Search

Liu CY, Wu JH, Chen ZY, et al. Int J Chron Obstruct Pulmon Dis. 2021;16:2375–2383. The Editor and Publisher of International Journal of Chronic Obstructive Pulmonary Disease are retracting the published article. Concerns were raised that the western blot results in Figure 6 had been duplicated with those from Figure 4 in Chen Z, Zhang Y, Wu J, Gao X, Huang C, Lin Y, Xu X, Li Y. The Mechanism of Penehyclidine Hydrochloride and Its Effect on the Inflammatory Response of Lung Tissue in Rats with Chronic Obstructive Pulmonary Disease During Mechanical Ventilation. Int J Chron Obstruct Pulmon Dis. 2021;16:877–885, https://doi.org/10.2147/COPD.S295329. Both sets of western blots are describing results from different studies. In addition, the image from Figure 2N was found to have been duplicated with the same image from Figure 1N from Chen Zy, Lin Ym, Wu Jh, et al. Effect of doxofylline on pulmonary inflammatory response and oxidative stress during mechanical ventilation in rats with COPD. BMC Pulm Med 22, 66 (2022), https://doi.org/10.1186/s12890-022-01859-6. The authors did not respond to our queries and as the findings could not be verified the Editor and Publisher made the decision to retract the article. The authors were notified of this decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Chu-Yun Liu,1 Jian-Hua Wu,1 Zhi-Yuan Chen,1 Yi Zhang,1 Chun-Ling Huang,2 Ai-Mei Lin,1 Xiao-Ting Xu,1 Xiao-Hua Gao1 1Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 2Department of Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People’s Republic of ChinaCorrespondence: Zhi-Yuan ChenDepartment of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People’s Republic of ChinaTel +86 595-26655108Fax +86 595-22770258Email chen_tyty@163.comObjective: To evaluate the effect of doxofylline on reducing the inflammatory response in mechanically ventilated rats with chronic obstructive pulmonary disease (COPD).Methods: A total of 40 eight-week-old male Sprague Dawley rats were randomly divided into four groups of 10 rats each: a control group (group C), a model group (group M), a model + natural saline group (group N), and a doxofylline group (group D). Then mechanical ventilation, drug intervention, and the extraction of the experimental material were performed in each group. Pulmonary tissue samples were taken after 120 minutes of mechanical ventilation and the pulmonary histopathological changes and the wet/dry (W/D) weight ratio of the pulmonary tissue were identified. The levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were detected using an enzyme-linked immunosorbent assay, and the expression levels of c-Jun-N-terminal kinase (JNK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using immunohistochemistry.Results: Compared with group C, the pulmonary histopathology in groups M, N, and D showed typical changes associated with COPD. Furthermore, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue increased in groups M, N, and D (P < 0.05), while the levels of IL-10 decreased (P < 0.05). Compared with group M, no statistically significant changes in the above indicators were detected in the pulmonary tissue of group N (P > 0.05). Compared with group N, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue decreased in group D (P < 0.05), while the levels of IL-10 increased (P < 0.05).Conclusion: Doxofylline might attenuate pulmonary inflammatory responses in mechanically ventilated rats with COPD, and the JNK/stress-activated protein kinase signaling pathway is involved in doxofylline’s inhibition of inflammatory responses in the pulmonary tissue of rats with COPD.Keywords: chronic obstructive pulmonary disease, TNF-α, IL-10, JNK, p-JNK

Newborn metabolite perturbations may identify potential biomarkers or mechanisms underlying adverse, smoking-related childhood health outcomes. We assessed associations between third-trimester smoking and newborn metabolite concentrations using the Tennessee Pregnancy Risk Assessment Monitoring System (PRAMS, 2009–2019) as the discovery cohort and INSPIRE (2012–2014) as the replication cohort. Children were linked to newborn screening metabolic data (33 metabolites). Third-trimester smoking was ascertained from birth certificates (PRAMS) and questionnaires (INSPIRE). Among 8600 and 1918 mother–child dyads in PRAMS and INSPIRE cohorts, 14% and 13% of women reported third-trimester smoking, respectively. Third-trimester smoking was associated with higher median concentrations of free carnitine (C0), glycine (GLY), and leucine (LEU) at birth (PRAMS: C0: adjusted fold change 1.11 [95% confidence interval (CI) 1.08, 1.14], GLY: 1.03 [95% CI 1.01, 1.04], LEU: 1.04 [95% CI 1.03, 1.06]; INSPIRE: C0: 1.08 [95% CI 1.02, 1.14], GLY: 1.05 [95% CI 1.01, 1.09], LEU: 1.05 [95% CI 1.01, 1.09]). Smoking cessation (vs. continued smoking) during pregnancy was associated with lower median metabolite concentrations, approaching levels observed in infants of non-smoking women. Findings suggest potential pathways underlying fetal metabolic programming due to in utero smoke exposure and a potential reversible relationship of cessation.

BackgroundResearch on health effects and potential harms of electronic cigarette (EC) use during pregnancy is limited. We sought to determine the risks of pregnancy EC use on pregnancy-related adverse birth outcomes and assess whether quitting ECs reduces the risks.MethodsWomen with singleton live births who participated in the US Pregnancy Risk Assessment Monitoring System (PRAMS) survey study 2016-2020 were classified into four mutually exclusive groups, by their use of ECs and combustible cigarettes (CCs) during pregnancy: non-use, EC only use, CC only use, and dual use. We determined the risk of preterm birth, low birth weight, and small-for-gestational-age (SGA) by comparing cigarette users to non-users with a modified Poisson regression model adjusting for covariates. In a subset of women who all used ECs prior to pregnancy, we determined whether quitting EC use reduces the risk of preterm birth, low birth weight, and SGA by comparing to those who continued its use. All analyses were weighted to account for the PRAMS survey design and non-response rate.ResultsOf the 190,707 women (weighted N = 10,202,413) included, 92.1% reported cigarette non-use, 0.5% EC only use, 6.7% CC only use, and 0.7% dual use during pregnancy. Compared with non-use, EC only use was associated with a significantly increased risk of preterm birth (adjusted risk ratio [aRR]: 1.29, 95% confidence interval [CI]: 1.00, 1.65) and low birth weight (aRR: 1.38, 95%CI: 1.09, 1.75), but not SGA (aRR: 1.04, 95%CI: 0.76, 1.44). Among 7,877 (weighted N = 422,533) women EC users, quitting use was associated with a significantly reduced risk of low birth weight (aRR: 0.76, 95%CI: 0.62, 0.94) and SGA (aRR: 0.77, 95%CI: 0.62, 0.94) compared to those who continued to use ECs during pregnancy.ConclusionsPregnancy EC use, by itself or dual use with CC, is associated with preterm birth and low birth weight. Quitting use reduces that risk. ECs should not be considered as a safe alternative nor a viable gestational smoking cessation strategy.

OBJECTIVES/GOALS: Children with Down syndrome are at increased risk of respiratory diseases including asthma. Prenatal antibiotic exposure has been shown to be associated with the development of childhood asthma. We aim to estimate the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome. METHODS/STUDY POPULATION: We conducted a retrospective cohort study of mother-child dyads of children with Down syndrome who were born 1995-2013. Both children and mothers were continuously enrolled in the Tennessee Medicaid Program (TennCare). Prenatal antibiotic exposure was measured using mother’s prescription fill records. Childhood asthma was defined between age 4.5-6 years by asthma-related healthcare encounters and asthma-specific medication fills. We assessed the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome using modified Poisson regression adjusting for maternal age, race, residence, education, marital status, smoking during pregnancy, maternal asthma status, delivery method, number of siblings, and children’s sex. RESULTS/ANTICIPATED RESULTS: Among 346 mother-child dyads of children with Down syndrome, 273 (78.9%) children were exposed prenatally to antibiotics and 104 (30.0%) had asthma by age 4.5-6 years. Among those who were exposed to at least one course, the median antibiotic course equaled 2 (interquartile range: 1-4). Prenatal antibiotic exposure was associated with a 20% increase in risk of childhood asthma in the unadjusted analysis (risk ratio [RR] 1.20, 95% confidence interval [CI] 0.78, 1.83) and a 26% increase in risk after adjustment (adjusted RR 1.26, 95% CI 0.79, 2.01). DISCUSSION/SIGNIFICANCE: In our study population, the majority of children with Down syndrome were exposed to antibiotics prenatally and the prevalence of asthma was high. Prenatal antibiotic exposure was associated with an increased risk of childhood asthma among children with Down syndrome; however, this increase was not statistically significant.

