TERT promoter mutations increase tumor aggressiveness by altering TERT mRNA splicing in papillary thyroid carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis compared with TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of two major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into three groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A + B/dB ratio in mut+/exp + was significantly higher than that in mut-/exp + PTCs. Analysis with clinicopathological data revealed that +A + B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Fatal systemic capillary leak syndrome in a patient with a COVID-19 infection.

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with COVID-19.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder impacting various organs, notably prevalent in women of reproductive age. This review explores the involvement of a disintegrin and metalloproteinases (ADAMs) in SLE pathogenesis. Despite advancements in understanding SLE through genome and transcriptome studies, the role of ADAMs in post-translational regulations remains insufficiently explored. ADAMs, transmembrane proteins with diverse functions, impact cell adhesion, migration, and inflammation by shedding cell surface proteins, growth factors, and receptors. Notably, ADAM9 is implicated in Th17 cell differentiation, which is crucial in SLE pathology. ADAM10 and ADAM17 play pivotal roles in T-cell biology, influencing immune cell development and differentiation. Elevated soluble ADAM substrates in SLE patients serve as potential biomarkers correlating with disease activity. Targeting ADAMs or their substrates offers promising therapeutic avenues for SLE management and treatment enhancement.

Anti-centromere antibody positivity is an independent variable associated with salivary gland ultrasonography score in Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by periductal lymphocytic infiltration of the salivary and lacrimal glands. SS also exhibits extra-glandular manifestations and specific autoantibodies. Salivary gland ultrasonography (SGUS) is a common procedure used to assess the severity of glandular involvement. However, the association between SGUS and extra-glandular lesions remains poorly understood. This study aimed to identify clinical indices, including disease activity, associated with glandular involvement using SGUS in patients with SS. We included 115 patients with SS and 90 without SS. Patients with SS had significantly higher ultrasonography (US) score than patients without SS. Multivariate analysis revealed focus score, Saxon test positivity, and anti-centromere antibody (ACA) positivity as independent variables associated with the US score in patients with SS. In addition, these results were similar to those obtained in patients with primary SS. Patients with SS and ACA positivity had higher US score and an increased prevalence of hyperechoic bands in the parotid glands and submandibular glands. In conclusion, this study indicated that ACA positivity is associated with the US score in patients with SS. These results suggest that US findings in patients with ACA positivity might show specific changes in the salivary glands, especially fibrosis.

Risk factor of non-tuberculous Mycobacterium infection in patients with rheumatoid arthritis and other autoimmune diseases receiving biologic agents: A multicenter retrospective study.

BACKGROUND: Evidence regarding the association of the usage of biologic agents (Etanercept, Tocilizumab, adalimumab and so on), such as anti-tumor necrosis factor α, with the incidence and risk factors of non-tuberculous Mycobacteria (NTM) infection is limited. Therefore, this study aimed to investigate the incidence and risk factors of NTM and their associations with biologic agents' usage, and also investigated the potential of Mycobacterium avium complex (MAC) antibodies as a predictor of NTM infection development. METHODS: This retrospective study included 672 patients with autoimmune diseases from four hospitals in Nagasaki, Japan, from January 1, 2011, to June 30, 2019, who fulfilled the inclusion criteria. RESULTS: Of the 672 patients, 9 (1.3%) developed complicated NTM infection, including two with disseminated infection, after the introduction of biologic agents. Of the nine patients, two died due to NTM infection but none tested positive for MAC antibodies prior to initiation of biologic agents. The mortality rate was higher in patients complicated with NTM than without NTM (22.2% vs 2.6%, P = 0.024). The corticosteroids dosage at the time of initiating the biologic agents was significantly higher in the NTM group than in the non-NTM group (median, 17 mg vs 3 mg, P = 0.0038). CONCLUSION: In the patients undergoing therapy with biologic agents, although NTM complication was rare, it could be fatal. In particular, for patients on a relatively high dose corticosteroids, careful observation is essential for identifying NTM complication, even if the MAC antibody test is negative.

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease.

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

Correction: Arimori et al. Association between Lifestyle Factors and Weight Gain among University Students in Japan during COVID-19 Mild Lockdown: A Quantitative Study. Healthcare 2023, 11, 2630.

In our published publication [...].

Improved Hearing Impairment of Granulomatosis with Polyangiitis Treated with Rituximab and Avacopan without Glucocorticoids.

A 78-year-old woman with a history of intractable otitis media presented with a fever, hearing impairment, thigh pain, and a skin rash. She had renal dysfunction, positive myeloperoxidase-antineutrophil cytoplasmic autoantibody, otitis media, and multiple nodules in both lungs. She was diagnosed with granulomatosis with polyangiitis, crescentic glomerulonephritis, and interstitial nephritis, which was confirmed in a kidney biopsy specimen. Induction therapy with rituximab and avacopan without glucocorticoids promptly resolved her fever and thigh pain and improved her auditory acuity and nodule in the right lung. The patient experienced no adverse effects with rituximab or avacopan.

