Multimessenger NuEM Alerts with AMON

The Astrophysical Multimessenger Observatory Network (AMON), has developed a real-time multi-messenger alert system. The system performs coincidence analyses of datasets from gamma-ray and neutrino detectors, making the Neutrino-Electromagnetic (NuEM) alert channel. For these analyses, AMON takes advantage of sub-threshold events, i.e., events that by themselves are not significant in the individual detectors. The main purpose of this channel is to search for gamma-ray counterparts of neutrino events. We will describe the different analyses that make-up this channel and present a selection of recent results

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility.

Beside its well-documented role in carcinogenesis, the function of p53 family has been more recently revealed in development and female reproduction, but it is still poorly documented in male reproduction. We specifically tested this possibility by ablating Mdm2, an E3 ligase that regulates p53 protein stability and transactivation function, specifically in Sertoli cells (SCs) using the AMH-Cre line and created the new SC-Mdm2-/- line. Heterozygous SC-Mdm2-/+ adult males were fertile, but SC-Mdm2-/- males were infertile and exhibited: a shorter ano-genital distance, an extra duct along the vas deferens that presents a uterus-like morphology, degenerated testes with no organized seminiferous tubules and a complete loss of differentiated germ cells. In adults, testosterone levels as well as StAR, P450c17 (Cyp17a1) and P450scc (Cyp11a1) mRNA levels decreased significantly, and both plasma LH and FSH levels increased. A detailed investigation of testicular development indicated that the phenotype arose during fetal life, with SC-Mdm2-/- testes being much smaller at birth. Interestingly, Leydig cells remained present until adulthood and fetal germ cells abnormally initiated meiosis. Inactivation of Mdm2 in SCs triggered p53 activation and apoptosis as early as 15.5 days post conception with significant increase in apoptotic SCs. Importantly, testis development occurred normally in SC-Mdm2-/- lacking p53 mice (SC-Mdm2-/-p53-/-) and accordingly, these mice were fertile indicating that the aforementioned phenotypes are entirely p53-dependent. These data not only highlight the importance of keeping p53 in check for proper testicular development and male fertility but also certify the critical role of SCs in the maintenance of meiotic repression.Cell Death and Differentiation advance online publication, 16 October 2015; doi:10.1038/cdd.2015.120

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: A Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial

none79Background: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. Methods: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P =.507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P =.105). Conclusions: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. Lay Summary: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.nonePasquali S.; Palmerini E.; Quagliuolo V.; Martin-Broto J.; Lopez-Pousa A.; Grignani G.; Brunello A.; Blay J.-Y.; Tendero O.; Diaz-Beveridge R.; Ferraresi V.; Lugowska I.; Infante G.; Braglia L.; Merlo D.F.; Fontana V.; Marchesi E.; Donati D.M.; Palassini E.; Bianchi G.; Marrari A.; Morosi C.; Stacchiotti S.; Bague S.; Coindre J.M.; Dei Tos A.P.; Picci P.; Bruzzi P.; Miceli R.; Casali P.G.; Gronchi A.; Dani C.; Villa C.; Messina A.; Rusi L.; Nuzzo A.M.; Nuzzo C.; De Paoli A.; Buonadonna A.; Comandone A.; Boglione A.; Livi L.; Greto D.; Riva N.; Monti M.; Pennacchioli E.; De Pas T.; Ippolito V.; Ledesma P.; Redondo A.; Valverde C.; Bratos R.; Cruz J.; Martinez Trufero J.; Cubedo R.; Sevilla I.; Luna P.; Lopez R.; Sancho P.; Bally O.; Brahmi M.; Ray-Coquard I.; Cassier P.; Marques N.; Tassy L.; Boudou-Rouquette P.; Tlemsani C.; Alexandre J.; Goldwasser F.; Bompas E.; Rolland F.; Perrin C.; Talarmin M.; Italiano A.; Toulmonde M.; Laramas M.; Bay J.-O.; Dubray-Longeras P.; Rutkowski P.Pasquali, S.; Palmerini, E.; Quagliuolo, V.; Martin-Broto, J.; Lopez-Pousa, A.; Grignani, G.; Brunello, A.; Blay, J. -Y.; Tendero, O.; Diaz-Beveridge, R.; Ferraresi, V.; Lugowska, I.; Infante, G.; Braglia, L.; Merlo, D. F.; Fontana, V.; Marchesi, E.; Donati, D. M.; Palassini, E.; Bianchi, G.; Marrari, A.; Morosi, C.; Stacchiotti, S.; Bague, S.; Coindre, J. M.; Dei Tos, A. P.; Picci, P.; Bruzzi, P.; Miceli, R.; Casali, P. G.; Gronchi, A.; Dani, C.; Villa, C.; Messina, A.; Rusi, L.; Nuzzo, A. M.; Nuzzo, C.; De Paoli, A.; Buonadonna, A.; Comandone, A.; Boglione, A.; Livi, L.; Greto, D.; Riva, N.; Monti, M.; Pennacchioli, E.; De Pas, T.; Ippolito, V.; Ledesma, P.; Redondo, A.; Valverde, C.; Bratos, R.; Cruz, J.; Martinez Trufero, J.; Cubedo, R.; Sevilla, I.; Luna, P.; Lopez, R.; Sancho, P.; Bally, O.; Brahmi, M.; Ray-Coquard, I.; Cassier, P.; Marques, N.; Tassy, L.; Boudou-Rouquette, P.; Tlemsani, C.; Alexandre, J.; Goldwasser, F.; Bompas, E.; Rolland, F.; Perrin, C.; Talarmin, M.; Italiano, A.; Toulmonde, M.; Laramas, M.; Bay, J. -O.; Dubray-Longeras, P.; Rutkowski, P

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3–2·4]; p=0·0001), and intensive treatment (1·8 [1·3–2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3–0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3–0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3–2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1–2·3]; p=0·020). Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute