Cucurbitacin: Ancient Compound Shedding New Light on Cancer Treatment

Cucurbitacins and their derivatives are triterpenoids found in medicinal plants known for their diverse pharmacological and biological activities, including anticancer effects, throughout human history. Although initial attention to cucurbitacin as a potential anticancer drug withered for decades, recent discoveries showing that cucurbitacin is a strong STAT3 (Signal Transducers and Activators of Transcription-3) inhibitor have reclaimed the attention of the drug industry one more time. There is increasing evidence showing that some cucurbitacins not only inhibit the JAK-STAT pathway, but also affect other signaling pathways, such as the MAPK pathway, which are also known to be important for cancer cell proliferation and survival. Moreover, some reports have shown the synergistic effect of cucurbitacins with known chemotherapeutic agents, such as doxorubicin and gemcitabine. In this review, we will summarize the recent discoveries regarding molecular mechanisms of action of cucurbitacins in human cancer cells and discuss the possibilities of cucurbitacin as a future anticancer drug in clinical settings

Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas

Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells

Beyond the Starobinsky model for inflation

We single out the Starobinsky model and its extensions among generic f(R) gravity as attractors at large field values for chaotic inflation. Treating a R3 curvature term as a perturbation of the Starobinsky model, we impose the phenomenological bounds on the additional term satisfying the successful inflationary predictions. We find that the scalar spectral index can vary in both the red or blue tilted direction, depending on the sign of the coefficient of the R3 term, whereas the tensor-to-scalar ratio is less affected in the Planck-compatible region. We also discuss the role of higher order curvature term for stability and the reheating dynamics for the unambiguous prediction for the number of efoldings up to the R3 term.We single out the Starobinsky model and its extensions among generic $f(R)$ gravity as attractors at large field values for chaotic inflation. Treating a $R^3$ curvature term as a perturbation of the Starobinsky model, we impose the phenomenological bounds on the additional term satisfying the successful inflationary predictions. We find that the scalar spectral index can vary in both the red or blue tilted direction, depending on the sign of the coefficient of the $R^3$ term, whereas the tensor-to-scalar ratio is less affected in the Planck-compatible region. We also discuss the role of higher order curvature term for stability and the reheating dynamics for the unambiguous prediction for the number of efoldings up to the $R^3$ term

The effects of ipsilateral tilt position on right subclavian venous catheterization: study protocol for a prospective randomized trial

Abstract Background The cross-sectional area of the subclavian vein (csSCV) is an important factor determining the success rate of SCV catheterization. The head-down position increases the csSCV. However, the effects of lateral tilting on subclavian venous cross-sectional area have not yet been explored. In this trial, we test our hypothesis that ipsilateral tilt during right SCV catheterization may significantly increase the csSCV by impeding blood flow to the heart, thereby increasing the primary venipuncture success rate and reducing the complication rate and procedure time. Methods/design This is a two-staged, prospective, randomized, controlled trial conducted on 237 neurosurgical patients requiring SCV catheterization. Seventeen patients in stage I will be placed in supine, 20° ipsilateral tilt, and 20° contralateral tilt positions in random order. The right csSCV will be measured using ultrasonography at each position. In stage II, 220 patients will be randomly assigned to the ipsilateral tilt group (n = 110) and supine group (n = 110) according to the position for right SCV catheterization. Data on catheterization-related characteristics and complications will be collected during and after catheterization. The primary outcome measures are the right csSCV for stage I and primary venipuncture success rate for stage II. The secondary outcome measures for stage II are time to venipuncture, total catheterization time, first-pass success rate, and complications, such as arterial puncture, hematoma, pneumothorax, air embolism, and catheter misplacement. Discussion This is the first trial to investigate the effects of the ipsilateral tilt position on right SCV catheterization. We will attest the beneficial effects of the ipsilateral tilt position on the csSCV and the primary venipuncture success rate during right SCV catheterization. Furthermore, comparisons of the first-pass success rate, complications, and total catheterization time during SCV catheterization in the ipsilateral tilt position vs. the supine position will help us determine which position is better for safe and easy SCV catheterization. Trial registration ClinicalTrials.gov, ID: NCT03296735. Registered on 25 September 2017 for stage I; NCT03303274 Registered on 6 October 2017 for stage II

Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas.

Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

Additional file 1: of The effects of ipsilateral tilt position on right subclavian venous catheterization: study protocol for a prospective randomized trial

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist. (DOC 125 kb

Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status

10.18632/oncotarget.28047Oncotarget12181749-176