Targeting metastatic breast cancer with peptide epitopes derived from autocatalytic loop of Prss14/ST14 membrane serine protease and with monoclonal antibodies

Background In order to develop a new immunotherapeutic agent targeting metastatic breast cancers, we chose to utilize autocatalytic feature of the membrane serine protease Prss14/ST14, a specific prognosis marker for ER negative breast cancer as a target molecule. Methods The study was conducted using three mouse breast cancer models, 4 T1 and E0771 mouse breast cancer cells into their syngeneic hosts, and an MMTV-PyMT transgenic mouse strain was used. Prss14/ST14 knockdown cells were used to test function in tumor growth and metastasis, peptides derived from the autocatalytic loop for activation were tested as preventive metastasis vaccine, and monoclonal and humanized antibodies to the same epitope were tested as new therapeutic candidates. ELISA, immunoprecipitation, Immunofluorescent staining, and flow cytometry were used to examine antigen binding. The functions of antibodies were tested in vitro for cell migration and in vivo for tumor growth and metastasis. Results Prss14/ST14 is critically involved in the metastasis of breast cancer and poor survival rather than primary tumor growth in two mouse models. The epitopes derived from the specific autocatalytic loop region of Prss14/ST14, based on structural modeling acted as efficient preventive metastasis vaccines in mice. A new specific monoclonal antibody mAb3F3 generated against the engineered loop structure could reduce cell migration, eliminate metastasis in PyMT mice, and can detect the Prss14/ST14 protein expressed in various human cancer cells. Humanized antibody huAb3F3 maintained the specificity and reduced the migration of human breast cancer cells in vitro. Conclusion Our study demonstrates that Prss14/ST14 is an important target for modulating metastasis. Our newly developed hybridoma mAbs and humanized antibody can be further developed as new promising candidates for the use in diagnosis and in immunotherapy of human metastatic breast cancer.This work is supported in part by the National Research Foundation (NRF) grant funded by the Korea government (MEST) (No. 2013R1A1A2009892 and No. 2017R1A2B4008109) and Inha Univeristy Research Grant awarded to MGK and (No. 2015R1A2A1A15054021) to SHK

Effect of meniscus on the permeability of mono-layered and multi-layered packed spheres

This study aims to numerically investigate the effect of meniscus curvature on the permeability of closely-packed spheres, which have widely used for heat pipes and vapor chambers. The shape of the meniscus curvature in the hexagonally-packed spheres is estimated based on surface energy minimization algorithm. The estimated meniscus shape is then imported into a CFD study for numerically predicting the permeability of the packed spheres. Based on the numerical results, the effect of contact angle and the number of sphere layers are investigated. The results show that the permeability is nearly independent to the contact angle when the contact angle is larger than 10. However, the permeability significantly increases with the contact angle decreases when the contact angle is lower than 10. The permeability quasi-linearly increases as the liquid filling ratio increases when 1 < l* < 2, where l* is liquid filling ratio. When contact angle is 5, the permeability is shown to slightly deviate from the linear behavior with respect to the liquid filling ratio. As the number of layers increases, the permeability significantly increases and approaches that obtained from Blake-Kozeny's equation. As the number of layers increases, the influence of meniscus curvature on the permeability decreases whereas the bottom surface plays an important role in determining the permeability. Based on extensive numerical results, correlations for predicting the packed spheres are proposed.ope

Old Wrestler (Yeoyu): 2

A retired wrestler struggles with amnesia and anxiety after he is invited to return to his home town for an event. Back in once-familiar surroundings, he wrestles to make sense of things as he is confronted by faces, scenes and smells recalled from a celebrated past

Parametric study on the permeability of micro-pillar wick with dual-height configuration

In this study, a parametric study on the permeability of micro-pillar wick with dual-height configuration, is performed. The effect of the primary and secondary pillar height on the nondimensional permeability is investigated. This work shows that the permeability of the micro-pillar wick can be significantly improved by appying the dual-height configuration. The permeability of the dual-height micro pillar array can be optimally designed by tayloring the geometric parameters. In this study, a mathematical correlation for predicting the permeability is proposed as a design guideline of the micro-pillar wick

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In this study, we numerically investigate the thermal performance of an enhanced radial heat sink with a perforation and chimney structure. We estimate the thermal performance of the enhanced radial heat sink, and compared it with that of a conventional radial heat sink. The results show that the radial heat sink with perforation has a higher thermal performance when either of the diameter and the number of perforations is high. With regards to the radial heat sink with a chimney structure, we investigate primarily the effect of the fin number, and the spacing between the chimney and the base plate on the thermal performance. The results show that there are optimal values for the fin number and the spacing between chimney and base plate. In addition, the enhanced radial heat sinks have maximum thermal performance when facing upward (0??), while it has worst performance when facing sideward (90??). The perforation and chimney are shown to cause thermal performance enhancements of 17% and 20%, respectively, compared with a conventional radial heat sink. The proposed method is useful for starting business, and is useful in terms of venture and entrepreneurship.ope

Enhanced photocatalytic activity of ZnS nanoparticles loaded with MoS2 nanoflakes by self-assembly approach

A hybrid consisting of ZnS nanoparticles supported on layered MoS2 ZnS was synthesized by a hydrothermal method based on self-assembly technique without using a template. XRD, SEM-EDX, TEM, HR-TEM, TG-DTA, XPS, N-2 adsorption-desorption, and UV Vis spectroscopies were used to characterize the structural features, morphology, and composition of the MoS2 ZnS hybrid. The results show that the MoS2 ZnS hybrid is mainly ZnS nanoparticles on layered MoS2 with a thickness of ca. 5-20 nm. The combination of the MoS2 and ZnS hybrid structure is beneficial for enhancing the photocatalytic degradation of rhodamine B (RhB) under visible light irradiation. A possible photoreaction mechanism of the MoS2 ZnS hybrid in the degradation is proposed. The photoexcited electrons from the ZnS could easily transfer to the conduction band of MoS2 , thus decreasing the recombination of photoinduced carriers and enabling the degradation of RhB under visible light irradiation.ope

Immune Gene Signature Delineates a Subclass of Papillary Thyroid Cancer with Unfavorable Clinical Outcomes

Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance

CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease