A global assessment of the mixed layer in coastal sediments and implications for carbon storage.

The sediment-water interface in the coastal ocean is a highly dynamic zone controlling biogeochemical fluxes of greenhouse gases, nutrients, and metals. Processes in the sediment mixed layer (SML) control the transfer and reactivity of both particulate and dissolved matter in coastal interfaces. Here we map the global distribution of the coastal SML based on excess Pb (Pb) profiles and then use a neural network model to upscale these observations.

Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals.

CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.

CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties.

Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy.

A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias.

Purpose: Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.

Methods: Twenty-six adults with acute leukemia were treated with CPX-351 for 1-2 induction cycles and ≤ 4 consolidation cycles.

CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML.

CPX-351, a liposomal formulation co-encapsulating cytarabine and daunorubicin (DNR) in a synergistic 5:1 M ratio, has shown favourable response in newly diagnosed elderly high-risk AML. This study assessed intracellular ara-CTP levels following in vitro exposure of human immortalised leukaemic cell lines and primary AML blasts to CPX-351, and investigated fludarabine potentiation of intracellular ara-CTP formation from CPX-351. Comparison of intracellular handling of CPX-351 to cytarabine in HL-60 cells indicated slower conversion to ara-CTP for CPX-351, but equivalent cytotoxicity to cytarabine and combined DNR/cytarabine (DA) at 48 h, mostly likely reflecting the need for intracellular liposome processing to release encapsulated drugs.

Improving combination cancer therapy: the CombiPlex development platform.

Current combination therapy approaches assume that better outcomes are achieved by combining drugs at their maximally tolerated doses. However, administration of individual agents cannot consistently deliver synergistic drug ratios to tumor cells due to differences in pharmacokinetics of the individual drugs. Further, the toxicity of combination regimens often necessitates administration of suboptimal dosages.

CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation.

Purpose: Identify AML patients most likely to respond to CPX-351, a nano-scale liposome formulation containing cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio.

Methods: We examined the ex vivo cytotoxic activity of CPX-351 against leukemic cells isolated from 53 AML patients and an additional 127 samples including acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasms, or chronic lymphocytic leukemia/lymphoma. We assessed activity with respect to common molecular lesions and used flow cytometry to assess CPX-351 cellular uptake.

The impact of drying on structure of sedimentary organic matter in wetlands: Probing with native and amended polycyclic aromatic hydrocarbons.

Wetland sediments undergo dry-wet cycles that may change their structural properties and affect geochemical behavior of associated organic compounds. In this study, we examined the effect of drying on particle size distributions and the rapid (24h) sorption reactions of polycyclic aromatic hydrocarbons (PAHs) with salt marsh sediments in Nueces Delta, South Texas. Drying reduced the fraction of fine particles in organically richer sediments, indicating structural rearrangement of organic matter and mineral aggregates.

Passive and semi-active targeting of bone marrow and leukemia cells using anionic low cholesterol liposomes.

Historically, the use of liposomes to enhance delivery of anticancer agents to cancer cells has focused primarily on solid tumors, which are characterized by rapid angiogenesis resulting in a poorly formed hypervasculature with abnormal vessel walls. The leaky vasculature in combination with poor lymphatic drainage has been demonstrated to lead to the accumulation of liposomes via the enhanced permeation and retention effect. However, only very limited information exists on the disposition of such delivery systems in the bone marrow compartment, the primary site of tumor cell origination and growth for many hematological malignancies.

Efficacy of CPX-351, (cytarabine:daunorubicin) liposome injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical Testing Program.

Background: CPX-351, a liposomal formulation of cytarabine and daunorubicin co-encapsulated at an optimized synergistic 5:1 molar ratio, has demonstrated improved clinical outcomes over conventional cytarabine/daunorubicin treatment in a randomized phase 2 trial in patients with AML as well as superior efficacy against preclinical leukemia models when compared to the free drugs in combination.

Procedures: Given the promising phase 2 data, limited toxicities observed, and the known clinical activities of cytarabine/daunorubicin, we assessed the efficacy of CPX-351 against a panel of childhood ALL xenograft models. Plasma pharmacokinetics of cytarabine and daunorubicin following CPX-351 treatment were determined by HPLC in order to correlate efficacy with drug exposure.

Concentrations and sources of polycyclic aromatic hydrocarbons in surface coastal sediments of the northern Gulf of Mexico.

Background: Coastal sediments in the northern Gulf of Mexico have a high potential of being contaminated by petroleum hydrocarbons, such as polycyclic aromatic hydrocarbons (PAHs), due to extensive petroleum exploration and transportation activities. In this study we evaluated the spatial distribution and contamination sources of PAHs, as well as the bioavailable fraction in the bulk PAH pool, in surface marsh and shelf sediments (top 5 cm) of the northern Gulf of Mexico.

Results: PAH concentrations in this region ranged from 100 to 856 ng g-1, with the highest concentrations in Mississippi River mouth sediments followed by marsh sediments and then the lowest concentrations in shelf sediments.

