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Background: Regional analgesia has been recommended to alleviate pain caused by hip fractures. Both the supra-inguinal fascia iliaca block (S-FIB) and the peri‑capsular nerve group (PENG) block provide better analgesia than conventional fascia iliaca block for patients with hip fractures, but which one is superior remains equivocal. This study aimed to determine the superiority of S-FIB or PENG block for patients awaiting hip surgery., Methods: In this prospective, double-blind, randomised comparative trial, patients with hip fractures awaiting operation were randomly allocated to receive either S-FIB with 30 ml 0.35 % ropivacaine or PENG block with 20 ml 0.35 % ropivacaine. Primary outcomes were pain scores (numeric rating scale, NRS, 0-10) at rest and during passive movement 30 min after nerve block. Secondary outcomes included pain scores at rest and during movement 10 and 20 min after nerve block and during positioning for spinal anaesthesia, time spent for performing nerve block and spinal anaesthesia, and the quality of positioning for spinal anaesthesia., Results: One-hundred patients were enrolled and 91 patients completed the trial (S-FIB group n = 46, PENG group n = 45). No significant difference was noted between these two groups in the pain scores (median [interquartile range]) either at rest (0 [0-0] vs 0 [0-0], P = 0.151) or during passive movement (3 [1-6] vs 3 [2-5], P = 0.99) at 30 min after nerve block. However, within-group analysis revealed that a significant reduction in pain score at rest was noted as early as 20 min after PENG block while that was noted only at 30 min after S-FIB. In addition, less time was required to perform PENG than S-FIB the block (3.1 [2.3-3.9] vs. 4.6 [3.1-5.6] minutes, P < 0.001)., Conclusions: Our result suggests that with a lower dose of local anaesthetic, a shorter procedure time and earlier analgesic effect, PENG block may be preferred to S-FIB for patients with hip fracture awaiting surgery., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background & Aims: Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after achieving sustained virologic response at off-treatment week 12 (SVR12) using direct-acting antivirals (DAAs) for HCV., Methods: A total of 1,598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC after achieving SVR12. MASLD was defined as presence of controlled attenuation parameter (CAP) ≥248 dB/m and ≥1 cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping., Results: The incidence rate of HCC was 1.44 per 100 person-years of follow-up (95% CI 1.19-1.74). Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p <0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, liver stiffness measurement, platelet count, and AFP, MASLD (adjusted hazard ratio 2.07; 95% CI 1.36-3.16; p <0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution hazard ratio of 2.07 (95% CI 1.34-3.19, p <0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development., Conclusion: After achieving SVR12, patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect of MASLD on HCC remain crucial for this population., Impact and Implications: The risk of de novo hepatocellular carcinoma (HCC) among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after attaining a sustained virologic response to direct-acting antivirals remains to be confirmed. In this study, recruiting 1,598 patients in Taiwan, individuals with MASLD had an approximately two-fold increased risk of de novo HCC compared to those without MASLD after achieving a sustained virologic response. MASLD significantly mediated cardiometabolic risk factors for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control cardiometabolic risk factors in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication., Competing Interests: Conflicts of interest All authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To develop and validate the Mobile Adherence Satisfaction Scale (MASS) for assessing user satisfaction with mobile health applications aimed to improve medication adherence., Methods: The study involved patients over 18 with asthma, hypertension, heart failure, or diabetes, who used the CareAide® app for six months. Scale development included a literature review, expert consultations, and patient interviews, initially identifying 129 items. These were refined to 27 using a two-round Delphi technique and grouped into six dimensions: user interface, perceived usability, system quality, service quality, feature satisfaction, and general satisfaction. A pilot study with 30 participants further refined the model, which was then validated with 135 participants using exploratory and confirmatory factor analyses in SPSS 29 and SmartPLS 4. Data were collected via self-administered questionnaires., Results: A total of 135 complete questionnaires were analysed. Respondents had an average age of 66.7 years (SD = 11.6) with 42.2 % male (n = 57) and 57.8 % female (n = 78). After removal of an item due to cross loading, exploratory factor analysis resulted six dimensions and 26 items with Kaiser-Meyer-Olkin measure of 0.837 and Bartlett's Test of Sphericity (χ 2 (n = 325) = 2085.673, P < 0.001). The confirmatory factor analysis confirmed high reliability and validity: Cronbach's alpha values > 0.70 for each dimension and an overall alpha of 0.89, with Composite Reliability and Average Variance Extracted both >0.70 and >0.50, respectively, for each dimension. Structural model indicated a significant positive impact of user interface (β = 0.226, P = 0.006) and feature satisfaction (β = 0.230, P = 0.002) on general satisfaction, explaining 23.1 % of the variance (R 2  = 0.231)., Conclusion: The study developed and validated the MASS, a reliable tool for assessing user satisfaction with mHealth apps. User interface design and feature satisfaction are key for long-term engagement and consistent medication adherence., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The Assessment of Quality of Life - 6 Dimensions (AQoL-6D), a generic preference-based measure, is an appealing alternative to EQ-5D-5L for assessing health status in patients with chronic heart failure (HF), given its expanded scope. However, without a Malaysian value set, the AQoL-6D cannot generate health state utility values (HSUVs) to support local economic evaluations. This study intended to develop algorithms for predicting EQ-5D-5L HSUVs from AQoL-6D in an HF population., Methods: Cross-sectional data from a multicenter cohort of 419 HF outpatients were used. Both direct and indirect mapping approaches were attempted using 5 sets of explanatory variables and 8 models (ordinary least squares, Tobit, censored least absolute deviations, generalized linear model, 2-part model [TPM], beta regression-based model, adjusted limited dependent variable mixture model, and multinomial ordinal regression [MLOGIT]). The models' predictive performance was assessed through 10-fold cross-validated mean absolute error [MAE] and root mean squared error [RMSE]). Potential prediction bias was also examined graphically. The best-performing models, with the lowest RMSE and no bias, were then identified., Results: Among the models evaluated, TPM, which included age, sex, and 5 AQoL-6D dimension scores as predictors, appears to be the best-performing model for directly predicting EQ-5D-5L HSUVs from AQoL-6D. TPM yielded the lowest MAE (0.0802) and RMSE (0.1116), and demonstrated predictive accuracy for HSUVs >0.2 without significant bias. A MLOGIT model developed for response mapping had suboptimal predictive accuracy., Conclusions: This study developed potentially useful mapping algorithms for generating Malaysian EQ-5D-5L HSUVs from AQoL-6D responses among patients with HF when direct EQ-5D-5L data are unavailable., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Materials section., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases., Methods: We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients: 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States. The effects of using a population-mismatched control cohort are simulated by swapping the control cohorts used for each patient cohort, with or without the popmax computational strategy., Results: Population-matched classifications revealed a combined 62 pathogenic or likely pathogenic (P/LP) variants in 34 genes across both cohorts. Using a population-mismatched control cohort resulted in misclassification of non-P/LP variants as P/LP, driven by the absence of ancestry-specific rare variants in the control cohort. Popmax was more effective in alleviating misclassifications for the Singapore cohort than the US cohort., Conclusion: Underrepresented population groups can suffer from higher rates of false-positive P/LP results. Popmax can partially alleviate these misclassifications, but its efficacy still depends on the degree with which the population groups are represented in the control cohort., Competing Interests: Conflict of Interest Soo-Chin Lee reports grant support/research collaborations with Pfizer, Eisai, Taiho, ACT Genomics, Bayer, and MSD; advisory board/speaker invitations from Pfizer, Novartis, Astra Zeneca, ACT Genomics, Eli Lilly, MSD, Roche, Eisai, and Daiichi-Sankyo; conference support from Amgen, Pfizer and Roche, all of which are outside the submitted work. All other authors declare no conflicts of interest. The funders played no role in the design of the study, collection and analysis of data and decision to publish., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Thallium (Tl) is a non-essential metal mobilized through industrial processes which can lead to it entering the environment and exerting toxic effects. Plants are fundamental components of all ecosystems. Therefore, understanding the impact of Tl on plant growth