Performance of a packed-bed anode bio-electrochemical reactor for power generation and for removal of gaseous acetone.

The packed anode bioelectrochemical system (Pa-BES) developed in this study is a type of BES that introduces waste gas into a cathode and then into an anode, thereby providing the cathode with sufficient oxygen and reducing the amount of oxygen to the anode to promote the output of electricity. When the empty-bed residence time was 45 s and the liquid flowrate was 35 mL/s, the system achieved optimal performance. Under these conditions, removal efficiency, mineralization efficiency, voltage output, and power density were 93.86%, 93.37%, 296.3 mV, and 321.12 mW/m3, respectively. The acetone in the waste gas was almost completely converted into carbon dioxide, indicating that Pa-BES can effectively remove acetone and has the potential to be used in practical situations. A cyclic voltammetry analysis revealed that the packings exhibited clear redox peaks, indicating that the Pa-BES has outstanding biodegradation and power generation abilities. Through microbial community dynamics, numerous organics degraders, electrochemically active bacteria, nitrifying and denitrifying bacteria were found, and the spatial distribution of these microbes were identified. Among them, Xanthobacter, Bryobacter, Mycobacteriums and Terrimonawas were able to decompose acetone or other organic substances, with Xanthobacter dominating. Bacterium_OLB10 and Ferruginibacter are the electrochemically active bacteria in Pa-BES, while Ferruginibacter is the most abundant in the main anode, which is responsible for electron collection and transfer.

Critical factors for enhancing the bioremediation of a toxic pollutant at high concentrations in groundwater: Toxicity evaluation, degrader tolerance, and microbial community.

Groundwater near refinery and natural gas plants often contain elevated concentrations of toxic sulfolane. Studies on any concentration of sulfolane are limited. Column experiment was conducted to investigate the effects of adding a low dose of H2O2 and nutrient on bioremediation. Vibrio fischeri light inhibition test was used evaluate the toxicity of effluents. The continuous column experiment conditions were sulfolane at 100 mg L-1, dissolved oxygen at 7 mg L-1, absence of phosphorus, and very short hydraulic retention time (7.9 h). A low dose of H2O2 (5.88 mM) enhanced the sulfolane (27.1%) and COD removal (11.8%) in comparison with the control set. Adding nutrient increased bicinchoninic acid protein assay levels, sulfolane removal (99.6%) and COD removal (80.3%). Addition of both H2O2 and nutrient further improved COD removal (90.3%) and COD/sulfolane ratio (0.90) and toxicity removal (Vibrio fischeri light inhibition ratio < 1%). Batch experiment indicated the degraders tolerated sulfolane up to 400 mg L-1. The DGGE method and dendrogram analysis were utilized to investigate the changes of degrader community structure.

[Driving Cessation and Mental Health in Persons With Dementia: A Preliminary Study].

BACKGROUND: The driving safety of persons with dementia (PwD) is an important public-health issue worldwide. Driving is closely related to personal autonomy, self-esteem, and independence. When PwD lose their driving privileges, this may lead to negative effects on mental health. PURPOSE: The purpose of this study was to evaluate the relationship between driving cessation and mental health in PwD. METHODS: A cross-sectional design with convenient sampling was used, Data were collected using structured questionnaires. Participants were all PwDs who were recruited from a medical center in northern Taiwan. RESULTS: A total of 78 PwD were recruited. Two-fifths (41%) of the participants were still driving, with motorcycle the most common vehicle used. The participants who had retired from driving were older, and most did not have a spouse, were less socially active, had a lower mean level of functional ability, and perceived a lower association between driving and quality of life. Driving cessation was found to be positively correlated with age and the instrumental activities of daily living. Depression and anxiety levels in former drivers were higher than in current drivers, although the differences were not significant. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Among PwD, depression and anxiety is higher in former drivers. It is suggested that a prospective study should be conducted, that driving safety issues for PwD should be addressed in public health education, and that standards of driving safety for PwD should be developed and enacted.

One-Pot CuI/DBU-Catalyzed Carboxylative Cyclization toward Oxazolidinones Using Recyclable Molecular Sieves as Efficient Promoters for Fixation of CO2 in Water Medium.

