Comparison of the Physical Care Burden on Formal Caregivers between Manual Human Care Using a Paper Diaper and Robot-Aided Care in Excretion Care.

Although the older population has been rapidly growing, the availability of formal caregivers remains limited. Assistance provided by care robots has helped lower this burden; however, whether using a care robot while providing excretion care (EC) is quantitatively increasing or decreasing caregivers' physical care burden has not been extensively studied. This study aimed to quantitatively compare the physical burden experienced by caregivers while providing manual excretion care (MC) using a paper diaper versus robot-aided care (RC). Ten formal caregivers voluntarily participated in the experiment. MC and RC tasks were structuralized according to phases and classified by characteristics. The experiment was conducted in a smart care space. The physical load of formal caregivers was estimated by muscular activity and subjective rating of perceived physical discomfort. The results demonstrated that although the physical load on the lower back and upper extremities during the preparation and post-care phases were greater in RC than MC, RC markedly alleviated caregivers' physical load when performing front tasks. In the preparation-care phases, the physical loads on the lower back and upper extremities were approximately 40.2 and 39.6% higher in the case of RC than MC, respectively. Similar to the preparation-care phases, the physical loads on the lower back and upper extremities during post-care phases were approximately 39.5 and 61.7% greater in the case of RC than MC, respectively. On the other hand, in the front-care phases, the physical loads on the lower back and upper extremities were approximately 25.6 and 34.9% lower in the case of RC than MC, respectively. These findings can quantitatively explain the effectiveness and features of a care robot to stakeholders and provide foundational research data for the development of EC robots. This study emphasizes the implementation and promotion of the dissemination, popularization, and development of care robots to fulfill formal caregiving needs.

Attention-Based Automated Feature Extraction for Malware Analysis.

Every day, hundreds of thousands of malicious files are created to exploit zero-day vulnerabilities. Existing pattern-based antivirus solutions face difficulties in coping with such a large number of new malicious files. To solve this problem, artificial intelligence (AI)-based malicious file detection methods have been proposed. However, even if we can detect malicious files with high accuracy using deep learning, it is difficult to identify why files are malicious. In this study, we propose a malicious file feature extraction method based on attention mechanism. First, by adapting the attention mechanism, we can identify application program interface (API) system calls that are more important than others for determining whether a file is malicious. Second, we confirm that this approach yields an accuracy that is approximately 12% and 5% higher than a conventional AI-based detection model using convolutional neural networks and skip-connected long short-term memory-based detection model, respectively.

Construction of histidine-containing hydrocarbon stapled cell penetrating peptides for in vitro and in vivo delivery of siRNAs.

A hydrocarbon stapled peptide based strategy was used to develop an optimized cell penetrating peptide for siRNA delivery. Various stapled peptides, having amphipathic Leu- and Lys-rich regions, were prepared and their cell penetrating potentials were evaluated. One peptide, stEK, was found to have high cell penetration and siRNA delivery abilities at low nanomolar concentrations. In order to improve its ability to promote gene silencing, stEK was modified by replacing several Lys residues with His moieties. The modified peptide, LKH-stEK, was found to facilitate endosomal escape and to display >90% knock-down with 50 nM of a siRNA targeting cyclophilin B in HeLa cells. The results of an in vivo animal wound healing model study demonstrate that LKH-stEK promotes delivery of an siRNA, which targets the connective tissue growth factor, and that this process leads to efficient gene silencing by the siRNA at a nanomolar level in mouse skin.

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis.

Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis.

Development of Cell-Penetrating Asymmetric Interfering RNA Targeting Connective Tissue Growth Factor.

Connective tissue growth factor (CTGF) is a multifunctional matricellular protein, playing a role as a central mediator in tissue remodeling and fibrosis. A number of reports have shown the pivotal roles of CTGF in the progression of fibrosis, suggesting CTGF as a promising therapeutic target for the treatment of fibrotic disorders including hypertrophic scars and keloids. In this study, we present the development of an interfering RNA molecule that efficiently inhibits the expression of CTGF via RNA interference mechanism both in vitro and in vivo. Chemical modifications were introduced to the asymmetric interfering RNA (asiRNA) backbone structure. The resulting RNA molecule, termed cell-penetrating asiRNA (cp-asiRNA), entered into cells and triggered RNA interference-mediated gene silencing without delivery vehicles. The gene-silencing activity of cp-asiRNA targeting CTGF (cp-asiCTGF) was examined both in vitro and in vivo. Furthermore, the administration of cp-asiCTGF in the rat skin excision wound model efficiently reduced the induction of CTGF and collagens during the wound-healing process. These results suggest that the cp-asiCTGF molecule could be developed into antifibrotic therapeutics such as antiscar drugs.

Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth.

In the tumor microenvironment, CD11b(+)Gr1(+) bone marrow-derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone-related protein (PTHrP) potentiates CD11b(+)Gr1(+) cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b(+)Gr1(+) cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b(+)Gr1(+) cell-derived MMP-9 but not tumor-derived VEGF-A. CD11b(+)Gr1(+) cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor-derived PTHrP potentiates this activity of CD11b(+)Gr1(+) cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b(+)Gr1(+) cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b(+)Gr1(+) cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer-derived PTHrP acts in the bone marrow to potentiate CD11b(+)Gr1(+) cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth.

Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone.

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.

Tetraarsenic oxide-mediated apoptosis in a cervical cancer cell line, SiHa.

PURPOSE: Diarsenic oxide, As(2)O(3), has been reported to be effective in treating acute leukemia, and induce apoptosis in many tumor cells. In this study, the ability of a novel arsenical compound, As(4)O(6) (tetraarsenic oxide), along with As(2)O(3), for its ability to induce cell growth inhibition, as well as apoptosis, in human cervical cancer cells, SiHa cells, were evaluated in vitro. MATERIALS AND METHODS: To examine the levels of apoptosis, SiHa cells were given two sensitive doses, 0.5 and 1 microM, of arsenical compounds, and a DNA fragmentation assay and FACS analysis were then conducted. In addition, a Western blotting assay was performed to identify target molecules for apoptosis. RESULTS: Both As(2)O(3) and As(4)O(6) induced dosedependent inhibition of SiHa cell proliferation. In particular, As(4)O(6) was more effective at suppressing SiHa cell growth than As(2)O(3). In parallel with the inhibition of cell proliferation, As(4)O(6) caused a significantly greater increase in the sub-G1 cell population than As(2)O(3), as determined by propidium iodide DNA staining. This was confirmed by a DNA fragmentation assay and annexin V staining. The Western blotting analysis also showed that the expression of proliferating cell nuclear antigen (PCNA) was suppressed to a significantly greater extent by As(4)O(6) than As(2)O(3) at a dose of 0.5 microM. However, the apoptosis-related protein, Bax, was expressed to a significantly greater extent due to As(4)O(6) than As(2)O(3). CONCLUSION: Taken together, these findings suggest that a novel arsenic compound, As(4)O(6), possesses more potent anti-proliferative effects on human cervical cancer cells, with the induction of apoptosis also, at least via the activation of Bax protein in vitro.