New outlook on the minimal model program, I

We give a new and self-contained proof of the finite generation of adjoint rings with big boundaries. As a consequence, we show that the canonical ring of a smooth projective variety is finitely generated.Comment: to appear in Duke Math.

On the anti-canonical ring and varieties of Fano type

We study the anti-canonical ring of a projective variety and we characterise varieties of log Fano type depending on the singularities of these models

On invariance of plurigenera for foliations on surfaces

We show that if $(X_t,\mathcal{F}_t)_t$ is a family of foliations with reduced singularities on a smooth family of surfaces, then invariance of plurigenera holds for sufficiently large $m$. On the other hand, we provide examples on which the result fails, for small values of $m$

Relative semi-ampleness in positive characteristic

Given an invertible sheaf on a fibre space between projective varieties of positive characteristic, we show that fibrewise semi-ampleness implies relative semi-ampleness. The same statement fails in characteristic zero

MMP for co-rank one foliation on threefolds

We prove existence of flips, special termination, the base point free theorem and, in the case of log general type, the existence of minimal models for F-dlt foliated log pairs of co-rank one on a projective threefold. As applications, we show the existence of F-dlt modifications and F-terminalisations for foliated log pairs and we show that foliations with canonical or F-dlt singularities admit non-dicritical singularities. Finally, we show abundance in the case of numerically trivial foliated log pairs

An optimization-based rigid block modeling approach to seismic assessment of dry-joint masonry structures subjected to settlements

A rigid block modeling approach is presented for rocking dynamics and nonlinear static analysis of dry-joint masonry structures subjected to settlements and earthquake excitations. For the different types of analysis, a unified optimization-based formulation is adopted, which is equivalent to the system governing the static and dynamic structural response. Sequential solution procedures are used for time integration and for pushover analysis which take into account the effects of large displacements under the combined action of support movements and lateral loads. No-tension elastic contacts with finite shear strength are considered at block in-terfaces for time-history analysis and to obtain the elastic branch of pushover curves in nonlinear static analysis. A unilateral rigid contact behavior is also considered to obtain the descending post-peak branch of pushover curves corresponding to the activation of the rigid-body rocking motion, according to displacement-based assessment methods of failure mechanisms adopted in the standards. Comparisons with numerical models and experimental tests on a rocking block and on a buttressed arch are presented to show the accuracy of the developed approach. Simple tests on dry-joint tuff panels on the tilting table were also carried out to show the effects of imposed movements at support on the response to lateral loads. Finally, an application is presented to a full-scale triumphal arch subjected to the combined action of support movements and earthquake excitation to discuss, on the basis of the developed model, the effects of settlement-induced damage on seismic performance. The numerical analyses showed that the lateral force, the displacement capacity and the rocking response can be significantly affected by support movements, pointing out the relevance of the current building condition in the seismic safety assessment.- The financial support of the research project DPC-ReLUIS 2022-2024: Work Package 5 "Integrated and low-impact strengthening interventions" funded by the Civil Protection Department IT (Grant no. 897-01/04/2022) is acknowledged. The authors are grateful to Prof. Chiara Calderini from the University of Genova for providing data from the experimental tests on the arch-pillars system investigated in the manuscript. The authors are also grateful to Mr. Domenico Imperatrice from the Department of Structures for Engineering and Architecture for his assistance and support throughout the experimental investigation on the wall panels subjected to support movement and lateral loads

Rewiring innate and adaptive immunity with TLR9 agonist to treat osteosarcoma

Background Osteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60-70% of event-free survival for localized disease at diagnosis. However, for metastatic disease, the prognosis is dismal. Exploiting immune system activation in the setting of such unfavorable mesenchymal tumors represents a new therapeutic challenge. Methods In immune competent OS mouse models bearing two contralateral lesions, we tested the efficacy of intralesional administration of a TLR9 agonist against the treated and not treated contralateral lesion evaluating abscopal effect. Multiparametric flow cytometry was used to evaluate changes of the tumor immune microenviroment. Experiments in immune- deficient mice allowed the investigation of the role of adaptive T cells in TLR9 agonist effects, while T cell receptor sequencing was used to assess the expansion of specific T cell clones. Results TLR9 agonist strongly impaired the growth of locally-treated tumors and its therapeutic effect also extended to the contralateral, untreated lesion. Multiparametric flow cytometry showed conspicuous changes in the immune landscape of the OS immune microenvironment upon TLR9 engagement, involving a reduction in M2-like macrophages, paralleled by increased infiltration of dendritic cells and activated CD8 T cells in both lesions. Remarkably, CD8 T cells were needed for the induction of the abscopal effect, whereas they were not strictly necessary for halting the growth of the treated lesion. T cell receptor (TCR) sequencing of tumor infiltrating CD8 T cells showed the expansion of specific TCR clones in the treated tumors and, remarkably, their selected representation in the contralateral untreated lesions, providing the first evidence of the rewiring of tumor-associated T cell clonal architectures. Conclusions Overall these data indicate that the TLR9 agonist acts as an in situ anti-tumor vaccine, activating an innate immune response sufficient to suppress local tumor growth while inducing a systemic adaptive immunity with selective expansion of CD8 T cell clones, which are needed for the abscopal effect