Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested. Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer. Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1–blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression. Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. Clin Cancer Res; 23(17); 5149–61. ©2017 AACR.

This study describes a corner selection strategy based on the Harris approach. Corners are usually defined as interest points for which intensity variation in the principal directions is locally maximised, as response from a filter given by the linear combination of the determinant and the trace of the autocorrelation matrix. The Harris corner detector, in its original definition, is only rotationally invariant, but scale-invariant and affine-covariant extensions have been developed. As one of the main drawbacks, corner detector performances are influenced by two user-given parameters: the linear combination coefficient and the response filter threshold. The main idea of the authors' approach is to search only the corners near enhanced edges and, by a z-score normalisation, to avoid the introduction of the linear combination coefficient. Combining these strategies allows a fine and stable corner selection without tuning the method. The new detector has been compared with other state-of-the-art detectors on the standard Oxford data set, achieving good results showing the validity of the approach. Analogous results have been obtained using the local detector evaluation framework on non-planar scenes by Fraundorfer and Bischof.

In the olfactory bulb, lateral inhibition mediated by granule cells has been suggested to modulate the timing of mitral cell firing, thereby shaping the representation of input odorants. Current experimental techniques, however, do not enable a clear study of how the mitral-granule cell network sculpts odor inputs to represent odor information spatially and temporally. To address this critical step in the neural basis of odor recognition, we built a biophysical network model of mitral and granule cells, corresponding to 1/100th of the real system in the rat, and used direct experimental imaging data of glomeruli activated by various odors. The model allows the systematic investigation and generation of testable hypotheses of the functional mechanisms underlying odor representation in the olfactory bulb circuit. Specifically, we demonstrate that lateral inhibition emerges within the olfactory bulb network through recurrent dendrodendritic synapses when constrained by a range of balanced excitatory and inhibitory conductances. We find that the spatio-temporal dynamics of lateral inhibition plays a critical role in building the glomerular-related cell clusters observed in experiments, through the modulation of synaptic weights during odor training. Lateral inhibition also mediates the development of sparse and synchronized spiking patterns of mitral cells related to odor inputs within the network, with the frequency of these synchronized spiking patterns also modulated by the sniff cycle. In the paper we address the role of lateral inhibition in a neuronal network. It is an essential and widespread mechanism of neural processing that has been demonstrated in many brain systems. A key finding that would reveal how and to what extent it can modulate input signals and give rise to some form of perception would involve network-wide recording of individual cells during in vivo behavioral experiments. While this problem has been intensely investigated, it is beyond current methods to record from a reasonable set of cells experimentally to decipher the emergent properties and behavior of the network, leaving the underlying computational and functional roles of lateral inhibition still poorly understood. We addressed this problem using a large-scale model of the olfactory bulb. The model demonstrates how lateral inhibition modulates the evolving dynamics of the olfactory bulb network, generating mitral and granule cell responses that account for critical experimental findings. It also suggests how odor identity can be represented by a combination of temporal and spatial patterns of mitral cell activity, with both feedforward excitation and lateral inhibition via dendrodendritic synapses as the underlying mechanisms facilitating network self-organization and the emergence of synchronized oscillations.

Facial expressions reflect psychological states and are crucial for understanding human emotions. Traditional facial expression recognition methods face challenges in real-world healthcare applications due to variations in facial structure, lighting conditions and occlusion. We present a methodology based on transfer learning with the pre-trained models VGG-19 and ResNet-152, and we highlight dataset-specific preprocessing techniques that include resizing images to 124 × 124 pixels, augmenting the data and selectively freezing layers to enhance the robustness of the model. This study explores the application of deep learning-based facial expression recognition in healthcare, particularly for remote patient monitoring and telemedicine, where accurate facial expression recognition can enhance patient assessment and early diagnosis of psychological conditions such as depression and anxiety. The proposed method achieved an average accuracy of 0.98 on the CK+ dataset, demonstrating its effectiveness in controlled environments. However performance varied across datasets, with accuracy rates of 0.44 on FER2013 and 0.89 on JAFFE, reflecting the challenges posed by noisy and diverse data. Our findings emphasize the potential of deep learning-based facial expression recognition in healthcare applications while underscoring the importance of dataset-specific model optimization to improve generalization across different data distributions. This research contributes to the advancement of automated facial expression recognition in telemedicine, supporting enhanced doctor–patient communication and improving patient care.