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Folding a thin sheet material such as paper along curves creates a developable surface composed of ruled surface patches. When using such surfaces in design, designers often repeat a process of folding along curves drawn on a sheet and checking the folded shape. Although several methods for constructing such shapes on a computer have been proposed, it is still difficult to check the folded shapes instantly from the crease patterns. In this paper, we propose a simple method that approximately realizes a simulation of curved folds with a triangular mesh from its crease pattern. The proposed method first approximates curves in a crease pattern with polylines and then generates a triangular mesh. In order to construct the discretized developable surface, the edges in the mesh are rearranged so that they align with the estimated rulings. The proposed method is characterized by its simplicity and is implemented on an existing origami simulator that runs in a web browser.

Background Recent studies indicate that complement plays pivotal roles in promoting or suppressing cancer progression. We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). However, its mechanism of action remains unclear. Here, we elucidated the functional roles of C4BPA in PDAC cells and the tumor microenvironment. Methods We assessed stromal C4BPA, the C4BPA binding partner CD40, and the number of CD8+ tumor-infiltrating lymphocytes in resected human PDAC tissues via immunohistochemical staining. The biological functions of C4BPA were investigated in peripheral blood mononuclear cells (PBMCs) and human PDAC cell lines. Mouse C4BPA (mC4BPA) peptide, which is composed of 30 amino acids from the C-terminus and binds to CD40, was designed for further in vitro and in vivo experiments. In a preclinical experiment, we assessed the efficacy of gemcitabine plus nab-paclitaxel (GnP), dual immune checkpoint blockades (ICBs), and mC4BPA peptide in a mouse orthotopic transplantation model. Results Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis (P=0.0005). Stromal C4BPA strongly correlated with the number of CD8+ tumor-infiltrating lymphocytes (P=0.001). In in vitro experiments, flow cytometry revealed that recombinant human C4BPA (rhC4BPA) stimulation increased CD4+ and CD8+ T cell numbers in PBMCs. rhC4BPA also promoted the proliferation of CD40-expressing PDAC cells. By contrast, combined treatment with gemcitabine and rhC4BPA increased PDAC cell apoptosis rate. mC4BPA peptide increased the number of murine T lymphocytes in vitro and the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment. Conclusions These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.

Background The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. Methods We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. Results Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-β-galactosidase (SA-β-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8+ tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8+/Foxp3+ Tregs populations in PDAC tissues. Conclusions Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.

Background Bone distraction lengthening has been used for hand reconstruction. The healing process involved in this technique is affected by many factors. Here, the effectiveness and rates of healing of the phalanges and the metacarpals were evaluated in cases of traumatic finger amputation treated using an Ilizarov mini-fixator. Methods Fourteen phalanges and twelve metacarpals in 15 patients (13 males and 2 females) were treated with distraction lengthening using an Ilizarov mini-fixator between 2014 and 2017. All the digits had been subjected to traumatic amputation, and shortening of the remaining digit had occurred despite successful replantation in some cases. The healing indices of phalanges and metacarpals were analyzed. Results The mean patient age was 42.8 years. The mean lengthening of the phalanges was 13.3 mm, while that of the metacarpals was 26.5 mm. The mean consolidation times were 144.4 days for the phalanges and 154.1 days for the metacarpals. The mean healing indices of the phalanges and metacarpals were 114 days/cm and 60 days/cm, respectively. No bone grafts were needed in any of the patients. Conclusions Distraction lengthening of the digits after traumatic amputation is an effective procedure for hand reconstructive surgery for either the phalanges or the metacarpals and is less invasive than other techniques. The rate of healing of the metacarpals is two times faster than that of the phalanges.

