Combination of Oncolytic Adenoviruses, T-cell Activation, and Blockade of IDO Metabolic Circuitry for the Treatment of Glioma

Glioblastoma is the most common malignant primary brain tumor in adults; the current aggressive treatment results in a 5% five-year survival rate. More effective therapies should be developed. One promising alternative is oncolytic adenovirus, Delta-24-RGD, which elicits cancer cell lysis and immunogenic cell death. In fact, Delta-24-RGD produced complete responses in 20% of recurrent glioblastoma patients through immune mechanisms that activate anti-tumor cytotoxic properties of T-cells. This cytolytic effect can further be enhanced by adding immune agonists, namely OX40L, which engages the OX40 receptor to co-stimulate activated T cells for enhanced proliferation. Hence, we produced the next generation of Delta-24-RGD, called Delta-24-RGDOX, which expresses OX40L. Our previous publications exhibited enhanced immune-activating responses and improved survival in glioma-bearing mice treated with Delta-24-RGDOX compared to Delta-24-RGD. Nevertheless, maximal survival of glioma-bearing mice is unattainable, suggesting the presence of sustained immunosuppression within the glioma microenvironment. For example, indoleamine-2,3-dioxygenase (IDO) is upregulated in glioblastoma, correlates with poor prognoses, and is a main source of immunosuppression. IDO is an IFN inducible enzyme that catabolizes tryptophan resulting in diminished proliferation or apoptosis of surrounding effector T cells. Furthermore, kynurenine (Kyn), a tryptophan metabolite, induces T-cell differentiation into Tregs. Excess Kyn also activates carcinogenic transcription factor, aryl hydrocarbon receptor (AhR), which further mediates lymphocyte dysfunction and immunosuppression. Relating to our studies, the immune stimulating effect of Delta-24-RGDOX triggers IFN production contributing to a positive IDO-Kyn-AhR feedback loop. Additionally, IDO-mediated tryptophan depletion hinders viral replication. Therefore, we hypothesized that combining Delta-24-RGDOX with IDO inhibitors will improve therapeutic outcomes and enhance antitumor immune responses of murine glioblastoma. Here, we showed that Delta-24-RGDOX activated the IDO-Kyn-AhR cascade in glioma cells. Furthermore, we demonstrated enhanced therapeutic effectiveness of combined IDO inhibitor and Delta-24-RGDOX treatment compared to single agents, which was validated in immunocompetent IDO-KO mice. The combination treatment efficacy required CD4+ T cell activation and associated with increased activation of T cells and decreased Tregs and MDSCs. This microenvironment remodeling correlated with complete tumor elimination. Altogether, Delta-24-RGDOX activates the IDO-Kyn-AhR cascade, identifying new targets, which when inhibited have the potential to enhance anti-glioma effects of oncolytic-viruses by reversing tumor immunosuppression

From pity to productivity: the case of social cash transfers in Mozambique

Submitted in partial fulfilment for the requirements for Masters of Arts in Development Studies by coursework and research report In the Graduate School of Social Sciences, Faculty of Humanities, University of the Witwatersrand, 2016Social cash transfer programmes on the African continent have more than doubled in the last decade, and this signifies a transformation in the perception of social cash transfers as ‘pity handouts’ to how they are seen today, as ‘productive investments’ in human capabilities. Southern Africa has been a pioneer in social protection growth in the last twenty years, but often accounts of these histories focus on pension schemes in places such as South Africa, Namibia, Botswana, and Lesotho. There is little incorporation of Mozambique’s social protection history, and most histories do not detail that Mozambique ranks fourth chronologically, in introduction of cash transfer programmes in Sub-Saharan Africa. This research puts forth that the Mozambican case of an early adoption of cash transfers in 1990 is a positive and unique example of a state’s active role in social protection despite neoliberal constraints. The state-led adoption of cash transfers in response to rising inequality and economic instability is unexpected at a time when these programmes were unpopular development interventions and when the state was supposedly rolled-back and confined because neoliberalism and the civil war. Tracing the history of Mozambican social cash transfers in the last 25 years illustrates two consistencies of the Mozambican government: 1. A supportive political position towards state involvement in welfare programmes, despite the government’s own political and development sector transformation from Marxist-Leninist orientation to welcoming of privatization; and 2. State financial and political support of social protection throughout a period when cash transfers in Sub-Saharan Africa went from unpopular hand-out interventions during crises, to lobbying for permanent social protection as a mechanism to address chronic poverty.GR201

