Publications by authors named "Marco Gobbi"

283 Publications

Inhibitors of A Disintegrin And Metalloproteinases-10 reduce Hodgkin lymphoma cell growth in 3D microenvironments and enhance brentuximab-vedotin effect.

Haematologica 2021 Jun 10. Epub 2021 Jun 10.

Division of Immunology, Transplants and Infectious Diseases, IRCCS San Raffaele Scientific Institute.

Shedding of A Disintegrin And Metalloproteinases (ADAM10) substrates, like TNFα or CD30, can affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. We have published two new ADAM10 inhibitors, LT4 and MN8 able to prevent such shedding in Hodgkin lymphoma (HL). Since tumor tissue architecture deeply influence the outcome of anti-cancer treatments, we set up new three-dimensional (3D) culture systemsto verify whether ADAM10 inhibitors can contribute to, or enhance, the anti-lymphoma effects of the ADC brentuximab-vedotin (BtxVed).To recapitulate some aspects of lymphoma structure and architecture, we assembled two 3D culture models: mixed spheroids made of HL lymph node (LN) mesenchymal stromal cells (MSC) and Reed Sternberg/Hodgkin lymphoma cells (HL cells) or collagen scaffolds repopulated with LN-MSC and HL cells. In these 3D systems we found that: 1) the ADAM10 inhibitors LT4 and MN8 reduce ATP content or glucose consumption, related to cell proliferation, increasing lactate dehydrogenase (LDH) release as a cell damage hallmark; 2) these events are paralleled by mixed spheroids size reduction and inhibition of CD30 and TNFα shedding; 3) the effects observed can be reproduced in repopulated HL LN-derived matrix or collagen scaffolds; 4) ADAM10 inhibitors enhance the antilymphoma effect of the anti-CD30 ADC BtxVed both in conventional cultures and in repopulated scaffolds. Thus, we provide evidence for direct and combined anti-lymphoma effect of ADAM10 inhibitors with BtxVed, leading to improvement of ADC effects; this is documented in 3D models recapitulating features of LN microenvironment, that can be proposed as reliable tool for antilymphoma drug testing.
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http://dx.doi.org/10.3324/haematol.2021.278469DOI Listing
June 2021

Non-phosphorylated Tau slows down Aβ aggregation, binds to Aβ oligomers and reduces Aβ toxicity.

J Biol Chem 2021 Apr 15:100664. Epub 2021 Apr 15.

Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. Electronic address:

The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer's disease (AD). Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, while plaques comprise fibrillar forms of amyloid-β (Aβ). Both form toxic oligomers during aggregation, and are thought to interact synergistically to each promote the accumulation of the other. Recent in vitro studies have suggested that the monomeric non-phosphorylated full-length tau protein hinders the aggregation of Aβ peptide, but whether the same is true for the more aggregation-prone Aβ was not determined. We used in vitro and in vivo techniques to explore this question. We have monitored the aggregation kinetics of Aβ by thioflavine T fluorescence in the presence or absence of different concentrations of non-phosphorylated tau. We observed that elongation of Aβ fibrils was inhibited by tau in a dose-dependent manner. Interestingly, the fibrils were structurally different in the presence of tau, but did not incorporate tau. Surface plasmon resonance indicated that tau monomers bound to Aβ oligomers (but not monomers) and hindered their interaction with the anti-Aβ antibody 4G8, suggesting that tau binds to the hydrophobic central core of Aβ recognized by 4G8. Tau monomers also antagonized the toxic effects of Aβ oligomers in Caenorhabditis elegans. This suggests that non-phosphorylated tau might have a neuroprotective effect by binding Aβ oligomers formed during the aggregation and shielding their hydrophobic patches.
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http://dx.doi.org/10.1016/j.jbc.2021.100664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113980PMC
April 2021

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

Crit Care 2021 03 19;25(1):113. Epub 2021 Mar 19.

Department of Cardiovascular Medicine, Mario Negri Institute for Pharmacological Research IRCCS, Via Mario Negri 2, 20156, Milan, Italy.

Background: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock.

Methods: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization.

Results: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points.

Conclusion: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time.

Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.
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http://dx.doi.org/10.1186/s13054-021-03545-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980645PMC
March 2021

Analysis of External and Internal Disorder to Understand Band-Like Transport in n-Type Organic Semiconductors.

Adv Mater 2021 Apr 25;33(13):e2007870. Epub 2021 Feb 25.

Université de Strasbourg, CNRS, ISIS UMR 7006, 8 allée Gaspard Monge, Strasbourg, 67000, France.

