Hierarchical 3D porous trimetallic palladium-iron and cobalt on nickel foam as electrocatalyst for large current density oxygen evolution reaction in alkaline seawater.

Electrolysis in seawater is a low-cost but difficult method of producing hydrogen. Herein, self-assembled hierarchical three-dimensional (3D) porous trimetallic palladium-iron and cobalt oxide anchored on a cheap and high surface area nickel foam (NF) (PdFeCo3-xO4/NF) were synthesized using a simple and low-cost impregnation-hydrothermal and thermal reduction strategy. The as-fabricated PdFeCo3-xO4/NF electrode showed both superhydrophilic and superaerophobic properties, which favored the fat removal of oxygen bubbles from the electrode surface owing to the close interaction between the electrode and electrolyte. Furthermore, the significant synergistic effect of trimetallics and the NF-matrix resulted in substantially enhanced oxygen evolution reaction (OER) intrinsic activity. The self-assembled PdFeCo3-xO4/NF catalyst exhibited critical low overpotentials of 300 and 340 mV to achieve an extremely large current density of 100 mA cm-2 in 1 M KOH solution and 1 M KOH seawater. Cell voltages as low as 1.44 and 1.51 V were required to drive 10 mA cm-2 in alkaline solution and seawater electrolytes for the full cell overall water splitting performance. This work suggests a promising strategy for developing next-generation electrocatalysts appropriate for natural seawater with cost-effective.

Association between smoking status and death from COVID-19 in South Korea: A nationwide cohort study.

INTRODUCTION: This study examined the association between smoking status and death from COVID-19. METHODS: This study used nationwide cohort data collected from the Korean National Health Insurance Service, linking to information on all individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The smoking status of subjects who participated twice in national health screenings between 2015 and 2018 was measured. This study investigated death from COVID-19 among those who tested positive from 1 January to 30 May 2020. RESULTS: This study included 4259 patients who tested positive for SARS-CoV-2 in Korea. After adjusting for all potential confounding factors, current smokers (adjusted odds ratio, AOR=3.75; 95% CI: 1.23-11.36) and recent quitters (AOR=3.74; 95% CI: 1.12-12.53) were associated with an increased risk of death from COVID-19 compared to never smokers. Compared with current smokers, long-term quitters (AOR=0.33; 95% CI: 0.11-0.95) and never smokers (AOR=0.27; 95% CI: 0.09-0.81) were associated with a reduced risk of death from COVID-19. CONCLUSIONS: Smoking was associated with an increased risk of death among patients with COVID-19. Given the lower possibility of death in long-term quitters with COVID-19, continuous smoking cessation among smokers or recent quitters is needed.

Mental Disorders and Suicide Risk among Cancer Patients: A Nationwide Cohort Study.

Although cancer patients are known to experience mental disorders and face suicide risk, little is known about the relationship between mental illness and death by suicide in this group. As such, this study aims to examine the association between mental disorders and suicide risk among cancer patients. We used nationally representative cohort data, and included newly diagnosed cancer patients from 2004 to 2012 with whom we followed-up throughout 2013. We used the clinical diagnoses of all mental disorders as an independent variable and suicide death as a dependent variable to estimate the adjusted hazard ratio (AHR) of suicide deaths in patients with cancer using a Cox proportional hazard model. Among total cancer patients (n = 36,220), the 10,567 patients with mental disorders showed higher suicide risk than non-cancer patients (AHR, 1.53; 95% confidence interval [CI], 1.07-2.17), particularly in those who experienced mental disorders prior to cancer diagnosis (AHR, 2.24; 95% CI, 1.35-3.71). Suicide risk among cancer patients who had mood disorders (AHR, 2.23, 95% CI, 1.31-3.81) or anxiety and somatoform disorders (AHR, 1.61, 95% CI, 1.02-2.55) was higher than for those without mental disorders. Suicide risk of stomach (AHR, 3.32; 95% CI, 1.36-8.10) and liver (AHR, 7.57; 95% CI, 1.86-30.72) cancer patients who had mental disorders was higher than for patients without mental disorders. Cancer patients with mental disorders are at increased risk for suicide. During follow-ups after cancer diagnosis, early mental health support needs were provided to patients with mental disorders.

Smoking Cessation, Weight Change, Diabetes, and Hypertension in Korean Adults.