and development is of great importance for assessing the potential environmental risks of Tl. Here, the responses of Arabidopsis thaliana to Tl were elucidated using physiological, genetic, and transcriptome analyses. Thallium can be absorbed by plant roots and translocated to the aerial parts, accumulating at comparable concentrations throughout plant parts. Genetic evidence supported the regulation of Tl uptake and movement by different molecular compartments within plants. Thallium primarily caused growth inhibition, oxidative stress, leaf chlorosis, and the impairment of K homeostasis. The disturbance of redox balance toward oxidative stress was supported by significant differences in the expression of genes involved in oxidative stress and antioxidant defense under Tl exposure. Reduced GSH levels in cad2-1 mutant rendered plants highly sensitive to Tl, suggesting that GSH has a prominent role in alleviating Tl-triggered oxidative responses. Thallium down-regulation of the expression of LCHII-related genes is believed to be responsible for leaf chlorosis. These findings illuminate some of the mechanisms underlying Tl toxicity at the physiological and molecular levels in plants with an eye toward the future environment management of this heavy metal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Alzheimer's disease (AD) has become one of the most prevalent neurodegenerative disorders among the elderly. The global cost of dementia is expected to reach US $2 trillion in 2030. In this systematic review, existing evidence on the cost of dementia specific to AD is appraised., Methods: A comprehensive search was done on 3 databases, namely PubMed, ScienceDirect, and Web of Science, to identify original cost-of-illness studies that only evaluate the economic burden of AD up to August 2022. The risk of bias in the studies was assessed using Consolidated Health Economic Evaluation Reporting Standards 2022 criteria. Cost articles without specifying etiology of AD or those in non-English were excluded., Results: Twelve of 5536 studies met the inclusion criteria. The total annual cost of AD per capita ranged from US $468.28 in mild AD to US $171 283.80 in severe AD. The cost of care raised nonlinearly with disease severity. Indirect caregiving cost represented the main contributor to societal cost in community-dwelling patients. When special caregiving accommodation was opted in daily care, it results in cost shifting from indirect cost to direct nonmedical cost. Formal caregiving accommodation caused increase in direct cost up to 67.3% of overall economic burden of the disease., Conclusions: AD exerts a huge economic burden on patients and caregivers. Overall rise of each cost component could be anticipated with disease deterioration. Choice of special caregiving accommodation could reduce caregiver's productivity loss but increase the direct nonmedical expenditure of the disease from societal perspective., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background/objective: Robotic pancreaticoduodenectomy in ampullary cancer has never been studied. This study aimed to clarify the feasibility and justification of robotic pancreaticoduodenectomy in ampullary cancer in terms of surgical risks, and oncologic and survival outcomes., Methods: A propensity score-matching comparison of robotic and open pancreaticoduodenectomy based on seven factors commonly used to predict the survival outcomes in ampullary cancer patients., Results: A total of 147 patients were enrolled, of which 101 and 46 underwent robotic and open pancreaticoduodenectomies, respectively. After propensity score-matching with a 2:1 ratio, 88 and 44 patients in the robotic and open pancreaticoduodenectomy groups were included. The operation time was of no significant difference after matching. The median intraoperative blood loss was much less in those who underwent robotic pancreaticoduodenectomy, both before (median, 120 vs. 320 c.c. P < 0.001) and after (100 vs. 335 mL P < 0.001) score-matching. There were no significant differences in terms of surgical risks, including surgical mortality, surgical morbidity, Clavien-Dindo severity classification, postoperative pancreatic fistula, delayed gastric emptying, post-pancreatectomy hemorrhage, chyle leak, bile leak, and wound infection, both before or after score-matching. The survival outcomes were also similar between the two groups, regardless of matching., Conclusions: Robotic pancreaticoduodenectomy for ampullary cancer is not only technically feasible and safe without increasing surgical risks, but also oncologically justifiable without compromising surgical radicality and survival outcomes., Competing Interests: Declaration of competing interest Bor-Shiuan Shyr, Shin-E Wang, Shih-Chin Chen, Yi-Ming Shyr, Bor-Uei Shyr have no conflicts of interest or financial ties to disclose., (Copyright © 2024 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Cadmium (Cd) is a prevalent heavy metal contaminant that can cause centrosome amplification (CA) and cancer. Since CA can initiate tumorigenesis, it is plausible that cadmium initiates tumorigenesis via CA. The present study investigated the signaling pathways underlying CA by Cd. Our findings confirmed that sub-toxic concentrations of Cd could induce CA in the HCT116 colon cancer cells, and revealed that reactive oxygen species (ROS), GCLM, CCDC85C and PLK4 were the signaling molecules that formed a pathway of ROS-GCLM-CCDC85C-PLK4. Cd not only increased the protein levels of CCDC85C and PLK4, but also promoted their distribution to the centrosomes. Molecular docking analysis revealed that CCDC85C and PLK4 had the binding potential. Indeed, antibodies against CCDC85C and PLK4 were able to pull down PLK4 and CCDC85C, respectively. Knockdown of CCDC85C decreased the Cd-promoted centrosomal distribution of PLK4. Similarly, knockdown of PLK4 reduced the centrosomal distribution of CCDC85C. Our results suggest that Cd activates ROS-GCLM pathway that triggers the expression of and binding between CCDC85C and PLK4, and promotes the translocation of CCDC85C-PLK4 complex to the centrosomes, which eventually leads to CA., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The outbreak of SARS-CoV-2 infections had led to the COVID-19 pandemic which has a significant impact on global public health and the economy. The spike (S) protein of SARS-CoV-2 contains the receptor binding domain (RBD) which binds to human angiotensin-converting enzyme 2 receptor. Numerous RBD-based vaccines have been developed and recently focused on the induction of neutralizing antibodies against the immune evasive Omicron BQ.1.1 and XBB.1.5 subvariants. In this preclinical study, we reported the use of a direct fusion of the type IIb Escherichia coli heat-labile enterotoxin A subunit with SARS CoV-2 RBD protein (RBD-LTA) as an intranasal vaccine candidate. The results showed that intranasal immunization with the RBD-LTA fusion protein in BALB/c mice elicited potent neutralizing antibodies against the Wuhan-Hu-1 and several SARS-CoV-2 variants as well as the production of IgA antibodies in bronchoalveolar lavage fluids (BALFs). Furthermore, the heterologous RBD representing the same strains used in the bivalent mRNA vaccine were used as a second-dose RBD-LTA/RBD protein booster after bivalent mRNA vaccination. The results showed that the neutralizing antibody titers elicited by the intranasal bivalent RBD-LTA/RBD protein booster were similar to the intramuscular bivalent mRNA booster, but the RBD-specific IgA titers in sera and BALFs significantly increased. Overall, this preclinical study suggests that the RBD-LTA fusion protein could be a promising candidate as a mucosal booster COVID-19 vaccine., Competing Interests: Declaration of competing interest The National Tsing Hua University has filed a patent application on the RBD-based COVID-19 mucosal vaccine candidates., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inflammation is implicated in the development of diabetic complications including vascular pathology. Centrosome is known to play a role in cell secretion. We have reported that diabetes can trigger centrosome amplification (CA). Thus, in the present study, we investigated the relationship between CA and the release of proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6 in hCMEC/D3 human endothelial cells treated with advanced glycation end products (AGEs). We found that AGEs induced CA via PLK4 and increased the biosynthesis of the three cytokines via NF-κB. Importantly, treatment of the cells with AGEs also increased the release of the three cytokines. Inhibiting CA by knockdown of polo like kinase 4 (PLK4) attenuated the cytokine release but not their biosynthesis. Knockdown of the cytokines inhibited the CA, while addition of the cytokines individually to the cell culture increased the protein level of PLK4 and CA to a moderate level. Addition of the three cytokines together into the cell culture markedly enhanced the CA, to a level higher than that in the AGEs-treated group. In conclusion, our results provide the direct evidence that the cytokines can induce CA, and suggest that there is a mutual promoting cycle between CA and cytokine release in the treated samples. It is proposed that the cycle of CA-cytokine release is a candidate biological link between diabetes and its complications such as vascular pathologies., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The pathogenesis of acute respiratory distress syndrome (ARDS) is attributed to the dysregulation of oxidative stress and neutrophil recruitment. We aimed to investigate the anti-inflammatory effects of apremilast on human neutrophils and assess its efficacy for treating ARDS., Methods: We analysed superoxide anion generation, integrin expression, and adhesion in activated human neutrophils using spectrophotometry, flow cytometry, and immunofluorescence microscopy. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined using immunoblotting. A murine lipopolysaccharide (LPS)-induced ARDS model was used to evaluate the therapeutic effects of apremilast., Results: Apremilast significantly decreased superoxide anion production, reactive oxygen species (ROS) generation, cluster of differentiation (CD)11 b expression, and neutrophil adhesion in formyl-l-methionyl-l-leucyl-l-phenylalanine activated human neutrophils. Apremilast elevated cyclic 3',5'-adenosine monophosphate (cAMP) and protein kinase A (PKA) activity in activated neutrophils. It reduced cellular cAMP-specific phosphodiesterase (PDE) activity and selectively inhibited enzymatic PDE4 activity. The activated cAMP/PKA pathway suppressed the phosphorylation of ERK and JNK as well as Ca 2+ mobilization in activated neutrophils. All inhibitory effects of apremilast on activated neutrophils were reversed by a PKA inhibitor. In vivo examinations indicated that apremilast alleviated lung neutrophil infiltration, myeloperoxidase (MPO) activity, pulmonary oedema, and alveolar damage in LPS-induced ARDS., Conclusion: Apremilast inhibits inflammatory responses after neutrophil activation via cAMP/PKA-dependent inhibition of ERK and JNK activation. Our study revealed apremilast suppresses oxidative stress and chemotaxis by selectively inhibiting PDE4 in neutrophils and thus protects against endotoxin-induced ARDS in mice. Apremilast can be used as an alternative off-label drug in treating acute lung damage., Competing Interests: Conflicts of Interest None., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Aims: Infiltration of activated neutrophils into the lungs is a hallmark of acute respiratory distress syndrome (ARDS). Neutrophilic inflammation, particularly neutrophil extracellular traps (NETs), is proposed as a useful target for treating ARDS. Carnosic acid (CA) is a food additive; however, its anti-neutrophilic activity in the treatment of ARDS has not been well established. The hypothesis of present study is to confirm that CA alleviates ARDS by suppressing neutrophilic inflammation and oxidative damage., Main Methods: Generation of superoxide anions and reactive oxygen species (ROS), induction of elastase degranulation, and formation of NETs by human neutrophils were assayed using spectrophotometry, flow cytometry, and immunofluorescent microscopy. Immunoblotting was performed to determine the cellular mechanisms involved. Cell-free radical systems were used to test antioxidant activities. The therapeutic effect of CA was evaluated in a lipopolysaccharide (LPS)-induced ARDS mouse model., Key Findings: CA greatly reduced superoxide anion production, ROS production, elastase release, cluster of differentiation 11b expression, and cell adhesion in activated human neutrophils. Mechanistic studies have demonstrated that CA suppresses phosphorylation of extracellular regulated kinase and c-Jun N-terminal kinase in activated neutrophils. CA effectively scavenges reactive oxygen and nitrogen species, but not superoxide anions. This is consistent with the finding that CA is effective against ROS-dependent NET formation. CA treatment significantly improved pulmonary neutrophil infiltration, oxidative damage, NET formation, and alveolar damage in LPS-induced mice., Significance: Our data suggested the potential application of CA for neutrophil-associated ARDS therapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: This review explores the cost-effectiveness of the strategies used in the breast cancer early detection programs of low- to middle-income countries., Methods: A systematic review was performed to identify related studies, published up to August 2021, on PubMed, Cochrane, ProQuest, and the Cumulative Index to Nursing and Allied Health Literature. The Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol were referenced during the reporting process. The Consolidated Health Economic Evaluation Reporting Standards 2022 criteria were used to assess the requirements of the selected studies. Articles with original data and full texts were included in the review. Non-low- to middle-income countries and non-English articles were excluded., Results: This review identified 12 suitable studies, wherein 6 investigated the cost-effectiveness of clinical breast examinations (CBEs), whereas 10 looked into mammogram (MMG) with or without CBE. In 2 studies, the cost-effectiveness of raising awareness through mass media and the use of ultrasounds combined with CBE were investigated. Although cost-effective, MMG incurs greater costs and requires more skill to be performed. MMG screenings before the age of 40 years were not cost-effective. The limitations of this review include variability in the methodological approaches of its selected studies. Most of the chosen studies met the Consolidated Health Economic Evaluation Reporting Standards 2022 criteria., Conclusions: This review shows that adopting an age- and risk-based MMG screening approach could be viable in countries with limited resources. Future cost-effectiveness analysis research should include a section on patient and stakeholder engagement with the study's results., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Hexavalent chromium can promote centrosome amplification (CA) as well as tumorigenesis. Since CA can lead to tumorigenesis, it is plausible that the chromium promotes the development of cancer via CA. In the present study, we investigated the signaling pathways of the chromium-induced CA., Results: Our results showed that sub-toxic concentration of chromium was able to cause CA in HCT116 cells, and decrease the expression of TMOD2 and NPM2. Furthermore, TMOD2 and NPM2 interacted to each other via their C-terminal and the N-terminal, respectively, which was inhibited by the chromium. Overexpression of TMOD2 and NPM2 increased their binding and significantly attenuated the CA. Moreover, TMOD2 and NPM2 were co-localized with the centrosomes. The chromium inhibited the centrosomeal localization of NPM2, which was reversed by the overexpression of TMOD2, C-terminal of TMOD2, but not the N-terminal of NPM2., Conclusion: Our results suggest that the chromium induces CA via inhibiting the binding between TMOD2 and NPM2 as well as the dissociation of NPM2 from centrosomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fetal growth restriction (FGR) is one of the most common obstetric diseases, and affects approximately 10 % of all pregnancies worldwide. Maternal cadmium (Cd) exposure is one of the factors that may increase the risk of the development of FGR. However, its underlying mechanisms remain largely unknown. In this study, using Cd-treated mice as an experimental model, we analyzed the levels of some nutrients in the circulation and the fetal livers by biochemical assays; the expression patterns of several key genes involved in the nutrient uptake and transport, and the metabolic changes in the maternal livers were also examined by quantitative real-time PCR and gas chromatography-time of flight-mass spectrometry method. Our results showed that, the Cd treatment specifically reduced the levels of total amino acids in the peripheral circulation and the fetal livers. Concomitantly, Cd upregulated the expressions of three amino acid transport genes (SNAT4, SNAT7 and ASCT1) in the maternal livers. The metabolic profiling of maternal livers also revealed that, several amino acids and their derivatives were also increased in response to the Cd treatment. Further bioinformatics analysis indicated that the experimental treatment activated the metabolic pathways, including the alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine biosynthesis, arginine and proline metabolism. These findings suggest that maternal Cd exposure activate the amino acid metabolism and increase the amino acid uptake in the maternal liver, which reduces the supply of amino acids to the fetus via the circulation. We suspect that this underlies the Cd-evoked FGR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objective: Pancreatic neuroendocrine tumors (P-NETs) are highly heterogeneous with wide spectrum of biological behaviors and growth patterns. Here, we aimed to assess the impact of tumor grading on P-NETs prognosis and survival outcomes., Methods: Patients with P-NET were recruited to determine correlations between grades and clinicopathological factors, survival outcomes and prognostic factors., Result: A total of 152 patients with P-NETs were enrolled. G1 P-NET were associated with significantly lower rates of perineural invasion, lymphovascular invasion, lymph node involvement and distant metastasis. The pancreatic head was the most common location of P-NETs. The 1-year, 5-year and 10-year overall survival rates of the patients were 94.4%, 89.1% and 78.8%, respectively. Majority of pancreatic neuroendocrine carcinoma (P-NEC) were unresectable (90.9%), and P-NECs patients had poor survival rates (1-year, 20% and no 5-year). Male sex, tumor size ≥2.5 cm, perineural invasion, lymph node invasion, metastasis, and advanced stage were significantly associated with poorer survival outcomes. Tumor grade and sex were independent survival predictors. Moreover, tumor grade was the most powerful prognostic factor., Conclusions: Tumor grade, sex, perineural invasion, tumor size, lymph node involvement, metastasis, and stage are survival predictors for patients with P-NETs. Tumor grade is the most powerful independent prognostic factor., Competing Interests: Declaration of competing interest Bor-Shiuan Shyr, Bor-Uei Shyr, Shih-Chin Chen, Yi-Ming Shyr, Shin-E Wang have no conflicts of interest or financial ties to disclose., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Uniparental disomy (UPD) is the