An efficient one-pot synthesis of oxazolidinones was developed through CuI/DBU/MS joint system-catalyzed carboxylative cyclization of arylacetylene, arylaldehyde, and arylamine in water medium under a 1 atm carbon dioxide (CO2) atmosphere. The 4 Šmolecular sieves (MSs) were added to improve CO2 capture and facilitate carboxylation to give the products in high yields. The CuI/DBU/MS system is robust and highly effective for the reactions with different substrates, and some target products were obtained in an excellent yield of ∼96%, with no side products in the final step.

Spironolactone ameliorates endothelial dysfunction through inhibition of the AGE/RAGE axis in a chronic renal failure rat model.

BACKGROUND: Spironolactone can improve endothelial dysfunction in the setting of heart failure and diabetes models. However, its beneficial effect in the cardiovascular system is not clear in the setting of non-diabetic renal failure. We conducted this study to investigate whether spironolactone can ameliorate endothelial dysfunction in a 5/6 nephrectomy model, and to determine the underlying mechanism. METHODS: Twenty-four Sprague-Dawley rats were divided into four groups. A renal failure model was created using the 5/6 nephrectomy method. The four groups included: Sham-operation group (Group1), chronic kidney disease (CKD; Group2), CKD + ALT-711 (advanced glycation end products [AGEs] breaker; Group 3), and CKD + spironolactone group (Group4). Acetylcholine (Ach)-mediated vasodilatation responses were compared between the four groups. To investigate the underlying mechanism, we cultured human aortic endothelial cells (HAECs) for in-vitro assays. Differences between two groups were determined with the paired student's t test. Differences between three or more groups were determined through one-way analysis of variance (ANOVA) with post-hoc analysis with LSD method. RESULTS: Compared with Group 1, Group 2 has a significantly impaired Ach-mediated vasodilatation response. Group 3 and 4 exhibited improved vasoreactivity responses. To determine the underlying mechanism, we performed an in-vitro study using cultured HAECs. We noted significant sirtuin-3 (SIRT3) protein downregulation, reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 (p-eNOS), and increased intracellular oxidative stress in cultured HAECs treated with AGEs (200 µg/mL). These effects were counter-regulated when cultured HAECs were pretreated with spironolactone (10 µM). Furthermore, the increased p-eNOS production by spironolactone was abrogated when the HAECs were pretreated with tenolvin (1 µM), a SIRT3 inhibitor. CONCLUSIONS: Spironolactone could ameliorate endothelial dysfunction in a 5/6 nephrectomy renal failure model through AGEs/Receptor for AGEs (RAGEs) axis inhibition, SIRT3 upregulation, and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) and its associated intracellular oxidative stress attenuation.

Regular exercise and the trajectory of health-related quality of life among Taiwanese adults: a cohort study analysis 2006-2014.

BACKGROUND: Physical activity is related to health-related quality of life, but little evidence from multiple waves of panel data in Asian countries area available. This study aims to explore the impacts of different degree of regular exercise on the trajectories of physical and mental dimensions of health-related quality of life (HRQOL) for community-dwelling Taiwanese adults during 2006-2014. METHODS: Data were derived from the "Landseed Integrated Outreaching Neighborhood Screening (LIONS)" study, with 6182 adults enrolled at the baseline and subsequently followed up to three times till 2014. Linear mixed-effects modeling approach was employed to evaluate the growth curve models of HRQOL (with 16,281 observations) by linear & quadratic time effects, regular exercise (5-level moderate-intensity physical activity), and major influential factors of HRQOL. RESULTS: Regular exercise showed significantly positive dose-response effects on physical HRQOL (ß =1.27~2.54), and regular exercise of 150 min or more showed positive effects on mental HRQOL (ß = 1.55~2.03). Besides, irregular exercise could also improve both physical and mental HRQOL (ß = 1.27 & ß = 0.87). However, such effects were not significant over time (at time slope) on HRQOL. In addition, physical and mental HRQOL improved across time (ß = 1.01 and 1.49, respectively), but the time quadratic effect would significantly offset a little bit on physical dimension (ß = - 0.22). Moreover, being female, increasing age, living alone, or poorer health status were related to lower physical HRQOL; and being younger, living alone, or poorer health status were associated with lower mental HRQOL. CONCLUSIONS: The positive dose-response relationship between regular exercise and HRQOL or its domains was demonstrated for community-dwelling Taiwanese adults. Thus, a regular exercise habit (better ≧150 min per week) is advised for community-based healthcare professionals and the government to incorporate into health promotion strategies and plans.

