Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells

Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells

A real-life experience with eculizumab and efgartigimod in generalized myasthenia gravis patients

Introduction: Eculizumab, a complement active antibody, and efgartigimod, an Fc fragment that blocks neonatal Fc receptor, are both approved to treat generalized myasthenia gravis (gMG) patients. The objective of this study is to describe the clinical response to both treatments in a real-life setting. Methods: We collected baseline and follow-up clinical data using the Myasthenia Gravis-Activities of Daily Living (MG-ADL), and Quantitative Myasthenia Gravis (QMG). We included 63 patients, 32 treated with eculizumab and 31 with efgartigimod. Of the efgartigimod-treated patients, 22 were anti-acetylcholine receptor antibody-positive (AChR-Ab +) and 9 were AChR-Ab- (3 MuSK-Ab + and 6 seronegative). Results: Both treatments showed similar efficacy relative to the MG-ADL scale reduction (p = 0.237). Efgartigimod had a similar effect on both AChR-Ab + and AChR-Ab- (p = 0.280). Eculizumab was superior to efgartigimod relative to the QMG score reduction for the entire dataset (p = 0.003) and was more likely to achieve a clinical response at the QMG compared to efgartigimod (OR 1.373; p = 0.016). Steroid-sparing effect was higher for eculizumab than efgartigimod (– 16.7 vs – 5.2 mg of the baseline daily dose at follow-up; p = 0.001). Mean speed of prednisone reduction was – 13.1 mg of the daily dose for each month of follow-up for eculizumab-treated patients and – 3.2 for efgartigimod (p = 0.001). We found three serious events, all not related to treatment in the investigator’s opinion. One eculizumab-treated patient experienced a severe pneumonia and died despite treatment. Conclusions: Our study provides evidence that eculizumab and efgartigimod can be used in clinical practice to reduce disability in gMG patients. Eculizumab-treated patients had a higher QMG response and steroid sparing effect. Efgartigimod may offer a more flexible schedule due to its cyclical use, no need for vaccination, and efficacy in AChR-Ab- patients

In vitro culture with gemcitabine augments death receptor and NKG2D ligand expression on tumour cells

Much effort has been made to try to understand the relationship between chemotherapeutic treatment of cancer and the immune system. Whereas much of that focus has been on the direct effect of chemotherapy drugs on immune cells and the release of antigens and danger signals by malignant cells killed by chemotherapy, the effect of chemotherapy on cells surviving treatment has often been overlooked. In the present study, tumour cell lines: A549 (lung), HCT116 (colon) and MCF-7 (breast), were treated with various concentrations of the chemotherapeutic drugs cyclophosphamide, gemcitabine (GEM) and oxaliplatin (OXP) for 24 hours in vitro. In line with other reports, GEM and OXP upregulated expression of the death receptor CD95 (fas) on live cells even at sub-cytotoxic concentrations. Further investigation revealed that the increase in CD95 in response to GEM sensitised the cells to fas ligand treatment, was associated with increased phosphorylation of stress activated protein kinase/c-Jun N-terminal kinase and that other death receptors and activatory immune receptors were co-ordinately upregulated with CD95 in certain cell lines. The upregulation of death receptors and NKG2D ligands together on cells after chemotherapy suggest that although the cells have survived preliminary treatment with chemotherapy they may now be more susceptible to immune cell-mediated challenge. This re-enforces the idea that chemotherapy-immunotherapy combinations may be useful clinically and has implications for the make-up and scheduling of such treatments

PO-1045 Retreatment using Ru-106 or I-125 plaque in uveal melanoma locally recurrent after brachytherapy

Purpose or Objective:To present the results of a patient therapeutic approach using a second course of Interventional Radiotherapy (Brachytherapy) in a setting of patients with local recurrence of uveal melanoma. Material and Methods: Patients who had already undergone ocular brachytherapy at IOC (Interventional Oncology Center) of the “Gemelli ART” (Advanced Radiation Therapy) of Rome were considered. In this group, five patients with a local recurrence that received a second course of treatment with a plaque were included in our analysis. The reirradiation was performed with a plaque of Ruthenium-106 (dose prescribed to the apex 100 Gy) or of Iodine-125 (dose prescribed to the apex 85Gy)

EROS 2.0 study: evaluation of two interventional radiotherapy (brachytherapy) schedules for endometrial cancer: a comparison of late vaginal toxicity rates

