Search for Spatial Correlations of Neutrinos with Ultra-high-energy Cosmic Rays

For several decades, the origin of ultra-high-energy cosmic rays (UHECRs) has been an unsolved question of high-energy astrophysics. One approach for solving this puzzle is to correlate UHECRs with high-energy neutrinos, since neutrinos are a direct probe of hadronic interactions of cosmic rays and are not deflected by magnetic fields. In this paper, we present three different approaches for correlating the arrival directions of neutrinos with the arrival directions of UHECRs. The neutrino data are provided by the IceCube Neutrino Observatory and ANTARES, while the UHECR data with energies above ∼50 EeV are provided by the Pierre Auger Observatory and the Telescope Array. All experiments provide increased statistics and improved reconstructions with respect to our previous results reported in 2015. The first analysis uses a high-statistics neutrino sample optimized for point-source searches to search for excesses of neutrino clustering in the vicinity of UHECR directions. The second analysis searches for an excess of UHECRs in the direction of the highest-energy neutrinos. The third analysis searches for an excess of pairs of UHECRs and highest-energy neutrinos on different angular scales. None of the analyses have found a significant excess, and previously reported overfluctuations are reduced in significance. Based on these results, we further constrain the neutrino flux spatially correlated with UHECRs

A Two-Year Comparison

The research within natural language processing has evolved rapidly, with emotion and 9 sentiment analysis tools becoming indispensable to understanding opinions expressed on social me- 10 dia, particularly Twitter. Twitter has been utilised within the field to allow for tracking of various 11 epidemics and natural disasters, and recently, COVID-19. The World Health Organisation (WHO) 12 declared the outbreak of COVID-19 as a global pandemic in March 2020, resulting in world leaders 13 initiating nation-wide lock lockdowns. Early indications suggested impacts from such lockdowns 14 with previous research alluding to effects of similar natural disasters lasting three years post-event. 15 To assess any long-term effects, the current research utilised lexicon-based and a recurrent neural 16 network (RRN) to assess and compare the emotion and mood found in COVID-19-related tweets 17 collected in 2020 and 2022. The current research found that emotion and mood were consistent 18 throughout the two years studied, with fear being the most prominent emotion and depression be- 19 ing the most prominent mood. Such findings are a starting point in the utilisation of natural lan- 20 guage processing techniques by governments and governing bodies to assess, monitor and provide 21 mitigation strategies to the public.Faculty of Science & Engineerin

Targeting the interleukin‐7 receptor alpha by an anti‐CD127 monoclonal antibody improves allergic airway inflammation in mice

International audienceBackground: Interleukin-7 (IL-7) is the most important cytokine for T cell homeostasis. IL-7 signals through the IL-7 receptor (IL-7R) which is composed of an alpha chain (IL-7Rα), also called CD127 and a common gamma chain. T lymphocytes, especially T helper type 2, play a crucial role in the pathobiology of allergic asthma.Objective: To study the effects of an anti-CD127 monoclonal antibody (mAb) in a murine model of allergic airway inflammation induced by house dust mite (HDM).Methods: Allergic airway inflammation was induced in mice using a protocol comprising 4 weekly percutaneous sensitizations followed by 2 weekly intranasal challenges with total HDM extracts and treated by intraperitoneal injections of an anti-CD127 mAb. Because CD127 is shared by both IL-7R and the receptor for thymic stromal lymphopoietin (TSLP), a group of mice was also treated with an anti-IL-7 mAb to block only the IL-7 signaling pathway.Results: Anti-CD127 mAb-treated mice showed significantly lower airway resistance in response to methacholine and improvement in lung histology compared to isotype mAb-treated animals. Anti-CD127 mAb treatment significantly decreased the mRNA expression of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL5/RANTES) in lung tissue, decreased the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CXCL1 and CCL11/eotaxin) in bronchoalveolar lavage fluid (BALF), decreased serum HDM-specific IgE, and reduced the number of total leukocytes and leukocyte subpopulations such as eosinophils, macrophages, lymphocytes, T lymphocytes, and ILC2 in BALF and lung tissue. Mice treated with anti-IL-7 mAb also showed less allergic airway inflammation as evidenced by significantly lower airway resistance and fewer leukocytes in BALF and lung tissue compared to mice treated with the corresponding isotype control mAb.Conclusion and clinical relevance: Targeting the IL-7Rα by an anti-CD127 mAb improves allergic airway inflammation in mice and presents as a potential therapeutic approach for allergic asthma

