We aimed to develop a prediction model to identify long-term survivors after developing distant metastasis from breast cancer.
From the institution's database, we collected data of 547 patients who ...developed distant metastasis during their follow-ups. We developed a model that predicts the post-metastasis overall survival (PMOS) based on the clinicopathologic factors of the primary tumors and the characteristics of the distant metastasis. For validation, the survival data of 254 patients from four independent institutions were used.
The median duration of the PMOS was 31.0 months. The characteristics of the initial primary tumor, such as tumor stage, hormone receptor status, and Ki-67 expression level, and the characteristics of the distant metastasis presentation including the duration of disease-free interval, the site of metastasis, and the presence of metastasis-related symptoms were independent prognostic factors determining the PMOS. The association between tumor stage and the PMOS was only seen in tumors with early relapses. The PMOS score, which was developed based on the above six factors, successfully identified patients with superior survival after metastasis. The median PMOS for patients with a PMOS score of <2 and for patients with a PMOS score of >5 were 71.0 and 12 months, respectively. The clinical significance of the PMOS score was further validated using independent multicenter datasets.
We have developed a novel prediction model that can classify breast cancer patients with distant metastasis according to their survival after metastasis. Our model can be a valuable tool to identify long-term survivors who can be potential candidates for more intensive multidisciplinary approaches. Furthermore, our model can provide a more reliable survival information for both physicians and patients during their informed decision-making process.
Background
Several studies have demonstrated that allergen‐specific immunotherapy (SIT) can be an effective treatment for atopic dermatitis (AD). However, there is no relevant mouse model to ...investigate the mechanism and validate the novel modality of SIT in AD.
Methods
NC/Nga mice with induced AD‐like skin lesions received a subcutaneous injection of SIT (an extract of the house dust mite Dermatophagoides farinae DfE) or placebo for 5 weeks). Clinical and histological improvements of AD‐like skin lesions were examined. The responses of local and systemic regulatory T (Treg) cells, natural killer (NK) cells, B cells, serum immunoglobulin, and T‐cell cytokine response to DfE were evaluated to determine the underlying mechanism of the observed results.
Results
Specific immunotherapy significantly improved AD‐like skin lesions. Histologically, SIT decreased epidermal thickness and reduced inflammatory cell infiltration, especially that of eosinophils. Concomitantly, SIT suppressed Th2 responses and induced local infiltration of Treg cells into the skin. Also, SIT induced the immunoglobulin G4 and attenuated allergen‐specific immunoglobulin E. Furthermore, SIT induced local and systemic IL‐10‐producing Treg cells and regulatory NK cells.
Conclusion
We established a SIT model on AD mice and showed that our model correlates well with previous reports about SIT‐treated patients. Also, we revealed NK cells as another possible resource of IL‐10 in SIT. Based on our results, we suggest our SIT model as a useful tool to investigate mechanism of action of SIT and to validate the efficacy of new SIT modalities for the treatment of AD.
The aims of this study were to validate the efficacy of progressive muscle relaxation (PMR) in patients with atopic dermatitis and to evaluate the serological parameters that may serve as objective ...measures of the efficacy of PMR. A total of 25 patients with atopic dermatitis were randomly assigned to either a PMR group (n = 15) or a control group (n = 10). Serum levels of nerve growth, neuropeptide Y, and Th2 cytokines (IL-4, IL-5, and IL-13) were measured at baseline and after one month. At baseline, only anxiety was positively correlated with pruritus score (state anxiety: R = 0.496, p = 0.014; trait anxiety: R = 0.423, p = 0.04). Serum levels of neuropeptide Y were inversely related to the State-Trait Anxiety Inventory (STAI) (state anxiety: R = -0.475, p = 0.019; trait anxiety: R = -0.418, p = 0.042) and pruritus scores (R = -0.451, p = 0.035). After one month of PMR therapy, the degree of pruritus and loss of sleep was significantly decreased in the PMR group (p < 0.001), but not among controls. State anxiety scores showed significant improvement after treatment only in the PMR group (p = 0.005). There were no significant changes in the serological parameters in either group. Reductions in Eczema Area and Severity Index (EASI) scores were significant, but similar, in both groups. PMR may be a useful adjunctive modality for the management of atopic dermatitis through the reduction of anxiety. No change was found in biological parameters, but it was observed that neuropeptide Y may be related to high levels of anxiety in atopic dermatitis at baseline.
