Despite various treatment attempts, the heterogenous group of soft tissue sarcomata (STS) with more than 100 subtypes still shows poor outcomes. Therefore, effective biomarkers for prognosis prediction and personalized treatment are of high importance. The Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (PLOD) gene family, which is related to multiple cancer entities, consists of three members which encode important enzymes for the formation of connective tissue. The relation to STS, however, has not yet been explored. In this study, data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to analyze the role of PLOD1–3 in STS. It was found that an overexpression of PLOD family members correlates with poor prognosis, which might be due to an increased infiltration of immune-related cells in the tumor microenvironment. In STS, the expression of PLOD genes could be a novel biomarker for prognosis and a personalized, more aggressive treatment in these patients.

The inclusion of lime in burials is observed in historical and archaeological records, in contemporary mass graves and forensic cases. Clearly there are controversies within the literature and there is a general misconception of the effects of lime on decomposition. Recent casework in Belgium and the UK involving the search for human remains buried with lime, have demonstrated the need for a more detailed understanding of the effect of different types of lime on cadaver decomposition and its micro-environment. Field and laboratory experiments using pigs as human body analogues were undertaken to obtain a better understanding of the taphonomic processes that govern lime burials. The changes observed in the experiments were related back to archaeological parallels in which white residues have been found. The combined results of these studies demonstrate that despite conflicting evidence in the literature, hydrated lime and quicklime both delay the initial stages of the decay process but do not arrest it completely. The end result is ultimately the same: skeletonisation. Furthermore this study stresses the importance of the specific microenvironment in taphonomic research and highlights the need for chemical analysis of white residues when encountered in a burial. Not all white powder is lime. White residue could be identified as calcium carbonate, building material, body decomposition products, minerals or degraded lead. This study has implications for the investigation of clandestine burials and for a better understanding of archaeological plaster burials. Knowledge of the effects of lime on decomposition processes also have bearing on practices involving the disposal of animal carcasses and potentially the management of mass graves and mass disasters by humanitarian organisation and DVI teams. / Arts and Humanities Research Council (AHRC) and the University of Bradford

Simple Summary Soft tissue sarcomas (STS) are a group of rare malignant tumors with high tissue heterogeneity and poor prognosis, and which are still without effective individualized immunotherapy approaches. In this study, four potential tumor antigens, six STS immune subtypes, and six functional gene modules were identified. The different immune subtypes have different molecular, cellular, and clinical characteristics. The superiority of mRNA vaccine therapies has been demonstrated during the current pandemic as well as in tumor vaccine studies, and the present study provides guidance for future mRNA vaccine development. Furthermore, in future individualized immunotherapies for STS, it is possible to select different immunotherapies based on the different immune subtypes identified in this study. In fact, the immune subtypes identified in this study explain, to some extent, the failure of immunotherapy for certain STS subtypes in previous clinical trials, and facilitate further understanding of strategy selection for the immunotherapy of STS. To our knowledge, this is the first study to address STS mRNA vaccine development and immunophenotyping. This study provides a theoretical framework for STS mRNA vaccine development and the selection of patients for vaccination and provides a reference for promoting individualized immunotherapy. Abstract Soft tissue sarcomas (STS) are a rare disease with high recurrence rates and poor prognosis. Missing therapy options together with the high heterogeneity of this tumor type gives impetus to the development of individualized treatment approaches. This study identifies potential tumor antigens for the development of mRNA tumor vaccines for STS and explores potential immune subtypes, stratifying patients for immunotherapy. RNA-sequencing data and clinical information were extracted from 189 STS samples from The Cancer Genome Atlas (TCGA) and microarray data were extracted from 103 STS samples from the Gene Expression Omnibus (GEO). Potential tumor antigens were identified using cBioportal, the Oncomine database, and prognostic analyses. Consensus clustering was used to define immune subtypes and immune gene modules, and graph learning-based dimensionality reduction analysis was used to depict the immune landscape. Finally, four potential tumor antigens were identified, each related to prognosis and antigen-presenting cell infiltration in STS: HLTF, ITGA10, PLCG1, and TTC3. Six immune subtypes and six gene modules were defined and validated in an independent cohort. The different immune subtypes have different molecular, cellular, and clinical characteristics. The immune landscape of STS reveals the immunity-related distribution of patients and intra-cluster heterogeneity of immune subtypes. This study provides a theoretical framework for STS mRNA vaccine development and the selection of patients for vaccination, and provides a reference for promoting individualized immunotherapy.