Obinutuzumab Versus Rituximab in Transplant Eligible Untreated MCL Patients, a Matching Comparison between the Lyma and Lyma-101 Trials

International audienceAim: Obinutuzumab (O) and Rituximab (R) have never been compared in a prospective randomized trial in mantle cell lymphoma (MCL). The LYMA-101 trial (NCT02896582) investigated the Obinutuzumab-DHAP (O-DHAP) regimen followed by autologous stem cell transplant (O-BEAM, ASCT) plus O maintenance (OM) in transplant eligible patients <66y with untreated MCL (Le Gouill et al, Lancet Hem 2020). The LYMA trial (NCT00921414) used the same regimen with Rituximab instead of Obinutuzumab (Le Gouill et al, NEJM 2017). Herein, we report the long-term outcome of patients enrolled in the LYMA-101 trial and used a propensity score matching (PSM) approach to allow a comparison with patients treated in the LYMA trial (i.e. O versus R group matched comparison). Method: LYMA (n=299 pts, of whom 120 received R Maintenance, RM) is a phase III prospective trial with a median follow-up of 7.5 years (7.4-7.7) from inclusion (Sarkozy et al, ASCO 2023) that randomized, after ASCT, 240 pts between observation and RM. LYMA-101 (n=86) is a prospective single arm phase 2 trial with a median FU of 5.1y (5-5.25) at the time of the present analysis. We first compared minimal residual disease (MRD) at end of induction (EOI), assessed in both trial with quantitative PCR of clonal immunoglobulin gene and used PSM based on clinical characteristics at inclusion (Sex, Ann Arbor stage, MIPI score, B symptoms, blastoid variant, bulky disease) to balance patients' discrepancies between LYMA-101 and LYMA. To compare PFS and OS from inclusion of patients treated with R versus O based regimen, half of the non-randomized LYMA patients (29 out of 58) were randomly reattributed to the RM arm to create an intention to treat RM (RM-ITT) arm including 149 pts (29 non-randomized and 120 randomized) subsequently matched with the 86 LYMA-101 pts. Balance between populations was checked using standardized mean differences (SMD). Results: Eighty-five LYMA-101 pts received the first course of O-DHAP (1 withdrew consent before treatment), 81 (95.3%) completed the 4 cycles and 73 (85.9%) underwent ASCT followed by OM in 69 (81.2%). The estimated 5y PFS and OS since inclusion were 83.4% (95%CI: 73.5-89.8%) and 86.9% (95%CI: 77.6-92.5%) respectively. At EOI, ORR were similar in both studies (89.6% versus 91.8% in LYMA versus LYMA-101 respectively), but within responders, pts treated in LYMA-101 (O-DHAP) had a more frequent MRD negativity than pts treated in LYMA (R-DHAP) both in bone marrow (BM, 82.1% versus 65.3% MRD negativity in O vs R group, Chi2 p=0.011) and blood (95.5% versus 79.2% of MRD negativity in O vs R group, Chi2 p=0.002). These results were confirmed using the propensity score matched populations, with a more frequent MRD negativity in the O versus R group in BM (82.1% vs 63.4%, Chi-2, p=0.01) and blood (95.5% vs 72.9%, Chi-2, p<0.001). To compare PFS and OS since induction, a PSM was performed using the 149 patients treated in the R-group with an RM-ITT and the 85 patients in the O group, resulting in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, patients treated with O presented a prolonged PFS (p=0.029, figure 1A) and OS (p=0.039, figure 1B) compared to those treated with R, with an estimated 5-year PFS of 82.8% versus 66.6% (HR 1.99, IC95 1.05-3.76) and OS of 86.4% versus 71.4% (HR 2.08, IC95 1.01-4.16) with O and R based regimen respectively. Finally, 37/120 (30.8%) patients in LYMA and 23/69 (33.3%) in LYMA-101 prematurely stopped R and OM respectively (with a similar mean maintenance duration of 29 and 29.4m with R and OM respectively). Reason for maintenance discontinuation were adverse events in 15 cases in R group (12.5% of the population) versus 14 cases in O group (20% of the population), progression or death in 10 (8.3%) versus 3 (4.3%) cases in the R versus O group respectively. Causes of death were comparable in O and R groups, the most common being lymphoma (42% in O and 53% in R group). Infectious deaths in the O group (N=3) were all COVID related (3/12 deaths, 25%), whereas in the R group (LYMA being conducted before the pandemic), 8 deaths were related to infection (8/97 deaths, 8%, including 1 infectious death out of 22 deaths during RM, 5%). Conclusion: O-DHAP followed by OM post ASCT provide prolonged PFS and OS in young patients with MCL. O-based therapy in MCL induce deeper response with increased MRD negativity and seems to outperform R-based therapy in term of PFS and OS, without any significant excess of toxicity

