Automated assessment of disease progression in Acute Myeloid Leukemia by probabilistic analysis of flow cytometry data

Objective: Flow cytometry (FC) is a widely acknowledged technology in diagnosis of acute myeloid leukemia (AML) and has been indispensable in determining progression of the disease. Although FC plays a key role as a post-therapy prognosticator and evaluator of therapeutic efficacy, the manual analysis of cytometry data is a barrier to optimization of reproducibility and objectivity. This study investigates the utility of our recently introduced non-parametric Bayesian framework in accurately predicting the direction of change in disease progression in AML patients using FC data. Methods: The highly flexible non-parametric Bayesian model based on the infinite mixture of infinite Gaussian mixtures is used for jointly modeling data from multiple FC samples to automatically identify functionally distinct cell populations and their local realizations. Phenotype vectors are obtained by characterizing each sample by the proportions of recovered cell populations, which are in turn used to predict the direction of change in disease progression for each patient. Results: We used 200 diseased and non-diseased immunophenotypic panels for training and tested the system with 36 additional AML cases collected at multiple time points. The proposed framework identified the change in direction of disease progression with accuracies of 90% (9 out of 10) for relapsing cases and 100% (26 out of 26) for the remaining cases. Conclusions: We believe that these promising results are an important first step towards the development of automated predictive systems for disease monitoring and continuous response evaluation. Significance: Automated measurement and monitoring of therapeutic response is critical not only for objective evaluation of disease status prognosis but also for timely assessment of treatment strategies

Coarse-graining microscopic strains in a harmonic, two-dimensional solid and its implications for elasticity: non-local susceptibilities and non-affine noise

In soft matter systems the local displacement field can be accessed directly by video microscopy enabling one to compute local strain fields and hence the elastic moduli using a coarse-graining procedure. We study this process for a simple triangular lattice of particles connected by harmonic springs in two-dimensions. Coarse-graining local strains obtained from particle configurations in a Monte Carlo simulation generates non-trivial, non-local strain correlations (susceptibilities), which may be understood within a generalized, Landau type elastic Hamiltonian containing up to quartic terms in strain gradients (K. Franzrahe et al., Phys. Rev. E 78, 026106 (2008)). In order to demonstrate the versatility of the analysis of these correlations and to make our calculations directly relevant for experiments on colloidal solids, we systematically study various parameters such as the choice of statistical ensemble, presence of external pressure and boundary conditions. We show that special care needs to be taken for an accurate application of our results to actual experiments, where the analyzed area is embedded within a larger system, to which it is mechanically coupled. Apart from the smooth, affine strain fields, the coarse-graining procedure also gives rise to a noise field made up of non-affine displacements. Several properties of this noise field may be rationalized for the harmonic solid using a simple "cell model" calculation. Furthermore the scaling behavior of the probability distribution of the noise field is studied and a master curve is obtained.Comment: 16 pages, 12 figure

Goldstone-type fluctuations and their implications for the amorphous solid state

In sufficiently high spatial dimensions, the formation of the amorphous (i.e. random) solid state of matter, e.g., upon sufficent crosslinking of a macromolecular fluid, involves particle localization and, concommitantly, the spontaneous breakdown of the (global, continuous) symmetry of translations. Correspondingly, the state supports Goldstone-type low energy, long wave-length fluctuations, the structure and implications of which are identified and explored from the perspective of an appropriate replica field theory. In terms of this replica perspective, the lost symmetry is that of relative translations of the replicas; common translations remain as intact symmetries, reflecting the statistical homogeneity of the amorphous solid state. What emerges is a picture of the Goldstone-type fluctuations of the amorphous solid state as shear deformations of an elastic medium, along with a derivation of the shear modulus and the elastic free energy of the state. The consequences of these fluctuations -- which dominate deep inside the amorphous solid state -- for the order parameter of the amorphous solid state are ascertained and interpreted in terms of their impact on the statistical distribution of localization lengths, a central diagnostic of the the state. The correlations of these order parameter fluctuations are also determined, and are shown to contain information concerning further diagnostics of the amorphous solid state, such as spatial correlations in the statistics of the localization characteristics. Special attention is paid to the properties of the amorphous solid state in two spatial dimensions, for which it is shown that Goldstone-type fluctuations destroy particle localization, the order parameter is driven to zero, and power-law order-parameter correlations hold.Comment: 20 pages, 3 figure

Role of cervical dendritic cell subsets, co-stimulatory molecules, cytokine secretion profile and beta-estradiol in development of sequalae to Chlamydia trachomatis infection

