486 research outputs found

    Pulse Shape Discrimination with a CLYC Crystal Read Out by SiPMs for Neutron Background Reduction in Prompt Gamma Range Monitoring

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    In the field of hadrontherapy, it is demonstrated that the Prompt Gamma (PG) measurements are strongly affected by the presence of a neutron background, which can limit the possibility to perform range monitoring, especially in the framework of Carbon ion therapy. This work is a first step towards the implementation of the Pulse Shape Discrimination (PSD) technique for neutron background reduction in PGI. A statistical analysis has been developed, that is intended to model the performances of a detection system based on the CLYC scintillator in performing Pulse Shape Discrimination, and a Figure Of Merit (FOM) of this detector is evaluated with respect to several parameters. This analysis serves the aim of deducing the optimal parameters to perform PSD, without having to carry out multiple experimental measures, and to assess if the obtained performances are sufficient to effectively perform neutron/gamma discrimination. Considering a setup made of a 1"x1" CLYC scintillator coupled to a NUV-HD SiPM tile the results show a good PSD capability even for low prompt gamma energies. An experimental setup is under development for the validation of the presented statistical analysis which presents a custom ASIC made for hadrontherapy applications

    Splenomegaly in patients with primary or secondary myelofibrosis who are candidates for allogeneic hematopoietic cell transplantation: a Position Paper on behalf of the Chronic Malignancies Working Party of the EBMT

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    : Splenomegaly is a hallmark of myelofibrosis, a debilitating haematological malignancy for which the only curative option is allogeneic haematopoietic cell transplantation (HCT). Considerable splenic enlargement might be associated with a higher risk of delayed engraftment and graft failure, increased non-relapse mortality, and worse overall survival after HCT as compared with patients without significantly enlarged splenomegaly. Currently, there are no standardised guidelines to assist transplantation physicians in deciding optimal management of splenomegaly before HCT. Therefore, the aim of this Position Paper is to offer a shared position statement on this issue. An international group of haematologists, transplantation physicians, gastroenterologists, surgeons, radiotherapists, and radiologists with experience in the treatment of myelofibrosis contributed to this Position Paper. The key issues addressed by this group included the assessment, prevalence, and clinical significance of splenomegaly, and the need for a therapeutic intervention before HCT for the control of splenomegaly. Specific scenarios, including splanchnic vein thrombosis and COVID-19, are also discussed. All patients with myelofibrosis must have their spleen size assessed before allogeneic HCT. Myelofibrosis patients with splenomegaly measuring 5 cm and larger, particularly when exceeding 15 cm below the left costal margin, or with splenomegaly-related symptoms, could benefit from treatment with the aim of reducing the spleen size before HCT. In the absence of, or loss of, response, patients with increasing spleen size should be evaluated for second-line options, depending on availability, patient fitness, and centre experience. Splanchnic vein thrombosis is not an absolute contraindication for HCT, but a multidisciplinary approach is warranted. Finally, prevention and treatment of COVID-19 should adhere to standard recommendations for immunocompromised patients

    SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

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    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence

    Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: comment

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    Implications of the Partial Ring Design for a Clinical SPECT Insert

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    The INSERT system is a stationary SPECT insert designed for clinical SPECT/MRI. The system has been evaluated as a standalone SPECT scanner and here the image reconstruction is evaluated to determine the implications of its design. A two-step image acquisition can be implemented to overcome the limitations of the partial ring design. The image quality and activity linearity are evaluated through a set of point sources and vials of varying activity concentration. The evaluation highlighted areas where image reconstruction and data processing needed to improve before proceeding to simultaneous SPECT/MRI acquisitions. We have shown that the proposed dual acquisition method can produce improved image quality through the use of modified data acquisition and reconstruction protocols

    A Statistical DOI Estimation Algorithm for a SiPM-Based Clinical SPECT Insert

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    A prototype clinical brain single-photon emission computed tomography (SPECT) insert has been designed for use in simultaneous SPECT/MRI. The system utilizes novel slit-slat collimators which, like pinhole collimators, suffers from parallax errors due to the large incident angle of photons. A statistical algorithm has been developed to determine the depth-of-interaction (DOI) with a view to improving image performance. The importance of DOI correction was demonstrated using Monte Carlo simulation. This simulation also indicated that four DOI layers ( 3Ă—1.5mm+3.5mm ) may be sufficient. The improvement in event localization was demonstrated on a single detector before implementing the algorithm on the full clinical prototype where some limitations in event localization in layers close to the readout plane were observed. Nevertheless, DOI enabled the rejection of poorly localized events with improved resolution in reconstructed line sources

    A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis

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    Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose,20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P 5.03), (2) palpable spleen length reduction from baseline #30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P 5.0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P 5.07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P 5.02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift

    Tissue fluidification promotes a cGAS–STING cytosolic DNA response in invasive breast cancer

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    : The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma

    Tissue fluidification promotes a cGAS-STING cytosolic DNA response in invasive breast cancer

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    : The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma
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