Università della Svizzera italiana

ABSTRACT While generalized additive models are widely used to estimate smooth nonlinear relationships between responses and covariates, their application to temporal data analysis is limited, as the smooth functions may fail to accurately capture temporal evolution in the data and may yield unstable out-of-sample predictions. To address this limitation, dynamic generalized additive models have been proposed, which comprise two components: a generalized additive component and a component of random effects that evolve according to latent stochastic processes. The model falls within the scope of non-Gaussian state space models. For posterior inference in a Bayesian perspective of the model, Markov chain Monte Carlo algorithms require many iterations to converge, particularly in cases involving high-dimensional non-Gaussian time series observations. Therefore, we employ a variational inference scheme to obtain reasonable results efficiently. Specifically for the coefficients of the spline bases and the random effects, a Gaussian variational approximation is assumed. The optimization of the evidence lower bound is performed using a coordinate ascent variational inference algorithm. The proposed variational approach is more efficient than several competing methods in the dynamic generalized additive model framework. We apply the method to study death counts as a function of observed predictors and temporally dependent multivariate random effects that incorporate dependence structures among geographical locations and among causes of death, using an Italian mortality dataset from January 2015 to December 2020.

We present observations of impulsive solar energetic particle events on 2025 March 20 observed at high heliolatitude by Solar Orbiter and compare them with near-ecliptic observations by the Wind spacecraft. Solar Orbiter, located at 0.38 au, a Carrington longitude of 139.7◦ and a latitude of −16.6◦, detected two ion events at ∼0.1-6 MeV and two electron events at ∼40-200 keV. These events exhibit clear velocity dispersion and strong field-aligned anisotropy. Velocity dispersion analysis of both ion and electron events yields path lengths consistent with the nominal Parker spiral length. Furthermore, the first electron event exhibits a double-power-law spectrum with an index of 2.3 ± 0.3 below a break energy of 58 ± 4 keV and an index of 4.0±0.2 at energies above, while the second electron event exhibits a single-power-law spectrum with an index of 4.6 ± 0.2. In contrast, the Wind spacecraft, located at 1 au, a Carrington longitude of 120.0◦, and a latitude of −7.1◦, observed only one electron event, which shows insignificant velocity dispersion and arrives ∼20 min later than expected. The Parker spiral footpoints of the two spacecraft were separated by ∼15◦ in longitude and ∼10◦ in latitude, providing a lower limit on the angular extent of impulsive electron events. The delayed arrival at Wind may be attributed to the electron diffusion in the solar source region.

The role of tumor-associated neutrophils (TANs) infiltrating colorectal cancers (CRCs) is still debated. Here, we unravel that TAN recruitment and functions are modulated by intratumoral microbiota and only defined bacterial species can unleash neutrophil cytotoxic potential. Fusobacterium nucleatum promotes the production of neutrophil-recruiting chemokines by tumor cells and enhances neutrophil migration more efficiently than Bacteroides fragilis. Importantly, Fusobacterium nucleatum, but not Bacteroides fragilis, triggers neutrophils to release cytotoxic proteins showing tumoricidal activity in vitro and in xenograft models. Mechanistically, these effects are elicited upon Fusobacterium nucleatum binding to sialic-acid-binding immunoglobulin-like lectin (Siglec)-14 expressed by neutrophils but are impaired upon Siglec-14 blockade or loss-of-function polymorphisms. Supporting these findings, in human CRCs, elevated Fusobacterium nucleatum loads and high TAN densities correlate with improved prognosis, whereas lack of Siglec-14 expression is associated with reduced patient survival. Our findings identify microbiota composition and host genetic background as critical determinants of neutrophil functional profiles, offering insights into neutrophil-targeted therapeutic strategies in CRC.

Background/Objectives: Immune checkpoint inhibitors (ICIs) are among the transformative and manageable systemic therapies for several cancer types, including colorectal cancer (CRC). Nevertheless, their clinical benefit is limited to mismatch-deficient or microsatellite instability-high diseases, which represent only a small percentage of cases. Despite this initial major and stringent selection, primary and acquired resistance remain clinically relevant. Therefore, the identification of additional biomarkers is essential to refine patient selection and guide rational combinational strategies. This review aims to summarize the current evidence regarding established and emerging biomarkers of response and resistance to ICIs in CRC. Methods: This narrative review identified and synthesized relevant clinical trials, translational studies, and reviews through a literature search of emerging biomarkers of immunotherapy response in colorectal cancer. Results: Deficient mismatch repair/high microsatellite instability remains the most reliable predictive biomarker of ICI response, emphasized by high tumor mutational burden, POLE/POLD mutations, and specific tumor microenvironment features. Emerging indicators, including molecular alterations, antigen presentation machinery integrity, PD-L1-mediated signaling, microbiome connections, and circulating tumor DNA kinetics, have demonstrated significant potential as sources for therapeutic response prediction and have informed the development of innovative combination strategies in both MSI-H and MSS CRCs. Conclusions: Immunotherapy response in CRC is determined by a complex interplay between tumor-intrinsic, immune, microenvironmental, and systemic factors. Integrating multiple biomarkers may provide superior stratification and guide therapeutic strategies. Prospective validation and standardized biomarker assessment will be imperative to translate these insights into clinical practice.