Improved Lysosomal Trafficking Can Modulate the Potency of Antibody Drug Conjugates.

Antibody drug conjugates (ADCs) provide an efficacious and relatively safe means by which chemotherapeutic agents can be specifically targeted to cancer cells. In addition to the selection of antibody targets, ADCs offer a modular design that allows selection of ADC characteristics through the choice of linker chemistries, toxins, and conjugation sites. Many studies have indicated that release of toxins bound to antibodies via noncleavable linker chemistries relies on the internalization and intracellular trafficking of the ADC. While this can make noncleavable ADCs more stable in the serum, it can also result in lower efficacy when their respective targets are not internalized efficiently or are recycled back to the cell surface following internalization. Here, we show that a lysosomally targeted ADC against the protein APLP2 mediates cell killing, both in vitro and in vivo, more effectively than an ADC against Trop2, a protein with less efficient lysosomal targeting. We also engineered a bispecific ADC with one arm targeting HER2 for the purpose of directing the ADC to tumors, and the other arm targeting APLP2, whose purpose is to direct the ADC to lysosomes for toxin release. This proof-of-concept bispecific ADC demonstrates that this technology can be used to shift the intracellular trafficking of a constitutively recycled target by directing one arm of the antibody against a lysosomally delivered protein. Our data also show limitations of this approach and potential future directions for development.

Effect of attachment site on stability of cleavable antibody drug conjugates.

The systemic stability of the antibody-drug linker is crucial for delivery of an intact antibody-drug conjugate (ADC) to target-expressing tumors. Linkers stable in circulation but readily processed in the target cell are necessary for both safety and potency of the delivered conjugate. Here, we report a range of stabilities for an auristatin-based payload site-specifically attached through a cleavable valine-citrulline-p-aminobenzylcarbamate (VC-PABC) linker across various sites on an antibody. We demonstrate that the conjugation site plays an important role in determining VC-PABC linker stability in mouse plasma, and that the stability of the linker positively correlates with ADC cytotoxic potency both in vitro and in vivo. Furthermore, we show that the VC-PABC cleavage in mouse plasma is not mediated by Cathepsin B, the protease thought to be primarily responsible for linker processing in the lysosomal degradation pathway. Although the VC-PABC cleavage is not detected in primate plasma in vitro, linker stabilization in the mouse is an essential prerequisite for designing successful efficacy and safety studies in rodents during preclinical stages of ADC programs. The divergence of linker metabolism in mouse plasma and its intracellular cleavage offers an opportunity for linker optimization in the circulation without compromising its efficient payload release in the target cell.

A multi-gene dataset reveals a tropical New World origin and Early Miocene diversification of croakers (Perciformes: Sciaenidae).

Widely distributed groups of living animals, such as the predominantly marine fish family Sciaenidae, have always attracted the attention of biogeographers to document the origins and patterns of diversification in time and space. In this study, the historical biogeography of the global Sciaenidae is reconstructed within a molecular phylogenetic framework to investigate their origin and to test the hypotheses explaining the present-day biogeographic patterns. Our data matrix comprises six mitochondrial and nuclear genes in 93 globally sampled sciaenid species from 52 genera. Within the inferred phylogenetic tree of the Sciaenidae, we identify 15 main and well-supported lineages; some of which have not been recognized previously. Reconstruction of habitat preferences shows repeated habitat transitions between marine and euryhaline environments. This implies that sciaenids can easily adapt to some variations in salinity, possibly as the consequence of their nearshore habitats and migratory life history. Conversely, complete marine/euryhaline to freshwater transitions occurred only three times, in South America, North America and South Asia. Ancestral range reconstruction analysis concomitant with fossil evidence indicates that sciaenids first originated and diversified in the tropical America during the Oligocene to Early Miocene before undergoing two range expansions, to Eastern Atlantic and to the Indo-West Pacific where a maximum species richness is observed. The uncommon biogeographic pattern identified is discussed in relation to current knowledge on origin of gradients of marine biodiversity toward the center of origin hypothesis in the Indo-West Pacific.