Zinc overload may be a key mechanism of neuronal death in acute brain injury. We have demonstrated previously that zinc overload neurotoxicity involves protein kinase C (PKC)-dependent rises in ...intracellular levels of reactive oxygen species (ROS). However, the cascade linking PKC activation to ROS generation in cultured cortical neurons has been unknown. A recent study has demonstrated that ROS-generating NADPH oxidase is present in sympathetic neurons and contributes to NGF deprivation-induced cell death. Because NADPH oxidase is activated by PKC, in the present study, we examined the possibility that NADPH oxidase is the effector for oxidative stress in zinc-overloaded cortical cells. Reverse transcription-PCR and Western blot analyses revealed that naive cultured cortical cells express subunits of NADPH oxidase at low levels. Exposure to zinc substantially increased levels of NADPH oxidase subunits in both neurons and astrocytes. In addition, zinc exposure induced translocation of the p47(PHOX) and p67(PHOX) subunits to the membrane, a signature event for NADPH oxidase activation. Addition of a selective PKC inhibitor, GF109203X, blocked both the induction and the membrane translocation of NADPH oxidase by zinc. Supporting the role for NADPH oxidase in zinc-triggered oxidative injury, NADPH oxidase inhibitors attenuated ROS production and cortical neuronal death induced by zinc. In addition, Cu/Zn-superoxide dismutase and catalase attenuated zinc-induced cortical neuronal death. Our results have demonstrated that zinc overload induces and activates NADPH oxidase in cortical neurons and astrocytes in a PKC-dependent manner. Thus, NADPH oxidase may be an enzyme contributing to ROS generation in zinc-overloaded cortical neurons and astrocytes.
Colloidal dispersions with liquid crystallinity hold great promise for fabricating their superstructures. As an example, when graphene oxide (GO) sheets are assembled in the liquid crystalline state, ...they can turn into ordered macroscopic forms of GO such as fibers via the wet spinning process. Here, we report that by reinforcing intersheet interactions, GO liquid crystals (LCs) turn into mechanically robust hydrogels that can be readily drawn into highly aligned fibrillar structures. GO hydrogel fibers with highly aligned sheets (orientation factor,
= 0.71) exhibit more than twice the ionic conductivity compared to those with partially aligned structures (
= 0.01). The hierarchically interconnected two-dimensional nanochannels within these neatly aligned GOLC hydrogel fibers may facilitate controlled transport of charge carriers and could be potentially explored as cables for interconnecting biosystems and/or human-made devices.
Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Hyo-Jeong Kim 1 ,
Takamasa Higashimori 1 ,
So-Young Park 1 ,
Hyejeong Choi 1 ,
Jianying Dong 1 ,
...Yoon-Jung Kim 1 ,
Hye-Lim Noh 1 ,
You-Ree Cho 1 ,
Gary Cline 1 ,
Young-Bum Kim 2 and
Jason K. Kim 1
1 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
2 Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts
Address correspondence and reprint requests to Jason K. Kim, PhD, Yale University School of Medicine, Department of Internal
Medicine, Section of Endocrinology and Metabolism, 300 Cedar St., The Anlyan Center, South 269C, P.O. Box 208020, New Haven,
CT 06520-8020. E-mail: jason.k.kim{at}yale.edu
Abstract
The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including
type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin
resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic
clamps in awake mice. Pretreatment of IL-6 blunted insulin’s ability to suppress hepatic glucose production and insulin-stimulated
insulin receptor substrate (IRS)-2–associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also
reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1–associated
PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of
IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6–induced defects in hepatic insulin action and signaling
activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action
and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the
first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in
vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. These findings implicate an
important role of inflammatory cytokines in the pathogenesis of insulin resistance.
2-14CDG, 2-deoxy-d-1-14Cglucose
HGP, hepatic glucose production
IKK, IκB kinase
IL, interleukin
IRS, insulin receptor substrate
PKB, protein kinase B
PKC, protein kinase C
PI, phosphatidylinositol
SOCS, suppressor of cytokine signaling
TNF, tumor necrosis factor
Footnotes
Accepted December 23, 2003.
Received July 17, 2003.
DIABETES
The diurnal pattern of the vertical distribution of biogenic pollen in the lower troposphere was investigated by LIDAR. Meteorological data were taken at the ground. Pollen concentrations were ...measured at the surface using a Burkard 7-day-recording volumetric spore sampler. Aerosol extinction coefficients and depolarization ratios at 532 nm were obtained from LIDAR measurements in spring (4 May–2 June) 2009 in Gwangju, South Korea. Linear volume depolarization ratios varied between 0.08 and 0.14 and were observed only during daytime (09:00–17:00 local time (LT)) during days of high pollen concentration (4 to 9 May). Daily average pollen concentrations ranged 1000–2500 cm−3 in the same period. The temporal evolution of the vertical distribution of the linear volume depolarization ratio showed a specific diurnal pattern. Linear volume depolarization ratios of more than 0.06, were measured near the surface in the morning. High depolarization ratios were detected up to 2 km aboveground between 12:00 and 14:00 LT, whereas high depolarization ratios were observed only close to the surface after 17:00 LT. Low values of depolarization ratios (≤0.05) were detected after 18:00 LT until the next morning. During the measurement period, the daily variations of the high depolarization ratios close to the surface showed correlation to number concentration measurements of pollen. This finding suggests that high depolarization ratios could be attributed to enhanced pollen concentrations. The diurnal characteristics of the high values of depolarization ratios are thought to be closely associated with turbulent transport. Diurnal and vertical characteristics of pollen, if measured continuously, could be used to improve the accuracy of pollen-forecasting models via data assimilation studies.
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