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1.
Blood ; 144(10): 1061-1068, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-38754046

ABSTRACT

ABSTRACT: Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.


Subject(s)
Adenine , Agammaglobulinaemia Tyrosine Kinase , Benzamides , Leukemia, Lymphocytic, Chronic, B-Cell , Mutation , Piperidines , Pyrazines , Pyrazoles , Pyrimidines , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Benzamides/therapeutic use , Disease Progression , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Pyrazines/therapeutic use , Pyrazines/administration & dosage , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Pyrimidines/administration & dosage
2.
Biodegradation ; 35(6): 993-1006, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39017970

ABSTRACT

Much attention is placed on organohalide-respiring bacteria (OHRB), such as Dehalococcoides, during the design and performance monitoring of chlorinated solvent bioremediation systems. However, many OHRB cannot function effectively without the support of a diverse group of other microbial community members (MCMs), who play key roles fermenting organic matter into more readily useable electron donors, producing corrinoids such as vitamin B12, or facilitating other important metabolic processes or biochemical reactions. While it is known that certain MCMs support dechlorination, a metric considering their contribution to bioremediation performance has yet to be proposed. Advances in molecular biology tools offer an opportunity to better understand the presence and activity of specific microbes, and their relation to bioremediation performance. In this paper, we test the hypothesis that a specific microbial consortium identified within 16S ribosomal ribonucleic acid (rRNA) gene next generation sequencing (NGS) data can be predictive of contaminant degradation rates. Field-based data from multiple contaminated sites indicate that increasing relative abundance of specific MCMs correlates with increasing first-order degradation rates. Based on these results, we present a framework for computing a simplified metric using NGS data, the Microbial Community Structure Index, to evaluate the adequacy of the microbial ecosystem during assessment of bioremediation performance.


Subject(s)
Biodegradation, Environmental , RNA, Ribosomal, 16S , RNA, Ribosomal, 16S/genetics , Microbial Consortia , Bacteria/metabolism , Bacteria/genetics , Chloroflexi/metabolism , Chloroflexi/genetics , Microbiota , High-Throughput Nucleotide Sequencing
3.
Appl Microbiol Biotechnol ; 103(10): 4177-4192, 2019 May.
Article in English | MEDLINE | ID: mdl-30968165

ABSTRACT

Quantifying functional biomarker genes and their transcripts provides critical lines of evidence for contaminant biodegradation; however, accurate quantification depends on qPCR primers that contain no, or minimal, mismatches with the target gene. Developing accurate assays has been particularly challenging for genes encoding fumarate-adding enzymes (FAE) due to the high level of genetic diversity in this gene family. In this study, metagenomics applied to a field-derived, o-xylene-degrading methanogenic consortium revealed genes encoding FAE that would not be accurately quantifiable by any previously available PCR assays. Sequencing indicated that a gene similar to the napthylmethylsuccinate synthase gene (nmsA) was most abundant, although benzylsuccinate synthase genes (bssA) also were present along with genes encoding alkylsuccinate synthase (assA). Upregulation of the nmsA-like gene was observed during o-xylene degradation. Protein homology modeling indicated that mutations in the active site, relative to a BssA that acts on toluene, increase binding site volume and accessibility, potentially to accommodate the relatively larger o-xylene. The new nmsA-like gene was also detected at substantial concentrations at field sites with a history of xylene contamination.


Subject(s)
Biotransformation , Enzymes/genetics , Genetic Markers , Microbial Consortia/genetics , Xylenes/metabolism , Anaerobiosis , Metagenomics
4.
Biodegradation ; 30(2-3): 127-145, 2019 06.
Article in English | MEDLINE | ID: mdl-30820709

