Tomoko Fujii

Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling

Transforming growth factor (TGF)-β plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-β inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-β signaling inhibition, including the induction of cancers by the repression of TGF-β-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-β type I receptor (TβR-I) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose TβR-I inhibitor altered neither TGF-β signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of TβR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TβR-I inhibitor. The use of TβR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.

Arkadia Induces Degradation of SnoN and c-Ski to Enhance Transforming Growth Factor-β Signaling

Transforming growth factor-β (TGF-β) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-β signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-β signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-β signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-β family signaling in target cells.

Risk Factors for Prolonged Treatment of Whiplash-Associated Disorders

Objectives Whiplash-associated disorders (WAD) are the most common injuries that are associated with car collisions in Japan and many Western countries. However, there is no clear evidence regarding the potential risk factors for poor recovery from WAD. Therefore, we used an online survey of the Japanese population to examine the association between potential risk factors and the persistence of symptoms in individuals with WAD. Materials and Methods An online survey was completed by 127,956 participants, including 4,164 participants who had been involved in a traffic collision. A random sample of the collision participants (n = 1,698) were provided with a secondary questionnaire. From among the 974 (57.4%) respondents to the secondary questionnaire, we selected 183 cases (intractable neck pain that was treated over a period of 6 months) and 333 controls (minor neck pain that was treated within 3 months). Multivariable logistic regression analysis was used to evaluate the potential risk factors for prolonged treatment of WAD. Results Female sex, the severity of the collision, poor expectations of recovery, victim mentality, dizziness, numbness or pain in the arms, and lower back pain were associated with a poor recovery from WAD. Conclusions In the present study, the baseline symptoms (dizziness, numbness or pain in the arms, and lower back pain) had the strongest associations with prolonged treatment for WAD, although the psychological and behavioral factors were also important. These risk factors should be considered when evaluating patients who may have the potential for poor outcomes.

Auditory Responses to Vocal Sounds in the Songbird Nucleus Taeniae of the Amygdala and the Adjacent Arcopallium

Many species of animals communicate with others through vocalizations. Over time, these species have evolved mechanisms to respond to biologically relevant vocal sounds via adaptive behaviors. Songbirds provide a good opportunity to search for the neural basis of this adaptation, because they interact with others through a variety of vocalizations in complex social relationships. The nucleus taeniae of the amygdala (TnA) is a structure located in the ventromedial arcopallium, which is akin to the mammalian medial amygdala. Studies on the anatomy and function of this nucleus have led to the speculation that the TnA is one of the possible neural substrates that represents the relevance of acoustic stimuli related to behavior. However, neural responses in this nucleus to auditory stimuli have not been studied in depth. To give a detailed description about auditory responses of the TnA in the songbird, we conducted neural recordings from the TnA and the adjacent arcopallium in adult male and female Bengalese finches under anesthesia. The birds were exposed to auditory stimuli including natural vocalizations as well as synthesized noise. We demonstrated that a substantial population of neurons in the TnA and the adjacent arcopallium responded to vocal sounds and that some neurons were selectively activated to specific stimuli. Proportions of responsive cells and stimulus-selective cells were larger in males than in females. In addition, a larger ratio of selective cells was observed in the arcopallium compared to the TnA. These findings support the idea that neuronal activity in the TnA and the neighboring area represents behavioral relevance of sounds. Further studies in electrophysiology combined with evidence from other fields, such as region-specific gene expression patterns, are required to fully understand the functions of the TnA as well as the evolution of the amygdala in songbirds and vertebrate animals.