inheritance of both homologous chromosomes from a single parent. Most chromosomes involving UPD have no pathogenic effects. However, abnormal phenotypes in cases with UPD can be mainly caused by disrupting genetic imprinting and by uncovering harmful autosomal recessive mutations. The documented phenotypes of UPD associated with imprinted genes include maternal UPD for chromosomes 7, 11, 14, 15, 16, and 20, and paternal UPD for chromosomes 6, 11, 14, 15, and 20. Prenatal awareness of UPD is important to provide accurate genetic counseling and prenatal UPD test is suggested when abnormal fetal ultrasound with suspicious phenotypes for UPD syndromes caused by genetic imprinting disorders or presence of chromosomal aberrations involving the imprinted chromosomes., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background/objective: This study is to assess immunological and graft survival outcomes after pancreas transplant at a single institute in Asia., Methods: Patients undergoing pancreas transplant with enteric drainage were included. Clinical data and outcomes were evaluated and compared between each subgroup., Results: There were 165 cases of pancreas transplant, including 38 (23 %) simultaneous pancreas-kidney transplant (SPK), 24 (15 %) pancreas after kidney transplant (PAK), 75 (46 %) pancreas transplant alone (PTA), and 28 (17 %) pancreas before kidney transplant (PBK). The overall surgical complication rate was 46.1 %, with highest (62.5 %) in PAK and lowest (32.0 %) in PTA, P = 0.008. The late complications included 32.7 % infection and 3.6 % malignancy. Overall rejection of pancreas graft was 24.8 % including 18.2 % acute and 9.7 % chronic rejection. Rejection was highest in PTA group (36.0 %) and lowest in PBK (3.6 %). There were 56 cases (33.9 %) with graft loss in total, with highest graft loss rate in PTA (38.7 %). The 1-year, 5-year and 10-year pancreas graft survivals for total patients were 98.0 %, 87.7 % and 70.9 % respectively., Conclusions: Enteric drainage in pancreas transplant could be applied safely not only in SPK but also in other subgroups. Enteric drainage itself would not compromise the immunological and graft survival outcomes., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Acute respiratory distress syndrome (ARDS) is difficult to treat and is associated with a high mortality rate. The most severe form of coronavirus disease 2019 (COVID-19) also leads to life-threatening ARDS. Neutrophil counts are positively correlated with disease severity in ARDS. Neutrophil activation not only plays a significant role in immune defense against infections, but also causes tissue damage and leads to inflammatory diseases. Activated neutrophils rapidly migrate to inflamed lung tissue, releasing toxic granular contents and generating neutrophil extracellular traps. In the last few decades, it has become apparent that neutrophils occupy a central role in ARDS pathology. In this review, we summarize the neutrophil inflammatory responses and their relationships to ARDS. According to the current literature, understanding the function of neutrophils may be helpful in the treatment of ARDS., Competing Interests: Conflicts of interest The authors declare no competing financial interests., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Accumulated evidence from genetically modified cell and animal models indicates that centrosome amplification (CA) can initiate tumorigenesis with metastatic potential and enhance cell invasion. Multiple human diseases are associated with CA and carcinogenesis as well as metastasis, including infection with oncogenic viruses, type 2 diabetes, toxicosis by environmental pollution and inflammatory disease. In this review, we summarize (1) the evidence for the roles of CA in tumorigenesis and tumor cell invasion; (2) the association between diseases and carcinogenesis as well as metastasis; (3) the current knowledge of CA in the diseases; and (4) the signaling pathways of CA. We then give our own thinking and discuss perspectives relevant to CA in carcinogenesis and cancer metastasis in human diseases. In conclusion, investigations in this area might not only identify CA as a biological link between these diseases and the development of cancer but also prove the causal role of CA in cancer and progression under pathophysiological conditions, potentially taking cancer research into a new era., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The lysophospholipase D autotaxin (ATX) generates lysophosphatidic acid (LPA) that activates six cognate G-protein coupled receptors (GPCR) in cancerous cells, promoting their motility and invasion. Four novel compounds were generated aided by molecular docking guided design and synthesis techniques to obtain new dual inhibitors of ATX and the lysophosphatidic acid receptor subtype 1 (LPAR1). Biological evaluation of these compounds revealed two compounds, 10 and 11, as new ATX enzyme inhibitors with potencies in the range of 218-220 nM and water solubility (>100 µg/mL), but with no LPAR1 inhibitory activity. A QSAR model was generated that included four newly designed compounds and twenty-one additional compounds that we have reported previously. The QSAR model provided excellent predictability of the pharmacological activity and potency among structurally related drug candidates. This model will be highly useful in guiding the synthesis of new ATX inhibitors in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors., Methods: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ 2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ 2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat., Results: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups., Conclusion: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest that is related to this submission., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: New developments in medications for metastatic breast cancer (MBC) can be of great benefit to patients, but unfortunately these medicines also increase expenditures. Cost-utility analyses (CUAs) are needed to allocate health resources properly, and health utility values are required to calculate quality-adjusted life years in those CUAs., Objective: The aims of this study were to measure health utility values for several MBC-related health states and certain breast cancer treatment-related grade 3/4 adverse drug reactions (ADRs). In addition, we examined whether different methods and respondents' characteristics would influence the utility values elicited., Methods: A cross-sectional survey was conducted. The visual analogue scale (VAS) and time trade-off (TTO) methods were used to measure health utilities. Four MBC and nine ADR health states were selected for evaluation based on literature review and expert opinion. Information about respondents' demographic and clinical characteristics were collected to examine the relationship between utilities and participant characteristics., Results: A total of 102 patients participated in this study. The TTO-elicited values were higher than the VAS-derived scores except for two MBC-related health states. Among the MBC health states assessed, the TTO preference score ranged from 0.04 (palliative MBC) to 0.62 (responding MBC). For grade 3/4 ADRs, the mean TTO-derived utility values ranged from 0.35 (nausea/vomiting) to 0.79 (fatigue). The ranking of the preference scores derived from the VAS was similar to that of the TTO-elicited scores., Conclusion: This study obtained health state utility values for MBC and grade 3/4 ADRs using both the TTO and the VAS, which provides useful data for future CUAs., Competing Interests: Declaration of competing interest All author declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia., Methods: A Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables., Results: Based on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY., Conclusion: The OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia., (Copyright © 2019 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Background/objective: There are no reports available on patient satisfaction and quality-of-life after robotic pancreaticoduodenectomy (RPD). This study aimed to evaluate not only surgical outcomes but also patient satisfaction after RPD., Methods: Prospectively collected data for RPD were analyzed for surgical outcomes. Questionnaires were sent to patients to assess patient satisfaction regarding RPD., Results: The study included 105 patients who underwent RPD, with 44 (41.9%) patients presenting with associated surgical complications. There were no significant differences between the without and with complication groups in median console time (390 min. Vs. 373 min.), blood loss (100 mL vs. 100 mL), and harvested lymph node number (14 vs. 15). There was no surgical mortality in this study. Major complications ≥ Clavien-Dindo III occurred in 7.6% of the total 105 RPD patients. The most common complication was chyle leakage (18.1%), followed by postoperative pancreatic fistula (5.7%), intra-abdominal abscess (4.8%), delayed gastric emptying (3.8%), and post pancreatectomy hemorrhage (3.8%). Almost all of the patients responded to this RPD-related survey with "fair" to "excellent" grades for all items, except 1 (<1%) poor grade for operation service and 2 (1.9%) "not good" grades for diet tolerance., Conclusions: RPD is a feasible procedure with acceptable surgical outcomes. This patient survey with high patient satisfaction rates indicates that RPD provides acceptable satisfaction results, and the robotic approach for a major operation such as RPD has probably a higher priority than cost concerns. RPD could be recommended not only to surgeons but also to patients in terms of surgical outcomes and patient satisfaction., (Copyright © 2019. Published by Elsevier Taiwan LLC.)