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Melanoma is a highly malignant neoplasia with high rates of metastasis in humans and dogs. Regardless of being considered a highly immunogenic neoplasm, the function of the immune system is hampered by the expression of immune checkpoint molecules by the cancer cells. In contrast, soft tissue sarcomas are poorly immunogenic, as Tumor infiltrating Lymphocytes are lacking, or when present they are usually at the periphery of the tumor. Still, soft tissue sarcomas are considered immunosuppressed. Checkpoint molecules from the PD-axis are overexpressed in numerous human malignant neoplasia and have recently gained attention with a few reports in canine tumors. Immunotherapies against these checkpoint molecules have shown great efficacy in humans, but in order to determine translational approaches into canine patients, more research is needed. Here we determined the gene expression of Programed Death receptor-1, and its ligands PD-L1 and PD-L2 in canine tumors with two distinct immune profiles. Our results show that regardless of their immune profiles, melanoma versus soft tissue sarcoma, checkpoint molecules expression was higher in malignant tumors with a higher grade. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal ultrasound focused therapy that induces mechanical stress to the cells, leading to liquefactive necrosis. Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of CD3+ T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasia, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia. / Doctor of Philosophy / Melanoma is a highly malignant tumor and very resistant to therapy for humans and dogs. At the same time, this neoplasia is usually highly infiltrated by cells from the immune system. However, this immune infiltration is often inhibited by molecules expressed by the melanoma cells. In contrast, soft tissue sarcoma is considered poorly immunogenic, as they often contain low levels of immune cell infiltrates but are still considered immune suppressed. In this study, we determined the expression of molecules that inhibit the effect of T lymphocytes, specifically Programed cell death receptor-1, PD-Ligand 1, and PD-Ligand 2 for these neoplasms with distinct immune profiles. We encounter that despite their immune profiles, the expression of these molecules is higher in malignant tumors. Additionally, we evaluated the expression of these molecules in a set of patients that received histotripsy, which is a non-invasive and non-thermal focused ultrasound therapy that induces mechanical stress to the cancerigenous cells, leading to its death (necrosis). Here we reported a focal decrease of the expression of these checkpoint molecules in tissue sections obtain at the treatment interface, compared to those taken from untreated areas of the tumor. In addition, a positive relationship was noticed between the infiltration of T lymphocytes and the expression of these checkpoint molecules in both canine melanoma, and soft tissue sarcoma. Our findings demonstrate that immunotherapies targeting these checkpoint molecules have a great potential for efficacy in canine neoplasms, along or combined with tumor ablation therapies that increased immune cell infiltration in poorly immunogenic neoplasia.

Snoring is a sleep disruption that can lead to obstructive sleep apnea (OSA), which interrupts breathing by obstructing the airway. Injecting a protein crosslinker, such as genipin, into the soft palate could decrease the severity of snoring and OSA by stiffening the soft palate. Equine soft palates modeled human palates due to a high incidence of awake snoring and apnea. The pilot in vivo study treated six horses with two 100 mM injections of the buffered genipin reagent. The efficacy phase horses underwent respiratory audio recordings to document snoring changes using Matlab and ImageJ in the time and frequency domains. Histological analysis was completed on the safety phase palates post treatment. All horses were successfully treated with the genipin injections. At least one horse showed high frequency amplitude reductions, and all horses had low frequency amplitude reductions, correlating to a reduction in palatal displacement and snoring loudness. One efficacy horse appears to have been completely cured. The histological analysis presented tissue damage, mucosal tissue damage, and mild inflammation due to palate expansion and errant injections. Different injection volumes and techniques should be investigated next. Applying this treatment to human studies for snoring and OSA applications is the ultimate goal.

Les sarcomes de haut grade présentent une progression métastatique dans approximativement 50 % des cas. Les bénéfices des traitements de chimiothérapie palliatifs pour les métastases à distance restent modestes. L’objectif primaire de cette étude est d’évaluer la progression de la maladie et la survie des patients diagnostiqués avec un sarcome des tissus mous métastatique traité par chimiothérapie palliative. Une revue de dossiers rétrospective des 68 patients ayant reçu de la chimiothérapie palliative pour leurs sarcomes métastatiques entre 2003 et 2013 à l’Hôpital Maisonneuve- Rosemont a été réalisée. Une mise en banque des données d’un groupe n’ayant pas eu de chimiothérapie de 36 patients ayant eu un diagnostic de sarcomes métastatiques des tissus mous sans traitement de chimiothérapie a été effectuée rétrospectivement. La survie globale médiane obtenue avec traitements de chimiothérapie était plus du double de celle sans traitement, soit de 20 mois et 7 mois, respectivement (p =0.0001). La survie globale de tous les groupes histologiques ayant eu des traitements de chimiothérapie était améliorée, particulièrement pour les léiomyosarcomes et sarcomes synoviaux, bien que la différence entre les groupes traités et non traités n’était pas statistiquement significative. Lorsque la chimiothérapie était administrée en thérapie combinée lors de la première ligne de traitement, la survie sans évènement était significativement augmentée (p=0.0184) et les taux de réponse favorables étaient deux fois plus élevés. En conclusion, les résultats ont montré une survie significativement améliorée pour tous les groupes histologiques ayant eu des traitements de chimiothérapie. Néanmoins, les patients avec une réponse favorable demeurent avec une faible espérance de vie. D’autres options de traitements sont nécessaires. / High-grade sarcomas present a metastatic progression in approximately 50% of cases. The effectiveness of palliative chemotherapy as a treatment of systemic metastases is still modest. The main objective of this study is to assess disease progression and survival of patients diagnosed with metastatic soft tissue sarcomas treated with palliative chemotherapy. A retrospective chart review of 68 patients treated with palliative chemotherapy for metastatic soft tissue sarcomas between 2003 and 2013 at Maisonneuve-Rosemont Hospital was achieved. Data for control group of 36 patients with metastatic soft tissue sarcomas not treated with chemotherapy was collected retrospectively. Median overall survival with chemotherapy treatments was more than two times overall survival without treatments, which were 20 months and 7 months, respectively (p=0.0001). Overall survival was improved for all histologic subtypes with chemotherapy treatments, especially for leiomyosarcomas and synovial sarcomas, even though the difference in survival was not statistically significant between treated and untreated groups. When chemotherapy was given in combined therapy during first line of treatment, event-free survival was statistically longer (p=0.0184) and favorable responses rates were doubled. In conclusion, results have shown a significantly improved overall survival in all histological groups with chemotherapy treatments. Nevertheless, patients with favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

