Glitches in Rotating Supersolids.

Glitches, spin-up events in neutron stars, are of prime interest, as they reveal properties of nuclear matter at subnuclear densities. We numerically investigate the glitch mechanism due to vortex unpinning using analogies between neutron stars and dipolar supersolids. We explore the vortex and crystal dynamics during a glitch and its dependence on the supersolid quality, providing a tool to study glitches from different radial depths of a neutron star. Benchmarking our theory against neutron-star observations, our work will open a new avenue for the quantum simulation of stellar objects from Earth.

Observation of vortices and vortex stripes in a dipolar condensate.

Quantized vortices are a prototypical feature of superfluidity that have been observed in multiple quantum gas experiments. But the occurrence of vortices in dipolar quantum gases-a class of ultracold gases characterized by long-range anisotropic interactions-has not been reported yet. Here we exploit the anisotropic nature of the dipole-dipole interaction of a dysprosium Bose-Einstein condensate to induce angular symmetry breaking in an otherwise cylindrically symmetric pancake-shaped trap. Tilting the magnetic field towards the radial plane deforms the cloud into an ellipsoid, which is then set into rotation. At stirring frequencies approaching the radial trap frequency, we observe the generation of dynamically unstable surface excitations, which cause angular momentum to be pumped into the system through vortices. Under continuous rotation, the vortices arrange into a stripe configuration along the field, in close agreement with numerical simulations.

Can Angular Oscillations Probe Superfluidity in Dipolar Supersolids?

Angular oscillations can provide a useful probe of the superfluid properties of a system. Such measurements have recently been applied to dipolar supersolids, which exhibit both density modulation and phase coherence, and for which robust probes of superfluidity are particularly interesting. So far, these investigations have been confined to linear droplet arrays, which feature relatively simple excitation spectra, but limited sensitivity to the effects of superfluidity. Here, we explore angular oscillations in systems with 2D structure which, in principle, have greater sensitivity to superfluidity. In both experiment and simulation, we find that the interplay of superfluid and crystalline excitations leads to a frequency of angular oscillations that remains nearly unchanged even when the superfluidity of the system is altered dramatically. This indicates that angular oscillation measurements do not always provide a robust experimental probe of superfluidity with typical experimental protocols.

Immunoreactivity against fibroblast growth factor 8 in alveolar rhabdomyosarcoma patients and its involvement in tumor aggressiveness.

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma characterized by a very poor prognosis when relapses occur after front-line therapy. Therefore, a major challenge for patients' management remains the identification of markers associated with refractory and progressive disease. In this context, cancer autoantibodies are natural markers of disease onset and progression, useful to unveil novel therapeutic targets. Herein, we matched autoantibody profiling of alveolar RMS (ARMS) patients with genes under regulatory control of PAX3-FOXO1 transcription factor and revealed fibroblast growth factor 8 (FGF8) as a novel ARMS tumor antigen of diagnostic, prognostic, and therapeutic potential. We demonstrated that high levels of FGF8 autoantibodies distinguished ARMS patients from healthy subjects and represented an independent prognostic factor of better event-free survival. FGF8 was overexpressed in ARMS tumors compared to other types of pediatric soft tissue sarcomas, acting as a positive regulator of cell signaling. Indeed, FGF8 was capable of stimulating ARMS cells migration and expression of pro-angiogenic and metastasis-related factors, throughout MAPK signaling activation. Of note, FGF8 was found to increase in recurrent tumors, independently of PAX3-FOXO1 expression dynamics. Risk of recurrence correlated positively with FGF8 expression levels at diagnosis and reduced FGF8 autoantibodies titer, almost as if to suggest a failure of the immune response to control tumor growth in recurring patients. This study provides evidence about the crucial role of FGF8 in ARMS and the protective function of natural autoantibodies, giving new insights into ARMS biology and laying the foundations for the development of new therapeutic strategies.

Autoantibody profiling of alveolar rhabdomyosarcoma patients unveils tumor-associated antigens with diagnostic and prognostic significance.