Background: Although at least 5 genes are implicated in Lynch Syndrome (LS), up to 50% of suspected cases are owing to undefined genes. We utilized next generation sequencing (NGS) to characterize the mutation profile of patients with cancer (CA) suspected to have LS., Patients and Methods: We enrolled 174 Asian patients with CA from our CA Genetics Clinic from 2000 to 2014 suspected to have LS, and obtained germline DNA for NGS using TruSight Cancer. Frameshift, nonsense, and known deleterious mutations were considered pathogenic. Polymorphisms ≤ 1% frequency in 1000 Genomes (Asian) were classified using established databases., Results: Of the 174 probands, 80.5% were Chinese, the median age at CA diagnosis was 45 years (range, 18-82 years), and 84.5% and 8.6% had colon and LS-like CA, respectively. Forty-seven of 100 evaluable colon CA probands had LS-like histopathologic features. Nineteen of 174 had family history fulfilling Amsterdam I/II Criteria, whereas the rest fulfilled Bethesda Guidelines. Thirty-one of 174 harbored pathogenic mutations with 10 in LS genes only, 20 in non-LS genes only, and 1 in both. Of the 11 with LS gene mutations, MLH1 was most commonly involved (n = 7), followed by MSH2, MSH6, and PMS2. Nine of 174 had pathogenic mutations diagnostic of alternative hereditary syndromes including 2 each in CDH1, APC, and BRCA1, and 1 each in BRCA2, SMAD4, and MUTYH. Ten unique mutations were detected in low-to-moderate penetrance genes: 6 individuals had a recurring novel KIT:c.2836C>T nonsense mutation (n = 3) or ERCC4:c.2169C>A nonsense mutation (n = 3) without LS gene mutation, which is of clinical interest., Conclusions: In this Asian study, NGS proved to be feasible in screening for causative mutations in patients with CA suspected to have LS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively. MBD4 is also involved in DNA damage response and transcriptional regulation. The interaction with other proteins is likely critical for understanding MBD4 functions. To identify novel proteins that interact with MBD4, we used tandem affinity purification (TAP) from HEK-293 cells. The MBD4-TAP fusion and its co-associated proteins were purified sequentially on IgG and calmodulin affinity columns; the final eluate was shown to contain MLH1 by western blotting, and MBD4-associated proteins were identified by mass spectrometry. Bands with molecular weight higher than that expected for MBD4 (˜66 kD) yielded peptides corresponding to MBD4 itself and the small ubiquitin-like molecule-1 (SUMO1), suggesting that MBD4 is sumoylated in vivo. MBD4 sumoylation was validated by co-immunoprecipitation in HEK-293 and MCF7 cells, and by an in vitrosumoylation assay. Sequence and mutation analysis identified three main sumoylation sites: MBD4 is sumoylated preferentially on K137, with additional sumoylation at K215 and K377. Patterns of MBD4 sumoylation were altered, in a DNA damage-specific way, by the anti-metabolite 5-fluorouracil, the alkylating agent N-Methyl-N-nitrosourea and the crosslinking agent cisplatin. MCF7 extract expressing sumoylated MBD4 displays higher thymine glycosylase activity than the unmodified species. Of the 67 MBD4 missense mutations reported in The Cancer Genome Atlas, 14 (20.9%) map near sumoylation sites. These results indicate that MBD4 is sumoylated in vivo in a DNA damage-specific manner, and suggest that sumoylation serves to regulate its repair activity and could be compromised in cancer. This study expands the role played by sumoylation in fine-tuning DNA damage response and repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The marsupialization of Stensen's duct after buccal cancer excision and free flap reconstruction has seldom been reported. In this study, we evaluated the alteration in Stensen's duct and parotid gland, without marsupialization or relocation, between the time of surgery and 24 months postoperatively to determine whether ductal management is needed in patients with buccal squamous cell carcinoma (BSCC)., Methods: Eighty-five patients with BSCC receiving primary radical surgery and free flap reconstruction were recruited. Alterations in Stensen's duct and parotid gland were assessed by computed tomography during the postoperative period., Results: The 81 males and 4 females enrolled in study had a tumor status of cT2 (n = 52, 61%) or cT3 (n = 33, 39%). In total, 52 (61%) patients received surgery alone, and 33 (39%) received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Stensen's duct on the affected side was significantly dilated compared to the non-affected side (p < 0.001). The difference in diameter of Stensen's duct between the surgery plus CCRT group and the surgery alone group was not significant (p > 0.05), indicating that changes in parotid gland occurred mainly due to surgery. In both the surgery and surgery plus CCRT groups, inflammation of parotid gland had regressed by 24 months., Conclusions: Stensen's duct in BSCC dilatation peaked in the 3rd month after surgery. Changes in parotid gland on the surgically treated side regressed into fatty change by 24 months after surgery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is one of the environmental pollutants, which has multiple toxic effects on fetuses and placentas. Placental fatty acid (FA) uptake and transport are critical for the fetal and placental development. We aimed to analyze the triglyceride (TG) level, the expression patterns of several key genes involved in FA uptake and transport, and the molecular mechanisms for the altered gene expressions in placentas in response to Cd treatment. Our results showed that the placental TG level was significantly decreased in the Cd-exposed placentas. Fatty acid transporting protein 1 (FATP1), FATP6 and fatty acid binding protein 3 (FABP3) were significantly down-regulated in the placentas from Cd-exposed mice. The expression level of phospho-p38 MAPK was increased by Cd treatment, while the protein level of total p38 MAPK remained unchanged. The expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) and the hypoxia-inducible factor-1α (HIF-1α) were significantly decreased in the Cd-exposed placentas. The methylation levels of the promoter regions of FATP1, FATP6 and FABP3 showed no significant differences between the treatment and control groups. In addition, the circulating non-esterified fatty acid (NEFA), total cholesterol (TC), and TG levels were not decreased in the maternal serum from the Cd-exposed mice. Therefore, our results suggest Cd exposure dose not reduce the maternal FA supply, but reduces the placental TG level. Cd treatment also downregulates the placental expressions of FATP1, FATP6 and FABP3, respectively associated with p38-MAPK, p38 MAPK/PPAR-γ and HIF-1α pathways., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Virus-like particle (VLP) technology is an attractive platform for the development of seasonal and pandemic influenza vaccines. Influenza VLPs can be obtained by the overexpression of HA, M1, NA, and/or M2 viral proteins in insect, mammalian, or plant cells. In this study, we reported to obtain highly immunogenic influenza VLPs by molecular incorporation with B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL). Since BAFF and APRIL act as homotrimers to interact with their receptors, we engineered the VLPs by direct fusion of BAFF or APRIL to the transmembrane anchored domain of H5HA gene. Results showed that immunizations with the HA-transmembrane anchored BAFF- or APRIL-VLPs only formulated in alum but not MPL adjuvant elicited significantly higher IgG titers in sera. However, only the BAFF-VLPs formulated in alum adjuvant elicited more broadly neutralizing antibodies against the homologous and two heterologous H5N1 clade/subclade viruses and conferred protective immunity against live virus challenges. As the multi-subtype influenza vaccines containing a variety of HA subtypes can confer broader protective immunity, we also obtained multi-subtype H5H7 BAFF-VLPs and H1H5H7 BAFF-VLPs and demonstrated that these multi-subtype BAFF-VLPs were able to induce the production of neutralizing antibodies against multiple HA subtypes. Our findings provided useful information for the development of highly immunogenic, multi-subtype influenza VLP vaccines., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The growth factor-like lipid mediator, lysophosphatidic acid (LPA), is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. The action of LPA is mediated through activation of multiple types of molecular targets, including six G protein-coupled receptors that are clear targets for drug development. However, the LPA signaling has been linked to pathological responses that include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis. Thus, a question arises: Can we harness, in an LPA-like drug, the many beneficial activities of this lipid without eliciting its dreadful actions? We developed octadecyl thiophosphate (OTP; subsequently licensed as Rx100), an LPA mimic with higher stability in vivo than LPA. This article highlights progress made toward developing analogs like OTP and exploring prosurvival and regenerative LPA signaling. We determined that LPA prevents cell death triggered by various cellular stresses, including genotoxic stressors, and rescues cells condemned to apoptosis. LPA 2 agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA 2 agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses.