INTRODUCTION: This study investigates the association of smoking cessation and postcessation weight gain with the development of type 2 diabetes mellitus and hypertension. METHODS: A total of 96,524 individuals without diabetes mellitus and hypertension aged ≥20 years between 2006 and 2008 were included, with follow-up until December 31, 2015. Smoking status and weight changes were monitored for 2 years. Hazard ratios and 95% CIs were calculated for the respective risks of the 2 conditions. Analyses were completed in 2020. RESULTS: Compared with current smokers, the adjusted hazard ratios for the risk of type 2 diabetes and hypertension were 0.90 (95% CI=0.85, 0.96) and 1.00 (95% CI=0.95, 1.05) in recent quitters, 0.89 (95% CI=0.84, 0.95) and 0.92 (95% CI=0.88, 0.97) in long-term quitters, and 0.82 (95% CI=0.78, 0.86) and 0.92 (95% CI=0.89, 0.95) in never smokers. Compared with current smokers, the adjusted hazard ratios for the risk of type 2 diabetes and hypertension were 0.86 (95% CI=0.80, 0.93) and 0.98 (95% CI=0.92, 1.04) in recent quitters with no weight gain, 0.94 (95% CI=0.87, 1.03) and 1.00 (95% CI=0.94, 1.07) in those with 0.1-5 kg weight gain, 0.93 (95% CI=0.73, 1.19) and 1.14 (95% CI=0.96, 1.36) in those with 5.1-10 kg weight gain, and 1.49 (95% CI=0.84, 2.62) and 1.10 (95% CI=0.68, 1.77) in those with a weight gain of >10 kg. CONCLUSIONS: Smoking cessation with no subsequent weight gain is associated with a reduced risk of developing type 2 diabetes. However, weight gain after smoking cessation attenuates the reduced risk of type 2 diabetes. The association between recent quitting and incident hypertension was nonsignificant, whereas long-term quitters had reduced risk of developing hypertension and type 2 diabetes.

Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs). METHODS: Fifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab. RESULTS: For buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone. CONCLUSIONS: The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN. CLINICAL TRIAL REGISTRATION: NCT01527877.

Association of smoking cessation after new-onset type 2 diabetes with overall and cause-specific mortality among Korean men: a nationwide population-based cohort study.

INTRODUCTION: This study aimed to examine the association between smoking cessation after new-onset type 2 diabetes and overall and cause-specific mortality risks among Korean men. RESEARCH DESIGN AND METHODS: The Korean National Health Insurance Service-National Health Screening Cohort database was searched, and 13 377 Korean men aged ≥40 years diagnosed with new-onset type 2 diabetes between 2004 and 2007 were included and followed up until 2013. We defined smoking status changes by comparing participants' answers in the last survey before diagnosis to those in the first survey after diagnosis. We estimated the adjusted HR (AHR) and 95% CI for mortality risk using multivariable Cox proportional hazards regression models. RESULTS: We identified 1014 all-cause mortality events (cancer, n=406 and cardiovascular disease (CVD), n=184) during an average follow-up duration of 7.2 years. After adjustment for all confounding factors, the reduced risk of all-cause mortality was more significant among short-term quitters (AHR 0.78; 95% CI 0.64 to 0.95), long-term quitters (AHR 0.68; 95% CI 0.54 to 0.85), and never smokers (AHR 0.66; 95% CI 0.56 to 0.78) compared with current smokers (p for trend <0.001). The lower risk of mortality from cancer was significant among the short-term quitters (AHR 0.60; 95% CI 0.44 to 0.83), long-term quitters (AHR 0.67; 95% CI 0.46 to 0.90), and never smokers (AHR 0.50; 95% CI 0.39 to 0.65) compared with current smokers (p for trend <0.001). There was no significant association between changes in smoking status and death from CVD. Smoking cessation after diagnosis in non-obese individuals (AHR 0.73; 95% CI 0.58 to 0.92) and exercisers (AHR 0.54; 95% CI 0.38 to 0.76) was significantly associated with reduced mortality risk than current smoking. CONCLUSIONS: Smoking cessation after new-onset type 2 diabetes was associated with reduced mortality risk.

Correction: Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.

BACKGROUND: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. METHODS: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. RESULTS: From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. CONCLUSIONS: Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.

Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

BACKGROUND: Oropharyngeal cancer (OPC) exhibits diverse immunological properties; however, their implications for immunotherapy are unknown. METHODS: We analysed 37 surgically resected and nine recurrent or metastatic anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-treated OPC tumours. OPCs were classified into immune-rich (IR), mesenchymal (MS) and xenobiotic (XB) subtypes based on RNA-sequencing data. RESULTS: All IR type tumours were human papillomavirus (HPV) positive, most XB types were HPV negative, and MS types showed mixed HPV status. The IR type showed an enriched T cell exhaustion signature with PD-1+ CD8+ T cells and type I macrophages infiltrating the tumour nest on multiplex immunohistochemistry. The MS type showed an exclusion of CD8+ T cells from the tumour nest and high MS and tumour growth factor-ß signatures. The XB type showed scant CD8+ T cell infiltration and focal CD73 expression. The IR type was associated with a favourable response signature during anti-PD-1/PD-L1 therapy and showed a high APOBEC mutation signature, whereas the MS and XB types showed resistance signature upregulation. Among anti-PD-1/PD-L1-treated OPC patients, the IR type showed a favourable clinical response (3/4 patients), whereas the XB type showed early progression (3/3 patients). CONCLUSION: Our analysis classified OPCs into three subtypes with distinct immune microenvironments that are potentially related to the response to anti-PD-1/PD-L1 therapy.

Suicide risk after cancer diagnosis among older adults: A nationwide retrospective cohort study.

OBJECTIVES: Cancer increases suicide risk, but little is known about associations between cancer and suicide among older adults. We aimed to investigate suicide risk within 1 year after cancer diagnosis in older adults. METHODS: Using National Health Insurance Service-Senior Cohort data, we included newly diagnosed older patients with cancer and older adults without cancer, selected by a 1:3 propensity score matching using sex, age, Charlson comorbidity index, and index year from 2004 to 2012 and followed them up throughout 2013. We used Cox proportional hazard models to estimate adjusted hazard ratios (AHR) of suicide risk. RESULTS: In the total sample of 259,688 older adults (aged 62-115 years), the highest proportion of observed suicide deaths occurred within one year after cancer diagnosis (36.1% of total); 64,922 older patients with cancer showed higher suicide risk after cancer diagnosis compared to non-cancer participants (AHR 2.05; 95% CI 1.64-2.56). Patients with mental disorder diagnosis before cancer diagnosis (AHR 2.98; 95% CI 2.12-4.18) had increased suicide risk than those without mental disorder diagnosis (AHR 1.78; 95% CI 1.38-2.29) compared to non-cancer participants. Suicide risk among older patients with bladder, head and neck, liver, lung, and stomach cancers was higher than in non-cancer participants (AHR 4.77, 2.28, 2.99, 1.98, 2.40; 95% CI 2.53-8.99, 1.47-3.54, 1.63-5.49, 1.15-3.40, 1.57-2.24), respectively. CONCLUSIONS: Older patients with cancer have a higher suicide risk. Early mental health support needs to be provided with consideration of prediagnosis mental disorders during follow-up after cancer diagnosis.

Molecular characterization of lung adenocarcinoma from Korean patients using next generation sequencing.

The treatment of Lung adenocarcinoma (LUAD) could benefit from the incorporation of precision medicine. This study was to identify cancer-related genetic alterations by next generation sequencing (NGS) in resected LUAD samples from Korean patients and to determine their associations with clinical features. A total of 201 tumors and their matched peripheral blood samples were analyzed using targeted sequencing via the Illumina HiSeq 2500 platform of 242 genes with a median depth of coverage greater than 500X. One hundred ninety-two tumors were amenable to data analysis. EGFR was the most frequently mutated gene, occurring in 106 (55%) patients, followed by TP53 (n = 67, 35%) and KRAS (n = 11, 6%). EGFR mutations were strongly increased in patients that were female and never-smokers. Smokers had a significantly higher tumor mutational burden (TMB) than never-smokers (average 4.84 non-synonymous mutations/megabase [mt/Mb] vs. 2.84 mt/Mb, p = 0.019). Somatic mutations of APC, CTNNB1, and AMER1 in the WNT signaling pathway were highly associated with shortened disease-free survival (DFS) compared to others (median DFS of 89 vs. 27 months, p = 0.018). Patients with low TMB, annotated as less than 2 mt/Mb, had longer DFS than those with high TMB (p = 0.041). A higher frequency of EGFR mutations and a lower of KRAS mutations were observed in Korean LUAD patients. Profiles of 242 genes mapped in this study were compared with whole exome sequencing genetic profiles generated in The Cancer Genome Atlas Lung Adenocarcinoma. NGS-based diagnostics can provide clinically relevant information such as mutations or TMB from readily available formalin-fixed paraffin-embedded tissue.