ABSTRACT

Knowledge of the conditions that promote the growth and activity of pharmaceutical and personal care product (PPCP)-degrading microorganisms within mixed microbial systems are needed to shape microbiomes in biotreatment reactors and manage process performance. Available carbon sources influence microbial community structure, and specific carbon sources could potentially be added to end-of-treatment train biotreatment systems (e.g., soil aquifer treatment [SAT]) to select for the growth and activity of a range of microbial phylotypes that collectively degrade target PPCPs. Herein, the impacts of primary carbon sources on PPCP biodegradation and microbial community structure were explored to identify promising carbon sources for PPCP biotreatment application. Six types of primary carbon sources were investigated: casamino acids, two humic acid and peptone mixtures (high and low amounts of humic acid), molasses, an organic acids mixture, and phenol. Biodegradation was tracked for five PPCPs (diclofenac, 5-fluorouracil, gemfibrozil, ibuprofen, and triclosan). Primary carbon sources were found to differentially impact microbial community structures and rates and efficiencies of PPCP biotransformation. Of the primary carbon sources tested, casamino acids, organic acids, and phenol showed the fastest biotransformation; however, on a biomass-normalized basis, both humic acid-peptone mixtures showed comparable or superior biotransformation. By comparing microbial communities for the different primary carbon sources, abundances of unclassified Beijerinckiaceae, Beijerinckia, Sphingomonas, unclassified Sphingomonadaceae, Flavobacterium, unclassified Rhizobiales, and Nevskia were statistically linked with biotransformation of specific PPCPs.


Subject(s)
Biotransformation , Carbon/metabolism , Microbiota , Biodegradation, Environmental
5.
Proc Natl Acad Sci U S A ; 112(14): 4322-7, 2015 Apr 07.
Article in English | MEDLINE | ID: mdl-25787252

ABSTRACT

Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10(12)) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.


Subject(s)
Immunoglobulins/chemistry , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Sequence Analysis, RNA/methods , Somatic Hypermutation, Immunoglobulin , Alleles , Base Sequence , Complementarity Determining Regions/chemistry , Complementarity Determining Regions/genetics , Genome , Humans , Immunoglobulin Variable Region/genetics , Molecular Sequence Data , Polymerase Chain Reaction , Prognosis , Sequence Homology, Nucleic Acid , Transcriptome , VDJ Recombinases/genetics
6.
Appl Microbiol Biotechnol ; 100(7): 3347-60, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26691516

ABSTRACT

Advances in our understanding of the microbial ecology at sites impacted by light non-aqueous phase liquids (LNAPLs) are needed to drive development of optimized bioremediation technologies, support longevity models, and develop culture-independent molecular tools. In this study, depth-resolved characterization of geochemical parameters and microbial communities was conducted for a shallow hydrocarbon-impacted aquifer. Four distinct zones were identified based on microbial community structure and geochemical data: (i) an aerobic, low-contaminant mass zone at the top of the vadose zone; (ii) a moderate to high-contaminant mass, low-oxygen to anaerobic transition zone in the middle of the vadose zone; (iii) an anaerobic, high-contaminant mass zone spanning the bottom of the vadose zone and saturated zone; and (iv) an anaerobic, low-contaminant mass zone below the LNAPL body. Evidence suggested that hydrocarbon degradation is mediated by syntrophic fermenters and methanogens in zone III. Upward flux of methane likely contributes to promoting anaerobic conditions in zone II by limiting downward flux of oxygen as methane and oxygen fronts converge at the top of this zone. Observed sulfate gradients and microbial communities suggested that sulfate reduction and methanogenesis both contribute to hydrocarbon degradation in zone IV. Pyrosequencing revealed that Syntrophus- and Methanosaeta-related species dominate bacterial and archaeal communities, respectively, in the LNAPL body below the water table. Observed phylotypes were linked with in situ anaerobic hydrocarbon degradation in LNAPL-impacted soils.


