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e21736
Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), are less toxic than conventional chemotherapy drugs, and benefit patients with EGFR-mutated ...non-small cell lung (NSCLC) cancer. However, there are a few patients who are not able to receive EGFR-TKI due to poor performance status, older age, or sever comorbidities. Here, we aimed to determine the prognostic significance of EGFR mutation in NSCLC patients who received best supportive care (BSC) alone, and compare the anti-tumor outcomes of only EGFR-TKI-treated patients vs. BSC patients. Methods: We retrospectively reviewed the medical records of patients diagnosed with NSCLC at Higashihiroshima Medical Center during April 1991–January 2019 and Hiroshima University Hospital during April 2008–August 2018. Results: A total of 1163 patients diagnosed with unresectable NSCLC were included in this analysis. Of these 1163 patients, 234 patients received BSC alone.Among 196 patients who underwent EGFR mutation analysis, 38 and 158 did and did not harbor an EGFR mutation, respectively, and the mean survival times (MST) did not differ significantly between these groups (121 vs. 85 days, p = 0.789). Consistent with the survival analysis, the multivariate Cox regression analyses showed EGFR mutation was not an independent prognostic factor. After propensity score matching, a comparison of only EGFR-TKI-treated (n = 35) and BSC patients (n = 35) with EGFR mutation revealed that the former had a significantly longer MST than the latter (372 vs. 121, p < 0.001). Conclusions: EGFR mutation itself was not a significant prognostic factor in untreated NSCLC patients. The patients who received EGFR-TKI had a significantly longer MST than their untreated counterparts. Our results may help to explain the benefit of EGFR-TKI, particularly for patients who would be directed towards treatment with BSC.
Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we ...demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4+ T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2−/−Smad3+/− T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.
Background: Suppression of IL-2 production from T cells is an important process for the immune regulation by transforming growth factor-beta (TGF-β).
Results: Smad2 and Smad3 were redundantly essential for IL-2 suppression and recruited histone H3K9 methyltransferase, Suv39h1 to the proximal region of the IL-2 promoter, thereby suppressing IL-2 transcription.
Conclusion: Smad2/3 mediated histone H3K9 trimethylation of the IL-2 promoter is an important mechanism for the suppression of IL-2 transcription.
Significance: Our finding will be useful to establish a novel therapy for autoimmune diseases and inflammatory diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that ...overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-gamma and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-gamma and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with alpha-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-gamma and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis.
Our previous mapping of allelic loss in γ-ray induced thymic lymphomas in F1 hybrid and backcross mice between BALB/c and MSM strains identified three regions with high frequencies of allelic loss ...which probably harbor a tumor suppressor gene. One region, Tlsr7, exists near the D16 Mit122 locus on chromosome 16. This study has further localized Tlsr7 by constructing a physical map and scanning a total of 587 thymic lymphomas. The map consists of 13 overlapping BAC clones and isolation of BAC-derived polymorphic probes leads to fine mapping of allelic losses. Eleven lymphomas show informative breakpoints of allelic loss regions relative to the flanking markers on the map. Pulsed-field gel electrophoresis of NotI digests of the clones shows that the commonly lost region is localized within an approximately 300 kb interval near D16Mit192. This map is invaluable to facilitate the identification of genes in the Tlsr7 region.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Humans obtain some tactile feeling when they touch and rub objects with their fingers, which should be associated with some information about the objects. It means tactile information exists in such ...tribological actions of their fingers inevitably. In the present study, discrimination of particles has been investigated by using tactile information in an artificial system. Two kinds of time-series signals, i.e. normal and tangential fluctuations, were obtained experimentally when two silicone-gum specimens were rubbed with sands between the surfaces of specimens, in which the sands with sizes of 180-710 1.im were classified into five samples by sieves. The particle diameters of samples were found to be correlated with two quantities obtained from the time-series signals ; one was the normal elastic recovery between before and after rubbing, and the other was the weighted mean frequency of dominant elements appearing in the spectrum of tangential fluctuation. By using the relationship between the two quantities and the particle diameters, the artificial system showed an ability of discrimination comparable with human subjects.
Discrimination of particles has been investigated by using tactile information in an artificial system. Two kinds of time-series signals, i.e. normal and tangential fluctuations, were obtained ...experimentally when two silicone-gum specimens were rubbed with sands between the surfaces of specimens, in which the sands with sizes of 20-710 μm were classified into nine samples by sieves. The particle diameters of samples were found to be correlated with two quantities obtained from the time-series signals; one was the normal elastic recovery between before and after rubbing, and the other was the weighted mean frequency of dominant elements appearing in the spectrum of tangential fluctuation. By using the relationship between the two quantities and the particle diameters, the artificial system showed an ability of discrimination comparable with human subjects. Information of the size of sands appears in three ways. In case of larger-size samples, it appears strongly in the weighted mean frequency with lower-range frequency. On the contrary, it appears strongly in the elastic recovery for middle-size samples, and in the weighted mean frequency with higher-range frequency for smaller-size samples. By considering such characteristics, an algorithm has been constructed for discriminating the all samples with a higher accuracy, which has a similarity to the functions of three kinds of tactile receptors.
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