Self-Assembled Lanthanum Oxide Nanoflakes by Electrodeposition Technique for Resistive Switching Memory and Artificial Synaptic Devices.

In recent years, many metal oxides have been rigorously studied to be employed as solid electrolytes for resistive switching (RS) devices. Among these solid electrolytes, lanthanum oxide (La2 O3 ) is comparatively less explored for RS applications. Given this, the present work focuses on the electrodeposition of La2 O3 switching layers and the investigation of their RS properties for memory and neuromorphic computing applications. Initially, the electrodeposited La2 O3 switching layers are thoroughly characterized by various analytical techniques. The electrochemical impedance spectroscopy (EIS) and Mott-Schottky techniques are probed to understand the in situ electrodeposition, RS mechanism, and n-type semiconducting nature of the fabricated La2 O3 switching layers. All the fabricated devices exhibit bipolar RS characteristics with excellent endurance and stable retention. Moreover, the device mimics the various bio-synaptic properties such as potentiation-depression, excitatory post-synaptic currents, and paired-pulse facilitation. It is demonstrated that the fabricated devices are non-ideal memristors based on double-valued charge-flux characteristics. The switching variation of the device is studied using the Weibull distribution technique and modeled and predicted by the time series analysis technique. Based on electrical and EIS results, a possible filamentary-based RS mechanism is suggested. The present results assert that La2 O3 is a promising solid electrolyte for memory and brain-inspired applications.

W Doping in Ni12P5 as a Platform to Enhance Overall Electrochemical Water Splitting.

Bifunctional electrocatalysts for efficient hydrogen generation from water splitting must overcome both the sluggish water dissociation step of the alkaline hydrogen evolution half-reaction (HER) and the kinetic barrier of the anodic oxygen evolution half-reaction (OER). Nickel phosphides are a promising catalysts family and are known to develop a thin active layer of oxidized Ni in an alkaline medium. Here, Ni12P5 was recognized as a suitable platform for the electrochemical production of γ-NiOOH─a particularly active phase─because of its matching crystallographic structure. The incorporation of tungsten by doping produces additional surface roughness, increases the electrochemical surface area (ESCA), and reduces the energy barrier for electron-coupled water dissociation (the Volmer step for the formation of Hads). When serving as both the anode and cathode, the 15% W-Ni12P5 catalyst provides an overall water splitting current density of 10 mA cm-2 at a cell voltage of only 1.73 V with good durability, making it a promising bifunctional catalyst for practical water electrolysis.

Analysis and Prediction of Hydrothermally Synthesized ZnO-Based Dye-Sensitized Solar Cell Properties Using Statistical and Machine-Learning Techniques.

Dye-sensitized solar cells (DSSCs) are one of the most versatile and low-cost solar cells. However, DSSCs are prone to low power conversion efficiency (PCE) compared to their counterparts, owing to their different synthesis parameters and process conditions. Therefore, designing efficient DSSCs and identifying the parameters that control the PCE of DSSCs are a critical tasks. We have collected data from hydrothermally synthesized DSSCs in the present work, published from 2005 to 2020. In line with publishing trends in the said period, we evaluate ZnO as a popular photoactive material for DSSC applications. We further analyzed the performance of hydrothermally synthesized ZnO DSSCs using different statistical techniques and provided some significant insights. We further applied the machine-learning technique with a decision tree algorithm to understand and discover the possible set of rules and heuristics that govern the morphology of the hydrothermally grown ZnO. In addition, we also employed supervised and unsupervised machine-learning models using conventional decision trees and classification and regression trees, respectively, to identify the dependence of the PCE of ZnO DSSCs on the different synthesis parameters. The reported work also evidences the PCE predictions of the ZnO DSSCs by using random forest and artificial neural network algorithms. The results substantiate that the random forest and artificial neural network algorithms successfully predict the PCE of the ZnO DSSCs with reasonable accuracy. Thus, we present a novel approach of applying statistical analysis and machine-learning algorithms to understand, discover, and predict the performance of DSSCs. We recommend extending the said know-how to other solar cells to identify rules and heuristics and experimentally realize highly efficient solar cells in shrinking manufacturing windows with a cost-effective approach.