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive subtype of childhood cancer for which efficacious treatments are needed. Immunotherapy represents a new therapeutic opportunity to pursue, but it requires the identification of worthwhile tumor antigens. Herein, we exploited the capacity of ARMS autoantibodies to recognize tumor self-antigens, probing human protein microarrays with plasma from ARMS patients and healthy subjects. We assessed the autoantibody response in ARMS, validated data with independent techniques, and estimated autoantibodies diagnostic and prognostic significance by receiver-operator characteristic curves (ROC), uni- and multivariate analysis. Of the 48 tumor antigens identified, General Transcription Factor II-I (GTF2i) and Protocadherin Gamma Subfamily C5 (PCDHGC5) were selected as candidate targets to validate tumor-restricted antigen expression and autoantibody reactivity through an independent technique and wider cohort of cases. GTF2i and PCDHGC5 overexpression was observed in tumor tissues compared to normal counterparts, and anti-GTF2i and -PCDHGC5 autoantibodies were found able to distinguish ARMS patients from healthy subjects as well as cases with different histology. Moreover, low levels of PCDHGC5 autoantibodies characterized patients with worse event-free survival and proved to be an independent negative prognostic factor. This approach provided the first comprehensive autoantibody profile of ARMS, gave novel insights into the immune response of this malignancy and paved the way toward novel potential antibody-based therapeutic applications suitable to improve the survival of ARMS patients.

Two-dimensional supersolidity in a dipolar quantum gas.

Supersolid states simultaneously feature properties typically associated with a solid and with a superfluid. Like a solid, they possess crystalline order, manifesting as a periodic modulation of the particle density; but unlike a typical solid, they also have superfluid properties, resulting from coherent particle delocalization across the system. Such states were initially envisioned in the context of bulk solid helium, as a possible answer to the question of whether a solid could have superfluid properties1-5. Although supersolidity has not been observed in solid helium (despite much effort)6, ultracold atomic gases provide an alternative approach, recently enabling the observation and study of supersolids with dipolar atoms7-16. However, unlike the proposed phenomena in helium, these gaseous systems have so far only shown supersolidity along a single direction. Here we demonstrate the extension of supersolid properties into two dimensions by preparing a supersolid quantum gas of dysprosium atoms on both sides of a structural phase transition similar to those occurring in ionic chains17-20, quantum wires21,22 and theoretically in chains of individual dipolar particles23,24. This opens the possibility of studying rich excitation properties25-28, including vortex formation29-31, and ground-state phases with varied geometrical structure7,32 in a highly flexible and controllable system.

Integrating irinotecan in standard chemotherapy: A novel dose-density combination for high-risk pediatric sarcomas.

BACKGROUND: Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. METHODS: Between November 2013 and January 2020, 23 patients ≤25 years old were included in the study. Eleven patients newly diagnosed with metastatic disease received nine cycles of IrIVA (irinotecan-ifosfamide-vincristine-actinomycin D; ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on day 1, actinomycin D 1.5 mg/m2 on day 1, irinotecan 20 mg/m2 for 5 consecutive days starting on day 8) as first-line therapy. Two relapsed patients received IrIVA and 10 IrVAC (irinotecan-vincristine-actinomycin D-cyclophosphamide; cyclophosphamide 1.5 g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. RESULTS: Seventeen rhabdomyosarcomas, four Ewing sarcomas, two desmoplastic small round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. Thirteen patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195 days (range 170-231), 83.4% of cycles were administered on time or with a delay <1 week. With a median follow-up of 2.6 years (range 0.2-5.0), 12 patients are alive, nine complete remissions, three with the disease. CONCLUSIONS: A dose-density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.

Prognostic Value of Circulating IGFBP2 and Related Autoantibodies in Children with Metastatic Rhabdomyosarcomas.

Insulin-like growth factor-binding protein 2 (IGFBP2) is a tumor-associated protein measurable in patients' biopsies and blood samples. Increased IGFBP2 expression correlates with tumor severity in rhabdomyosarcoma (RMS). Thus, we examined the plasmatic IGFBP2 levels in 114 RMS patients and 15 healthy controls by ELISA assay in order to evaluate its value as a plasma biomarker for RMS. Additionally, we looked for the presence of a humoral response against IGBFP2 protein measurable by the production of anti-IGFBP2 autoantibodies. We demonstrated that both circulating IGFBP2 protein and autoantibodies were significantly higher in RMS patients with respect to controls and their combination showed a better discriminative capacity. IGFBP2 protein identified metastatic patients with worse event-free survival, whereas both IGFBP2 and anti-IGFBP2 antibodies negatively correlated with overall survival. Our study suggests that IGFBP2 and anti-IGFBP2 antibodies are useful for diagnostic and prognostic purposes, mainly as independent negative prognostic markers in metastatic patients. This is the first study that reports a specific humoral response in RMS plasma samples and proves the value of blood-based biomarkers in improving risk assessment and outcome of metastatic RMS patients.