Association of employment status and income with self-rated health among waged workers with disabilities in South Korea: population-based panel study.

OBJECTIVE: This study aimed to examine the association of employment status and income with self-rated health among waged workers with disabilities in South Korea. METHODS: This study used the Panel Survey of Employment for the Disabled from 2011 to 2015. A total of 951 waged workers with disabilities were selected as baseline subjects in 2011 and were followed up for 5 years. This study used a generalised linear mixed model after adjusting for covariates. RESULTS: Among 951 waged workers with disabilities, the results showed that 39.3% of workers with disabilities reported poor self-rated health. Workers with disabilities with a precarious employment status and lower income were 1.22 (95% CI 1.21 to 1.23) and 1.81 (95% CI 1.80 to 1.83) times more likely to have poor self-rated health than those with permanent employment and higher income, respectively. A subgroup analysis found that precarious workers with disabilities in lower income households had higher possibilities of poor self-rated health. CONCLUSION: This study suggests that precarious employment and lower income of waged workers with disabilities are significantly associated with poor self-rated health compared with those with permanent jobs or higher income.

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer.

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFßR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors.

Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma.

OBJECTIVES: Radon, a natural radiation, is the leading environmental cause of lung cancer in never-smokers. However, the radon exposure impact on the mutational landscape and tumor mutation burden (TMB) of lung cancer in never-smokers has not been explored. The aim of this study was to investigate the mutational landscape of lung adenocarcinoma in never-smokers who were exposed to various degrees of residential radon. MATERIALS AND METHODS: To investigate the effect of indoor radon exposure, we estimated the cumulative exposure to indoor radon in each house of patients with lung cancer with a never-smoking history. Patients with at least 2 year-duration of residence before the diagnosis of lung adenocarcinoma were included. Patients were subgrouped based on the median radon exposure level (48 Bq/m3): radon-high vs. radon-low and targeted sequencing of tumor and matched blood were performed in all patients. RESULTS: Among 41 patients with lung adenocarcinoma, the TMB was significantly higher in the radon-high group than it was in the radon-low group (mean 4.94 vs. 2.6 mutations/Mb, P = 0.01). The recurrence rates between radon-high and radon-low group did not differ significantly. Mutational signatures of radon-high tumors showed features associated with inactivity of the base excision repair and DNA replication machineries. The analysis of tumor evolutionary trajectories also suggested a series of mutagenesis induced by radon exposure. In addition, radon-high tumors revealed a significant protein-protein interaction of genes involved in DNA damage and repair (P < 0.001). CONCLUSIONS: Indoor radon exposure increased the TMB in never-smoker patients with lung adenocarcinoma and their mutational signature was associated with defective DNA mismatch repair.

Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. MATERIALS AND METHODS: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. RESULTS: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)-negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). CONCLUSION: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Remediation of metal-contaminated marine sediments using active capping with limestone, steel slag, and activated carbon: a laboratory experiment.

The objectives of this study are to assess the effectiveness of limestone (LS), steel slag (SS), and activated carbon (AC) as capping materials to sequester trace metals including As, Cd, Cr, Cu, Ni, Pb, and Zn in heavily contaminated marine sediments and to minimize the release of these metals into the water column. A flat flow tank was filled with 10 mm of capping material, contaminated sediments, and seawater, and the metal concentrations were monitored over 32 d. After completion of the flow tank experiments, the sediments below the capping material were sampled and were sequentially extracted. SS effectively reduced the As, Cr, Cu, Ni, Pb, and particularly Cd elution from the contaminated sediments to the overlying seawater. Adsorption and surface precipitation were the key mechanisms for interrupting the release of cationic trace metals by SS. LS was appropriate for interrupting the release of only Cu and Pb with high hydrolysis reaction constants. AC capping could interrupt the release of Cr, Cu, Ni, and particularly Zn from the sediments by binding with the metals via electrostatic interaction. The results obtained from the sequential extraction revealed that LS capping is appropriate for stabilizing Zn, whereas AC is appropriate for Cd and Pb. LS, SS, and AC can be applied effectively for remediation of sediments contaminated by trace metals because it interrupts their release and stabilizes the trace metals in the sediments.