Identification of Risk Factors for New-Onset Sciatica in Japanese Workers: Findings From the Japan Epidemiological Research of Occupation-Related Back Pain Study

Study Design. Two-year, prospective cohort data collected for the Japan epidemiological research of Occupation-related Back pain study were used for the analysis. Objective. To identify potential risk factors for the development of new-onset sciatica in initially symptom-free Japanese workers with no history of sciatica. Summary of Background Data. Although the associations between individual and occupational factors and cases of new-onset sciatica are established, the effect of psychosocial factors on the development of sciatica has still not been adequately clarified. Methods. In total, 5310 participants responded to a self-administered baseline questionnaire (response rate: 86.5%). Furthermore, 3194 (60.2%) completed both 1- and 2-year follow-up questionnaires. The baseline questionnaire assessed individual characteristics, ergonomic work demands, and work-related psychosocial factors. The outcome of interest was new-onset sciatica with or without low back pain during the 2-year follow-up period. Incidence was calculated for participants who reported no low back pain in the preceding year and no history of lumbar radicular pain (sciatica) at baseline. Logistical regression assessed risk factors associated with new-onset sciatica. Results. Of 765 eligible participants, 141 (18.4%) reported a new episode of sciatica during the 2-year follow-up. In crude analysis, significant associations were found between new-onset sciatica and age and obesity. In adjusted analysis, significant associations were found for obesity and mental workload in a qualitative aspect after controlling for age and sex. Consequently, in multivariate analysis with all the potential risk factors, age and obesity remained statistically significant (odds ratios: 1.59, 95% confidence interval: 1.01–2.52; odds ratios: 1.77, 95% confidence interval: 1.17–2.68, respectively). Conclusion. In previously asymptomatic Japanese workers, the risk of developing new-onset sciatica is mediated by individual factors. Our findings suggest that the management of obesity may prevent new-onset sciatica. Level of Evidence: 3

Prognostic psychosocial factors for disabling low back pain in Japanese hospital workers

Background Although the occupational health field has identified psychosocial factors as risk factors for low back pain that causes disability, the association between disabling low back pain and psychosocial factors has not been examined adequately in Japanese hospital workers. Therefore, this study examined the association between low back pain, which interfered with work, and psychosocial factors in Japanese hospital workers. Method This cross-sectional study was conducted at a hospital in Japan. In total, 280 hospital workers were recruited from various occupational settings. Of these, 203 completed a self-administered questionnaire that included items concerning individual characteristics, severity of low back pain, fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), somatic symptoms (Somatic Symptom Scale-8), psychological distress (K6), workaholism, and work-related psychosocial factors (response rate: 72.5%). Logistic regression was used to explore risk factors associated with disabling low back pain. Results Of the 203 participants who completed questionnaires, 36 (17.7%) reported low back pain that interfered with their work. Multivariate analyses with individual factors and occupations adjusted for showed statistically significant associations between disabling low back pain and fear-avoidance beliefs (adjusted odds ratio [OR]: 2.619, 95% confidence interval [CI]: 1.003–6.538], somatic symptoms (OR: 4.034, 95% CI: 1.819–9.337), and interpersonal stress at work (OR: 2.619, 95% CI: 1.067–6.224). Conclusions Psychosocial factors, such as fear-avoidance beliefs, somatic symptoms, and interpersonal relationships at work, were important risk factors in low back pain that interfered with work in Japanese hospital workers. With respect to occupational health, consideration of psychosocial factors is required to reduce disability related to low back pain.

A case of eosinophilic orbital myositis associated with CSS

We report a novel case of eosinophilic orbital myositis associated with Churg–Strauss syndrome. A 56-year-old man with a 20-year history of chronic sinusitis and seasonal allergic rhinitis was admitted because of fever, swelling of cheeks and extremities, diplopia, and eosinophilia. With findings from gadolinium-enhanced FST1WI of the orbits and a muscle biopsy of the skeletal muscle, the diagnosis was made. He was treated with oral corticosteroid, and his symptoms rapidly improved.

