Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences.

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-ß (TGF-ß), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/ß-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

[A case of immune-related gastroesophagitis with laryngopharyngitis caused by immune checkpoint inhibitors in nonsmall cell lung cancer].

With the advent of immune checkpoint inhibitors (ICI), cancer treatment options have widened in recent years. However, ICI-specific adverse events (irAEs) have been reported. Lower gastrointestinal lesions, such as colitis and enteritis, account for most gastrointestinal irAEs, and reports of upper gastrointestinal lesions are rare. We report a rare case of gastroesophagitis associated with ICI. The patient was a 64-year-old male. He was diagnosed with lung adenocarcinoma stage IIIB (cT2aN3M0), and pembrolizumab (PEM) was started as a first-line treatment. Severe gastroesophagitis with laryngopharyngitis was confirmed 5 months after PEM administration. These improved after withdrawal of PEM and steroid administration. Reports of ICI-associated gastritis remain limited, especially with laryngopharyngitis;therefore, we consider this case as valuable, in which we confirmed the clinical features of ICI-associated gastroesophagitis and its therapeutic effects.

Demographics, clinical characteristics, and treatment patterns among keloid patients: United States Electronic Health Records (EHR) Database Study.

INTRODUCTION: There is limited epidemiologic evidence on keloids using real-world data, especially in the United States (US) across race and ethnicity. METHODS: We conducted a retrospective cohort study using Cerner Real-World Data, between 2015 and 2021, to describe the demographic and clinical characteristics of US adults with keloids. Keloids were identified using a combination of ICD-10 and (Systemized Nomenclature of Medicine-Clinical Terms [SNOMED] codes). Demographics (including race and ethnicity), clinical characteristics, treatment patterns, and healthcare utilization were compared across keloid and non-keloid populations. RESULTS: Among 5,457 keloid patients identified in the study, the majority were female (61.8%) with a mean age of 34.2 years and of non-Hispanic Black, Hispanic, and Asian descent (P < 0.001). Relative to non-keloid cohorts, patients with keloids had significantly higher rates of integumentary, cardiorespiratory, general, auditory, and ocular surgeries and burns (all P < 0.05). Patients with keloids were also more likely to have comorbidities like obesity, hypertension, hyperlipidemia, and diabetes (P < 0.05) when compared to those with no keloids. A large proportion of keloids were untreated; among those treated, the most common keloid treatments were medication therapy (51.5%) and surgical excision (10.6%). Non-Hispanic Black and Hispanic keloid patients were significantly more likely to receive medication therapy and surgical excision (P < 0.001) compared to keloid patients of other races or ethnicities. CONCLUSIONS: This study provided real-world insights into the keloid population in the US. Our findings emphasize the high burden of keloids and its substantial impact on ethnic minorities. Given high keloid recurrence rates and limited standardized treatments for keloids, further research into keloids is crucial to the development of keloid-specific therapeutic options.

Atypical Clinical Courses of Graves' Disease Confound Differential Diagnosis of Hyperthyroidism.

BACKGROUND: This study examined the appropriateness of the current paradigm for differential diagnosis of painless thyroiditis and Graves' disease (GD) in patients with thyrotoxicosis. METHODS: We retrospectively evaluated the clinical course of 343 consecutive patients with hyperthyroidism diagnosed by Tc-99m pertechnetate thyroid uptake (TcTU) testing at our hospital from January 2011 to December 2017. RESULTS: Of the 263 patients with normal or high TcTU levels (≥1.0%), 255 (97%) had unequivocal GD and 5 had spontaneous remission GD or atypical GD. Of the 10 patients with low TcTU levels (<1.0% and ≥0.5%), 7 had GD, while others had subclinical GD, spontaneous remission GD with later relapse, and painless thyroiditis. Of those with very low TcTU levels (<0.5%), most had thyroiditis (painless thyroiditis, 33/67 [49%]; subacute thyroiditis, 29/67 [43%]), and some were positive for anti-TSH receptor antibodies. CONCLUSION: Given that atypical GD may confound the diagnosis of thyrotoxicosis, it is essential to follow the patient as a tentative diagnosis, whatever the diagnosis. This is the first report clearly demonstrating that so far there is no gold standard for the diagnosis of GD. It is therefore urgent to establish a consensus on the definition of GD so that the specificity and sensitivity of future diagnostic tests can be determined.

Natural History of Keloids: A Sociodemographic Analysis Using Structured and Unstructured Data.

