Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.

Prevalence of whiplash injury and its association with quality of life in local residents in Japan: A cross sectional study.

BACKGROUND: Associations between whiplash injuries and quality of life (QOL) have been previously published by conducting surveys among patients. This study aimed to investigate the prevalence of whiplash injuries in a Japanese community, and the association between whiplash injuries and QOL was also determined. METHODS: In all, 1140 volunteers participated in this study, filled out a questionnaire about whether they had experienced a whiplash injury, or had any neck pain or neck-shoulder stiffness in the previous 3 months, and completed the Medical Outcomes Study 36-Item Short-Form Health Survey. QOL was evaluated from the eight domain scores, and the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. We compared the characteristics, habits, history, medication, body mass index, and health-related QOL (eight domains, PCS and MCS scores) between the groups with whiplash injuries and no whiplash injuries for each sex. Multiple linear regressions with the forced-entry procedure were performed to evaluate the effects of a whiplash injury on the PCS and MCS. A p-value of <0.05 was considered statistically significant. RESULTS: The prevalence of whiplash injuries was 7.7% and 9.6% in men and women, respectively. The percentage of those who experienced whiplash injuries with symptoms persisting for more than 3 months was 34.3% and 24.2% in men and women, respectively. The prevalence of neck symptoms was significantly higher in the whiplash injury group than in the non-whiplash injury group. Multiple linear regression analysis showed that, although whiplash injuries were associated with poor health-related QOL in men, age was more associated with health-related QOL than whiplash injuries in both sexes. CONCLUSION: The prevalence of whiplash injuries was 7.7% and 9.6% in men and women in local residents in Japan, respectively. Whiplash injuries were poorly associated with a poor health-related QOL in men (P = 0.015).

CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation.

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1ß-a specific ligand for CCR5 receptors-was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression-a marker of activated eosinophils-as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)ß, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRß, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.

Efficacy of Combination Therapy with Lenvatinib and Radioactive Iodine in Thyroid Cancer Preclinical Model.

Patients with differentiated thyroid cancer (DTC) usually have good prognosis, while those with advanced disease have poor clinical outcomes. This study aimed to investigate the antitumor effects of combination therapy with lenvatinib and 131I (CTLI) using three different types of DTC cell lines with different profiling of sodium iodide symporter (NIS) status. The radioiodine accumulation study revealed a significantly increased radioiodine uptake in K1-NIS cells after lenvatinib treatment, while there was almost no uptake in K1 and FTC-133 cells. However, lenvatinib administration before radioiodine treatment decreased radioiodine uptake of K1-NIS xenograft tumor in the in vivo imaging study. CTLI synergistically inhibited colony formation and DTC cell migration, especially in K1-NIS cells. Finally, 131I treatment followed by lenvatinib administration significantly inhibited tumor growth of the NIS-expressing thyroid cancer xenograft model. These results provide important clinical implications for the combined therapy that lenvatinib should be administered after 131I treatment to maximize the treatment efficacy. Our synergistic treatment effects by CTLI suggested its effectiveness for RAI-avid thyroid cancer, which retains NIS function. This potential combination therapy suggests a powerful and tolerable new therapeutic strategy for advanced thyroid cancer.

Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients' DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2'-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2'OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions.

Eosinophils not only play a critical role in the pathogenesis of eosinophil-associated diseases, but they also have multiple important biological functions, including the maintenance of homeostasis, host defense against infections, immune regulation through canonical Th1/Th2 balance modulation, and anti-inflammatory and anti-tumorigenic activities. Recent studies have elucidated some emerging roles of eosinophils in steady-state conditions; for example, eosinophils contribute to adipose tissue metabolism and metabolic health through alternatively activated macrophages and the maintenance of plasma cells in intestinal tissue and bone marrow. Moreover, eosinophils exert tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic airway inflammation, leading to diseases including asthma and chronic rhinosinusitis with nasal polyps characterized by fibrin deposition through excessive response by eosinophils-induced. Thus, eosinophils possessing these various effects reflect the heterogenous features of these cells, which suggests the existence of distinct different subpopulations of eosinophils between steady-state and pathological conditions. Indeed, a recent study demonstrated that instead of dividing eosinophils by classical morphological changes into normodense and hypodense eosinophils, murine eosinophils from lung tissue can be phenotypically divided into two distinct subtypes: resident eosinophils and inducible eosinophils gated by Siglec-Fint CD62L+ CD101low and Siglec-Fhigh CD62L- CD101high, respectively. However, it is difficult to explain every function of eosinophils by rEos and iEos, and the relationship between the functions and subpopulations of eosinophils remains controversial. Here, we overview the multiple roles of eosinophils in the tissue and their biological behavior in steady-state and pathological conditions. We also discuss eosinophil subpopulations.

