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Cutaneous delayed drug hypersensitivity reactions (DHRs) are common iatrogenic events with potentially life-threatening consequences. Delayed DHRs encompass diverse phenotypes and can be classified by their distinct T-cell responses to drug antigens. Interaction between the immune receptors, human leukocyte antigen (HLA) and T-cell receptor (TCR), and the complementary antigenic peptide is required for the development of delayed DHRs. These idiosyncratic interactions can be elicited by the formation of antigenic drug-protein adducts (hapten hypothesis) or from direct interactions of drugs with the immune receptors (pharmacological interaction of drugs with immune receptors concept, altered peptide repertoire model, and altered TCR model). In addition, viral infections may play a role by providing co-stimulatory signals or enhancing TCR/HLA expression on T-cells. The associations of HLA allele polymorphisms and DHRs are phenotype and ethnicityspecific. The discovery of genetic polymorphisms associated with DHRs has provided a strategy to prevent and diagnose potentially life-threatening reactions. Recently, advances in next-generation sequencing technologies, such as the incorporation of whole-exome or whole-genome sequencing, enabled the comprehensive detection of susceptibility loci. Several HLA associations have shown clinical utility and cost-effectiveness, such as HLA-B*15:02 (carbamazepine-induced Stevens–Johnson syndrome/toxic epidermal necrolysis in Han Chinese), HLA-B*58:01 (allopurinol-induced severe cutaneous adverse reactions in Han Chinese), HLA-B*57:01 (abacavir hypersensitivity reactions in Caucasians), and HLA-B*13:01 (dapsone-induced drug reaction with eosinophilia and systemic symptoms in Han Chinese). Herein, we summarize the current knowledge of the pathogenesis, antigen presentation models, and HLA associations of cutaneous delayed DHRs.

Autoimmune encephalitis is a rare but critical complication of COVID-19. The management of COVID-19-associated autoimmune encephalitis includes the use of steroids, intravenous immunoglobulin (IVIG), plasmapheresis, and monoclonal antibody therapy. This study presented a patient with critical COVID-19 autoimmune encephalitis who rapidly recovered after the initiation of corticosteroids and IVIG therapy. This study reviewed the current literature on the pathophysiological mechanisms, diagnosis, and management of COVID-19-associated autoimmune encephalitis.

Drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome (DRESS/DIHS) is one type of severe cutaneous adverse reaction (SCAR). It is featured by fever, widespread skin lesions, protracted clinical course, internal organ involvement, and possibly long-term autoimmune sequelae. The presence of high-risk human leukocyte antigen (HLA) alleles, hypersensitivity reaction after culprit drug ingestion, and human herpesvirus reactivation may all contribute to its complex clinical manifestations. Some recent studies focusing on the roles of involved cytokines/chemokines and T cells co-signaling pathways in DRESS/DIHS were conducted. In addition, some predictors of disease severity and prognosis were also reported. In this review, we provided an update on the current understanding of the pathogenesis, potential biomarkers, and the relevant therapeutic rationales of DRESS/DIHS.

Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.

IntroductionKimura’s disease (KD) is an uncommon lymphoproliferative fibroinflammatory disorder. Patients present with head and neck subcutaneous nodules with or without lymphadenopathy. Peripheral blood eosinophilia and elevated serum immunoglobulin E (IgE) levels are typical. This study was designed to delineate the clinicopathological features, pattern of care, and disease course of 23 Taiwanese patients with KD.MethodsWe retrospectively analyzed the clinical data of 23 consecutive cases (16 male and 7 female; age at diagnosis: 12–77 years) of KD diagnosed at our institution from 2015 to 2020.ResultsThe median time from presentation to diagnosis was 1 month. Twenty-one patients presented with unilateral or bilateral head and neck masses. The remaining two presented with right flank and right arm lesions, respectively. Peripheral blood eosinophilia was observed in nine, and elevated IgE levels were observed in four. All were diagnosed using either excisional or core-needle biopsy. Seven patients underwent fine needle aspiration without a diagnostic yield. Salivary gland and lymph node involvement was observed in three and seven patients, respectively. Most lesions showed tissue eosinophilia (100%) and florid follicular hyperplasia (78.26%). Three cases had histological KD-IgG4-RD overlap and three had comorbid IgG4-RD were recognized. Thirteen patients underwent surgical resection, one received adjuvant therapy, and two received prednisolone monotherapy.ConclusionKD should be considered in patients with subcutaneous masses, eosinophilia, and elevated IgE levels. Biopsy remains the gold standard of diagnosis. Increased recruitment of IgG4+ plasma cells is a common feature. Consideration of IgG4-RD in all KD patients may be prudent.