Background: A palmaris longus (PL) to extensor pollicis longus (EPL) is a standard tendon transfer used to restore thumb extension in patients with radial nerve palsy. This transfer is done by withdrawing the EPL from the third compartment and passing it subcutaneously to reach the PL. We modified this transfer by rerouting the EPL through the second extensor compartment to improve the retropulsion of the thumb. The aim of this study is to report the outcomes of this modified transfer. Methods: Four patients with traumatic radial nerve palsy underwent the modified PL to EPL transfer. They also underwent transfer of the pronator teres (PT) to extensor carpi radialis brevis (ECRB) and flexor carpi radialis (FCR) to extensor digitorum communis (EDC). Patients were followed up for at least 1 year after surgery. The data with regard to age, gender, cause of radial nerve palsy, duration between injury and surgery, and duration of follow-up was recorded. At final follow-up, the arc of motion at the interphalangeal joint (IPJ), metacarpophalangeal joint (MCPJ), palmar and radial abduction and retropulsion were measured for the reconstructed thumb and contralateral normal thumb. Results: All patients were male, with a mean age of 34.3 (range, 19–46) years. The mean duration between the injury and surgery was 15.9 (7–27) months, and the mean post-operative follow-up period was 16.8 (12–25) months. All patients recovered good thumb function. The mean arc of motion of the affected and contralateral thumb were IPJ flexion: 52°/80°; IPJ extension: 21°/14°; MCPJ flexion: 30°/33°; MCPJ extension:24°/31°; radial abduction: 70°/74°; palmar abduction: 68°/75° and retropulsion: 4.8cm/5.0cm. Conclusion: Rerouting the PL to EPL tendon transfer through the second extensor compartment in radial nerve palsy can restore good thumb function especially retropulsion. Level of Evidence: Level IV (Therapeutic)

The use of lipid nanoparticles (LNPs) for nucleic acid delivery is now becoming a promising strategy with a number of clinical trials as vaccines or as novel therapies against a variety of genetic and infectious diseases. The use of microfluidics for the synthesis of the LNPs has attracted interest because of its considerable advantages over other conventional synthetic methods including scalability, reproducibility, and speed. However, despite the potential usefulness of large particles for nucleic acid delivery to dendritic cells (DCs) as a vaccine, the particle size of the LNPs prepared using microfluidics is typically limited to approximately from 30 to 100 nm. In this study, focusing on Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, the effect of some synthetic parameters, including total flow rate, flow rate ratio, buffer pH, lipid concentration, molar ratio of PEG-lipid as well as salt concentration, on particle size was systematically examined by means of the design of experiment approaches. The findings indicated that the simple addition of salt (e.g. NaCl) to a buffer containing nucleic acids contributed greatly to the synthesis of large LNPs over 200 nm and this effect was concentration-dependent with respect to the salt. The effect of salt on particle size was consistent with a Hofmeister series. The systemic injection of larger mRNA-loaded LNPs resulted in a higher transgene expression in mouse splenic DCs, a higher activation of various splenic immune cells, and had a superior effect as a therapeutic cancer vaccine in a syngeneic mouse model compared to the smaller-sized counterpart with constant lipid composition prepared with lower NaCl concentration. Collectively, size-regulation by the simple addition of salt is a promising strategy for developing potent LNPs.

This study aims to identify the relationship between dysphagia and developing hospital-acquired disability (HAD) in older patients with heart failure (HF). This single-center retrospective cohort study included 360 patients (median age, 84 years: 58.1% female, 41.9% male) who had undergone rehabilitation and were aged 65 years and older. Patients were divided into dysphagia and non-dysphagia groups and compared based on the Functional Oral Intake Scale score. HAD was defined as a decline in the Barthel Index score (indication of daily activity levels) at discharge relative to that before admission. The relationship between dysphagia and HAD was analyzed using bivariate analysis after adjusting for age, sex, body mass index, medical history, clinical and laboratory data, short physical performance battery (SPPB), and cognitive function at the start of rehabilitation, using propensity score matching. HAD was observed in 38.1% of the patients. Patients with dysphagia were significantly older, and had lower body mass index and physical and cognitive function than those without. After propensity score matching, the prevalence of HAD was significantly higher in the dysphagia group than in the non-dysphagia group (61.9% vs. 42.9%, P = 0.032). Dysphagia at the start of rehabilitation was an independent predictor of HAD. The results of this study may contribute to risk stratification of HAD.

