Linear Accelerator Test Facility at LNF Conceptual Design Report

Test beam and irradiation facilities are the key enabling infrastructures for research in high energy physics (HEP) and astro-particles. In the last 11 years the Beam-Test Facility (BTF) of the DA{\Phi}NE accelerator complex in the Frascati laboratory has gained an important role in the European infrastructures devoted to the development and testing of particle detectors. At the same time the BTF operation has been largely shadowed, in terms of resources, by the running of the DA{\Phi}NE electron-positron collider. The present proposal is aimed at improving the present performance of the facility from two different points of view: extending the range of application for the LINAC beam extracted to the BTF lines, in particular in the (in some sense opposite) directions of hosting fundamental physics and providing electron irradiation also for industrial users; extending the life of the LINAC beyond or independently from its use as injector of the DA{\Phi}NE collider, as it is also a key element of the electron/positron beam facility. The main lines of these two developments can be identified as: consolidation of the LINAC infrastructure, in order to guarantee a stable operation in the longer term; upgrade of the LINAC energy, in order to increase the facility capability (especially for the almost unique extracted positron beam); doubling of the BTF beam-lines, in order to cope with the signicant increase of users due to the much wider range of applications.Comment: 71 page

Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.

BACKGROUND: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. METHODS: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. RESULTS: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. CONCLUSIONS: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy

The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabetes: Data from the OpT2mise Study

Background: The OpT2mise randomized trial was designed to compare the effects of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) on glucose profiles in patients with type 2 diabetes. Research Design and Methods: Patients with glycated hemoglobin (HbA1c) levels of ≥8% (64 mmol/mol) and ≤12% (108 mmol/mol) despite insulin doses of 0.7-1.8 U/kg/day via MDI were randomized to CSII (n=168) or continued MDI (n=163). Changes in glucose profiles were evaluated using continuous glucose monitoring data collected over 6-day periods before and 6 months after randomization. Results: After 6 months, reductions in HbA1c levels were significantly greater with CSII (-1.1±1.2% [-12.0±13.1 mmol/mol]) than with MDI (-0.4±1.1% [-4.4±12.0 mmol/mol]) (P<0.001). Similarly, compared with patients receiving MDI, those receiving CSII showed significantly greater reductions in 24-h mean sensor glucose (SG) (treatment difference, -17.1 mg/dL; P=0.0023), less exposure to SG >180 mg/dL (-12.4%; P=0.0004) and SG >250 mg/dL (-5.5%; P=0.0153), and more time in the SG range of 70-180 mg/dL (12.3%; P=0.0002), with no differences in exposure to SG<70 mg/dL or in glucose variability. Changes in postprandial (4-h) glucose area under the curve >180 mg/dL were significantly greater with CSII than with MDI after breakfast (-775.9±1,441.2 mg/dL/min vs. -160.7±1,074.1 mg/dL/min; P=0.0015) and after dinner (-731.4±1,580.7 mg/dL/min vs. -71.1±1,083.5 mg/dL/min; P=0.0014). Conclusions: In patients with suboptimally controlled type 2 diabetes, CSII significantly improves selected glucometrics, compared with MDI, without increasing the risk of hypoglycemia

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients

A second polymorph of bis(triphenyl-λ5-phosphanylidene)ammonium chloride–boric acid adduct

The title crystal structure is a new triclinic polymorph of [(Ph3P)2N]Cl·(B(OH)3) or C36H30NP2+·Cl−·BH3O3. The crystal structure of the orthorhombic polymorph was reported by [Andrews et al. (1983). Acta Cryst. C39, 880–882]. In the crystal, the [(Ph3P)2N]+ cations have no significant contacts to the chloride ions nor to the boric acid molecules. This is indicated by the P—N—P angle of 137.28 (8)°, which is in the expected range for a free [(Ph3P)2N]+ cation. The boric acid molecules form inversion dimers via pairs of O—H...O hydrogen bonds, and each boric acid molecule forms two additional O—H...Cl hydrogen bonds to one chloride anion. These entities fill channels, created by the [(Ph3P)2N]+ cations, along the c-axis direction