Objectives: Epidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models. Methods: Beginning at 8 weeks of age, C57BL/6 J mice were concurrently fed a high-fat diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured INS-1 β-cells and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide accumulation in the lung and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry. Results: Compared to HFD-fed, ambient air-exposed mice, HFD-fed and CS-exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and had accelerated worsening of their glucose tolerance. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p = 0.017), reduced β-cell proliferation (p = 0.006), and increased islet ceramide content compared to non-smoking control mice. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide levels, which was correlated with reduced insulin gene expression and glucose-stimulated insulin secretion, and increased β-cell oxidative and endoplasmic reticulum (ER) stress. Treatment with the antioxidant N-acetylcysteine markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress. Conclusions: Our results indicate that CS exposure leads to impaired insulin production, processing, secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of the mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

Kimura's disease (KD) is an immune‐mediated disorder which mainly affects Asian men. It appears as head and neck subcutaneous masses, with inflammatory infiltrate and elevated serum immunoglobulin E levels. The clinical presentation of KD resembles that of various diseases. Here, we report the case of a 30‐year‐old Filipino man with KD mimicking cavernous hemangioma who was treated by surgery. Careful survey for possible KD cases is crucial. Misdiagnoses are prone to futile interventions and unwanted effects. Surgery with adjuvant therapy is superior to other forms of KD treatment. [ABSTRACT FROM AUTHOR]

Early detection of lung cancer offers an important opportunity to decrease mortality while it is still treatable and curable. Thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells, and alveolar myeloid cells of the CCSPrtTA/( tetO)7-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. Further analyses showed that TTR treatment enhanced the reactive oxygen species production in myeloid cells and enabled them to become functional myeloid-derived suppressive cells. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, these 13 Stat3 downstream inducible secretory protein biomarkers potentially can be used for lung cancer diagnosis, classification, and as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood. [ABSTRACT FROM AUTHOR]

Store-operated Ca2+ entry (SOCE) is a dynamic process that leads to refilling of endoplasmic reticulum (ER) Ca2+ stores through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Pathogenic reductions in β-cell ER Ca2+ have been observed in diabetes. However, a role for impaired SOCE in this phenotype has not been tested. We measured the expression of SOCE molecular components in human and rodent models of diabetes and found a specific reduction in STIM1 mRNA and protein levels in human islets from donors with type 2 diabetes (T2D), islets from hyperglycemic streptozotocin-treated mice, and INS-1 cells (rat insulinoma cells) treated with proinflammatory cytokines and palmitate. Pharmacologic SOCE inhibitors led to impaired islet Ca2+ oscillations and insulin secretion, and these effects were phenocopied by β-cell STIM1 deletion. STIM1 deletion also led to reduced ER Ca2+ storage and increased ER stress, whereas STIM1 gain of function rescued β-cell survival under proinflammatory conditions and improved insulin secretion in human islets from donors with T2D. Taken together, these data suggest that the loss of STIM1 and impaired SOCE contribute to ER Ca2+ dyshomeostasis under diabetic conditions, whereas efforts to restore SOCE-mediated Ca2+ transients may have the potential to improve β-cell health and function. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPAR expression. PPAR knockdown increased HCC cell growth, migration, and angiogenesis, while PPAR overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPAR expression is an independent predictor of more MVI in HCC patients. PPAR contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPAR may be a therapeutic target in HCC patients. [ABSTRACT FROM AUTHOR]

