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Abstract Introduction Generalized pustular psoriasis (GPP) is a rare and severe psoriasis subtype characterized by the rapid onset of coalescing sterile pustules over broad body areas and systemic inflammation. Data on its clinical course and outcomes in Taiwan are limited. We evaluated the clinical profile and outcomes of patients with GPP flares in Taiwan. Methods This retrospective analysis included adult patients with moderate-to-severe GPP flares occurring in January 2008–December 2021. Data were extracted from medical charts and electronic health records in the Chang Gung Research Database. Statistical analyses were performed using SAS for Windows (version 9.4). Multivariate Poisson regression models were built to investigate different predictors of GPP flare rate. Results Thirty-four patients with 81 moderate-to-severe GPP flares were identified. Of the 14 patients undergoing genetic analysis, 10 (71.4%) had an IL36RN mutation. Patients’ mean age at the index GPP flare was 47.1 ± 16.5 years; 58.0% of the flares were severe, while 42.0% were moderate. Overall, 96.3% of GPP flares were treated with at least one systemic therapy, acitretin being the most prescribed (85.2%), followed by cyclosporine (45.7%) and methotrexate (18.5%). After treatment, the proportion of flares responding positively increased from 0% on day 2 to 6.2% by week 12. Patients were newly diagnosed with psoriasis (23.5%), hypertension (20.6%), diabetes mellitus (14.7%), psoriatic arthritis (2.9%), malignant tumor (8.8%), and depression/anxiety (2.9%) after enrollment. Complications occurring within 12 weeks of GPP flares included arthritis (25.9% of the flares), skin infection (8.6%), and other infections (2.5%). No fatalities were reported. In the multivariate model, former smokers, patients with hepatic disease, and patients with psoriatic arthritis had an increased GPP rate ratio (RR) of 13.33 (95% confidence interval, CI, 2.87–61.78), 14.08 (95% CI 3.04–65.29), and 34.84 (95% CI 4.77- 254.42), respectively. Contrarily, obese and rheumatoid arthritis patients had a lower GPP rate ratio of 0.21 (95% CI 0.08–0.54) and 0.07 (95% CI 0.006–0.78), respectively. Conclusions Our findings highlight the complexity of GPP flare presentations and the need for individualized, patient-centered management approaches and continued research to improve affected individuals’ care and outcomes.

Abstract Background This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. Method Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. Results Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. Conclusions This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.

Background: There are few studies concerning the impact of serum vitamin D status on the risk of allergen sensitization and atopic dermatitis (AD) during early childhood. Method: Children with AD and age-matched healthy controls (HC) were prospectively enrolled at age 0.5, 2, and 4 years. Serum 25-hydroxyvitamin D (25[OH]D) level was measured using Elecsys Vitamin D Total assay. The study utilized the ImmunoCAP assay to analyze specific IgE for food and inhalant allergens, along with total serum IgE levels. It explored the connection between vitamin D levels and allergen sensitization, as well as their influence on AD at different ages. Results: A total of 222 children including 95 (59 AD and 36 HC), 66 (37 AD and 29 HC), and 61 (32 AD and 29 HC) children were classified at age 0.5, 2, and 4 years, respectively. In children with AD, there was a significantly lower vitamin D level at age 2 and 4, but a significantly higher prevalence of food and mite sensitization at all ages in comparison with HC (P

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

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.

Background: The midfacial fat is highly compartmentalized, and the deep fat compartments provide structural support for the midface. Understanding the age-related changes in the midfacial deep fat compartments is important for midfacial rejuvenation physiologically. However, previous studies showed conflicted results of these changes. Objectives: This study aims to quantify the age-related changes of deep fat compartments in the midface using ultrasound. Methods: A cross-sectional study was conducted to evaluate subjects with age more than 25 years old and the subjects were divided into four age groups equally (25–34, 35–44, 45–54, and ≥55). The thickness of the suborbicularis oculi fat compartment (SOOF) and deep medial cheek fat compartment (DMCF) was measured using a portable ultrasound device. Mean thickness differences among different age groups were analyzed by one-way analysis of variance. Multiple linear regression adjusted for body mass index (BMI) and sex was also conducted. Results: A total of 60 subjects were enrolled. The thickness of SOOF and DMCF tends to decrease with age. The mean decrease of SOOF and DMCF from the youngest group to the oldest group was 0.63 mm (36%) and 0.70 mm (25.83%), respectively. The relationship between aging and thickness of SOOF and DMCF remains significant after adjusting for BMI and sex (both P < 0.001). Conclusion: The thickness of deep fat compartments decreases with the natural aging process. The study may offer clinical implications for targeted volume rejuvenation to achieve a more youthful and natural face.