Charge transport in organic semiconductors is notoriously extremely sensitive to the presence of disorder, both internal and external (i.e., related to interactions with the dielectric layer), especially for n-type materials. Internal dynamic disorder stems from large thermal fluctuations both in intermolecular transfer integrals and (molecular) site energies in weakly interacting van der Waals solids and sources transient localization of the charge carriers. The molecular vibrations that drive transient localization typically operate at low-frequency (
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http://dx.doi.org/10.1002/adma.202007870DOI Listing
April 2021

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions.

Oncogene 2021 Mar 2;40(9):1721-1736. Epub 2021 Feb 2.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.
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http://dx.doi.org/10.1038/s41388-021-01659-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932925PMC
March 2021

Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.

Neurology 2021 01 20. Epub 2021 Jan 20.

Gianluigi Mancardi Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa and Ospedale Policlinico San Martino, IRCCS, Genoa, Italy and IRCCS Scientific Clinical Institutes Maugeri, Pavia-Genoa Nervi/Italy.

Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.

Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.

Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.

Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.

Classification Of Evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.
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http://dx.doi.org/10.1212/WNL.0000000000011461DOI Listing
January 2021

Genetic Screening for Potential New Targets in Chronic Myeloid Leukemia Based on Drosophila Transgenic for Human BCR-ABL1.

Cancers (Basel) 2021 Jan 14;13(2). Epub 2021 Jan 14.

Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the () sequence and the () gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the transgenic as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression.
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http://dx.doi.org/10.3390/cancers13020293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830713PMC
January 2021

Multiscale Charge Transport in van der Waals Thin Films: Reduced Graphene Oxide as a Case Study.

ACS Nano 2021 Feb 19;15(2):2654-2667. Epub 2021 Jan 19.

Consiglio Nazionale delle Ricerche, Istituto per la Sintesi Organica e la Fotoreattività, (CNR-ISOF), via Gobetti 101, 40129 Bologna, Italy.

Large area van der Waals (vdW) thin films are assembled materials consisting of a network of randomly stacked nanosheets. The multiscale structure and the two-dimensional (2D) nature of the building block mean that interfaces naturally play a crucial role in the charge transport of such thin films. While single or few stacked nanosheets (., vdW heterostructures) have been the subject of intensive works, little is known about how charges travel through multilayered, more disordered networks. Here, we report a comprehensive study of a prototypical system given by networks of randomly stacked reduced graphene oxide 2D nanosheets, whose chemical and geometrical properties can be controlled independently, permitting to explore percolated networks ranging from a single nanosheet to some billions with room-temperature resistivity spanning from 10 to 10 Ω·m. We systematically observe a clear transition between two different regimes at a critical temperature *: Efros-Shklovskii variable-range hopping (ES-VRH) below * and power law behavior above. First, we demonstrate that the two regimes are strongly correlated with each other, both depending on the charge localization length ξ, calculated by the ES-VRH model, which corresponds to the characteristic size of overlapping sp domains belonging to different nanosheets. Thus, we propose a microscopic model describing the charge transport as a geometrical phase transition, given by the metal-insulator transition associated with the percolation of quasi-one-dimensional nanofillers with length ξ, showing that the charge transport behavior of the networks is valid for all geometries and defects of the nanosheets, ultimately suggesting a generalized description on vdW and disordered thin films.
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http://dx.doi.org/10.1021/acsnano.0c07771DOI Listing
February 2021

Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury.

Brain Behav Immun 2021 03 11;93:299-311. Epub 2021 Jan 11.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.

C1 esterase inhibitor (C1INH) is known to exert its inhibitory effect by binding to several target proteases of the contact and complement systems. One of C1INH's targets comprise mannose-binding lectin (MBL), a critical player in post-stroke pathophysiology. We therefore explored the effects of recombinant human (rh) and plasma derived (pd) C1INH in C57BL/6J mice subjected to transient occlusion of the middle cerebral artery (tMCAo), receiving 15U/mouse of pd or rhC1INH intravenously, at reperfusion. We analyzed the compounds' (i)neuroprotective effects, (ii) plasma presence, (iii)effects on circulating and brain MBL, (iv)time course of endothelial deposition, and (v) effects on the formation of active complement products. rhC1INH-treated mice had neuroprotective effects, including reduced behavioral deficits and neuronal loss, associated with decreased MBL brain deposition and decreased formation of complement C4b active fragments. In contrast, pdC1INH did not show these neuroprotective effects despite its longer plasma residence time. We also analyzed the response to tMCAo in C1INH-deficient mice, observing a poorer ischemic outcome compared to the wild type mice, which could be partially prevented by rhC1INH administration. In conclusion, we show that rhC1INH exhibits stronger neuroprotective effects than the corresponding plasma-derived protein after experimental ischemia/reperfusion injury in the brain, placing it as a promising drug for stroke. Differential effects are likely related to more effective MBL inhibition which further confirms it as a useful pharmacological target for stroke.
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http://dx.doi.org/10.1016/j.bbi.2021.01.002DOI Listing
March 2021

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of -ITD in Mutated AML, Irrespectively of -ITD Allelic Burden.