OBJECTIVES/GOALS: Nearly half of mothers who report electronic (e)-cigarette use during pregnancy believe e-cigarettes are less harmful than traditional cigarettes. We aim to determine the association of quitting e-cigarette use in pregnancy with the risk of preterm birth and low birth weight. METHODS/STUDY POPULATION: We conducted a cross-sectional study of women participating in the Pregnancy Risk Assessment Monitoring System and with live singleton birth during 2016-2019. Women were classified based on their e-cigarette use: before pregnancy only (quitters), last three months of pregnancy only (initiators), at both times (sustained users), and neither time (non-users). We used a modified Poisson regression to determine the association between quitting e-cigarette use and preterm birth (

Vivian Juang,1 Hsin-Pin Lee,2 Anya Maan-Yuh Lin,1,3 Yu-Li Lo1 1Department and Institute of Pharmacology, National Yang-Ming University, 2Department of Biological Sciences and Technology, National University of Tainan, 3Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Abstract: Antimicrobial peptides (AMPs) have been recently evaluated as a new generation of adjuvants in cancer chemotherapy. In this study, we designed PEGylated liposomes encapsulating epirubicin as an antineoplastic agent and tilapia hepcidin 2–3, an AMP, as a multidrug resistance (MDR) transporter suppressor and an apoptosis/autophagy modulator in human cervical cancer HeLa cells. Cotreatment of HeLa cells with PEGylated liposomal formulation of epirubicin and hepcidin 2–3 significantly increased the cytotoxicity of epirubicin. The liposomal formulations of epirubicin and/or hepcidin 2–3 were found to noticeably escalate the intracellular H2O2 and O2- levels of cancer cells. Furthermore, these treatments considerably reduced the mRNA expressions of MDR protein 1, MDR-associated protein (MRP) 1, and MRP2. The addition of hepcidin 2–3 in liposomes was shown to markedly enhance the intracellular epirubicin uptake and mainly localized into the nucleus. Moreover, this formulation was also found to trigger apoptosis and autophagy in HeLa cells, as validated by significant increases in the expressions of cleaved poly ADP ribose polymerase, caspase-3, caspase-9, and light chain 3 (LC3)-II, as well as a decrease in mitochondrial membrane potential. The apoptosis induction was also confirmed by the rise in sub-G1 phase of cell cycle assay and apoptosis percentage of annexin V/propidium iodide assay. We found that liposomal epirubicin and hepcidin 2–3 augmented the accumulation of GFP-LC3 puncta as amplified by chloroquine, implying the involvement of autophagy. Interestingly, the partial inhibition of necroptosis and the epithelial–mesenchymal transition by this combination was also verified. Altogether, our results provide evidence that coincubation with PEGylated liposomes of hepcidin 2–3 and epirubicin caused programmed cell death in cervical cancer cells through modulation of multiple signaling pathways, including MDR transporters, apoptosis, autophagy, and/or necroptosis. Thus, this formulation may provide a new platform for the combined treatment of traditional chemotherapy and hepcidin 2–3 as a new adjuvant for effective MDR reversal. Keywords: multidrug resistance, liposomes, antimicrobial peptide, epirubicin, apoptosis, autophagy

ABSTRACT IMPACT: Our study suggests that maternal e-cigarette use may reduce fetal growth and pose harm to newborns. OBJECTIVES/GOALS: Women are motivated to quit smoking during pregnancy. Many view electronic cigarettes (e-cigarettes) as a safer and healthier alternative to traditional tobacco smoke. We aim to determine the effect of third-trimester e-cigarette use on the risk of infant related outcomes. METHODS/STUDY POPULATION: We conducted a cross-sectional survey study using Pregnancy Risk Assessment Monitoring System (PRAMS). Women who gave live singleton births in 2016-2018 and at states that met response rate threshold criteria were included. Women were classified as never smokers, sole e-cigarette smokers, sole traditional cigarette smokers, and dual-users. Logistic regression was conducted to determine the association between third-trimester cigarette use and preterm birth (

We present an accuracy evaluation of a semiautomatic registration technique for 3D volume reconstruction from fluorescent confocal laser scanning microscope (CLSM) imagery. The presented semiautomatic method is designed based on our observations that (a) an accurate point selection is much harder than an accurate region (segment) selection for a human, (b) a centroid selection of any region is less accurate by a human than by a computer, and (c) registration based on structural shape of a region rather than based on intensity-defined point is more robust to noise and to morphological deformation of features across stacks. We applied the method to image mosaicking and image alignment registration steps and evaluated its performance with 20 human subjects on CLSM images with stained blood vessels. Our experimental evaluation showed significant benefits of automation for 3D volume reconstruction in terms of achieved accuracy, consistency of results, and performance time. In addition, the results indicate that the differences between registration accuracy obtained by experts and by novices disappear with the proposed semiautomatic registration technique while the absolute registration accuracy increases.

Thermal landfill leachate evaporator systems can reduce the volume of leachate by up to 97%, while releasing water vapor and producing residuals (volume-reduced leachate and sludge) that are managed on-site. On-site thermal evaporators offer landfill operators leachate management autonomy without being subject to increasingly stringent wastewater treatment plant requirements. However, little is known about the partitioning of PFAS within these systems, nor the extent to which PFAS may be emitted into the environment via vapor. In this study, feed leachate, residual evaporated leachate, sludge, and condensed vapor were sampled at two active full-scale thermal landfill leachate evaporators and from a laboratory-scale leachate evaporation experiment. Samples were analyzed for 91 PFAS via ultra-high pressure liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS). Similar trends were observed from Evaporator 1, Evaporator 2, and the laboratory-scale evaporator; ∑PFAS were concentrated in the residual evaporated leachate during evaporation by a factor of 5.3 to 20. All condensed vapors sampled (n = 5) contained PFAS, predominantly 5:3 fluorotelomer carboxylic acid (5:3FTCA), (full-scale vapors 729 - 4087 ng/L PFAS; lab-scale vapor 61.0 ng/L PFAS). For Evaporators 1 and 2, an estimated 9 - 24% and 10%, respectively, of the PFAS mass entering the evaporators in leachate was released with vapor during the days of sample collection. '., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. John A. Bowden reports financial support was provided by Hinkley Center for Solid and Hazardous Waste Management. Timothy G. Townsend reports a relationship with Hinkley Center for Solid and Hazardous Waste Management that includes: employment. Timothy G. Townsend is currently employed as Executive Director of the Hinkley Center for Solid and Hazardous Waste Management. This employment relationship began after funding was awarded for the research in this manuscript, and Timothy G. Townsend was not involved in the grant selection process which funded the work. Timothy G. Townsend’s involvement with the project was limited to manuscript revision and writing feedback. John A. Bowden, corresponding author, was the project principal investigator and primary decision-maker. If there are other authors, they 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 Elsevier B.V. All rights reserved.)