MoS2 and CdMoS4 nanostructure-based UV light photodetectors.

We have developed MoS2 nanosheets and CdMoS4 hierarchical nanostructures based on a UV light photodetector. The surface morphologies of the as-prepared samples were investigated via field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). The performance parameters for the present photodetectors are investigated under the illumination of UV light having a wavelength of ∼385 nm. Upon the illumination of UV light, the CdMoS4-based photodetector device showed a better response to UV light compared to the MoS2 device in terms of photoresponsivity, response time (∼72 s) and recovery time (∼94 s). Our results reveal that CdMoS4 hierarchical nanostructures are practical for enhancing the device performance.

Structural Transformation of SnS2 to SnS by Mo Doping Produces Electro/Photocatalyst for Hydrogen Production.

SnS and SnS2 are layered semiconductors, with potential promising properties for electro- and photocatalytic hydrogen (H2 ) production. The vast knowledge in preparation and modification of layered structures was still not employed successfully in this system to fully maximize its potential. Here, the first report of structural transformation of SnS2 into SnS with Mo-doping as a bifunctional catalyst for the hydrogen evolution reaction (HER) is reported. The structural phase transition optimized the properties of the material, providing a more delicate morphology with additional catalytic sites. The electrochemical studies showed overpotential of 377 mV at 10 mA cm-2 for HER with Tafel slopes of 100 mV dec-1 in 0.5 m H2 SO4 for 10 % Mo-SnS. The same structure acts as an efficient photocatalyst in the generation of H2 from water under visible illumination with rate of 0.136 mmol g-1 h-1 of H2 , which is 20 times higher than pristine SnS2 under visible light.

Synergic effects of the decoration of nickel oxide nanoparticles on silicon for enhanced electrochemical performance in LIBs.

Significant efforts continue to be directed toward the construction of anode materials with high specific capacity and long cycling stability for lithium-ion batteries (LIBs). In this context, silicon is preferred due to its high capacity even though it has a problem of excessive volume expansion during electrochemical reactions as well as poor cyclability due to a reduction in conductivity. Hence, the hybridization of silicon with suitable materials could be a promising approach to overcome the abovementioned problems. Herein, we demonstrate the uniform decoration of nickel oxide (NiO) nanoparticles (15-20 nm) on silicon nanosheets using bis(cyclopentadienyl) nickel(ii) (C10H10Ni) at low temperatures, taking advantage of the presence of two unpaired electrons in an antibonding orbital in the cyclopentadienyl group. The formation and growth mechanism are discussed in detail. The electrochemical study of the nanocomposite revealed an initial delithiation capacity of 2507 mA h g-1 with a reversible capacity of 2162 mA h g-1, having 86% retention and better cycling stability for up to 500 cycles. At the optimum concentration, NiO nanoparticles facilitate Li+-ion adsorption, which in turn accelerates the transport of Li+-ions to active sites of silicon. The Warburg coefficient and Li+-ion diffusion at the electrodes confirm the enhancement in the charge transfer process at the electrode/electrolyte interface with NiO nanoparticles. Further, the NiO nanoparticles with uniform distribution suppress the agglomeration of Si nanosheets and provide sufficient space to accommodate a volume change in Si during cycling, which also reduces the diffusion path length of the Li-ions. It also helps to strengthen the mechanical stability, which might be helpful in preventing the cracking of silicon due to volume expansion and maintains the Li-ion transport pathway of the active material, resulting in enhanced cycling stability. Due to the synergic effect between NiO nanoparticles and Si sheets, the nanocomposite delivers high reversible capacity.

Unique CdS@MoS2 Core Shell Heterostructure for Efficient Hydrogen Generation Under Natural Sunlight.

