concentrations of the S100A8, S100A11, and S100A12 proteins in the sera and synovial fluids of RA patients were tested and correlated with clinical parameters. We demonstrated that RA monocytes had significantly increased levels of S100A8, S100A9, S100A11, S100A12, MYD88, JAK3, and IQGAP1 and decreased levels of IL10RA and TGIF1 transcripts. In addition, stimulation of THP-1 cells with budesonide statistically reduced the expression of the S100 family, IL-8, and TNF genes. In contrast, THP-1 cells treated with RG108 had increased levels of the S100 family and TNF genes. We also revealed a significant upregulation of S100A8, S100A11, and S100A12 in RA patients, especially in early RA compared to HC sera. In addition, protein levels of S100A8, S100A11, and S100A12 in RA synovial fluids compared to HC sera were significantly increased. Overall, our data suggest that the S100A8 and S100A12 proteins are strongly elevated during ongoing inflammation, so they could be used as a better biomarker of disease activity than CRP. Interestingly, epigenetic drugs can regulate these S100 proteins, suggesting their potential use in targeting RA inflammation. [ABSTRACT FROM AUTHOR]

Emerging evidence has revealed a cross-talk in the etiopathogenesis of burning mouth syndrome (BMS) related to peripheral nerve fibers (NF) and neuropeptides secreted by mast cells. Here, we investigated the S-100+ d ensity a nd P GP 9 .5+ integrity of peripheral NF and the tryptase+ mast cell density in the oral mucosa of BMS patients and healthy individuals. A total of 23 oral mucosa specimens (12 BMS and 11 controls) were evaluated. The clinical diagnosis of BMS was based on a careful examination, excluding other local and systemic causes. Samples were taken from an incisional biopsy of the tongue mucosa of individuals with symptomatic BMS, while the margins of the non-neoplastic tongue biopsy served as controls of healthy individuals. Immunohistochemistry was performed to determine the density/mm² of S-100+, PGP 9.5+ peripheral NF, and tryptase+ mast cells. Similar densities of S-100+, PGP 9.5+ peripheral NF, and tryptase+ mast cells were found in cases of BMS, with a median value of 3.70, 0.70, and 29.24/mm², respectively, and in the control group, with a median value of 2.60, 0.80, and 26.01/mm², respectively (p > 0.05). Moreover, the relationship between S100+ a nd P GP 9 .5+ peripheral NF was the same in both groups (p = 0.70). This study demonstrated that there were no alterations in the density and integrity of peripheral NF in the tongue of symptomatic BMS patients. However, the sensitization of peripheral NF in this disease may not depend on mast cell density. [ABSTRACT FROM AUTHOR]

Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset—such as non-remitting high fever, headache, rash, or arthralgia—and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care—a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS—so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease. [ABSTRACT FROM AUTHOR]

Psoriasis is one of the most common inflammatory skin diseases affecting about 1–3% of the population. One of the characteristic abnormalities in psoriasis is the excessive production of antimicrobial peptides and proteins, which play an essential role in the pathogenesis of the disease. Antimicrobial peptides and proteins can be expressed differently in normal and diseased skin, reflecting their usefulness as diagnostic biomarkers. Moreover, due to their very important functions in innate immunity, members of host defense peptides and proteins are currently considered to be promising new therapeutic targets for many inflammatory diseases. Koebnerisin (S100A15) belongs to an S100 family of antimicrobial proteins, which constitute the multigenetic group of calcium-binding proteins involved in ion-dependent cellular functions and regulation of immune mechanisms. S100A15 was first discovered to be overexpressed in 'koebnerized' psoriatic skin, indicating its involvement in the disease phenotype and the same promising potential as a new therapeutic target. This review describes the involvement of antimicrobial peptides and proteins in inflammatory diseases' development and therapy. The discussion focuses on S100 proteins, especially koebnerisin, which may be involved in the underlying mechanism of the Köebner phenomenon in psoriasis, as well as other immune-mediated inflammatory diseases described in the last decade. [ABSTRACT FROM AUTHOR]

Endothelial cells respond to blood vessel injury by the acute release of the procoagulant von Willebrand factor, which is stored in unique secretory granules called Weibel-Palade bodies (WPBs). Stimulated WPB exocytosis critically depends on their proper recruitment to the plasma membrane, but factors involved in WPB-plasma membrane tethering are not known. Here we identify Munc13-4, a protein mutated in familial hemophagocytic lymphohistiocytosis 3, as a WPB-tethering factor. Munc13-4 promotes histamine-evoked WPB exocytosis and is present on WPBs, and secretagogue stimulation triggers an increased recruitment of Munc13-4 to WPBs and a clustering of Munc13-4 at sites of WPB-plasma membrane contact. We also identify the S100A10 subunit of the annexin A2 (AnxA2)-S100A10 protein complex as a novel Munc13-4 interactor and show that AnxA2-S100A10 participates in recruiting Munc13-4 to WPB fusion sites. These findings indicate that Munc13-4 supports acute WPB exocytosis by tethering WPBs to the plasma membrane via AnxA2-S100A10.