Cancers (Basel) 2020 Dec 24;13(1). Epub 2020 Dec 24.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, 16132 Genova, Italy.

The mutations of and -ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an mutation reduces the negative prognostic impact of -ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the and/or -ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both mut ( < 0.05) and ELN 2017 risk score ( < 0.05) were significant predictors of survival. -mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant -ITD ( = 0.372), irrespective of -ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with mut and question the role of HSCT in 1st CR in mut patients with concomitant -ITD.
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http://dx.doi.org/10.3390/cancers13010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796342PMC
December 2020

Characterization of the neutralizing anti-emicizumab antibody in a patient with hemophilia A and inhibitor.

J Thromb Haemost 2021 03 1;19(3):711-718. Epub 2021 Feb 1.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The genetically engineered, humanized, bispecific monoclonal antibody emicizumab (Hemlibra) that mimics the cofactor activity of activated factor VIII (FVIII) has been approved for treatment of hemophilia A patients with and without inhibitor. In the pivotal premarketing clinical trials, emicizumab prophylaxis significantly reduced bleeding rates compared with previous treatments and was well tolerated. However, a consequence of this novel therapy may be the host immune response to a foreign protein.

Objective: Characterization of the neutralizing anti-emicizumab antibody associated with the loss of treatment efficacy.

Patient: A pediatric hemophilia A patient with inhibitor enrolled in the HAVEN2 (Study of Emicizumab Administered Subcutaneously (SC) in Pediatric Participants With Hemophilia A and Factor VIII (FVIII) Inhibitors) clinical trial.

Methods: The anti-emicizumab antibody has been characterized with Western blot and enzyme-linked immunosorbent assay (ELISA). The antibody was affinity purified and sequenced. Binding affinity to full-length and papain-digested emicizumab was analyzed using surface plasmon resonance and byo-layer interferometry.

Results: The neutralizing anti-emicizumab antibody was highly polyclonal with high-affinity binding mainly to the Fab portion of emicizumab with a small amount of binding to the Fc portion. Molecular interaction experiments between emicizumab and the purified antibody indicated the presence of at least two components with similar affinities.

Conclusions: Although the incidence of neutralizing anti-emicizumab antibody is rare, this study highlights the importance of a close monitoring and the need of a simple laboratory assay to promptly detect these antibodies in patients with a history of poor drug efficacy.
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http://dx.doi.org/10.1111/jth.15226DOI Listing
March 2021

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration.

Front Pharmacol 2020 26;11:591908. Epub 2020 Nov 26.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the () gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a "hot spot" for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.
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http://dx.doi.org/10.3389/fphar.2020.591908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725797PMC
November 2020

Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs.

J Am Heart Assoc 2020 12 8;9(24):e016494. Epub 2020 Dec 8.

Department of Anesthesiology, Intensive Care and Emergency Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (<0.0001). Histology showed less neuronal degeneration in the cortex (<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (<0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (<0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.
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http://dx.doi.org/10.1161/JAHA.120.016494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955395PMC
December 2020

Tailoring Superconductivity in Large-Area SingleLayer NbSe via Self-Assembled Molecular Adlayers.

Nano Lett 2021 Jan 4;21(1):136-143. Epub 2020 Dec 4.

CIC nanoGUNE BRTA, Donostia-San Sebastian, Basque Country 20018, Spain.

Two-dimensional transition metal dichalcogenides (TMDs) represent an ideal testbench for the search of materials by design, because their optoelectronic properties can be manipulated through surface engineering and molecular functionalization. However, the impact of molecules on intrinsic physical properties of TMDs, such as superconductivity, remains largely unexplored. In this work, the critical temperature () of large-area NbSe monolayers is manipulated, employing ultrathin molecular adlayers. Spectroscopic evidence indicates that aligned molecular dipoles within the self-assembled layers act as a fixed gate terminal, collectively generating a macroscopic electrostatic field on NbSe. This results in an ∼55% increase and a 70% decrease in depending on the electric field polarity, which is controlled via molecular selection. The reported functionalization, which improves the air stability of NbSe, is efficient, practical, up-scalable, and suited to functionalize large-area TMDs. Our results indicate the potential of hybrid 2D materials as a novel platform for tunable superconductivity.
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http://dx.doi.org/10.1021/acs.nanolett.0c03386DOI Listing
January 2021

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.

