Pembrolizumab-induced asthma exacerbation with hypereosinophilia and elevated interleukin-5 in endometrial cancer: A case report.

Pembrolizumab is an anti-programmed cell death-1 (PD-1) antibody used to treat various cancer types. Treatments with such immune checkpoint inhibitors cause immune-related adverse events. However, airway inflammation caused by immune-related adverse events has rarely been reported. A 54-year-old woman with endometrial cancer experienced asthma exacerbation, and increased blood eosinophil counts 3 months after pembrolizumab administration. Although asthma exacerbation improved, the resumption of pembrolizumab caused the recurrence of dry cough and hypereosinophilia. The discontinuation of pembrolizumab improved her symptoms. Serum interleukin-5 levels increased during pembrolizumab treatment but decreased upon discontinuation. The blockade of PD-1 and its ligand may exacerbate asthma through eosinophilic inflammation.

Renal tubular acidosis without interstitial nephritis in Sjögren's syndrome: a case report and review of the literature.

BACKGROUND: Renal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren's syndrome. Renal tubular dysfunction due to interstitial nephritis has been considered the underlying pathophysiology connecting renal tubular acidosis and primary Sjögren's syndrome. However, the detailed mechanisms underlying the pathophysiology of renal tubular acidosis in primary Sjögren's syndrome is not fully understood. CASE PRESENTATION: A 30-year-old woman was admitted with complaints of weakness in the extremities. The patient was hospitalized thirteen years earlier for similar issues and was diagnosed with hypokalemic paralysis due to distal renal tubular acidosis with primary Sjögren's syndrome. This diagnosis was based on a positive Schirmer's test. Besides, anti-Sjögren's syndrome-related antigen A was also detected. Laboratory tests indicated distal RTA; however, a renal biopsy showed no obvious interstitial nephritis. Laboratory tests conducted during the second admission indicated distal renal tubular acidosis. Therefore, a renal biopsy was performed again, which revealed interstitial nephritis. Histological analysis of acid-base transporters revealed the absence of vacuolar type H+-ATPases in the collecting duct. The vacuolar type H+-ATPase was also absent in the past renal biopsy, suggesting that the alteration in acid-base transporters is independent of interstitial nephritis. CONCLUSIONS: This case study demonstrates that vacuolar-type H+-ATPases are associated with distal renal tubular acidosis, and distal renal tubular acidosis precedes interstitial nephritis in patients with primary Sjögren's syndrome.

The Clinical Characteristics of Allergic Bronchopulmonary Mycosis Differ Among Pathogenic Fungi.

Background: Allergic bronchopulmonary mycosis (ABPM) occurs with fungi, other than Aspergillus fumigatus. However, the clinical characteristics of ABPM caused by non-Aspergillus species are unspecified. Methods: We retrospectively reviewed all patients with ABPM who visited to our hospital between April 2005 and December 2020. The causative fungi and clinical characteristics were analyzed. Patients were divided into the Aspergillus group and the non-Aspergillus group. Results: Fourteen patients and five patients were included in the Aspergillus group and the non-Aspergillus group, respectively. Compared to the Aspergillus group, the non-Aspergillus group had a significantly low serum immunoglobulin E level and low forced vital capacity. In addition, the non-Aspergillus group had a lower rate of the requirement for oral corticosteroid treatment and a low frequency of recurrence. Conclusion: Patients with non-Aspergillus ABPM had lower type 2 inflammation than did patients with allergic bronchopulmonary aspergillosis.

Rheumatoid Arthritis Symptoms Diagnosed by Rheumatic Immune-related Adverse Events Caused by Nivolumab in a Patient with Esophageal Cancer.

This report described the case of a 70-year-old man who developed polyarthralgia after nivolumab treatment for recurrent esophageal cancer. Arthritis developed after initiating nivolumab therapy, and the patient tested positive for rheumatoid factor and anti-citrullinated peptide antibodies. The hand and elbow joints were already deformed, suggesting that he had had rheumatoid arthritis for several years and that the symptoms had only become apparent after nivolumab administration. This patient had rheumatoid arthritis, which was diagnosed as a nivolumab-induced rheumatic immune-related adverse event (rh-irAEs). Arthralgia during nivolumab administration can occur in rh-irAE cases. Patients should be assessed for autoimmune diseases before initiating immune checkpoint inhibitors.

