Assays of drug action typically evaluate biochemical activity. However, accurately matching therapeutic efficacy with biochemical activity is a challenge. High-content cellular assays seek to bridge this gap by capturing broad information about the cellular physiology of drug action. Here, we present a method of predicting the general therapeutic classes into which various psychoactive drugs fall, based on high-content statistical categorization of gene expression profiles induced by these drugs. When we used the classification tree and random forest supervised classification algorithms to analyze microarray data, we derived general ''efficacy profiles'' of biomarker gene expression that correlate with antidepressant, antipsychotic and opioid drug action on primary human neurons in vitro. These profiles were used as predictive models to classify naïve in vitro drug treatments with 83.3% (random forest) and 88.9% (classification tree) accuracy. Thus, the detailed information contained in genomic expression data is sufficient to match the physiological effect of a novel drug at the cellular level with its clinical relevance. This capacity to identify therapeutic efficacy on the basis of gene expression signatures in vitro has potential utility in drug discovery and drug target validation.pharmacogenomics ͉ predictive efficacy ͉ drug screening M icroarray-based gene expression patterns can be used as fingerprints of cellular physiology. The variety of cellular physiologies discernable by gene expression profile fingerprinting is expanding as an increasing range of cell types and cellular manipulations are investigated, and statistical methods of expression profile classification are refined. In yeast, distinctive profiles of genomic expression have been used to characterize cellular responses to diverse environmental transitions (1), functionally classify genetic manipulations, and discover a novel target for a drug of partially characterized function (2). In cancer studies, microarray data has been used to classify solid tumors (3), correlate tumor characteristics to clinical outcome (4), and cluster cell lines on the basis of their tissue of origin and response to drugs (5-9). In the area of toxicogenomics, large-scale gene expression analysis of toxin-treated cells and animals has yielded a highly accurate capacity to recognize the toxic potential of novel drug candidates (10-14), resulting in an increase in the efficiency of drug triage in the pharmaceutical development pipeline.Multiple statistical methods have been applied to classification and recognition of expression profiles. Supervised classification analysis methods, which can classify patterns of novel data based on prior knowledge of sample classes, include linear discriminant analysis and genetic algorithm/K-nearest neighbors (11, 15), Fisher discriminant analysis (16), support vector machines (17), neural networks (18), and tree-based analysis (19). Here, we use human primary neurons treated with multiple members of multiple classes of antidepressan...

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the gene encoding the bone morphogenetic protein (BMP) type I receptor, ACVR1 (ALK2), the most prevalent of which results in an arginine to histidine substitution at position 206 (ACVR1[R206H]). The fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in fibro-adipogenic progenitors (FAPs), which drives HO. We developed a monoclonal blocking antibody (JAB0505) against the extracellular domain of ACVR1 and tested its effect on HO in 2 independent FOP mouse models. Although JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines, JAB0505 treatment profoundly exacerbated injury-induced HO. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. This was accompanied by dysregulated FAP population growth and an abnormally sustained immunological reaction following muscle injury. JAB0505 drove injury-induced HO in the absence of activin A, indicating that JAB0505 has receptor agonist activity. These data raise serious safety and efficacy concerns for the use of bivalent anti-ACVR1 antibodies to treat patients with FOP.

The relevant frequency of MPS VI and IVA in the sample allows us to compare the changes occurring in both groups of patients, therefore enabling us to further comprehend the oral manifestations in specific types of MPS.

The variations in exposure parameters did not interfere with the diagnosis of vertical root fractures, independent of the root canal restorative status. Metallic posts were associated with greater artefact formation and compromised the diagnostic performance. It is possible to decrease the kVp/mA settings to reduce the probability of biological effects due to radiation, without losing diagnostic accuracy.

Objectives: To assess patients with and without temporomandibular disorders (TMD) infrared thermography according to the differences in thermal radiance using quantitative sensitivity and specificity tests; and to evaluate the thermal asymmetry and the correlation of the thermal intensity with the intensity of pain upon palpation. Methods: This cross-sectional study performed a quantitative evaluation of clinical and thermographic examinations. The volunteers were evaluated for the presence of TMD using RDC/TMD (Diagnostic Research Criteria for Temporomandibular Disorders), and were divided into two groups: TMD group (n = 45); control group (n = 41), composed of volunteers without TMD, according to the Fonseca Anamnestic Index. The images were assessed for selected regions of interest for the masseter, anterior temporal and TMJ muscles. The mean values ​​of the areas of both groups were compared under the receiver operating characteristic curve. Spearman correlation analysis (non-parametric data) between pain level and mean temperature, by region, and the Pearson's χ2 test was used to verify the association between the presence of temperature and pain asymmetry. The level of significance was set at p < 0.05. Results: Both Groups, with and without TMD, presented with absolute and non-dimensional mean temperature without statistical differences (p>0.05). When correlating temperature with intensity of pain upon palpation, a negative correlation was observed for the masseter muscle. Conclusion: Infrared Thermography resulted in low area under the curve, making it difficult to differentiate TMD via thermographic analysis. The intensity of pain upon palpation in patients with TMD may be accompanied by a decrease in local temperature.