In recent years, soil screening levels have been adopted by regulatory agencies for certain per- and polyfluoroalkyl substances (PFAS) to assess the risk of groundwater contamination through leaching. These soil screening levels, determined using an established equilibrium-based partitioning equation, have high variability among regulatory groups largely attributed to the diverse reported partitioning coefficients in the literature. This variability between reported partitioning coefficients, and subsequently soil screening levels, is due to the complex leaching behavior of PFAS not being predicted well by the standard equilibrium-based model. This has led one regulatory group to require batch leaching to assess risk rather than setting default soil screening levels based on partitioning equations. In this work, we conducted leaching experiments on five field-sampled soils impacted by aqueous film-forming foams (AFFF), following Leaching Environmental Assessment Framework (LEAF) Method 1316 and compared the results to expected leaching utilizing an equilibrium-based partitioning equation commonly employed by regulatory agencies to establish soil screening levels. Our analysis found among the six PFAS detected in the soils, which have regulatory leaching thresholds established, the partitioning values assumed by the U.S. EPA exhibited the highest accuracy in predicting leachate concentrations. These partitioning values predicted actual leaching within a ± 20 % margin of error for approximately 50 % of sample points, highlighting limitations in relying solely on equilibrium-based partitioning values as predictors of leaching behavior. This discrepancy between predicted and actual leaching has implications for site managers and regulatory entities overseeing PFAS-contaminated sites, suggesting that soil screening level determinations for PFAS might need to be revised to account for the unique transport characteristics of PFAS., 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. Published by Elsevier B.V.)

Background: Patient recruitment for clinical trials faces major challenges with current methods being costly and often requiring time-consuming acquisition of medical histories and manual matching of potential subjects., Objectives: Designing and implementing an Electronic Health Record (EHR) and domain-independent automation architecture using Clinical Decision Support (CDS) standards that allows researchers to effortlessly enter standardized trial criteria to retrieve eligibility statistics and integration into a clinician workflow to automatically trigger evaluation without added clinician workload., Methods: Cohort criteria are translated into the Clinical Quality Language (CQL) and integrated into Measures and CDS-Hooks for patient- and population-level evaluation., Results: Successful application of simplified real-world trial criteria to Fast Healthcare Interoperability Resources (FHIR®) test data shows the feasibility of obtaining individual patient eligibility and trial details as well as population eligibility statistics and a list of qualifying patients., Conclusion: Employing CDS standards for automating cohort definition and evaluation shows promise in streamlining patient selection, aligning with increasing legislative demands for standardized healthcare data.

Background: Nipple-sparing mastectomy is commonly performed for breast cancer treatment or prevention. The authors present one of the largest breast reconstruction series in the literature., Methods: A single-institution retrospective review was conducted from 2007 to 2019., Results: The authors' query identified 3035 implant-based breast reconstructions after nipple-sparing mastectomy, including 2043 direct-to-implant and 992 tissue expander-to-implant reconstructions. The overall major complication rate was 9.15%, and the nipple necrosis rate was 1.20%. Therapeutic mastectomy was associated with higher overall complications and explantations compared with prophylactic mastectomy ( P < 0.01). In comparisons of unilateral and bilateral procedures, bilateral mastectomy had an increased risk for complications (OR, 1.46; 95% CI, 0.997 to 2.145; P = 0.05). Tissue-expander reconstructions had higher rates of nipple necrosis (1.9% versus 0.88%; P = 0.015), infection (4.2% versus 2.8%; P = 0.04), and explantation (5.1% versus 3.5%; P = 0.04) compared with direct-to-implant reconstruction. When assessing plane of reconstruction, the authors found similar rates of complications between subpectoral dual-plane and prepectoral reconstruction. There was no difference in complications between reconstruction with acellular dermal matrix or mesh compared with total or partial muscle coverage without acellular dermal matrix/mesh (OR, 0.749; 95% CI, 0.404 to 1.391; P = 0.361). Multivariable regression analysis revealed preoperative radiotherapy (OR, 2.465; 95% CI, 1.579 to 3.848; P < 0.001), smoking (OR, 2.53; 95% CI, 1.581 to 4.054; P < 0.001), and a periareolar incision (OR, 3.657; 95% CI, 2.276 to 5.875; P < 0.001) to be the strongest predictors of complications and nipple necrosis ( P < 0.05)., Conclusions: Nipple-sparing mastectomy and immediate breast reconstruction has a low rate of complications. In this series, radiation therapy, smoking, and incision choice predicted overall complications and nipple necrosis, whereas direct-to-implant reconstruction and acellular dermal matrix or mesh did not increase risk., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

This study analyzed spent activated carbon (AC) from a landfill gas (LFG) treatment system for an expanded suite of lesser studied volatile metals, revealing elevated levels of As and Sb in the LFG, exceeding those previously reported, with minimum average concentrations of 640 µg m -3 and 590 µg m -3 , respectively. The annual release of As and Sb through landfill gas was found to be significant, surpassing leachate emissions by an order of magnitude. Extrapolating these findings to all US landfills suggests that the release of As and Sb through landfill gas could be a major, previously overlooked source of these metals in global emission estimates, underscoring the need to include them when developing future inventories. The spent AC was further found to exceed US toxicity limits established for As, classifying it as hazardous waste under US regulations. However, findings suggest that the AC scrubber employed at the landfill effectively prevented substantial releases of As and Sb. This research emphasizes that landfill gas is a primary contributor to environmental release of As and Sb from landfills, even more so than leachate, highlighting the significance of implementing effective LFG treatment measures to mitigate the release of volatile metal emissions., 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.)

The environmental risks associated with the storage, reuse, and disposal of unencapsulated reclaimed asphalt pavement (RAP) has been previously examined, but because of a lack of standardized column testing protocols and recent interest on emerging constituents with higher toxicity, questions surrounding leaching risks from RAP continue. To address these concerns, RAP from six, discrete stockpiles in Florida was collected and leach tested following the most up-to-date, standard column leaching protocol - United States Environmental Protection Agency (US EPA) Leaching Environmental Assessment Framework (LEAF) Method 1314. Sixteen EPA priority polycyclic aromatic hydrocarbons (PAHs), 23 emerging PAHs, identified through relevance in literature, and heavy metals were investigated. Column testing showed minimal leaching of PAHs; only eight compounds, three priority PAHs and five emerging PAHs, were released at quantifiable concentrations, and where applicable, were below US EPA Regional Screening Levels (RSL). Though emerging PAHs were identified more frequently, in most cases, priority compounds dominated contributions to overall PAH concentration and benzo(a)pyrene (BaP) equivalent toxicity. Except for arsenic, molybdenum, and vanadium in two samples, metals were found below limits of detection (LOD) or below risk thresholds. Arsenic and molybdenum concentrations diminished over time with increased exposure to liquid, but elevated vanadium concentrations persisted in one sample. Further batch testing linked vanadium to the aggregate component of the sample, unlikely to be encountered in typical RAP sources. As demonstrated by generally low constituent mobility observed during testing, the leaching risks associated with the beneficial reuse of RAP are limited, and under typical reuse conditions, factors of dilution and attenuation would likely reduce leached concentrations below relevant risk-based thresholds at a point of compliance. When considering emerging PAHs with higher toxicities, analyses indicated minimal impact to overall leachate toxicity, further suggesting that with proper management, this heavily recycled waste stream is unlikely to pose leaching risk., 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 Ltd. All rights reserved.)

Introduction: The obesity epidemic is an important public health problem in the United States. Previous studies have revealed the association between obesity and various surgical complications. Tracheostomy which is an important lifesaving procedure may prove technically challenging in an obese patient. This study sought to evaluate the association between obesity and early complications following standard tracheostomy using a national registry., Methods: Adult patients who underwent tracheostomy from 2007 to 2017 were analyzed using the Nationwide Inpatient Sample (NIS). The population was stratified into obese and non-obese groups. Early complications following standard tracheostomy were identified and compared between the two groups. Multivariable logistic regression analyses were performed to assess the association between obesity and early complications following tracheostomy., Results: Data pertaining to 205 032 adult patients were evaluated. Obese patients accounted for 12.1% (n = 21 816) of the entire cohort. The most common complication in the cohort was perioperative bleeding (4316 [2.1%]). A total of 1382 (0.67%), 949 (0.46%), and 134 (0.07%) patients developed pneumothorax/pneumomediastinum, stoma/surgical site infection, and tracheal injury following standard tracheostomy, respectively. There was no difference in the odds of tracheal injury, perioperative bleeding, and pneumomediastinum/pneumothorax following standard tracheostomy in the obese and non-obese group in multivariable analysis. However, obesity was associated with 60% increased odds of developing stoma/surgical site infection following standard tracheostomy (OR 1.60 [1.33-1.92], P < 0.01)., Conclusion: Obesity is associated with an increased risk of developing stoma/surgical site infection following standard tracheostomy. This adds to the growing need for measures to help curb the obesity epidemic in a bid to improve surgical outcomes.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously present in our indoor living environments. Dust is thought to accumulate PFAS released indoors and serve as an exposure pathway for humans. Here, we investigated whether spent air conditioning (AC) filters can be exploited as opportunistic samplers of airborne dust for assessing PFAS burden in indoor environments. Used AC filters from campus facilities (n = 19) and homes (n = 11) were analyzed for 92 PFAS via targeted ultra-high pressure liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS). While 27 PFAS were measured (in at least one filter), the predominant species were polyfluorinated dialkylated phosphate esters (diPAPs), with the sum of 6:2-, 8:2-, and 6:2/8:2diPAPs accounting for approximately 95 and 98 percent of ∑ 27 PFAS in campus and household filters, respectively. Exploratory screening of a subset of the filters revealed the presence of additional species of mono-, di-, and tri-PAPs. Considering the constant human exposure to dust indoors and the potential of PAPs to degrade into terminal species with well-established toxicological risks, assessing dust for these precursor PFAS warrants further investigation with respect to both human health and PFAS loading to landfills from this under studied waste stream., 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 Ltd. All rights reserved.)

