directional response of structures to thunderstorm outflows

Due to the combined effect of the background wind, the translation of the downburst and the radial nature of the downdraft after the touchdown, a peculiar characteristic of a thunderstorm outflow as detected by an anemometer or experienced by a structure is the potential variation of the flow direction. The study of the wind-excited response of structures has habitually neglected this issue because, dealing traditionally with synoptic events, their direction is endowed with a regular pattern. This paper proposes two families of methods to take into account directional changes in the evaluation of the wind-excited response of structures. The first one generalizes the method usually applied to downbursts, which by its nature implicitly assumes a non-directional response. The second one is based on a new directional decomposition strategy of the wind speed that represents a generalization to thunderstorm outflows of what is historically done for synoptic events. The conceptual aspects involved in and the results provided by these methods are critically discussed and compared both to each other and with regard to the traditional non-directional structural analysis of thunderstorm outflows

Dynamic response of structures to thunderstorm outflows taking directionality effects into account

Due to the combinate effect of the background wind, the translation of the downburst and the radial nature of the jet after the touchdown, a peculiar characteristic of a signal associated to a thunderstorm outflow measured by an anemometer is the potential variation of direction during the life of the event. Despite this situation, the study of the dynamic response of structures to thunderstorm outflows has traditionally neglected the angle of attack and the effects induced by that, implicitly assuming the response as alongwind. This paper proposes two methods to consider the role of the direction and its possible variation into the evaluation of dynamic response of structures subjected to Aeolian events. In particular, the second one is based on a decomposition method of the wind speed which constitutes a generalization of what historically defined for stationary events. Thus, it allows to establish a robust parallelism between the dynamic response due to synoptic winds and thunderstorm outflows

Parp1 inhibitor and trabectedin combination does not increase tumor mutational burden in advanced sarcomas—a preclinical and translational study

SIMPLE SUMMARY: Immunotherapy has revolutionized cancer treatment, but not for all tumor types. Indeed, sarcomas are considered “immune-cold” tumors, which are relatively unresponsive to immunotherapy. One strategy to potentiate immunotherapy efficacy is to increase tumor immunogenicity, for instance by boosting the number of candidate targets (neoantigens) to be recognized by the immune system. Tumor mutational burden indicates the number of somatic mutations identified in the tumor and normalized per megabase. Tumor mutational burden is considered as an acceptable, measurable surrogate of tumor neoantigens. Here, we explored whether the combination of two DNA-damaging agents, trabectedin and olaparib, could increase tumor mutational burden in sarcomas, to prime subsequent immunotherapy. We found no variation in tumor mutational burden after trabectedin + olaparib in preclinical and clinical samples. Therefore, other aspects should be considered to increase sarcoma immunogenicity, by exploiting different pathways such as the potential modulation of the tumor microenvironment induced by trabectedin + olaparib. ABSTRACT: Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use

Array-Comparative Genomic Hybridization Analysis in Fetuses with Major Congenital Malformations Reveals that 24% of Cases Have Pathogenic Deletions/Duplications

Karyotyping and aCGH are routinely used to identify genetic determinants of major congenital malformations (MCMs) in fetal deaths or terminations of pregnancy after prenatal diagnosis. Pathogenic rearrangements are found with a variable rate of 9-39% for aCGH. We collected 33 fetuses, 9 with a single MCM and 24 with MCMs involving 2-4 organ systems. aCGH revealed copy number variants in 14 out of 33 cases (42%). Eight were classified as pathogenic which account for a detection rate of 24% (8/33) considering fetuses with 1 or more MCMs and 33% (8/24) taking into account fetuses with multiple malformations only. Three of the pathogenic variants were known microdeletion syndromes (22q11.21 deletion, central chromosome 22q11.21 deletion, and TAR syndrome) and 5 were large rearrangements, adding up to >11 Mb per subject and comprising strong phenotype-related genes. One of those was a de novo complex rearrangement, and the remaining 4 duplications and 2 deletions were 130-900 kb in size, containing 1-7 genes, and were classified as variants of unknown clinical significance. Our study confirms aCGH as a powerful technique to ascertain the genetic etiology of fetal major congenital malformations