L'utilisation du virus oncolytique VSVΔ51 comme option thérapeutique en cancer pancréatique

Abstract : Context As of 2020, Pancreatic Cancer is the 3rd leading cause of cancer-related deaths in Canada. The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of all pancreatic cancer cases diagnosed every year. Limited therapeutic strategies are available to patients. Standard of Care (SOC) for PDAC patients has remained unchanged in the last three decades. Gemcitabine remains the backbone of therapy for most patients. However, the efficacy of SOC is limited as multiple factors in PDAC contribute to therapeutic resistance. The tumour microenvironment (TME) in PDAC is known to be fibrotic and immunologically cold. To better target and eradicate cancer cells, more specific therapies such as oncolytic viruses have been developed to improve patient outcome. Oncolytic viruses such as VSVΔ51, will specifically replicate in the cancer cells. VSVΔ51also has the ability to lyse cancer cells and induce immunogenic cell death (ICD). The release of damage associated molecular patterns (DAMPs) from the dying PDAC cells will lead to a tumour specific immune response. Hypothesis PDAC therapy could be improved by the induction of ICD through the addition of the oncolytic virus VSVΔ51to SOC gemcitabine. Objectives The objectives are to characterize the immune-targeting effects of VSVΔ51 following PDAC cell lines and combine VSVΔ51 with SOC gemcitabine to evaluate the potential synergy of the therapies. Methods The evaluation of both the cytotoxic and replication abilities of VSVΔ51 in PDAC cell lines were done. To evaluate cell viability following infection, MTT assays were performed. To evaluate replication, viral plaque assays were done. Additionally, the release of DAMPs (HSP90, HMGB1) was also measured, by Western Blot to ensure the induction of ICD. The cell viability following the combination of gemcitabine and VSVΔ51was also measured, by crystal violet staining as well as the DAMP release (HSP70, HSP90, and HMGB1) by Western Blot. Results Our results demonstrate that VSVΔ51 is functional and is able to infect, lyse and replicate amongst PDAC cells. VSVΔ51 on its own is able to induce the release of DAMPs. We have also demonstrated that VSVΔ51 in combination with gemcitabine is able to induce cell death and release DAMPs as well Conclusion VSVΔ51 presents a novel more specific potential therapeutic strategy for PDAC. VSVΔ51 can be used in combination with current SOC to further eradicate cancer cells.Contexte En 2020, le cancer du pancréas est la 3e cause de décès liés au cancer au Canada. Le sous-type de cancer du pancréas le plus courant est l'adénocarcinome canalaire pancréatique (PDAC) qui représente environ 90 % de tous les cas de cancer du pancréas diagnostiqués chaque année. Depuis plus de 20 ans, la norme de soins (SOC) pour les patients PDAC demeure la gemcitabine. Cependant, l'efficacité du SOC est limitée car de multiples facteurs dans le PDAC contribuent à la résistance thérapeutique. Pour mieux cibler et éradiquer les cellules cancéreuses, des thérapies plus spécifiques telles que les virus oncolytiques ont été développées. Les virus oncolytiques tels que le VSVΔ51, se répliqueront spécifiquement dans les cellules cancéreuses. VSVΔ51 a également la capacité de lyser les cellules cancéreuses et d'induire la mort cellulaire immunogène (ICD). La libération de motifs moléculaires associés aux dommages (DAMP) des cellules PDAC mourantes entraînera une réponse immunitaire spécifique à la tumeur. Hypothèse La thérapie PDAC pourrait être améliorée par l'induction d’une mort immunogénique par l'utilisation du virus oncolytique VSVΔ51 en combinaison avec la gemcitabine. Objectifs Les objectifs sont de caractériser les effets du VSVΔ51 suivant l’infection des lignées cellulaires PDAC et de combiner le VSVΔ51 avec la gemcitabine pour évaluer la synergie potentielle des thérapies. Méthodes L'évaluation des capacités cytotoxiques et de réplication de VSVΔ51 dans des lignées cellulaires PDAC a été effectuée. Pour évaluer la viabilité cellulaire après l'infection, des essais MTT ont été effectués. Pour évaluer la réplication, des tests de plaques virales ont été effectués. De plus, la libération de DAMP (HSP90, HMGB1) a également été mesurée par Western Blot. La viabilité cellulaire suite à la combinaison de gemcitabine et de VSVΔ51 a également été mesurée, par coloration au cristal violet ainsi que la libération de DAMP (HSP70, HSP90 et HMGB1) par Western Blot. Résultats Nos résultats démontrent que VSVΔ51 est fonctionnel et est capable d'infecter, de lyser et de se répliquer parmi les cellules PDAC. Le VSVΔ51 à lui seul est capable d'induire la libération de DAMP. Nous avons également démontré que le VSVΔ51 en combinaison avec la gemcitabine est capable d'induire la mort cellulaire et de libérer également des DAMP. Conclusion Le VSVΔ51 présente une nouvelle stratégie thérapeutique potentielle plus spécifique pour le PDAC. Le VSVΔ51 peut être utilisé en combinaison avec le SOC actuel pour éradiquer davantage les cellules cancéreuses