Bullous pemphigoid (BP) is one of the most common autoimmune bullous diseases and mainly affects an elderly population with multi-morbidity. Due to the frailty of many BP patients, existing treatment options are limited. The blisters associated with BP result from IgG and IgE autoantibodies binding to the central components of hemidesmosome, BP180, and BP230, stimulating a destructive inflammatory process. The known characteristic features of BP, such as intense pruritus, urticarial prodrome, peripheral eosinophilia, elevated IgE, as well as recent expanding evidence from in vitro and in vivo studies implicate type 2 inflammation as an important driver of BP pathogenesis. Type 2 inflammation is an inflammatory pathway involving a subset of CD4+ T cells that secrete IL-4, IL-5, and IL-13, IgE-secreting B cells, and granulocytes, such as eosinophils, mast cells, and basophils. It is believed that effectors in type 2 inflammation may serve as novel and effective treatment targets for BP. This review focuses on recent understandings of BP pathogenesis with a particular emphasis on the role of type 2 inflammation. We summarize current clinical evidence of using rituximab (B-cell depletion), omalizumab (anti-IgE antibody), and dupilumab (anti-IL-4/13 antibody) in the treatment of BP. The latest advances in emerging targeted therapeutic approaches for BP treatment are also discussed.

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.

Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.

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.

Serine/arginine-rich proteins are a class of highly conserved splicing factor proteins involved in constitutive and alternative splicing. We screened a low molecular weight serine/arginine rich protein from silkworms and named it BmUP. Temporal and spatial expression analysis indicated that the BmUP gene was specifically expressed in the silkworm testis, and the highest expression occurred in the pre-pupa stage from the fifth instar to the moth stages. Here, we generated BmUP knockout individuals with the CRISPR/Cas9 system. Both the internal and external genitalia of knockout individuals were abnormal in knockout compared with wild-type male silkworms. In transgenic silkworms overexpressing BmUP, male silkworms showed a phenotype similar to that of the knockout individuals, whereas female individuals showed no significant differences from the wild type. In addition, by conducting promoter analysis, we identified Bmachi, a transcription factor that regulates the BmUP gene. Gel migration experiments revealed that BmAchi specifically binds the BmUP promoter. Quantitative real-time PCR showed that an increase in Bmachi expression up-regulated the expression of BmUP. In contrast, when the expression of Bmachi decreased, the expression of BmUP also downregulated in the experimental group compared with the control group. These results provide new insights for studying the effects of serine/arginine-rich proteins on the development of silkworm genitals.

The immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combination treatment is currently the first-line treatment for metastatic renal cell carcinoma (mRCC). However, its efficacy beyond the third-line setting is expected to be relatively poor, and high-grade toxicities can develop by prior exposure to multiple drugs, resulting in a relatively poor performance in patients. Determining the best treatment regimen and sequence remains difficult and requires further investigation in patients with mRCC. In this study, two cases of mRCC, who failed several lines of TKI and nivolumab but exhibited a good anticancer effect after rechallenging with axitinib, are described. Both patients had a faster time to best response and better progression-free survival (PFS) than during previous treatments. Moreover, the axitinib dose could be reduced to 2.5 mg daily when used in combination with nivolumab while continuing to exert an impressive anticancer effect. To determine the cytotoxic effect, we performed a lymphocyte activation test and found that the level of granzyme B released by cytotoxic T lymphocytes and natural killer cells was higher when axitinib was combined with nivolumab. To evaluate this result, a bioinformatics approach was used to analyze the PRISM database. In conclusion, based on the results of a lymphocyte activation test and PD-1 expression, our findings indicate that sequential therapy with axitinib rechallenge after nivolumab resistance is reasonable for the treatment of mRCC.

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK–STAT signal transduction. Furthermore, JAK–STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK–STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK–STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.

