The stock price prediction using Bayesian network has been presented by some researches. Their results showed that the prediction algorithm using Bayesian network has good prediction accuracy, This paper presents the improved algorithm in which the prediction accuracy of Nikkei stock average is enhanced by using NASDAQ index data. The accuracy of the present algorithm is compared with the precious algorithms in order to confirm the validity.
<p>A schematic summary of the reduction in Treg cells by pimitespib. HSP90 inhibition by pimitespib impairs Treg cells via STAT5 degradation. The IL-2/STAT5 signaling pathway is essential for the development and maintenance of Treg cells (left). STAT5, a client protein of HSP90, is inhibited by pimitespib treatment, resulting in the inhibition of FOXP3 transcription. Decreased FOXP3 expression inhibits the development, maintenance, and immunosuppressive function of Treg cells (right). Treg cell impairment, therefore, is mainly caused by pimitespib–induced STAT5 degradation.</p>
<p>Antitumor efficacy of combined treatment with anti–PD-1 mAb and pimitespib is not observed in CD8+ T cell–depleted mice. (A). Representative flow cytometry staining of PBMCs from C57BL/6 mice. For CD4+ T-cell and CD8+ T-cell depletion, anti-CD4 mAb (0.5 mg/body) or anti-CD8β mAb (0.2 mg/body), respectively, was administered intraperitoneally once weekly. CD4+ T-cell or CD8+ T-cell depletion was confirmed by flow cytometry. (B). Antitumor efficacy of combined treatment with anti–PD-1 mAb and pimitespib in CD4+ or CD8+ T cell–depleted mice. A total of 2 × 106 MC-38 cells were injected subcutaneously, and the cancer size was monitored twice weekly (n = 6). After the cancer volumes reached 100–150 mm3, the mice were randomized, and some mice received intraperitoneal administration of anti–PD-1 mAb (0.05 mg/body) on that day (day 0) and/or oral administration of pimitespib (14 mg/kg/body) five times weekly from day 0. Anti-CD4 mAb or anti-CD8β mAb was administered intraperitoneally every 7 days. All in vivo experiments were performed at least twice. *, P < 0.05; **, P < 0.01; n.s., not significant.</p>
AbstractNostocionone (Nost), a compound isolated from Nostoc commune, and its synthesized derivatives (NostDs) were evaluated for in vitro cytotoxicity against human T-cell leukemia Jurkat cells. NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-1,4-dien-3-one] inhibited cell growth more potently than Nost. To elucidate the mechanisms of NostD3-induced cell death, we examined changes in cell morphology, the loss of mitochondrial membrane potential (MMT), and DNA fragmentation. From these results, the cytotoxic effects of NostD3 were found to be mainly due to Type I programmed cell death (PCDI; i.e., apoptosis). Using caspase inhibitors, we further found that NostD-3-induced PCDI occurred through a caspase-independent pathway. Moreover, NostD3 decreased MMT and modulated multiple signaling molecules (MAPKs, Akt, Bcl-2, Bax, and c-Myc) in Jurkat cells, thereby inducing the release of endonuclease G (Endo-G) from mitochondria. The level of intracellular reactive oxygen species (ROS) in cells treated with NostD3 was elevated up to 1 h after the treatment. However, suppression of ROS by N-acetyl-l-cysteine restored Jurkat cell growth. Taken together, our data suggested that ROS production acted as a trigger in NostD3-induced PCDI in Jurkat cells through release of Endo-G from the mitochondria.
<p>Pimitespib–induced reduction in FOXP3 expression depends on STAT5 degradation in MJ cells. (A). Immunoprecipitation of HSP90 and STAT5. MJ cell lysates were incubated with normal rabbit IgG, anti-HSP90 mAb, or anti-STAT5 mAb, and immunocomplexes were purified, separated, and blotted. (B, C). The effect of STAT5B knockdown on FOXP3 expression. siRNA was used for knockdown of STAT5B (B). MJ cells after knockdown of STAT5B were cultured with the indicated concentrations of pimitespib for 48 hours. FOXP3 expression was examined in the MJ cells (C). (D). MJ cells were mock transduced or transduced with STAT5B to develop an MJ cells with STAT5b overexpression (OE). MJ cells with or without STAT5b overexpression were cultured in the presence or absence of pimitespib (1 μM) for 48 hours, and the mean fluorescence intensity (MFI) of FOXP3 was evaluated. (E). MJ cells were cultured with the indicated concentrations of pimitespib for 48 hours. Protein expression of the TCR-related signaling molecules LCK was examined. GAPDH was used as the internal control. All in vivo experiments were performed at least twice. **, P < 0.01; *, P < 0.05; **, P < 0.01; n.s., not significant.</p>
<p>Pimitespib augments the antitumor efficacy of anti–PD-1 mAb. (A–C). Antitumor efficacy of combined treatment with anti–PD-1 mAb and pimitespib against CMT-93. A total of 2 × 106 CMT-93 cells were inoculated subcutaneously, and the cancer size was monitored twice weekly (n = 6). The mice were randomized, and some mice received intraperitoneal administration of anti–PD-1 mAb (0.5 mg/body) on that day (day 0) and/or oral administration of pimitespib (14 mg/kg/body) five times weekly from day 0. Cancer growth (A for summary and B for each mouse) and PFS (C) are shown. PFS was defined as the time from day 0 until the cancer was twice as large as when treatment was initiated. All in vivo experiments were performed at least twice. *, P < 0.05; **, P < 0.01.</p>
<div>Abstract<p>Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to PD-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment, has been intensively studied. Inhibition of HSP90, a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. In this study, we show that the number of Treg cells is selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3<sup>high</sup> effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8<sup>+</sup> T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the tumor microenvironment by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell–targeted cancer immunotherapy.</p></div>