We describe a patient with incomplete high median nerve palsy after surgical treatment of pediatric supracondylar humeral fracture (SCHF). Preoperative images after 11 months after the surgical treatment of the SCHF showed rotational deformity and an isolated median nerve entrapped between the proximal humerus anteriorly and callus posteriorly in the bony tunnel of the distal humerus. Two years after neurolysis, he showed clinical recovery. Four cases similar to our case were reported previously.Common pediatric fractures may cause unusual neuropathy. Rotational deformity of fracture might be an important factor for isolated median nerve entrapment after SCHF.

Introduction In-person cognitive behavioral therapy (CBT) can reduce self-reported anxiety in older adults. However, studies are limited for remote CBT. We assessed the effectiveness of remote CBT in mitigating self-reported anxiety in older adults. Methods We conducted a systematic review and meta-analysis based on a literature search of PubMed, Embase, PsycInfo, and Cochrane databases up to March 31, 2021, for randomized controlled clinical trials comparing the effectiveness of remote CBT versus non-CBT controls on mitigating self-reported anxiety in older adults. We calculated within-group pre-to-post-treatment standardized mean difference using Cohen's d, obtained the difference between a remote CBT group and a non-CBT control group as our effect size for cross-study comparison, and conducted a random-effects meta-analysis. Changes in scores on self-reported anxiety symptoms (Generalized Anxiety Disorder-7 item Scale, Penn State Worry Questionnaire, or Penn State Worry Questionnaire – Abbreviated), and self-reported depressive symptoms (Patient Health Questionnaire-9 item Scale or Beck Depression Inventory) were primary and secondary outcomes, respectively. Results Six eligible studies, containing 633 participants with a pooled mean age of 66.6 years, were included in the systematic review and meta-analysis. There was a significant mitigating effect of intervention on self-reported anxiety, favoring remote CBT over non-CBT controls (between-group effect size: −0.63; 95% CI: −0.99 to −0.28). We also found a significant mitigating effect of intervention on self-reported depressive symptoms (between-group effect size: −0.74; 95% CI: −1.24 to −0.25). Discussion Remote CBT is more effective in reducing self-reported anxiety and depressive symptoms than non-CBT control in older adults.

Background: Ischemic gastropathy (IG) is a major complication after distal pancreatectomy with en bloc celiac axis resection (DP-CAR) for locally advanced body/tail pancreatic ductal adenocarcinoma (PDAC), and its incidence is still unknown. Methods: To evaluate the occurrence of IG, 77 and 18 consecutive patients with body/tail PDAC were analyzed in a retrospective and a prospective study, respectively. We utilized perioperative gastroendoscopy, Gastrointestinal Quality of Life Index (GIQLI) score, and quantitative assessment for gastric arterial blood flow using the HyperEye Medical System (HEMS) with indocyanine green (ICG) fluorescence imaging in the prospective arm. Results: In the retrospective arm, no significant difference was noted in the occurrence rate of IG between the DP-CAR (8.7%) and DP groups (5.5%). In the prospective arm, the postoperative endoscopic scores were significantly higher in the DP-CAR group (45%) than in the DP group (11%) (p

