Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation.

Systemic mastocytosis (SM) is a myeloproliferative neoplasm displaying abnormal mast cell proliferation. It is subdivided into different forms, including aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Oncogenic genetic alterations include point mutations, mainly the KIT D816V, conferring poor prognosis and therapy resistance, and fusion genes, with those involving PDGFRA/PDGFRB as the most recurrent events. We here describe an ASM case negative to the KIT D816V and JAK2 V617F alterations but showing a RUNX1 frameshift heterozygous mutation and the co-occurrence of three fusion transcripts. The first one, PRKG2::PDGFRB, was generated by a balanced t(4;5)(q24;q32) translocation as the sole abnormality. Other two novel chimeras, KAT6A::NCOA2 and RXRA::NOTCH1, originated from cryptic intra-chromosomal abnormalities. The patient rapidly evolved towards SM-AHN, characterized by the persistence of the PRKG2::PDGFRB chimera, due to the presence of an extra copy of the der(5)t(4;5)(q24;q34) chromosome and an increase in the RUNX1 mutation allelic frequency. The results indicated that the transcriptional landscape and the mutational profile of SM deserve attention to predict the evolution and prognosis of this complex disease, whose classification criteria are still a matter of debate.

Measurement of the 2νßß Decay Half-Life of

We report on the results obtained with the global CUPID-0 background model, which combines the data collected in the two measurement campaigns for a total exposure of 8.82 kg×yr of ^{82}Se. We identify with improved precision the background sources within the 3 MeV energy region, where neutrinoless double ß decay of ^{82}Se and ^{100}Mo is expected, making more solid the foundations for the background budget of the next-generation CUPID experiment. Relying on the excellent data reconstruction, we measure the two-neutrino double ß-decay half-life of ^{82}Se with unprecedented accuracy: T_{1/2}^{2ν}=[8.69±0.05(stat)_{-0.06}^{+0.09}(syst)]×10^{19} yr.

Characterization of a kg-scale archaeological lead-based PbWO4 cryogenic detector for the RES-NOVA experiment.

Core-collapse Supernovae (SNe) are one of the most energetic events in the Universe, during which almost all the star's binding energy is released in the form of neutrinos. These particles are direct probes of the processes occurring in the stellar core and provide unique insights into the gravitational collapse. RES-NOVA will revolutionize how we detect neutrinos from astrophysical sources, by deploying the first ton-scale array of cryogenic detectors made from archaeological lead. Pb offers the highest neutrino interaction cross-section via coherent elastic neutrino-nucleus scattering (CEνNS). Such process will enable RES-NOVA to be equally sensitive to all neutrino flavours. For the first time, we propose the use archaeological Pb as sensitive target material in order to achieve an ultra-low background level in the region of interest (O(1 keV)). All these features make possible the deployment of the first cm-scale neutrino telescope for the investigation of astrophysical sources. In this contribution, we will characterize the radiopurity level and the performance of a small-scale proof-of-principle detector of RES-NOVA, consisting in a PbWO4 crystal made from archaeological-Pb operated as cryogenic detector.

Final Result on the Neutrinoless Double Beta Decay of

CUPID-0, an array of Zn^{82}Se cryogenic calorimeters, was the first medium-scale demonstrator of the scintillating bolometers' technology. The first project phase (March 2017-December 2018) allowed the most stringent limit on the neutrinoless double beta decay half-life of the isotope of interest, ^{82}Se, to be set. After a six month long detector upgrade, CUPID-0 began its second and last phase (June 2019-February 2020). In this Letter, we describe the search for neutrinoless double beta decay of ^{82}Se with a total exposure (phase I+II) of 8.82 kg yr^{-1} of isotope. We set a limit on the half-life of ^{82}Se to the ground state of ^{82}Kr of T_{1/2}^{0ν}(^{82}Se)>4.6×10^{24} yr (90% credible interval), corresponding to an effective Majorana neutrino mass m_{ßß}<(263-545) meV. We also set the most stringent lower limits on the neutrinoless decays of ^{82}Se to the 0_{1}^{+}, 2_{1}^{+}, and 2_{2}^{+} excited states of ^{82}Kr, finding 1.8×10^{23} yr, 3.0×10^{23} yr, and 3.2×10^{23} yr (90% credible interval) respectively.

Antineoplastic treatment class modulates COVID-19 mRNA-BNT162b2 vaccine immunogenicity in cancer patients: a secondary analysis of the prospective Vax-On study.

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.

Background identification in cryogenic calorimeters through α - α delayed coincidences.

Localization and modeling of radioactive contaminations is a challenge that ultra-low background experiments are constantly facing. These are fundamental steps both to extract scientific results and to further reduce the background of the detectors. Here we present an innovative technique based on the analysis of α - α delayed coincidences in 232 Th and 238 U decay chains, developed to investigate the contaminations of the ZnSe crystals in the CUPID-0 experiment. This method allows to disentangle surface and bulk contaminations of the detectors relying on the different probability to tag delayed coincidences as function of the α decay position.

Final Result of CUPID-0 Phase-I in the Search for the

CUPID-0 is the first pilot experiment of CUPID, a next-generation project for the measurement of neutrinoless double beta decay (0νDBD) with scintillating bolometers. The detector, consisting of 24 enriched and 2 natural ZnSe crystals, has been taking data at Laboratori Nazionali del Gran Sasso from June 2017 to December 2018, collecting a ^{82}Se exposure of 5.29 kg×yr. In this Letter we present the phase-I results in the search for 0νDBD. We demonstrate that the technology implemented by CUPID-0 allows us to reach the lowest background for calorimetric experiments: (3.5_{-0.9}^{+1.0})×10^{-3} counts/(keV kg yr). Monitoring 3.88×10^{25} ^{82}Se nuclei×yr we reach a 90% credible interval median sensitivity of T_{1/2}^{0ν}>5.0×10^{24} yr and set the most stringent limit on the half-life of ^{82}Se 0νDBD: T_{1/2}^{0ν}>3.5×10^{24} yr (90% credible interval), corresponding to m_{ßß}<(311-638) meV depending on the nuclear matrix element calculations.

Evidence of Single State Dominance in the Two-Neutrino Double-ß Decay of

We report on the measurement of the two-neutrino double-ß decay of ^{82}Se performed for the first time with cryogenic calorimeters, in the framework of the CUPID-0 experiment. With an exposure of 9.95 kg yr of Zn^{82}Se, we determine the two-neutrino double-ß decay half-life of ^{82}Se with an unprecedented precision level, T_{1/2}^{2ν}=[8.60±0.03(stat) _{-0.13}^{+0.19}(syst)]×10^{19} yr. The very high signal-to-background ratio, along with the detailed reconstruction of the background sources allowed us to identify the single state dominance as the underlying mechanism of such a process, demonstrating that the higher state dominance hypothesis is disfavored at the level of 5.5σ.

Production and separation of 163Ho for nuclear physics experiments.

This paper describes the production and chemical separation of the 163Ho isotope that will be used in several nuclear physics experiments aiming at measuring the neutrino mass as well as the neutron cross section of the 163Ho isotope. For this purpose, several batches of enriched 162Er have been irradiated at the Institut Laue-Langevin high flux reactor to finally produce 6 mg or 100 MBq of the desired 163Ho isotope. A portion of the Er/Ho mixture is then subjected to a sophisticated chemical separation involving ion exchange chromatography to isolate the Ho product from the Er target material. Before irradiation, a thorough analysis of the impurity content was performed and its implication on the produced nuclide inventory will be discussed.

First Result on the Neutrinoless Double-ß Decay of

We report the result of the search for neutrinoless double beta decay of ^{82}Se obtained with CUPID-0, the first large array of scintillating Zn^{82}Se cryogenic calorimeters implementing particle identification. We observe no signal in a 1.83 kg yr ^{82}Se exposure, and we set the most stringent lower limit on the 0νßß ^{82}Se half-life T_{1/2}^{0ν}>2.4×10^{24} yr (90% credible interval), which corresponds to an effective Majorana neutrino mass m_{ßß}<(376-770) meV depending on the nuclear matrix element calculations. The heat-light readout provides a powerful tool for the rejection of α particles and allows us to suppress the background in the region of interest down to (3.6_{-1.4}^{+1.9})×10^{-3} counts/(keV kg yr), an unprecedented level for this technique.