This study implements a compact solid-state lighting chip with changeable illumination map as well as radiation pattern. The lighting chip consists of a microprism array, light-emitting diode (LED) chip and Si carrier. The polydimethylsiloxane (PDMS) and polymer-dispersed liquid crystal (PDLC) layers are respectively employed to implement the passive and active microprism arrays. The specific radiation pattern can be defined by the shape of the passive PDMS-microprism. Moreover, by using the scattering and transmitting modes of the PDLC layer, the PDLC-microprism enables the changing of light shaping by applying voltage. Thus, the radiation pattern can be changed by the driving voltage on the PDLC layer, and the deformable and movable micro optical components are not required. This study has established the low-temperature fabrication and packaging processes to realize the lighting chip, and the damage of the PDMS and PDLC material is prevented. Typical dimensions of the PDMS lighting chip are 5 mm wide, 6 mm long and 1 mm thick, and The PDLC lighting chip is 550 µm thick. The measurement results show that the PDMS-microprism array can change the radiation pattern from a 70° half-maximum viewing angle to 52° and 40° half-maximum viewing angles on two orthogonal axes. In addition, the PDLC-microprism array can change the radiation pattern from 51° and 43° half-maximum viewing angles at 0 V (i.e. scattering mode) to 48° and 33° half-maximum viewing angles at 100 V (i.e. transmitting mode). [ABSTRACT FROM AUTHOR]

Although Escherichia coli does not have a natural transformation process, strains of E. coli can incorporate extracellular plasmids into cytoplasm ‘naturally’ at low frequencies. A standard method was developed in which stationary phase cells were concentrated, mixed with plasmids, and then plated on agar plates with nutrients which allowed cells to grow. Transformed cells could then be selected by harvesting cells and plating again on selective agar plates. Competence developed in the lag phase, but disappeared during exponential growth. As more plasmids were added to the cell suspension, the number of transformants increased, eventually reaching a plateau. Supercoiled monomeric or linear concatemeric DNA could transform cells, while linear monomeric DNA could not. Plasmid transformation was not related to conjugation and was recA-independent. Most of the E. coli strains surveyed had this process. All tested plasmids, except pACYC184, could transform E. coli. Insertion of a DNA fragment containing the ampicillin resistance gene into pACYC184 made the plasmid transformable. By inserting random 20-base-pair oligonucleotides into pACYC184 and selecting for transformable plasmids, a most frequent sequence was identified. This sequence resembled the bacterial interspersed medium repetitive sequence of E. coli, suggesting the existence of a recognition sequence. We conclude that plasmid natural transformation exists in E. coli.Copyright © 2002 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with proinflammatory cytokines. Others have reported that miR-146a-5p overexpression is associated with β cell apoptosis and impaired insulin secretion. However, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with proinflammatory cytokines (interleukin-1β, interferong, and tumor necrosis factor a) to model type 1 diabetes in vitro. We found that overexpression of miR-146a-5p increased cell death under conditions of inflammatory stress and led to mitochondrial membrane depolarization, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased insulin secretion, mitochondrial DNA copy number, respiration rate, and ATP production. Further, RNA-seq data showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR- 146a-5p were altered. Finally, a temporal increase in miR-146a-5p expression levels and a decrease in mitochondria function markers were observed in islets derived from nonobese diabetic mice. Collectively, these data suggest that miR-146a-5p may promote β cell dysfunction and death during inflammatory stress by suppressing mitochondrial function. [ABSTRACT FROM AUTHOR]

This study presents the approach to implement the electrostatically-controlled thin film optical filter by using a nanoporous anodic aluminum oxide (np-AAO) layer as the key suspended micro structure. The bi-stable optical filter operates in the visible spectral range. In this work, the presented bi-stable optical filter has averaged reflectivity of 60%, and the central wavelengths are 580 and 690 nm respectively for on and off states. The presented np-AAO layer offers the following merits for the thin film optical filter: (1) material properties of np-AAO film, such as refractive index, elastic modulus and dielectric constant, can be easily changed by a low temperature pore-widening process, (2) in-use stiction of the suspended np-AAO structure can be reduced by the small contact area of nanoporous textures, (3) driving (pull-in) voltage can be reduced due to a large dielectric constant (εAAO is 7.05) and small stiffness of np-AAO film and (4) dielectric charging can be reduced by the np-AAO material; thus the offset voltage is small. The study reports the design, fabrication and experimental results of the bi-stable optical filter to demonstrate the advantages of the presented device. The np-AAO material also has the potential for applications of other electrostatic drive micro devices. [ABSTRACT FROM AUTHOR]