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The relatively low aqueous solubility of EW-7197 that was administered orally may have affected the desired concentration in the systemic circulation for treating peritoneal adhesion. This experimental study aimed to compare the efficacy of different routes of administering EW-7197 (2-fluoro-N-[(5-[6-methylpyridin-2-yl]-4-[(1,2,4)triazolo(1,5-a)pyridin-6-yl]-1H-imidazol-2-yl)methyl]aniline) and EW-7197·hydrobromide (HBr), with improved aqueous solubility, for inhibiting peritoneal adhesion in a rat model.After peritoneal adhesion induction, 30 male Sprague-Dawley rats were randomly divided into 5 groups with 6 rats in each: group A, sham control; group B, orally administered 25 mg/kg of EW-7197·HBr for 7 days; group C, locally administered 25 mg/kg of EW-7197·HBr; group D, orally administered 20 mg/kg of EW-7197 for 7 days; and group E, locally administered 20 mg/kg of EW-7197. Gross examination, histologic staining (hematoxylin and eosin and Masson's trichrome), and immunohistochemical analyses (Ki-67 and α-smooth muscle actin marker [α-SMA]) were performed to evaluate the efficacy of both drugs.All procedures were technically successful. All treatment groups, except for group C, showed significantly reduced incidence, quality, tenacity, fibrosis, and collagen deposition scores and lowered expressions of Ki-67- and α-SMA-positive cells compared with group A. When comparing between groups, all scores were significantly lower in group B than in group C (all P.001), whereas no significant difference was noted in any of the scores between groups D and E and groups B and E (all P.05).Orally administering EW-7197·HBr and both orally and locally administering EW-7197 significantly prevented peritoneal adhesion formation, and orally administering EW-7197·HBr was the most effective overall.

In many workplaces, temporary teams convene to coordinate complex work, despite team members having not worked together before. Most related research has found consistent performance benefits when members of temporary teams work together multiple times (team familiarity). Recent work in this area broke new conceptual ground by instead exploring the learning and performance benefits that team members gain by being exposed to many new partners (partner exposure). In contrast to that new work that examined partner exposure between team members who are peers, in this paper, we extend this research by developing and testing theory about the performance effects of partner exposure for team members whose roles are differentiated by authority and skill. We use visit-level data from a hospital emergency department and leverage the ad hoc assignment of attendings, nurses, and residents to teams and the round-robin assignment of patients to these teams as our identification strategy. We find a negative performance effect of both nurses’ and resident trainees’ partner exposure to more attendings and of attendings’ and nurses’ exposure to more residents. In contrast, both attendings and residents experience a positive impact on performance from working with more nurses. The respective effects of residents working with more attendings and with more nurses is attenuated on patient cases with more structured workflows. Our results suggest that interactions with team members in decision-executing roles, as opposed to decision-initiating roles, is an important but often unrecognized part of disciplinary training and team learning. Funding: This work was supported by the New Faculty Startup Fund from Seoul National University; Harvard Business School; Stanford Center for Work, Technology, and Organization; and Stanford Center for Designing Organizational Change. Supplemental Material: The online supplement is available at https://doi.org/10.1287/orsc.2022.1585 .

This study aimed to investigate the efficacy of a closed-cell self-expandable metallic stent (SEMS) with or without expanded-polytetrafluoroethylene (e-PTFE)-covering membrane in a porcine iliac artery model. Twelve Yorkshire domestic pigs were divided into a bare closed-cell SEMS (B-SEMS) group (n = 6) and covered closed-cell SEMS (C-SEMS) group (n = 6). Both closed-cell SEMSs were placed in the right or left iliac artery. Thrombogenicity score in the C-SEMS group was significantly higher than that in the B-SEMS group (p = 0.004) after 4 weeks. Angiographic findings of mean luminal diameters at 4 weeks follow-up did not differ significantly between B-SEMS and C-SEMS groups. Neointimal hyperplasia thickness as well as degree of inflammatory cell infiltration and collagen deposition in the C-SEMS group was significantly greater than that in the B-SEMS group (p

Multifunctional porous microspheres (MPMs) containing oncolytic bacterial spores provide a promising strategy for targeted cancer immunotherapy.