Uromodulin Regulates Murine Aquaporin-2 Activity via Thick Ascending Limb-Collecting Duct Cross-Talk during Water Deprivation.

Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin-2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross-talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.

Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts.

Background: Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, is involved in the pathogenesis of rheumatoid arthritis (RA). The omega-3 unsaturated fatty acid-derived metabolites resolvin (Rv) D1, RvE1, and maresin-1 (MaR1) have been reported as anti-inflammatory lipid mediators and are known as specialized pro-resolving mediators (SPMs). In this study, we aimed to investigate the anti-inflammatory effects of SPMs on TNF-α-induced responses in synovial fibroblasts. Methods: We investigated the effects of SPMs on gene expression and/or production of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), interleukin (IL)-6, and matrix metalloproteinase (MMP)-3, which are involved in TNF-α-induced synovitis in RA or OA synovial fibroblasts, by quantitative real-time PCR. We also investigated the effects of SPMs on the mitogen-activated protein kinase (MAPK) signaling pathway by western blotting. Anti-inflammatory effects of SPMs were evaluated by applying SPMs to cultured synovial fibroblasts, followed by TNF-α stimulation. Results: The induction of COX-2, mPGES-1, IL-6, and MMP-3 by TNF-α in synovial fibroblasts was not suppressed by omega 3-derived SPMs regardless of their origin such as RA or OA. SPMs had no effect on lipid mediator receptor gene expression induce by TNF-α and did not inhibit the TNF-α-activated MAPK signaling pathway. The production of COX-2 and IL-6 protein was significantly decreased by p38 inhibitor. Conclusion: Despite reports on the anti-inflammatory effect of omega 3-derived SPMs, its anti-inflammatory effect on TNF-α-induced responses was not observed in synovial fibroblasts. The reason may be that SPMs have no suppressive effect on p38 activation, which plays an important role in the production of inflammatory cytokines in synovial fibroblasts.

The efficacy and safety of reduced-dose sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with rheumatic diseases.

OBJECTIVES: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection. Sulfamethoxazole-trimethoprim (SMX/TMP) is the first-line drug for PCP prophylaxis. However, adverse events (AEs) force clinicians to alter or reduce the drug dosage. METHODS: We retrospectively reviewed all patients with rheumatic diseases who received SMX/TMP for prophylaxis and glucocorticoid therapy between April 2004 and March 2018. The rates of AEs, SMX/TMP discontinuation, and incidence of PCP were analyzed. Patients were divided into the conventional group and the dose-reduction group. RESULTS: One hundred forty-five patients and 75 patients were included in the conventional group and the dose-reduction group, respectively. Compared to the dose-reduction group, the conventional group had a significantly high frequency of AEs (10.7% vs. 24.1%; p = .017); however, the rate of discontinuing SMX/TMP was not significantly different (8.0% vs. 14.5%; p = .165). Thirteen conventional group patients required a reduced SMX/TMP dose because of AEs; no patient developed PCP. The conventional SMX/TMP dose and renal dysfunction were associated with AEs in multivariate analysis. CONCLUSION: Patients who received a reduced SMX/TMP dose did not have PCP and had a lower frequency of AEs. A reduction in SMX/TMP for PCP prophylaxis is effective and safe in patients with rheumatic disease.

OTUD6B-AS1 Might Be a Novel Regulator of Apoptosis in Systemic Sclerosis.

