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A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n  = 16), with anti-PD-1 antibody nivolumab (Arm B; n  = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n  = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells ( p  = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p  = 0.242; HR = 0.51, p  = 0.173) and overall survival (HR = 0.59, p  = 0.377; HR = 0.53, p  = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study. GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.

BackgroundData analysis of specimens from prior clinical trials identified the immune co-simulatory molecule CD137 within the tumor microenvironment(TME) of pancreatic ductal adenocarcinoma(PDAC) that remain to be activated following vaccine induced T cell and PD-1 inhibitory treatments. The requirement of CD137 was subsequently supported by preclinical studies. Therefore, we conducted a clinical trial of combining anti-CD137 agonist antibody urelumab, anti-PD-1 antagonist antibody nivolumab and a GM-CSF-secreting allogeneic tumor cell vaccine(GVAX) as neoadjuvant and adjuvant therapy for resectable PDAC.MethodsPatients of >=18 years old with radiographic evidence of resectable PDACs were eligible for Arm C of this trial(NCT02451982) with an accrual goal of 10 evaluable subjects. The primary objective was to evaluate changes in numbers of tumor infiltrating CD137+CD8+ T cells. Secondary objectives were safety, overall survival, disease free survival, and other immune parameters. Patients who underwent R0/R1 resection were considered evaluable. All subjects received 480mg nivolumab and 8 mg urelumab both intravenously one day prior to receiving GVAX intradermally and two weeks before surgical resection (figure 1). After surgery, eligible patients continued to receive 5 combination immunotherapy cycles in addition to standard of care chemotherapy. Treatment-related toxicity and perioperative complications are monitored.ResultsBetween February 2019 and August 2020, we completed planned enrollment and treated 10 evaluable patients, who underwent R0 surgical resection of their PDACs. Nausea is the most common adverse event attributed to urelumab (table 1). Other adverse events and perioperative complication were observed in a type, frequency and degree similar to other treatment arms. After repeated dosing, 1 patient demonstrated grade 1 arthritis; 1 patient demonstrated self-limited, transient grade 2 elevated LFTs; 1 patient developed grade 3 rashes, which responded quickly to oral steroid and did not recur after re-dosing. Interestingly, two out of 10 resected patients demonstrated CAP grade 2 pathologic responses in the resected PDACs after a single neoadjuvant treatment; this was not observed with other treatment cohorts(GVAX alone or GVAX+nivolumab) in this neoadjuvant platform trial. Nine out of 10 resected patients remain disease free after a median follow up of 12 months. Immunology endpoints are being analyzed by multiplex immunohistochemistry, DNA sequencing for neoantigen loads, and RNA/TCR sequencing.Abstract 812 Figure 1Study SchemaAbstract 812 Table 1Adverse EventsConclusionsPrevious observations of liver toxicity with urelumab or other T cells agonists and severe immune-related adverse events were not observed in this trial, suggesting urelumab(8 mg) is safe as neoadjuvant/adjuvant therapy in this resectable PDAC patient population. Immune and clinical efficacy of anti-CD137 agonist-based combinations warrant further investigation.AcknowledgementsThis is an investigator initiated clinical trial and supported by the funding from the Rare Disease Program at Bristol-Myers Squibb.Trial RegistrationNCT02451982Ethics ApprovalThe study was approved by the Johns Hopkins Medical Institution Institutional Review Board, approved number IRB00050517