The self-expanding metal stent (SEMS) is a versatile, palliative treatment method for unresectable, malignant, non-vascular strictures. Colorectal cancer (CRC) is one of the candidates for the application of the SEMS, in combination with the photothermal ablation (PTA) technique that enhances its therapeutic efficacy. The objective of this study was to investigate the efficacy of stent-mediated PTA therapy in an endoscopy-guided, orthotopic rectal cancer model. A total of 30 of 40 mice with the tumor size of grade 4 were included and were divided into three groups of 10 mice each. Group A underwent a gold nanoparticle (AuNP)-coated SEMS but no near-infrared (NIR) irradiation, group B received an uncoated control SEMS with NIR irradiation, and group C received a AuNP-coated SEMS and NIR irradiation together. Colonoscopy and in vivo imaging, immunohistochemical analysis, and quantitative reverse-transcription polymerase chain reaction of major tumor markers were performed. Stent placement and PTA were technically successful using colonoscopy. The tumor grade reduction after PTA is significant in group C, compared with groups A or B (p < 0.001). Molecular analysis validated this observation with a significantly reduced Mapk1 proliferation marker or increased Jnk expression. Histological analysis confirmed the localized PTA therapy using AuNP-coated SEMS profoundly ablated tumor outgrowth through the stent. Our results indicate that this novel strategy of localized PTA therapy could be a promising option for palliative treatment of CRC and to support prolonged stent patency with a decreased tumor volume.

As a non-thermal ablation method, irreversible electroporation (IRE) has been widely investigated in the treatment of prostate cancer. However, no consensus has been achieved on the optimal parameters of IRE for prostate cancer. Since high voltage is known to carry risks of muscle contraction and patient discomfort, it is crucial to identify the minimum but effective and safer applied voltage to inhibit tumor growth. In this study, the effect of different applied voltages of IRE on prostate cancer was evaluated in BALB/c nude mice. Mathematical simulation and measurement of the actual ablation area revealed a larger ablation area at a higher voltage. In in vivo experiment, except for the three different voltages applied, all groups received identical electrical conditions: pulse number, 180 (20 groups × 9 pulses/group); pulse width, 100 µs; pulse interval, 2 ms; distance between the electrodes, 5 mm; and electrode exposure length, 15 mm. Whilst the tumor volume initially decreased in the 500 V (1000 V/cm) and 700 V (1400 V/cm) groups and subsequently increased, only a transient increase followed by a continuous decrease until the sacrifice was observed in the 900 V (1800 V/cm) group. This result demonstrated a lasting effect of a higher applied voltage on tumor growth inhibition. The histological, immunohistochemical, and western blot findings all confirmed IRE-induced apoptosis in the treatment groups. Taken together, 900 V seemed to be the minimum applied voltage required to reduce tumor growth, though subsequent studies are anticipated to further narrow the voltage intervals and lower the minimum voltage required for tumor inhibition.

This study investigated whether interwoven self-expandable metallic stent (I-SEMS) placement suppresses stent-induced tissue hyperplasia compared with conventional knitted self-expandable metallic stent (K-SEMS) placement in a rat esophageal model. Twelve rats were randomly assigned to the I-SEMS (n = 6) and K-SEMS (n = 6) groups. All rats were sacrificed 4 weeks after the stent placement. The degree of stent-induced tissue hyperplasia on esophagography and histologic examination was compared between the groups. Stent placement was technically successful in all rats. Esophagography revealed significantly greater mean luminal diameter of the stented esophagus in the I-SEMS group than in the K-SEMS group (p < 0.001). Histologic examination revealed a significantly lower percentage of tissue hyperplasia area and a significantly thinner submucosal fibrosis in the I-SEMS group than in the K-SEMS group (all p < 0.001). There were no significant differences in the thickness of the epithelial layers (p = 0.290) and degree of inflammatory cell infiltration (p = 0.506). Formation of stent-induced tissue hyperplasia was evident with both I-SEMS and K-SEMS. Placement of I-SEMSs with a small cell size and high flexibility seems to be effective in suppressing stent-induced tissue hyperplasia compared with placement of K-SEMSs in rat esophageal models.