NELL1, whose high expression correlates with negative outcomes, has different methylation patterns in alveolar and embryonal rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), which represents the most frequent soft tissue sarcoma in pediatric populations, is classified into two major subtypes: embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS subtype, which shows greater aggressiveness and proneness to metastasis with respect to ERMS, are characterized, in about 75% of cases, by specific chromosomal translocations that involve PAX and FOXO1 genes. Many findings have demonstrated that PAX/FOXO1-positive ARMS have a worse prognosis than PAX/FOXO1-negative ones and that distinct molecular features characterize RMS with different gene fusion statuses. DNA methylation, which presently represents a challenging research area, is involved in the modulation of gene expression.We performed a genome-wide DNA methylation analysis using reduced-representation bisulfite sequencing (RRBS) in RMS samples and we found that fusion-positive alveolar and embryonal subgroups have different DNA methylation signatures and that ARMS fusion-positive subtypes are characterized by overall hypomethylation levels. While NELL1 was found to be hypomethylated and transcriptionally enhanced in RMS alveolar subtypes, high NELL1 expression levels, which proved to be correlated with negative RMS prognostic factors such as fusion status and histology (P < 0.0001), were found to discriminate between RMS patients with different outcomes (P < 0.05).In conclusion, our results demonstrated that different DNA methylation patterns distinguish between different RMS subgroups and they suggest that epigenetic signatures could be useful for risk stratification of patients.

Understanding the Interplay between Expression, Mutation and Activity of ALK Receptor in Rhabdomyosarcoma Cells for Clinical Application of Small-Molecule Inhibitors.

BACKGROUND: Receptor tyrosine kinases (RTKs) have a central role in cancer initiation and progression, since changes in their expression and activity potentially results in cell transformation. This concept is essential from a therapeutic standpoint, as clinical evidence indicates that tumours carrying deregulated RTKs are particularly susceptible to their activity but also to their inhibition. Rhabdomyosarcoma (RMS) is an aggressive childhood cancer where emerging therapies rely on the use kinase inhibitors, and among druggable kinases ALK represents a potential therapeutic target to commit efforts against. However, the functional relevance of ALK in RMS is not known, likewise the multi-component deregulated RTK profile to which ALK belongs. METHODS: In this study we used RMS cell lines representative of the alveolar and embrional histotype and looked at ALK intracellular localization, activity and cell signalling. RESULTS: We found that ALK was properly located at the plasma membrane of RMS cells, though in an unphosphorylated and inactive state due to intracellular tyrosine phosphatases (PTPases) activity. Indeed, increase of ALK phosphorylation was observed upon PTPase inhibition, as well as after ligand binding or protein overexpression. In these conditions, ALK signalling proceeded through the MAPK/ERK and PI3K/AKT pathways, and it was susceptible to ATP-competitive inhibitors exposure. However, drug-induced growth inhibition, cell cycle arrest and apoptosis did not correlate with ALK expression only, but relied also on the expression of other RTKs with akin drug binding affinity. Indeed, analysis of baseline and inducible RTK phosphorylation confirmed that RMS cells were susceptible to ALK kinase inhibitors even in the absence of the primary intended target, due to the presence of compensatory RTKs signalling pathways. CONCLUSIONS: These data, hence, provided evidences of a potentially active role of ALK in RMS cells, but also suggest caution in considering ALK a major therapeutic target in this malignancy, particularly if expression and activity cannot be accurately determined.

DAX-1 Expression in Pediatric Rhabdomyosarcomas: Another Immunohistochemical Marker Useful in the Diagnosis of Translocation Positive Alveolar Rhabdomyosarcoma.

OBJECTIVES: The aim of this study was to investigate the expression of DAX-1 in a series of pediatric rhabdomyosarcomas (RMS) with known translocation and compare it to Ap2ß, known to be selectively expressed in ARMS. DESIGN: We revised a series of 71 alveolar rhabdomyosarcomas (ARMS), enrolled in the Italian Protocols RMS 79 and 96, and 23 embryonal rhabdomyosarcomas (ERMS) as controls. Before investigating Ap2ß and DAX-1, ARMS were reviewed and reclassified as 48 ARMS and 23 non-ARMS. RESULTS: Translocation positive ARMS showed a characteristic Ap2ß/DAX-1+ staining pattern in 78% of cases, while 76% of classic ERMS were negative for both. Ap2ß alone was positive in 3.9% of RMS lacking translocation, whereas DAX-1 alone was positive in 25.4%. Conversely, 9% and 6% of translocation positive ARMS were positive only for DAX-1 or Ap2ß, respectively. The 23 non-ARMS shared the same phenotype as ERMS but had a higher frequency of DAX-1 expression. CONCLUSIONS: DAX-1 is less specific than Ap2ß, however it is a sensitive marker for translocation positive ARMS and can be helpful in their diagnosis if used in combination with Ap2ß.