Vancomycin is a commonly used antibiotic; however, it can cause life-threatening severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). A previous study has reported a strong association between HLA-A*32:01 and vancomycin-induced DRESS in European ethnicity. Herein, we aim to investigate the genetic predisposition of vancomycin-induced DRESS in the Han-Chinese population. In this study, we enrolled a total of 26 patients with vancomycin-induced DRESS, 1,616 general population controls, and 51 subjects tolerant to vancomycin. In vitro granulysin-based lymphocyte activation tests (LAT) were conducted among 6 vancomycin-induced DRESS patients who were concomitantly receiving other medicines. HLA-A and HLA-B genotypes were determined by sequencing-based typing. Our results found that vancomycin-induced DRESS was associated with HLA-A*32:01 [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 1.7–35.8; p-value = 0.035], HLA-B*07:05 (OR = 32.3, 95% CI = 2.8–367.7; p-value = 0.047), HLA-B*40:06 (OR = 4.7, 95% CI = 1.3–16.1; p-value = 0.036) and HLA-B*67:01 (OR = 44.8, 95% CI = 7.2–280.4; p-value = 0.002) when comparing the vancomycin-induced DRESS patients with the general population controls. LAT results showed that granulysin significantly increased in the vancomycin-induced DRESS patients upon vancomycin stimulation (4.7 ± 3.7 fold increased), but not upon other co-medicines. This study identified that, in addition to HLA-A*32:01, HLA-B*07:05, HLA-B*40:06, and HLA-B*67:01 were also genetic markers for vancomycin-induced DRESS in the Han-Chinese population. Associations of ethnic variances in HLA with vancomycin-DRESS were observed.

BackgroundAcute graft-versus-host disease (aGVHD) is a severe and fatal complication after orthotopic liver transplantation (OLT). Clinical manifestations of severe aGVHD can resemble drug-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and there are also various medications, such as antibiotics and immunosuppressants, used after transplantation, causing a diagnostic dilemma. Furthermore, there have been no standardized diagnostic and therapeutic strategies for OLT-aGVHD due to its rarity.Case summaryA 52-year-old man presented with generalized maculopapular eruptions, fever, and pancytopenia 1 month after OLT and 4 days after taking sulfamethoxazole/trimethoprim. After assessment of the scoring criteria for drug causality of drug allergy, histopathological findings of skin biopsy, lymphocyte activation test of the potential offending drug, and microchimerism study, the diagnosis was in favor of aGVHD mimicking SJS/TEN. Considering severe sepsis, the anti-tumor necrosis factor alpha (TNF-α) agent, etanercept, was used to replace tacrolimus and corticosteroid. Skin lesions resolved gradually after anti-TNF-α biologics rescue; tacrolimus and corticosteroid therapy were re-administrated after controlling sepsis. Pancytopenia recovered and the patient was discharged in a stable condition.ConclusionWe demonstrated a diagnostic strategy for OLT-aGVHD. Targeting therapy with anti-TNF-α blockade and a temporary withdrawal of traditional immunosuppressants may be among effective and safe therapeutic options of OLT-aGVHD for those with severe sepsis.

The efficacy and the safety of psoriasis medications have been proved in trials, but unideal responses and side effects are noted in clinical practice. Genetic predisposition is known to contribute to the pathogenesis of psoriasis. Hence, pharmacogenomics gives the hint of predictive treatment response individually. This review highlights the current pharmacogenetic and pharmacogenomic studies of medical therapy in psoriasis. HLA-Cw*06 status remains the most promising predictive treatment response in certain drugs. Numerous genetic variants (such as ABC transporter, DNMT3b, MTHFR, ANKLE1, IL-12B, IL-23R, MALT1, CDKAL1, IL17RA, IL1B, LY96, TLR2, etc.) are also found to be associated with treatment response for methotrexate, cyclosporin, acitretin, anti-TNF, anti-IL-12/23, anti-IL-17, anti-PDE4 agents, and topical therapy. Due to the high throughput sequencing technologies and the dramatic increase in sequencing cost, pharmacogenomic tests prior to treatment by whole exome sequencing or whole genome sequencing may be applied in clinical in the future. Further investigations are necessary to manifest potential genetic markers for psoriasis treatments.