Background: Current monitoring and evaluation methods challenge the healthcare system. Specifically for the use case of immunization coverage calculation, person-level data retrieval is required instead of inaccurate aggregation methods. The Clinical Quality Language (CQL) by HL7®, has the potential to overcome current challenges by offering an automated generation of quality reports on top of an HL7® FHIR® repository., Objectives: This paper provides a method to author and evaluate an electronic health quality measure as demonstrated by a proof-of-concept on immunization coverage calculation., Methods: Five artifact types were identified to transform unstructured input into CQL, to define the terminology, to create test data, and to evaluate the new quality measures., Results: CQL logic and FHIR® test data were created and evaluated by using the different approaches of manual evaluation, unit testing in the HAPI FHIR project, as well as showcasing the functionality with a developed user interface for immunization coverage analysis., Conclusion: Simple, powerful, and transparent evaluations on a small population can be achieved with existing open-source tools, by applying CQL logic to FHIR®.

Ellagic acid, the marker component of peels of Punica granatum L., is known traditionally to treat traumatic hemorrhage. In this study, the cellular mechanism underlying ellagic acid-induced anti-inflammation was investigated using lipopolysaccharides (LPSs) as a neuroinflammation inducer. Our in vitro data showed that LPS (1 μg/mL) consistently phosphorylated ERK and induced neuroinflammation, such as elevation in tumor necrosis factor-α (TNF-α) and nitric oxide production in treated BV-2 cells. Incubation of ellagic acid significantly inhibited LPS-induced ERK phosphorylation and subsequent neuroinflammation in treated BV-2 cells. Furthermore, our in vivo study of neuroinflammation employed an intranigral infusion of LPS that resulted in a time-dependent elevation in phosphorylated ERK levels in the infused substantia nigra (SN). Oral administration of ellagic acid (100 mg/kg) significantly attenuated LPS-induced ERK phosphorylation. A four-day treatment of ellagic acid did not alter LPS-induced ED-1 elevation but ameliorated LPS-induced reduction in CD206 and arginase-1 (two biomarkers of M2 microglia). A seven-day treatment of ellagic acid abolished LPS-induced increases in heme-oxygenase-1, cyclo-oxygenase 2, and α-synuclein trimer levels (a pathological hallmark) in the infused SN. At the same time, ellagic acid attenuated LPS-induced increases in active caspase 3 and receptor-interacting protein kinase-3 levels (respective biomarkers of apoptosis and necroptosis) as well as reduction in tyrosine hydroxylase-positive cells in the infused SN. In silico analysis showed that ellagic acid binds to the catalytic site of MEK1. Our data suggest that ellagic acid is capable of inhibiting MEK1-ERK signaling and then attenuated LPS-induced neuroinflammation, protein aggregation, and programmed cell deaths. Moreover, M2 microglial polarization is suggested as a novel antineuroinflammatory mechanism in the ellagic acid-induced neuroprotection.

Dysregulational EGFR, KRAS, and mTOR pathways cause metabolic reprogramming, leading to progression of gastric cancer. Afatinib (Afa) is a broad-spectrum tyrosine kinase inhibitor that reduces cancer growth by blocking the EGFR family. MicroRNA 125 (miR-125) reportedly diminishes EGFRs, glycolysis, and anti-apoptosis. Here, a one-shot formulation of miR-125 and Afa was presented for the first time. The formulation comprised solid lipid nanoparticles modified with mitochondrial targeting peptide and EGFR-directed ligand to suppress pan-ErbB-facilitated epithelial-mesenchymal transition and mTOR-mediated metabolism discoordination of glycolysis-glutaminolysis-lipids. Results showed that this cotreatment modulated numerous critical proteins, such as EGFR/HER2/HER3, Kras/ERK/Vimentin, and mTOR/HIF1-α/HK2/LDHA pathways of gastric adenocarcinoma AGS cells. The combinatorial therapy suppressed glutaminolysis, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. The cotreatment also notably decreased the levels of lactate, acetyl-CoA, and ATP. The active involvement of mitophagy supported the direction of promoting the apoptosis of AGS cells, which subsequently caused the breakdown of tumor-cell homeostasis and death. In vivo findings in AGS-bearing mice confirmed the superiority of the anti-tumor efficacy and safety of this combination nanomedicine over other formulations. This one-shot formulation disturbed the metabolic reprogramming; alleviated the "Warburg effect" of tumors; interrupted the supply of fatty acid, cholesterol, and triglyceride; and exacerbated the energy depletion in the tumor microenvironment, thereby inhibiting tumor proliferation and aggressiveness. Collectively, the results showed that the two-in-one nanoparticle formulation of miR-125 and Afa was a breakthrough in simplifying drug preparation and administration, as well as effectively inhibiting tumor progression through the versatile targeting of pan-ErbB- and mTOR-mediated mitochondrial dysfunction and dysregulated metabolism.

Background: During the COVID-19 pandemic, cardiovascular patients were found to be presenting to hospitals with myocardial infarctions and cerebrovascular accidents at progressed disease states. We noticed a parallel in acute limb ischemia (ALI) patients presenting during Massachusetts' COVID-19 State of Emergency declaration. We question whether patients developed a hesitancy to seek medical attention at hospitals due to fear of COVID-19. Our objective was to compare acuity of ALI, interventions, and limb survival in patients presenting before, during, and after a state of emergency., Methods: Four timeframes were set to compare patients presenting peri-2020 COVID-19 State of Emergency and patients presenting during a pre-pandemic era at a tertiary, academic institution. A reference period from 2019, Pre-State of Emergency period, State of Emergency period, and Post-State of Emergency period were designated. Patient characteristics, interventions, and outcomes data were collected. Unpaired t-test, ANOVA, and Chi-square statistical analyses were used., Results: A total of 95 patients presenting with ALI were identified. Compared to Reference group, state of emergency group had more patients presenting with Rutherford Class III, 12.9% vs 35%, and less patient presenting with Class I, 45.1% vs 0%, P = .02. State of emergency group had more delayed presentations with ≥6 hours after symptom onset, 45% vs 85%, P = .01. Above-knee amputations were performed in 20% of patients during state of emergency and 31.6% for Post-State of Emergency, vs 6.5% in the Reference group; P = .03. There was no difference in intensive care unit admission, length of stay, or mortality between patients from different groups., Conclusion: During a state of emergency, ALI patients were noted to present later from symptom onset, have greater disease severity, and more likely to undergo amputations. We suspect delay in presentation and limb lost to be attributed to reluctance to seek immediate medical attention.

