Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.

Pressure-Enabled Drug Delivery (PEDD) of a class C TLR9 agonist in combination with checkpoint inhibitor therapy in a murine pancreatic cancer model.

BACKGROUND: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma. This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent preclinical cancer models and early-phase clinical trials have demonstrated the potential of toll-like receptor 9 agonists, including the synthetic CpG oligonucleotide SD-101, to stimulate a wide range of immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure-Enabled Drug Delivery via Pancreatic Retrograde Venous Infusion of toll-like receptor 9 agonist would improve responsiveness to systemic anti-programmed death receptor-1 checkpoint inhibitor therapy in a murine orthotopic pancreatic ductal adenocarcinoma model. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to one of the following treatment groups: Pancreatic Retrograde Venous Infusion delivery of saline, Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist, systemic anti-programmed death receptor-1, systemic toll-like receptor 9 agonist, or the combination of Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist and systemic anti-programmed death receptor-1 (Combo). Fluorescently labeled toll-like receptor 9 agonist (radiant efficiency) was used to measure uptake of the drug on day 1. Changes in tumor burden were evaluated by necropsy at 2 different time points, 7 and 10 days after toll-like receptor 9 agonist treatment. Blood and tumors were collected at necropsy 10 days after toll-like receptor 9 agonist treatment for flow cytometric analysis of tumor-infiltrating leukocytes and plasma cytokines. RESULTS: All mice analyzed survived to necropsy. Site of tumor fluorescence measurements revealed 3-fold higher intensity fluorescence in Pancreatic Retrograde Venous Infusion delivery of toll-like receptor 9 agonist compared to systemic toll-like receptor 9 agonist mice. Tumor weights were significantly lower in the Combo group compared to Pancreatic Retrograde Venous Infusion delivery of saline. Flow cytometry of the Combo group demonstrated significantly increased overall T-cell number, specifically CD4+ T-cells, and a trend toward increased CD8+ T-cells. Cytokine analysis showed significantly decreased IL-6 and CXCL1. CONCLUSION: Pressure-Enabled Drug Delivery of toll-like receptor 9 agonist by Pancreatic Retrograde Venous Infusion with systemic anti-programmed death receptor-1 demonstrated improved pancreatic ductal adenocarcinoma tumor control in a murine pancreatic ductal adenocarcinoma model. These results support study of this combination therapy in pancreatic ductal adenocarcinoma patients and expansion of ongoing Pressure-Enabled Drug Delivery clinical trials.

Mindfulness in Politics: A Qualitative Study on Mindfulness Training in the UK Parliament.

Objectives: While mindfulness in the workplace has received substantial scientific attention in the past decades, it is not yet well-understood if, under what circumstances, and in what ways mindfulness training may be helpful for individuals working in political environments. The aim of this study was to explore the experience of mindfulness training among British politicians, as well as mindfulness facilitators who had taught mindfulness to politicians in the UK Parliament. Method: Between September and November 2021, semi-structured in-depth interviews were conducted with British politicians (n = 18) who had experience of mindfulness training and mindfulness facilitators (n = 4) who had taught mindfulness to politicians in the UK Parliament. The interview material was analyzed using reflexive thematic analysis. Results: Two main themes related to the experience of mindfulness training in politics were developed during the analytic process: (1) mindfulness approaches addressing particular challenges in political work, and (2) mindfulness sessions and group dynamics. Taken together, mindfulness training helped the politicians to better deal with the demands and stresses of political work, to reconnect with themselves and be more grounded, and - especially when taught in a group setting - to relate to other politicians and their viewpoints in a more humane and constructive way. Conclusions: The results suggest that mindfulness training can be beneficial at both the personal and professional level for individuals working in political contexts, which can provide a rationale for governments to introduce mindfulness-based programs to politicians. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-023-02156-x.

Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model.

BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). METHODS: KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. RESULTS: The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4-6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. CONCLUSIONS: IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.

Bridging the (Brexit) divide: Effects of a brief befriending meditation on affective polarization.

The European Union Brexit referendum has divided the British electorate, with high levels of animosity between those who affiliate with the Remain side (Remainers) and the Leave side (Leavers) of the debate. Previous research has shown that a brief befriending meditation reduces affective polarization among Democrats and Republicans in the United States, but the results have not been replicated in a non-US sample and the psychological mechanisms underlying the effects have yet to be examined. The present study therefore used a post-test only randomized controlled design to investigate the effects of a brief befriending meditation on affective polarization among Remainers and Leavers (n = 922). Results showed that participants in the befriending condition scored modestly lower on affective polarization than participants in the attentional control condition (t(921) = 2.17, p = .030, d = 0.14) and that perceived commonality with the political outgroup mediated the effects. In sum, audio-guided befriending practices may be a highly scalable means to reduce high levels of affective polarization through increasing perceived commonality.

Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.

Oxaliplatin-induced peripheral neuropathy can be minimized by pressurized regional intravascular delivery in an orthotopic murine pancreatic cancer model.

PURPOSE: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. METHODS: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. RESULTS: Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. CONCLUSION: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

An App-Based Workplace Mindfulness Intervention, and Its Effects Over Time.

We investigated the week-to-week effects of a mindfulness intervention on emotional exhaustion, work engagement, and job satisfaction in a field study involving 218 participants who participated and reported their weekly outcomes during the 8-week program. To examine how mindfulness impacted work outcomes, we used intraindividual modeling of the 8-week data. Mindfulness increased over time, and time also had indirect effects on emotional exhaustion, work engagement, and job satisfaction, through mindfulness. Supplementary growth curve analyses on the improvement of mindfulness over time showed a slight decrease in the positive effect of time on mindfulness.

COVID-19 and the workplace: Implications, issues, and insights for future research and action.

The impacts of COVID-19 on workers and workplaces across the globe have been dramatic. This broad review of prior research rooted in work and organizational psychology, and related fields, is intended to make sense of the implications for employees, teams, and work organizations. This review and preview of relevant literatures focuses on (a) emergent changes in work practices (e.g., working from home, virtual teamwork) and (b) emergent changes for workers (e.g., social distancing, stress, and unemployment). In addition, potential moderating factors (demographic characteristics, individual differences, and organizational norms) are examined given the likelihood that COVID-19 will generate disparate effects. This broad-scope overview provides an integrative approach for considering the implications of COVID-19 for work, workers, and organizations while also identifying issues for future research and insights to inform solutions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model.

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.

Anti-KIT DNA Aptamer for Targeted Labeling of Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo.

Stay Mindful and Carry on: Mindfulness Neutralizes COVID-19 Stressors on Work Engagement via Sleep Duration.

We examine whether mindfulness can neutralize the negative impact of COVID-19 stressors on employees' sleep duration and work engagement. In Study 1, we conducted a field experiment in Wuhan, China during the lockdown between February 20, 2020, and March 2, 2020, in which we induced state mindfulness by randomly assigning participants to either a daily mindfulness practice or a daily mind-wandering practice. Results showed that the sleep duration of participants in the mindfulness condition, compared with the control condition, was less impacted by COVID-19 stressors (i.e., the increase of infections in the community). In Study 2, in a 10-day daily diary study in the United Kingdom between June 8, 2020, and June 19, 2020, we replicate our results from Study 1 using a subjective measure of COVID-19 stressors and a daily measure of state mindfulness. In addition, we find that mindfulness buffers the negative effect of COVID-19 stressors on work engagement mediated by sleep duration. As the COVID-19 pandemic is ongoing and the number of reported cases continues to rise globally, our findings suggest that mindfulness is an evidence-based practice that can effectively neutralize the negative effect of COVID-19 stressors on sleep and work outcomes. The findings of the present study contribute to the employee stress and well-being literature as well as the emerging organizational research on mindfulness.

Irreversible Electroporation Combined with Checkpoint Blockade and TLR7 Stimulation Induces Antitumor Immunity in a Murine Pancreatic Cancer Model.

Irreversible electroporation (IRE) is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. We hypothesize that IRE can induce an in situ vaccination effect by releasing tumor neoantigens in an inflammatory context. Using an immunocompetent mouse model, we demonstrated that IRE alone produced complete regression of subcutaneous tumors in approximately 20% to 30% of mice. IRE was not effective in immunodeficient mice. Mice with complete response to IRE demonstrated prophylactic immunity and remained tumor free when rechallenged with secondary tumors on the contralateral flank. CD8+ T cells from IRE-responsive mice were reactive against peptides representing model-inherent alloantigens and conferred protection against tumor challenge when adoptively transferred into immunocompromised, tumor-naïve mice. Combining IRE with intratumoral Toll-like receptor-7 (TLR7) agonist (1V270) and systemic anti-programmed death-1 receptor (PD)-1 checkpoint blockade resulted in improved treatment responses. This combination also resulted in elimination of untreated concomitant distant tumors (abscopal effects), an effect not seen with IRE alone. These results suggest that the systemic antitumor immune response triggered by IRE can be enhanced by stimulating the innate immune system with a TLR7 agonist and the adaptive immune system with anti-PD-1 checkpoint blockade simultaneously. Combinatorial approaches such as this may help overcome the immunosuppressive pancreatic cancer microenvironment.

