Antimicrobial Stewardship Training for Infectious Diseases Fellows: Program Directors Identify a Curriculum Need

A needs assessment survey of infectious diseases (ID) training program directors identified gaps in educational resources for training and evaluating ID fellows in antimicrobial stewardship. An Infectious Diseases Society of America-sponsored core curriculum was developed to address that need

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities

Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

Cells preferentially expressing GluR4-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors are particularly sensitive to excitotoxicity mediated through non-N-methyl-D-aspartate receptors. However, the excitotoxic signalling pathways associated with GluR4-containing AMPA receptors are not known. In this work, we investigated the downstream signals coupled to excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors, using a HEK 293 cell line constitutively expressing the GluR4flip subunit of AMPA receptors (HEK-GluR4). Glutamate stimulation of GluR4-containing AMPA receptors decreased cell viability, in a calcium-dependent manner, when the receptor desensitisation was prevented with cyclothiazide. The excitotoxic stimulation mediated through GluR4-containing AMPA receptors increased activator protein-1 (AP-1) DNA-binding activity. Inhibition of the AP-1 activity by overexpression of a c-Jun dominant-negative form protected HEK-GluR4 cells against excitotoxic damage. Taken together, the results indicate that overactivation of Ca2+-permeable GluR4-containing AMPA receptors is coupled to a death pathway mediated, at least in part, by the AP-1 transcription facto

Active Assistive Knee Device

This project aimed to develop an active assistive knee device to aid the user in their gait cycle and stair ascent and descent. Currently, few devices exist on the market that offer a solution for those desiring a small amount of assistive torque in a low profile, cost-effective design. Experimental and literary research were performed to determine the amount of assistance needed from the device, and the ideal structure. A novel hinge design was created and, once partnered with the electromyograph and motor, provides 10% of the required torque at the knee for the user. Due to COVID-19, the team was unable to fabricate and assemble a working prototype. Improvements include refining the design to be smaller and lighter, and adding a second motor for increased torque

Radiation Therapy Modulates Tumor Physical Characteristics to Reduce Intratumoral Pressure and Enhance Intratumoral Drug Delivery and Retention

Purpose: High intratumoral pressure, caused by tumor cell-to-cell interactions, interstitial fluid pressure, and surrounding stromal composition, plays a substantial role in resistance to intratumoral drug delivery and distribution. Radiation therapy (XRT) is commonly administered in conjunction with different intratumoral drugs, but assessing how radiation can reduce pressure locally and help intratumoral drug administration and retention is important. Methods and Materials: 344SQ-parental or 344SQ-anti-programmed cell death protein 1-resistant lung adenocarcinoma cells were established in 129Sv/Ev mice, and irradiated with either 1 Gy × 2, 5 Gy × 3, 8 Gy × 3, 12 Gy × 3, or 20 Gy × 1. Intratumoral pressure was measured every 3 to 4 days after XRT. Contrast dye was injected into the tumors 3- and 6-days after XRT, and imaged to measure drug retention. Results: In the 344SQ-parental model, low-dose radiation (1 Gy × 2) created an early window of reduced intratumoral pressure 1 to 3 days after XRT compared with untreated control. High-dose stereotactic radiation (12 Gy × 3) reduced intratumoral pressure 3 to 12 days after XRT, and 20 Gy × 1 showed a delayed pressure reduction on day 12. Intermediate doses of radiation did not significantly affect intratumoral pressure. In the more aggressive 344SQ-anti-programmed cell death protein 1-resistant model, low-dose radiation reduced pressure 1 to 5 days after XRT, and 12 Gy × 3 reduced pressure 1 to 3 days after XRT. Moreover, both 1 Gy × 2 and 12 Gy × 3 significantly improved drug retention 3 days after XRT; however, there was no significance detected 6 days after XRT. Lastly, a histopathologic evaluation showed that 1 Gy × 2 reduced collagen deposition within the tumor, and 12 Gy × 3 led to more necrotic core and higher extracellular matrix formation in the tumor periphery. Conclusions: Optimized low-dose XRT, as well as higher stereotactic XRT regimen led to a reduction in intratumoral pressure and increased drug retention. The findings from this work can be readily translated into the clinic to enhance intratumoral injections of various anticancer agents

High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses

Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control

Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy

Abstract Background The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice. Methods 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated. Results Remarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes. Conclusions The MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival. Graphical Abstrac

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy

Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. Methods A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types. Results The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004). Conclusions Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.Varian; Bristol-Myers Squibb; Merck & CompanyOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]