Immunocytochemical Localization of Monoamine Oxidase Type B in Rat's Peripheral Nervous System.

Immunohistochemistry is used to investigate subcellular localization of monoamine oxidase type B (MAOB) in the axon of the rat's peripheral nervous system. Through light and electron microscopy, the presence of MAOB-immunoreactive structures in the propria lamina of tongue and on the outer membranes of mitochondria in both myelinated and unmyelinated axons can be detected. As a result, MAOB may potentially play a crucial role in the axons of the rat's peripheral nervous system and may be closely associated with both axonal transport and nerve conduction.

Delayed time from first medical visit to diagnosis for breast cancer patients in Taiwan.

BACKGROUND/PURPOSE: Delay in diagnosis may affect the survival of breast cancer patients. The purpose of this study was to investigate delayed diagnosis for breast cancer patients in Taiwan. METHODS: This study was conducted via one-to-one interviews with structured questionnaires in hospital outpatient visit. Included were 600 breast cancer patients seeking medical care in two medical centers in central Taiwan. RESULTS: Average delay in breast cancer diagnosis was 27.8 days. Service level of the patients' first visit and number of hospitals patients visited before obtaining a correct diagnosis were significantly associated with delay in diagnosis. Logistic regression analysis found that patients who had visited two, and three or more hospitals before getting a correct diagnosis had longer delays in diagnosis than patients who had visited one hospital (odds ratio = 2.23 and 9.26, 95% confidence interval 1.37-3.63 and 95% CI:3.87-22.15, respectively). CONCLUSION: Results of this study are anticipated to serve as a reference for the government and medical institutions to develop policies to reduce the number of hospitals visited before diagnosis for breast cancer patients, and ultimately to achieve the goal of early detection and treatment.

Optimized combination of zero-valent iron and oxygen-releasing biochar as cathodes of microbial fuel cells to enhance copper migration in sediment.

Membrane-less single-medium sediment microbial fuel cells (single-SMFC) can remove Cu2+ from sediment through electromigration. However, the high mass transfer resistance of the sediment and amount of oxygen at the cathode of the SMFC limit its Cu2+ removal ability. Therefore, this study used an oxygen-releasing bead (ORB) for slow oxygen release to increase oxygen at the SMFC cathode and improve the mass transfer property of the sediment. Resultantly, the copper removal efficiency of SMFC increased significantly. Response surface methodology was used to optimize the nano zero-valent iron (nZVI)-modified biochar as the catalyst to enhance the ability of the modified ORB (ORBm) to remove Cu2+ and slow release of O2. The maximum Cu2+ removal (95 %) and the slowest O2 release rate (0.41 mg O2/d·g ORBm) were obtained when the CaO2 content and ratio of nZVI-modified biochar to unmodified biochar were 0.99 g and 4.95, respectively. When the optimized ORBm was placed at the single-SMFC cathode, the voltage output and copper removal increased by 4.6 and 2.1 times, respectively, compared with the system without ORBm. This shows that the ORBm can improve the migration of Cu2+ in the sediment, providing a promising remediation method for Cu-contaminated sediments.

Lapatinib-induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors.

INTRODUCTION: Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. METHODS: Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. RESULTS: Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. CONCLUSIONS: These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.

Urinary tract infection increases subsequent urinary tract cancer risk: a population-based cohort study.

This study examines the possible association between urinary tract infection (UTI) and urinary tract cancer (UTC). Data from the National Health Insurance system of Taiwan were used for the analysis. The UTI cohort included 70 116 patients who were diagnosed and recruited between 1997 and 2010. Each patient was randomly frequency-matched with two people without UTI from the general population based on their age, sex, and month of UTI diagnosis. Cox's proportional hazard regression analysis was used to estimate the effects of UTI on UTC risk until the end of follow-up on December 31, 2010. Patients with UTI had a significantly higher risk of developing UTC than healthy people (adjusted hazard ratio, 4.66; 95% confidence interval, 3.55-6.10). Further analyses indicated that risks are potentially related to the level of the lesion site. This study indicated that patients with UTI had a higher risk of developing UTC.