L19IL2 is a clinical-stage antibody-cytokine fusion protein that has been investigated for the treatment of various cancer types. Despite its promising antitumor activity, the precise mechanism of action is still not fully understood. In this work, we employed a myc-driven B-cell lymphoma murine model to demonstrate that systemic administration of L19IL2 induced a robust CD8⁺ T cell-dependent tumor regression across multiple organs without expansion of regulatory T cells. Following L19IL2 administration, intratumoral CD8+ T cells proliferated and acquired effector and memory phenotypes, associated with private clonal expansion and enhanced killing. Moreover, the spatial behavior of peritumoral CD8+ T cells studied by intravital microscopy demonstrated a rapid increase in tumor-directed motility and infiltration following L19IL2 administration. These findings described the detailed mechanism of action of L19IL2 against B cell lymphoma and revealed for the first time the dynamic responses of peritumoral CD8+ T cells to targeted IL2 stimulation, supporting the use of L19IL2 for patients with aggressive B cell lymphoma.

Exercise-induced purpura is a distinctive condition occurring after prolonged physical exertion. It is often misdiagnosed as an immune-mediated vasculitis, raising concerns about autoimmune disorders. Although this condition affects physically active individuals, it remains underrepresented in comprehensive reviews on purpura and nontraumatic sports dermatology. To enhance awareness about this condition and to advance understanding of its clinical and histologic features, we conducted a systematic literature review. This study was preregistered in the International Prospective Register of Systematic Reviews (CRD42024557652). The United States National Library of Medicine, Excerpta Medica, and Google Scholar were screened for the terms "exercise-induced vasculitis" OR "exercise-induced purpura" OR "exercise-induced capillaritis." Data extraction encompasses demographics, symptoms, time latency and recovery, predisposing factors, ancillary tests (blood values and histology), and popular terminology. We identified 40 typical cases and three case series reporting an additional 71 individuals. Exercise-induced purpura predominantly affected middle-aged women, often in association with chronic venous disease. Petechiae, purpura, or ecchymoses-often accompanied by burning, itching, or mild pain-appeared within 24 hours after prolonged physical activity, especially in warm conditions, and characteristically involved the lower limbs, sparing areas covered by clothing. Symptoms and lesions resolved spontaneously within 1 to 2 weeks. Laboratory tests were unremarkable, and histology revealed leukocytoclastic vasculitis without IgA deposits. Exercise-induced purpura deserves greater visibility in sports medicine due to its frequency, benign course, and potential for misdiagnosis. Diagnosis is clinical. Early recognition avoids unnecessary investigations and unwarranted concern.

DNA double-strand breaks (DSBs) both pose threats to genome integrity and are commonly used for genome editing applications. Structural features of DSB ends play key roles in determining DNA repair pathway usage and outcomes during genome editing, but the cellular factors involved in these processes are only partially known. Through genome-wide CRISPRi screening, we identify ERCC6L2 as critical for repairing Cas12a-induced staggered DSBs but irrelevant for Cas9-induced blunt DSBs. We show that ERCC6L2 acts as a protection factor for staggered DSBs with either 5' or 3' polarity, preventing large deletions and translocations stemming from DNA damage induced by Cas12a, TALENs, or dual Cas9 nicks. Furthermore, ERCC6L2 loss hyper-sensitizes cells to multiple staggered DSBs induced by promiscuous Cas12a activity or etoposide-induced TOP2 trapping. By combining genetics and biochemical reconstitution, we find that ERCC6L2 counteracts MRE11-RAD50-NBS1 (MRN)-mediated resection by binding and melting staggered DNA ends, thereby promoting accurate end joining. Our data reveal a protective role of ERCC6L2 in staggered-end DSB repair, which suggests the molecular underpinnings of pathology in patients with ERCC6L2 mutations and cautions against using overhang-inducing genome editing tools for their treatment.