Search of the neutrino-less double beta decay of 82 Se into the excited states of 82 Kr with CUPID-0.

The CUPID-0 experiment searches for double beta decay using cryogenic calorimeters with double (heat and light) read-out. The detector, consisting of 24 ZnSe crystals 95 % enriched in 82 Se and two natural ZnSe crystals, started data-taking in 2017 at Laboratori Nazionali del Gran Sasso. We present the search for the neutrino-less double beta decay of 82 Se into the 0 1 + , 2 1 + and 2 2 + excited states of 82 Kr with an exposure of 5.74 kg · yr (2.24 × 10 25  emitters · yr). We found no evidence of the decays and set the most stringent limits on the widths of these processes: Γ ( 82 Se → 82 Kr 0 1 + )8.55 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 1 + ) < 6.25 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 2 + )8.25 × 10 - 24  yr - 1 (90 % credible interval).

CUPID-0: the first array of enriched scintillating bolometers for 0 ν ß ß decay investigations.

The CUPID-0 detector hosted at the Laboratori Nazionali del Gran Sasso, Italy, is the first large array of enriched scintillating cryogenic detectors for the investigation of 82 Se neutrinoless double-beta decay ( 0 ν ß ß ). CUPID-0 aims at measuring a background index in the region of interest (RoI) for 0 ν ß ß at the level of 10 - 3  counts/(keV kg years), the lowest value ever measured using cryogenic detectors. CUPID-0 operates an array of Zn 82 Se scintillating bolometers coupled with bolometric light detectors, with a state of the art technology for background suppression and thorough protocols and procedures for the detector preparation and construction. In this paper, the different phases of the detector design and construction will be presented, from the material selection (for the absorber production) to the new and innovative detector structure. The successful construction of the detector lead to promising preliminary detector performance which is discussed here.

Analysis of cryogenic calorimeters with light and heat read-out for double beta decay searches.

The suppression of spurious events in the region of interest for neutrinoless double beta decay will play a major role in next generation experiments. The background of detectors based on the technology of cryogenic calorimeters is expected to be dominated by α particles, that could be disentangled from double beta decay signals by exploiting the difference in the emission of the scintillation light. CUPID-0, an array of enriched Zn 82 Se scintillating calorimeters, is the first large mass demonstrator of this technology. The detector started data-taking in 2017 at the Laboratori Nazionali del Gran Sasso with the aim of proving that dual read-out of light and heat allows for an efficient suppression of the α background. In this paper we describe the software tools we developed for the analysis of scintillating calorimeters and we demonstrate that this technology allows to reach an unprecedented background for cryogenic calorimeters.

A low noise and high precision linear power supply with thermal foldback protection.

A low noise and high precision linear power supply was designed for use in rare event search experiments with macrobolometers. The circuit accepts at the input a "noisy" dual supply voltage up to ±15 V and gives at the output precise, low noise, and stable voltages that can be set between ±3.75 V and ±12.5 V in eight 1.25 V steps. Particular care in circuit design, component selection, and proper filtering results in a noise spectral density of 50nV/Hz at 1 Hz and 20nV/Hz white when the output is set to ±5 V. This corresponds to 125 nV RMS (0.8 µV peak to peak) between 0.1 Hz and 10 Hz, and 240 nV RMS (1.6 µV peak to peak) between 0.1 Hz and 100 Hz. The power supply rejection ratio (PSRR) of the circuit is 100 dB at low frequency, and larger than 40 dB up to high frequency, thanks to a proper compensation design. Calibration allows to reach a precision in the absolute value of the output voltage of ±70 ppm, or ±350 µV at ±5 V, and to reduce thermal drifts below ±1 ppm/(∘)C in the expected operating range. The maximum peak output current is about 6 A from each output. An original foldback protection scheme was developed that dynamically limits the maximum output current to keep the temperature of the output transistors within their safe operating range. An add-on card based on an ARM Cortex-M3 microcontroller is devoted to the monitoring and control of all circuit functionalities and provides remote communication via CAN bus.

First array of enriched Zn[Formula: see text]Se bolometers to search for double beta decay.

