The widespread presence of pepsin-like enzymes in eukaryotes together with their relevance in the control of multiple biological processes is reflected in the large number of studies published so far for this family of enzymes. By contrast, pepsin homologs from bacteria have only recently started to be characterized. The work with recombinant shewasin A from Shewanella amazonensis provided the first documentation of this activity in prokaryotes. Here we extend our studies to shewasin D, the pepsin homolog from Shewanella denitrificans, to gain further insight into this group of bacterial peptidases that likely represent ancestral versions of modern eukaryotic pepsin-like enzymes. We demonstrate that the enzymatic properties of recombinant shewasin D are strongly reminiscent of eukaryotic pepsin homologues. We determined the specificity preferences of both shewasin D and shewasin A using proteome-derived peptide libraries and observed remarkable similarities between both shewasins and eukaryotic pepsins, in particular with BACE-1, thereby confirming their phylogenetic proximity. Moreover, we provide first evidence of expression of active shewasin D in S. denitrificans cells, confirming its activity at acidic pH and inhibition by pepstatin. Finally, our results revealed an unprecedented localization for a family A1 member by demonstrating that native shewasin D accumulates preferentially in the cytoplasm.

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Venetoclax is a selective, first-in-class, Bcl-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: 1) a bioequivalence study to compare the bioavailability of the film-coated tablet to that of an earlier uncoated tablet and 2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions in each of two periods; one period used the uncoated tablet and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100 mg tablet under fasting conditions, after a low-fat breakfast, or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet which indicates that the film coating does not impact the bioavailability. Median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared to fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 hours versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food, and without specific recommendations for fat content, to ensure adequate and consistent bioavailability. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

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Cancer is a serious disease that causes many deaths every year. We urgently need to design effective treatments to cure this disease. Tumor suppressor genes (TSGs) are a type of gene that can protect cells from becoming cancerous. In view of this, correct identification of TSGs is an alternative method for identifying effective cancer therapies. In this study, we performed gene ontology (GO) and pathway enrichment analysis of the TSGs and non-TSGs. Some popular feature selection methods, including minimum redundancy maximum relevance (mRMR) and incremental feature selection (IFS), were employed to analyze the enrichment features. Accordingly, some GO terms and KEGG pathways, such as biological adhesion, cell cycle control, genomic stability maintenance and cell death regulation, were extracted, which are important factors for identifying TSGs. We hope these findings can help in building effective prediction methods for identifying TSGs and thereby, promoting the discovery of effective cancer treatments.

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To explore suitable imaging probes for early and specific detection of pancreatic cancer, we demonstrated that α6β4integrin is a good target and employed single-photon emission computed tomography (SPECT) or near-infrared (NIR) imaging for immunotargeting. Expression levels of α6β4were examined by Western blotting and flow cytometry in certain human pancreatic cancer cell lines. The human cell line BxPC-3 was used for α6β4-positive and a mouse cell line, A4, was used for negative counterpart. We labeled antibody against α6β4with Indium-111 ((111)In) or indocyanine green (ICG). After injection of(111)In-labeled probe to tumor-bearing mice, biodistribution, SPECT, autoradiography (ARG), and immunohistochemical (IHC) studies were conducted. After administration of ICG-labeled probe, in vivo and ex vivo NIR imaging and fluorescence microscopy of tumors were performed. BxPC-3 tumor showed a higher radioligand binding in SPECT and higher fluorescence intensity as well as a delay in the probe washout in NIR imaging when compared to A4 tumor. The biodistribution profile of(111)In-labeled probe, ARG, and IHC confirmed the α6β4specific binding of the probe. Here, we propose that α6β4is a desirable target for the diagnosis of pancreatic cancer and that it could be detected by radionuclide imaging and NIR imaging using a radiolabeled or ICG-labeled α6β4antibody.
© The Author(s) 2016.

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