Data Recovery Investigations at the Tank Destroyer Site (41CV1378) at Fort Hood, Coryell County, Texas

Data recovery investigations at the Tank Destroyer site (41CV1378) were conducted in August 2007 for the Texas Department of Transportation (TxDOT). This work was required because of potential impacts to the site from TxDOT’s planned improvements of Tank Destroyer Boulevard and State Highway 9. The investigations focused on a burned rock mound (Feature 1), one-half of which has been destroyed by an adjacent tank trail. The mound contained two internal features: an off-centered earth oven and a small cluster of Rabdotus sp. shells. With the exception of the location of its earth oven, the mound at the Tank Destroyer is typical of a classic central Texas domed mound, though slightly flattened by postdepositional processes. In all, an area of 30.5 m2 and volume of 11.8 m3 of cultural deposits were hand excavated, and an additional ca. 17.3 m2 was mechanically stripped. The mound excavations yielded 5,570.5 kg of burned rocks. Artifacts recovered from mound and nonmound contexts consist of 129 chipped stone tools, 9 cores and core fragments, 4,466 pieces of unmodified debitage, 1 ground stone tool, 2 unmodified bone fragments, 1,415 Rabdotus sp. shells, and 40 historic artifacts. In addition, 413 pieces of microdebitage and 251 Rabdotus sp. shells were recovered from flotation and soil column samples taken from the mound. There was virtually no preservation of vertebrate faunal remains and poor preservation of botanical remains. No economic plants (i.e., food resources) were recovered despite the collection and processing of flotation samples. Sixteen radiocarbon assays on charred wood and Rabdotus sp. shells date the site occupation to 1500 b.c. through a.d. 1650. The date range for the diagnostic projectile points recovered from the site (200 b.c. to a.d. 1200) fits nicely within the range of radiocarbon dates. As a group, the radiocarbon dates and the projectile points suggest that the most intensive period of site use occurred intermittently between 1000 b.c. and a.d. 1200. Like most burned rock mounds, the mound at the Tank Destroyer site consisted of a jumbled mass of burned rocks that episodically accreted around an earth oven. These processes and repeated use over centuries limit our ability to recognize distinct components for analysis. Given these limitations, our analysis took a different approach. While it includes traditional analyses of the lithic, burned rock, and snail assemblages, it also examines social identity during the Late Archaic period in central Texas and the relationships between burned rock mounds and middens and environmental variables through a landscape analysis

New discoveries at Woolsey Mound, MC118, northern Gulf of Mexico

Woolsey Mound, a 1km-diameter carbonate-gas hydrate complex in the northern Gulf of Mexico, is the site of the Gulf’s only seafloor monitoring station-observatory in its only research reserve, Mississippi Canyon 118. Active venting, outcropping hydrate, and a thriving chemosynthetic community recommend the site for study. Since 2005, the Gulf of Mexico Hydrates Research Consortium has been conducting multidisciplinary studies to 1. Characterize the site, 2. Establish a facility for real-time monitoring-observing of gas hydrates in a natural setting, 3. Study the effects of gas hydrates on seafloor stability, 4. Establish fluid migration routes and estimates of fluid-flux at the site, 5. Establish the interrelationships between the organisms at the vent site and the association-dissociation of hydrates. A variety of novel geological, geophysical, geochemical and biological studies has been designed and conducted, some in survey mode, others in monitoring mode. Geophysical studies involving merging multiple seismic data acquisition systems accompanied by the application of custom processing techniques verify communication of surface features with deep structures. Supporting geological data derive from innovative recovery techniques. Geochemical sensors, used experimentally in survey mode, including aboard an AUV, double as monitoring devices. A suite of pore-fluid sampling devices has returned data that capture change at the site in daily increments; using only noise as an energy source, hydrophones have returned daily fluctuations in physical properties. Ever-expanding capabilities of a custom-ROV have been determined by research needs. Processing of new as well as conventional data via unconventional means has resulted in the discovery of new features…..vents, faults, benthic fauna…..and modification of others including pockmarks, hydrate outcrops, vent activity, and water-column chemical plumes. Though real-time monitoring awaits communications and power link to land, periodic data-collection reveals a carbonate-hydrate mound, part of an immensely complex hydrocarbon system

Paleobiology of a Large Mammal Community From the Late Pleistocene of Sonora, Mexico