The Dark Side of the Ivory Tower: Examining Incivility and Microaggressions Against Ethnic Minorities in Academia

Discrimination is still prevalent and pervasive in society, though there have been many attempts to mitigate its impact. Though often not as overt, “modern” discrimination is more subtle in nature, often slipping through as passable social interactions because of its ambiguity. However, the negative impact that ethnic and racial minorities experience because of this subtle discrimination cannot be ignored. In academia, as with many other workplaces, ethnic and racial minorities are impacted by subtle discrimination. During the Black Lives Matter movement that has surged in 2020 in the wake of social injustices against Black and Brown people, this issue has been brought to the forefront. Though academia is often held to a higher standard, discrimination still permeates throughout the institution. The present study investigated the incidences of subtle discrimination via workplace incivility and microaggressions experienced by ethnic and racial minorities in academia by utilizing Twitter as a data source and data-mining experiences through #BlackintheIvory that promote the sharing of said experiences. Specifically, I analyzed self-reported discriminatory (incivility and microaggressions) experiences reported through the use of #BlackintheIvory between the dates of June 7, 2020 – June 17, 2020. Frequencies of reported experiences, narrative descriptions, and analyses of intersectionalities are reported. Future research directions and practical implications are discussed

The Relation between Perceived Parental Refugee Experience and Psychological Distress and Adjustment of U.S.-Raised Vietnamese Americans.

Given their experiences of war, migration, and acculturation, Vietnamese refugees are at greater risk for psychological disorders. Although multiple studies have documented high prevalence rates of mental health problems in this population, the intergenerational impacts of trauma and dislocation have not been well-studied among the children of Vietnamese refugees. Specifically, the long-term effects of these parental traumas on the psychological status of their children remain unknown. The current study aimed to add to the intergenerational trauma literature by investigating the relation between current psychological functioning among 221 adult children of Vietnamese American refugees and their perceptions of parents’ refugee experiences and family processes. A second goal was to generate information on the psychosocial status of this generation of Vietnamese Americans. A survey method was used to assess perceptions of parents’ past refugee experiences and communication patterns about these parental experiences, and their relation to adult children’s reports of family conflict, general family communication, and parental bonding. The psychological outcomes in the adult children included psychological distress (anxiety and depression symptomatology), self-esteem, and perceived life satisfaction. Acculturation/enculturation levels, and gender of participants were also assessed as mediating and moderating variables respectively. Structural Equation Modeling revealed that parental refugee hardship and communication about parental refugee experiences were not directly related to psychological outcomes of distress, self-esteem, or life satisfaction. However, communication about refugee experiences was linked to enculturation, acculturation, and family processes. In turn, these variables were linked to negative and positive well-being. Thus, though there was no evidence for a direct link, there may be indirect associations between communication about parental refugee experiences and psychological well-being.PHDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/102432/1/nguyentu_1.pd

Functionalized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as Platform for the Targeted Multimodal Tumor Therapy