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear. METHODS: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69. RESULTS: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking. CONCLUSIONS: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma.

Critical role of CCL4 in eosinophil recruitment into the airway.

BACKGROUND: Excessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1ß (MIP-1ß or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships between eosinophils and CCL4, have not been fully elucidated. OBJECTIVE: To examine the involvement of CCL4 in eosinophilic airway inflammation. METHODS: We analysed supernatants of activated eosinophils and BALF from 16 patients with eosinophilic pneumonia (EP). Further, we examined the effects of CCL4 on eosinophil functions in vitro and those of anti-CCL4 neutralizing antibody in an in vivo model. RESULTS: We found that purified human eosinophils stimulated with IL-5 predominantly secreted CCL4 and that patients with EP had elevated CCL11 and CCL4 levels in BALF compared with samples from individuals without EP. Because CCL4 levels were more strongly correlated with eosinophil count and expression of eosinophil granule proteins than CCL11, in vitro experiments using purified eosinophils concentrated on the former chemokine. Interestingly, CCL4 acted as a chemoattractant for eosinophils. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, these findings highlight an important role of CCL4 in the mechanisms underlying eosinophil recruitment into the airway and may provide a novel insight into this potential therapeutic target.

Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity.

We have reported that phosphorylation of the glucocorticoid receptor (GR) at Ser226 reduces GR nuclear translocation, resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase 2A, which regulates c-Jun N-terminal kinase (JNK) 1 and GR-Ser226 signaling, is involved in this mechanism. Here, we further explored protein kinase dual-specificity phosphatases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity. The effects of knocking down DUSPs (DUSP1, 4, 8, 16, and 22) by small interfering RNA (siRNA) were evaluated in a monocytic cell line (U937). Corticosteroid sensitivity was determined by dexamethasone enhancement of FK506-binding protein 51 or inhibition of tumor necrosis factor α (TNFα)-induced interferon γ and interleukin 8 expression and GR translocation from cell cytoplasm to nucleus. The nuclear/cytoplasmic GR, phosphorylation levels of GR-Ser226 and JNK1, coimmunoprecipitated GR-JNK1-DUSP4, and DUSP4 expression were analyzed by western blotting and/or imaging flow cytometry. Phosphatase activity of immunoprecipitated (IP)-DUSP4 was measured by fluorescence-based assay. Knockdown of DUSP4 enhanced phosphorylation of GR-Ser226 and JNK1 and reduced GR nuclear translocation and corticosteroid sensitivity. Coimmunoprecipitation experiments showed that DUSP4 is associated with GR and JNK1. In peripheral blood mononuclear cells from severe asthmatics, DUSP4 expression was reduced versus healthy subjects and negatively correlated with phosphorylation levels of GR-Ser226 and JNK1. Formoterol enhanced DUSP4 activity and restored corticosteroid sensitivity reduced by DUSP4 siRNA. In conclusion, DUSP4 regulates corticosteroid sensitivity via dephosphorylation of JNK1 and GR-Ser226 DUSP4 activation by formoterol restores impaired corticosteroid sensitivity, indicating that DUSP4 is crucial in regulating corticosteroid sensitivity, and therefore might be a novel therapeutic target in severe asthma.

Replacement of SFC-DPI with SFC-MDI exhaled through the nose improves eosinophilic chronic rhinosinusitis in patients with bronchial asthma.

