Repurposing fluphenazine as an autophagy modulator for treating liver cancer.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system with a low early diagnosis rate. Owing to the side effects, tolerance, and patient contraindications of existing therapies, effective drug treatments for HCC remain a major clinical challenge. However, using approved or investigational drugs not initially intended for cancer therapy is a promising strategy for resolving this problem because their safety have been tested in clinic. Therefore, this study evaluated differentially expressed genes between liver cancer and normal tissues in a cohort of patients with HCC from The Cancer Genome Atlas and applied them to query a connectivity map to identify candidate anti-HCC drugs. As a result, fluphenazine was identified as a candidate for anti-HCC therapy in vitro and in vivo. Fluphenazine suppressed HCC cell proliferation and migration and induced cell cycle arrest and apoptosis, possibly owing to disrupted lysosomal function, blocking autophagy flux. Additionally, in vivo studies demonstrated that fluphenazine suppresses HCC subcutaneous xenografts growth without causing severe side effects. Strikingly, fluphenazine could be used as an analgesic to alleviate oxaliplatin-induced pain as well as pain related anxiety-like behavior. Therefore, fluphenazine could be a novel liver cancer treatment candidate.

Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling.

Hepatocellular carcinoma (HCC) is one of the most lethal tumours worldwide. However, the effects of first-line sorafenib treatment in advanced HCC fail to prolong patients' survival due to the highly heterogeneous characteristics of HCC etiology. Cyclin-dependent kinase 9 (CDK9) is an important target in the continuous development of cancer therapy. Here, we demonstrate that CDK9 is closely associated with the progression of HCC and can serve as an HCC therapeutic target by modulating the recovery of wild-type p53 (wt-p53) function. We prove that mouse double minute 2 homologue (MDM2) and Sirtuin 1 (SIRT1) are phosphorylated by CDK9 at Ser166 and Ser47, respectively. Inhibition of CDK9 not only reduces the MDM2-mediated ubiquitination and degradation of wt-p53 but also increases wt-p53 stability by suppressing deacetylase activity of SIRT1. Thus, inhibition of CDK9 promotes the wt-p53 stabilization and prevents HCC progression. However, excessive inhibition by high concentrations of specific CDK9 inhibitors counteracts the promotion of p53 stability and reduces their anti-HCC activity because of extreme general transcription repression. The effects of a novel CDK9 inhibitor named oroxylin A (OA) from Scutellaria baicalensis are explored, with the results indicating that OA shows moderate and controlled inhibition of CDK9 activity and expression, and stabilizes wt-p53 by inhibiting CDK9-regulated MDM2 and SIRT1 signaling. These outcomes indicate the high therapeutic potential of OA against HCC and its low toxicity in normal tissue. This study demonstrates a novel mechanism for the regulation of wt-p53 by CDK9 and indicates that OA is a potential candidate for HCC therapy.

Pistol image retrieval by shape representation.

Databases have been used to record data in forensic science, such as fingerprints, shoeprints, and photos. In traditional databases, we use "text" as the "keyword" for retrieving data (text-keyword retrieval); however, in some applications, "text" is not proper to describe the searching target, and in this case, "image" plays an important role. In this paper, we use "image features" as the "keywords", and show its potential for building up a prototype of pistol image databases. In current firearm databases of forensic science, the retrieval method is still by text-keyword retrieval. For experienced forensic examiners, this kind of databases may satisfy their requirement. However, for people who have little gun knowledge, how can they find the possible gun candidates or similar guns in the databases, if there are not any available words or marks on the gun? In this paper, we try to retrieve similar pistol images by the pistol shape instead of "text-keyword". This method can narrow down the searching range while identifying pistols by firearm databases. There are more than 300 pistol images in our pistol image database. From the experimental results, we can retrieve the similar pistol images in top five candidates for each pistol image.