89 research outputs found
Validation of Soft Classification Models using Partial Class Memberships: An Extended Concept of Sensitivity & Co. applied to the Grading of Astrocytoma Tissues
We use partial class memberships in soft classification to model uncertain
labelling and mixtures of classes. Partial class memberships are not restricted
to predictions, but may also occur in reference labels (ground truth, gold
standard diagnosis) for training and validation data.
Classifier performance is usually expressed as fractions of the confusion
matrix, such as sensitivity, specificity, negative and positive predictive
values. We extend this concept to soft classification and discuss the bias and
variance properties of the extended performance measures. Ambiguity in
reference labels translates to differences between best-case, expected and
worst-case performance. We show a second set of measures comparing expected and
ideal performance which is closely related to regression performance, namely
the root mean squared error RMSE and the mean absolute error MAE.
All calculations apply to classical crisp classification as well as to soft
classification (partial class memberships and/or one-class classifiers). The
proposed performance measures allow to test classifiers with actual borderline
cases. In addition, hardening of e.g. posterior probabilities into class labels
is not necessary, avoiding the corresponding information loss and increase in
variance.
We implement the proposed performance measures in the R package
"softclassval", which is available from CRAN and at
http://softclassval.r-forge.r-project.org.
Our reasoning as well as the importance of partial memberships for
chemometric classification is illustrated by a real-word application:
astrocytoma brain tumor tissue grading (80 patients, 37000 spectra) for finding
surgical excision borders. As borderline cases are the actual target of the
analytical technique, samples which are diagnosed to be borderline cases must
be included in the validation.Comment: The manuscript is accepted for publication in Chemometrics and
Intelligent Laboratory Systems. Supplementary figures and tables are at the
end of the pd
Label-free surface-enhanced Raman spectroscopy of biofluids: fundamental aspects and diagnostic applications
In clinical practice, one objective is to obtain diagnostic
information while minimizing the invasiveness of the
tests and the pain for the patients. To this end, tests based on
the interaction of light with readily available biofluids including
blood, urine, or saliva are highly desirable. In this review
we examine the state of the art regarding the use of surfaceenhanced
Raman spectroscopy (SERS) to investigate
biofluids, focusing on diagnostic applications. First, a critical
evaluation of the experimental aspects involved in the collection
of SERS spectra is presented; different substrate types are
introduced, with a clear distinction between colloidal and noncolloidal
metal nanostructures. Then the effect of the excitation
wavelength is discussed, along with anomalous bands
and artifacts which might affect SERS spectra of biofluids.
The central part of the review examines the literature available
on the SERS spectra of blood, plasma, serum, urine, saliva,
tears, and semen. Finally, diagnostic applications are critically
discussed in the context of the published evidence; this section
clearly reveals that SERS of biofluids is most promising as a
rapid, cheap, and non-invasive tool for mass screening for
cancer
On the possibility of low cost, adherent therapeutic drug monitoring in oncology
A frequent quantification of drugs concentrations in plasma of patients subject to chemotherapy is seldom performed, mostly because the standard methods (Gas or Liquid Chromatography coupled with Mass Spectroscopy) are expensive and time consuming. In this paper we report the approach pursued in one of the research units of the EU project RAMAN4CLINICS to tackle the problem of a low cost, time adherent quantification of drugs used for oncological patients using a Surface Enhanced Raman Scattering (SERS) spectroscopy. More specifically, the issues concerning the repeatability of the nanostructured substrates will be presented and some promising results to increase the selectivity of the measures toward specific drugs will be discussed, with examples concerning one cytotoxic agent, Irinotecan and one kinase inhibitor, Sunitinib
SERS analysis of serum for detection of early and locally advanced breast cancer
n this contribution, we investigated whether surface-enhanced Raman scattering (SERS) of serum can be a candidate method for detecting \u201cluminal A\u201d breast cancer (BC) at different stages. We selected three groups of participants aged over 50 years: 20 healthy women, 20 women with early localized small BC, and 20 women affected by BC with lymph node involvement. SERS revealed clear spectral differences between these three groups. A predictive model using principal component analysis (PCA) and linear discriminant analysis (LDA) was developed based on spectral data, and its performance was estimated with cross-validation. PCA-LDA of SERS spectra could distinguish healthy from BC subjects (sensitivity, 92 %; specificity, 85 %), as well as subjects with BC at different stages, with a promising diagnostic performance (sensitivity and specificity, 6580 %; overall accuracy, 84 %). Our data suggest that SERS spectroscopy of serum, combined with multivariate data analysis, represents a minimally invasive, easy to use, and fast approach to discriminate healthy from BC subjects and even to distinguish BC at different clinical stages
Label-Free Quantification of Anticancer Drug Imatinib in Human Plasma with Surface Enhanced Raman Spectroscopy
Therapeutic drug monitoring (TDM) for anticancer drug imatinib has been suggested as the best way to improve the treatment response and minimize the risk of adverse reactions in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients. TDM of oncology treatments with standard analytical methods, such as liquid chromatography-tandem mass spectrometry (LC-MS/ MS) is, however, complex and demanding. This paper proposes a new method for quantitation of imatinib in human plasma, based on surface enhanced raman spectroscopy (SERS) and multivariate calibration using partial least-squares regression (PLSR). The best PLSR model was obtained with three latent variables in the range from 123 to 5000 ng/mL of imatinib, providing a standard error of prediction (SEP) of 510 ng/mL. The method was validated in accordance with international guidelines, through the estimate of figures of merit, such as precision, accuracy, systematic error, analytical sensitivity, limits of detection, and quantitation. Moreover, the feasibility and clinical utility of this approach have also been verified using real plasma samples taken from deidentified patients. The results were in good agreement with a clinically validated LC-MS/MS method. The new SERS method presented in this preliminary work showed simplicity, short analysis time, good sensitivity, and could be considered a promising platform for TDM of imatinib treatment in a point-of-care setting
Surface-enhanced Raman spectroscopy of urine for prostate cancer detection: a preliminary study
Surface-enhanced Raman scattering (SERS) spectra were obtained from urine samples from subjects diagnosed with prostate cancer as well as from healthy controls, using Au nanoparticles as substrates. Principal component analysis (PCA) of the spectral data, followed by linear discriminant analysis (LDA), leads to a classification model with a sensitivity of 100 %, a specificity of 89 %, and an overall diagnostic accuracy of 95 %. Even considering the very limited number of samples involved in this report, preliminary results from this approach are extremely promising, encouraging further investigation
Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies
The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Purpose Enhancing oral bioavailability of vinpocetine by forming its
amorphous citrate salt through a solvent-free mechanochemical
process, in presence of micronised crospovidone and citric acid.