OBJECTIVE: Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is a refractory disease closely associated with bronchial asthma. We recently reported on the efficacy of ultra-fine particle inhaled corticosteroids (ICS) (hydrofluoroalkane-134a-beclomethasone dipropionate: HFA-BDP) exhalation through the nose (ETN) treatment for mild-to-moderate asthmatics with ECRS. However, the effect of HFA-BDP ETN was found to be transient in some cases with severe ECRS and asthma, requiring treatment with higher-dose ICS and long-acting ß2-agonists (LABA). Here, we present a case of refractory ECRS with severe asthma treated with a combination of high-dose ICS and LABA ETN, and we discuss the mechanisms for its effectiveness. METHODS: A 57-year-old man was treated with the combined regimen of HFA-BDP ETN and salmeterol/fluticasone combination (SFC) dry powder inhaler (DPI) for his refractory ECRS with severe asthma. For better control, we replaced SFC-DPI with SFC metered-dose inhaler (MDI) ETN and evaluated the clinical effect and corticosteroid sensitivity. We also examined the flow and deposition of fine particles released by SFC-MDI ETN. RESULTS: After switching to SFC-MDI ETN, the patient's conditions markedly resolved with the restoration of corticosteroid sensitivity and PP2A activity. The fine particles released by SFC-MDI ETN at least partially flowed out through the external nares and seemed to be deposited on the ethmoid sinus. CONCLUSION: Fine particle ICS/LABA ETN might be an additional therapeutic option for refractory ECRS with severe asthma and corticosteroid insensitivity.
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Residual Recurrent Nerve Paralysis After Esophagectomy is Associated with Preoperative Lower Serum Albumin.

Esophagectomy for esophageal cancer is invasive thoracic surgery with a high incidence rate of postoperative complications and prolongation of hospitalization, even if the standardized clinical pathway improves the outcome (mortality and morbidity). Postoperative recurrent nerve paralysis (RNP) is related to respiratory complications concomitant with prolonged hospitalization. However, it has not been elucidated which factors affect the incidence and recovery of RNP. To detect the predictive factor for postoperative RNP, we focused on preoperative serum albumin. Patients who had esophageal cancer with standard esophagectomy were evaluated. In total, 94 patients were divided into three groups depending on the presence of RNP (46 in patients without RNP, 29 in those with transient RNP who recovered within 6 months follow-up and 19 in those with residual RNP). We retrospectively investigated factors associated with residual RNP. Preoperative lower serum albumin was associated with residual RNP. In addition, days to the resumption of oral intake and duration of stay in the hospita postoperatively were delayed in the group of residual RNP. Multiple regression analysis indicated that preoperative serum albumin was a predictive factor for residual RNP. Preoperative lower serum albumin level might be linked to residual RNP which could prolong the resumption of postoperative oral intake and shorten the period of stay at the hospital after esophagectomy, leading to unfavorable outcomes for patients.

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression.

BACKGROUND: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. RESULTS: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. CONCLUSIONS: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity.

BACKGROUND: We have recently reported that protein phosphate 2A (PP2A) inactivation resulted in increased phosphorylation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase 1 (JNK1) and glucocorticoid receptors (GR) at Ser(226), thereby reducing GR nuclear translocation and causing corticosteroid insensitivity in severe asthmatics. Protein tyrosine phosphatases (PTPs) are also known to be critically involved in the regulation of MAPKs, such as JNK and therefore potentially associated with GR function. The aim of study was to elucidate the involvement of MAPK-PTPs (PTP-RR, PTP-N5 and PTP-N7), which can dephosphorylate MAPKs, in the regulation of corticosteroid sensitivity. METHODS: Corticosteroid sensitivity, GR nuclear translocation, phosphorylation levels of GR-Ser(226), JNK1 and PP2A catalytic subunit (PP2AC)-Tyr(307) and protein expression levels and activities of PTP-RR and PP2AC were evaluated in U937 cells and/or peripheral blood mononuclear cells (PBMCs). Knock-down effects of MAPK-PTPs using siRNA were also evaluated. RESULTS: Knock-down of PTP-RR, but not of PTP-N5 or PTP-N7 impaired corticosteroid sensitivity, induced GR-Ser(226) phosphorylation and reduced GR nuclear translocation. Under IL-2/IL-4-induced corticosteroid insensitivity, PTP-RR expression, activity and associations with JNK1 and GR were reduced but PTP-RR activity was restored by formoterol. Also in PBMCs from severe asthmatic patients, PTP-RR and JNK1 expression were reduced and GR-Ser(226) phosphorylation increased. Furthermore, PTP-RR was associated with PP2A. PTP-RR reduction enhanced PP2AC-Tyr(307) phosphorylation leading to impairment of PP2A expression and activity. CONCLUSIONS: We demonstrated that with corticosteroid insensitivity PTP-RR fails to reduce phosphorylation of JNK1 and GR-Ser(226), resulting in down-regulation of GR nuclear translocation. Reduced PTP-RR may represent a novel cause of corticosteroid insensitivity in severe asthmatics.

Residual exhaled nitric oxide elevation in asthmatics is associated with eosinophilic chronic rhinosinusitis.