Antisense long non-coding RNAs (AS lncRNAs) have increasingly been recognized as important regulators of gene expression and they have been found to play key roles in several diseases. However, very little is known about the role of AS lncRNAs in fibrotic diseases such as systemic sclerosis (SSc). Our recent screening experiments by RNA sequencing showed that ovarian tumor domain containing 6B antisense RNA1 (OTUD6B-AS1) and its sense gene OTUD6B were significantly downregulated in SSc skin biopsies. Therefore, we aimed to identify key regulators of OTUD6B-AS1 and to analyze the functional relevance of OTUD6B-AS1 in SSc. OTUD6B-AS1 and OTUD6B expression in SSc and healthy control (HC) dermal fibroblasts (Fb) after stimulation with transforming growth factor-ß (TGFß), Interleukin (IL)-4, IL-13, and platelet-derived growth factor (PDGF) was analyzed by qPCR. To identify the functional role of OTUD6B-AS1, dermal Fb or human pulmonary artery smooth muscle cells (HPASMC) were transfected with a locked nucleic acid antisense oligonucleotide (ASO) targeting OTUD6B-AS1. Proliferation was measured by BrdU and real-time proliferation assay. Apoptosis was measured by Caspase 3/7 assay and Western blot for cleaved caspase 3. While no difference was recorded at the basal level between HC and SSc dermal Fb, the expression of OTUD6B-AS1 and OTUD6B was significantly downregulated in both SSc and HC dermal Fb after PDGF stimulation in a time-dependent manner. Only mild and inconsistent effects were observed with TGFß, IL-4, and IL-13. OTUD6B-AS1 knockdown in Fb and HPASMC did not affect extracellular matrix or pro-fibrotic/proinflammatory cytokine production. However, OTUD6B-AS1 knockdown significantly increased Cyclin D1 expression at the mRNA and protein level. Moreover, silencing of OTUD6B-AS1 significantly reduced proliferation and suppressed apoptosis in both dermal Fb and HPASMC. OTUD6B-AS1 knockdown did not affect OTUD6B expression at the mRNA level and protein level. Our data suggest that OTUD6B-AS1 regulates proliferation and apoptosis via cyclin D1 expression in a sense gene independent manner. This is the first report investigating the function of OTUD6B-AS1. Our data shed light on a novel apoptosis resistance mechanism in Fb and vascular smooth muscle cells that might be relevant for pathogenesis of SSc.

Effect of Cetuximab and EGFR Small Interfering RNA Combination Treatment in NSCLC Cell Lines with Wild Type EGFR and Use of KRAS as a Possible Biomarker for Treatment Responsiveness.

BACKGROUND: The epidermal growth factor receptor (EGFR) is a therapeutic target for patients with non-small cell lung cancer (NSCLC). Cetuximab is an anti-EGFR monoclonal antibody that inhibits EGFR signaling and proliferation of colorectal cancer and head and neck cancers. Since only few NSCLC patients benefit from cetuximab therapy, we evaluated a novel combination treatment using cetuximab and EGFR small interfering RNA (siRNA) to strongly suppress EGFR signaling and searched for a biomarker in NSCLC cell lines harboring wild-type EGFR. METHODS: Alterations in EGFR and its downstream genes in five NSCLC cell lines (A549, Lu99, 86-2, Sq19 and Ma10) were assessed through sequencing. The protein expression levels of these molecules were assessed through western blotting. The effect of combination treatment was determined through cell proliferation assay, caspase-3/7 assay, invasion assay, and migration assay. RESULTS: All cell lines were harboring wild-type EGFR, whereas KRAS, PTEN, TP53 and TP53 were mutated in A549 and Lu99; Lu99 and Sq19; Lu99, 86-2, Sq19 and Ma10; and A549, 86-2, and Sq19 cell lines, respectively. PTEN was not expressed in Sq19, and LKB1 was not expressed in both A549 and Sq19. TP53 was not expressed in both A549 and Lu99. The combination of cetuximab and EGFR siRNA significantly suppressed cell proliferation in 86-2, Sq19 and Ma10, which express wild-type KRAS. It induced apoptosis in A549, 86-2 and Ma10 cells, which express wild type PTEN. The combination treatment had no effect either on cell invasion nor migration in all cell lines. CONCLUSION: EGFR targeted therapy using the combination of cetuximab and EGFR siRNA is effective in NSCLC cell lines harboring wild-type EGFR. Wild-type KRAS may act as a potential biomarker for response to combination treatment by the induction of apoptosis in cells with wild-type PTEN.

Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis.

Objective: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM). Methods: In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed. Results: Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3-48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5-11.4) nmol/L at 6 months after treatment introduction. Conclusions: Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.

Leukocytapheresis for the treatment of acute exacerbation of idiopathic interstitial pneumonias: a pilot study.