Subject(s)
Archaea/classification , Deltaproteobacteria/classification , Groundwater/microbiology , Hydrocarbons/metabolism , Water Pollutants, Chemical/metabolism , Archaea/genetics , Archaea/metabolism , Biodegradation, Environmental , Deltaproteobacteria/genetics , Deltaproteobacteria/metabolism , High-Throughput Nucleotide Sequencing , Humans , Methane/biosynthesis , Microbial Consortia/genetics , Oil and Gas Industry , Oxidation-Reduction , Oxygen/metabolism , Phylogeny , RNA, Ribosomal, 16S/genetics , Sulfates/metabolism
7.
Biodegradation ; 25(4): 569-85, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24469406

ABSTRACT

Thermally-enhanced bioremediation is a promising treatment approach for petroleum contamination; however, studies examining temperature effects on anaerobic biodegradation in zones containing light non-aqueous phase liquids (LNAPLs) are lacking. Herein, laboratory microcosm studies were conducted for a former refinery to evaluate LNAPL transformation, sulfate reduction, and methane generation over a one-year period for temperatures ranging from 4 to 40 °C, and microbial community shifts were characterized. Temperatures of 22 and 30 °C significantly increased total biogas generation compared to lower (4 and 9 °C) and higher temperatures (35 and 40 °C; p < 0.1). Additionally, at 22 and 30 °C methane generation commenced ~6 months earlier than for 35 and 40 °C. Statistically significant biodegradation of benzene, toluene and xylenes was observed at elevated temperatures but not at lower temperatures (p < 0.1). Additionally, a novel differential chromatogram approach was developed to overcome challenges associated with resolving losses in complex mixtures of hydrocarbons, and application of this method revealed greater losses of hydrocarbons at 22 and 30 °C as compared to lower and higher temperatures. Finally, molecular biology assays revealed that the composition and activity of microbial communities shifted in a temperature-dependent manner. Collectively, results demonstrated that anaerobic biodegradation processes can be enhanced by increasing the temperature of LNAPL-containing soils, but biodegradation does not simply increase as temperature increases likely due to a lack of microorganisms that thrive at temperatures well above the historical high temperatures for a site. Rather, optimal degradation is achieved by holding soils at the high end of, or slightly higher than, their natural range.


Subject(s)
Archaea/metabolism , Bacteria/metabolism , Environmental Pollutants/metabolism , Microbial Consortia , Temperature , Anaerobiosis , Biodegradation, Environmental , Biofuels , Biotransformation , Hydrocarbons/metabolism , Methane/biosynthesis , Oxidation-Reduction , Sulfates/metabolism
8.
J Hazard Mater ; 477: 135059, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39053064

ABSTRACT

To optimally employ Natural Source Zone Depletion (NSZD) and Enhanced Source Zone Depletion (ESZD) at sites impacted by light non-aqueous phase liquids (LNAPL), monitoring strategies are required. Emerging use of subsurface oxidation-reduction potential (ORP) sensors shows promise for tracking redox evolution, which reflects ongoing biogeochemical processes. However, further understanding of how soil redox dynamics relate to subsurface microbial activity and LNAPL degradation pathways is needed. In this work, soil ORP sensors and DNA and RNA sequencing-based microbiome analysis were combined to elucidate NSZD and ESZD (biostimulation via periodic sulfate addition and biosparging) processes in columns containing LNAPL-impacted soils from a former petroleum refinery. Results show expected relationships between continuous soil redox and active microbial communities. Continuous data revealed spatial and temporal detail that informed interpretation of the hydrocarbon biodegradation data. Redox increases were transient for sulfate addition, and sequencing revealed how hydrocarbon concentration and composition impacted microbiome structure and naphthalene degradation. Periodic biosparging did not result in fully aerobic conditions suggesting observed biodegradation improvements could be explained by alternative anaerobic metabolisms (e.g., iron reduction due to air oxidizing reduced iron). Collectively, data suggest combining continuous redox sensing with microbiome analysis provides insights beyond those possible with either monitoring tool alone.


Subject(s)
Soil , Soil/chemistry , Soil Microbiology , Oxidation-Reduction , Laboratories , Hydrocarbons/chemistry , Hydrocarbons/metabolism , Microbiota , Biodegradation, Environmental
9.
Blood Adv ; 8(19): 5137-5145, 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39074263

ABSTRACT

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM.


