Nuclear factors NF-YC3 and NF-YBs positively regulate arbuscular mycorrhizal symbiosis in tomato.

The involvement of nuclear factor Y (NF-Y) in transcriptional reprogramming during arbuscular mycorrhizal symbiosis has been demonstrated in several plant species. However, a comprehensive picture is lacking. We showed that the spatial expression of NF-YC3 was observed in cortical cells containing arbuscules via the cis-regulatory element GCC boxes. Moreover, the NF-YC3 promoter was transactivated by the combination of CYCLOPS and autoactive calcium and calmodulin-dependent kinase (CCaMK) via GCC boxes. Knockdown of NF-YC3 significantly reduced the abundance of all intraradical fungal structures and affected arbuscule size. BCP1, SbtM1, and WRI5a, whose expression associated with NF-YC3 levels, might be downstream of NF-YC3. NF-YC3 interacted with NF-YB3a, NF-YB5c, or NF-YB3b, in yeast (Saccharomyces cerevisiae) and in planta, and interacted with NF-YA3a in yeast. Spatial expression of three NF-YBs was observed in all cell layers of roots under both mock and mycorrhizal conditions. Simultaneous knockdown of three NF-YBs, but not individually, reduced the fungal colonization level, suggesting that there might be functional redundancy of NF-YBs to regulate AM symbiosis. Collectively, our data suggest that NF-YC3 and NF-YBs positively regulate AM symbiosis in tomato, and arbuscule-related NF-YC3 may be an important downstream gene of the common symbiosis signaling pathway.

Effective suppression of myocardial glucose uptake using predesigned low-carbohydrate boxed meals.

BACKGROUND: Dietary preparation protocols are an effective means to suppress physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake. This study aimed to investigate the efficacy of various carbohydrate-restricted diets using predesigned boxed meals. METHODS: The patients were divided into four groups to undergo different preparatory protocols as follows: a minimum 15-hour fast alone, two meals of high-fat, low-carbohydrate diet (HFLCD), two meals of high-animal-protein, low-carbohydrate diet (HAPLCD), and two meals of high-plant-based-protein, low-carbohydrate diet (HPPLCD). Boxed meals were prepared to meet the required carbohydrate restrictions. Myocardial SUVmax and SUVmean were measured and the suppression rate was analyzed. RESULTS: The average myocardial SUVmax of fast alone, HFLCD, HAPLCD, and HPPLCD were 8.26 ± 5.85, 2.21 ± 1.50, 2.34 ± 1.88, and 4.10 ± 3.61, respectively, and the suppression rates were 36.6%, 93.3%, 93.3%, and 70%, respectively. The effectiveness of HFLCD, HAPLCD, and HPPLCD was all statistically superior to that of a 15-hour fast alone. SUVmax of HFLCD and HAPLCD showed no significant differences (p = 1), whereas HFLCD and HPPLCD had significant differences (p = .046). CONCLUSIONS: Using the predesigned boxed meals based on carbohydrate restriction, HFLCD, HAPLCD, and HPPLCD can be administered to patients with different dietary needs while providing a substantial reduction in physiological myocardial FDG uptake.

Meta-analysis of the effectiveness of heparin in suppressing physiological myocardial FDG uptake in PET/CT.

BACKGROUND: The present meta-analysis aims to investigate the effectiveness of heparin administration in suppressing physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/computed tomography (CT), as its role in this regard has not been well investigated. METHODS: PRISMA guidelines were used to interrogate the PubMed, Embase, Cochrane library, Web of Knowledge, and www.clinicaltrail.gov databases from the earliest records to March 2023. The final analysis included five randomized controlled trials (RCTs). Meta-analysis was conducted to compare the effectiveness of unfractionated heparin (UFH) administration versus non-UFH administration, and subgroup analysis based on fixed and variable fasting durations was conducted. Effect sizes were pooled using a random-effects model, and the pooled odds ratios (ORs) were calculated. RESULTS: Five eligible RCTs with a total of 910 patients (550 with heparin, 360 without heparin) were included. The forest plot analysis initially indicated no significant difference in the suppression of myocardial FDG uptake between the UFH and non-UFH groups (OR 2.279, 95% CI 0.593 to 8.755, p = 0.23), with a high degree of statistical heterogeneity (I2 = 91.16%). Further subgroup analysis showed that the fixed fasting duration group with UFH administration had statistically significant suppression of myocardial FDG uptake (OR 4.452, 95% CI 1.221 to 16.233, p = 0.024), while the varying fasting duration group did not show a significant effect. CONCLUSIONS: According to the findings of our meta-analysis, we suggest that intravenous administration of UFH can be considered as a supplementary approach to suppress myocardial FDG uptake.