Background To compare the late toxicity rates after two different high dose rate (HDR) adjuvant intravaginal interventional radiotherapy (IRT-brachytherapy) dose schedules in stage I-II endometrial cancer. Methods Stage I-II patients with endometrial cancer treated with surgery (with or without lymphadenectomy) and adjuvant HDR-IRT between 2014 and 2020 were included in this analysis. Patients were treated with two schedules. In the first cohort (C1), 21 Gy were delivered in three weekly fractions (7 Gy) prescribed 0.5 cm from the applicator surface. In the second cohort (C2), 24 Gy were delivered in four weekly fractions (6 Gy). The clinical target volume was the upper third of the vagina for C1 and the upper 3 cm for C2. HDR-IRT technique and point prescription (5 mm depth from the applicator surface) were the same for all patients. Vaginal toxicity was scored according to the CTCAE 5.0 scale in terms of the presence versus absence of any toxicity grade. The correlation among toxicity and clinical covariates (age, lymphadenectomy, fractionation, stage) was tested by Pearson correlation test (univariate) and by logistic regression (multivariable). Results 114 stage I and three stage II patients, median age 62 (range: 32-85) years, were included in this analysis. The mean follow-up was 56.3 months in C1 (40-76) and 20 months in C2 (8-42). Vaginal late toxicity was recorded in 40 and 15 patients in C1 and 2, respectively. Age, lymphadenectomy, and fractionation were significantly correlated with toxicity at univariate analysis (p value = 0.029, 0.006, and 0.002, respectively), while stepwise logistic regression confirmed only age and fractionation as significantly correlated parameters (p value = 0.02 and 0.001, respectively). Three-year local relapse-free, distant metastasis-free and cause-specific survival rates were 96.6%, 94.8%, and 99.1%, respectively. Conclusions This analysis showed lower vaginal late toxicity rate in C2 compared to C1

Ent cobra ontology: the covariates classification system proposed by the Head & Neck and Skin GEC-ESTRO Working Group for interdisciplinary standardized data collection in head and neck patient cohorts treated with interventional radiotherapy (brachytherapy)

Purpose: Clinical data collecting is expensive in terms of time and human resources. Data can be collected in different ways; therefore, performing multicentric research based on previously stored data is often difficult. The primary objective of the ENT COBRA (COnsortium for BRachytherapy data Analysis) ontology is to define a specific terminological system to standardized data collection for head and neck (H&N) cancer patients treated with interventional radiotherapy. Material and methods: ENT-COBRA is a consortium for standardized data collection for H&N patients treated with interventional radiotherapy. It is linked to H&N and Skin GEC-ESTRO Working Group and includes 11 centers from 6 countries. Its ontology was firstly defined by a multicentric working group, then evaluated by the consortium followed by a multi-professional technical commission involving a mathematician, an engineer, a physician with experience in data storage, a programmer, and a software expert. Results: Two hundred and forty variables were defined on 13 input forms. There are 3 levels, each offering a specific type of analysis: 1. Registry level (epidemiology analysis); 2. Procedures level (standard oncology analysis); 3. Research level (radiomics analysis). The ontology was approved by the consortium and technical commission; an ad-hoc software architecture (\u201cbroker\u201d) remaps the data present in already existing storage systems of the various centers according to the shared terminology system. The first data sharing was successfully performed using COBRA software and the ENT COBRA Ontology, automatically collecting data directly from 3 different hospital databases (L\ufcbeck, Navarra, and Rome) in November 2017. Conclusions: The COBRA Ontology is a good response to the multi-dimensional criticalities of data collection, retrieval, and usability. It allows to create a software for large multicentric databases with implementation of specific remapping functions wherever necessary. This approach is well-received by all involved parties, primarily because it does not change a single center\u2019s storing technologies, procedures, and habits

INFN What Next: Ultra-relativistic Heavy-Ion Collisions

This document was prepared by the community that is active in Italy, within INFN (Istituto Nazionale di Fisica Nucleare), in the field of ultra-relativistic heavy-ion collisions. The experimental study of the phase diagram of strongly-interacting matter and of the Quark-Gluon Plasma (QGP) deconfined state will proceed, in the next 10-15 years, along two directions: the high-energy regime at RHIC and at the LHC, and the low-energy regime at FAIR, NICA, SPS and RHIC. The Italian community is strongly involved in the present and future programme of the ALICE experiment, the upgrade of which will open, in the 2020s, a new phase of high-precision characterisation of the QGP properties at the LHC. As a complement of this main activity, there is a growing interest in a possible future experiment at the SPS, which would target the search for the onset of deconfinement using dimuon measurements. On a longer timescale, the community looks with interest at the ongoing studies and discussions on a possible fixed-target programme using the LHC ion beams and on the Future Circular Collider.Comment: 99 pages, 56 figure

Tailored postoperative treatment of prostate cancer: final results of a phase I/II trial.