Subject(s)
Busulfan , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Humans , Busulfan/therapeutic use , Busulfan/administration & dosage , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Male , Infant , Female , Child, Preschool , Child , Treatment Outcome , Adolescent , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Transplantation, Homologous
10.
AAPS PharmSciTech ; 14(1): 312-20, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23319298

ABSTRACT

The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemistry , Drug Combinations , Tablets , Chromatography, High Pressure Liquid , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Drug Stability
11.
J Environ Qual ; 52(6): 1152-1165, 2023.
Article in English | MEDLINE | ID: mdl-37729590

ABSTRACT

Sustainable manure management technologies are needed, and combining anaerobic digestion (AD) for energy generation and aerobic composting (AC) to stabilize digestate and remove emerging contaminants (ECs), including veterinary pharmaceuticals and steroid hormones, is promising. This study identified post-AD, AC operating conditions that maximized degradation of study ECs, expected to be present in cattle manure digested using treated municipal wastewater as the water source. Study ECs included sulfamethoxazole (SMX), chlortetracycline (CTC), oxytetracycline (OTC), estrone (E1), and naproxen (NPX). Composting conditions were simulated in bench-scale reactors, with microorganisms from digestate produced in an AD system (25L scale), by varying temperatures, pH, and carbon source compositions (representing food waste/manure co-digestion with different residence times). Results indicate maximum SMX biodegradation occurred at 35°C, pH 7, and with high levels of easily degradable carbon (≥99%, 99%, and 98%), and maximum E1 biodegradation occurred at 35°C, and with low levels of easily degradable carbon (≥97% and 99%). Abiotic degradation was responsible for the nearly complete removal of tetracyclines under all conditions and for partial degradation of NPX (between 20% and 48%). Microorganisms originating from the AD system putatively capable of SMX and E1 biodegradation, or of contributing to biodegradation during the AC phase, were identified, including phylotypes previously shown to biodegrade SMX (Brevundimonas and Alcaligenes).


Subject(s)
Composting , Refuse Disposal , Veterinary Drugs , Animals , Cattle , Manure , Anaerobiosis , Food , Carbon
12.
J Cross Cult Gerontol ; 27(2): 119-37, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22566111

ABSTRACT

Contemporary Japan is known both for its high tech culture and its rapidly aging population, with 22 % of people currently 65 years and older. Yet there has been little attention to the material culture of the elderly. This paper explores the way aging bodies, official ideology, and consumption of what are called "assistive devices" and "life technologies" come together in the experience of frail old people who depend not only on human caregivers but on "things" such as walkers, kidney dialysis machines, and electric massage chairs. It begins to consider the questions: What technology to aid failing bodies is available, and to whom? How does the advocacy of independence create new forms of consumption? How do "things" mediate ideological change regarding elder care and help to create new understandings of self and one's relation to others? Data come from interviews conducted in 2003-2007 as part of a study of elder care in Japan under the public long term care insurance system that began in 2000. These interviews point both to acceptance of the technology as a way to avoid over-dependence on caregivers, and to resistance to the limitations of aging and to its 21st century definition by the state.


Subject(s)
Activities of Daily Living/psychology , Aging , Insurance, Long-Term Care , Self-Help Devices , Aged , Aged, 80 and over , Frail Elderly , Humans , Interviews as Topic , Japan , Long-Term Care/methods , Long-Term Care/trends , Qualitative Research , Surveys and Questionnaires , Technology , Thinking
13.
J Microbiol Methods ; 197: 106481, 2022 06.
Article in English | MEDLINE | ID: mdl-35526669

ABSTRACT

For many contaminants, biomarker genes are unknown or assays are unavailable, and most biomarker assays target the first pathway step. Herein, we obtained sequences for all of the genes in a previously hypothesized o-xylene degradation pathway based on similarities to analogous genes in a known toluene degradation pathway. Comparative metatranscriptomics resulted in sequences for genes annotated as bssA, bbsEF, bbsCD, and bbsB, while genes for bbsG and bbsH were notably missing. Prokaryotic Suppressive Subtractive Hybridization PCR cDNA Subtraction (Prokaryotic SSH-PCR cDNA Subtraction) was applied for the first time to a mixed-species microbiome to enrich abundances of genes up-regulated during o-xylene degradation prior to metatranscriptomic sequencing. The subtracted metatranscriptome was sequenced using the MinION; this approach was highly effective at retrieving sequences for biodegradation genes including the previously missing bbsG and bbsH. Reverse transcription quantitative PCR (RT-qPCR) analysis confirmed up-regulation. Thus, data reported herein lend credence to the previously hypothesized anaerobic o-xylene degradation pathway, and new biomarker assays are presented. A novel biomarker development tool for mixed species systems, Subtractive Community Metatranscriptomics (SCM), is demonstrated.