Avaliação de aspectos pragmáticos em crianças com desvios fonológicos

Objetivo investigar as habilidades pragmáticas em crianças com desvio fonológico. Método por meio de triagem fonoaudiológica foram selecionadas 12 crianças com diagnóstico de desvio fonológico, com idades entre 3:7 e 7:8, sendo três do sexo feminino e nove do sexo masculino. Foi realizada análise dos aspectos pragmáticos destas crianças, utilizando-se o instrumento ABFW – pragmática. Além disso, as crianças foram classificadas de acordo com a gravidade do desvio fonológico por meio de uma abordagem quantitativa – Percentual de Consoantes Corretas-Revisado e outra qualitativa. Resultados não foi encontrada correlação estatisticamente significante entre gravidade do desvio fonológico e desempenho pragmático. Os sujeitos com desvio fonológico apresentaram número de atos comunicativos por minuto inferior aos parâmetros oferecidos pelo teste, de acordo com cada faixa etária. Conclusão a partir dos resultados obtidos não foi possível afirmar que existe uma relação significante entre a gravidade do desvio fonológico e o desempenho pragmático, no entanto, estes sujeitos apresentam desempenho inferior aos parâmetros do teste

Avaliação de aspectos pragmáticos em crianças com desvios fonológicos Evaluation of pragmatic aspects of children with phonological disorders

OBJETIVO: investigar as habilidades pragmáticas em crianças com desvio fonológico. MÉTODO: por meio de triagem fonoaudiológica foram selecionadas 12 crianças com diagnóstico de desvio fonológico, com idades entre 3:7 e 7:8, sendo três do sexo feminino e nove do sexo masculino. Foi realizada análise dos aspectos pragmáticos destas crianças, utilizando-se o instrumento ABFW - pragmática. Além disso, as crianças foram classificadas de acordo com a gravidade do desvio fonológico por meio de uma abordagem quantitativa - Percentual de Consoantes Corretas-Revisado e outra qualitativa. RESULTADOS: não foi encontrada correlação estatisticamente significante entre gravidade do desvio fonológico e desempenho pragmático. Os sujeitos com desvio fonológico apresentaram número de atos comunicativos por minuto inferior aos parâmetros oferecidos pelo teste, de acordo com cada faixa etária. CONCLUSÃO: a partir dos resultados obtidos não foi possível afirmar que existe uma relação significante entre a gravidade do desvio fonológico e o desempenho pragmático, no entanto, estes sujeitos apresentam desempenho inferior aos parâmetros do teste.PURPOSE: to investigate the pragmatic abilities in children with phonological disorder. METHOD: 12 children (three girls and nine boys) with phonological disorders aged from 3:7 to 7:8 were chosen by triage. Pragmatic analysis was executed using the instrument ABFW - pragmatic through speech and hearing screening. Furthermore, we calculated the level of severity of the phonological evolutionary disorder using a quantitative - Percentage of Consonants Correct - Revised (Shiriberg & Kwiatkowski, 1982) and a qualitative approach (Keske-Soares, 2001). RESULTS: there are no statistically significant correlation between the level of severity of the phonological disorder and pragmatic performance. However, we observed that subjects with phonological disorder showed a number of communicative acts per minute lower than the default values of the test when ranged by age group. CONCLUSION: based on the results, it is not possible to state a direct relationship between level of severity of the phonological disorder and pragmatic performance even if these subjects have a lower performance than the default values of the test

Multipoles Minimization in the DAPHNE Wigglers

The wigglers of the DAFNE main rings have been one of the major sources of the non-linearities in the collider at Frascati. A method to minimize the odd integrated multipoles around the beam trajectory (the even ones tend to vanish due to the periodicity of the magnet) has been developed and already described. After a study, including both multipolar and tracking analysis has been performed to determine the optimal configuration, the DAFNE wigglers have been modified accordingly. The results of the simulations have been validated by field map measurement

Targeting protumoral tumor-associated macrophages with nanobody-functionalized nanogels through strain promoted azide alkyne cycloaddition ligation

Tumor-associated macrophages (TAMs) with high expression levels of the Macrophage Mannose Receptor (MMR, CD206) exhibit a strong angiogenic and immune suppressive activity. Thus, they are a highly attractive target in cancer immunotherapy, with the aim to modulate their protumoral behavior. Here, we introduce polymer nanogels as potential drug nanocarriers which were site-specifically decorated with a Nanobody (Nb) specific for the MMR. Using azide-functionalized RAFT chain transfer agents, they provide access to amphiphilic reactive ester block copolymers that self assemble into micelles and are afterwards core-cross-linked toward fully hydrophilic nanogels with terminal azide groups on their surface. MMR-targeting Nb can site-selectively be functionalized with one single cyclooctyne moiety by maleimide-cysteine chemistry under mildly reducing conditions which enables successful chemoorthogonal conjugation to the nanogels. The resulting Nb-functionalized nanogels were highly efficient in targeting MMR-expressing cells and TAMs both in vitro and in vivo. We believe that these findings pave the road for targeted eradication or modulation of pro-tumoral MMRhigh TAMs