Objectives To our knowledge, no cases have been reported so far regarding the treatment of proximal humerus fracture with intramedullary nail fixation via the Neviaser portal. This study aimed at evaluating the results of intramedullary nail fixation via the Neviaser portal for proximal humerus fracture. Methods Four patients with 2-part proximal humerus fracture, who underwent the intramedullary nail fixation via the Neviaser portal, were included in this study. All the patients were females, and the mean age was 78.8 years. We evaluated their clinical and radiographic findings retrospectively. Results The mean follow-up period was 12 months. All the patients achieved a bone-union without severe complications, such as deep wound infections or any neurological deficits. At the final follow-up, mean shoulder flexion, abduction, and external rotation were 123.5°, 118°, and 36°, respectively. Mean visual analog pain scale (VAS) score at the final follow-up was 21/100. Complications related to the implants were observed in two patients. In one patient, protrusion of the proximal tip of the nail occurred from the entry point, and this caused secondary subacromial impingement. In the other patient, insertion of the end-cap from the Neviaser portal was not possible, and this resulted in the failure of fixation postoperatively. Conclusion The Neviaser portal may be suitable for the insertion of an intramedullary nail, because it facilitates to make an entry-point at the top of the humeral head. However, the problems related to the use of the present instruments still remain and need to be improved.

C4b-binding protein α-chain (C4BPA) was previously identified as a novel serum biomarker for pancreatic ductal adenocarcinoma (PDAC). To apply this biomarker for clinical diagnosis, a lectin ELISA was established to measure serum fucosylated (Fuc)-C4BPA levels in 45 patients with PDAC, 20 patients with chronic pancreatitis (CP) and 50 healthy volunteers (HVs) in one training and three validation sets. The lecithin ELISA developed in the current study exhibited satisfactory within-run (2.6-6.7%) and between-day (1.8-3.6%) coefficient of variations. Serum Fuc-C4BPA levels in patients with PDAC (0.54±0.27 AU/ml) was significantly higher than that in HVs (0.21±0.06 AU/ml; P

Sub 100 nm-sized lipid nanoparticles (LNPs) have been widely used in drug delivery systems (DDSs). The size of the LNPs is an important parameter for the DDS performance, such as biodistribution and gene silencing using siRNAs. However, the LNPs prepared by the conventional preparation method show a wide size distribution. To improve the LNP size distribution, we developed a microfluidic device, named the iLiNP™ device, in a previous study. This device could produce LNPs in the size range of 20 to 150 nm, but the size distribution of the large-sized LNPs needs to be further improved. From the viewpoint of the LNP formation process, a homogeneous and slow rate dilution of ethanol plays an important role in improving the large-size LNP size distribution. In this study, we developed a three-dimensional, symmetrically assembled microfluidic device named the 3D-iLiNP device with the aim of precise size control of large-sized LNPs. We designed the 3D-iLiNP device using a computational fluid dynamics simulation and demonstrated that the 3D-iLiNP device can improve the LNP size distribution. The gene silencing activity of four kinds of siRNA-loaded LNPs was investigated via in vitro and in vivo experiments to elucidate the effect of the LNP size distribution. The results revealed that the LNPs with a size between 90 and 120 nm showed higher gene silencing activity than those with other sizes. The 3D-iLiNP device is expected to improve DDS performance by precisely controlling the size of LNPs.

This paper presents a novel exact order reduction approach for the Roesser (state-space) model of multidimensional systems using a common invariant subspace. It will be shown that this new exact order reduction approach can be applied even to those systems for which the existing approach based on common eigenvectors cannot do any further exact order reduction on them. As a consequence, the approach based on common eigenvectors can be viewed as a special case of the new proposed approach using a common invariant subspace. Examples will be also given to show the effectiveness as well as the details of the proposed approach.

Staphylococcus aureus strains that are susceptible to the β-lactam antibiotic oxacillin despite carrying mecA (OS-MRSA) cause serious clinical problems globally because of their ability to easily acquire β-lactam resistance. Understanding the genetic mechanism(s) of acquisition of the resistance is therefore crucial for infection control management. For this purpose, a whole-genome sequencing-based analysis was performed using 43 clinical OS-MRSA strains and 100 mutants with reduced susceptibility to oxacillin (MICs 1.0–256 µg/mL) generated from 26 representative OS-MRSA strains. Genome comparison between the mutants and their respective parent strains identified a total of 141 mutations in 46 genes and 8 intergenic regions. Among them, the mutations are frequently found in genes related to RNA polymerase (rpoBC), purine biosynthesis (guaA, prs, hprT), (p)ppGpp synthesis (relSau), glycolysis (pykA, fbaA, fruB), protein quality control (clpXP, ftsH), and tRNA synthase (lysS, gltX), whereas no mutations existed in mec and bla operons. Whole-genome transcriptional profile of the resistant mutants demonstrated that expression of genes associated with purine biosynthesis, protein quality control, and tRNA synthesis were significantly inhibited similar to the massive transcription downregulation seen in S. aureus during the stringent response, while the levels of mecA expression and PBP2a production were varied. We conclude that a combination effect of mecA upregulation and stringent-like response may play an important role in acquisition of β-lactam resistance in OS-MRSA.