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis.

Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)-associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although pre-clinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2α-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1+ cell-specific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1+ pericytes sorted from littermate controls, Gli1+ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1α or HIF-2α did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

Affinity Purification Coupled to Stable Isotope Dilution LC-MS/MS Analysis to Discover IgG4 Glycosylation Profiles for Autoimmune Pancreatitis.

Type 1 autoimmune pancreatitis (AIP) is categorized as an IgG4-related disease (IgG4-RD), where a high concentration of plasma IgG4 is one of the common biomarkers among patients. IgG Fc-glycosylation has been reported to be potential biosignatures for diseases. However, human IgG3 and IgG4 Fc-glycopeptides from populations in Asia were found to be isobaric ions when using LC-MS/MS as an analytical tool. In this study, an analytical workflow that coupled affinity purification and stable isotope dilution LC-MS/MS was developed to dissect IgG4 glycosylation profiles for autoimmune pancreatitis. Comparing the IgG4 and glycosylation profiles among healthy controls, patients with pancreatic ductal adenocarcinoma (PDAC), and AIP, the IgG4 glycosylations from the AIP group were found to have more digalactosylation (compared to PDAC) and less monogalactosylation (compared to HC). In addition, higher fucosylation and sialylation profiles were also discovered for the AIP group. The workflow is efficient and selective for IgG4 glycopeptides, and can be used for clinical biosignature discovery.

[Applying Self-Management Strategies to the Control of Interdialytic Weight Gain in Hemodialysis Patients].

BACKGROUND & PROBLEMS: The control of interdialytic weight gain (IDWG) in hemodialysis patients is crucial for maintaining dialysis quality. The results of a survey in our department revealed patients to be unmotivated, have poor self-control, not regularly manage their fluid intake or measure their body weight, and discount the importance of controlling IDWG. The nursing instruction adherence for IDWG control among nurses was only 61.6%. Moreover, the leaflet used for nursing instruction used highly repetitive messaging and lacked pictorial aids. Consequently, up to 48.6% of the patients in our department had an IDWG dry weight percentage of ≥ 5%. PURPOSE: To reduce the proportion of hemodialysis patients with an IDWG dry weight percentage of ≥ 5% from the current 48.6% to 29.2%. RESOLUTION: From August 1, 2019 to May 31, 2020, the improvement program developed in this project included: (1) the addition of an IDWG calculation and reminder function in the information system; (2) development of nursing instruction tools for IDWG control; (3) utilization of self-management strategies to establish care operations for IDWG control; (4) the organization of group health education sessions, dialysis patient seminars, and on-the-job training sessions; and (5) implementation of an audit program for IDWG-control nursing instruction. RESULTS: The proportion of patients with an IDWG dry weight percentage of ≥ 5% decreased to 28.8% and the number of patients who developed acute complications during dialysis decreased from 42 to 15 (35.7%). CONCLUSIONS: IDWG in dialysis patients was effectively decreased by establishing a standard operating procedure for IDWG control, designing a self-management record form, and implementing nursing instruction for IDWG control. It is hoped that the adopted measures promote dialysis quality and reduce complications during dialysis.

[A Project to Improve the Ability of Hemodialysis Staff to Respond to Fire Emergencies].

