Minimal flavour violation extensions of the seesaw

We analyze the most natural formulations of the minimal lepton flavour violation hypothesis compatible with a type-I seesaw structure with three heavy singlet neutrinos N, and satisfying the requirement of being predictive, in the sense that all LFV effects can be expressed in terms of low energy observables. We find a new interesting realization based on the flavour group $SU(3)_e\times SU(3)_{\ell+N}$ (being $e$ and $\ell$ respectively the SU(2) singlet and doublet leptons). An intriguing feature of this realization is that, in the normal hierarchy scenario for neutrino masses, it allows for sizeable enhancements of $\mu \to e$ transitions with respect to LFV processes involving the $\tau$ lepton. We also discuss how the symmetries of the type-I seesaw allow for a strong suppression of the N mass scale with respect to the scale of lepton number breaking, without implying a similar suppression for possible mechanisms of N productionComment: 14 pages, 6 figure

Minimal Flavour Violation with hierarchical squark masses

In a supersymmetric model with hierarchical squark masses we analyze a pattern of flavour symmetry breaking centered on the special role of the top Yukawa coupling and, by extension, of the full Yukawa couplings for the up-type quarks. For sufficiently heavy squarks of the first and second generation this leads to effective Minimal Flavour Violation of the Flavour Changing Neutral Current amplitudes. For this to happen we determine the bounds on the masses of the heavy squarks with QCD corrections taken into account, properly including previously neglected effects. We believe that the view presented in this paper altogether strengthens the case for hierarchical sfermions.Comment: 13 pages, 1 figure. v2: an equation correcte

Flavoured soft leptogenesis and natural values of the B term

We revisit flavour effects in soft leptogenesis relaxing the assumption of universality for the soft supersymmetry breaking terms. We find that with respect to the case in which the heavy sneutrinos decay with equal rates and equal CP asymmetries for all lepton flavours, hierarchical flavour configurations can enhance the efficiency by more than two orders of magnitude. This translates in more than three order of magnitude with respect to the one-flavour approximation. We verify that lepton flavour equilibration effects related to off-diagonal soft slepton masses are ineffective for damping these large enhancements. We show that soft leptogenesis can be successful for unusual values of the relevant parameters, allowing for $B\sim {\cal O}({\rm TeV})$ and for values of the washout parameter up to $m_{\rm eff}/m_* \sim 5\times 10^{3}$.Comment: 23 pages, 5 figures postscript, Minor changes to match the published version in JHE

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

Predominant VH1-69 IgBCR Clones Show Higher Expression of CD5 in Heterogeneous Chronic Lymphocytic Leukemia Populations

The immunoglobulin B cell receptor (IgBCR) expressed by chronic lymphocytic leukemia (CLL) B cells plays a pivotal role in tumorigenesis, supporting neoplastic transformation, survival, and expansion of tumor clones. We demonstrated that in the same patient, two or more CLL clones could coexist, recognized by the expression of different variable regions of the heavy chain of IgBCR, composing the antigen-binding site. In this regard, phage display screening could be considered the easier and most advantageous methodology for the identification of small peptide molecules able to mimic the natural antigen of the tumor IgBCRs. These molecules, properly functionalized, could be used as a probe to specifically identify and isolate single CLL subpopulations, for a deeper analysis in terms of drug resistance, phenotype, and gene expression. Furthermore, CLL cells express another surface membrane receptor, the CD5, which is commonly expressed by normal T cells. Piece of evidence supports a possible contribution of CD5 to the selection and maintenance of autoreactivity in B cells and the constitutive expression of CD5 on CLL cells could induce pro-survival stimuli. In this brief research report, we describe a peptide-based single-cell sorting using as bait the IgBCR of tumor cells; in the next step, we performed a quantitative analysis of CD5 expression by qRT-PCR related to the expressed IgBCR. Our approach could open a new perspective for the identification, isolation, and investigation of all subsets of IgBCR-related CLL clones, with particular attention to the more aggressive clones

Physical activity influences adherence to pharmacological treatments in patients with severe mental disorders: results from the multicentric, randomized controlled LIFESTYLE trial

Introduction: Poor adherence to pharmacological treatment is frequent in people with severe mental disorders and it often causes lack of effectiveness of many psychotropic drugs. Thus, efforts should be made to improve adherence to pharmacological treatments in patients with these disorders.Methods: In this paper, based on the LIFESTYLE randomized, controlled multicentric trial, we aim to: 1) assess the level of adherence in a real-world sample of patients with severe mental disorders; 2) evaluate differences in treatment adherence according to patients’ socio-demographic and clinical characteristics; 3) evaluate the impact of an innovative psychosocial intervention, on patients’ adherence to treatments. The Lifestyle Psychosocial Group Intervention consists of group sessions, focused on different lifestyle behaviours, including healthy diet; physical activity; smoking habits; medication adherence; risky behaviours; and regular circadian rhythms. At end of each session a 20-min moderate physical activity is performed by the whole group.Results: The sample consists of 402 patients, mainly female (57.1%, N = 229), with a mean age of 45.6 years (±11.8). Less than 40% of patients reported a good adherence to pharmacological treatments. Adherence to treatments was not influenced by gender, age, diagnosis and duration of illness. At the end of the intervention, patients receiving the experimental intervention reported a significant improvement in the levels of adherence to treatments (T0: 35.8% vs. T3: 47.6%, p < 0.005). Patients practicing moderate physical activity reported a two-point improvement in the levels of adherence [odds ratio (OR): 1,542; 95% confidence intervals (CI): 1,157–2,055; p < 0.001], even after controlling for several confounding factors.Discussion: The experimental lifestyle intervention, which can be easily implemented in the routine clinical practice of mental health centres, was effective in improving adherence to pharmacological treatments

Timing of surgery following SARS‐CoV‐2 infection: an international prospective cohort study

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4–1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0–2 weeks, 3–4 weeks and 5–6 weeks of the diagnosis (odds ratio (95%CI) 4.1% (3.3–4.8), 3.9% (2.6–5.1) and 3.6% (2.0–5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5% (0.9– 2.1%)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2–8.7) vs. 2.4% (95%CI 1.4–3.4) vs. 1.3% (95%CI 0.6–2.0%), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia

Correction to: Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members

Background: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years