The lipid mediator lysophosphatidic acid (LPA) in biological fluids is primarily produced by cleavage of lysophospholipids by the lysophospholipase D enzyme Autotaxin (ATX). LPA has been identified and abundantly detected in the culture medium of various cancer cell types, tumor effusates, and ascites fluid of cancer patients. Our current understanding of the physiological role of LPA established its role in fundamental biological responses that include cell proliferation, metabolism, neuronal differentiation, angiogenesis, cell migration, hematopoiesis, inflammation, immunity, wound healing, regulation of cell excitability, and the promotion of cell survival by protecting against apoptotic death. These essential biological responses elicited by LPA are seemingly hijacked by cancer cells in many ways; transcriptional upregulation of ATX leading to increased LPA levels, enhanced expression of multiple LPA GPCR subtypes, and the downregulation of its metabolic breakdown. Recent studies have shown that overexpression of ATX and LPA GPCR can lead to malignant transformation, enhanced proliferation of cancer stem cells, increased invasion and metastasis, reprogramming of the tumor microenvironment and the metastatic niche, and development of resistance to chemo-, immuno-, and radiation-therapy of cancer. The fundamental role of LPA in cancer progression and the therapeutic inhibition of the ATX-LPA axis, although highly appealing, remains unexploited as drug development to these targets has not reached into the clinic yet. The purpose of this brief review is to highlight some unique signaling mechanisms engaged by the ATX-LPA axis and emphasize the therapeutic potential that lies in blocking the molecular targets of the LPA system., (Copyright © 2018. Published by Elsevier Ltd.)

Scanning tunneling microscope (STM) is a powerful tool for studying the structural and electronic properties of materials at the atomic scale. The combination of low temperature and high magnetic field for STM and related spectroscopy techniques allows us to investigate the novel physical properties of materials at these extreme conditions with high energy resolution. Here, we present the construction and the performance of an ultrahigh vacuum 3 He fridge-based STM system with a 7 Tesla superconducting magnet. It features a double deck sample stage on the STM head so we can clean the tip by field emission or prepare a spin-polarized tip in situ without removing the sample from the STM. It is also capable of in situ sample and tip exchange and preparation. The energy resolution of scanning tunneling spectroscopy at T = 310 mK is determined to be 400 mK by measuring the superconducting gap with a niobium tip on a gold surface. We demonstrate the performance of this STM system by imaging the bicollinear magnetic order of Fe 1+x Te at T = 5 K., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Increased intracranial pressure (ICP) is a well-known complication after aneurysmal subarachnoid hemorrhage (aSAH). This study focused on the different temporal changes in ICP, mean arterial pressure, and cerebral perfusion pressure at the early stage of aSAH, throughout aneurysm embolization, and their effects on improvement in angiographic perfusion patterns., Methods: Twenty-seven patients with aSAH were evaluated who underwent coiling and cerebrospinal fluid (CSF) drainage. Diagnostic angiography was performed to confirm the presence and location of the vascular lesion. The transit time of the capillary filling phase was defined as a surrogate of cerebral perfusion. Capillary filling transit times were compared before and after CSF drainage. Univariate and multivariate analyses were performed to identify associations between different physical parameters and capillary filling transit times., Results: By univariate analysis, average capillary transit time before CSF drainage had a significant correlation with initial ICP (P = 0.0004; R 2  = 0.398) but not systemic pressure (mean arterial pressure or cerebral perfusion pressure). Improvement in capillary filling pattern (i.e., a decrease in angiographic capillary transit time after CSF drainage) was seen in patients with high initial ICP and correlated with ICP difference after ventricular drainage (P = 0.0001 and P < 0.0001, respectively). Using multivariate regression analysis, improved control in postprocedural ICP levels significantly correlated with angiographic evidence of improved cerebral perfusion (P = 0.0243)., Conclusions: Decreasing ICP by CSF drainage strongly correlated with improved cerebral microcirculation after aSAH. Further development of ICP control protocols that can provide better ICP management of patients with aSAH is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Simultaneous measurement of plant functional traits and the regeneration environment should shed light on the plant-environment interactions and feedbacks as secondary forest regenerates. However, little of such work has been done in the wet tropics, and even fewer studies have examined soil nutrients. We investigated whether plant functional traits and environmental variables explain the varied recovery of secondary forests in Singapore. Our study plots included three primary forest plots and eight approximately 60-year-old secondary forest plots regenerating from intensive agricultural activities. Using 35 seedling quadrats, we asked: Q1) How do environmental variables explain the variation in seedling functional traits observed in primary and secondary forests? Q2) How do seedling traits, adult traits and environmental variables relate and explain variation in species richness and stem density in secondary forests? We found that both light and soil fertility explained the shifts in plants functional traits from poorly recovering secondary forests to primary forests. Poor forest regrowth was correlated with high soil aluminum levels and lower leaf nitrogen concentrations. Low nutrients and high aluminum saturation were also negatively correlated with seedling species richness, but not stem density, in the secondary forests. Forest recovery is probably slowed by positive feedback between slower nutrient returns from slow decaying litter and further recruitment of nutrient conserving species, as indicated by positive correlations among adult leaf CN ratio, litter depth, soil CN ratio and quadrat level CN ratio. Plant functional traits are indicative of the strategies of successful seedlings and do not necessarily relate to overall forest recovery. Hence, while some specialist plant species are able to accrue high nutrients on degraded soils with aluminum toxicity and low nutrients, species richness on these soils was poor. This underscores the need to concurrently measure environmental variables and plant traits when investigating the mechanisms driving changes during forest recovery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

DNA nanostructures can show dynamic responses to molecular triggers for a wide variety of applications. While DNA sequence signal triggers are now well-established, there is a critical need for a broader diversity of molecular triggers to drive dynamic responses in DNA nanostructures. DNA aptamers are ideal; they can both seamlessly integrate into DNA nanostructure scaffolds and transduce molecular recognition into functional responses. Here, we report construction and optimization of a DNA origami nanobox locked by a pair of DNA double strands where one strand is a DNA aptamer targeting the malaria biomarker protein Plasmodium falciparum lactate dehydrogenase. The protein acts as the key which enables box opening. We observe highly specific protein-mediated box opening by both transmission electron microscopy and fluorescence. Aptamer-enabled DNA boxes have significant potential for enabling direct responses to proteins and other biomolecules in nanoscale diagnostics, drug delivery and sensing devices., (Copyright © 2018. Published by Elsevier Inc.)