Urinary tract stone raises subsequent risk for urinary tract cancer: a population-based cohort study.

OBJECTIVE: To evaluate the association between urinary tract stone (UTS) and urinary tract cancer (UTC) in Taiwanese patients, as the results of epidemiological studies about the relationship between UTS and the development of UTC remain inconclusive. PATIENTS/SUBJECTS AND METHODS: We conducted a population-based cohort study using data from the Taiwanese National Health Insurance system. The UTS cohort included 21 862 patients, and each patient was randomly frequency-matched for age, sex, and index year with two insured members of the general population who did not have UTS. Cox proportional hazard regression analysis was performed to estimate the effect of UTS on the risk of UTC. RESULTS: Patients with UTS were at a significantly higher risk of developing UTC compared with the comparison group (adjusted hazard ratio 4.66; 95% confidence interval 2.97-7.30). Women were at higher risk than men. Further analyses showed that the level of UTC was associated with that of UTS, and that the risk for UTC became more divergent for the two groups over time. CONCLUSIONS: Taiwanese patients with UTS, particularly women, had a higher risk for developing UTC than patients without UTS. The risk became more marked over time for this group.

Sensitivity and reusability of a simple microbial fuel cell-based sensor for detecting bisphenol A in wastewater.

Polycarbonate plastic processing wastewater contains high concentrations of bisphenol A (BPA), requiring a real-time technology to monitor wastewater containing BPA. Since the activity of electrogenic microorganisms on the anode surface of the microbial fuel cell (MFC) sensor is inhibited by exposure to contaminants, the toxicity of contaminants in wastewater can be determined by observing the variation in voltage output from the MFC sensor. The simple MFC sensor that is developed in this work exhibited a significant decrease in voltage output in BPA-containing wastewater concentration of 5-100 mg/L. Sensitivity analysis revealed that the voltage change (ΔV) was strongly correlated with the BPA concentration, with R2 as high as 0.97. This study was the first to investigate the number of repeated uses of the MFC sensor, using sodium acetate as the regeneration solution for the MFC sensor, leading to a successful recovery of detection performance. However, as the number of uses increased (up to the third or fourth use), the ΔV of the MFC sensor for BPA gradually decreased and the sensitivity decreased significantly from 0.238 mV/mg/L to 0.027 mV/mg/L. In the low BPA concentration range (≦20 mg/L), the MFC sensor can be reused up to 5 times, demonstrating that the proposed MFC sensor can be reused. Microorganisms contribute to the power generation of the MFC sensor, which can be exploited in the detection of pollutants, enabling the determination of wastewater toxicity and providing early warnings of thereof. Conventional MFC sensors are complex and lack the ability to explore repeated use, so they are not easily applied to actual wastewater detection. The proposed MFC sensor has many advantages such as simplicity, rapid detection, and reusability, solving the problem of the high cost of using disposable MFC sensors and making them feasible for practical use.

Effects of biodegradation, biotoxicity and microbial community on biostimulation of sulfolane.

To evaluate the effectiveness of biostimulation in remediating soil-free groundwater and groundwater with soil, experiments were conducted using soil and groundwater samples that were contaminated with sulfolane. The main objective was to characterize the differences in sulfolane removal efficiency and biotoxicity between in situ soil-free groundwater and groundwater with soil and different concentrations of dissolved oxygen (1 mg/L and 5 mg/L) and various nutrient salts (in situ and spiked). Optimizing the nutrient salt conditions improved the removal efficiency of sulfolane by 1.8-6.5 that under in situ nutrient salt conditions. Controlling the dissolved oxygen concentration enhanced the efficiency of removal of sulfolane by 1.5-4.5 times over that at the simulated in situ dissolved oxygen concentration, suggesting that the degradation of sulfolane by indigenous microorganisms requires nutrient salts more than it requires dissolved oxygen. Biotoxicity data showed that the luminescence inhibition of Aliivibrio fischeri by sulfolane was lower in the biostimulated samples than in the pre-treated samples. Biostimulation reduced the biotoxicity of the treated samples by 42-51%, revealing that it was effective in removing sulfolane and reducing biotoxicity. Microbial community analysis showed that the biostimulation did not change the dominant species in the original in situ community, and increased the proportion of sulfolane-degraders. The outcome of this study can be used to set parameters for the remediation of groundwater that is contaminated by sulfolane in oil refineries.