Abstract Background The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. Methods We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Results: Overall, the patients who experienced grade 1–2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27–0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24–1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21–0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17–0.69, p = 0.003) than patients without any of these irAEs. Conclusions Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1–2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Cutaneous squamous cell carcinoma (cSCC) as one of the most prevalent cancers worldwide is associated with significant morbidity and mortality. Full-body skin exam and biopsy is the gold standard for cSCC diagnosis, but it is not always feasible given constraints on time and costs. Furthermore, biopsy fails to reflect the dynamic changes in tumor genomes, which challenges long-term medical treatment in patients with advanced diseases. Extracellular vesicle (EV) is an emerging biological entity in oncology with versatile clinical applications from screening to treatment. In this systematic review, pre-clinical and clinical studies on cSCC-derived EVs were summarized. Seven studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were identified. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in EVs. Desmoglein 2 protein (Dsg2) is an important molecule in the biogenesis of cSCC-derived EVs. Ct-SLCO1B3 mRNA, and CYP24A1 circular RNA (circRNA) are enriched in cSCC-derived EVs, suggesting potentials in cSCC screening and diagnosis. p38 inhibited cSCC-associated long intergenic non-coding RNA (linc-PICSAR) and Dsg2 involved in EV-mediated tumor invasion and drug resistance served as prognostic and therapeutic predictors. We also proposed future directions to devise EV-based cSCC treatment based on these molecules and preliminary studies in other cancers.

To determine phenotype-related dupilumab response in adult patients with atopic dermatitis (AD), this multicenter, retrospective study included 111 adults with moderate-to-severe AD in Taiwan, with median age of 31.5 years (18–87) and 71 (64.0%) males. Patients received dupilumab 300 mg per two to three weeks up to 12 months. We found a significant improvement after 4 and 16 weeks of treatment in all patients for all the assessed scores, including eczema area and severity index (EASI) improvement ≥50% (EASI-50) and 75% (EASI-75), EASI reaching minimal clinically important difference (MCID), and Investigator’s Global Assessment (IGA) improvement ≥2. Importantly, prior to asthma, early AD onset and 3-week drug intervals were significantly associated with a high proportion of EASI-75 at month 12, while prurigo and lichenoid phenotypes were associated with a lower proportion of EASI-75 at month 12. However, the majority of adverse events were mild in severity. In conclusion, our study results identify phenotype-related dupilumab response at month 12 in adults with moderate-to-severe AD, and we suggest that treatment should not be discontinued until reaching a satisfactory clinical response.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are T cells-mediated life-threatening immune reactions, most commonly induced by drug. The last decade has seen significant progress in SCARs research. Recent studies have unveiled the pathogenesis of SCARs involved in susceptible genes, including human leukocyte antigens (HLA) and drugs-T cell receptor (TCR) interaction that may trigger T cell activation with downstream immune signaling of cytokines/chemokines and specific cytotoxic proteins releases. Advances in identification of multiple genetic alleles associated with specific drugs related SCARS in different populations is an important breakthrough in recent years for prevention of SCARs. This article summarized the findings on genetic factors related to SJS/TEN, especially for HLA.

In this paper, we present a wound-dressing-based antenna fabricated via screen-printed and inkjet-printed technologies. To inkjet print a conductive film on wound dressing, it must be screen-printed, UV-curable-pasted, and hard-baked to provide appropriate surface wettability. Two passes were UV-curable-pasted and hard-baked at 100 °C for 2 h on the wound dressing to obtain 65° WCA for silver printing. The silver film was printed onto the wound dressing at room-tempature with 23 μm droplet spacing for three passes, then sintered at 120 °C for 1 h. By optimizing the inkjet printing conditions by modifying the surface morphologies and electrical properties, three-pass printed silver films with 3.15 μm thickness and 1.05 × 107 S/m conductivity were obtained. The insertion losses at the resonant frequency (17 and 8.85 GHz) were −2.9 and −2.1 dB for the 5000 and 10,000 μm microstrip transmission lines, respectively. The material properties of wound dressing with the relative permittivity and loss-tangent of 3.15–3.25 and 0.04–0.05, respectively, were determined by two transmission line methods and used for antenna design. A quasi-Yagi antenna was designed and implemented on the wound-dressing with an antenna bandwidth of 3.2–4.6 GHz, maximal gain of 0.67 dBi, and 42% radiation efficiency. The bending effects parallel and perpendicular to the dipole direction of three fixtures were also examined. The gain decreased from 0.67 to −1.22 dBi and −0.44 dBi for a flat to curvature radius of 5 cm fixture after parallel and perpendicular bending, respectively. Although the maximal gain was reduced with the bending radius, the directivity of the radiation pattern remained unchanged. The feasibility of a wound-dressing antenna demonstrates that inkjet-printed technology enables fast fabrication with low cost and environmental friendliness. Additionally, inkjet-printed technology can be combined with sensing technology to realize remote medical monitoring, such as with smart bandages, for assessment of chronic wound status or basic physical conditions.

Purpose: Over the last decade, there has been tremendous progress in the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). To understand whether this has resulted in better ophthalmic outcomes, we aimed to study the incidence of severe ocular complications (SOCs) in the acute and chronic stage among SJS/TEN patients, major causative medications, and therapeutic effect of medical and surgical treatment.Methods: Using electronic medical records review of patients of Chang Gung Memorial Hospital Linkou Branch from 2010 to 2020, 119 patients (236 eyes) received ophthalmic consultation during the acute stage and were retrospectively studied. Sotozono's grading score systems for acute and chronic SJS/TEN were employed for accessing correlation between acute and chronic presentations, the therapeutic effect of systemic etanercept treatment, and outcome of early amniotic membrane transplantation (AMT) performed in patients with severe acute SOCs.Results: There were 46 male and 73 female patients with a mean age of 45.6 ± 22.7 years old (2–90 years), and follow-up time of 408.3 ± 351.0 (116–1,336) days. The numbers of patients with SJS, overlap syndrome, and TEN were 87, 9, and 23, respectively. In total, 109 eyes (55 patients) had acute SOCs, which comprised 46.2% of patients who underwent ophthalmic examination. Antiepileptics were the most common category of culprit drugs causing SOCs in the acute stage. At the end of follow-up, there were 14 eyes (9 patients) with chronic SOCs (5.9%), and non-steroidal anti-inflammatory drugs and cold medicine were the most common causative medications that were associated with severe chronic sequela. The correlation between Sotozono's acute and chronic grading score showed a positive relationship [Spearman's rank correlation coefficient (r) = 0.52, p < 0.001]. The average chronic grading scores in patients receiving systemic corticosteroid combined with etanercept treatment were significantly lower than those receiving corticosteroid only, Finally, the average chronic grading scores in patients receiving AMT

Severe cutaneous adverse reactions (SCAR) is a T cell-mediated, potentially lethal drug hypersensitivity (DH). Here, the authors identify a carbamazepine-specific TCR common among patients with carbamazepine-induced SCAR that confers SCAR-like pathology in mice upon carbamazepine exposure, thereby implicating specific TCRs in DH etiology.

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

Long non-coding RNAs (lncRNAs) have been suggested to play important roles in some biological processes. However, the detailed mechanisms are not fully understood. We previously identified an antisense lncRNA, Bmdsx-AS1, that is involved in pre-mRNA splicing of the sex-determining gene Bmdsx in the silkworm. In this study, we analyzed the changes in the male external genitalia of transgenic overexpressed Bmdsx-AS1 silkworm lines and analyzed downstream and upstream responses. We found that Bmdsx-AS1 transgenic silkworms, compared with wild type, showed more claspers in the male external genitalia. Quantitative real-time PCR (qPCR) results indicated that overexpression of Bmdsx-AS1 decreased the expression of genes in the EGFR signaling pathway. Knockdown of Bmdsx-AS1 increased the activity of the EGFR pathway. Through promoter prediction, promoter truncation and electrophoretic mobility shift assay (EMSA) analyses, we found that the protein encoded by the Hox gene BmAbd-B specifically binds to the promoter of Bmdsx-AS1. Moreover, overexpression of BmAbd-B in the silkworm BmE cell line indicated that BmAbd-B negatively regulates the mRNA expression of Bmdsx-AS1. Our study provides insights into the regulatory mechanism of the lncRNA in the silkworm.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are idiosyncratic and unpredictable drug-hypersensitivity reactions with a high-mortality rate ranging from 10% to over 30%, thus causing a major burden on the healthcare system. Recent pharmacogenomic studies have revealed strong associations between SCAR and the genes encoding human-leukocyte antigens (HLAs) or drug-metabolizing enzymes. Some of pharmacogenetic markers have been successfully applied in clinical practice to protect patients from SCAR, such as HLA-B*15:02 and HLA-A*31:01 for new users of carbamazepine, HLA-B*58:01 for allopurinol, and HLA-B*57:01 for abacavir. This article aims to update the current knowledge in the field of pharmacogenomics of drug hypersensitivities or SCAR, and its implementation in the clinical practice.