Background and Objective: It is well demonstrated that adequate burns first aid treatment (BFAT) improves clinical outcomes for the injured but adequacy remains low in many studies. This study presents a twelve month assessment of the adequacy of burns first aid treatment for patients managed by the Burns Service, Royal Darwin Hospital (RDH)., Methods: Prospective study design of all patients managed by the Burns Service, Royal Darwin Hospital. Data were collated from two sources; RDH Burns Registry, and the Burns Registry of Australia and New Zealand (BRANZ). Inclusion criterion was all patients managed by the Burns Service, Royal Darwin Hospital for the period 1 January 2014-31 December 2014. Variables collected and analysed include: demographics, burn mechanism, burn wound depth and adequacy of and circumstances around first aid., Results: Overall 310 cases were analysed. Most injuries involved adults (68%), 19% Indigenous persons and 70% of all patients had their burn injury occur in the urban region. Adequate BFAT occurred in 41% of cases. Adults, contact burns and those where the burn injury occurred in the remote regions were less likely to receive adequate BFAT. Indigenous persons were less likely to attempt any BFAT at all and when they did receive BFAT it was more likely applied by an emergency responder or health professional., Conclusion: Overall adequacy of BFAT is low in the Top End of the Northern Territory. Remote dwellers and Indigenous persons are at increased risk of not applying or receiving adequate BFAT. The poor level of adequate BFAT demonstrated in this study suggests that the Top End community particularly remote and Indigenous persons would benefit from targeted BFAT education programs that are delivered in a culturally and linguistically appropriate fashion., (Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.)

Humans infected with H7N9 avian influenza viruses can result in severe pneumonia and acute respiratory syndrome with an approximately 40% mortality rate, and there is an urgent need to develop an effective vaccine to reduce its pandemic potential. In this study, we used a novel PELC/CpG adjuvant for recombinant H7HA (rH7HA) subunit vaccine development. After immunizing BALB/c mice intramuscularly, rH7HA proteins formulated in this adjuvant instead of an alum adjuvant elicited higher IgG, hemagglutination-inhibition, and virus neutralizing antibodies in sera; induced higher numbers of H7HA-specific IFN-γ-secreting T cells and antibody secreting cells in spleen; and provided improved protection against live virus challenges. Our results indicate that rH7HA proteins formulated in PELC/CpG adjuvant can induce potent anti-H7N9 immunity that may provide useful information for H7N9 subunit vaccine development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To investigate possible errors in T1 and T2 quantification via MR fingerprinting with balanced steady-state free precession readout in the presence of intra-voxel phase dispersion and RF pulse profile imperfections, using computer simulations based on Bloch equations., Materials and Methods: A pulse sequence with TR changing in a Perlin noise pattern and a nearly sinusoidal pattern of flip angle following an initial 180-degree inversion pulse was employed. Gaussian distributions of off-resonance frequency were assumed for intra-voxel phase dispersion effects. Slice profiles of sinc-shaped RF pulses were computed to investigate flip angle profile influences. Following identification of the best fit between the acquisition signals and those established in the dictionary based on known parameters, estimation errors were reported. In vivo experiments were performed at 3T to examine the results., Results: Slight intra-voxel phase dispersion with standard deviations from 1 to 3Hz resulted in prominent T2 under-estimations, particularly at large T2 values. T1 and off-resonance frequencies were relatively unaffected. Slice profile imperfections led to under-estimations of T1, which became greater as regional off-resonance frequencies increased, but could be corrected by including slice profile effects in the dictionary. Results from brain imaging experiments in vivo agreed with the simulation results qualitatively., Conclusion: MR fingerprinting using balanced SSFP readout in the presence of intra-voxel phase dispersion and imperfect slice profile leads to inaccuracies in quantitative estimations of the relaxation times., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Objects falling outside of the true elliptical field-of-view (FOV) in Propeller imaging show unique aliasing artifacts. This study proposes a de-aliasing approach to restore the signal intensities in Propeller images without extra data acquisition., Materials and Methods: Computer simulation was performed on the Shepp-Logan head phantom deliberately placed obliquely to examine the signal aliasing. In addition, phantom and human imaging experiments were performed using Propeller imaging with various readouts on a 3.0 Tesla MR scanner. De-aliasing using the proposed method was then performed, with the first low-resolution single-blade image used to find out the aliasing patterns in all the single-blade images, followed by standard Propeller reconstruction. The Propeller images without and with de-aliasing were compared., Results: Computer simulations showed signal loss at the image corners along with aliasing artifacts distributed along directions corresponding to the rotational blades, consistent with clinical observations. The proposed de-aliasing operation successfully restored the correct images in both phantom and human experiments., Conclusion: The de-aliasing operation is an effective adjunct to Propeller MR image reconstruction for retrospective restoration of aliased signals., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Virus-like particle (VLP) technology is an attractive platform for seasonal and pandemic influenza vaccine development. We previously showed that influenza VLPs can be modified using M2 fusion with molecular adjuvants such as Salmonella typhimurium flagellin (FliC) to enhance VLP immunogenicity. For this study, three types of chimeric VLPs were incorporated with FliC, granulocyte-macrophage colony-stimulating factor (GM-CSF), or both GM-CSF and FliC (GM-CSF/FliC) to enhance anti-influenza immunogenicity. Our results indicate that immunizations with the chimeric FliC VLPs and GM-CSF/FliC H5N1 VLPs elicited more potent and broadly neutralizing antibodies and neuraminidase-inhibiting antibodies in sera, and induced higher numbers of hemagglutinin-specific antibody-secreting cells and germinal center B cell subsets in splenoctyes. Immunization with the chimeric GM-CSF H5N1 VLPs induced stronger Th1 and Th2 cellular responses. The chimeric GM-CSF/FliC H5N1 VLP constructs were further obtained to include H7 or H1H7 bi- or tri-subtype. It is our hope that these findings provide useful information for developing multi-subtype influenza vaccines., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Enterovirus A71 (EV-A71) is responsible for epidemics of hand, foot and mouth disease (HFMD) in young children. To circumvent difficulties in obtaining clinical enterovirus isolates that might be contaminated with other viruses, a platform technology was developed to quickly generate vaccine virus strains based on the published enterovirus genomic sequences. A recombinant plasmid containing the full-length infectious cDNA clone of EV-A71 vaccine strain E59 was directly generated after transfecting the recombinant plasmid into Vero, RD or HEK293A cells, and phenotypic characteristics similar to the parental strain were observed. The cDNA-derived infectious EV-A71 virus grown in Vero cells produced relatively stable virus titers in both T-flasks and microcarrier culture systems. To evaluate the genetic stability of the cDNA-derived EV-A71 viruses, the immunodominant structural proteins, VP1 and VP2, of the recombinant EV-A71 viruses were sequenced and analyzed. The cDNA-derived EV-A71 virus showed weak pathogenicity in a human SCARB2 mouse model. These results show the successful generation of a recombinant virus derived from a published viral genomic sequence that demonstrated good genetic stability and viral yields, which could represent an efficient and safe vaccine strain for cGMP-grade manufacturing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to compare perioperative outcomes after Blumgart pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) for pancreatic-enteric reconstruction following pancreaticoduodenectomy., Methods: Data of patients undergoing Blumgart PJ and PG were retrieved from prospectively-collected database. Matched patients in each surgical groups were included based on the Callery risk scoring system for clinically relevant postoperative pancreatic fistula (CR-POPF) (grades B and C). Surgical parameters and risks were compared between these two groups., Results: A total of 206 patients undergoing PD were included. Blumgart PJ was associated with shorter postoperative hospital stay (median (range) 25 (10-99) vs. 27 (10-97) days, P = 0.022). There was no surgical mortality in the Blumgart PJ group, but a 4.9% perioperative mortality in the PG, P = 0.030. The CR-POPF by Blumgrt PG is significantly lower than that by PG for overall patients (7% vs. 20%, P = 0.007), especially for those in intermediate fistula risk zone (6% vs. 21%, P =0.048) and high fistula risk zone (14% vs. 47%, P=0.038)., Conclusions: Blumgart PJ is superior to PG in terms of pancreatic leakage and surgical mortality. Blumgart PJ can be recommended for pancreatic reconstruction after PD for all pancreatic remnant subtypes., (Copyright © 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis., (© 2014 by The American Society of Hematology.)