Association between somatic symptom burden and health-related quality of life in people with chronic low back pain

Depression is a relevant risk factor for low back pain and is associated with the outcomes of low back pain. Depression also often overlaps with somatisation. As previous studies have suggested that somatisation or a higher somatic symptom burden has a role in the outcomes of low back pain, the aim of the present cross-sectional study was to examine whether somatic symptom burden was associated with health-related quality of life in individuals with chronic low back pain independent of depression. We analyzed internet survey data on physical and mental health in Japanese adults aged 20–64 years with chronic low back pain (n = 3,100). Health-related quality of life was assessed using the EuroQol five dimensions (EQ-5D) questionnaire. Somatic symptom burden and depression were assessed using the Somatic Symptom Scale-8 (SSS-8) and the Patient Health Questionnaire-2 (PHQ-2), respectively. SSS-8 score was categorized as no to minimal (0–3), low (4–7), medium (8–11), high (12–15), and very high (16–32). The association between SSS-8 and EQ-5D was examined using linear regression models, adjusting for depression and other covariates, including age, sex, BMI, smoking, marital status, education, exercise, employment, and the number of comorbid diseases. A higher somatic symptom burden was significantly associated with a lower health-related quality of life independent of depression and the number of comorbid diseases (regression coefficient = 0.040 for SSS-8 high vs. very high and 0.218 for non to minimal vs. very high, p trend <0.0001). In conclusion, somatic symptom burden might be important for the health-related quality of life of individuals with chronic low back pain.

The utility of 25-question Geriatric Locomotive Function Scale for evaluating functional ability and disease activity in Japanese rheumatoid arthritis patients: a cross-sectional study using NinJa database

Abstract Objectives: To investigate the distribution of 25-question Geriatric Locomotive Function Scale (GLFS-25) scores in Japanese rheumatoid arthritis (RA) patients and evaluate relationships with clinical variables. Methods: Among 15,115 patients registered in the NinJa database for fiscal year 2015, 1710 with complete GLFS-25 and disease activity score-28 (DAS28) data were analyzed. Correlations between GLFS-25 score and clinical variables were assessed by Spearman coefficients. Mean GLFS-25 scores were compared among DAS28 groups (<2.6, 2.6−3.1, 3.2−5.0, ≥5.1) using the Kruskal–Wallis test. To evaluate the performance of the GLFS-25 and Health Assessment Questionnaire Disability Index (HAQ-DI) for predicting DAS28 ≥ 3.2 (moderate/high disease activity), receiver operator characteristic (ROC) curves were constructed. Results: GLFS-25 score was significantly correlated with age, disease duration, DAS28, and HAQ-DI. GLFS-25 score increased in parallel with DAS28. The proportion of patients with locomotive syndrome stage 2 also increased with DAS28. Area under the curve values for HAQ-DI and GLFS-25 score were 0.739 and 0.768, respectively. At a GLFS-25 positive cutoff score ≥16, sensitivity was 0.716 and specificity was 0.661 for predicting DAS28 ≥ 3.2. Conclusion: This study documents the GLFS-25 score distribution in Japanese RA patients and demonstrates that GLFS-25 is a useful measure for evaluating functional ability in RA.

The effect of the “One Stretch” exercise on the improvement of low back pain in Japanese nurses: a large-scale, randomized, controlled trial

Abstract Objectives: To evaluate the ‘One Stretch’ exercise’s effect on improvements in low back pain (LBP), psychological factors, and fear avoidance in a large number of nurses. Methods: Between July 2015 and June 2016, we performed a prospective, randomized, parallel-group, multi-center study with central evaluations. Eligible patients were randomly assigned (1:1:1 ratio) to either the control group (Group A) or an intervention group (Group B: 30-min seminar about the ‘One Stretch’ exercise, Group C: B + physical and psychological approaches to LBP treatment). The primary outcome was subjective improvement from baseline to 6 months (improved/unchanged/worsened) and overall exercise habits (good/poor). Results: There were 4767 participants: 1799, 1430, and 1548 in Groups A, B, and C, respectively. We collected data on 3439 participants (949, 706, and 751 in Groups A, B, and C, respectively) at the 6-month follow-up. The improvement rates in Groups A, B, and C were 13.3%, 23.5%, and 22.6%, respectively. The worsened pain rates were 13.0%, 9.6%, and 8.1%, which decreased as the intervention degree increased (the Cochran–Armitage trend test: p < .0001). In Groups A, B, and C, 15.6%, 64.9%, 48.8% of the patients, respectively, exhibited exercise habits. Conclusion: The ‘One Stretch’ exercise is useful for improving LBP.