Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

PURPOSE: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. PATIENTS AND METHODS: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. RESULTS: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. CONCLUSION: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

In situ polymerization and electrical conductivity of polypyrrole/cellulose nanocomposites using Schweizer's reagent

Cellulose-based composites have attracted interest given the shift towards ‘green’ materials, but achieving uniform dispersions of cellulose in polymer matrices and/or enhancement of interfacial interactions between components remains challenging. Herein we report the preparation of polypyrrole/cellulose nanocomposites in [Cu(NH₃)₄(H₂O)₂](OH)₂ (Schweizer''s reagent/cuoxam)-based reaction media via in situ polymerization. The effect of cellulose template morphology and reaction media on the microstructure, electrical conductivity, and surface wettability was studied. Aqueous reaction media favored the formation of a uniform polypyrrole coating encapsulating the cellulose fibers; concentrated cuoxam solutions promoted inhomogeneity and exhibited a progressive decline in conductivity. The maximum conductivity attained was 3.08 S cm⁻¹ from a bacterial cellulose-templated composite prepared in aqueous reaction media and afforded an approximately threefold increase in conductivity when compared with pure PPy at 1.14 S cm⁻¹. Generally, the composites resembled wetting surfaces – with highly concentrated cuoxam solutions yielding improved hydrophilicity, while substitution of bacterial cellulose with nanocrystalline cellulose engendered a shift towards hydrophobicity. Most composites displayed a contact angle of less than 90° suggesting PPy/cellulose composites tended towards hydrophilic behavior. This study highlights investigations into the viability of cellulose solvents as a facile means to control the structure and performance of in situ functionalized cellulose nanocomposites.

The in situ polymerization of polypyrrole/cellulose nanocomposites using Schweizer''s reagent is demonstrated and measured against a number of structural, electrical, and colligative properties.     

Hernia formation after single‐stage umbilical vein marsupialization in three Percheron foals diagnosed with septic omphalophlebitis

Septic omphalophlebitis is a common disease process with a variety of morbidities and possible mortality. Affected umbilical remnant resection is highly successful but may not always be possible. Umbilical marsupialization can be implemented when total resection cannot be accomplished with minimally reported complications. Umbilical vein marsupialization was performed on three Percheron foals with extensive septic omphalophlebitis using the one‐stage paramedian translocation technique and prolonged postoperative antimicrobial therapy. Long‐term follow‐up revealed herniation at the marsupialization site in all foals. Two foals were subsequently treated with herniorrhaphy at the prior marsupialization site. One foal died due to septic peritonitis with hernia formation 3 months after marsupialization. This case series highlights hernia formation as a potential complication following one‐stage umbilical vein marsupialization in foals diagnosed with septic omphalophlebitis and should be considered as a possible postoperative complication.     

Frequency of bystander exposure to antibiotics for enteropathogenic bacteria among young children in low-resource settings

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

Antibiotic use causes selection pressure for antimicrobial resistance (AMR), a growing global public health crisis that threatens to render antibiotics ineffective against many high-burden infections (1). Most of the concern is placed on the development of resistance in the target pathogen of treatment (i.e., the pathogen causing the treated illness). However, systemic treatment also results in antibiotic exposure for commensal bacteria and pathogens carried asymptomatically at the time of treatment (2). Selective pressure for resistance among organisms that are not the target pathogen has been called “bystander selection” (3, 4). While the public health relevance of resistance in nonpathogenic commensal organisms is less clear, bystander selection among pathogens carried asymptomatically at the time of treatment has direct consequences for the development of resistance in those pathogens (4). This type of selection has the potential to promote antibiotic-resistant disease in settings where subclinical carriage of pathogens is common.Children in low-resource settings frequently carry enteric pathogens in the absence of diarrheal symptoms (5). Enteroaggregative Escherichia coli (EAEC), for example, was detected in nearly half (49%) of nondiarrheal stools collected in the first 2 y of life in the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) birth cohort study conducted in South America, South Asia, and sub-Saharan Africa (6). Campylobacter and Shigella, which are on the World Health Organization priority pathogen list for concern for AMR (7), were detected in 28% (5) and 10% (8) of nondiarrheal stools, respectively. Antibiotic treatment is also highly common in these populations, with approximately five treatment courses per child-year observed in MAL-ED (9). Children were treated with more than one antibiotic course per child year for diarrhea alone (10), despite treatment guidelines that only recommend treatment for dysentery (11), which comprised less than 5% of diarrheal episodes (10). For these reasons, children in low-resource settings represent a unique population in which the burden of bystander selection on enteric pathogens could be particularly high.Antimicrobial stewardship interventions to prevent antibiotic overuse and interventions to prevent illnesses that prompt antibiotic treatment, such as vaccines, could have the ancillary benefit of reducing bystander selection (12). However, the magnitude of this potential impact is unknown. A prior study quantified the proportion of antibiotic exposures for specific pathogens that were not related to the treatment of that pathogen based on modeled data from unrelated sources (3). The observational birth cohort study, MAL-ED, provides a unique opportunity to characterize bystander antibiotic exposure directly since testing for enteric pathogen carriage was conducted monthly in nondiarrheal stools from birth to 2 y of age, and antibiotic use was comprehensively documented during twice-weekly surveillance visits. Here, we aimed to quantify the absolute frequency of bystander antibiotic exposures for enteric bacterial pathogens carried asymptomatically at the time of treatment among children in MAL-ED. We compared the frequency of antibiotic exposures that occurred when the bacteria were the target pathogen to when they were bystanders and attributed bystander exposure to specific indications for treatment. We also identified child characteristics that were associated with bystander antibiotic exposures. Finally, we assessed the association between bystander antibiotic exposure and resistance both at the individual and the community level using E. coli as a model organism.     