A Syngeneic Pancreatic Cancer Mouse Model to Study the Effects of Irreversible Electroporation.

Pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded several therapeutic approaches including the promising immunotherapeutic strategies. Irreversible electroporation (IRE) is a non-thermal ablation technique that induces tumor cell death without destruction of adjacent collagenous structures, thus enabling the procedure to be performed in tumors very close to blood vessels. Unlike thermal ablation techniques, IRE results in gradual apoptotic cell death, along with immediate ablation induced necrosis, and is currently in clinical use for selected patients with locally advanced PC. An ablative, non-target specific procedure like IRE can induce a myriad of responses in the tumor microenvironment. A few studies have addressed the effects of IRE on tumor growth in other tumor types, but none have focused on PC. We have developed a syngeneic mouse model of PC in which subcutaneous (SQ) and orthotopic tumors can be successfully treated with IRE in a highly controlled setting, facilitating various longitudinal studies post procedure. This animal model serves as a robust system to study the effects of IRE and ways to improve the clinical efficacy of IRE.

People in more racially diverse neighborhoods are more prosocial.

Five studies tested the hypothesis that people living in more diverse neighborhoods would have more inclusive identities, and would thus be more prosocial. Study 1 found that people residing in more racially diverse metropolitan areas were more likely to tweet prosocial concepts in their everyday lives. Study 2 found that following the 2013 Boston Marathon bombings, people in more racially diverse neighborhoods were more likely to spontaneously offer help to individuals stranded by the bombings. Study 3 found that people living in more ethnically diverse countries were more likely to report having helped a stranger in the past month. Providing evidence of the underlying mechanism, Study 4 found that people living in more racially diverse neighborhoods were more likely to identify with all of humanity, which explained their greater likelihood of having helped a stranger in the past month. Finally, providing causal evidence for the relationship between neighborhood diversity and prosociality, Study 5 found that people asked to imagine that they were living in a more racially diverse neighborhood were more willing to help others in need, and this effect was mediated by a broader identity. The studies identify a novel mechanism through which exposure to diversity can influence people, and document a novel consequence of this mechanism. (PsycINFO Database Record

Thought-control difficulty motivates structure seeking.

Struggling to control one's mind can change how the world appears. In prior studies testing the compensatory control theory, reduced control over the external environment motivated the search for perceptual patterns and other forms of structured knowledge, even in remote domains. Going further, the current studies test whether difficulty controlling thoughts similarly predicts structure seeking. As hypothesized, thought-control difficulty positively predicted perceptions of causal connections between remote events (Study 1a) and nonexistent objects in visual noise (Study 1b). This effect was mediated by aversive arousal (Study 2) and caused specifically by thought-control difficulty as distinct from general difficulty (Study 3). Study 4 replicated the effect with a sample of meditators learning to control their thoughts, showing that thought-control difficulty was a powerful predictor of structure seeking. These findings reveal a novel form of motivated perception. (PsycINFO Database Record

Preliminary evidence that acute stress moderates basal testosterone's association with retaliatory behavior.

A contribution to a special issue on Hormones and Human Competition. Testosterone is theorized to increase retaliation after social provocation. However, empirical evidence in support of these theories is mixed. The present research investigated whether acute stress causally suppresses testosterone's association with retaliation. We also explored sex differences in behavioral responses to acute stress. Thirty-nine participants (51.28% male) were randomly assigned to a high- or low-stress condition. Then participants engaged in 20 one-shot rounds of the ultimatum game, which was used to assess retaliatory behavioral responses to unfair treatment. Participants provided two saliva samples to measure testosterone and cortisol concentrations - one sample before the stress manipulation, and the second after the ultimatum game (20minutes post-stressor). Results revealed a positive association between basal testosterone and retaliation in the low-stress condition, but not in the high-stress condition. Further, cortisol concentrations increased in the high- compared to the low-stress condition, and these cortisol changes moderated the association between basal testosterone and retaliation. The associations between basal testosterone and retaliation under varying levels of stress were similar in men and women. However, there was a sex difference in behavioral responses to the stress manipulation that was independent of testosterone. In women, the high-stress condition reduced retaliation compared to the low-stress condition, whereas in men the opposite pattern emerged. Collectively, this study (i) provides preliminary evidence that experimentally manipulated stress blocks basal testosterone's association with retaliation, and (ii) reveals a sex difference in retaliation under varying levels of stress. Discussion focuses on mechanisms, limitations, and the need for follow-up studies with larger sample sizes.