Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It encompasses a spectrum ranging from simple steatosis to fatty liver with hepatocellular injury, termed ...nonalcoholic steatohepatitis. Recent studies have demonstrated hepatic autophagy being impaired in NAFLD. In the present study, we investigated the impact of Rubicon, a Beclin1‐interacting negative regulator for autophagosome‐lysosome fusion, in the pathogenesis of NAFLD. In HepG2 cells, BNL‐CL2 cells, and murine primary hepatocytes, Rubicon was posttranscriptionally up‐regulated by supplementation with saturated fatty acid palmitate. Up‐regulation of Rubicon was associated with suppression of the late stage of autophagy, as evidenced by accumulation of both LC3‐II and p62 expression levels as well as decreased autophagy flux. Its blockade by small interfering RNA attenuated autophagy impairment and reduced palmitate‐induced endoplasmic reticulum stress, apoptosis, and lipid accumulation. Rubicon was also up‐regulated in association with autophagy impairment in livers of mice fed a high‐fat diet (HFD). Hepatocyte‐specific Rubicon knockout mice generated by crossing Rubicon floxed mice with albumin‐Cre transgenic mice did not produce any phenotypes on a normal diet. In contrast, on an HFD, they displayed significant improvement of both liver steatosis and injury as well as attenuation of both endoplasmic reticulum stress and autophagy impairment in the liver. In humans, liver tissues obtained from patients with NAFLD expressed significantly higher levels of Rubicon than those without steatosis. Conclusion: Rubicon is overexpressed and plays a pathogenic role in NAFLD by accelerating hepatocellular lipoapoptosis and lipid accumulation, as well as inhibiting autophagy. Rubicon may be a novel therapeutic target for regulating NAFLD development and progression. (Hepatology 2016;64:1994‐2014).
Background: Although aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are ...not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and the relevance of such miRNAs to fibroblast-to-myofibroblast differentiation are not well understood. In this study, we attempted to identify exosome-derived miRNAs relevant to fibrosis development. Methods: Using miRNA array analysis, we profiled exosome-derived miRNA expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblast-to-myofibroblast differentiation was investigated in human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in vivo model of pulmonary fibrosis. Results: MiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. Conclusions: Exosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present findings warrant further study, which could shed light on miR-22 as a novel therapeutic target in IPF.
While community-wide interventions to promote physical activity have been encouraged in older adults, evidence of their effectiveness remains limited. We conducted a qualitative study among older ...adults participating in regular group exercise to understand their perceptions of the physical, mental, and social changes they underwent as a result of the physical activity.
We conducted a qualitative study with purposeful sampling to explore the experiences of older adults who participated in regular group exercise as part of a community-wide physical activity intervention. Four focus group interviews were conducted between April and June of 2016 at community halls in Fujisawa City. The participants in the focus group interviews were 26 older adults with a mean age of 74.69 years (range: 66-86). The interviews were analysed using the constant comparative method in the grounded theory approach. We used qualitative research software NVivo10® to track the coding and manage the data.
The finding 'regular group exercise contributes to balanced health in older adults' emerged as an overarching theme with seven categories (regular group exercise, functional health, active mind, enjoyment, social connectedness, mutual support, and expanding communities). Although the participants perceived that they were aging physically and cognitively, the regular group exercise helped them to improve or maintain their functional health and enjoy their lives. They felt socially connected and experienced a sense of security in the community through caring for others and supporting each other. As the older adults began to seek value beyond individuals, they gradually expanded their communities beyond geographical and generational boundaries.
The participants achieved balanced health in the physical, mental, and social domains through regular group exercise as part of a community-wide physical activity intervention and contributed to expanding communities through social connectedness and mutual support. Health promotion through physical activity is being increasingly emphasized. The study results can help to develop effective physical activity programs for older adults in the community.
Sarcopenia and frailty often worsen in older adults because of declines in activities of daily living and social connections that are associated with chronic diseases and traumatic injuries such as ...falls and fractures. Exercise intervention for sarcopenia can take >3 months to improve muscle mass, muscle strength, and walking speed. Thus, a specialized intervention system for shorter periods of time is needed. In this study, we aimed to evaluate the short-term efficacy of an exercise program using the wearable cyborg Hybrid Assistive Limb (HAL) lumbar type in physical function in mobility-limited older adults who do not require transition to long-term care.
This randomized, single-blind, parallel-group study involved 79 community-dwelling older adults with physical frailty or locomotive syndrome assigned to an intervention group (n = 40) with the HAL lumbar type exercise program or a control group (n = 39) without the exercise program. The intervention group underwent trunk training (including trunk and hip flexion, standing and sitting from a single sitting position, and squats) and gait training (treadmill and parallel bars) twice a week for 5 weeks while wearing the HAL lumbar type. The 10-m usual and maximum walking speeds, Timed Up and Go test results, 5-times chair-standing test results, 5-question Geriatric Locomotive Function Scale (GLFS-5) scores, body-fat percentage, and muscle mass were measured before and after the intervention and analyzed using the intention-to-treat method.