Comparative neuronal differentiation of self-renewing neural progenitor cell lines obtained from human induced pluripotent stem cells.

Most human neuronal disorders are associated with genetic alterations that cause defects in neuronal development and induce precocious neurodegeneration. In order to fully characterize the molecular mechanisms underlying the onset of these devastating diseases, it is important to establish in vitro models able to recapitulate the human pathology as closely as possible. Here we compared three different differentiation protocols for obtaining functional neurons from human induced pluripotent stem cells (hiPSCs): human neural progenitors (hNPs) obtained from hiPSCs were differentiated by co-culturing them with rat primary neurons, glial cells or simply by culturing them on matrigel in neuronal differentiation medium, and the differentiation level was compared using immunofluorescence, biochemical and electrophysiological methods. We show that the differentiated neurons displayed distinct maturation properties depending on the protocol used and the faster morphological and functional maturation was obtained when hNPs were co-cultured with rat primary neurons.

ATM-deficient human neural stem cells as an in vitro model system to study neurodegeneration.

Loss of ATM kinase, a transducer of the DNA damage response and redox sensor, causes the neurodegenerative disorder ataxia-telangiectasia (A-T). While a great deal of progress has been made in elucidating the ATM-dependent DNA damage response (DDR) network, a key challenge remains in understanding the selective susceptibility of the nervous system to faulty DDR. Several factors appear implicated in the neurodegenerative phenotype in A-T, but which of them plays a crucial role remains unclear, especially since mouse models of A-T do not fully mirror the respective human syndrome. Therefore, a number of human neural stem cell (hNSC) systems have been developed to get an insight into the molecular mechanisms of neurodegeneration as consequence of ATM inactivation. Here we review the hNSC systems developed by us an others to model A-T.

Brain and induced pluripotent stem cell-derived neural stem cells as an in vitro model of neurodegeneration in ataxia-telangiectasia.

The ataxia telangiectasia mutated (ATM) kinase is a key transducer of the cellular response to DNA double strand breaks and its deficiency causes ataxia-telangiectasia (A-T), a pleiotropic genetic disorder primarily characterized by cerebellar neuropathy, immunodeficiency and cancer predisposition. While enormous progress has been achieved in elucidating the biochemical and functional regulation of ATM in DNA damage response, and more recently in redox signalling and antioxidant defence, the factors that make neurons in A-T extremely vulnerable remain unclear. Given also that ATM knockout mice do not recapitulate the central nervous system phenotype, a number of human neural stem cell (hNSC) model systems have been developed to provide insights into the mechanisms of neurodegeneration associated with ATM dysfunction. Here we review the hNSC systems developed by us an others to model A-T.

A nonparametric procedure for defining a new humoral immunologic profile in a pilot study on HIV infected patients.

This work aims at identifying a set of humoral immunologic parameters that improve prediction of the activation process in HIV patients. Starting from the well-known impact of humoral immunity in HIV infection, there is still a lack of knowledge in defining the role of the modulation of functional activity and titers of serum antibodies from early stage of infection to the development of AIDS. We propose an integrated approach that combines humoral and clinical parameters in defining the host immunity, implementing algorithms associated with virus control. A number of humoral parameters were simultaneously evaluated in a whole range of serum samples from HIV-positive patients. This issue has been afforded accounting for estimation problems typically related to "feasibility" studies where small sample size in each group and large number of parameters are jointly estimated. We used nonparametric statistical procedures to identify biomarkers in our study which included 42 subjects stratified on five different stages of HIV infection, i.e., Elite Controllers (EC), Long Term Non Progressors (LTNP), HAART, AIDS and Acute Infection (AI). The main goal of the paper is to illustrate a novel profiling method for helping to design a further confirmatory study. A set of seventeen different HIV-specific blood humoral factors were analyzed in all subjects, i.e. IgG and IgA to gp120IIIB, to gp120Bal, to whole gp41, to P1 and T20 gp41 epitopes of the MPER-HR2 region, to QARILAV gp41 epitope of the HR1 region and to CCR5; neutralization activity against five different virus strains and ADCC were also evaluated. Patients were selected on the basis of CD4 cell counts, HIV/RNA and clinical status. The Classification and Regression Trees (CART) approach has been used to uncover specific patterns of humoral parameters in different stages of HIV disease. Virus neutralization of primary virus strains and antibodies to gp41 were required to classify patients, suggesting that clinical profiles strongly rely on functional activity against HIV.