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•Non-dimensionalisation of electric networks of conductive fibres provide unified macroscale models for the conductance•Dimensionless conductance modelling provides definitions for ...different regime ranges•Solid volume fraction of fibre systems can be linked to the transmittance allowing for alternative solid volume fraction measurements
The electric properties of conductive fibre networks, which can be representative of carbon nanotube networks, are investigated by means of numerical simulations and a dimensionless unified macroscale model is developed. Fibres are represented as rigid chains of discrete element method particles and we compress systems of fibres in a representative volume element periodic in three dimensions. In the used electric resistor network method, the particles are used as discretisation points to construct a system of linear equations linking the particle conductivities to their local electric potentials and in turn allowing for predictions on the electric macroscale properties of the fibre system. A carried out dimensional analysis suggests suitable scaling laws to unify different macroscale fibre systems in two different regimes - a percolating and a conductive regime. The dimensionless macroscale conductance is found to depend on the percolation threshold and percolation probability. It is moreover found that the critical solid volume fraction for rigid fibres is not only dependent on the fibre aspect ratio, but can also depend on the compression height of the system. Additionally, correlations between transmittance and solid volume fractions are found allowing for possibly simple solid volume fraction estimations in experiments.
We carried out a multicenter dose‐escalation phase I study of oral OPB‐51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory ...hematological malignancies to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB‐51602 at doses of 1, 2, 3, 4, and 6 mg in the “3 + 3” dose escalation design. The most common treatment‐related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug‐related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose‐limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1–2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB‐51602 was rapidly absorbed, and exposure tended to increase in a dose‐dependent manner. Accumulation of OPB‐51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB‐51602 was 6 mg. OPB‐51602 was safe and well tolerated in a dose range of 1–4 mg. However, long‐term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB‐51602 for hematological malignancies with a daily dosing schedule was terminated.
In Phase I study of OPB‐51602 for hematological malignancy, MTD was 6 mg and was safe and well tolerated in a dose range of 1 to 4 mg. However, long‐term administration at higher doses was difficult with a daily dosing schedule, and no clear therapeutic response was observed.
Background:Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan.Methods and Results:From the Chronic ...Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000–2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio adjHR, 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%.Conclusions:Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. (Trial registration: clinicaltrials.gov identifier: NCT00418041) (Circ J 2015; 79: 2396–2407)
Highlights • Adipose tissues of younger people possess more adipose stem cells and SSEA3+ Muse cells than elder people. • Isolated cells showed pluripotency and growth curves equally regardless age ...of donors. • Adipose-Muse can differentiate to functional melanocytes, which expressed MC1R and enhanced melanin production by a-MSH. • This melanocyte-induction procedure provides a useful model to understand melanocyte differentiation from stem cells.
•Androgens enhance AREG, EREG, FGF10, and IGFBP5 production from fibroblasts through androgen receptors.•AREG, EREG, FGF10, and IGFBP5 are more abundant in dermis of acne than normal skin.•The ...cytokeratin 10/cytokeratin 14 ratio was significantly lower in acne lesions compared to normal skin controls.•Androgens suppressed cytokeratin 1 and 10 expression in co-culture of keratinocytes and fibroblasts.•Androgen-dependent growth factor productions were suppressed by androgen receptor antagonist flutamide.
The main pathogenesis of acne vulgaris is increase in sebum production and abnormal keratinization of the hair infundibulum. The androgens are involved in acne pathogenesis by modulating sebaceous glands to enhance sebum production. However, the molecular mechanisms of abnormal keratinization of the hair infundibulum are not fully elucidated.
We hypothesized that the androgens affect the dermal fibroblasts, another androgen receptor-positive cells in the skin, resulting in abnormal keratinization through keratinocyte-fibroblast interaction.
We investigated effects of androgens and estrogens on growth factors expressions by RT-PCR and western blot analysis in human fibroblast (hFB), human keratinocyte (hKC), and fibroblast-keratinocyte co-culture. In vivo, we examined the growth factor expression in acne lesions compared to normal hair follicles by laser-assisted confocal microscope.