BACKGROUND & PROBLEMS: In case of fire in the hemodialysis room, it is necessary to help patients get away from dialysis machines smoothly and safely and evacuate the room rapidly. Our unit is located on a higher floor. An investigation showed that the accuracy rate for fire response awareness among the staffs in our unit was only 57.9%, while the accuracy rate of fire response skill operations was only 57.4%. Moreover, 62.0% of the staffs were not clear about the task grouping and task content of fire response. Confusion in our unit regarding the definition of patient mobility led to staffs classifying patients based on subjective perceptions and standards. Moreover, the unit also lacked an audit system for fire emergency operations and fire-response-related learning materials. PURPOSE: To improve staff knowledge and skills related to fire emergency response in the hemodialysis room to 100%. RESOLUTION: The project team worked out solutions such as adding a self-defense fire-fighting group to the dialysis information system, producing fire emergency response learning materials, establishing a seed personnel system, organizing on-the-job education, organizing fire response simulation drills, and implementing an audit system. RESULTS: The awareness of fire emergency response and the accuracy of skill operation among the staff were both improved to 100%, and there were statistically significant differences between the pre-test and post-test paired t-test results. Furthermore, consistent implementation of these resolution measures maintained the staff`s fire emergency response skills at 100% between June 2019 and May 2020. CONCLUSIONS: Tabletop simulation, practice drills, and skill operation audits are effective tools for improving the ability of staff in the hemodialysis room to respond to fire emergencies. It is recommended that institutions produce tabletop simulation props and combine regular on-site drills to improve the readiness of their staffs to respond to fire emergencies, which will shorten the response time during incidents.

Regulation of drug metabolizing enzymes in the leukaemic bone marrow microenvironment.

The bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukaemia (AML) and multiple myeloma (MM). We have shown that the critical drug metabolizing enzymes cytochrome P450 (CYP) 3A4 and cytidine deaminase (CDA) are highly expressed by BM stroma, and play an important role in this resistance to chemotherapy. However, what factors influence the chemoprotective capacity of the BM microenvironment, specifically related to CYP3A4 and CDA expression, are unknown. In this study, we found that the presence of AML cells decreases BM stromal expression of CYP3A4 and CDA, and this effect appears to be at least partially the result of cytokines secreted by AML cells. We also observed that stromal CYP3A4 expression is up-regulated by drugs commonly used in AML induction therapy, cytarabine, etoposide and daunorubicin, resulting in cross-resistance. Cytarabine also up-regulated CDA expression. The up-regulation of CYP3A4 associated with disease control was reversed by clarithromycin, a potent inhibitor of CYP3A4. Our data suggest that minimal residual disease states are characterized by high levels of stromal drug metabolizing enzymes and thus, strong microenvironment-mediated drug resistance. These results further suggest a potential role for clinically targeting drug metabolizing enzymes in the microenvironment.

Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer.

BACKGROUND: Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients. METHODS: The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed. RESULTS: Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70 ng/ml) than in the HRIs (17.52 ± 6.23 ng/ml). At a level of ≥ 29.8 ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8 ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs. CONCLUSIONS: TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.

High accuracy differentiating autoimmune pancreatitis from pancreatic ductal adenocarcinoma by immunoglobulin G glycosylation.

BACKGROUND: Misdiagnosis of autoimmune pancreatitis (AIP) as pancreatic cancer (PDAC) or vice versa can cause dismal patents' outcomes. Changes in IgG glycosylation are associated with cancers and autoimmune diseases. This study investigated the IgG glycosylation profiles as diagnostic and prognostic biomarkers in PDAC and AIP. METHODS: Serum IgG-glycosylation profiles from 86 AIP patients, 115 PDAC patients, and 57 controls were analyzed using liquid chromatography-electrospray ionization mass spectrometry. Classification and regression tree (CART) analysis was applied to build a decision tree for discriminating PDAC from AIP. The result was validated in an independent cohort. RESULTS: Compared with AIP patients and controls, PDAC patients had significantly higher agalactosylation, lower fucosylation, and sialylation of IgG1, a higher agalactosylation ratio of IgG1 and a higher agalactosylation ratio of IgG2. AIP patients had significantly higher fucosylation of IgG1 and a higher sialylation ratio of IgG subclasses 1, 2 and 4. Using the CART analysis of agalactosylation and sialylation ratios in the IgG to discriminate AIP from PDAC, the diagnostic accuracy of the glycan markers was 93.8% with 94.6% sensitivity and 92.9% specificity. There were no statistically significant difference of IgG-glycosylation profiles between diffuse type and focal type AIP. CONCLUSIONS: AIP and PDAC patients have distinct IgG-glycosylation profilings. IgG-glycosylation could different PDAC from AIP with high accuracy.