S100A1 has been suggested as a therapeutic agent to enhance myocyte Ca(2+) cycling in heart failure, but its molecular mode of action is poorly understood. Using FRET, we tested the hypothesis that S100A1 directly competes with calmodulin (CaM) for binding to intact, functional ryanodine receptors type I (RyR1) and II (RyR2) from skeletal and cardiac muscle, respectively. Our FRET readout provides an index of acceptor-labeled CaM binding near donor-labeled FKBP (FK506-binding protein 12.6) on the cytoplasmic domain of RyR in isolated sarcoplasmic reticulum vesicles. S100A1 (0.01-400 μm) partially inhibited FRET (i.e. CaM binding), with Ki > 10 μm, for both RyR1 and RyR2. The high [S100A1] required for partial effects on FRET indicates a lack of competition by S100A1 on CaM/RyR binding under normal physiological conditions. High-resolution analysis of time-resolved FRET detects two structural states of RyR-bound CaM, which respond to [Ca(2+)] and are isoform-specific. The distribution of these structural states was perturbed only by high micromolar [S100A1], which promoted a shift of bound CaM to a lower FRET orientation (without altering the amount of CaM bound to RyR). Thus, high micromolar S100A1 does alter the CaM/RyR interaction, without involving competition. Nevertheless, submicromolar S100A1 can alter RyR function, an effect that is influenced by both [Ca(2+)] and [CaM]. We conclude that CaM and S100A1 can concurrently bind to and functionally modulate RyR1 and RyR2, but this does not involve direct competition at the RyR CaM binding site.

After the onset of intracerebral hemorrhage (ICH), the immune storm causes the massive death of neurons and their supporting cells. Cytotoxic substances such as hemoglobin, heme and iron ions released by red blood cells lysis also promote death of neurons. After neurons died, damage⁃associated molecular patterns (DAMP) are released to activate the innate immune response, leading to a vicious circle of "inflammatory response⁃cell death⁃DAMP release⁃inflammatory response", which is an important mechanism of secondary brain injury after ICH. A series of studies have explored the role of DAMP in secondary brain injury after ICH. This review summarizes the research progress and provides references for further basic research and clinical translational research. doi：10.3969/j.issn.1672⁃6731.2021.02.004

Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and cluster of differentiation 33 (CD33). The receptors initiate kinase signaling cascades that activate inflammation through the NF-kB pathway. Receptor activation by CP leads to upregulation of both receptor and ligand, a positive feedback loop associated with specific chronic inflammatory syndromes. Hence, CP and its two constituent homodimers have been viewed as potential targets to suppress certain chronic inflammation pathologies. A variety of inhibitors of CP and other S100 proteins have been investigated for more than 30 years, but no candidates have advanced significantly into clinical trials. Here, current knowledge of the interactions of CP with its receptors is reviewed along with recent progress towards the development of CP-directed chemotherapeutics. [ABSTRACT FROM AUTHOR]

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

AimsTo evaluate the ability of N-acetylglucosamine (GlcNAc) decorated nanoparticles and their cargo to modulate calcium handling in failing cardiac myocytes (CMs).Materials & methodsPrimary CMs isolated from normal and failing hearts were treated with GlcNAc nanoparticles in order to assess the ability of the nanoparticles and their cargo to correct dysfunctional calcium handling in failing myocytes.Results & conclusionGlcNAc particles reduced aberrant calcium release in failing CMs and restored sarcomere function. Additionally, encapsulation of a small calcium-modulating protein, S100A1, in GlcNAc nanoparticles also showed improved calcium regulation. Thus, the development of our bioactive nanoparticle allows for a 'two-hit' treatment, by which the cargo and also the nanoparticle itself can modulate intracellular protein activity.

Background: The goal of this study is the identification of potential marker molecules for characterizing different basal cell carcinoma entities, to help improve clinical decisions for surgical resection therapy. Methods: Three different entities, sclerodermiform, solid and superficial basal cell carcinomas, were subjected to immunohistochemical microscopy and histomorphometric analyses for human α- (DEFA1/3; DEFA4) and β-defensins (hBD1/2/3) and special S100 proteins (S100A4/7/8/9). Thirty specimens of the three entities were evaluated. Analyses were performed by comparing tissue and cellular localization and staining intensities of tumorous with non-tumorous areas. Staining intensities were semiquantitatively examined by using an RGB-based model. Results: Human defensins are present in all three entities of basal cell carcinomas. They all show cytoplasmic immunostaining in cells of the epithelium, stroma and tumor. Notably, human β-defensin3 is accumulated in the cell nuclei of sclerodermiform and superficial basal cell carcinomas. S100A4 and A7 are undetectable in tumor regions. However, S100A4 occurs in cancer-associated stroma cells with nuclear staining in superficial basal cell carcinomas. Conclusion: Two candidates, namely hBD3 and S100A4, might be used as potential clinical tools for evaluating successful surgical resection therapy to avoid aesthetic and functional facial deformation.