Statistical optimization of preparing marine macroalgae derived activated carbon/iron oxide magnetic composites for sequestering acetylsalicylic acid from aqueous media using response surface methodologys.

This study focuses on the optimization of synthetic conditions for preparing marine macroalgae-derived activated carbon/iron oxide magnetic composites (AC/Fe-MC) and its feasibility for the removal of acetylsalicylic acid from aqueous media. Response surface methodology coupled with a 3k Box-Behnken design was applied to determine the optimal conditions (independent variables: impregnation ratio, activation temperature, and activation time) towards two response variables (production yield and adsorption capacity). According to the analysis of variance and numerical desirability function approaches, the optimal conditions were impregnation ratio of 2.62:1, activation temperature of 727 °C, and activation time of 129 min. Physicochemical properties of the prepared composite revealed that AC/Fe-MC possesses a porous structure and superparamagnetic property, which substantially contributed to the effective adsorption capacity and separation from the solution using an external magnetic field. Adsorption kinetics and equilibrium studies delineated that the pseudo-second-order and Sips isotherm models represent the adsorption behavior of AC/Fe-MC accurately. The maximum adsorption capacity of AC/Fe-MC was found to be around 127 mg/g at 10 °C, as fitted by Sips isotherm model, which is higher than that of other adsorbents reported in the literature. Intraparticle diffusion and Boyd models suggested that the adsorption process was mainly controlled by film diffusion mechanism. Lastly, thermodynamic and isosteric heat of adsorption analyses demonstrated that the adsorption process was controlled by physisorption and exothermic mechanisms.

Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation.

BACKGROUND: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy. METHODS: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients. RESULTS: Using samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform. CONCLUSION: The establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.

Strong chromate-adsorbent based on pyrrolic nitrogen structure: An experimental and theoretical study on the adsorption mechanism.

Chromate is considered a toxic contaminant in various water sources because it poses a risk to animal and human health. To meet the stringent limits for chromium in water and wastewater, pyrrolic nitrogen structure was investigated as a chromate adsorbent for aqueous solutions, employing a polypyrrole coating on carbon black. The characteristics of the adsorbent were analyzed by high-resolution transmission electron microscopy, energy-filtered transmission electron microscopy, and X-ray photoelectron spectroscopy. Chromate was adsorbed as both Cr(III) and Cr(VI). The chromate adsorption capacity increased (from 50.84 to 174.81 mg/g) with increasing amounts of pyrrole monomers (from 50 to 86%) in the adsorbent. The adsorption capacity was well-correlated with the pyrrolic nitrogen content (from 2.06 to 6.57 at%) in the adsorbent, rather than other types of nitrogen. The optimized adsorption capacity (174.81 mg/g in the equilibrium batch experiment and 211.10 mg/g at an initial pH of 3) was far superior to those of conventional adsorbents. We investigated the mechanism behind this powerful chromate adsorption on pyrrolic nitrogen via physical/chemical analyses of the pH-dependent adsorption behavior, supported by first-principles calculation based on density functional theory. We found that Cr(III) and Cr(VI) adsorption followed different reaction paths. Cr(III) adsorption occurred in two sequential steps: 1) A Jones oxidation reaction (JOR)-like reaction of Cr(VI) with pyrrolic N that generates Cr(III), and 2) Cr(III) adsorption on the deprotonated pyrrolic N through Cr(III)-N covalent bonding. Cr(VI) adsorption followed an alternative path: hydrogen-bonding to the deprotonation-free pyrrolic N sites. The pH-dependent fractional deprotonation of the pyrrolic N sites by the JOR-like reaction in the presence of chromate played an important role in the adsorption.

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors.

Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with ALK fusion-positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a pan-histone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and EML4-ALK transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy.Significance: Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer. Cancer Res; 78(12); 3350-62. ©2018 AACR.