Subject(s)
Xylenes , Anaerobiosis , Biodegradation, Environmental , DNA, Complementary/metabolism , Xylenes/metabolism
14.
Transplant Cell Ther ; 28(2): 104.e1-104.e7, 2022 02.
Article in English | MEDLINE | ID: mdl-34883294

ABSTRACT

Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD.


Subject(s)
Hematopoietic Stem Cell Transplantation , Metabolic Diseases , Body Weight , Busulfan/therapeutic use , Child , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Metabolic Diseases/chemically induced , Transplantation Conditioning , Young Adult
15.
Environ Sci Technol ; 45(21): 9449-56, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21939252

ABSTRACT

Although numerous lifecycle assessments (LCA) of microalgae-based biofuels have suggested net reductions of greenhouse gas emissions, limited experimental data exist on direct emissions from microalgae cultivation systems. For example, nitrous oxide (N(2)O) is a potent greenhouse gas that has been detected from microalgae cultivation. However, little quantitative experimental data exist on direct N(2)O emissions from microalgae cultivation, which has inhibited LCA performed to date. In this study, microalgae species Nannochloropsis salina was cultivated with diurnal light-dark cycling using a nitrate nitrogen source. Gaseous N(2)O emissions were quantitatively measured using Fourier transform infrared spectrometry. Under a nitrogen headspace (photobioreactor simulation), the reactors exhibited elevated N(2)O emissions during dark periods, and reduced N(2)O emissions during light periods. Under air headspace conditions (open pond simulation), N(2)O emissions were negligible during both light and dark periods. Results show that N(2)O production was induced by anoxic conditions when nitrate was present, suggesting that N(2)O was produced by denitrifying bacteria within the culture. The presence of denitrifying bacteria was verified through PCR-based detection of norB genes and antibiotic treatments, the latter of which substantially reduced N(2)O emissions. Application of these results to LCA and strategies for growth management to reduce N(2)O emissions are discussed.


Subject(s)
Microalgae/metabolism , Nitrous Oxide/analysis , Biofuels
16.
MethodsX ; 8: 101503, 2021.
Article in English | MEDLINE | ID: mdl-34754774

ABSTRACT

Microbially-mediated hydrocarbon degradation is well documented. However, how these microbial processes occur in complex subsurface petroleum impacted systems remains unclear, and this knowledge is needed to guide technologies to enhance microbial degradation effectively. Analysis of RNA derived from soils impacted by petroleum liquids would allow for analysis of active microbial communities, and a deeper understanding of the dynamic biochemistry occurring during site remediation. However, RNA analysis in soils impacted with petroleum liquids is challenging due to: (A) RNA being inherently unstable, and (B) petroleum impacted soils containing problematic levels of polymerase chain reaction (PCR) inhibitors that must be removed to yield high-purity RNA for downstream analysis. A previously published soil wash pretreatment step and a commercially available DNA extraction kit protocol were combined and modified to be able to purify RNA from soils containing petroleum liquids.•A key modification involved reformulation of the pretreatment solution via replacing water as the diluent with a commercially-available RNA preservation solution.•Methods were developed and demonstrated using cryogenically preserved soils from three former petroleum refineries. Results showed the new soil washing approach had no adverse effects on RNA recovery but did improve RNA quality, by PCR inhibitor removal, which in turn allows for characterization of active microbial communities present in petroleum impacted soils.•In summary, our method for extracting RNA from petroleum-impacted soils provides a promising new tool for resolving metabolic processes at sites as they progress toward restoration via natural and/or engineered remediation.