Evaluating the safety profile of calcineurin inhibitors: cancer risk in patients with systemic lupus erythematosus from the LUNA registry-a historical cohort study.

BACKGROUND: Previous studies have shown conflicting evidence regarding the incidence of cancer in patients with systemic lupus erythematosus (SLE) compared with that in healthy individuals. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been widely used to treat SLE; however, their effects on cancer risk remain unclear. We aimed to investigate the incidence of cancer in patients with SLE and determine the potential association between CNI use and cancer risk. METHODS: The standardized incidence ratio (SIR) of cancer among patients with lupus in the Lupus Registry of Nationwide Institutions (LUNA) was calculated based on the age-standardized incidence rate of cancer reported by Japan's Ministry of Health, Labour and Welfare. We also examined the association between CNI exposure and cancer risk, while considering potential confounding factors. The analysis accounted for confounding variables such as age, sex, smoking history, maximum glucocorticoid dose, treatment history with cyclophosphamide, ongoing hydroxychloroquine, Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) value (excluding cancer occurrence), comorbidity of diabetes mellitus, and smoking history. RESULTS: The study included 704 patients with SLE (625 females; 88.8%) with a median age of 44 years [interquartile range (IQR) = 34-55] years. The median past maximum glucocorticoid dose was 40 mg/day [IQR = 30-60 mg/day], and the SDI at registration was 1 [IQR = 0-2]. Among the patients, 246 (35.1%) had smoking histories, and 38 (5.4%) experienced cancer complications. Gynecological malignancies accounted for 63.2% of all cancers. The SIR of cancer in the LUNA cohort was 1.08 (95% confidence interval [CI] = 0.74-1.43). No statistically significant risks of cancer were found in relation to CNI treatment history; the odds ratio using multiple logistic regression was 1.12 (95% CI = 0.42-3.00), the risk ratio using standardization was 1.18 (95% CI = 0.47-2.16), and the risk ratio using inverse probability weighting was 1.8 (95% CI = 0.41-4.66). CONCLUSIONS: The incidence of cancer in patients with SLE in the LUNA cohort did not significantly differ from that in the general population. These findings suggest that CNI treatment in this cohort did not pose a risk factor for cancer development.

New onset of isolated adrenocorticotropin deficiency associated with encephalopathy following coronavirus disease 2019 in a healthy elderly man.

Coronavirus disease 2019 (COVID-19) due to a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can include various systemic organ disorders including endocrinopathies and neurological manifestations. We report the case of a 65-year-old Japanese man who developed isolated adrenocorticotropic hormone (ACTH) deficiency and encephalopathy following SARS-CoV-2 infection. Two weeks after his COVID-19 diagnosis, he was emergently admitted to our hospital because of subacute-onset delirium. On admission, he presented hyponatremia (128 mEq/L) and secondary adrenal insufficiency (ACTH <1.5 pg/mL, cortisol 0.53 µg/dL). Brain imaging and laboratory examinations including SARS-CoV-2 polymerase chain reaction testing in the cerebrospinal fluid revealed no abnormalities. His consciousness level worsened despite the amelioration of hyponatremia by intravenous hydrocortisone (100 mg/day), but his neurological presentations completely resolved after three consecutive days of high-dose (400 mg/day) hydrocortisone. His encephalopathy did not deteriorate during hydrocortisone tapering. He continued 15 mg/day hydrocortisone after discharge. His encephalopathy might have developed via a disturbance of the autoimmune system, or a metabolic effect associated with adrenal insufficiency, although the time lag between the hyponatremia's improvement and the patient's neurological response to the steroid was incompatible with common cases of delirium concurrent with adrenal insufficiency. At 13 months after his hospitalization, the patient's neurological symptoms have not recurred and he has no endocrinological dysfunctions other than the remaining ACTH deficiency. A thorough consideration of the immunological and metabolic characteristics of SARS-CoV-2 is advisable when clinicians treat patients during and even after their COVID-19 disease period.

Independent mesenchymal progenitor pools respectively produce and maintain osteogenic and chondrogenic cells in zebrafish.

Skeletal tissues including cartilage and bones are characteristic features of vertebrates that are crucial for supporting body morphology and locomotion. Studies mainly in mice have shown that osteoblasts and chondroblasts are supplied from several progenitors like the sclerotome cells in the embryonic stage, osteo-chondroprogenitors in growing long bones, and skeletal stem cells of bone marrow in the postnatal period. However, the exact origins of progenitor cells, their lineage relationships, and their potential to differentiate into osteoblasts and chondroblasts from embryos to adult tissues are not well understood. In this study, we conducted clonal cell tracking in zebrafish and showed that sox9a+ cells are already committed to either chondrogenic or osteogenic fates during embryonic stages and that respective progenies are independently maintained as mesenchymal progenitor pools. Once committed, they never change their lineage identities throughout animal life, even through regeneration. In addition, we further revealed that only osteogenic mesenchymal cells replenish the osteoblast progenitor cells (OPCs), a population of reserved tissue stem cells found to be involved in the de novo production of osteoblasts during regeneration and homeostasis in zebrafish. Thus, our clonal cell tracking study in zebrafish firstly revealed that the mesenchymal progenitor cells that are fated to develop into either chondroblasts or osteoblasts serve as respective tissue stem cells to maintain skeletal tissue homeostasis. Such mesenchymal progenitors dedicated to producing either chondroblasts or osteoblasts would be important targets for skeletal tissue regeneration.

Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study.

AIM: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and ß-hydroxybutyrate. RESULTS: The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial ß-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in ß-hydroxybutyrate levels. CONCLUSIONS: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.

Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

OBJECTIVES: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and 6 and 12 months. RESULTS: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Live tracking of basal stem cells of the epidermis during growth, homeostasis and injury response in zebrafish.

Basal stem cells of the epidermis continuously differentiate into keratinocytes and replenish themselves via self-renewal to maintain skin homeostasis. Numerous studies have attempted to reveal how basal cells undergo differentiation or self-renewal; however, this has been hampered by a lack of robust basal cell markers and analytical platforms that allow single-cell tracking. Here, we report that zebrafish integrin beta 4 is a useful marker for basal cell labelling, irrespective of the body region, stage and regenerative status. We employed Cre-loxP recombination in combination with live cell tracking of single basal clones in the caudal fin and investigated the embryonic origin and behaviour of basal cells during fish growth and homeostasis. Although most basal cells, including those in fins, became quiescent in the adult stage, genetic cell ablation showed that basal cells were reactivated to either self-renew or differentiate, depending on the injured cell type. Our study provides a simple and easy-to-use platform for quantitative in vivo imaging of basal stem cells at wider stages and under various conditions.

The double shared epitope: Its impact on clinical features and ultrasound findings in rheumatoid arthritis.

OBJECTIVES: The link between the HLA-DRB1 locus and the risk of rheumatoid arthritis (RA) shown in genome-wide association studies strengthens the shared epitope (SE) hypothesis. We aimed to assess the impact of the double dose of the SE (double SE) on RA and explore its clinical associations, including the response to abatacept. METHODS: We evaluated RA patients treated with csDMARDs or abatacept for HLA-DRB1 typing, clinical characteristics at baseline, and disease activity and ultrasound findings over 12 months. RESULTS: Patients with the double SE (n = 12) had significantly higher anti-citrullinated protein antibody (ACPA) titers, higher total grayscale (GS) score, and power Doppler (PD) score at baseline than patients without the double SE. Patients with the double SE exhibited reduced rates of SDAI remission and pronounced improvements in multiple disease activity between baseline and 12 months, including SDAI, CDAI, total GS score, and total PD score. When focusing on abatacept-treated patients, the decreases in SDAI, CDAI, and total PD score between baseline and 12 months were significantly larger in patients with the double SE. CONCLUSIONS: Patients with the double SE exhibited distinct characteristics, increased disease activity, and improved response to abatacept treatment.

Anti-melanoma Differentiation-associated Gene 5 Antibody-positive Dermatomyositis Presenting as Refractory Gingivitis at the First Clinical Manifestation.

We herein report a case of melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis that developed in a patient with refractory gingivitis. The diagnosis of anti-MDA5 antibody-positive dermatomyositis was made based on a characteristic skin rash, weakness of proximal muscles, interstitial pneumonia, and positivity for anti-MDA5 antibody. The patient was started on triple therapy with high-dose prednisolone, tacrolimus, and intravenous cyclophosphamide. After treatment, the refractory gingivitis disappeared, and the other skin rash and interstitial lung disease also improved. In the diagnosis and treatment of anti-MDA5 antibody-positive dermatomyositis, it is necessary to pay attention to the intraoral findings, including the gingiva.

Peripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease.

Castleman disease (CD) is a rare lymphoproliferative disorder. Among subtypes of CD, idiopathic multicentric CD-not otherwise specified (iMCD-NOS) has a poor prognosis and its pathogenesis is largely unknown. Here we present a xenotransplantation model of iMCD-NOS pathogenesis. Immunodeficient mice, transplanted with lymph node (LN) cells from iMCD-NOS patients, develop iMCD-like lethal inflammation, while mice transplanted with LN cells from non-iMCD patients without inflammation serve as negative control. Grafts depleted of human CD3+ T cells fail to induce inflammation in vivo. Upon engraftment, peripheral helper T (Tph) cells expand and levels of human CXCL13 substantially increase in the sera of mice. A neutralizing antibody against human CXCL13 blocks development of inflammation and improves survival in the recipient mice. Our study thus indicates that Tph cells, producing CXCL13 play a critical role in the pathogenesis of iMCD-NOS, and establishes iMCD-NOS as an immunoregulatory disorder.