Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Factors influencing physical activity and rehabilitation in survivors of critical illness: a systematic review of quantitative and qualitative studies

PURPOSE: To identify, evaluate and synthesise studies examining the barriers and enablers for survivors of critical illness to participate in physical activity in the ICU and post-ICU settings from the perspective of patients, caregivers and healthcare providers. METHODS: Systematic review of articles using five electronic databases: MEDLINE, CINAHL, EMBASE, Cochrane Library, Scopus. Quantitative and qualitative studies that were published in English in a peer-reviewed journal and assessed barriers or enablers for survivors of critical illness to perform physical activity were included. Prospero ID: CRD42016035454. RESULTS: Eighty-nine papers were included. Five major themes and 28 sub-themes were identified, encompassing: (1) patient physical and psychological capability to perform physical activity, including delirium, sedation, illness severity, comorbidities, weakness, anxiety, confidence and motivation; (2) safety influences, including physiological stability and concern for lines, e.g. risk of dislodgement; (3) culture and team influences, including leadership, interprofessional communication, administrative buy-in, clinician expertise and knowledge; (4) motivation and beliefs regarding the benefits/risks; and (5) environmental influences, including funding, access to rehabilitation programs, staffing and equipment. CONCLUSIONS: The main barriers identified were patient physical and psychological capability to perform physical activity, safety concerns, lack of leadership and ICU culture of mobility, lack of interprofessional communication, expertise and knowledge, and lack of staffing/equipment and funding to provide rehabilitation programs. Barriers and enablers are multidimensional and span diverse factors. The majority of these barriers are modifiable and can be targeted in future clinical practice

Pimplinae

<p> <i>2.3. Pimplinae Collections</i></p> <p>We collected pimplines using 30 Malaise traps (a form a flight interception trap) distributed at 15 broad elevation sites throughout the transect, with two replicate traps at each site. Malaise traps are one of the most efficient methods for sampling Ichneumonidae and are widely used in ecological studies of insects [94]. Traps were set at ground level, with the collecting head 1.5 m above the ground. Traps were placed at least 50 m from the road and the 15 sites were roughly spaced at 100 m to 200 m elevation intervals. At each elevational site, the two traps were placed at least 50 m apart from each other to ensure that neither trap affected the catch of the other and to sample different environmental space [65]. Trap collecting bottles (1 L capacity) contained 98% ethanol for preservation of the sampled material and were replaced monthly (after 30 days of collecting). The samples were collected during both the rainy hot season, from December 2014 to February 2015, and the dry cooler season from June to August 2015, totaling 180 Malaise trap months. These months were chosen to represent the opposite environmental extremes throughout the year to capture seasonal variations in species composition, but also to encompass the warmest, wettest months when insect activity is expected to be highest (December–February).</p> <p>Insects were preserved in 98% ethanol and stored in plastic bottles. Sample sorting was performed in the laboratory using a stereoscopic microscope. Identification was initially carried out according to subfamily by D.R.R.F. and D.G.P. following [92]. Then, the Pimplinae were identified according to genus following [89]. Thereafter, morphospecies were identified by D.G.P. in conjunction with I.E.S., and where possible, species (using specific bibliography and large reference collections of neotropical Darwin wasps in the Biodiversity Unit, University of Turku, Finland). All the researchers involved in identification were experienced in neotropical ichneumonid taxonomy. The use of morphospecies (i.e., individuals sorted based on phenotypic characteristics) as surrogates for species is widely used in the estimation of species richness for comparisons over time and space [95, 96]. Although the designation of morphospecies can lead to the split of a single species into many different morphospecies (“splitting”) or aggregation of different species into a single species (“lumping”), it is often the only way to assess species diversity in groups that have not been fully described [95, 96].</p> <p>Collections were performed under license number 21409-10 (Ministério do Meio Ambiente—MMA; Instituto Chico Mendes de Conservação da Biodiversidade—ICMBio; Sistema de Autorização e Informação em Biodiversidade—SISBIO) to Ricardo Ferreira Monteiro.</p> <p>The sampled material is deposited at the following Brazilian entomological collections: Invertebrate Collection of Instituto Nacional de Pesquisas da Amazônia, Manaus, Brazil (INPA), (curator: Marcio L. Oliveira); Museu de Zoologia da Universidade de São Paulo, São Paulo, Brazil (MZUSP), (curator: Gabriela P. Camacho); and Taxonomic Collection of the Departamento de Ecologia e Biologia Evolutiva from Universidade Federal de São Carlos, São Carlos, Brazil (DCBU), (curator: Angelica M. Penteado-Dias).</p>Published as part of <i>Flinte, Vivian, Pádua, Diego G., Durand, Emily M., Hodgin, Caitlin, Khattar, Gabriel, da Silveira, Luiz Felipe L., Fernandes, Daniell R. R., Sääksjärvi, Ilari E., Monteiro, Ricardo F., Macedo, Margarete V. & Mayhew, Peter J., 2023, Variation in a Darwin Wasp (Hymenoptera: Ichneumonidae) Community along an Elevation Gradient in a Tropical Biodiversity Hotspot: Implications for Ecology and Conservation, pp. 109461 in Insects 14 (11)</i> on pages 5-6, DOI: 10.3390/insects14110861, <a href="http://zenodo.org/record/10133741">http://zenodo.org/record/10133741</a&gt