Standard cancer treatments involve surgery, radiotherapy, chemotherapy, and immunotherapy. In clinical practice, the respective drugs are applied orally or intravenously leading to their systemic circulation in the whole organism. For chemotherapeutics or immune modulatory agents, severe side effects such as immune depression or autoimmunity can occur. At the same time the intratumoral drug doses are often too low for effective cancer therapy. Since monotherapies frequently cannot cure cancer, due to their synergistic effects multimodal therapy concepts are applied to enhance treatment efficacy. The targeted delivery of drugs to the tumor by employment of functionalized nanoparticles might be a promising solution to overcome these challenges. For multimodal therapy concepts and individualized patient care nanoparticle platforms can be functionalized with compounds from various therapeutic classes (e.g. radiosensitizers, phototoxic drugs, chemotherapeutics, immune modulators). Superparamagnetic iron oxide nanoparticles (SPIONs) as drug transporters can add further functionalities, such as guidance or heating by external magnetic fields (Magnetic Drug Targeting or Magnetic Hyperthermia), and imaging-controlled therapy (Magnetic Resonance Imaging)

Cice Magazine, No. 8

I am From... Operation Save: A Volunteer\u27s Reflection Big Girls Climb Too: Dismantling Exclusionary Outdoor Culture The Forgotten: Low-Income and Indebted at Puget Soundhttps://soundideas.pugetsound.edu/cicemagazine/1007/thumbnail.jp

Identification of apple fruit-skin constitutive laws by full-field methods using uniaxial tensile loading

The protective and preservative role of apple skin in maintaining the integrity of the fruit is well-known, with its mechanical behaviour playing a pivotal role in determining fruit storage capacity. This study employs a combination of experimental and numerical methodologies, specifically utilising the digital image correlation (DIC) technique. A specially devised inverse strategy is applied to evaluate the mechanical behaviour of apple skin under uniaxial tensile loading. Three apple cultivars were tested in this work: Malus domestica Starking Delicious, Malus pumila Rennet, and Malus domestica Golden Delicious. Stress–strain curves were reconstructed, revealing distinct variations in the mechanical responses among these cultivars. Yeoh’s hyperelastic model was fitted to the experimental data to identify the coefficients capable of reproducing the non-linear deformation. The results suggest that apple skin varies significantly in composition and structure among the tested cultivars, as evidenced by differences in elastic properties and non-linear behaviour. These differences can significantly affect how fruit is handled, stored, and transported. Thus, the insights resulting from this research enable the development of mathematical models based on the mechanical behaviour of apple tissue, constituting important data for improvements in the economics of the agri-food industry.The authors acknowledge the Portuguese Foundation for Science and Technology (FCT—MCTES) for the conceded financial support through the reference grant EXPL/EMEAPL/0587/2021. The second author also acknowledges FCT for his grant ref. BI/UTAD/22/2022. The third author also acknowledges FCT for its financial support via the projects UIDB/00667/2020 and UIDP/00667/2020 (UNIDEMI)

Circular use of plastics-transformation of existing petrochemical clusters into thermochemical recycling plants with 100% plastics recovery

Plastics represent a serious waste-handling problem, with only 10% of the plastic waste (PW) generated world-wide being recycled. The remainder follows a linear economy model, involving disposal or incineration. Thermochemical recycling provides an opportunity to close the material cycle, and this work shows how this can be achieved using the existing petrochemical infrastructure. The transformation of a generic petrochemical cluster based on virgin fossil feedstocks into a cluster that is based on PW has the following proposed sequence: (1) the feedstock is partially replaced (45% on carbon basis) by PW; (2) the feedstock is totally replaced by PW; (3) the process undergoes electrification; and (4) oxy-combustion and carbon capture and storage are introduced to achieve 100% carbon recovery in the form of monomers or permanent storage. An alternative transformation pathway that includes the introduction of biomass is also considered. The energy and carbon balances of the proposed implementation steps are resolved, and cost estimates of the savings related to the feedstock and required investments are presented. The main conclusion drawn is that switching the feedstock from virgin fossil fuels to PW (Implementation steps 1 and 2) confers economic advantages. However, the subsequent transformation steps (Implementation steps 3 and 4) can only be justified if a value is assigned to the environmental benefits, e.g., CO2 savings, increased share of biogenic carbon in plastic products, increasing recycling quotas, and/or the potential of the process to compensate for the intermittency of renewable power. It is also discussed how utilisation of the diverse compositions of PW streams by additional processes can meet the other demands of a chemical cluster