17.
Bioresour Technol ; 323: 124532, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33422791

ABSTRACT

Conversion of organic wastes to fatty acids rather than methane through anaerobic digestion-based technologies has considerable promise. However, the relationships between microbiome structure and fatty acids produced from cellulosic feedstocks are not well understood. This study investigated the nature of those relationships for anaerobic digester sludge, bison rumen, and cattle rumen inocula grown on cellulose. Acetic acid production was highest in anaerobic sludge reactors, while propionic acid production was highest in cattle rumen reactors. Butyric and pentanoic acid were produced at the highest rates in bison rumen before Day 5. Reactor microbiomes remained distinct, despite identical operating conditions. Novel associations linked Alistipes with butyric acid production and Eubacterium nodatum and Clostridiales bacterium with pentanoic acid production. This study provides new insights into the ability of microbiomes to convert cellulose to different fatty acid mixtures and adds impetus for the rewiring of anaerobic digestion to generate high-value products.


Subject(s)
Bioreactors , Microbiota , Anaerobiosis , Animals , Cattle , Fatty Acids , Methane , Sewage
18.
medRxiv ; 2021 Feb 03.
Article in English | MEDLINE | ID: mdl-33564791

ABSTRACT

Background: Wastewater surveillance for SARS-CoV-2 is an emerging approach to help identify the risk of a COVID-19 outbreak. This tool can contribute to public health surveillance at both community (wastewater treatment system) and institutional (e.g., colleges, prisons, nursing homes) scales. Objectives: This research aims to understand the successes, challenges, and lessons learned from initial wastewater surveillance efforts at colleges and university systems to inform future research, development and implementation. Methods: This paper presents the experiences of 25 college and university systems in the United States that monitored campus wastewater for SARS-CoV-2 during the fall 2020 academic period. We describe the broad range of approaches, findings, resource needs, and lessons learned from these initial efforts. These institutions range in size, social and political geographies, and include both public and private institutions. Discussion: Our analysis suggests that wastewater monitoring at colleges requires consideration of information needs, local sewage infrastructure, resources for sampling and analysis, college and community dynamics, approaches to interpretation and communication of results, and follow-up actions. Most colleges reported that a learning process of experimentation, evaluation, and adaptation was key to progress. This process requires ongoing collaboration among diverse stakeholders including decision-makers, researchers, faculty, facilities staff, students, and community members.

19.
Article in English | MEDLINE | ID: mdl-33922263

ABSTRACT

Wastewater surveillance for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging approach to help identify the risk of a coronavirus disease (COVID-19) outbreak. This tool can contribute to public health surveillance at both community (wastewater treatment system) and institutional (e.g., colleges, prisons, and nursing homes) scales. This paper explores the successes, challenges, and lessons learned from initial wastewater surveillance efforts at colleges and university systems to inform future research, development and implementation. We present the experiences of 25 college and university systems in the United States that monitored campus wastewater for SARS-CoV-2 during the fall 2020 academic period. We describe the broad range of approaches, findings, resources, and impacts from these initial efforts. These institutions range in size, social and political geographies, and include both public and private institutions. Our analysis suggests that wastewater monitoring at colleges requires consideration of local information needs, sewage infrastructure, resources for sampling and analysis, college and community dynamics, approaches to interpretation and communication of results, and follow-up actions. Most colleges reported that a learning process of experimentation, evaluation, and adaptation was key to progress. This process requires ongoing collaboration among diverse stakeholders including decision-makers, researchers, faculty, facilities staff, students, and community members.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Public Health Surveillance , Universities , Wastewater
20.
J Nurses Staff Dev ; 26(3): 96-101; quiz 102-3, 2010.
Article in English | MEDLINE | ID: mdl-20508422

ABSTRACT

Podcasting is a useful addition to the repertoire of distance learning technologies that provides a fresh and mobile learning option particularly for millennial learners. Nurse educators should capitalize on this new educational approach, which has much to offer in the line of audio recordings.


Subject(s)
Education, Distance/methods , Education, Nursing/methods , Educational Technology , Faculty, Nursing , Internet , Webcasts as Topic , Education, Nursing/trends , Humans , Software , Staff Development/methods , Students, Nursing
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