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

The 23 October 2011 M(w)7.0 Van (Eastern Turkey) Earthquake: Interpretations of Recorded Strong Ground Motions and Post-Earthquake Conditions of Nearby Structures

A major thrust-fault earthquake of M-w = 7.0 occurred on 23 October 2011 at 10:41:21 UTC in the eastern Anatolian region of Turkey, severely affecting the nearby towns of Van and Ercis. In this study, a few strong-motion records from the epicentral area are analyzed in order to investigate the characteristics of the ground motions. Also reported are the post-earthquake field observations for various types of structures, such as buildings, bridges, historical structures, tunnels, and dams within the vicinity of the fault plane. The spatial distribution of damage indicates a noticeable hanging-wall effect. The special-type structures are observed to experience far less damage, as opposed to the building structures in the region pointing to the need for strict compliance to seismic building code and the corresponding construction requirements

Fault Process and Broadband Ground-Motion Simulations of the 23 October 2011 Van (Eastern Turkey) Earthquake

On 23 October 2011 an M-w 7.1 earthquake occurred in eastern Turkey, close to the towns of Van and Ercis, causing more than 600 casualties and widespread structural damage. The earthquake ruptured a 60-70 km long northeast-southwest fault with a thrust mechanism, in agreement with regional tectonic stress regime. We studied the fault process of the event and the recorded ground motions using different sets of data. Regional records (0.005-0.010 Hz) are used to constrain the centroid moment tensor solution. Near-regional data, 100-200 km from the fault, are used for relocation of the hypocenter and, in the frequency range 0.05-0.15 Hz, for inversion of the rupture propagation by two methods: multiple point-source model (ISOLA) and multiple finite-extent (MuFEx) source model. MuFEx also provides an estimate of the model uncertainty, which is quite large due to unfavorable station distribution. We arrive at several plausible scenarios (equally well fitting the observed data including Global Positioning System coseismic displacements) with different styles of the rupture propagation. A few alternative source models are used for broadband (0.1-10 Hz) ground-motion simulations by means of the hybrid integral-composite source model. Only models comprising source complexities, such as a delayed rupture of shallow asperities, enable explanation of the acceleration record at the only available near-fault station, which exhibits a long duration and two prominent wave groups. These complex rupture models are used to simulate the ground motion in the near-fault area, specifically, at Van and Ercis, where records of the mainshock were missing, providing reasonable agreement with the observed spatial distribution of damage

The role of site effects on elevated seismic demands and corollary structural damage during the October 30, 2020, M7.0 Samos Island (Aegean Sea) Earthquake

On October 30, 2020 14:51 (UTC), a moment magnitude (M) 7.0 (USGS, EMSC) earthquake occurred in the Aegean Sea. This paper presents the reconnaissance findings regarding the site effects on recorded strong ground motion intensities and duration, along with the resulting induced-structural damage in Izmir Bay and Samos Island, respectively. In all rock records, relatively high intensity long period rock spectral accelerations were observed in the mid to long period range of 0.5–1.5 s, which are attributed to the source, more specifically, to the slower rupture-mechanism of the event. These rich spectral intensities were further amplified by soil site effects and soil-superstructure resonance, leading to two to six times amplified overall responses and prolonged seismic shaking durations, more pronounced in Bayrakli and other Izmir Bay sites in Turkey. However, these amplified and prolonged excitations are still below design basis earthquake levels, which addresses the lack of proper structural design and construction deficiencies, as the underlying causes for the collapse to heavy damage performance of 795 buildings. On the other hand, although located only about 10 km from the rupture (22 km from the epicenter) and within the near fault zone, the town of Vathy on Samos Island (Greece) was rather lightly affected by the earthquake, with relatively few collapsed or heavily damaged buildings, partially attributed to the low height/low weight of structures in the area. However, a concentration of damage in low-rise buildings in Ano Vathy hill is considered indicative of a combination of coupled valley and topography effects on the strong motion. This event once again addressed the need to develop region-specific zonation and provisions, when more general code practices are proven to be inadequate to assess these extreme site effects