This study aimed to evaluate the prognostic value of metabolic tumor burden as measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as SUVmax on initial staging and posttreatment F-FDG PET/CT in patients with stage IV non-small cell lung cancer (NSCLC).Sixty-three NSCLC patients with stage IV who underwent staging and posttreatment FDG PET/CT after completion of the first-line chemotherapy were retrospectively enrolled. SUVmax, MTV, and TLG of primary cancer and all metastatic lesions (lymph node and distant metastases) on both PET/CT images were measured and their association with progression-free survival (PFS) and overall survival (OS) analyzed.Median PFS and OS in the patient population were 5.9 and 23.1 months, respectively. Among the PET/CT parameters, MTV and TLG of primary cancer lesions on initial PET/CT and MTV and TLG of metastatic lesions on posttreatment PET/CT were independent prognostic factors for both PFS and OS (P < 0.05). The median OS in patients who showed low values of those PET/CT parameters was more than 26.0 months, whereas patients with high values of those parameters had a median OS of less than 15.0 months.Metabolic tumor burdens of primary cancer lesions on staging PET/CT and metastatic lesions on posttreatment PET/CT were independent prognostic factors in patients with stage IV NSCLC. Volume-based PET parameters could further stratify the prognosis of stage IV NSCLC patients.
ABSTRACT Exogenously applied brassinolide (BL) increased both gravitropic curvature and length of primary roots of Arabidopsis at low concentration (10 −10 M), whereas at higher concentration, BL further increased gravitropic curvature while it inhibited primary root growth. BRI1‐GFP plants possessing a high steady‐state expression level of a brassinosteroid (BR) receptor kinase rendered the plant's responses to gravity and root growth more sensitive, while BR‐insensitive mutants, bri1‐301 and bak1 , delayed root growth and reduced their response to the gravitropic stimulus. The stimulatory effect of BL on the root gravitropic curvature was also enhanced in auxin transport mutants, aux1‐7 and pin2 , relative to wild‐type plants, and increasing concentration of auxin attenuated BL‐induced root sensitivity to gravity. Interestingly, IAA treatment to the roots of bri1‐301 and bak1 plants or of plants pretreated with a BL biosynthetic inhibitor, brassinazole, increased their sensitivity to gravity, while these treatments for the BL‐hypersensitive transgenic plants, BRI1‐GFP and 35S‐BAK1 , were less effective. Expression of a CYP79B2 gene, encoding an IAA biosynthetic enzyme, was suppressed in BL‐hypersensitive plant types and enhanced in BL‐insensitive or ‐deficient plants. In conclusion, our results indicate that BL interacts negatively with IAA in the regulation of plant gravitropic response and root growth, and its regulation is achieved partly by modulating biosynthetic pathways of the counterpart hormone.
The Hippo signaling pathway regulates cell proliferation and organ growth, and its activation is mainly reflected by the phosphorylation levels of Yes-associated protein (YAP). In this study, we show that YAP facilitates embryonic neural stem cell proliferation by elevating their responsiveness to fibroblast growth factor 2 (FGF2), one of the major growth factors for neural stem cells, in vivo as well as in vitro. Western blot and quantitative real-time PCR analyses revealed that expression of the FGF receptors (FGFRs) FGFR1 to FGFR4 were greatly increased by YAP expression upon FGF2 treatment, followed by upregulation of the mitogen-activated protein kinase and protein kinase B signaling pathways. Furthermore, as assessed by quantitative real-time PCR analyses, YAP-induced FGFR expression was found to be TEA domain transcription factor (TEAD)-independent, and transcriptional coactivator with PDZ-binding motif, the other homolog of Yorki in the Drosophila Hippo signaling pathway, was found to possess similar activity to YAP. Finally, adjustment of FGFR signaling activity in the YAP-expressing cells to control levels efficiently offset the cell proliferative effects of YAP, suggesting that the increased proliferation of YAP-expressing neural stem cells was mainly attributable to enhanced FGFR signaling. Our data indicate that YAP plays an important role in neural stem cell regulation by elevating FGFR expression, subsequently leading to enhanced cell proliferation.
Abstract Although astrocytes have gained increased recognition as an important regulator in normal brain function and pathology, the mechanisms underlying their genesis are not well understood. In this study, we show that constitutive YAP activation by in utero introduction of a non-degradable form of the YAP gene (YAP 5SA) causes productive GFAP + cell generation at late embryonic periods, and this activity is nuclear localization- and TEAD transcription factor-dependent. Moreover, we found that the GFAP + cells were not YAP 5SA-expressing cells themselves but cells in the vicinity in vivo . Conditioned medium prepared from YAP 5SA-expressing cells induced GFAP + cell production in vitro , suggesting that a soluble factor(s) was mediating the astrogenic activity of YAP 5SA. Indeed, YAP 5SA expression greatly increased CNTF and BMP4 transcription in neural progenitor cells, and a neutralizing antibody against CNTF reduced the astrogenic effects of YAP 5SA-conditioned medium. Furthermore, the YAP 5SA-expressing cells were identified as FN1 + mesenchymal cells which are responsible for the precocious astrogenesis. These results suggest a novel molecular mechanism by which YAP activation can induce astrogenesis in a non-cell autonomous manner.
The diagnostic and treatment rates of early thyroid cancer have been increasing, including those of aggressive variants of papillary thyroid cancer (AVPTC). This study aimed to analyze the need for completion total thyroidectomy after lobectomy for clinically low-to-intermediate-risk AVPTC. Overall, 249 patients who underwent hemithyroidectomy (HT, n = 46) or bilateral total thyroidectomy (BTT, n = 203) for AVPTC between November 2005 and December 2019 at our single institution were examined. The average follow-up period was 14.9 years, with a recurrence rate of 4.3% and 10.8% in the HT and BTT groups, respectively. Multivariate Cox analysis revealed that palpable tumor on the neck during evaluation (HR, 2.7; 95% CI, 1.1-6.4; p = 0.025), clinical N1b (HR, 8.3; 95% CI, 1.1-63.4; p = 0.041), tumor size (cm) (HR, 1.3; 95% CI, 1.0-1.7; p = 0.036), gross extrathyroidal extension (HR, 3.1; 95% CI, 1.4-7.0; p = 0.007), and pathologic T3b (HR, 3.4; 95% CI, 1.0-11.4; p = 0.045) or T4a (HR, 6.0; 95% CI, 1.9-18.8; p = 0.002) were associated with an increased risk of recurrence. Incidentalomas identified during diagnosis had a significantly lower risk of recurrence (HR, 0.4; 95% CI, 0.2-0.9; p = 0.033). Close follow-up may be performed without completion total thyroidectomy for AVPTC found incidentally after HT.
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