This thesis addresses the challenges of researching affect and emotion. It wrangles with the debates and definitions that accompany these terms and adopts an affective practice approach informed by Margaret Wetherell's work. The thesis extends this approach by considering the role of digital technologies in affect research. It asks what technologies might offer the researcher, specifically in developing the tools currently available to understand museum affective visitor experience. The thesis draws on critical data studies to provide a necessary and critical investigation of technologies that monitor physiological response and questions whether such technology reveals the affective relationships enacted between museums and their visitors. It had three formal aims. First, to understand the embodied and social organisation of emotion and affect. Second, to engage with the debates and methodological approaches that are associated with these pervasive concepts. And third, explore the value of using wearable physiological monitoring in such a study. These aims were addressed via two comparative case studies and engagement with primary self-report and physiological data, collected in Summer 2019. These cases studies were: Snakes, National Museum Cardiff's summer exhibition in 2019 and Museum ExplorAR, an Augmented Reality (AR), trilingual, self-led mobile experience providing visitors with an immersive experience of the museum's permanent exhibitions. An analysis of physiological and self-report survey data is presented. The results are discussed within the context of Wetherell's theory of affective practices and Leach's cognitive tools model (Wetherell, 2012; Leach, 2009). The thesis validates the cognitive tools model and the visitors' use of its associated practices to relay their affective experience. Second, the thesis interrogates links between such practices and physiological response. It examines the value of electrodermal data in understanding visitor emotion and subjects this data to analysis at group and individual levels. Based on the study's evidence and informed by its critical approach to data, methodological and ethical caveats for physiological data are established. The result is a comprehensive interdisciplinary thesis that explores visitors' affective processes and the value of electrodermal activity data.

Education Secretary Michael Gove changed the exam regime because he believes modules prevent students from gaining a \"deep and rounded\" knowledge of a subject and that they are \"fo r -cing England down international league tables\".

The Young Expressions, which caters for girls and boys aged 8 to 14, has been nominated for the National Operatic and Dramatic Association's Best Pantomime gong for its adaptation of Robert Louis Stevenson's Treasure Island.

Besides ballet, the school offers training in tap, jazz, modern and musical theatre dancing.

Apical periodontitis is an inflammatory disease of microbial etiology. It has been suggested that endodontic bacterial DNA might translocate to distant organs via blood vessels, but no studies have been conducted. We aimed first to explore overall extraradicular infection, as well as specifically by Porphyromonas spp; and their potential to translocate from infected root canals to blood through peripheral blood mononuclear cells. In this cross-sectional study, healthy individuals with and without a diagnosis of apical periodontitis with an associated apical lesion of endodontic origin (both, symptomatic and asymptomatic) were included. Apical lesions (N=64) were collected from volunteers with an indication of tooth extraction. Intracanal samples (N=39) and respective peripheral blood mononuclear cells from apical periodontitis (n=14) individuals with an indication of endodontic treatment, as well as from healthy individuals (n=14) were collected. The detection frequencies and loads (DNA copies/mg or DNA copies/μL) of total bacteria, Porphyromonas endodontalis and Porphyromonas gingivalis were measured by qPCR. In apical lesions, the detection frequencies (%) and median bacterial loads (DNA copies/mg) respectively were 70.8% and 4521.6 for total bacteria; 21.5% and 1789.7 for Porphyromonas endodontalis; and 18.4% and 1493.9 for Porphyromonas gingivalis . In intracanal exudates, the detection frequencies and median bacterial loads respectively were 100% and 21089.2 (DNA copies/μL) for total bacteria, 41% and 8263.9 for Porphyromonas endodontalis ; and 20.5%, median 12538.9 for Porphyromonas gingivalis. Finally, bacteria were detected in all samples of peripheral blood mononuclear cells including apical periodontitis and healthy groups, though total bacterial loads (median DNA copies/μL) were significantly higher in apical periodontitis (953.6) compared to controls (300.7), p<0.05. Porphyromonas endodontalis was equally detected in both groups (50%), but its bacterial load tended to be higher in apical periodontitis (262.3) than controls (158.8), p>0.05; Porphyromonas gingivalis was not detected. Bacteria and specifically Porphyromonas spp. were frequently detected in endodontic canals and apical lesions. Also, total bacteria and Porphyromonas endodontalis DNA were detected in peripheral blood mononuclear cells, supporting their plausible role in bacterial systemic translocation.