AIM To investigate whether iodine density measurements from contrast-enhanced dual-energy computed tomography (CT) data can non-invasively stage liver fibrosis. METHODS This single-center, prospective study was approved by our IRB with written informed consent. Forty-seven consecutive patients (26 men and 21 women; mean age, 63.1 years) with chronic liver disease underwent contrast-enhanced dual-energy CT of the liver (non-contrast, arterial, portal venous, and equilibrium phase images), followed by liver biopsy. Iodine density of liver and aorta were obtained by two independent observers. Iodine uptake of the liver (Δ Liver), representing the difference in iodine density between equilibrium phase and non-contrast images, was calculated and normalized by aorta (Δ Liver/Aorta). We accounted for contrast agent distribution volume by using hematocrit level. Accuracy of iodine density measurements for staging liver fibrosis was assessed by using receiver operating characteristic (ROC) curves. Multivariate linear regression analysis was used to assess the impact of independent variables (liver fibrosis stage and patient-related confounders) on iodine uptake. RESULTS The Δ Liver/Aorta significantly increased and moderately correlated with METAVIR liver fibrosis stage (ρ = 0.645, P

Purpose To assess the ability of fast-kilovolt-peak switching dual-energy computed tomography (CT) by using the multimaterial decomposition (MMD) algorithm to quantify liver fat. Materials and Methods Fifteen syringes that contained various proportions of swine liver obtained from an abattoir, lard in food products, and iron (saccharated ferric oxide) were prepared. Approval of this study by the animal care and use committee was not required. Solid cylindrical phantoms that consisted of a polyurethane epoxy resin 20 and 30 cm in diameter that held the syringes were scanned with dual- and single-energy 64-section multidetector CT. CT attenuation on single-energy CT images (in Hounsfield units) and MMD-derived fat volume fraction (FVF; dual-energy CT FVF) were obtained for each syringe, as were magnetic resonance (MR) spectroscopy measurements by using a 1.5-T imager (fat fraction [FF] of MR spectroscopy). Reference values of FVF (FVFref) were determined by using the Soxhlet method. Iron concentrations were determined by inductively coupled plasma optical emission spectroscopy and divided into three ranges (0 mg per 100 g, 48.1-55.9 mg per 100 g, and 92.6-103.0 mg per 100 g). Statistical analysis included Spearman rank correlation and analysis of covariance. Results Both dual-energy CT FVF (ρ = 0.97; P < .001) and CT attenuation on single-energy CT images (ρ = -0.97; P < .001) correlated significantly with FVFref for phantoms without iron. Phantom size had a significant effect on dual-energy CT FVF after controlling for FVFref (P < .001). The regression slopes for CT attenuation on single-energy CT images in 20- and 30-cm-diameter phantoms differed significantly (P = .015). In sections with higher iron concentrations, the linear coefficients of dual-energy CT FVF decreased and those of MR spectroscopy FF increased (P < .001). Conclusion Dual-energy CT FVF allows for direct quantification of fat content in units of volume percent. Dual-energy CT FVF was larger in 30-cm than in 20-cm phantoms, though the effect of object size on fat estimation was less than that of CT attenuation on single-energy CT images. In the presence of iron, dual-energy CT FVF led to underestimateion of FVFref to a lesser degree than FF of MR spectroscopy led to overestimation of FVFref. © RSNA, 2016 Online supplemental material is available for this article.