Age and cystic size are associated with clinical impact of endoscopic ultrasonography-guided fine-needle aspiration on the management of pancreatic cystic neoplasms.

Objectives: The clinical impact of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) in managing pancreatic cystic neoplasms (PCNs) remains controversial. The aim of this study was to identify which patients with PCNs would benefit from EUS-FNA. Methods: A retrospective study was performed on patients with PCNs who underwent EUS-FNA between January 2009 and June 2018. A discordant or a consistent diagnosis after EUS-FNA was analyzed and was correlated with the clinical demographic data and cystic features. Predictors of the change in the diagnosis after EUS-FNA were analyzed. Results: One hundred eighty-eight cases of PCNs were analyzed. EUS-FNA changed the diagnosis in 45.7% of all patients with PCNs and 54.5% patients with presumed branch ductal type intraductal papillary mucinous neoplasm (BD-IPMN) and impacted the recommendation in 35.6% of patients with PCNs and 50.5% patients with BD-IPMN. Patients with a discordant diagnosis after EUS-FNA were younger in age (54.8 ± 12.6 vs. 61.2 ± 14.2; p=.037) and had a cyst size larger than 3 cm than patients with a consistent diagnosis after EUS-FNA. The only worrisome feature (WF) that differed between patients with a discordant and a consistent diagnosis after EUS-FNA was the main pancreatic duct (MPD) between 5 and 9 mm (p=.013). In multivariate analysis, a cyst size >3 cm and age were independent predictors of diagnostic changes after EUS-FNA (OR: 5.33, 95% CI: 1.79-15.88, p = .003; OR: 0.96, 95% CI: 0.93-0.99, p = .031). Conclusions: EUS-FNA made a significant change in the management of nearly half of the patients with PCNs, especially in younger patients and in patients with a cyst size larger than 3 cm.

Performance of hydrogen evolution reaction of R3C ferroelectric ZnSnO3 nanowires.

The synthesis of LiNbO3-type R3C ZnSnO3 is still a challenging task under an extremely high-pressure condition. In this work, we have not only successfully synthesized R3C ZnSnO3 nanowires (NWs) through a hydrothermal process, but ZnSnO3 NWs with a high concentration of oxygen vacancies (referred to as [Formula: see text] NWs), exhibiting a highly efficient hydrogen evolution reaction compared to unannealed ZnSnO3 and ZnO NWs. The x-ray diffraction pattern and Raman spectra both confirm that the as-synthesized ZnSnO3 NWs mainly belong to the R3C space group with a second phase of ZnSn(OH)6. The conversion efficiency of the solar-to-hydrogen [Formula: see text] NWs and the unannealed ZnSnO3 NWs is 4.8% and 1.5%, respectively. The enhancement factor of the [Formula: see text] NWs is up to 320%. The photocurrent of the ZnSnO3 NWs and the [Formula: see text] NW photoelectrodes is even 5.39 and 16.23 times higher than that of the ZnO NWs, demonstrating that the high concentration of oxygen vacancies is regarded as a useful approach to enhance the photoelectrochemical response. To the best of our knowledge, this is the first report to reveal the performance of hydrogen evolution reaction by LiNbO3-type R3C ZnSnO3 NWs, which could offer a promising way of energy harvesting when using ferroelectric materials.

Advanced physical examination training course improves medical students' confidence in physical examination.

BACKGROUND: Physical examination (PE) is a basic diagnostic tool in clinical settings. It is important to enhance medical students' skills and confidence in PE. SUBJECTS AND METHODS: Our medical students begin learning PE in the fourth medical year (M4). They undergo hands-on clinical training in the fifth medical year (M5). To improve the teaching of PE, we implemented an advanced PE training course (APETC) for M5 students. In APETC, PE skills for chest (CH), cardiovascular system (CV), and abdomen (GI) domains were demonstrated by senior specialists. Under tutors' supervision, students performed PE on selected patients with positive signs. To evaluate the effect of this training course, we designed a checklist to evaluate students' confidence level in PE before and after APETC. Average confidence scores of PE in CH, CV, and GI domains among different years and genders were compared using ANOVA tests. RESULTS: M5 students' confidence in PE for individual items on the CH, CV, and GI checklists increased significantly after the APETC, in both 2014 and 2015 (all p < 0.0001).The average post-course confidence scores of all items in CH, CV, and GI domains increased significantly over average pre-course confidence scores. The average post-course confidence score in PE was higher in the year 2015 than that in the year 2014. Male students tended to have higher confidence scores in PE than female students. CONCLUSION: APETC enhanced medical students' confidence in PE. Long-term effects of the training course and the impact of students' gender on learning outcomes remain to be investigated.