Antibody-Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer.

Antibody-drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety-exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS-TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of the T moiety-exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs. SIGNIFICANCE: ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options. See related commentary by Gupta et al., p. 817. This article is highlighted in the In This Issue feature, p. 799.

A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed Antibody-Drug Conjugate for Targeting Melanoma.

Recent advances in targeted therapy and immunotherapy have substantially improved the treatment of melanoma. However, therapeutic strategies are still needed for unresponsive or treatment-relapsed patients with melanoma. To discover antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma, we developed an atlas of melanoma cell surface-binding antibodies (pAb) using a proteome-scale antibody array platform. Target identification of pAbs led to development of melanoma cell killing ADCs against LGR6, TRPM1, ASAP1, and MUC18, among others. MUC18 was overexpressed in both tumor cells and tumor-infiltrating blood vessels across major melanoma subtypes, making it a potential dual-compartment and universal melanoma therapeutic target. AMT-253, an MUC18-directed ADC based on topoisomerase I inhibitor exatecan and a self-immolative T moiety, had a higher therapeutic index compared with its microtubule inhibitor-based counterpart and favorable pharmacokinetics and tolerability in monkeys. AMT-253 exhibited MUC18-specific cytotoxicity through DNA damage and apoptosis and a strong bystander killing effect, leading to potent antitumor activities against melanoma cell line and patient-derived xenograft models. Tumor vasculature targeting by a mouse MUC18-specific antibody-T1000-exatecan conjugate inhibited tumor growth in human melanoma xenografts. Combination therapy of AMT-253 with an antiangiogenic agent generated higher efficacy than single agent in a mucosal melanoma model. Beyond melanoma, AMT-253 was also efficacious in a wide range of MUC18-expressing solid tumors. Efficient target/antibody discovery in combination with the T moiety-exatecan linker-payload exemplified here may facilitate discovery of new ADC to improve cancer treatment. SIGNIFICANCE: Discovery of melanoma-targeting antibodies using a proteome-scale array and use of a cutting-edge linker-payload system led to development of a MUC18-targeting antibody-exatecan conjugate with clinical potential for treating major melanoma subtypes.

High rate of qacA- and qacB-positive methicillin-resistant Staphylococcus aureus isolates from chlorhexidine-impregnated catheter-related bloodstream infections.

Chlorhexidine has been widely used for infection control. Although the use of chlorhexidine-impregnated catheters has reduced catheter-related infections, chlorhexidine-resistant Staphylococcus aureus has emerged. The correlation between the existence of the chlorhexidine-resistant genes qacA and qacB (qacA/B) in methicillin-resistant Staphylococcus aureus (MRSA) isolates and the effectiveness of chlorhexidine-impregnated catheters in the prevention of MRSA infections is unknown. Sixty methicillin-sensitive Staphylococcus aureus (MSSA) and 96 MRSA isolates from the blood cultures of different patients were collected, and a case-control study was conducted to determine whether more clinical S. aureus isolates from chlorhexidine-impregnated catheter-related bloodstream infections (CRBSI) have the biocide-resistant genes (qacA/B or smr) than those from other infections. The chlorhexidine MIC(50)s of MSSA and MRSA isolates were 1 µg/ml and 2 µg/ml, respectively. Results of PCR analyses showed that 3.3% (n = 2) of MSSA and 43.8% (n = 42) of MRSA isolates harbored qacA/B and 5% (n = 3) of MSSA and 25% (n = 24) of MRSA isolates contained smr. With multivariate logistic regression analyses, the significant risk factors for definite CRBSI with chlorhexidine-impregnated catheters were determined to be S. aureus isolates with qacA/B and a chlorhexidine MIC of ≥2 µg/ml (odds ratios [OR], 9.264 and 8.137, respectively, in all 156 S. aureus isolates and 6.097 and 4.373, respectively, in the 96 MRSA isolates). Further prospective studies are needed to investigate the transmission of these biocide-resistant genes.