The intervention (23 % male; mean age, 74.7 ± 4.7 years) and control (21 % male; mean age, 75.1 ± 4.1 years) groups did not differ significantly in baseline characteristics. Seventy-seven participants completed the program; two withdrew for personal reasons. The mean difference (standard error) between the groups for the primary outcome (usual walking speed) was 0.35 (0.04) m/s; the time-by-group interaction was significant (p < 0.001). Secondary outcomes (maximum walking speed, Timed Up and Go test results, 5-times chair-standing test results, and GLFS-5 scores) significantly improved in the intervention group. Body composition was unchanged in both groups.
A 5-week exercise program using the HAL lumbar type is a promising option for community-dwelling older adults with limited mobility who do not require nursing care, resulting in clinically meaningful improvements in most physical functions within a short period.
•We tested the short-term efficacy of an exercise program with a HAL lumbar type.•Mobility function improved in those with physical frailty or locomotive syndrome.•Most physical functions improved clinically within a short period of 5 weeks.
Molecular targeted drugs have become the mainstream for cancer therapy, and they have contributed to improving the outcome for cancer patients. On the other hand, molecular targeted drugs are ...associated with a variety of adverse drug reactions. Drug-induced interstitial lung disease (DILD) is a typical adverse drug reaction that has been an important problem with regard to safety management during cancer treatment. In the past, there was a lack of detailed and accurate epidemiological data about DILD. However, most of the molecular targeted drugs have been subject to all-case post-marketing surveillance since gefitinib-induced ILD became a concern. These surveillance data present useful information about DILD, such as frequency of adverse events, mortality, and risk factors, and as a result, the epidemiological profile of DILD associated with molecular targeted drugs has become apparent during the past decade. Further, it has been considered that the principal management for DILD is early detection and cessation of the suspected cause. However, ILD associated with everolimus and temsirolimus requires unusual management; i.e., patients with asymptomatic ILD are allowed to continue treatment with everolimus or temsirolimus, and even after symptomatic ILD, both everolimus and temsirolimus are allowed to be readministered after the resolution of ILD. As a result of the collected data, a change has begun in the field of DILD associated with molecular targeted drugs. The features of DILD can differ for each drug, and clinicians should thus keep this information about DILD in mind while treating patients.
Smoking-related interstitial lung diseases (SRILDs) are a group of heterogeneous diffuse pulmonary parenchymal diseases associated with tobacco exposure. Smoking-related interstitial fibrosis (SRIF) ...is relatively recent, a pathologically defined form of SRILDs. SRIF is characterized by the accumulation of macrophages in the alveolar spaces, which is associated with interstitial inflammation and fibrosis. The macrophages frequently contain light brown pigment and are called 'smoker's macrophages'. Patients with SRIF who have clinical evidence of interstitial lung disease are most commonly relatively young, heavy smokers with abnormalities on chest computed tomography showing ground-glass opacities, peripheral consolidation, and reticulation. Although SRIF is caused by cigarette smoking, the exact pathophysiological mechanisms by which smoking causes this type of interstitial fibrosis remain unknown. The degree of fibrosis and appearance of macrophage aggregates are important points of distinction when evaluating and diagnosing SRIF. Macrophage heterogeneity, particularly the activation and function of monocyte-derived alveolar macrophages (Mo-AMs) and interstitial macrophages (IMs), has important implications for the pathogenesis of SRIF and developing treatments. Further researches focused on smoker's macrophages are needed to understand of the pathogenesis of SRIF.
Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in ...a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.
Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan.
Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated ...with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018.
The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% 104/3578) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% 5/3578), 5.9% (212/3578; Grade ≥ 3, 1.0% 35/3578) and 11.4% (409/3578; Grade ≥ 3, 2.9% 104/3578) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval CI, 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively.
These data support the currently established benefit-risk assessment of osimertinib in this patient population.
Abstract
Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable ...biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis.
Aim
Liver‐specific signal transducer and activator of transcription (STAT)5‐deficient mice (STAT5KO) show lipid accumulation in the liver. We investigated the role of hepatic STAT5 in lipid ...metabolism in vitro and in vivo.
Methods and Results
High expression of CD36, one of the receptors for free fatty acids, is associated with a high concentration of hepatic triglyceride (TG) in STAT5KO mice. Peroxisome proliferator‐activated receptor (PPAR)γ, one of the regulatory factors of CD36, was upregulated and microRNA (miR)‐20b was downregulated in STAT5KO mice. Reporter assays revealed direct regulation involving miR‐20b and the 3′‐untranslated region of CD36 mRNA. Treatment with free fatty acids enhanced accumulation of TG in STAT5‐deleted hepatoma cells, and this was partially canceled by introduction of siRNA for PPARγ and/or pre‐miR‐20b through inhibition of CD36 expression. In vivo, STAT5/CD36 double knockout mice displayed hepatic TG was decreased compared to STAT5KO mice and it was also reduced by treatment with PPARγ antagonists, GW9662, and/or pre‐miR‐20b.
Conclusions
Signal transducer and activator of transcription 5 plays an important role in hepatic fat metabolism through regulation of CD36, and is a potential therapeutic candidate for liver steatosis.
PDF