Purpose To assess the ability of fast-kilovolt-peak switching dual-energy computed tomography (CT) by using the multimaterial decomposition (MMD) algorithm to quantify liver fat. Materials and Methods Fifteen syringes that contained various proportions of swine liver obtained from an abattoir, lard in food products, and iron (saccharated ferric oxide) were prepared. Approval of this study by the animal care and use committee was not required. Solid cylindrical phantoms that consisted of a polyurethane epoxy resin 20 and 30 cm in diameter that held the syringes were scanned with dual- and single-energy 64-section multidetector CT. CT attenuation on single-energy CT images (in Hounsfield units) and MMD-derived fat volume fraction (FVF; dual-energy CT FVF) were obtained for each syringe, as were magnetic resonance (MR) spectroscopy measurements by using a 1.5-T imager (fat fraction [FF] of MR spectroscopy). Reference values of FVF (FVF

In this article, we explain how to process and interpret stage directions in order to support actors’ performances. To this end, we specify the function of coverbal gesture and movement as an additional statement by an actor. We introduce a classification of communicative gestures by individuals and groups based on a description with typical body triangles and their sensor-detectable vertices moving in time. We claim that with the help of a speech and gesture recognition system, the occurrence of semantic isotopies to characterize a scene with speech and accompanying metaphoric gestures described in the stage directions can be detected and encoded in a feature vector. As a proof of concept, we highlight the ritual theater play Orphee d’Afrique, which was written as a second part of a homonymous chant novel and presents an implementation of a gesture- and voice-detection cuing system.

Our goal is to facilitate real-time serial cooperative work. In real-time serial cooperative work, the order of subtasks is important because a failure of the order leads to a failure of the whole task. So, coordinating the order of workers’ subtasks is necessary to smoothly accomplish the tasks. In this paper, we propose a method that uses vibration to present the action order and coordinate the orders. We conducted a user study to verify the effectiveness of the method in theatrical performance practice, which was an example of real-time serial cooperative work. As a result, order coordination reduced mistakes in the order of speech and action and in the contents of lines and action. This result suggests that order coordination can improve real-time serial cooperative work.

Understanding intratumoral fat in hepatocellular carcinoma (HCC) is clinically important to elucidate prognosis. We sought to quantify HCC and liver fat with a multimaterial decomposition (MMD) algorithm with rapid kilovoltage-switching dual-energy computed tomography (DECT) relative to chemical-shift magnetic resonance imaging (CSI). In this retrospective study, 40 consecutive patients with HCC underwent non-contrast-enhanced (non-CE) and four-phases contrast-enhanced (four-CE) DECT (80 and 140 kVp) and abdominal MR imaging (including CSI) between April 2011 and December 2012. Fat volume fraction (FVFDECT) maps were generated by MMD algorithm to quantify HCC and liver fat. Fat fraction measured by CSI (FFCSI) was determined for HCC and liver on dual-echo sequence using 1.5- or 3-Tesla MR systems. The correlation between FVFDECT and FFCSI was evaluated using Pearson correlation test, while non-CE FVFDECT and four-CE FVFDECT were compared by one-way ANOVA and Bland–Altman analysis. Forty patients (mean age, 70.1 years ± 7.8; 25 males) were evaluated. FVFDECT and FFCSI exhibited weak to moderate correlations for HCC in non-CE and four-CE except in equilibrium phase (r = 0.42, 0.44, 0.35, and 0.33; all P