Conventional irreversible electroporation (IRE) with low-frequency pulsed electric field (LF-PEF) is used to induce cell death; however, it has several disadvantages including a long procedure time and severe muscle contraction due to high-voltage electric field. This study investigates a novel IRE protocol with high-frequency pulsed electric field (HF-PEF) of 500 Hz repetition to ablate the prostate tissue in beagles for treatment of prostate cancer. A finite element analysis was performed to validate optimal electrical field strength for the procedure. In total, 12 beagles received HF-PEF of 500 Hz and were sacrificed at 4 h, 4 days, and 28 days (3 each). The remaining three beagles underwent sham procedure. The outcomes of HF-PEF were assessed by histological responses. HF-PEF successfully decellularized the prostate tissues 4 h after the treatment. The prostate glands, duct, and urethra were well preserved after IRE with HF-PEF. The ablated prostatic tissues were gradually regenerated and appeared similar to the original tissues 28 d after IRE with HF-PEF. Moreover, electrocardiography and hematology demonstrated that IRE with HF-PEF did not seriously affect the cardiac tissue. HF-PEF was effective and safe in the beagle prostate and effectively induced the ablation and gradually recovered with cellular regeneration.

Several investigations on the feasibility of stent placement into the Eustachian tube (ET) are being conducted. However, stents optimized for the anatomical structure of the ET have not yet been developed. In this study, the efficacy and safety of a self-expandable metallic stent (SEMS) optimized for porcine ET morphology was investigated. Silicone was injected into a cadaveric porcine ET to analyze the ET morphology. The three-dimensional-reconstructed porcine ET phantom images obtained after a computed tomography scan were measured to determine the dimensions of the porcine ET. The SEMS was designed as a tapered structure on the basis of the morphological findings of the porcine ET. The tapered SEMS (T-SEMS) and conventional SEMS (C-SEMS) were placed into the porcine ET to compare the safety and efficacy of the two types of SEMSs. Stent-induced tissue hyperplasia in the T-SEMS group was significantly lower than that in the C-SEMS group (p

CD47 is expressed in all human cancer cells, including head and neck cancer, and initiates a signaling cascade to inhibit macrophage phagocytosis. However, the mechanism underlying CD47 overexpression has not been elucidated in radioresistant head and neck cancer. The present study demonstrated that decreased Tristetraprolin (TTP) expression induced a sustained overexpression of CD47 using reverse transcription-quantitative PCR and western blotting, and that CD47 overexpression prevented phagocytosis using a phagocytosis assay in a radioresistant HN31R cell line. Subsequently, using TTP transfection, RNA interference, duel-luciferase assay and EMSA, it was revealed that TTP transfection enhanced phagocytosis through degradation of CD47 mRNA by directly binding to CD47 AREs within the CD47 3'UTR. Based on our previous study, methylation-specific PCR and western blotting revealed that DNMT1 was overexpressed in radioresistant HN31R cell line and TTP expression was decreased epigenetically by DMNT1 associated DNA methylation. Overall, these findings provided novel insight into the role of TTP as a biomarker of CD47-positive head and neck cancer patients.

Background: Irreversible electroporation (IRE) has been investigated in the alimentary tract; however, the lack of dedicated electrodes and insufficient tissue responses made its application limited. The aim of this study was to investigate the efficacy and safety of image-guided stent-directed IRE in the rat esophagus.Methods: The bipolar self-expandable electrode (SE) was developed using the braiding technique. A finite element analysis was performed to validate optimal electrical field strength for the rat esophagus. A total of 40 out of 50 rats received stent-directed IRE and were sacrificed at 10 h, 3 days, 7 days, and 28 days of 10 each. The remaining ten rats underwent a sham procedure. The outcomes of stent-directed IRE were assessed by esophagography and histological responses.Results: Stent-directed IRE was technically successful in all rats with mild muscle contraction. The heart rate dropped immediately and gradually recovered at 180 s. TUNEL and caspase-3 with submucosal thickness significantly increased at 10 h and Day 3 compared with those of the sham control (all p < 0.001). The thickness of epithelial layers with collagen deposition significantly decreased at 10 h and Day 3 (all p < 0.001), however, increased at Day 7 compared with that of the sham control (all p < 0.05). The Ki67-positive deposition significantly increased at Day 3 and 7 compared with that of the sham control (all p < 0.001). All variables were similar to those of the sham control at Day 28.Conclusion: Image-guided stent-directed IRE was effective and safe in the rat esophagus. It seems to have effectively and evenly induced cell death and gradually recovered with cellular regeneration.