A nutrient relay sustains subtropical ocean productivity

The expansive gyres of the subtropical ocean account for a significant fraction of global organic carbon export from the upper ocean. In the gyre interior, vertical mixing and the heaving of nutrient-rich waters into the euphotic layer sustain local productivity, in turn depleting the layers below. However, the nutrient pathways by which these subeuphotic layers are themselves replenished remain unclear. Using a global, eddy-permitting simulation of ocean physics and biogeochemistry, we quantify nutrient resupply mechanisms along and across density surfaces, including the contribution of eddy-scale motions that are challenging to observe. We find that mesoscale eddies (10 to 100 km) flux nutrients from the shallow flanks of the gyre into the recirculating interior, through time-varying motions along density surfaces. The subeuphotic layers are ultimately replenished in approximately equal contributions by this mesoscale eddy transport and the remineralization of sinking particles. The mesoscale eddy resupply is most important in the lower thermocline for the whole subtropical region but is dominant at all depths within the gyre interior. Subtropical gyre productivity may therefore be sustained by a nutrient relay, where the lateral transport resupplies nutrients to the thermocline and allows vertical exchanges to maintain surface biological production and carbon export.

The sinking of particulate organic carbon from the sunlit euphotic zone into the deeper, dark ocean maintains an oceanic reservoir of dissolved inorganic carbon, changes in which can significantly modify atmospheric CO₂ (1). The ocean’s subtropical gyres exhibit low surface concentrations of nutrients and biomass but, due to their very large surface area, may contribute a significant fraction of global export. For example, the North Pacific subtropical gyre is estimated to represent ~20 to 50% of the total North Pacific organic sinking flux (2, 3). The wind forcing over the subtropical basins leads to a downward doming of the density surfaces that contain an extensive volume of low-nutrient waters (4), as revealed in an observed transect from the North Pacific (Fig. 1) (5). The mode of nutrient resupply and the long-term maintenance of biological productivity in subtropical gyres have presented a conundrum for several decades. Inorganic nutrients are incorporated into photosynthetic phytoplankton and pass through the food web, but despite efficient recycling within the sunlit euphotic zone (6, 7), gravitational sinking and the subduction of organic matter deplete the surface nutrients of the subtropical gyres. These surface nutrient losses are largely viewed as being offset by the physical transport of nutrient-enriched, deeper waters back into the sunlit zone, together with smaller contributions from atmospheric deposition and nitrogen fixation. However, the nature of the nutrient pathways recharging the subtropical nutrient reservoir below the euphotic zone remains poorly constrained.Open in a separate windowFig. 1.PO43− concentration (μmol kg⁻¹) in the North Pacific basin obtained from the Global Ocean Data Analysis Project (GLODAP) V2.2 atlas and plotted using Data-Interpolating Variational Analysis (DIVA) gridding in Ocean Data View. (A) Transect along 155 ^∘W, with contours of constant density σ_o (thick dashed lines) and sampling locations (gray points). The solid black line indicates the σ_o = 26.0 surface. (B) PO43− distribution along σ_o = 26.0 with sampling locations indicated by gray points.The sharp vertical gradient of nutrients just below the euphotic layer can sustain the vertical supply of nutrients up to the surface. Transfer of nutrients upward into the subtropical euphotic zone has been attributed to vertical diapycnal mixing (8–11); the passage of mesoscale eddies, which adiabatically lift nutrient-rich, subeuphotic layers into the light (12–19); and submesoscale (1 to 10 km) features that are associated with strong vertical circulations (20–24). However, all of these localized processes deliver nutrients into the euphotic layer while depleting the subeuphotic layers below (17, 25). A long-standing question is how the nutrient inventory of this subeuphotic layer, which fuels the local vertical supplies, is maintained over the longer term (26, 27).At the flanks of the subtropical gyre, wind-driven upwelling brings nutrient-rich waters toward the surface, forming nutrient gradients in the subpolar and equatorial regions, as seen in observed transects (Fig. 1A). Within the frictional boundary layer of the ocean, the wind-driven, meridional Ekman transport acts on these lateral gradients to transfer nutrients into the subtropical gyre, significantly supplementing vertical processes in sustaining local productivity (4, 28, 29). However, this lateral transport contribution is confined to the upper few tens of meters and diminishes away from the gyre margins due to biological consumption (4).Mesoscale eddies can provide a lateral transport of nutrients, which involves both stirring and advective transfer along density surfaces (11, 17, 25, 30, 31). Idealized simulations and theory suggest an important combined nutrient supply to the gyre from lateral eddy diffusion and Ekman transport (30). Diagnostics of a more realistic, global eddy-resolving model show that lateral eddy transfers do provide an important nutrient flux across the boundaries of the subtropical gyre (31). Stimulated by these model-based inferences, an observational field study, measuring microscale turbulence and nutrients, reveal signals of eddy stirring along density surfaces, providing a weak nutrient supply within the thermocline over the center of the North Atlantic subtropical gyre (11). A closure for the nutrient supply then suggests that the nutrient delivery by mesoscale eddy stirring should be one to two orders of magnitude larger over the flanks of the subtropical gyre due to an increase in nutrient gradients and a greater tilt of the density surfaces (11). These enhanced nutrient gradients and isopycnal slopes are evident near the margins of the subtropical gyre, particularly at its southern flank, between σ₀ = 24.0 and 26.5 (Fig. 1). An eddying numerical simulation reveals the associated mesoscale flux of nutrients, visible as streamers of high-phosphate waters emanating from nutrient-rich currents all around the margins of the subtropical gyre (Fig. 2A and Movie S1).Open in a separate windowFig. 2.Snapshot of simulated PO43− concentration (mmol m⁻³) during the month of September and along the σ₀ = 26.0 isopycnal (A) over the north subtropical Pacific basin and (B) in the proximity of the Hawaiian islands. The black line contours in B depict the depth of the isopycnal surface with 10-m contour intervals. Mesoscale features transport nutrients into the North Pacific subtropical gyre through the combined action of eddy stirring that draws out filaments of tracer and advection by coherent eddy structures.In this study, we quantify the nutrient pathways and fluxes of the subtropical North Pacific Ocean, in the context of a global eddy-permitting numerical model with explicit representation of biogeochemical and ecological processes (Materials and Methods). In doing so, we test and illustrate the hypothesis of ref. 11 that the lateral eddy transfer contribution is stronger at the gyre margins and in the thermocline. Complementing previous work (31), we resolve along- and across-density surface fluxes and the depth and intragyre structures in fluxes and balances, as well as the contribution of dissolved organics.We find that a nutrient relay occurs in the subtropical gyre (11), involving the eddying transfer of nutrients from the upwelling flanks of the gyre, downward along sloping isopycnals into the subtropical gyre interior. This nutrient supply into the thermocline offsets the export of organic matter to the deep ocean and fuels upward vertical transfer to the surface, helping to sustain biological production in the euphotic layer. We illustrate this nutrient relay in the following, detailed analysis of the nutrient budget for density layers over the North Pacific subtropical gyre.     