Introduction Methodological and ethical arguments support the involvement of individuals with lived experience in research to reduce engagement barriers and ensure those directly affected by studies contribute to knowledge generation. However, there is limited evidence on the impact of including researchers with lived experience of serving a prison or community sentence in clinical trials. This qualitative study aimed to explore the value of involving researchers with lived experience of the criminal justice system as data collectors in the Mentalization for Offending Adult Males (MOAM), a multisite RCT conducted in the National Probation Service in England and Wales. Methods Semi‐structured interviews were conducted with 30 trial participants and 17 key stakeholders, either in person or via telephone. The interviews were transcribed verbatim and analysed thematically. Findings Five themes emerged for trial participants and 11 for key stakeholders. For some, lived experience researchers helped overcome engagement barriers by fostering common ground with participants who were serving a prison or community sentence during recruitment. Participants reported that the involvement of lived experience researchers enhanced the study by facilitating knowledge transfer in certain instances. However, their inclusion did not eliminate all barriers and, for some participants, introduced new challenges to engagement. Conclusion Forensic lived experience researchers bridged the gap by fostering trust between data collectors and participants. Future studies should ensure that lived experience researchers receive adequate clinical supervision to support their role. The adopted methodology challenged assumptions about knowledge generation and stereotypes associated with being an ex‐offender, benefiting both lived experience and traditional researchers. Patient or Public Contribution The study was developed in collaboration with User Voice (charity number: 1136047), who contributed to the study's design and conduct. The service user organisation co‐designed the interview schedule and directed the protocol for participant payments, emphasising a consistent approach to avoid tokenism and ensure equal recognition of all contributions. The dissemination plan was developed in partnership with individuals with lived experience of the criminal justice system.

is a Gram-negative oral bacterium with high immunostimulatory and pathogenic potential involved in the onset and progression of periodontitis, a chronic disease characterized by aberrant immune responses followed by tooth-supporting bone resorption, which eventually leads to tooth loss. While several studies have provided evidence related to the virulence factors of involved in the host cell death and immune evasion, such as its most studied primate-specific virulence factor, leukotoxin, the role of specific lipopolysaccharide (LPS) domains remain poorly understood. Here, we analyzed the role of the immunodominant domain of the LPS of termed O-polysaccharide (O-PS), which differentiates the distinct bacterial serotypes based on its antigenicity. To determine the role of the O-PS in the immunogenicity and virulence of during periodontitis, we analyzed the and effect of an O-PS-defective transposon mutant serotype strain, characterized by the deletion of the gene encoding the α-L-rhamnose sugar biosynthetic enzyme. Induction of experimental periodontitis using the O-PS-defective mutant strain resulted in lower tooth-supporting bone resorption, infiltration of Th1, Th17, and Th22 lymphocytes, and expression of , , , , , and RANKL ( ) in the periodontal lesions as compared with the wild-type strain. In addition, the O-PS-defective mutant strain led to impaired activation of antigen-presenting cells, with less expression of the co-stimulatory molecules CD40 and CD80 in B lymphocytes and dendritic cells, and downregulated expression of and in splenocytes. In conclusion, these data demonstrate that the O-PS from the serotype of plays a key role in the capacity of the bacterium to prime oral innate and adaptive immune responses, by triggering the Th1 and Th17-driven tooth-supporting bone resorption during periodontitis.

Periodontitis, characterized by persistent inflammation in the periodontium, is intricately connected to systemic diseases, including oral cancer. Bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, play a pivotal role in periodontitis development because they contribute to dysbiosis and tissue destruction. Thus, comprehending the interplay between these bacteria and their impacts on inflammation holds significant relevance in clinical understanding and treatment advancement. In the present work, we explored, for the first time, their impacts on the expressions of pro-inflammatory mediators after infecting oral keratinocytes (OKs) with a co-culture of pre-incubated P. gingivalis and F. nucleatum. Our results show that the co-culture increases IL-1β, IL-8, and TNF-α expressions, synergistically augments IL-6, and translocates NF-kB to the cell nucleus. These changes in pro-inflammatory mediators—associated with chronic inflammation and cancer—correlate with an increase in cell migration following infection with the co-cultured bacteria or P. gingivalis alone. This effect depends on TLR4 because TLR4 knockdown notably impacts IL-6 expression and cell migration. Our study unveils, for the first time, crucial insights into the outcomes of their co-culture on virulence, unraveling the role of bacterial interactions in polymicrobial diseases and potential links to oral cancer.