Methods The impact of formulation and process variables
(amount of polymer and citric acid, and milling time) on
vinpocetine solubilization kinetics from the coground was
studied through an experimental design. The best performing
samples were characterized by employing a multidisciplinary
approach, involving Differential scanning calorimetry, X-ray
diffraction, Raman imaging/spectroscopy, X-ray photoelectron
spectroscopy, solid-state NMR spectroscopy, porosimetry and
in vivo studies on rats to ascertain the salt formation, their solidstate
characteristics and oral bioavailability in comparison to
vinpocetine citrate salt (Oxopocetine®).
Results The analyses attested that the mechanochemical
process is a viable way to produce in absence of solvents
vinpocetine citrate salt in an amorphous state.
Conclusion From the in vivo studies on rats the obtained salt
was four times more bioavailable than its physical mixture and
bioequivalent to the commercial salt produced by conventional
synthetic process implying the use of solvent
Long-term stability of an injection-molded zirconia bone-level implant: A testing protocol considering aging kinetics and dynamic fatigue
Abstract
Objective
Separately addressing the fatigue resistance (ISO 14801, evaluation of final product) and aging behavior (ISO 13356, standardized sample) of oral implants made from yttria-stabilized zirconia proved to be insufficient in verifying their long-term stability, since (1) implant processing is known to significantly influence transformation kinetics and (2) aging, up from a certain level, is liable to decrease fatigue resistance. Therefore, the aim of this investigation was to apply a new testing protocol considering environmental conditions adequately inducing aging during dynamic fatigue.
Methods
Zirconia implants were dynamically loaded (107 cycles), hydrothermally aged (85\ub0, 60 days) or subjected to both treatments simultaneously. Subsequent, monoclinic intensity ratios (Xm) were obtained by locally resolved X-ray microdiffraction (\u3bc-XRD2). Transformation propagation was monitored at cross-sections by \u3bc-Raman spectroscopy and scanning electron microscopy (SEM). Finally, implants were statically loaded to fracture. Linear regression models (fracture load) and mixed models (Xm) were used for statistical analyses.
Results
All treatments resulted in increased fracture load (p 64 0.005), indicating the formation of transformation induced compressive stresses around surface defects during all treatment modalities. However, only hydrothermal and combinational treatment were found to increase Xm (p < 0.001). No change in Xm was observed for solely dynamically loaded samples (p 65 0.524). Depending on the variable observed, a monoclinic layer thickness of 1\u20132 \u3bcm (SEM) or 6\u20138 \u3bcm (Raman spectroscopy) was measured at surfaces exposed to water during treatments.
Significance
Hydrothermal aging was successfully induced during dynamic fatigue. Therefore, the presented setup might serve as reference protocol for ensuring pre-clinically long-term reliability of zirconia oral implants
Towards long lasting zirconia-based composites for dental implants: Transformation induced plasticity and its consequence on ceramic reliability
Zirconia-based composites were developed through an innovative processing route able to tune compositional and microstructural features very precisely. Fully-dense ceria-stabilized zirconia ceramics (84 vol% Ce-TZP) containing equiaxed alumina (8 vol%Al2O3) and elongated strontium hexa-aluminate (8 vol% SrAl12O19) second phases were obtained by conventional sintering. This work deals with the effect of the zirconia stabilization degree (CeO2 in the range 10.0\u201311.5 mol%) on the transformability and mechanical properties of Ce-TZP-Al2O3-SrAl12O19 materials.
Vickers hardness, biaxial flexural strength and Single-edge V-notched beam tests revealed a strong influence of ceria content on the mechanical properties. Composites with 11.0 mol% CeO2 or above exhibited the classical behaviour of brittle ceramics, with no apparent plasticity and very low strain to failure. On the contrary, composites with 10.5 mol% CeO2 or less showed large transformation-induced plasticity and almost no dispersion in strength data.
Materials with 10.5 mol% of ceria showed the highest values in terms of biaxial bending strength (up to 1.1 GPa) and fracture toughness (>10 MPa 1am). In these ceramics, as zirconia transformation precedes failure, the Weibull modulus was exceptionally high and reached a value of 60, which is in the range typically reported for metals. The results achieved demonstrate the high potential of using these new strong, tough and stable zirconia-based composites in structural biomedical applications
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Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes
Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes' energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.</p
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