In vitro, androgens but not estrogens significantly increased amphiregulin (AREG), epiregulin (EREG), fibroblast growth factor (FGF) 10, and insulin-like growth factor binding protein (IGFBP) 5 mRNA and protein expressions in human fibroblasts but not in keratinocytes. In vivo, AREG, EREG, FGF10, and IGFBP5 were more abundant in acne lesion compared to normal facial skin. FGF10 suppressed cytokeratin 1 and cytokeratin 10 expression in hKC, which was along with the decreased ratio of cytokeratin 10 against cytokeratin 14 in acne lesions compared to normal facial skin. Also, DHT suppressed cytokeratin 1 and cytokeratin 10, in fibroblast-keratinocyte co-culture similarly to the effect of FGF10 to hKC.
These observations suggested that androgens enhance growth factors production from dermal fibroblasts, and growth factors from fibroblasts alter keratinocyte differentiation in acne lesion.
Background:The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF).Methods and Results:Among 4,544 consecutive HF patients ...registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins 8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58–0.94; P<0.001, which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49–0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62–0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43–0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36–0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35–0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73–1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients.Conclusions:These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death. (Circ J 2015; 79: 574–582)
The light-promoted recovery of epidermal barrier of skin was evaluated by the associated recovery of transepidermal potential (TEP), the potential difference between the surface and dermis of skin, ...by using porcine skin samples. An accelerated recovery of TEP was observed by irradiation of red light with the irradiance of 40 mW/cm2 and a duration of > 10 min. The influence of the light stimulation to the surroundings (~ 20 mm) was also observed. The irradiations of blue and purple lights were ineffective in accelerating the barrier recovery. These characteristics of the light stimulation would be useful for the design of effective and safe phototherapy devices for skin. The present study proves that the TEP can serve as a spatiotemporal indicator of the epidermal barrier function.
Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related ...adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits melanoma growth by modulating an immune response against tumors. In vitro experiments revealed that EGCG treatment inhibited interferon-gamma (IFN-γ)-induced PD-L1 and PD-L2 expression and JAK-STAT signaling. We confirmed that this effect was driven by inhibiting
gene expression and STAT1 phosphorylation, thereby downregulating the PD-L1/PD-L2 transcriptional regulator IRF1 in both human and mouse melanoma cells. Animal studies revealed that the in vivo tumor-inhibitory effect of EGCG was through CD8+ T cells and that the inhibitory effect of EGCG was comparable to anti-PD-1 therapy. However, their mechanisms of action were different. Dissimilar to anti-PD-1 treatment that blocks PD-1/PD-L1 interaction, EGCG inhibited JAK/STAT signaling and PD-L1 expression in tumor cells, leading to the re-activation of T cells. In summary, we demonstrate that EGCG enhances anti-tumor immune responses by inhibiting JAK-STAT signaling in melanoma. EGCG could be used as an alternative treatment strategy to target the PD-L1/PD-L2-PD-1 axis in cancers.
Background:The prognostic impact of atrial fibrillation (AF) among patients at high risk for heart failure (HF) remains unclear. In addition, there is no risk estimation model for AF development in ...these patients.Methods and Results:The present study included 5,382 consecutive patients at high risk of HF enrolled in the CHART-2 Study (n=10,219). At enrollment, 1,217 (22.6%) had AF, and were characterized, as compared with non-AF patients, by higher age, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP) level and lower left ventricular ejection fraction. A total of 116 non-AF patients (2.8%) newly developed AF (new AF) during the median 3.1-year follow-up. AF at enrollment was associated with worse prognosis for both all-cause death and HF hospitalization (adjusted hazard ratio (aHR) 1.31, P=0.027 and aHR 1.74, P=0.001, for all-cause death and HF hospitalization, respectively) and new AF was associated with HF hospitalization (aHR 4.54, P<0.001). We developed a risk score with higher age, smoking, pulse pressure, lower eGFR, higher BNP, aortic valvular regurgitation, LV hypertrophy, and left atrial and ventricular dilatation on echocardiography, which effectively stratified the risk of AF development with excellent accuracy (AUC 0.76).Conclusions:These results indicated that AF is associated with worse prognosis in patients at high risk of HF, and our new risk score may be useful to identify patients at high risk for AF onset.
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