Objectives: This study evaluates complications and reconstructive failure rates in implant-based reconstruction with radiotherapy., Background: Postmastectomy radiotherapy may adversely affect breast reconstructive outcomes. However, the comparative effect of radiotherapy on direct-to-implant versus tissue expander-implant reconstruction has not been examined., Methods: Single institution retrospective review was performed and patients were followed 2 to 10 years., Results: Of 1566 patients, 265 patients received radiation (149 immediate implants and 116 tissue expanders). Demographics were similar except more smokers in the expander group (7.7% vs 1.3%; P = 0.012). Patients who received radiation with an expander in place had overall more complications (32.8% vs 11.4%; P < 0.001), skin necrosis (10.3% vs 4.0%; P = 0.043), wound breakdown (9.5% vs 2.7%; P = 0.029), and infections (16.4% vs 4.03%; P = 0.001) leading to a higher rate of explantation (16.4% vs 4.0%; P < 0.001). A radiation boost likewise predicted complications [odds ratio (OR) 2.199, 95% confidence interval (CI) 1.154-4.188, P = 0.017]. When comparing reconstructive outcomes, radiated expanders had a higher failure rate (21.6% vs 11.4%; P = 0.025). Revision for capsular contracture was similar between the 2 cohorts (11.4% vs 11.2%; P = 0.959) as were revision rates for contour asymmetry and breast asymmetry. In our multivariable logistic regression analysis, radiation to the expander had a higher risk of reconstruction failure than radiation to the permanent implant (OR 2.020, 95% CI 1.010-4.037, P = 0.047)., Conclusion: Most patients had successful implant-based reconstructions after mastectomy and radiotherapy. Our study showed radiotherapy after direct-to-implant breast reconstruction had a lower rate of complications and reconstructive failure compared to tissue expander-implant reconstruction., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Head and neck cancer (HNC) has a high incidence and a poor prognosis. Epirubicin, a topoisomerase inhibitor, is a potential anthracycline chemotherapeutic for HNC treatment. HuR (ELAVL1), an RNA-binding protein, plays a critical role in promoting tumor survival, invasion, and resistance. HuR knockout via CRISPR/Cas9 (HuR CRISPR) is a possible strategy for the simultaneous modulation of the various pathways of tumor progression. Multifunctional nanoparticles modified with pH-sensitive epidermal growth factor receptor (EGFR)-targeting and nucleus-directed peptides were designed for the efficient delivery of HuR CRISPR and epirubicin to human tongue squamous carcinoma SAS cells and SAS tumor-bearing mice. The pH-sensitive nanoparticles responded to the acidic pH value as a switch to expose the targeting peptides. The cellular uptake and transfection efficiency of these nanoparticles in SAS cells increased via EGFR targeting, ligand-mediated endocytosis, and endosomal escape. These nanoparticles showed low cytotoxicity towards normal oral keratinocyte NOK cells. CRISPR/Cas9 was transported into the nucleus via the nuclear directing peptide and successfully knocked out HuR to suppress proliferation, metastasis, and resistance in SAS cells. The multiple inhibition of EGFR/β-catenin/epithelial-mesenchymal transition pathways was mediated through modulating the EGFR/PI3K/mTOR/AKT axis. The co-treatment of epirubicin and HuR CRISPR in SAS cells further facilitated apoptosis/necroptosis/autophagy and caused cancer cell death. In combination with HuR CRISPR nanoparticles, the efficacy and safety of epirubicin nanoparticles against cancer in SAS tumor-bearing mice improved significantly. Collectively, these nanoparticles showed a tumor pH response, active EGFR targeting, and nuclear localization and thus offered a combinatorial spatiotemporal platform for chemotherapy and the CRISPR/Cas gene-editing system.

Abnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present study, the neuroprotective effect of selumetinib (a MEK-ERK inhibitor) on acrolein-induced neurotoxicity was investigated in vitro using primary cultured cortical neurons. Incubation of acrolein consistently increased phosphorylated ERK levels. Co-treatment of selumetinib blocked acrolein-induced ERK phosphorylation. Furthermore, selumetinib reduced acrolein-induced increases in heme oxygenase-1 (a redox-regulated chaperone protein) and its transcriptional factor, Nrf-2 as well as FDP-lysine (acrolein-lysine adducts) and α-synuclein aggregation (a pathological biomarker of neurodegeneration). Morphologically, selumetinib attenuated acrolein-induced damage in neurite outgrowth, including neuritic beading and neurite discontinuation. Moreover, selumetinib prevented acrolein-induced programmed cell death via decreasing active caspase 3 (a hallmark of apoptosis) as well as RIP (receptor-interacting protein) 1 and RIP3 (biomarkers for necroptosis). In conclusion, our study showed that selumetinib inhibited acrolein-activated Nrf-2-HO-1 pathway, acrolein-induced protein conjugation and aggregation as well as damage in neurite outgrowth and cell death, suggesting that selumetinib, a MEK-ERK inhibitor, may be a potential neuroprotective agent against acrolein-induced neurotoxicity in the CNS neurodegenerative diseases.

Objectives: Long-term volunteering has been associated with better physical, mental, and cognitive health in correlational studies. Few studies, however, have examined the longitudinal benefits of volunteering with randomized experimental designs (e.g., intervention studies). Even fewer studies have examined whether such benefits can be shown after short-term volunteering. To fill this gap, we conducted four 1-hour volunteering intervention sessions to promote volunteering among a group of older adults with limited volunteering experience and examined the impact of volunteering on depressive symptoms, meaning in life, general self-efficacy, and perceived autonomy. Methods: A total of 384 participants aged 50-96 years were assigned at random to either an intervention group to promote volunteering behaviors or an active control group to promote physical activity. The participants' monthly volunteering minutes, depressive symptoms, meaning in life, general self-efficacy and perceived autonomy were measured at baseline and six weeks, three months, and six months after the intervention. Results: Being in the volunteering intervention condition was not directly associated with depressive symptoms, meaning in life, general self-efficacy, or perceived autonomy at the 6-week, 3-month, or 6-month follow-ups after the intervention. However, there was an indirect effect of the intervention on depressive symptoms: participants in the intervention group, who had increased their volunteering at the 3-month follow-up, reported fewer depressive symptoms at the 6-month follow-up. Discussion: Our randomized controlled trial suggests that short-term volunteering does not reliably lead to short-term changes in psychosocial health measures as correlational studies would suggest. Efforts need to be made to encourage older adults to maintain long-term volunteering.

Epidermal growth factor receptor ( EGFR ) mutations are the most common driver genes in non-small cell lung cancer (NSCLC), especially in the Asian population. Although EGFR-tyrosine kinase inhibitors (TKIs) are influential in the treatment of EGFR -mutant NSCLC patients, acquired resistance inevitably occurs. Therefore, there is an urgent need to develop strategies to overcome this resistance. In addition, cancer cells with particular mutations appear more vulnerable to deficiency related to the availability of specific amino acids. However, it is still unknown which amino acid is affected in the case of EGFR -mutant NSCLC. In the present study, we established a screening platform based on amino acid deprivation and found that EGFR -mutant NSCLC cells are sensitive to short-term lysine deprivation. Moreover, we found that expression of the gene for the lysine catabolism enzyme α-aminoadipate aminotransferase ( AADAT ) increased under lysine deprivation, revealing that AADAT can be regulated by EGFR-AKT signaling. Finally, we found that lysine reduction can not only enhance the cytostatic effect of single-agent osimertinib but also overcome the resistance of EGFR-TKIs in EGFR -mutant NSCLC cells. In summary, our findings suggest that the introduction of lysine stress might act as an advancement in EGFR -mutant NSCLC therapy and offer a strategy to overcome EGFR-TKI resistance.

Many thanks to Dr. Mordaunt for his thoughtful Comment, which we were delighted to read with great interest[...].