S100 proteins are small, dimeric, Ca2+-binding proteins of considerable interest due to their associations with cancer and rheumatic and neurodegenerative diseases. They control the functions of numerous proteins by forming protein–protein complexes with them. Several of these complexes were found to display “fuzzy” properties. Examining these highly flexible interactions, however, is a difficult task, especially from a structural biology point of view. Here, we summarize the available in vitro techniques that can be deployed to obtain structural information about these dynamic complexes. We also review the current state of knowledge about the structures of S100 complexes, focusing on their often-asymmetric nature.

Abstract Background Serum phagocyte-derived alarmins S100A8/9 and S100A12 are considered useful for the assessment of inflammatory diseases. Our study evaluated the use of S100 proteins in a pediatric clinical setting for estimating disease activity and supporting diagnosis. Methods Patients (n = 136) who had S100 proteins tested as part of clinical care were included in this study and relevant information obtained from the medical record: C-reactive protein (CRP), disease activity status (inactive: = 0 joint; active: > 0 active joint), systemic symptoms in systemic JIA (sJIA), and symptoms of flare of other autoinflammatory and fever syndromes. Patients were categorized as: sJIA, non-systemic JIA (nsJIA), other defined autoinflammatory syndromes (AID) and systemic undifferentiated recurring fever syndromes (SURFS). Results Patients with sJIA (n = 21) had significantly higher levels of S100A8/9 and S100A12 compared to patients with nsJIA (n = 49), other AIDs (n = 8) or SURFS (n = 14) (all p

Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.

Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC. [ABSTRACT FROM AUTHOR]

Background/aim: Postnatal corticosteroids are commonly used to treat bronchopulmonary dysplasia (BPD). We aimed to show whether S100 calcium-binding B (S100B), neuron-specific enolase (NSE), Tau protein or microtubule-associated protein tau (MAPT), and glial fibrillary acid protein (GFAP) levels would provide any evidence of early neurological damage in premature infants receiving postnatal low dose dexamethasone therapy for BPD treatment. Materials and methods: In this cohort study, 136 preterm infants diagnosed with BPD at ≤32 weeks of gestation formed the study group, and 64 preterm infants formed the control group. NSE, S100B, GFAP, and MAPT levels were first measured before the postnatal corticosteroid treatment in both the patient and the control group on the 28th day and, for a second time, after treatment termination in the patient group. Results: There were significant differences between the measured GFAP, MAPT, and NSE values of the BPD and control groups on the 28th day, whereas there was no significant difference between the measured S100B values of the two groups. There were a statistically significant difference between the NSE values measured on the 28th day and after the treatment within the BPD group, whereas no significant difference existed between the GFAP, MAPT, and S100B values. Conclusion: NSE levels, which indicate brain damage in the early period, increased in preterm babies with BPD who had been administered postnatal dexamethasone. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effects of dexmedetomidine on the incidence of postoperative delirium (POD) and plasma S-100ß protein levels in elderly patients undergoing hip surgery. Methods: A total of 110 elderly patients who underwent hip surgery were enrolled in this study and grouped using the random number table method. The study group (55 patients) received 0.5 pg/kg dexmedetomidine before anesthesia induction and the control group (55 patients) received an equal dose of 0.9% sodium chloride injection before anesthesia induction. Results: Compared with the control group, the study group had lower fentanyl and propofol consumption, shorter time to waking up, shorter time to respiratory recovery, shorter extubation time, and lowerincidence of POD (p<0.05). Mean arterial pressure, oxygen saturation, and heartrateat T1 and T2 were lower than those at T0 in the control group as well as lower than those in the study group at the same time point (p < 0.05). Both groups showed higher S-100ß levels at T1, T2, and T3 compared with those at T0(p < 0.05); however, the levels were lowerin the studygroup than in the controlgroup at the abovementioned time points (p < 0.05). Conclusion: Dexmedetomidine could decrease the consumption of anesthetic drugs, shorten postoperative recovery time, stabilize hemodynamics, decrease adverse reactions caused by anesthesia, and decrease the incidence of POD, which may be achieved by improving cerebral metabolism, regulating serum S-100ß levels. [ABSTRACT FROM AUTHOR]

The calcium binding protein S100 family in humans contains 21 known members, with each possessing a molecular weight between 10 and 14 kDa. These proteins are characterized by a unique helix-loop-helix EF hand motif, and often form dimers and multimers. The S100 family mainly exists in vertebrates and exerts its biological functions both inside cells as a calcium sensor/binding protein, as well as outside cells. S100A11, a member of the S100 family, may mediate signal transduction in response to internal or external stimuli and it plays various roles in different diseases such as cancers, metabolic disease, neurological diseases, and vascular calcification. In addition, it can function as chemotactic agent in inflammatory disease. In this review, we first detail the discovery of S100 proteins and their structural features, and then specifically focus on the tissue and organ expression of S100A11. We also summarize its biological activities and roles in different disease and signaling pathways, providing an overview of S100A11 research thus far.