Nanoscale particulate systems for multidrug delivery: towards improved combination chemotherapy.

While combination chemotherapy has led to measurable improvements in cancer treatment outcomes, its full potential remains to be realized. Nanoscale particles such as liposomes, nanoparticles and polymer micelles have been shown to increase delivery to the tumor site while bypassing many drug resistance mechanisms that limit the effectiveness of conventional therapies. Recent efforts in drug delivery have focused on coordinated, controlled delivery of multiple anticancer agents encapsulated within a single particle system.

The impact of complex chronic diseases on care utilization among assisted living residents.

Purpose: Many residents of assisted living (AL) have chronic diseases that are difficult to manage, including congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM). We estimated the amount and intensity of care delivered by the staff for residents with these conditions.

Methods: We performed a secondary data analysis from the Maryland Assisted Living (MDAL) Study (399 residents, 29 facilities).

Cohort differences in dementia recognition and treatment indicators among assisted living residents in Maryland: did a change in the resident assessment tool make a difference?

Background: There is a lack of empirical evidence about the impact of regulations on dementia care quality in assisted living (AL). We examined cohort differences in dementia recognition and treatment indicators between two cohorts of AL residents with dementia, evaluated prior to and following a dementia-related policy modification to more adequately assess memory and behavioral problems.

Methods: Cross-sectional comparison of two AL resident cohorts was done (Cohort 1 [evaluated 2001-2003] and Cohort 2 [evaluated 2004-2006]) from the Maryland Assisted Living studies.

Prediction of nanoparticle prodrug metabolism by pharmacokinetic modeling of biliary excretion.

Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats.

12-month incidence, prevalence, persistence, and treatment of mental disorders among individuals recently admitted to assisted living facilities in Maryland.

Background: To estimate the 12-month incidence, prevalence, and persistence of mental disorders among recently admitted assisted living (AL) residents and to describe the recognition and treatment of these disorders.

Methods: Two hundred recently admitted AL residents in 21 randomly selected AL facilities in Maryland received comprehensive physician-based cognitive and neuropsychiatric evaluations at baseline and 12 months later. An expert consensus panel adjudicated psychiatric diagnoses (using DSM-IV-TR criteria) and completeness of workup and treatment.

Effects of block copolymer properties on nanocarrier protection from in vivo clearance.

Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation.

Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations.

The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model.

The use of radioactive marker as a tool to evaluate the drug release in plasma and particle biodistribution of block copolymer nanoparticles.

Diblock copolymer nanoparticles encapsulating a paclitaxel prodrug, Propac 7, have been used to demonstrate the usefulness of a nonmetabolizable radioactive marker, cholesteryl hexadecyl ether (CHE), to evaluate nanoparticle formulation variables. Since CHE did not exchange out of the nanoparticles, the rate of clearance of the CHE could be used as an indicator of nanoparticle stability in vivo. We simultaneously monitored prodrug circulation and carrier circulation in the plasma and the retention of CHE relative to the retention of prodrug in the plasma was used to distinguish prodrug release from nanoparticle plasma clearance.

Liposomal encapsulation of a synergistic molar ratio of cytarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia progenitors as compared to analogous normal hematopoietic cells.

Objective: To evaluate the possibility of improved selective killing of acute myeloid leukemia (AML) cells with CPX-351 (a liposomal formulation of cytarabine and daunorubicin). CPX-351 and the same molar ratio of free drugs were compared for cytotoxicity against colony-forming cells (CFCs) and subpopulations of cells enriched for primitive progenitors from AML patients and normal granulocyte colony-stimulating factor-mobilized peripheral blood (PB) and bone marrow (BM) donors.

Materials And Methods: AML blasts (n = 13) and normal PB and BM cells (n = 7) were incubated for 24 hours in various concentrations of CPX-351 or free drugs before plating in CFC assay or staining with anti-CD34 and anti-CD38 antibodies, Annexin-V, and propidium iodide followed by fluorescence-activated cell sorting analysis.

Use of nanoscale delivery systems to maintain synergistic drug ratios in vivo.

Importance Of The Field: Drug combinations have been the standard of care in the treatment of cancer for > 50 years. Typically, combination chemotherapy uses agents with non-overlapping toxicities which are escalated to their maximum tolerated dose. However, emerging evidence indicates that this approach may not be providing optimal efficacy depending on the drug ratios to which the tumor is exposed.

History of manic and hypomanic episodes and risk of incident cardiovascular disease: 11.5 year follow-up from the Baltimore Epidemiologic Catchment Area Study.

Background: While several studies have suggested that bipolar disorder may elevate risk of cardiovascular disease, few studies have examined the relationship between mania or hypomania and cardiovascular disease. The purpose of this study is to examine history of manic and hypomanic episodes as an independent risk factor for cardiovascular disease (CVD) during an 11.5 year follow-up of the Baltimore Epidemiologic Catchment Area Follow-up Study.