The hierarchical nanostructured CdS@MoS2 core shell was architectured using template free facile solvothermal technique. More significantly, the typical hexagonal phase of core CdS and shell MoS2 has been obtained. Optical study clearly shows the two steps absorption in the visible region having band gap of 2.4 eV for CdS and 1.77 eV for MoS2. The FESEM of CdS@MoS2 reveals the formation of CdS microsphere (as a core) assemled with 40-50 nm nanoparticles and covered with ultrathin nanosheets of MoS2 (Shell) having size 200-300 nm and the 10-20 nm in thickness. The overall size of the core shell structure is around 8 µm. Intially, there is a formation of CdS microsphre due to high affinity of Cd ions with sulfur and further growth of MoS2 thin sheets on the surface. Considering band gap ideally in visible region, photocatalytic hydrogen evolution using CdS@MoS2 core shell was investigated under natural sunlight. The utmost hydrogen evolution rate achieved for core shell is 416.4 µmole h-1 with apparent quantum yield 35.04%. The photocatalytic activity suggest that an intimate interface contact, extended visible light absorption and effective photo generated charge carrier separation contributed to the photocatalytic enhancement of the CdS@MoS2 core shell. Additional, the enhanced hole trapping process and effective electrons transfer from CdS to MoS2 in CdS@MoS2 core shell heterostructures can significantly contribute for photocatalytic activity. Such core shell heterostructure will also have potential in thin film solar cell and other microelectronic devices.

Correction: Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach.

Correction for 'Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach' by Rajendra P. Panmand et al., Nanoscale, 2017, 9, 4801-4809.

Hierarchical CdMoO4 nanowire-graphene composite for photocatalytic hydrogen generation under natural sunlight.

Herein, a facile in situ solvothermal technique for the synthesis of a CdMoO4/graphene composite photocatalyst is reported. Graphene oxide (GO) was synthesised by an improved Hummers' method and was further used for the in situ synthesis of graphene via GO reduction and the formation of a CdMoO4 nanowire/graphene composite. The structural phase formation of tetragonal CdMoO4 was confirmed from X-ray diffraction measurements. The small nanoparticle assembled nanowires, prismatic microsphere morphology and crystalline nature of the synthesized material were investigated using field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). Due to its unique morphology and stability, the CdMoO4/graphene composite was used as a photocatalyst for H2O splitting. In comparison to pristine CdMoO4, the CdMoO4/graphene composite showed the best hydrogen evolution rate, i.e. 3624 µmole h-1 g-1, with an apparent quantum yield of 30.5%. The CdMoO4/graphene composite has a higher photocatalytic activity due to the inhibition of charge carrier recombination. H2 production measurements showed that the ternary semiconductor/graphene composite has enhanced photocatalytic activity for H2 generation.

Surface modified Li4Ti5O12 by paper templated approach for enhanced interfacial Li+ charge transfer in Li-ion batteries.

The Li4Ti5O12 (LTO) and lithium silicate (LS) surface modified LTO have been demonstrated by a unique paper templated method. Comparative study of structural characterization with electrochemical analysis was demonstrated for pristine and modified Li4Ti5O12. Structural and morphological study shows the existence of the cubic spinel structure with highly crystalline 250-300 nm size particles. The LS modified LTO shows the deposition of 10-20 nm sized LS nanoparticles on cuboidal LTO. Further, X-ray photoelectron spectroscopy (XPS) confirms the existence of Li2SiO3 (LS) in the modified LTO. The electrochemical performance was investigated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and galvanostatic charge-discharge. The modified LTO with 2% LS (LTS2) exhibited excellent rate capability compare to pristine LTO i.e. 182 mA h g-1 specific capacity at a current rate, 50 mA g-1 with remarkable cycling stability up to 1100 cycles at a current rate of 800 mA g-1. The lithium ion full cell of modified LTO with LS as an anode and LiCoO2 as a cathode exhibited a remarkably reversible specific capacity i.e. 110 mA h g-1. Both electronic and ionic conductivities of pristine LTO are observed to be enhanced by incorporation of appropriate amount of LS in LTO due to a larger surface contact at the interface of electrode and electrolyte. More significantly, the versatile paper templated synthesis approach of modified LTO with LS provides densely packed highly crystalline particles. Additionally, it exhibits lower Warburg coefficient and higher Li ion diffusion coefficient which in turn accelerate the interfacial charge transfer process, which is responsible for enhanced stable electrochemical performance. The detailed mechanism is expressed and elaborated for better understanding of enhanced electrochemical performance due to the surface modification.

Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach.

Herein, we demonstrated a green approach for the synthesis of high surface area (850 m2 g-1) mesoporous perforated graphene (PG) from Bougainvillea flower for the first time using a template free single-step method. The existence of PG was confirmed by XRD, Raman spectroscopy, FESEM, and FETEM. Surprisingly, FETEM clearly showed 5-10 nm perforation on the graphene sheets. More significantly, these mesoporous perforated graphene sheets can be produced in large scale using the present green approach. Considering high surface area and unique perforated graphene architecture, these PGs were studied for supercapacitor applications in detail without any chemical or physical activation. The nanoporosity and high conductivity of PG derived from Bougainvillea flower exhibited excellent supercapacitive performance. According to the supercapacitor study, the synthesized perforated graphene sheets conferred a very high specific capacitance of 458 F g-1 and an energy density of 63.7 Wh kg-1 at the power density of around 273.2 Wh kg-1 in aqueous 1 M Na2SO4. Significantly, the areal capacitance of PG was observed to be very high, i.e. 67.2 mF cm-2. The cyclability study results showed excellent stability of synthesized perforated graphene sheets up to 10 000 cycles. Note that the specific and areal capacitance and the energy density of the synthesized PGs are much higher than the earlier reported values. The high supercapacitive performance may be due to high surface area and mesoporosity of PG. The present approach has a good potential to produce cheaper and high surface area PG. These PGs are good candidates as an anode material in the lithium-ion battery.

Nanostructured CdS sensitized CdWO4 nanorods for hydrogen generation from hydrogen sulfide and dye degradation under sunlight.

In this report, CdS nanoparticles have been grown on the surface of CdWO4 nanorods via an in-situ approach and their high photocatalytic ability toward dye degradation and H2 evolution from H2S splitting under visible light has been demonstrated. The structural and optical properties as well as morphologies with varying amount of CdS to form CdS@CdWO4 have been investigated. Elemental mapping and high resolution transmission electron microscopy (HRTEM) analysis proved the sensitization of CdWO4 nanorods by CdS nanoparticles. A decrease in the PL emission of CdWO4 was observed with increasing amount of CdS nanoparticles loading possibly due to the formation of trap states. Considering the band gap in visible region, the photocatalytic study has been performed for H2 production from H2S and dye degradation under natural sunlight. The steady evolution of H2 was observed from an aqueous H2S solution even without noble metal. Moreover, the rate of photocatalytic H2 evolution over CdS modified CdWO4 is ca. 5.6 times higher than that of sole CdWO4 under visible light. CdS modified CdWO4 showed a good ability toward the photo-degradation of methylene Blue. The rate of dye degradation over CdS modified CdWO4 is ca. 7.4 times higher than that of pristine CdWO4 under natural sunlight. With increase in amount of CdS nanoparticle loading on CdWO4 nanorods the hydrogen generation was observed to be decreased where as dye degradation rate is increased. Such nano-heterostructures may have potential in other photocatalytic reactions.

A phase I dose-escalation study to a predefined dose of a transforming growth factor-ß1 monoclonal antibody (TßM1) in patients with metastatic cancer.

Transforming growth factor ß (TGF-ß) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-ß ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TßM1 is a humanized mAb optimized for neutralizing activity against TGF-ß1. The objective of this clinical trial was to assess the safety and tolerability of TßM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤ 2 on the ECOG scale were administered TßM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TßM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TßM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-ß1 expression signature in patients' whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study.

Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

Biomarkers of the Hedgehog/Smoothened pathway in healthy volunteers.