BACKGROUD: The European Organization for Research and Treatment of Cancer (EORTC) trial 22,911 reported 74% 5-year biochemical disease-free survival (bDFS) in patients with prostate carcinoma treated with radical prostatectomy (RP) followed by postoperative radiotherapy (RT). This study aimed to improve these outcomes by using a combined-intensified-modulated-adjuvant treatment, including RT and hormone therapy (HT) after RP. MATERIALS AND METHODS: This phase I/II trial treatment was designed to improve 5-year bDFS from ~\u200975 to 90%. Patients were consecutively enrolled using the following inclusion criteria: age\u2009<\u200980 years, histological diagnosis of prostate adenocarcinoma without known metastases, stage pT2-4N0-1, and Eastern Cooperative Oncology Group performance status of 0-2. All patients had at least one of these pathologic features: capsular perforation, positive surgical margins, seminal vesicle invasion, and pelvic lymph nodes involvement. A minimum dose of 64.8\u2009Gy to the tumor bed was delivered in all patients. Depending on tumor characteristics at diagnosis, patients received a higher dose (70.2\u2009Gy; 85.4%) and/or prophylactic pelvic lymph nodes irradiation (57.7%) and/or HT (69.1%). Biochemical relapse was defined as two consecutive rising prostate-specific antigen (PSA) values\u2009>\u20090.2\u2009ng/ml. RESULTS: A total of 123 patients were enrolled in the study and completed the scheduled treatment. Median preoperative and postoperative PSA were: 8.8 and 0.06\u2009ng/mL, respectively. The percentages of patients with pathologically involved nodes and positive resection margins were: 14.6% and 58.5%, respectively. With a median follow-up of 67 months (range: 37-120 months), the actuarial 5-year bDFS, local control, metastasis-free survival, and overall survival (OS) were: 92.9%, 98.7%, 96.1%, and 95.1%, respectively. CONCLUSION: A higher 5-year bDFS (92.9%) was recorded compared to studies based on standard adjuvant RT, even though patients with nodal disease and detectable postoperative PSA were enrolled. Clinical end points, as long-term disease-free survival and OS, will require further assessments

Multi-particle azimuthal correlations in p-Pb and Pb-Pb collisions at the CERN Large Hadron Collider

Measurements of multi-particle azimuthal correlations (cumulants) for charged particles in p-Pb and Pb-Pb collisions are presented. They help address the question of whether there is evidence for global, flow-like, azimuthal correlations in the p-Pb system. Comparisons are made to measurements from the larger Pb-Pb system, where such evidence is established. In particular, the second harmonic two-particle cumulants are found to decrease with multiplicity, characteristic of a dominance of few-particle correlations in p-Pb collisions. However, when a $|\Delta \eta|$ gap is placed to suppress such correlations, the two-particle cumulants begin to rise at high-multiplicity, indicating the presence of global azimuthal correlations. The Pb-Pb values are higher than the p-Pb values at similar multiplicities. In both systems, the second harmonic four-particle cumulants exhibit a transition from positive to negative values when the multiplicity increases. The negative values allow for a measurement of $v_{2}\{4\}$ to be made, which is found to be higher in Pb-Pb collisions at similar multiplicities. The second harmonic six-particle cumulants are also found to be higher in Pb-Pb collisions. In Pb-Pb collisions, we generally find $v_{2}\{4\} \simeq v_{2}\{6\}\neq 0$ which is indicative of a Bessel-Gaussian function for the $v_{2}$ distribution. For very high-multiplicity Pb-Pb collisions, we observe that the four- and six-particle cumulants become consistent with 0. Finally, third harmonic two-particle cumulants in p-Pb and Pb-Pb are measured. These are found to be similar for overlapping multiplicities, when a $|\Delta\eta| > 1.4$ gap is placed.Comment: 25 pages, 11 captioned figures, 3 tables, authors from page 20, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/87