Background and Purpose: Self-management programs may improve quality of life and self-efficacy for stroke survivors, but participation is low. In a randomized controlled trial of a complex, multidisciplinary, team-based secondary stroke prevention intervention, we offered participants Chronic Disease Self-Management Program (CDSMP) workshops in addition to clinic visits and home visits. To enhance participation, workshops were facilitated by community health workers who were culturally and linguistically concordant with most participants and scheduled CDSMP sessions at convenient venues and times. Over time, we implemented additional strategies such as free transportation and financial incentives. In this study, we aimed to determine factors associated with CDSMP participation and attendance., Methods: From 2014 to 2018, 18 CDSMP workshop series were offered to 241 English and Spanish-speaking individuals (age ≥40 years) with recent stroke or transient ischemic attack. Zero-inflated Poisson regression was used to identify factors associated with participation and attendance (ie, number of sessions attended) in CDSMP. Missing values were imputed using multiple imputation methods., Results: Nearly one-third (29%) of intervention subjects participated in CDSMP. Moderate disability and more clinic/home visits were associated with participation. Participants with higher numbers of clinic and home visits (incidence rate ratio [IRR], 1.06 [95% CI, 1.01-1.12]), severe (IRR, 2.34 [95% CI, 1.65-3.31]), and moderately severe disability (IRR, 1.55 [95% CI, 1.07-2.23]), and who enrolled later in the study (IRR, 1.12 [95% CI, 1.08-1.16]) attended more sessions. Individuals with higher chaos scores attended fewer sessions (IRR, 0.97 [95% CI, 0.95-0.99])., Conclusions: Less than one-third of subjects enrolled in the SUCCEED (Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities) intervention participated in CDSMP; however, participation improved as transportation and financial barriers were addressed. Strategies to address social determinants of health contributing to chaos and engage individuals in healthcare may facilitate attendance. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01763203.

Background and Objectives: Volunteering has consistently been associated with better mental, physical, and cognitive health in older adulthood. However, the volunteering rate of older adults in Hong Kong is much lower than in Western countries. Few studies have examined whether interventions can be effective in motivating older adults to volunteer in Hong Kong. To fill this gap, we conducted a randomized controlled trial to examine the impact of a theory-based social-cognitive intervention on volunteering., Research Design and Methods: A total of 264 community-dwelling older adults in Hong Kong (Mage = 69.95 years, SDage = 6.90 years, 81.06% female) were randomly assigned to either an experimental group or an active control group. Participants in the experimental group received 4 weekly 1-hr face-to-face volunteering intervention sessions. Those in the active control group received parallel sessions targeting physical activity instead of volunteering. The time spent on volunteering per month was self-reported and measured at baseline, 6 weeks, 3 months, and 6 months after the intervention. Self-efficacy, intention, action planning, and self-monitoring of volunteering were measured as mediators., Results: Monthly volunteering minutes increased among participants in the experimental group when compared with the active control group at 6-week, 3-month, and 6-month follow-ups. Self-efficacy, intention, and action planning consistently mediated the effect of the intervention on volunteering minutes., Discussion and Implications: The findings demonstrate the effectiveness of the intervention on volunteering behavior in older adults in Hong Kong through well-established behavior change techniques., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Head and neck cancer (HNC) is a major cause of morbidity and mortality and has a poor treatment outcome. Irinotecan, a topoisomerase-I inhibitor, induces cell death by decreasing the religation of double-strand DNA. However, epithelial-mesenchymal transition (EMT), therapy resistance, and systemic toxicity caused by available antineoplastic agents hinder the efficacy and safety of HNC treatment. Chemotherapy combined with gene therapy shows potential application in circumventing therapy resistance and EMT. miR-200 exerts a remarkable suppressing effect on EMT-associated genes. Herein, liposomes and solid lipid nanoparticles (SLNs) modified with a pH-sensitive, self-destructive polyethylene glycol (PEG) shell and different peptides were designed as irinotecan and miR-200 nanovectors to enhance tumor-specific accumulation. These peptides included one ligand targeting the angiogenic tumor neovasculature, one mitochondrion-directed apoptosis-inducing peptide, and one cell-penetrating peptide (CPP) with high potency and selectivity toward cancer cells. Methods: Physicochemical characterization, cytotoxicity analysis, cellular uptake, regulation mechanisms, and in vivo studies on miR-200- and irinotecan-incorporated nanoparticles were performed to identify the potential antitumor efficacy and biosafety issues involved in HNC treatment and to elucidate the underlying signaling pathways. Results: We found that the cleavable PEG layer responded to low extracellular pH, and that the CPP and targeting peptides were exposed to improve the uptake and release of miR-200 and irinotecan into HNC human tongue squamous carcinoma (SAS) cells. The apoptosis of SAS cells treated with the combinatorial therapy was significantly induced by regulating various pathways, such as the Wnt/β-catenin, MDR, and EMT pathways. The therapeutic efficacy and safety of the proposed co-treatment outperformed the commercially available Onivyde and other formulations used in a SAS tumor-bearing mouse model in this study. Conclusion: Chemotherapy and gene therapy co-treatment involving pH-sensitive and targeting peptide-modified nanoparticles may be an innovative strategy for HNC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Process mining can provide greater insight into medical treatment processes and organizational processes in healthcare. To enhance comparability between processes, the quality of the labelled-data is essential. A literature review of the clinical case studies by Rojas et al. in 2016 identified several common aspects for comparison, which include methodologies, algorithms or techniques, medical fields, and healthcare specialty. However, clinical aspects are not reported in a uniform way and do not follow a standard clinical coding scheme. Further, technical aspects such as details of the event log data are not always described. In this paper, we identified 38 clinically-relevant case studies of process mining in healthcare published from 2016 to 2018 that described the tools, algorithms and techniques utilized, and details on the event log data. We then correlated the clinical aspects of patient encounter environment, clinical specialty and medical diagnoses using the standard clinical coding schemes SNOMED CT and ICD-10. The potential outcomes of adopting a standard approach for describing event log data and classifying medical terminology using standard clinical coding schemes are further discussed. A checklist template for the reporting of case studies is provided in the Appendix A to the article.

Clinically, high levels of acrolein (a highly reactive α, β-unsaturated aldehyde) and acrolein adducts are detected in the brain of patients with CNS neurodegenerative diseases, including Alzheimer's disease and spinal cord injury. Our previous study supports this notion by showing acrolein as a neurotoxin in a Parkinsonian animal model. In the present study, the effect of AZD6244 (an ATP non-competitive MEK1/2 inhibitor) on acrolein-induced neuroinflammation was investigated using BV-2 cells and primary cultured microglia. Our immunostaining study showed that lipopolysaccharide (LPS, an inflammation inducer as a positive control) increased co-localized immunoreactivities of phosphorylated ERK and ED-1 (a biomarker of activated microglia) in the treated BV-2 cells. Similar elevation in co-localized immunoreactivities of phosphorylated ERK and ED-1 was detected in the acrolein-treated BV-2 cells. Furthermore, Western blot assay showed increases in phosphorylated ERK in BV-2 cells subjected to LPS (1 μg/mL) or acrolein (30 μM); these increases were blocked by AZD6244 (10 μM). At the same time, AZD6244 attenuated LPS-induced TNF-α (a pro-inflammatory cytokine) and cyclooxygenase-II (COX II, a pro-inflammatory enzyme). Consistently, AZD6244 reduced acrolein-induced elevations in COX-II mRNA and COX-II protein expression. In addition, AZD6244 inhibited acrolein-induced increases in activated caspase 1 (a biomarker of inflammasome activation) and heme oxygenase-1 (a redox-regulated chaperone protein) in BV-2 cells. Using a transwell migration assay, AZD6244 attenuated acrolein (5 μM)-induced migration of BV-2 cells and primary cultured microglia. In conclusion, our study shows that acrolein is capable of inducing neuroinflammation which involved ERK activation in microglia. Furthermore, AZD6244 is capable of inhibiting acrolein-induced neuroinflammation. Our study suggests that ERK inhibition may be a neuroprotective target against acrolein-induced neuroinflammation in the CNS neurodegenerative diseases.

Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of lipopolysaccharides (LPS, 4 μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100 mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1 μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in iNOS mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. The anti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37 °C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA is anti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammation in CNS neurodegenerative diseases.