The R&D activity performed during the last years proved the potential of ZnSe scintillating bolometers to the search for neutrino-less double beta decay, motivating the realization of the first large-mass experiment based on this technology: CUPID-0. The isotopic enrichment in [Formula: see text]Se, the Zn[Formula: see text]Se crystals growth, as well as the light detectors production have been accomplished, and the experiment is now in construction at Laboratori Nazionali del Gran Sasso (Italy). In this paper we present the results obtained testing the first three Zn[Formula: see text]Se crystals operated as scintillating bolometers, and we prove that their performance in terms of energy resolution, background rejection capability and intrinsic radio-purity complies with the requirements of CUPID-0.

Double-beta decay investigation with highly pure enriched [Formula: see text]Se for the LUCIFER experiment.

The LUCIFER project aims at deploying the first array of enriched scintillating bolometers for the investigation of neutrinoless double-beta decay of [Formula: see text]Se. The matrix which embeds the source is an array of ZnSe crystals, where enriched [Formula: see text]Se is used as decay isotope. The radiopurity of the initial components employed for manufacturing crystals, that can be operated as bolometers, is crucial for achieving a null background level in the region of interest for double-beta decay investigations. In this work, we evaluated the radioactive content in 2.5 kg of 96.3 % enriched [Formula: see text]Se metal, measured with a high-purity germanium detector at the Gran Sasso deep underground laboratory. The limits on internal contaminations of primordial decay chain elements of [Formula: see text]Th, [Formula: see text]U and [Formula: see text]U are respectively: [Formula: see text]61, [Formula: see text]110 and [Formula: see text]74 [Formula: see text]Bq/kg at 90 % C.L. The extremely low-background conditions in which the measurement was carried out and the high radiopurity of the [Formula: see text]Se allowed us to establish the most stringent lower limits on the half-lives of the double-beta decay of [Formula: see text]Se to 0[Formula: see text], 2[Formula: see text] and 2[Formula: see text] excited states of [Formula: see text]Kr of 3.4[Formula: see text]10[Formula: see text], 1.3[Formula: see text]10[Formula: see text] and 1.0[Formula: see text]10[Formula: see text] y, respectively, with a 90 % C.L.

HOLMES: The electron capture decay of [Formula: see text]Ho to measure the electron neutrino mass with sub-eV sensitivity.

The European Research Council has recently funded HOLMES, a new experiment to directly measure the neutrino mass. HOLMES will perform a calorimetric measurement of the energy released in the decay of [Formula: see text]Ho. The calorimetric measurement eliminates systematic uncertainties arising from the use of external beta sources, as in experiments with beta spectrometers. This measurement was proposed in 1982 by A. De Rujula and M. Lusignoli, but only recently the detector technological progress allowed to design a sensitive experiment. HOLMES will deploy a large array of low temperature microcalorimeters with implanted [Formula: see text]Ho nuclei. The resulting mass sensitivity will be as low as 0.4 eV. HOLMES will be an important step forward in the direct neutrino mass measurement with a calorimetric approach as an alternative to spectrometry. It will also establish the potential of this approach to extend the sensitivity down to 0.1 eV. We outline here the project with its technical challenges and perspectives.

TeO[Formula: see text] bolometers with Cherenkov signal tagging: towards next-generation neutrinoless double-beta decay experiments.

CUORE, an array of 988 TeO[Formula: see text] bolometers, is about to be one of the most sensitive experiments searching for neutrinoless double-beta decay. Its sensitivity could be further improved by removing the background from [Formula: see text] radioactivity. A few years ago it was pointed out that the signal from [Formula: see text]s can be tagged by detecting the emitted Cherenkov light, which is not produced by [Formula: see text]s. In this paper we confirm this possibility. For the first time we measured the Cherenkov light emitted by a CUORE crystal, and found it to be 100 eV at the [Formula: see text]-value of the decay. To completely reject the [Formula: see text] background, we compute that one needs light detectors with baseline noise below 20 eV RMS, a value which is 3-4 times smaller than the average noise of the bolometric light detectors we are using. We point out that an improved light detector technology must be developed to obtain TeO[Formula: see text] bolometric experiments able to probe the inverted hierarchy of neutrino masses.