INTRODUCTION: Keloids are lesions characterized by the growth of dense fibrous tissue extending beyond original wound boundaries. Research into the natural history of keloids and potential differences by sociodemographic factors in the USA is limited. This real-world, retrospective cohort study aimed to characterize a population of patients with keloids compared with matched dermatology and general cohorts. METHODS: Patients with ≥ 2 International Classification of Diseases codes for keloid ≥ 30 days apart and a confirmed keloid diagnosis from clinical notes enrolled in the OM1 Real-World Data Cloud between 1 January 2013 and 18 March 2022 were age- and sex-matched 1:1:1 to patients without keloids who visited dermatologists ("dermatology cohort") and those who did not ("general cohort"). Results are presented using descriptive statistics and analysis stratified by cohort, race, ethnicity, household income, and education. RESULTS: Overall, 24,453 patients with keloids were matched to 23,936 dermatology and 24,088 general patients. A numerically higher proportion of patients with keloids were Asian or Black. Among available data for patients with keloids, 67.7% had 1 keloid lesion, and 68.3% had keloids sized 0.5 to < 3 cm. Black patients tended to have larger keloids. Asian and Black patients more frequently had > 1 keloid than did white patients (30.6% vs. 32.5% vs. 20.5%). Among all patients with keloids who had available data, 56.4% had major keloid severity, with major severity more frequent in Black patients. Progression was not significantly associated with race, ethnicity, income, or education level; 29%, 25%, and 20% of the dermatology, keloid, and general cohorts were in the highest income bracket (≥ US$75,000). The proportion of patients with income below the federal poverty line (< US$22,000) and patterns of education level were similar across cohorts. CONCLUSION: A large population of patients in the USA with keloids was identified and characterized using structured/unstructured sources. A numerically higher proportion of patients with keloids were non-white; Black patients had larger, more severe keloids at diagnosis.

Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo.

BACKGROUND: Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. OBJECTIVE: This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV). METHODS: Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry. RESULTS: Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response. CONCLUSIONS: Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.

The effect of Dunaliella tertiolecta supplementation on diet-induced obesity in UCP1-deficient mice.

We previously demonstrated that dietary supplementation with Dunaliella tertiolecta (DT) increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) and improves diet-induced obesity (DIO) in C57BL/6 J mice at thermoneutrality (30 °C). Here, we investigated whether DT improves DIO in a thermoneutral UCP1-deficient (KO) animal. KO mice were fed a high-fat diet supplemented with DT for 12 weeks. Compared to control group without DT, body weight was significantly reduced in DT group with no difference in food intake. Dunaliella tertiolecta-supplemented mice exhibited lower adiposity and well-maintained multilocular morphology in BAT, in which a significant increase in gene expression of PR domain containing 16 was detected in DT group compared to control group. Moreover, increase in UCP2 level and/or decrease in ribosomal protein S6 phosphorylation were detected in adipose tissues of DT group relative to control group. These results suggest that DT supplementation improves DIO by stimulating UCP1-independent energy dissipation at thermoneutrality.

Assessing attentional task-related electroencephalogram signal variations by using mobile electroencephalogram technology: An experimental study.

BACKGROUND: A better understanding of the network responses of cortical activities during rest and cognitive tasks is necessary. Therefore, in this study, we aimed to evaluate cerebral activities during attentional tasks by using mobile electroencephalography, identifying the types of attentional components and brain waves. METHODS: In this experimental study, we enrolled 12 healthy young adults. The attentional tasks comprised parts A and B of the Trail-Making Test (TMT). Nineteen electroencephalography electrodes were placed over various brain regions. The Wilcoxon signed-rank test was used to examine the differences in power levels between the rest and TMT conditions. RESULTS: During TMT part A, the electroencephalography power level of the delta waves was significantly higher in the right frontal, left central, left occipital, left inferior frontal, right mid-temporal, right posterior temporal, and middle parietal areas (P < .05) than those during the resting state; that of the alpha waves was significantly lower in the left posterior temporal area (P = .006); and that of the high gamma waves was significantly lower in the left parietal (P = .05) and left occipital (P = .002) areas. During TMT part B, the electroencephalography power level of the beta waves was significantly higher in the right frontal area (P = .041) than that during the resting state, and that of the low gamma waves was significantly higher in the left frontal pole, right frontal, and right inferior frontal areas (P < .05). During the focused attentional task, the power level of the delta waves increased and that of the alpha waves decreased, and during the alternating attentional task, those of both the beta and gamma waves increased. The delta waves were related to the whole brain, the alpha and high gamma waves to the left posterior lobe, and the beta and low gamma waves to both frontal lobes. CONCLUSION: These findings contribute to the basic knowledge necessary to develop new attentional assessment methods for clinical situations.

Role of Innate Immunity in Allergic Contact Dermatitis: An Update.

Our understanding of allergic contact dermatitis mechanisms has progressed over the past decade. Innate immune cells that are involved in the pathogenesis of allergic contact dermatitis include Langerhans cells, dermal dendritic cells, macrophages, mast cells, innate lymphoid cells (ILCs), neutrophils, eosinophils, and basophils. ILCs can be subcategorized as group 1 (natural killer cells; ILC1) in association with Th1, group 2 (ILC2) in association with Th2, and group 3 (lymphoid tissue-inducer cells; ILC3) in association with Th17. Pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) in innate immune cells recognize damage-associated molecular patterns (DAMPs) and cascade the signal to produce several cytokines and chemokines including tumor necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-1ß, IL-4, IL-6, IL-12, IL-13, IL-17, IL-18, and IL-23. Here we discuss the recent findings showing the roles of the innate immune system in allergic contact dermatitis during the sensitization and elicitation phases.

Nostochopcerol, a new antibacterial monoacylglycerol from the edible cyanobacterium Nostochopsis lobatus.

A new antibacterial 3-monoacyl-sn-glycerol, nostochopcerol (1), was isolated from a cultured algal mass of the edible cyanobacterium Nostochopsis lobatus MAC0804NAN. The structure of compound 1 was established by the analysis of NMR and MS data while its chirality was established by comparison of optical rotation values with synthetically prepared authentics. Compound 1 inhibited the growth of Bacillus subtilis and Staphylococcus aureus at MIC of 50 µg/mL and 100 µg/mL, respectively.

Determinants of quality of life in elderly rehabilitation users at a day care service center.

[Purpose] We investigated the relationship of quality of life (QOL) with cognitive function, physical function, and activity ability, and aimed to identify functions related to QOL improvement, among elderly people who use day-care rehabilitation. [Participants and Methods] The participants were 37 elderly rehabilitation users, whose QOL was assessed using the Health Organization QOL26 (WHOQOL26), which consists of a 26-item self-report questionnaire. Cognitive function was assessed using the Mini-Mental State Examination, while physical function was assessed with seated forward bending, knee extension, grip, 30-second chair stand test, timed up and go test, and gait speed. Activity ability was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG index). [Results] A positive correlation was found between five WHOQOL26 categories (psychological QOL, social QOL, environmental QOL, total QOL, and QOL average) and social role in the TMIG index. There was also a positive correlation between four WHOQOL26 categories (psychological QOL, social QOL, environmental QOL, and QOL average) and instrumental activity of daily living in the TMIG index. To identify factors influencing the QOL score, association with TMIG index was investigated. Social role in the TMIG index was a positive factor in psychological and social QOL. [Conclusion] Enhancing social role is important to improve QOL of elderly rehabilitation users.

Prevalence of Vitiligo among Children and Adolescents in the United States.

BACKGROUND: Vitiligo is an autoimmune disorder that causes patchy loss of skin pigmentation. Up to 2.16% of pediatric patients may have vitiligo. This study estimated vitiligo point prevalence in children and adolescents (ages: 4-11 and 12-17 years) in the United States (US). METHODS: An online, population-based survey of a nationally representative sample of individuals based on 2017 US Census Bureau estimates for age, race, Hispanic origin, income, and geographic region was conducted from December 2019 to March 2020. Parent/legal guardian proxies responded on behalf of their children or adolescents to vitiligo screening questions. Proxy-reported vitiligo status was adjudicated by expert dermatologists who reviewed photographs of vitiligo lesions uploaded by proxies using a teledermatology application. Estimated point prevalence (including diagnosed and undiagnosed vitiligo and its subtypes) was calculated for proxy-reported and clinician-adjudicated vitiligo. RESULTS: There were 9,118 eligible proxy responses (5,209 children, mean age 7.7 years; 3,909 adolescents, mean age 14.4 years). The proxy-reported vitiligo prevalence (95% confidence interval) for children and adolescents was 1.52% (1.11-1.93) and 2.16% (1.66-2.65), respectively. The clinician-adjudicated prevalence (sensitivity analysis bounds) was 0.84% (0.83-1.23) and 1.19% (1.18-1.74), respectively. Approximately 69% of children and 65% of adolescents had nonsegmental vitiligo (clinician adjudicated) and up to 50% may be undiagnosed. CONCLUSION: Based on the clinician-adjudicated prevalence estimates, there were more than 591,000 cases of vitiligo in children and adolescents in the US in 2020. More than two-thirds had nonsegmental vitiligo and nearly half may be undiagnosed. Future studies should confirm these findings.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

A case of pheochromocytoma associated with liver abscess and intestinal pseudo-obstruction.

Pheochromocytomas can present with various symptoms. Nonspecific manifestations of pheochromocytoma include intestinal pseudo-obstruction and weight loss. Here, we present a case of pheochromocytoma in which prolonged intestinal pseudo-obstruction due to excess catecholamines was one of the factors leading to the development of a liver abscess. An 18-year-old male patient with a history of status epilepticus and severe intellectual disability was transferred to our hospital for a thorough examination of fever and constipation that had lasted for 2 months. When admitted to our hospital, he had fever, and his body mass index was 9.5 kg/m2. Upon comprehensive examination of the patient's fever, the blood culture was found positive for Bacteroides. Computed tomography showed findings of intestinal pseudo-obstruction and a low density region in the liver that indicated a liver abscess. Imaging studies also revealed a right adrenal mass and endocrinological test showed elevated plasma norepinephrine and urine normetanephrine levels. In addition, the right adrenal mass showed uptake on 123I-metaiodobenzylguanidine scintigraphy. These findings led to a definite diagnosis of pheochromocytoma. The patient was eventually diagnosed with a pheochromocytoma coexisting with a liver abscess. After treating the liver abscess with antibiotics and ultrasound-guided drainage, an adrenalectomy was performed. The pathological findings were consistent with pheochromocytoma. Postoperatively, the catecholamine excess normalized and intestinal pseudo-obstruction and weight loss improved. We suspected that prolonged intestinal pseudo-obstruction resulted in bacterial translocation and development of a liver abscess. To the best of our knowledge, this is the first report of a pheochromocytoma associated with a liver abscess. Moreover, the clinical presentation of this patient was unusual for pheochromocytoma, as the patient did not have typical symptoms such as hypertension or tachycardia, but rather presented with constipation, intestinal pseudo-obstruction, and weight loss. This case provides valuable insight regarding the impact of catecholamine excess on the intestinal tract and body weight.

Use of the Tokyo Cognitive Assessment for mild cognitive impairment to characterize elderly people that use day care services in Japan.

[Purpose] This study compared the motor skills and cognitive functions of elderly participants who required support with those who did not require support. We aimed to evaluate the characteristics of impairment in sub-items of cognitive function in patients who needed support to predict future clinical issues. [Participants and Methods] We surveyed 31 participants requiring support under the day care service insurance system for which they attended day care service centers in Japan (rehabilitation users) and 10 healthy participants who attended a university for lifelong learning (healthy elders). Data on personal attributes of the participants were collected, and the Cardio-Ankle Vascular Index and motor and cognitive functions were assessed. [Results] Although the participants undergoing rehabilitation were, on average, 6 years older than the healthy elders, we found no significant differences between the two groups in closed-eye, one-legged standing, grip strength, or quadriceps muscle strength. In terms of the Tokyo Cognitive Assessment for mild cognitive impairment, we found no significant differences between those undergoing rehabilitation and healthy elders in clock drawing performance, serial 7 task performance, or orientation; however, there were significant differences in erase character, copy of triangular pyramid, composition, read of digits, go/no-go, word recall, story reproduction, ToCA total score. [Conclusion] We believe that it is imperative for day care service centers to conduct programs that maintain cognitive function in addition to programs for improvement of physical function.

Perioperative glycemic status is linked to postoperative complications in non-intensive care unit patients with type-2 diabetes: a retrospective study.

Background: Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D. Materials and Methods: Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis. Results: Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85-0.98), P = 0.01) and mean postoperative BG (1.11 (1.05-1.18), P < 0.001) were independently associated with postoperative complications. Conclusion: Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

HLA analysis of immune checkpoint inhibitor-induced and idiopathic isolated ACTH deficiency.

PURPOSE: Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD). DESIGN AND METHODS: Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population. RESULTS: Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls. CONCLUSIONS: ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

Combined action of FOXO1 and superoxide dismutase 3 promotes MDA-MB-231 cell migration.

Superoxide dismutase 3 (SOD3), one of SOD isozymes, maintains extracellular redox homeostasis through the dismutation reaction of superoxide. Loss of SOD3 in tumor cells induces oxidative stress and exacerbates tumor progression; however, interestingly, overexpression of SOD3 also promotes cell proliferation through the production of hydrogen peroxide. In this study, we investigated the functional role of SOD3 in human breast cancer MDA-MB-231 cell migration and the molecular mechanisms involved in high expression of SOD3 in MDA-MB-231 cells and human monocytic THP-1 cells. The level of histone H3 trimethylation at lysine 27 (H3K27me3), a marker of gene silencing, was decreased in 12-O-tetra-decanoylphorbol-13-acetate (TPA)-treated THP-1 cells. Also, that reduction was observed within the SOD3 promoter region. We then investigated the involvement of H3K27 demethylase JMJD3 in SOD3 induction. The induction of SOD3 and the reduction of H3K27me3 were inhibited in the presence of JMJD3 inhibitor, GSK-J4. Additionally, it was first determined that the knockdown of the transcription factor forkhead box O1 (FOXO1) significantly suppressed TPA-elicited SOD3 induction. FOXO1-mediated SOD3 downregulation was also observed in MDA-MB-231 cells, and knockdown of FOXO1 and SOD3 suppressed cell migration. Our results provide a novel insight into epigenetic regulation of SOD3 expression in tumor-associated cells, and high expression of FOXO1 and SOD3 would participate in the migration of MDA-MB-231 cells.