A paleontological deposit near San Clemente de Térapa represents one of the very few Rancholabrean North American Land Mammal Age sites within Sonora, Mexico. During that time, grasslands were common, and the climate included cooler and drier summers and wetter winters than currently experienced in northern Mexico. Here, we demonstrate restructuring in the mammalian community associated with environmental change over the past 40,000 years at Térapa. The fossil community has a similar number of carnivores and herbivores whereas the modern community consists mostly of carnivores. There was also a 97% decrease in mean body size (from 289 kg to 9 kg) because of the loss of megafauna. We further provide an updated review of ungulates and carnivores, recognizing two distinct morphotypes of Equus, including E. scotti and a slighter species; as well as Platygonus compressus; Camelops hesternus; Canis dirus; and Lynx rufus; and the first regional records of Palaeolama mirifica, Procyon lotor, and Smilodon cf. S. fatalis. The Térapa mammals presented here provide a more comprehensive understanding of the faunal community restructuring that occurred in northern Mexico from the late Pleistocene to present day, indicating further potential biodiversity loss with continued warming and drying of the region

Negotiating stance within discourses of class: reactions to Benefits Street

In this article, we examine the way that audiences respond to particular representations of poverty. Using clips from the Channel 4 television programme Benefits Street we conducted focus groups in four locations across the UK, working with people from different socioeconomic backgrounds who had different experiences with the benefits system. Benefits Street (2014) is an example of reality television where members of the public are followed by film crews as they perform everyday tasks and routines. Our choice to focus on this particular programme was prompted by the huge media response that it received when it was broadcast; Benefits Street generated 950 complaints to regulatory watchdog Ofcom (2014) and was referred to as ‘poverty porn’ (Clark, 2014). We focus on the way that viewers of this programme produce assessments of those on benefits, analysing the discursive strategies used by our participants when evaluating representations of those on benefits. Specifically, we consider how the participants in our study construct their own stance and attribute stance to others through naming and agency practices, the negotiation of opinion, and stake inoculation. We invited our participants to judge the people they saw on screen, but they went beyond this. They used clips of the programme as stimuli to collaboratively construct an overarchingly-negative stereotype of those on benefits. We conclude that Benefits Street is not just an entertainment programme, but is rather a site for ideological construction and the perpetuation of existing stereotypes about benefit claimants. The programme (and others like it) invites negative evaluations of those on benefits and is thus a worthy site for critical linguistic analysis

Early Life Exposure to Unpredictable Parental Sensory Signals Shapes Cognitive Development Across Three Species

Exposure to early life adversity has long term consequences on cognitive function. Most research has focused on understanding components of early life adversities that contribute to later risk, including poverty, trauma, maltreatment, and neglect. Whereas these factors, in the aggregate, explain a significant proportion of emotional and cognitive problems, there are serious gaps in our ability to identify potential mechanisms by which early life adversities might promote vulnerability or resilience. Here we discuss early life exposure to unpredictable signals from the caretaker as an understudied type of adversity that is amenable to prevention and intervention. We employ a translational approach to discover underlying neurobiological mechanisms by which early life exposure to unpredictable signals sculpts the developing brain. First, we review evidence that exposure to unpredictable signals from the parent during sensitive periods impacts development of neural circuits. Second, we describe a method for characterizing early life patterns of sensory signals across species. Third, we present published and original data illustrating that patterns of maternal care predict memory function in humans, non-human primates, and rodents. Finally, implications are discussed for identifying individuals at risk so that early preventive-intervention can be provided

Domestic Cooking and Food Skills: A Review

Domestic cooking skills (CS) and food skills (FS) encompass multiple components, yet there is a lack of consensus on their constituent parts, inter-relatedness or measurement, leading to limited empirical support for their role in influencing dietary quality. This review assessed the measurement of CS and FS in adults (>16 years); critically examining study designs, psychometric properties of measures, theoretical basis and associations of CS/FS with diet. Electronic databases (PsychInfo), published reports and systematic reviews on cooking and home food preparation interventions (Rees et al. 2012 ; Reicks et al. 2014 ) provided 834 articles of which 26 met the inclusion criteria. Multiple CS/FS measures were identified across three study designs: qualitative; cross-sectional; and dietary interventions; conducted from 1998-2013. Most measures were not theory-based, limited psychometric data was available, with little consistency of items or scales used for CS/FS measurements. Some positive associations between CS/FS and FV intake were reported; though lasting dietary changes were uncommon. The role of psycho-social (e.g., gender, attitudes) and external factors (e.g. food availability) on CS/FS is discussed. A conceptual framework of CS/FS components is presented for future measurement facilitation, which highlights the role for CS/FS on food-related behaviour and dietary quality. This will aid future dietary intervention design