Past studies evaluating the esthetics of orthodontic treatment have been done using 2-D images. New 3-D imaging offers an improved, real-life representation of a subject. The purpose of this study was to determine how laypeople perceived differences in lip position (flat versus ideal lip fullness) in 2-D compared to 3-D. 3dMD images of 8 Caucasian subjects were adjusted to an ideal and flat lip position in 3-D and then in 2-D from the profile view. 2 surveys were created with paired ideal and flat images on the screen, either in 2-D or 3-D, and evaluators were asked to choose which image they preferred and by how much. Evaluators were more likely to be neutral, and were less decisive of their preference in 3-D compared to 2-D. People might be less sensitive to small differences in facial soft tissue and esthetics than previous research in 2-D has led orthodontists to believe.

Objetivo: Determinar la prevalencia de patologías bucales en bebés atendidos en el programa de seguimiento del Niño de Alto riesgo del INMP durante el período Enero 2016 a Diciembre 2017 Materiales y métodos: Se recolectó la información de 455 historias clínicas de pacientes pertenecientes al programa de atención estomatológica Niños de Alto Riesgo en el consultorio de Odontopediatría del Instituto Nacional Materno Perinatal. Los datos fueron analizados mediante estadística descriptiva para el análisis univariado donde se aplicaron las medidas estadísticas de frecuencia absoluta y relativa, y análisis bivariado donde se aplicó la prueba de Chi2 y Exacta de Fisher (α=0,05). Resultados: Del total de 455 pacientes, 319 (70.11%) fueron diagnosticados con patologías orales y 136 (29.89%) con boca sana. Además; 127 presentaron patologías en el tejido blando (39.81%) y 192 en el tejido duro (60.19%), siendo este último el más prevalente. Del total de 24 patologías encontradas en la cavidad oral de esta población, las tres más prevalentes fueron síndrome de erupción (18.24%), defecto de desarrollo del esmalte (17.14%) y anquiloglosia (12.97%). Conclusiones: La prevalencia de los pacientes con patologías bucales fue alta (70.11%) y pacientes diagnosticados con boca sana (29.89%). / Objective: The aim of this study was to determine the prevalence of oral pathologies in babies treated in the follow-up program of the High Risk Child of the INMP during the period January 2016 to December 2017 Materials and methods: Information was collected from 455 medical records of patients belonging to the stomatological care program Children of High Risk in the pediatric dentistry office of the National Maternal and Perinatal Institute. The data were analyzed by means of descriptive statistics for the univariate analysis where statistical measurements of absolute and relative frequency were applied, and bivariate analysis where the Chi2 and Fisher Exacta test were applied. (α = 0.05). Results: Of the total of 455 patients, 319 (70.11%) were diagnosed with oral pathologies and 136 (29.89%) with a healthy mouth. Further; 127 presented pathologies in the soft tissue (39.81%) and 192 in the hard tissue (60.19%), the latter being the most prevalent. Of the total of 24 pathologies found in the oral cavity of this population, the three most prevalent were eruption syndrome (18.24%), enamel development defect (17.14%) and ankyloglossia (12.97%). Conclusions: The prevalence of patients with oral pathologies was high (70.11%) and patients diagnosed with healthy mouth (29.89%). / CAPÍTULO 1: INTRODUCCIÓN…………………………………………… CAPÍTULO 2: PLANTEAMIENTO DE LA INVESTIGACIÓN………….. 2.1. Justificación…………………………………………………………… CAPÍTULO 3: OBJETIVOS…………………………………………………. 3.1. Objetivo general………………………………………………………. 3.2. Objetivos específicos………………………………………………… CAPÍTULO 4: MATERIALES Y MÉTODOS……………………………….. 4.1 Diseño del estudio……………………………………………………... 4.2 Población y/o Muestra………………………………………………….. 4.3 Operacionalización de variables………………………………………. 4.4 Técnicas y/o procedimientos………………………………………….. 4.5 Plan de análisis…………………………………………………………. 4.6 Consideraciones éticas…………………………………………………. CAPÍTULO 5: RESULTADOS…………………………………………………. CAPÍTULO 6: DISCUSIÓN…………………………………………………….. CAPÍTULO 7: CONCLUSIONES………………………………………………… CAPÍTULO 8: REFERENCIAS BIBLIOGRÁFICAS…………………………………. ANEXOS……………………………………………………………………. / Tesis