BACKGROUND: Chlamydia trachomatis infection of the female genital tract can lead to serious sequelae resulting in fertility related disorders. Little is known about the mechanism leading to Chlamydia induced pathology and factors responsible for it. As only some of the women develops reproductive disorders while majority of the women clears infection without any severe sequalae, mucosal immune response in women with or without fertility disorders was studied to identify factors which may lead to final clinical outcome of chlamydial infection. METHODS: Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) populations in cervical mucosa and peripheral blood were analyzed in controls and Chlamydia positive women with or without fertility disorders with multicoloured flow cytometric analysis. Cervical cytokines (IL-6, IL-8, IL-10, IL-12, TNF-alpha and IFN-gamma), C-reactive protein levels and sex hormone levels in serum were quantified by ELISA. RESULTS: In cervix of Chlamydia positive women with fertility disorders, significantly high (P < 0.05) numbers of pDCs were present with increased CD80 expression. pDCs correlated significantly with C-reactive protein levels, IL-6 and IFN-gamma levels in women with fertility disorders. In contrast, mDCs showed significant upregulation of CD1a during chlamydial infection and correlated significantly with IL-12 levels in Chlamydia positive fertile women. β-estradiol levels were significantly higher in women having fertility disorders as compared to fertile women and have significant correlations (r = 0.65; P < 0.05) with pDCs numbers, CD80 expression, IL-6 levels and IFN-gamma levels in these women. CONCLUSION: These results suggest that development of sequalae in some women can be a result of interplay of many factors including type of dendritic cell, co stimulatory molecule expression, cytokine secretion pattern and hormone levels

Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species

Significant levels of circulating immune complexes (ICs) containing rheumatoid factors and immunoglobulin G in peripheral blood are a characteristic feature of rheumatoid arthritis (RA). ICs interact through Fcγ receptors (FcγR) to activate phagocytes in numerous inflammatory processes. The high concentration of neutrophils in synovial fluid during active phases of the disease, together with their destructive capacity, pose important questions as to their role in the pathogenesis of RA. Functional defects in RA or control peripheral blood neutrophil FcγRs were examined with a specific FcγR-mediated reactive oxygen species (ROS) assay. Heterologous cross-linking of FcγRIIa and FcγRIIIb on neutrophils resulted in a significantly decreased production of ROS by RA cells compared with controls matched for age and sex. However, expression and homologous ligation of receptors did not differ between these groups. These data suggest that neutrophil priming does occur before emigration into the joint and that blood neutrophils from patients with RA have a functional impairment in cooperative FcγR-mediated ROS generation. This may account for the increased susceptibility to bacterial infection that arises in patients with severe disease

Electrical characterization of top-gated molybdenum disulfide field-effect-transistors with high-k dielectrics

High quality HfO2 and Al2O3 substrates are fabricated in order to study their impact on top-gate MoS2 transistors. Compared with top-gate MoS2 FETs on a SiO2 substrate, the field effect mobility decreased for devices on HfO2 substrates but substantially increased for devices on Al2O3 substrates, possibly due to substrate surface roughness. A forming gas anneal is found to enhance device performance due to a reduction in charge trap density of the high-k substrates. The major improvements in device performance are ascribed to the forming gas anneal. Top-gate devices built upon Al2O3 substrates exhibit a near-ideal subthreshold swing (SS) of ~ 69 mV/dec and a ~ 10 × increase in field effect mobility, indicating a positive influence on top-gate device performance even without any backside bias

Chemical and electrical characterization of the HfO2/InAlAs interface

InAlAs has the potential to be used as a barrier layer in buried channel quantum well field effect transistor devices due to favorable lattice-matching and carrier confinement properties with InGaAs. Field effect device structures of this nature may also require a high-k oxide deposited on the InAlAs surface to reduce leakage current. This study investigates the impact of surface preparations and atomic layer deposition of HfO2 on these surfaces using x-ray photoelectron spectroscopy to analyse the chemical interactions taking place, as well as the electrical performance of associated capacitor devices. A large concentration of As related surface features is observed at the InAlAs surface, and is attributed to a large D-it response in electrical measurements. (C) 2013 AIP Publishing LLC

Predicting Persistent Opioid Use, Abuse, and Toxicity Among Cancer Survivors.

BackgroundAlthough opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse.MethodsWithin a cohort of 106 732 military veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent posttreatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator regression technique.ResultsThe rate of persistent opioid use in cancer survivors was 8.3% (95% CI = 8.1% to 8.4%); the rate of opioid abuse or dependence was 2.9% (95% CI = 2.8% to 3.0%); and the rate of opioid-related admissions was 2.1% (95% CI = 2.0% to 2.2%). On multivariable analysis, several patient, demographic, and cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under the curve [AUC] = 0.85), future diagnoses of opioid abuse or dependence (AUC = 0.87), and admission for opioid abuse or toxicity (AUC = 0.78).ConclusionThis study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk-stratification approaches could guide management when prescribing opioids in cancer patients

In-situ characterization of Ga2O passivation of In0.53Ga0.47As prior to high-k dielectric atomic layer deposition

Ga2O interfacial passivation layers (IPLs) on In0.53Ga0.47As are investigated using in-situ monochromatic x-ray photoelectron spectroscopy. The oxide is entirely composed of Ga2O when deposited with an effusion cell temperature of 1500 degrees C and substrate temperature of 425 degrees C. The growth on In0.53Ga0.47As reveals slight chemical modification of the surface. The Ga2O behavior and ability to protect the III-V surface are observed following Al2O3 deposition by atomic layer deposition following each precursor pulse. Al2O3 growth by trimethyl-Al (TMA) and water reveals that the IPL undergoes the "clean-up" effect following TMA exposures causing As-As bonding formation resulting in a high interface state density. (C) 2011 American Institute of Physics. (doi:10.1063/1.3615666