Innate immunity is classically defined as unable to build up immunological memory. Recently however, the assumption of the lack of immunological memory within innate immune responses has been reconsidered. Plants and invertebrates lacking adaptive immune system can be protected against secondary infections. It has been shown that mammals can build cross-protection to secondary infections independently of T-lymphocytes and B-lymphocytes. Moreover, recent studies have demonstrated that innate immune cells such as NK cells and monocytes can display adaptive characteristics, a novel concept for which the term trained immunity has been proposed. Several mechanisms are involved in mediating innate immune memory, among which epigenetic histone modifications and modulation of recognition receptors on the surface of innate immune cells are likely to play a central role., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: In multiple cervical root transection injuries, motor and sensory recovery has been demonstrated after repairing both dorsal and ventral roots with autologous grafts applied to the dorsal and ventral aspects, respectively. However, in clinical situations, autologous grafts may not be sufficient to repair both roots in this situation. In this study, the authors evaluated whether repairing ventral root alone is sufficient for simultaneous sensory and motor function recovery., Main Methods: In the transected group, the left 6th-8th cervical roots were pulled and transected at the spinal cord junction. In the repair group, the transected root was anastomosed to a single autologous nerve graft, which was inserted into the ventral horn through a pial incision. Acidic fibroblast growth factor mixed with fibrin glue was applied to the surgical area. Motor function, sensory function, cortical somatosensory evoked potentials (SSEPs), axon tracing, and CGRP(+) fibers were evaluated., Key Findings: The repaired rats exhibited simultaneous sensory and motor function recovery. At the 16th weeks, SSEPs reappeared in all animals of the repair group, but not in the transected group. Retrograde axon tracing demonstrated an increased number of sensory neurons in the dorsal root ganglia and regenerating nerve fibers in the dorsal horn. CGRP(+) fibers were significantly increased in the repair group and restricted to laminae I and II., Significance: This is the first report that in multiple root avulsions with insufficient grafts, repairing ventral roots alone leads to both sensory recovery and motor recovery. This finding may help patients with multiple cervical root avulsions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to present the incidence, prenatal and postnatal findings, and modes of ascertainment in chromosomal deletions detected at amniocentesis., Materials and Methods: We reviewed all the cases with chromosomal deletions, which were detected by amniocentesis in Mackay Memorial Hospital, Taipei, Taiwan, between January 1987 and December 2012. Data on the locations and types of deletion, reasons for performing amniocentesis, maternal age, gestational age at amniocentesis, fetal karyotypes, inheritance of deletions, and relative prenatal findings were collected., Results: Amniocentesis was performed in 33,305 cases within this period of time. Among these, 31 cases of chromosomal deletions were considered for the study. The mean gestational age at amniocentesis was 21.0 weeks (range from 15 weeks to 32 weeks) and the mean maternal age at amniocentesis was 32.1 years (range from 26 years to 37 years). Nineteen cases (61.3%) manifested fetal structural abnormalities on ultrasound, nine (29.0%) presented no ultrasound abnormalities, and three had an unknown status. The main modes of ascertainment included abnormal ultrasound findings in 10 cases (32.2%), advanced maternal age in 11 cases (35.5%), abnormal maternal serum screening results in six cases (19.6%), and other reasons in four cases (13.0%). Of the 27 cases with known inheritance, the deletion was inherited in two (6.6%) and de novo in 25 (92.6%). Males accounted for 11 (35.5%) and females for 20 (64.5%) cases. Chromosomal deletions are more often to occur in chromosomal 5(4 cases, 12.9%), chromosomal 18 (4 cases, 12.9%), chromosomal 4 (3 cases, 9.7%), chromosomal 7 (3 cases, 9.7%), chromosomal 10 (3 cases, 9.7%), chromosomal 11 (3 cases, 9.7%), and chromosomal 1 (2 cases, 6.5%). There were four cases of chromosomal mosaicism: two involved chromosome 5, one involved chromosome 10, and one involved chromosome 18. Twenty-three cases (74.2%) had terminal deletions and the other eight cases (26.7%) had interstitial-type deletions., Conclusion: In summary, we have presented the results of prenatal diagnosis for chromosomal deletions using amniocentesis. Chromosomal deletions are more likely to occur in females and more often in chromosomal 5p and 18q. Prenatal diagnosis at amniocentesis is frequently associated with advanced maternal age, abnormal ultrasound findings, and abnormal maternal serum screening. The frequency of ascertainment in chromosome deletion seems to be directly correlated with advanced maternal age and abnormal ultrasound findings. In cases with terminal deletions, prenatal ultrasound plays a more important role for prenatal diagnosis., (Copyright © 2014. Published by Elsevier B.V.)

Objectives: The aim of this study was to identify predictors for longterm survival following pancreaticoduodenectomy (PD) for pancreatic and other periampullary adenocarcinomas., Methods: Clinicopathological factors were compared between short-term (<5 years) and longterm (≥ 5 years) survival groups. Rates of actual 5-year and actuarial 10-year survival were determined., Results: There were 109 (21.8%) longterm survivors among a sample of 501 patients. Patients with ampullary adenocarcinoma represented 76.1% of the longterm survivors. Favourable factors for longterm survival included female gender, lack of jaundice, lower blood loss, classical PD, absence of postoperative bleeding or intra-abdominal abscess, non-pancreatic primary cancer, earlier tumour stage, smaller tumour size (≤ 2 cm), curative resection, negative lymph node involvement, well-differentiated tumours, and absence of perineural invasion. Independent factors associated with longterm survival were diagnosis of primary tumour, jaundice, intra-abdominal abscess, tumour stage, tumour size, radicality, lymph node status and cell differentiation. The prognosis was best for ampullary adenocarcinoma, for which the rate of actual 5-year survival was 32.8%, and poorest for pancreatic head adenocarcinoma, for which actual 5-year survival was only 6.5%., Conclusions: The majority of longterm survivors after PD for periampullary adenocarcinomas are patients with ampullary adenocarcinoma. The longterm prognosis in pancreatic head adenocarcinoma remains dismal., (© 2013 International Hepato-Pancreato-Biliary Association.)