OBJECTIVE: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous diffuse parenchymal lung disorders of unknown etiology. An acute exacerbation (AE) is an acute respiratory deterioration that occurs in IIPs. The prognosis of AE of IIPs (AE-IIPs) is extremely severe; however, no established therapies exist. We aimed to evaluate the efficacy of leukocytapheresis (LCAP) to treat patients with AE-IIPs. PATIENTS AND METHODS: Six chronic IIPs patients who developed AE were enrolled in this study. We performed LCAP on days 2, 3, 9 and 10 in all six patients. All patients were also treated with high-dose corticosteroids and a continuous administration of low-molecular-weight heparin. We observed 30-day survival after the diagnosis of AE to evaluate the efficacy of LCAP. We also assessed oxygenation, high-resolution computed tomography (HRCT) findings, and certain chemical mediators in the peripheral blood. RESULTS: Five of six patients survived more than 30 days. One patient died of progressive respiratory failure. Oxygenation and HRCT findings tended to improve in all survivors. The serum levels of lactate dehydrogenase, high mobility group box-1, and interleukin-18 were significantly decreased statistically post-LCAP. No severe adverse events occurred. CONCLUSION: We suggest that LCAP is a safe and effective therapy for treating patients with AE-IIPs. J. Med. Invest. 64: 110-116, February, 2017.

γ-Tocotrienol Inhibits TGF-ß1-Induced Contractile Phenotype Expression of Human Airway Smooth Muscle Cells.

BACKGROUND: Tocotrienols, members of the vitamin E family, exist in four different isoforms (α, ß, γ and δ tocotrienol) that have can be protective against brain damage, as well as having anticancer effects in vivo and in vitro. We have shown that γ-tocotrienol inhibits human airway smooth muscle cell proliferation and migration induced by platelet-derived growth factor (PDGF)-BB by suppressing RhoA activation. In this study, we tested whether γ-tocotrienol modulates transforming growth factor (TGF) -ß-induced induction of human airway smooth muscle (ASM) into a contractile phenotype and concomitant synthesis of extracellular matrix proteins. METHODS: ASM cells were stimulated with TGF-ß1 (2 ng/mL) for 48 hours and the effect of γ-tocotrienol (50 µM) on α-smooth muscle actin, fibronectin and collagen I expression was assessed using Western blotting. The signaling pathways involved in TGF-ß1 stimulation were also investigated. RESULTS: TGF-ß1 increased α-smooth muscle actin, fibronectin and collagen Ⅰ abundance by 3- to 5-fold. This response was inhibited significantly by γ-tocotrienol. Furthermore, γ-tocotrienol suppressed RhoA activation, but did not affect Smad2 or Smad3 phosphorylation. CONCLUSION: These results indicate that γ-tocotrienol has potential for benefit in modulating on airway remodeling in asthma, likely via a mechanism involving the suppression of TGF-ß activation of RhoA.

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration.

AIMS: Vitamin E is an antioxidant that occurs in 8 different forms (α, ß, γ, and δ tocopherol and tocotrienol). Clinical trials of tocopherol supplementation to assess the impact of antioxidant activity in asthma have yielded equivocal results. Tocotrienol exhibits greater antioxidant activity than tocopherol in several biological phenomena in vivo and in vitro. We tested the effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma. MAIN METHODS: We measured platelet-derived growth factor-BB (PDGF-BB)-induced ASM cell proliferation and migration by colorimetric and Transwell migration assays in the presence and absence of γ-tocotrienol (an isoform of tocotrienol). KEY FINDINGS: PDGF-BB-induced ASM cell proliferation and migration were inhibited by γ-tocotrienol. This effect was associated with inhibition of RhoA activation, but it had no effect on p42/p44 mitogen-activated protein kinase (MAPK) or Akt1 activation. We confirmed that pharmacological inhibition of Rho kinase activity was sufficient to inhibit PDGF-BB-induced ASM cell proliferation and migration. SIGNIFICANCE: γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

Causes of death in patients with asthma and asthma-chronic obstructive pulmonary disease overlap syndrome.