[Project for Promoting the Completeness of Electronic Dialysis Nursing Records].

BACKGROUND & PROBLEMS: Obtaining complete electronic dialysis nursing records, a tool that facilitates communication between medical teams, is critical in terms of maintaining the continuity of nursing procedures and nursing quality. An analysis of our unit indicated that nurses lacked sufficient familiarity with electronic dialysis nursing record systems. Moreover, they received insufficient training in operating these systems and lacked the guidelines necessary to maintain these records properly. Furthermore, these systems tend to be poorly designed, and an inspection system for dialysis nursing records is currently unavailable. These factors led to a rate of record completeness of only 58.2%. PURPOSE: To raise the rate of completeness for electronic nursing records to above 90%. RESOLUTION: An intervention was conducted to accomplish seven tasks. These tasks included: modify the electronic dialysis nursing record system, input preset phrases in order to facilitate record compilation in the system, devise a manual to instruct staff on recordkeeping procedures, organize in-service training on system operations, conduct clinical scenario simulations for nurses to practice operating the system, recruit informatics nurses to teach other nurses about the operations, and implement an inspection system for these electronic records. RESULTS: After implementing the intervention, the rate of completeness for electronic nursing records improved to 96% and the average time required for nurses to complete a nursing record decreased from 21 mins 35 s to 8 mins 15 s. CONCLUSIONS: The developed intervention significantly improved the completeness of electronic nursing records, reduced the time required for recordkeeping, and ensured adequate nursing quality for dialysis patients.

Multiparametric PET/MR imaging biomarkers are associated with overall survival in patients with pancreatic cancer.

PURPOSE: To correlate the overall survival (OS) with the imaging biomarkers of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy, and glucose metabolic activity derived from integrated fluorine 18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI in patients with pancreatic cancer. METHODS: This prospective study was approved by the institutional review board and informed consent was obtained from all participants. Sixty-three consecutive patients (mean age, 62.7 ± 12 y; men/women, 40/23) with pancreatic cancer underwent PET/MRI before treatment. The imaging biomarkers were comprised of DCE-MRI parameters (peak, IAUC 60 , K trans , k ep , v e ), the minimum apparent diffusion coefficient (ADCmin), choline level, standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) of the tumors. The relationships between these imaging biomarkers with OS were evaluated with the Kaplan-Meier and Cox proportional hazard models. RESULTS: Seventeen (27%) patients received curative surgery, with the median follow-up duration being 638 days. Univariate analysis showed that patients at a low TNM stage (≦3, P = 0.041), high peak (P = 0.006), high ADCmin (P = 0.002) and low TLG (P = 0.01) had better OS. Moreover, high TLG/peak ratio was associated with poor OS (P = 0.016). Multivariate analysis indicated that ADCmin (P = 0.011) and TLG/peak ratio (P = 0.006) were independent predictors of OS after adjustment for age, gender, tumor size, and TNM stage. The TLG/peak ratio was an independent predictor of OS in a subgroup of patients who did not receive curative surgery (P = 0.013). CONCLUSION: The flow-metabolism mismatch reflected by the TLG/peak ratio may better predict OS than other imaging biomarkers from PET/MRI in pancreatic cancer patients.

Optimization of the Production of Covalently Circularized Nanodiscs and Their Characterization in Physiological Conditions.