The Hedgehog (Hh) pathway is involved in oncogenic transformation and tumor maintenance. The primary objective of this study was to select surrogate tissue to measure messenger ribonucleic acid (mRNA) levels of Hh pathway genes for measurement of pharmacodynamic effect. Expression of Hh pathway specific genes was measured by quantitative real time polymerase chain reaction (qRT-PCR) and global gene expression using Affymetrix U133 microarrays. Correlations were made between the expression of specific genes determined by qRT-PCR and normalized microarray data. Gene ontology analysis using microarray data for a broader set of Hh pathway genes was performed to identify additional Hh pathway-related markers in the surrogate tissue. RNA extracted from blood, hair follicle, and skin obtained from healthy subjects was analyzed by qRT-PCR for 31 genes, whereas 8 samples were analyzed for a 7-gene subset. Twelve sample sets, each with ≤500 ng total RNA derived from hair, skin, and blood, were analyzed using Affymetrix U133 microarrays. Transcripts for several Hh pathway genes were undetectable in blood using qRT-PCR. Skin was the most desirable matrix, followed by hair follicle. Whether processed by robust multiarray average or microarray suite 5 (MAS5), expression patterns of individual samples showed co-clustered signals; both normalization methods were equally effective for unsupervised analysis. The MAS5- normalized probe sets appeared better suited for supervised analysis. This work provides the basis for selection of a surrogate tissue and an expression analysis-based approach to evaluate pathway-related genes as markers of pharmacodynamic effect with novel inhibitors of the Hh pathway.

Quantitative measurement of cell-free plasma DNA and applications for detecting tumor genetic variation and promoter methylation in a clinical setting.

An elevated cell-free DNA (cfDNA) level is often reported in patients with advanced cancer and is thought to represent nuclear material from a distant inaccessible tumor. cfDNA can become a valuable source to monitor tumor dynamics and evaluate genetic markers for predictive, prognostic, and diagnostic testing. DNA extraction and quantification were optimized with plasma collected from 20 patients with advanced cancer and 16 healthy controls. Plasma cfDNA from patients with advanced cancer was evaluated for TP53 genetic variation and methylation status of CpG islands in several promoters of known disease-related genes. Tumor biopsy and corresponding plasma specimens were collected from study participants to determine whether the same genetic variations were present in both samples. The cfDNA isolation method provided a lower DNA detection limit of 144 pg, equivalent to DNA from approximately 24 cells. Normal pooled human plasma cfDNA averaged 110 copies/mL of the ACTB gene. Extracted cfDNA was suitable for gene-specific variant detection, sequencing, and promoter methylation analysis. DNA extracted from tumor biopsy and corresponding plasma specimens from two patients with advanced cancer revealed an identical, nonsynonymous variant present in both samples. Immunohistochemical analysis confirmed the TP53 mutant phenotype in the tumor specimens. Quantitative measurement of cfDNA represents a useful biomarker to follow treatment outcome and is a valuable tool with which to characterize specific genetic alterations for both patient selection and personalized treatment.

A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.

PURPOSE: The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors. EXPERIMENTAL DESIGN: A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein. RESULTS: Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). CONCLUSIONS: LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.

Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study.

PURPOSE: Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA. PATIENTS AND METHODS: A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression. RESULTS: A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and [(11)C]LY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days. CONCLUSIONS: The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.

Precision profiling and components of variability analysis for Affymetrix microarray assays run in a clinical context.

Although gene expression profiling using microarray technology is widely used in research environments, adoption of microarray testing in clinical laboratories is currently limited. In an attempt to determine how such assays would perform in a clinical laboratory, we evaluated the analytical variability of Affymetrix microarray probesets using two generations of human Affymetrix chips (U95Av2 and U133A). The study was designed to mimic potential clinical applications by using multiple operators, machines, and reagent lots, and by performing analyses throughout a period of several months. A mixed model analysis was used to evaluate the relative contributions of multiple factors to overall variability, including operator, instrument, run, cRNA/cDNA synthesis, and changes in reagent lots. Under these conditions, the average probeset coefficient of variation (CV) was relatively low for present probesets on both generations of chips (mean coefficient of variation, 21.9% and 27.2% for U95Av2 and U133A chips, respectively). The largest contribution to overall variation was chip-to-chip (residual) variability, which was responsible for between 40 to 60% of the total variability observed. Changes in individual reagent lots and instrumentation contributed very little to the overall variability. We conclude that the approach demonstrated here could be applied to clinical validation of Affymetrix-based assays and that the analytical precision of this technique is sufficient to answer many biological questions.

Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.