BACKGROUND: The administration of inhaled corticosteroids and worldwide usage of several asthma guidelines have improved asthma mortality. Elderly patients with asthma show high mortality rates, and may have several comorbidities, including overlap with chronic obstructive pulmonary disease (COPD). Among patients showing asthma overlapped with COPD (asthma-COPD overlap syndrome; ACOS), mortality is worse than for asthma alone. Therefore, we investigated comorbidities, malignancies, and causes of death in patients with asthma and ACOS. METHODS: This was a retrospective study. From January 2000 to March 2012, 650 patients were followed up at Tottori University Hospital. Medical records were reviewed to collect data regarding patient characteristics and comorbidities, and causes of death were recorded for patients who died during the study period. RESULTS: Eighty-seven patients died during the study period. The most frequent cause of death was malignancy. The proportion of malignant disease was 21.7% in all patients, 19.4% in patients with asthma alone, and 32.4% in patients with ACOS. One patient died from an asthma attack during this period. CONCLUSION: The most frequent cause of death in patients with asthma and ACOS was malignant disease. It is necessary to control not only asthma but also comorbidities in patients with asthma, especially in those with ACOS.

The relationships among sleep efficiency, pulmonary functions, and quality of life in patients with asthma.

BACKGROUND: Sleep disturbance is commonly observed in patients with asthma, especially in those with poorly controlled asthma. Evaluating sleep quality to achieve good control of asthma is important since nocturnal asthmatic symptoms such as cough, wheezing, and chest tightness may disturb sleep. Actigraphy is an objective, ambulatory monitoring method for tracking a patient's sleep and wake activities and for assessing sleep quality, as reflected by total sleep time, sleep efficiency, duration of awakening after sleep onset (WASO), and sleep onset latency. PATIENTS AND METHODS: Fifty patients with asthma were enrolled in this study. Sleep quality was assessed employing wristwatch-type actigraphy (Actiwatch 2). The level of asthma control was assessed by the Asthma Control Questionnaire (ACQ), and asthma-related quality of life was assessed by the Asthma Quality of Life Questionnaire (AQLQ). The parameters for sleep quality were compared using ACQ scores, AQLQ scores, and pulmonary function test results. RESULTS: The total sleep time was 387.2 minutes, WASO was 55.8 minutes, sleep efficiency was 87.01%, sleep onset latency was 8.17 minutes, and the average ACQ was 0.36. Neither sleep efficiency nor WASO correlated with respiratory functions, ACQ scores, or AQLQ scores. CONCLUSION: Sleep-related parameters assessed by actigraphy in well-controlled asthma do not correlate with pulmonary functions, the asthma control level, or daytime quality of life. Sleep quality should be evaluated independently when asthma is well-controlled.

The effects of recycling loops in food waste management in Japan: based on the environmental and economic evaluation of food recycling.

In Japan, a revised Food Recycling Law went into effect in 2007 to promote a "recycling loop" that requires food industries to purchase farm products that are grown using food waste-derived compost/animal feed. To realize and expand food recycling, it is necessary to evaluate how the recycling facilities work in the recycling loop. The purpose of this study is to assess the environmental and economic efficiency of the food recycling facilities that are involved in the recycling loop, which are also known as looped facilities. The global warming potential and running cost of five looped facilities were evaluated by LCA (life cycle assessment) and LCC (life cycle cost) approaches: machine integrated compost, windrow compost, liquid feed, dry feed, and bio-gasification. The LCA results showed low total GHG (greenhouse gas) emissions of -126 and -49 kg-CO(2)/t-waste, respectively, for dry feed and bio-gasification facilities, due to a high substitution effect. The LCC study showed a low running cost for composting facilities of -15,648 and -18,955 yen/t-waste, respectively, due to high revenue from the food waste collection. It was found that the mandatory reporting of food waste emitters to the government increased collection fees; however, the collection fee in animal feed facilities was relatively low because food waste was collected at a low price or nutritious food waste was purchased to produce quality feed. In the characterisation survey of various treatment methods, the composting facilities showed a relatively low environmental impact and a high economic efficiency. Animal feed facilities had a wide distribution of the total GHG emissions, depending on both the energy usage during the drying process and the substitution effect, which were related to the water content of the food waste and the number of recycled products. In comparison with incineration, the majority of the food recycling facilities showed low GHG emissions and economic effectiveness. This paper also reported on the effects of recycling loops by comparing looped and non-looped animal feed facilities, and confirmed that the looped facilities were economically effective, due to an increased amount of food waste collection.