Lipid nanodiscs are widely used platforms for studying membrane proteins in a near-native environment. Lipid nanodiscs made with membrane scaffold proteins (MSPs) in the linear form have been well studied. Recently, a new kind of nanodisc made with MSPs in the circular form, referred to as covalently circularized nanodiscs (cNDs), has been reported to have some possible advantages in various applications. Given the potential of nanodisc technology, researchers in the field are very interested in learning more about this new kind of nanodisc, such as its reproducibility, production yield, and the possible pros and cons of using it. However, research on these issues is lacking. Here, we report a new study on nanodiscs made with circular MSPs, which are produced from a method different from the previously reported method. We show that our novel production method, detergent-assisted sortase-mediated ligation, can effectively avoid high-molecular-weight byproducts and also significantly improve the yield of the target proteins up to around 80% for larger circular MSP constructs. In terms of the application of circular MSPs, we demonstrate that they can be used to assemble nanodiscs using both synthetic lipids and native lipid extract as the source of lipids. We also show that bacteriorhodopsin can be successfully incorporated into this new kind of cND. Moreover, we found that cNDs have improved stability against both heat and high-concentration-induced aggregations, making them more beneficial for related applications.

A novel photodynamic therapy-based drug delivery system layered on a stent for treating cholangiocarcinoma.

This study aimed to investigate the drug delivery efficacy and bio-effectiveness of a novel photodynamic therapy (PDT)-matrix drug delivery system for cholangiocarcinoma (CCA). Metallic stents were coated with polyurethane (PU) as the first layer. A 2-hydroxyethyl methacrylate (2-HEMA)/ethylene glycol dimethacrylate (EGDMA)/benzoyl peroxide (BPO) layer and a poly(ethylene-co-vinyl acetate) (PEVA)/poly(n-butyl methacrylate) (PBMA)/polyvinylpyrrolidone K30 (K30) layer containing various concentrations of Photofrin were then incorporated onto the stent as the second and third layers. After incubating the layered membranes with cultured CCA cell line, the release of Photofrin, cell viability, the intracellular uptake of Photofrin, reactive oxygen species (ROS) generation, and apoptosis were determined. Using a single-layer diffusion model, the maximum release of Photofrin from the 5 to 10% K30 formulas was 80 and 100%, respectively, after 24 h. When using the multiple-layer diffusion model, the released Photofrin showed an initial burst of the loading dose from the PEVA/PBMA/K30 layer. In the immobilized model, less than 5% of the Photofrin from the 2-HEMA/EGDMA/BPO layer was released over the 24-h period. Cell viability decreased linearly with increasing Photofrin concentrations, and ROS generation and apoptosis were shown to increase significantly with increasing Photofrin concentrations, until the concentration of Photofrin reached a saturation point of 1.5 µg/ml. This new, multiple-layered, PDT-based stent with dual-release mechanisms is a promising treatment for CCA and cancer-related ductal stenosis.

Correction: Chon-Kit Chou, et al. The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases. Int. J. Mol. Sci. 2017, 18, 483.

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The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases.

Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-ß receptor-signaling pathways by deubiquitinating the TGF-ß receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-ß target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson's disease, virus infection, and cancer-related signaling networks.

Clinical Significance of Circulating Tumor Microemboli as a Prognostic Marker in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Characterization of circulating tumor cells (CTCs) has been used to provide prognostic, predictive, and pharmacodynamic information in many different cancers. However, the clinical significance of CTCs and circulating tumor microemboli (CTM) in patients with pancreatic ductal adenocarcinoma (PDAC) has yet to be determined. METHODS: In this prospective study, CTCs and CTM were enumerated in the peripheral blood of 63 patients with PDAC before treatment using anti-EpCAM (epithelial cell adhesion molecule)-conjugated supported lipid bilayer-coated microfluidic chips. Associations of CTCs and CTM with patients' clinical factors and prognosis were determined. RESULTS: CTCs were abundant [mean (SD), 70.2 (107.6)] and present in 81% (51 of 63) of patients with PDAC. CTM were present in 81% (51 of 63) of patients with mean (SD) 29.7 (1101.4). CTM was an independent prognostic factor of overall survival (OS) and progression free survival (PFS). Patients were stratified into unfavorable and favorable CTM groups on the basis of CTM more or less than 30 per 2 mL blood, respectively. Patients with baseline unfavorable CTM, compared with patients with favorable CTM, had shorter PFS (2.7 vs 12.1 months; P < 0.0001) and OS (6.4 vs 19.8 months; P < 0.0001). Differences persisted if we stratified patients into early and advanced diseases. The number of CTM before treatment was an independent predictor of PFS and OS after adjustment for clinically significant factors. CONCLUSIONS: The number of CTM, instead of CTCs, before treatment is an independent predictor of PFS and OS in patients with PDAC.