Lancet Haematol 2020 Dec;7(12):e861-e873

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.

Methods: In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484.

Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group.

Interpretation: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.

Funding: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.
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http://dx.doi.org/10.1016/S2352-3026(20)30323-9DOI Listing
December 2020

Fatal systemic toxoplasmosis in a 3-month-old young tibetan goat (Capra hircus).

BMC Vet Res 2020 Nov 4;16(1):423. Epub 2020 Nov 4.

Zooprophylactic Experimental Institute of Umbria and Marche "Togo Rosati", Via G. Salvemini, 1, 06126, Perugia, Italy.

Background: Toxoplasmosis is one of the most common parasitic infections in both humans and animals. It is a frequent cause of abortion and stillbirth in intermediate hosts, especially sheep and goats but rarely causes fatal clinical form in adult animals.

Case Presentation: In contrast, the study reports an unusual fatal case of toxoplasmosis in a young goat naturally infected with type II strain of Toxoplasma gondii. A three-month-old female goat was presented with dyspnea and died few days later. Grossly, lungs were firm, edematous and mottled with disseminated whitish areas. Generalized lymphadenopathy was found. The histopathological examination showed necrotic interstitial bronchopneumonia and necrotizing lymphadenitis with intralesional free and clustered within macrophages tachyzoites of T. gondii. DNA extracted from lungs and lymph nodes was positive for T. gondii by a fast qPCR. PCR-RFLP analysis and sequencing of GRA6 gene showed that the isolated strains belonged to type II genotype.

Conclusions: This is an unusual report of acute systemic toxoplasmosis caused by the type II strain of T. gondii with a fatal outcome in a young goat.
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http://dx.doi.org/10.1186/s12917-020-02641-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640701PMC
November 2020

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.

I is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
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http://dx.doi.org/10.3390/ijms21207674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589297PMC
October 2020

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs.

Haematologica 2020 10 1;105(10):2420-2431. Epub 2020 Oct 1.

University of Genoa, DiMI; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.
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http://dx.doi.org/10.3324/haematol.2019.224956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556675PMC
October 2020

Graphene transistors for real-time monitoring molecular self-assembly dynamics.

Nat Commun 2020 Sep 18;11(1):4731. Epub 2020 Sep 18.

University of Strasbourg, CNRS, ISIS UMR 7006, 8 allée Gaspard Monge, 67000, Strasbourg, France.

Mastering the dynamics of molecular assembly on surfaces enables the engineering of predictable structural motifs to bestow programmable properties upon target substrates. Yet, monitoring self-assembly in real time on technologically relevant interfaces between a substrate and a solution is challenging, due to experimental complexity of disentangling interfacial from bulk phenomena. Here, we show that graphene devices can be used as highly sensitive detectors to read out the dynamics of molecular self-assembly at the solid/liquid interface in-situ. Irradiation of a photochromic molecule is used to trigger the formation of a metastable self-assembled adlayer on graphene and the dynamics of this process are monitored by tracking the current in the device over time. In perspective, the electrical readout in graphene devices is a diagnostic and highly sensitive means to resolve molecular ensemble dynamics occurring down to the nanosecond time scale, thereby providing a practical and powerful tool to investigate molecular self-organization in 2D.
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http://dx.doi.org/10.1038/s41467-020-18604-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501237PMC
September 2020

Bcl-xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms.

J Cell Mol Med 2020 09 13;24(18):10978-10986. Epub 2020 Aug 13.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