Formation of Nanoscale Al2O3 Protective Layer by Preheating Treatment for Improving Corrosion Resistance of Dilute Fe-Al Alloys

In this work, an attempt was made to improve the corrosion resistance of dilute Fe-Al alloys (1.0 mass% Al) by preheating treatment at 1073 K in H₂ atmosphere. In comparison with pure Fe and unpreheated Fe-Al alloys, the resistance to oxidation at 673 K in pure O₂ and to electrochemical corrosion in 5 wt.% NaCl solution is significantly improved for preheated Fe-Al alloys. This improvement is attributed to the formation of a 20 nm thin, but dense Al₂O₃ protective layer on the surface of preheated Fe-Al alloys.     

Persistent Transmission of HCV among Men Who Have Sex with Men despite Widespread Screening and Treatment with Direct-Acting Antivirals

Background: In the Netherlands, unrestricted access to direct-acting antivirals (DAAs) halved the incidence of acute hepatitis C virus (HCV) infections among HIV-infected men who have sex with men (MSM). To develop strategies that can further reduce the spread of HCV, it is important to understand the transmission dynamics of HCV. We used phylogenetic analysis of a dense sample of MSM to provide insight into the impact of unrestricted access to DAAs on HCV transmission in the Netherlands and in Belgium. Methods: We included 89 MSM that were recently infected with HCV genotype 1a in ten Dutch and one Belgian HIV treatment centers. Sequences were generated using next gene sequencing and Sanger sequencing. Maximum likelihood phylogenetic analysis (general time reversible model) was performed on concatenated NS5A and NS5B sequences and a reference set of 389 highly similar control sequences selected from GenBank. A cluster was based on a minimum bootstrap support of 90% and a 3% genetic distance threshold. Results: We found that 78 (88%) of individuals were part of seven major clusters. All clusters included individuals from across the study region, however, different cities were part of different clusters. In three clusters, HIV-negative MSM clustered with sequences from HIV-positive MSM. All clusters that were observed before the introduction of DAAs persisted after unrestricted access to DAAs became available. Conclusion: Recently acquired HCV infections among MSM in the Netherlands and Belgium are strongly clustered and therefore highly suitable for targeted prevention strategies, such as contact tracing and partner notification. Importantly, despite an HCV incidence reduction after high DAA uptake and continuously monitoring, HCV transmission persisted in the same clusters.