CD19-Targeting CAR T-Cell Therapy in Transformed Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Descar-T and US Collaborative Study

International audienceIntroduction: Patients with histological transformation (HT) of Waldenström macroglobulinemia (WM) who relapse or are refractory (R/R) have a poor prognosis with standard chemoimmunotherapy, notably patients who are unable to undergo high dose chemotherapy (HCT) and autologous stem cell transplantation (ASCT) or who relapse after HCT/ASCT. CD19-targeted chimeric antigen receptor (CAR) T-cell therapies can lead to durable responses in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and thus may represent a promising therapeutic option in R/R transformed WM (tWM); however, data from pivotal trials is lacking. This study aimed to evaluate the efficacy and safety of anti-CD19 CAR T-cells in real-word patients with R/R tWM. Methods: We retrospectively identified patients with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in the French DESCAR-T registry (NCT04328298) and 2 US centers. The primary endpoint was best complete response rate (CRR). Secondary outcomes were best overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Responses were assessed according to the Lugano 2014 criteria at 1 month, 3 months and 6 months. Subsequent assessments were per institutional pratice. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Results: Between June 2017 and May 2023, 22 patients (18 from DECAR-T centers and 4 from US centers) with R/R tWM were treated with anti-CD19 CAR T-cells (13 axi-cel and 9 tisa-cel). Median age at WM diagnosis was 58 years (range 35-72). MYD88 L265P and CXCR4 mutations were present in 85% (11/13) and 29% (2/7) of patients with available data, respectively. Patients received a median of 1 prior line of treatment (range, 0-4) for WM and 2 prior lines (range, 1-4) for HT. Eight patients had received prior ASCT (2 for WM and 6 for HT) and 1 patient allogeneic SCT. The median time from WM to HT diagnosis was 4.5 years (range, 0-32) and 26 months (range, 3-90) from HT diagnosis to CAR T infusion. Of note, CNS involvement was present in 3 patients at DLBCL relapse before CAR T-cell therapy. At time of infusion, the median age was 66 years (range, 41-82) and 8 patients (36%) were older than 70 years. Median Eastern Cooperative Oncology Group (ECOG) was 1 (range, 0-2). Bridging therapy was administered to 16 patients (73%). Following bridging therapy, 6 patients had progressive disease (PD), 4 stable disease (SD) and 6 were responders (2 complete responses (CR) and 4 partial responses (PR)). After CAR T-cell infusion, best CRR was 82% and best ORR was 95%. The ORR/CRR was 95%/77% at 1 month, 76%/71% at 3 months and 68%/68% at 6 months. Seventeen patients (78%) experienced CRS, including 2 grade 3 (all after axi-cel), and 9 ICANS occurred (41%), including 1 grade 3 and 1 grade 4 (all after axi-cel). Eight patients (36%) presented infections, including 3 grade 3 and 1 grade 4. Neutropenia was reported in 78% (grade 3-4 = 68%), thrombocytopenia in 86% (grade 3-4 = 45%) and anemia in 86% (grade 3-4 = 32%) of patients. After a median follow-up of 17 months (range, 1-47), the 1-year PFS and OS were 70% and 84% respectively (figure). Five deaths were reported, 4 due to progressive disease and 1 from SARS-CoV-2 infection. Conclusion: This study shows a high efficacy of anti-CD19 CAR T-cell therapy in R/R tWM with no unexpected toxicity. Longer follow-up is needed to confirm the long-term efficacy of CAR T-cells in tWM