Lipid nanoparticles (LNPs) are one of the more promising technologies for efficiently delivering short interfering RNA (siRNA) in vivo. A pH-sensitive cationic lipid that facilitates the targeting of hepatocytes and endosomal escape, strongly influences the availability of siRNA, thus making it a key material for efficient siRNA delivery. A systematic knowledge regarding lipid structure-activity relationships would greatly facilitate the development of sophisticated pH-sensitive cationic lipids for use in siRNA-based therapeutics. The systemic derivatization of a hydrophilic head group and hydrophobic tails of YSK12-C4, a pH-sensitive cationic lipid that was developed in our laboratory, revealed that hydrophilic head significantly affected the apparent pKa of the final product, a key factor in both intrahepatic distribution and endosomal escape. The clogP value of a hydrophilic head group was found to be associated with the apparent pKa of the product. In contrast, the hydrophobic tail structure strongly affected intrahepatic distribution without depending on apparent pKa. A structure-activity relationship study enabled the selection of an adequate combination of a hydrophilic head group and hydrophobic tails and permitted a potent LNP composed of a pH-sensitive cationic lipid CL4H6 (CL4H6-LNPs) to be developed that showed efficient gene silencing activity (50% effective dose: 0.0025 mg/kg), biodegradability and was tolerated. In vivo experiments revealed that the CL4H6-LNPs showed a superior efficiency for endosomal escape, cytosolic release and the RNA-induced silencing for the complex-loading of siRNAs compared to the previously developed LNPs.

Introduction: We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for pancreatic ductal adenocarcinoma (PDAC). Serum C4BPA level was significantly higher, especially in the early stage of PDAC patients, than in healthy controls as well as in patients with pancreatitis and other malignancies (Br J Cancer 2016). C4BPA is known as a potent soluble inhibitor of the complement system; however, the functional role of C4BPA remains unknown during tumor progression. In this study, we investigated the clinical significance of C4BPA expression and explored the possibility of correlation between C4BPA and antitumoral immunity in PDAC progression. Materials and Methods: Immunohistochemistry (IHC) for C4BPA was performed in resected PDAC tissues. PDAC tissues were obtained from 172 consecutive patients who underwent pancreatectomy at the Department of General Surgery, Chiba University Hospital, Japan from January 2011 to December 2014. In in vitro experiments, we evaluated C4BPA expression in human pancreatic duct epithelial (HPDE) cell, 7 human PDAC cell lines, resected PDAC sample, and the adjacent normal pancreatic tissues. C4BPA is known as a soluble inhibitor of the complement system and an activating ligand for CD40, which alters tumor microenvironment. The binding of CD40 on B cells or macrophages activates antitumoral T cells and antigen-presenting cells and induces a variety of downstream effects. To elucidate the molecular mechanism, we have addressed the association between C4BPA and CD40 expression in PDAC cells. Results: In IHC analysis, we found that C4BPA was mainly expressed in the stroma surrounding PDAC cells. Based on the staining intensity, PDAC samples were categorized into two groups: 75 cases as a high-expression group and 97 cases as a low-expression group. The Kaplan-Meier analysis showed that patients with low C4BPA expression presented a significantly shorter disease-free (P=0.011) and overall survival time than those with high C4BPA expression (P=0.0016, log-rank test). On multivariate analyses, high venous invasion and low C4BPA expression were observed as an independent prognostic factor in patients with PDAC after curative surgery. In in vitro experiment, C4BPA was strongly expressed in human pancreatic duct epithelial (HPDE) cell line but not in PDAC cell lines by Western blotting. Now, we have confirmed C4BPA expression in frozen section of PDAC tissues and the adjacent normal pancreas tissues, and CD40 expression in various PDAC cell lines. Discussion: Our results suggested that low C4BPA expression in the stroma of PDAC is associated with unfavorable prognosis of PDAC patients. These results also suggested that C4BPA might play a role in the process of elimination and equilibrium phase based on the immunoediting theory. Citation Format: Kosuke Sasaki, Shigetsugu Takano, Hideyuki Yoshitomi, Kazuyuki Sogawa, Shingo Kagawa, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Takashi Mishima, Eri Nakadai, Masayuki Ohtsuka. C4BPA identified as a novel biomarker is associated with favorable outcome of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C64.