Background and Purpose: Ischemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes in Taiwan. Neurons contain high concentrations of polyamines, which are prone to various pathological states in the brain and are perturbed after cerebral ischemia. Acrolein, an α,β-unsaturated aldehyde, has been suggested as the primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear., Methods: Urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione (GSH) metabolite, plasma acrolein-protein conjugates (Acr-PC) and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients compared with control subjects. In vivo middle cerebral artery occlusion (MCAO) animal models and an in vitro oxygen glucose deprivation (OGD) stroke model were used to investigate the mechanisms of acrolein-induced neuronal damage., Results: A deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma GSH levels, was found in stroke patients compared to control subjects. We further observed that acrolein was produced during ischemia resulting in brain damage in in vivo MCAO animal model. The induction of acrolein in neuronal cells during OGD occurred due to the increased expression of spermidine/spermine N1-acetyltransferase (SSAT) by NF-kB pathway activation. In addition, acrolein elicited a vicious cycling of oxidative stress resulting in neurotoxicity. Finally, N-acetylcysteine effectively prevented OGD-induced neurotoxicity by scavenging acrolein., Conclusion: Overall, our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients. The mechanism underlying the role of acrolein in stroke-related neuronal damage occurs through SSAT-induced polyamine oxidation by NF-kB pathway activation. These results provide a novel mechanism of neurotoxicity in stroke patients, aid in the development of neutralizing or preventive measures, and further our understanding of neural protection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial-mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells., Results: Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways., Conclusion: This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib.

Background: Patients with biochemically recurrent prostate cancer and short prostate-specific antigen doubling time (PSADT) are at risk for metastasis yet may wish to avoid androgen deprivation therapy. Itraconazole may have antitumor activity without affecting circulating androgen levels. We therefore evaluated itraconazole as a potentially noncastrating treatment approach in biochemically recurrent prostate cancer., Patients and Methods: Patients with biochemically recurrent prostate cancer and PSADT ≤ 15 months, with serum testosterone > 150 ng/dL, were prospectively enrolled. The primary end point was the proportion of patients who experienced ≥ 50% decline from baseline in serum prostate-specific antigen (PSA) by week 12., Results: Twenty-one patients were enrolled. The median (range) age, baseline PSA, and PSADT at study entry was 72 (49-76) years, 7.6 (1.5-45.5) ng/mL, and 5.7 (1.2-13.0) months, respectively. Among 19 patients with evaluable data, 1 patient (5%) had a > 50% PSA decline. Nine patients (47%) experienced any PSA decline (mean decline 25.0%, range 2%-60%) by week 12. Among 10 patients without a PSA decline, the on-treatment versus pretreatment PSADT was not significantly longer (median 6.8 vs. 4.3 months, P = .17). There was no significant change from baseline to week 12 in serum testosterone (median change = 32.4%, P = .21) or androstenedione (median change = -8.3%, P = .85). The most common adverse events were edema (52%), fatigue (38%), hypertension (24%), and hypokalemia (24%)., Conclusion: Itraconazole modulates serum PSA levels without lowering serum testosterone. However, the magnitude of effect is modest, and treatment carries risk of toxicities associated with mineralocorticoid excess., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Volunteering could be a win-win opportunity for older adults: Links between volunteering and societal improvements as well as older adults' own health and longevity are found in several observational studies. RCTs to increase volunteering in older adults are however sparse, leaving the question of causality unanswered. This study protocol describes a theory-based social-cognitive intervention with multiple behavior change techniques to increase volunteering among community-dwelling older adults in Hong Kong., Methods: In a parallel group, two-arm, randomized controlled trial, an initial N = 360 are assigned to receive either the volunteering intervention or the active control intervention (parallel content targeting physical activity). The primarily outcome measure is self-reported volunteering minutes per month at baseline, six weeks, three months and six months after the intervention. Participants in the treatment group are expected to increase their weekly volunteering minutes over time as compared to participants in the control group. Possible active ingredients of the intervention as well as mental and physical health outcomes of increased volunteering are investigated by means of mediation analyses., Discussion: Like many industrialized nations, Hong Kong faces a rapid demographic change. An effective psychological intervention to encourage retirees to engage in formal volunteering would alleviate some of the societal challenges a growing proportion of older adults entails., Trial Registration: Primary Registry and Trial Identifying Number ChiCTR-IIC-17010349 , secondary CCRB trial number CUHK&#95;CCRB00543, registration date 2016/12/28.

Background and Purpose- The American Heart Association's Life's Simple 7 (LS7) defines ideal cardiovascular health by 7 metrics: not smoking, regular physical activity, normal body mass index, blood pressure, plasma glucose, and total cholesterol levels, and a healthy diet. We assessed prevalence and predictors of ideal LS7 among US stroke survivors. Methods- Among 67 514 participants in the National Health and Nutrition Examination Surveys from 1988 to 1994 and 1999 to 2014, 1597 adults (≥18 years) had self-reported history of stroke. LS7 metrics were categorized as poor, intermediate, and ideal; ideal LS7 scores were calculated (1 point for each ideal metric met). Trends in poor, intermediate, and ideal cardiovascular health were assessed. Odds of low (0-1) versus high (≥4) ideal LS7 scores were assessed according to sex, race, poverty income ratio, and education level, before and after adjusting for covariates. Results- Only 1 participant met all ideal LS7 metrics. The proportion with low LS7 score increased from 17.9% in 1988 to 1994 to 35.4% in 2011 to 2014 ( P <0.001). Over that time frame, prevalence of poor blood pressure (≥140/90 mm Hg) and poor cholesterol (≥240 mg/dL) decreased (45.2%-26.5% and 37.2%-10.3%), whereas prevalence of poor body mass index (≥30 kg/m 2 ), poor diet (healthy eating index score <50), and poor physical activity (0 minutes moderate/vigorous activity per week) increased (26.9%-39.0%; 14.2%-50.6%; 44.6%-70.9%; all P <0.05). After adjustment, black race (odds ratio, 2.29; 95% CI, 1.17-4.48), poverty income ratio ≤200% (odds ratio, 2.20, 95% CI, 1.11-4.36), and ≤12th grade education (odds ratio, 4.50; 95% CI, 2.27-8.92) were associated with low ideal LS7 scores. Conclusions- Over the past 3 decades, blood pressure and cholesterol control among stroke survivors improved, but rates of obesity, poor diet, and physical inactivity increased. Stroke survivors who are black, poor, or less educated are less likely to have ideal cardiovascular health.

Background: Le Fort I maxillary advancements affect nasal proportions. However, there are no data on the three-dimensional nasal changes that occur with differential lateral plane adjustment (clockwise and counterclockwise movements) during Le Fort I maxillary advancements. This study analyzes and compares nasolabial soft-tissue changes after Le Fort I clockwise and counterclockwise repositioning., Methods: Single-piece Le Fort I advancements were included. A retrospective study of patients split into clockwise and counterclockwise groups was performed. Preoperative and postoperative three-dimensional photographs (VECTRA 3D) were analyzed. Nasolabial anthropometric measurements were recorded using Mirror software. Statistical analysis involved paired t test to compare preoperative and postoperative measurements., Results: Twenty-four patients were evaluated (12 per group), with 22 distinct nasolabial relationships measured. Counterclockwise movement showed a statistically significant increase in alar width (3.6 mm; p < 0.001), alar base width (1.6 mm; p = 0.009), oral width (3.2 mm; p = 0.02), and lip projection (3.4 mm; p = 0.04). Clockwise movement showed no statistically significant changes, with the largest position changes noted in alar width (2.7 mm; p = 0.07) and alar base width (1.7 mm; p = 0.09)., Conclusions: Clockwise and counterclockwise Le Fort I advancements have a different effect on postoperative nasolabial morphology. Counterclockwise movements exhibit significant changes, widening the alar base and width and the oral and philtral widths. The impact on the nostril morphology and columella was similar between the groups. The differential impact on nasolabial appearance is important to recognize for treatment planning and patient counseling., Clinical Question/level of Evidence: Therapeutic, III.

Glycine N-methyltransferase (GNMT) is a tumor suppressor for HCC. It is down-regulated in HCC, but the mechanism is not fully understood. MicroRNA-224 (miR-224) acts as an onco-miR in HCC. This study is the first to investigate miR-224 targeting the coding region of GNMT transcript. The GNMT-MT plasmid containing a miR-224 binding site silent mutation of the GNMT coding sequence can escape the suppression of miR-224 in HEK293T cells. Expression of both exogenous and endogenous GNMT was suppressed by miR-224, while miR-224 inhibitor enhanced GNMT expression. miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. The levels of miR-224 and GNMT mRNA showed a significant inverse relationship in tumor specimens from HCC patients. Utilizing CCl4-treated hepatoma cells and mice as a cell damage of inflammatory or liver injury model, we observed that the decreased expression levels of GNMT were accompanied with the elevated expression levels of miR-224 in hepatoma cells and mouse liver. Finally, hepatic AAV-mediated GNMT also reduced CCl4-induced miR-224 expression and liver fibrosis. These results indicated that AAV-mediated GNMT has potential liver protection activity. miR-224 can target the GNMT mRNA coding sequence and plays an important role in GNMT suppression during liver tumorigenesis.

Lessons Learned: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space., Background: Selinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins., Methods: This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide., Results: Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m 2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability., Conclusion: Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using genetic and pharmacological approaches. MPTP (15 mg/kg) was intraperitoneally injected in sEH knockout (KO) mice and C57BL/6J mice as wild-type (WT) mice. Compared with the MPTP-treated WT mice, MPTP-induced reductions in striatal dopamine content and nigral tyrosine hydroxylase level (TH, a biomarker of dopaminergic neurons) were less significant in the treated sEH mice. Furthermore, MPTP-induced HO-1 elevation (a redox-regulated protein), α-synuclein aggregation, and caspase 12 activation (a hallmark of ER stress) were less prominent in sEH KO mice than in WT mice. These data indicate that sEH KO mice are more resistant to MPTP-induced neurotoxicity. The pharmacological effect of N-[1-(1-oxopropyl)-4-piperidinyl]-N0-[4-(trifluoromethoxy)phenyl)-urea (TPPU, an sEH inhibitor) on MPTP-induced neurotoxicity was investigated in WT mice. TPPU (1 mg/kg, i.p.) attenuated MPTP-induced reduction in striatal dopamine content, TH-positive cell numbers, TH, and pro-caspase 9 protein levels (an initiator caspase of apoptosis) in mouse SN. Moreover, TPPU reduced MPTP-induced HO-1 elevation, α-synuclein aggregation and caspase 12 activation, indicating that TPPU is effective in attenuating MPTP-induced oxidative stress, apoptosis, protein aggregation, and ER stress. In conclusion, our study suggests that sEH is a potential target for developing therapies for parkinsonism. Furthermore, sEH inhibitors may be of clinical significance for treating CNS neurodegenerative diseases.

Elevated levels of acrolein, an α,β-unsaturated aldehyde are detected in the brain of patients with Parkinson's disease (PD). In the present study, the neuroprotective effect of baicalein (a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi) on acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using local infusion of acrolein in the substantia nigra (SN) of rat brain. Systemic administration of baicalein (30 mg/kg, i.p.) significantly attenuated acrolein-induced elevations in 4-hydroxy-2-noneal (a product of lipid peroxidation), N-(3-formyl-3,4-dehydropiperidino)lysine (a biomarker of acrolein-conjugated proteins), and heme-oxygenase-1 levels (a redox-regulated protein) in the infused SN, indicating that baicalein inhibited acrolein-induced oxidative stress and protein conjugation. Furthermore, baicalein reduced acrolein-induced elevations in glial fibrillary acidic protein (a biomarker of activated astrocytes), ED-1 (a biomarker of activated microglia), and mature cathepsin B levels (a cysteine lysosomal protease), suggesting that baicalein attenuated acrolein-induced neuroinflammation. Moreover, baicalein attenuated acrolein-induced caspase 1 activation (a pro-inflammatory caspase) and interleukin-1β levels, indicating that baicalein prevented acrolein-induced inflammasome activation. In addition, baicalein significantly attenuated acrolein-induced caspase 3 activation (a biomarker of apoptosis) as well as acrolein-induced elevation in receptor interacting protein kinase (RIPK) 3 levels (an initiator of necroptosis), indicating that baicalein attenuated apoptosis and necroptosis. At the same time, baicalein mitigated acrolein-induced reduction in dopamine levels in the striatum ipsilateral to acrolein-infused SN. In conclusion, our data suggest that baicalein is neuroprotective via inhibiting oxidative stress, protein conjugation, and inflammation. Furthermore, baicalein prevents acrolein-induced program cell deaths, suggesting that baicalein is therapeutically useful for slowing PD progression.

Background: Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy., Patients and Methods: Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate-specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA., Results: Forty-one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard-dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines ≥ 30% nor radiographic responses were observed after 12 weeks of dose-escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard-dose therapy., Conclusion: Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The traditional abdominoplasty is one of the most common surgical procedures performed. This study evaluates the impact of different surgical techniques and clinical patient factors on abdominoplasty outcomes., Methods: A retrospective review of consecutive patients undergoing abdominoplasty was performed., Results: Seven hundred seventy-nine patients with a mean age of 43.7 years and a body mass index of 27 kg/m underwent abdominoplasty. The majority were women (92.9 percent), and massive weight loss was present in 34.8 percent. Abdominoplasty techniques included traditional (59.4 percent), belt lipectomy (17.9 percent), fleur-de-lis (16.4 percent), umbilical float (9.2 percent), and mini-abdominoplasty (2.8 percent). Half of the study population [n = 384 (49.3 percent)] had concurrent surgical procedures. Total complications (23.0 percent) consisted primarily of wound- and scar-related complications (15.3 percent). Approximately 60 percent of patients received heparin chemoprophylaxis, with overall thromboembolic and hematoma rates less than 1 percent. Univariate analysis revealed that massive weight loss (p = 0.04), fleur-de-lis (p = 0.03) or belt lipectomy (p = 0.05) techniques, and concurrent medial thigh lift (p < 0.001) all significantly increased complications. Previous scars, amount of weight loss, operative time, liposuction, and other concurrent procedures did not affect total complications. Male sex (OR, 1.96; p = 0.04), fleur-de-lis technique (OR, 1.71; p = 0.04), and medial thigh lift (OR, 3.3; p < 0.001) were independent risk factors for total postoperative complications., Conclusion: This study demonstrates that abdominoplasty alone or in combination with liposuction and aesthetic breast surgery can be performed safely, with an acceptable complication profile., Clinical Question/level of Evidence: Risk, III.

Background  Earlier, digit viability judged the success of digital replantation. Now, utility health-related quality of life (HRQOL) measures can better assess the impact of digital replantation. Methods  Overall, 264 digital injury patients were sent a regimen of utility measures: Disabilities of the Arm, Shoulder and Hand (DASH) score, European Quality of Life 5 Dimensions, visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG). Overall, 51 patients responded completely to all of these-36 replantation patients and 15 revision amputation patients. The utility results of these patients were stratified between replantation versus revision amputation; dominant hand replantation versus nondominant hand replantation; and dominant hand revision amputation versus nondominant hand revision amputation. Results  The mean VAS score of replant (0.84) and revision amputation (0.75) groups was significantly different ( p  = 0.05). The mean DASH score of dominant hand replantations (29.72) and nondominant hand replantations (17.97) was significantly different ( p  = 0.027). The dominant hand revision amputation had higher anxiety levels in comparison to nondominant hand revision amputation ( p  = 0.027). Patients with two or more digits replanted showed a significant decrease in VAS, TTO, and SG scores in comparison to patients who only had one digit replanted ( p  = 0.009, 0.001, and 0.001, respectively). Conclusions  This study suggests that HRQOL can offer better indices for outcomes of digital replantation. This shows some specific replantation cohorts have a significantly better quality of life when compared with their specific correlating revision amputation cohort. These findings can be employed to further refine indications and contraindications to replantation and help predict the quality of life outcomes., Competing Interests: Conflict of Interest: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Lessons Learned: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored., Background: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance., Methods: This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy., Results: Six patients ( n  = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed., Conclusion: The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)