Neonatal lupus erythematosus (NLE) is a rare acquired condition caused by the transplacental passage of maternal autoantibodies. It is characterized by cutaneous, cardiac, hepatobiliary, hematological and neurological involvement. Cutaneous findings of NLE are variable, but few reports in the literature describe the presence of erosions or epidermal loss in NLE. Herein, we describe the case of an infant with NLE presenting as Stevens-Johnson syndrome (SJS), with cardiac, hematologic, hepatobiliary and neurologic abnormalities. The characteristic features by which to differentiate SJS-like NLE from infant SJS include subacute course, cardiac abnormalities, positive serology tests and direct immunofluorescence, histopathologic findings with melanin incontinence, periadnexal infiltrates, and mucin deposit. Though rare, it is important to consider lupus erythematosus as a potential cause of acute syndrome with focal epidermal necrosis or pan-epidermolysis. Keywords: Epidermolysis, Neonatal lupus erythematosus, Stevens-Johnson syndrome

The bacterial microbiota in the skin and intestine of patients with psoriasis were different compared with that of healthy individuals. However, the presence of a distinct blood microbiome in patients with psoriasis is yet to be investigated. In this study, we investigated the differences in bacterial communities in plasma-derived extracellular vesicles (EVs) between patients with moderate to severe psoriasis (PSOs) and healthy controls (HCs). The plasma EVs from the PSO (PASI > 10) (n = 20) and HC (n = 8) groups were obtained via a series of centrifugations, and patterns were examined and confirmed using transmission electron microscopy (TEM) and EV-specific markers. The taxonomic composition of the microbiota was determined by using full-length 16S ribosomal RNA gene sequencing. The PSO group had lower bacterial diversity and richness compared with HC group. Principal coordinate analysis (PCoA)-based clustering was used to assess diversity and validated dysbiosis for both groups. Differences at the level of amplicon sequence variant (ASV) were observed, suggesting alterations in specific ASVs according to health conditions. The HC group had higher levels of the phylum Firmicutes and Fusobacteria than in the PSO group. The order Lactobacillales, family Brucellaceae, genera Streptococcus, and species Kingella oralis and Aquabacterium parvum were highly abundant in the HC group compared with the PSO group. Conversely, the order Bacillales and the genera Staphylococcus and Sphihgomonas, as well as Ralstonia insidiosa, were more abundant in the PSO group. We further predicted the microbiota functional capacities, which revealed significant differences between the PSO and HC groups. In addition to previous studies on microbiome changes in the skin and gut, we demonstrated compositional differences in the microbe-derived EVs in the plasma of PSO patients. Plasma EVs could be an indicator for assessing the composition of the microbiome of PSO patients.

Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune responses interacting with genetics and the environment. The close connections between co-signaling pathways and SLE have gradually been established in past research. Also, the recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the co-inhibitory receptors in cancer immunotherapy. Moreover, immune checkpoint blockade could result in substantial immune-related adverse events that mimic autoimmune diseases, including lupus. Together, immune checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. Therefore, it appears reasonable to treat SLE by restoring the out-of-order co-signaling axis or by manipulating collateral pathways to control the pathogenic immune responses. Here, we review the current state of knowledge regarding the relationships between SLE and the co-signaling pathways of T cells, B cells, dendritic cells, and neutrophils, and highlight their potential clinical implications. Current clinical trials targeting the specific co-signaling axes involved in SLE help to advance such knowledge, but further in-depth exploration is still warranted.

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite). Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.