Stent-grafts composed of expanded polytetrafluoroethylene (e-PTFE), polyethylene terephthalate (PET) and polyurethane (PU) are characterized by poor endothelialization, high modulus, and low compliance, leading to thrombosis and intimal hyperplasia. A composite synthetic/natural matrix is considered a promising alternative to conventional synthetic stent-grafts. This study aimed to investigate the efficacy of thermoplastic polyurethane (TPU) and gelatin (GL) blended nanofibers (NFs) covered stent-graft in the porcine iliac artery. Twelve pigs were randomly sacrificed 7 days (n = 6) and 28 days (n = 6) after stent-graft placement. The thrombogenicity score at 28 days was significantly increased compared at 7 days (p p

Absorbable magnesium (Mg) stents have an attractive biocompatibility and rapid degradation rate, but their degradable behavior and efficacy in the Eustachian tube (ET) have not yet been investigated. In this study, the degradable behavior of the Mg stent in artificial nasal mucus was evaluated. The Mg stents in the porcine ET model were also investigated to evaluate their safety and efficacy. Four Mg stents were placed into the four ETs of two pigs. The mass loss rate of the Mg stents gradually decreased over time. The decrease rates were 30.96% at one week, 49.00% at two weeks, and 71.80% at four weeks. On the basis of histological findings, the thickness of submucosal tissue hyperplasia and the degree of inflammatory cell infiltration significantly decreased at four weeks compared with two weeks. Biodegradation of the Mg stent occurred before tissue proliferative reactions, and the ET patency was successfully maintained without stent-induced tissue hyperplasia at four weeks. The Mg stent that biodegrades rapidly seems to be effective and safe in porcine ET. Further investigation is required to verify the optimal stent shape and indwell period in the ET.

Frequently, policy makers seek to roll out an intervention previously proven effective in a research study, perhaps subject to resource constraints. However, because different subpopulations may respond differently to the same treatment, there is no a priori guarantee that the intervention will be as effective in the targeted population as it was in the study. How then should policy makers target individuals to maximize intervention effectiveness? We propose a novel robust optimization approach that leverages evidence typically available in a published study. Our model can be easily optimized in minutes for realistic instances with off-the-shelf software and is flexible enough to accommodate a variety of resource and fairness constraints. We compare our approach with current practice by proving performance guarantees for both approaches, which emphasize their structural differences. We also prove an intuitive interpretation of our model in terms of regularization, penalizing differences in the demographic distribution between targeted individuals and the study population. Although the precise penalty depends on the choice of uncertainty set, we show that for special cases we can recover classical penalties from the covariate matching literature on causal inference. Finally, using real data from a large teaching hospital, we compare our approach to common practice in the particular context of reducing emergency department utilization by Medicaid patients through case management. We find that our approach can offer significant benefits over common practice, particularly when the heterogeneity in patient response to the treatment is large. This paper was accepted by Chung-Piaw Teo, optimization.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity and its ability to induce apoptosis in cancer cells while sparing most normal cells. We evaluated whether docetaxel enhances TRAIL-mediated apoptosis in prostate cancer (PCa) cells and its mechanism.LNCap-LN3, PC3, and DU 145 PCa cell lines were used to investigate the effects of TRAIL with docetaxel treatment (dosages, 1, 3, 5, and 10 nmol). To evaluate the mechanism, death receptor 4 (DR4), DR5, enhancer of zeste homolog 2 (EZH2) and E2F1 levels were assessed in PCa cells.Hormone-sensitive LNCap-LN3 showed apoptosis in proportion to the concentration of docetaxel. Castration-resistant PC3 and DU 145 showed no change irrespective of the docetaxel concentration. However, combinations of docetaxel (2 nM) and TRAIL (100 ng/mL) had a significant effect on apoptosis of DU 145 cells. In DU 145 cells, docetaxel reduced EZH2 and elevated expression of DR4. The decrease of EZH2 by docetaxel was correlated with the E2F1 level, which was considered as the promoter of EZH2. DZNep reduced EZH2 and elevated DR4 in all PCa cells. Additionally, DZNep-enhanced TRAIL mediated reduction of PCa cell viability.Docetaxel and the EZH2 inhibitor reduced EZH2 and elevated expression of DR4 in all PCa cell lines. Docetaxel-enhanced TRAIL mediated apoptosis in PCa