OBJECTIVE: Eosinophilic chronic rhinosinusitis (ECRS) is as a subgroup of chronic rhinosinusitis (CRS) with nasal polyps. ECRS is a refractory disease closely related to bronchial asthma. Fractionated exhaled nitric oxide (FeNO) levels were reportedly elevated in some asthmatics with CRS after adequate treatment, suggesting that residual eosinophilic airway inflammation or ECRS might affect FeNO levels. METHODS: To investigate the association between asthma with ECRS and FeNO levels, we examined FeNO levels in 133 asthmatics (99 with ECRS and 34 without ECRS) and 13 patients with ECRS without asthma. The severity of asthma was defined by the Global Initiative for Asthma guidelines and that of sinusitis was evaluated by the sinus CT score based on the Lund-Mackay scale. RESULTS AND CONCLUSIONS: FeNO levels were elevated even in well-controlled asthmatics with ECRS, whereas asthmatics without ECRS and ECRS patients without asthma did not have high FeNO levels (>50 ppb). Although FeNO levels were not correlated with asthma severity, they were positively correlated with the sinus CT score. In asthmatics with ECRS, patients with higher FeNO levels had more severe ECRS and asthma. There is a possibility of having comorbid ECRS, particularly in asthmatics with high FeNO levels even after adequate treatment, including ICS, suggesting that asthma and ECRS may be closely associated as one airway disease with eosinophilic inflammation. Continual awareness of the coexistent ECRS is ideally recommended for asthmatics with high FeNO levels.

A novel therapeutic use of HFA-BDP metereddose inhaler for asthmatic patients with rhinosinusitis: Case series.

OBJECTIVE: Most asthmatics have been found to have rhinosinusitis (RS). Patients with ethmoid sinusitis, in particular, often suffer from an impaired sense of smell; this is clinically important and necessitates concurrent treatment for both asthma and RS. As a rational therapeutic strategy, we focused on a fine particle HFA-134abeclomethasone dipropionate (HFA-BDP) metered-dose inhaler. Because of its small size, the medication is still present in the exhaled breath after inhalation. METHODS: Five mild-to-moderate asthmatics with ethomoidpredominant sinusitis characterized by an impaired sense of smell and mild peripheral blood eosinophilia received a single-agent treatment with orally-inhaled HFA-BDP which was then exhaled through the nose. In addition, the stained small particles were created by an ultrasonic nebulizer and flow image of them during oral inhalation and nasal exhalation was evaluated by using nasal endoscopy. RESULTS: After treatment, the sense of smell was restored in all cases with a concomitant improvement in sinusitis as confirmed by computerized tomography. In addition, amelioration of peripheral blood eosinophilia as well as small airway obstruction as indicated by pulmonary function tests was observed. Macroscopical imaging revealed that small particles flow toward olfactory cleft during both the inhalation and exhalation phases. CONCLUSION: We have presented 5 cases of asthmatic patients with RS treated with a concurrent single therapy, HFA-BDP exhaled through the nose (ETN). A clinical trial must be considered to establish this new therapeutic strategy based on the concept of "one airway, one disease."

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.

Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

Association between Gut Microbiota and Muscle Strength in Japanese General Population of the Iwaki Health Promotion Project.

The association between the gut microbiota and muscle strength has garnered attention in the context of mitigating muscle decline. However, many study subjects have been individuals with existing illnesses or the elderly only. This study aims to elucidate the association between the gut microbiota and muscle strength indicators using grip strength/BMI in a large-scale study of community residents. The mean age of men (n = 442) and women (n = 588) was 50.5 (15.3) and 51.2 (15.9) years, respectively. The muscle strength indicator used was grip/BMI. The association between total read count and genus-level gut microbiota and muscle strength was analyzed. The mean grip/BMI was 1.8 (0.3) for men and 1.2 (0.2) for women. The genus of the gut microbiota that showed an association in both sexes was Eggerthella (men: ß = 0.18, CI: 0.04-0.31, p = 0.009; women: ß = 0.07, CI: 0.00-0.12, p = 0.028). Blautia, Eggerthella and Faecalibacterium were found to be significantly associated with grip/BMI in both the multiple regression analysis and Spearman's correlation analysis after the multiple comparison adjustment. These results suggest that an increase in Blautia and Eggerthella, coupled with a decrease in Faecalibacterium, may contribute to muscle strengthening or the suppression of muscle weakness.