Myeloproliferative neoplasms are divided into essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Although ruxolitinib was proven to be effective in reducing symptoms, patients rarely achieve complete molecular remission. Therefore, it is relevant to identify new therapeutic targets to improve the clinical outcome of patients. Bcl-xL protein, the long isoform encoded by alternative splicing of the Bcl-x gene, acts as an anti-apoptotic regulator. Our study investigated the role of Bcl-xL as a marker of severity of MPN and the possibility to target Bcl-xL in patients. 129 MPN patients and 21 healthy patients were enrolled in the study. We analysed Bcl-xL expression in leucocytes and in enriched CD34+ and CD235a+ cells. Furthermore, ABT-737, a Bcl-xL inhibitor, was tested in HEL cells and in leucocytes from MPN patients. Bcl-xL was found progressively over-expressed in cells from ET, PV and PMF patients, independently by JAK2 mutational status. Moreover, our data indicated that the combination of ABT-737 and ruxolitinib resulted in a significantly higher apoptotic rate than the individual drug. Our study suggests that Bcl-xL plays an important role in MPN independently from JAK2 V617F mutation. Furthermore, data demonstrate that targeting simultaneously JAK2 and Bcl-xL might represent an interesting new approach.
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http://dx.doi.org/10.1111/jcmm.15730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521327PMC
September 2020

Strong Interfacial Exchange Field in a Heavy Metal/Ferromagnetic Insulator System Determined by Spin Hall Magnetoresistance.

Nano Lett 2020 Sep 29;20(9):6815-6823. Epub 2020 Aug 29.

CIC nanoGUNE BRTA, 20018 Donostia-San Sebastian, Basque Country, Spain.

Spin-dependent transport at heavy metal/magnetic insulator interfaces is at the origin of many phenomena at the forefront of spintronics research. A proper quantification of the different interfacial spin conductances is crucial for many applications. Here, we report the first measurement of the spin Hall magnetoresistance (SMR) of Pt on a purely ferromagnetic insulator (EuS). We perform SMR measurements in a wide range of temperatures and fit the results by using a microscopic model. From this fitting procedure, we obtain the temperature dependence of the spin conductances (, , and ), disentangling the contribution of field-like torque (), damping-like torque (), and spin-flip scattering (). An interfacial exchange field of the order of 1 meV acting upon the conduction electrons of Pt can be estimated from , which is at least three times larger than below the Curie temperature. Our work provides an easy method to quantify this interfacial spin-splitting field, which plays a key role in emerging fields such as superconducting spintronics and caloritronics as well as topological quantum computation.
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http://dx.doi.org/10.1021/acs.nanolett.0c02834DOI Listing
September 2020

A portable optical-fibre-based surface plasmon resonance biosensor for the detection of therapeutic antibodies in human serum.

Sci Rep 2020 07 7;10(1):11154. Epub 2020 Jul 7.

Department of Biochemistry and Molecular Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20157, Milan, Italy.

Different lines of evidence indicate that monitoring the blood levels of therapeutic antibodies, characterized by high inter-individual variability, can help to optimize clinical decision making, improving patient outcomes and reducing costs with these expensive treatments. A surface plasmon resonance (SPR)-based immunoassay has recently been shown to allow highly reliable and robust monitoring of serum concentrations of infliximab, with significant advantages over classical ELISA. The next level of advancement would be the availability of compact and transportable SPR devices suitable for easy, fast and cheap point-of-care analysis. Here we report the data obtained with recently developed, cost-effective, optical-fibre-based SPR sensors (SPR-POF), which allow the construction of a compact miniaturized system for remote sensing. We carried out an extensive characterization of infliximab binding to an anti-infliximab antibody immobilized on the SPR-POF sensor surface. The present proof-of-principle studies demonstrate the feasibility of the proposed SPR-POF platform for the specific detection of infliximab, in both buffer and human serum, and pave the way for further technological improvements.
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http://dx.doi.org/10.1038/s41598-020-68050-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341820PMC
July 2020

Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Standard of Care for Relapsing-Remitting Multiple Sclerosis Patients.

Neurol Ther 2020 Dec 16;9(2):197-203. Epub 2020 Jun 16.

SSD Terapia oncoematologica intensiva e trapianto CSE, AOU San Luigi Gonzaga, Dipartimento di Scienze Cliniche e Biologiche, University of Turin, Turin, Italy.

Autologous hematopoietic stem cell transplantation (AHSCT) has been used in the treatment of highly active multiple sclerosis (MS) for over two decades. It has been demonstrated to be highly efficacious in relapsing-remitting (RR) MS patients failing to respond to disease-modifying drugs (DMDs). AHSCT guarantees higher rates of no evidence of disease activity (NEDA) than those achieved with any other DMDs, but it is also associated with greater short-term risks which have limited its use. In the 2019 updated EBMT and ASBMT guidelines, which review the clinical evidence of AHSCT in MS, AHSCT indication for highly active RRMS has changed from "clinical option" to "standard of care". On this basis, AHSCT must be proposed on equal footing with second-line DMDs to patients with highly active RRMS, instead of being considered as a last resort after failure of all available treatments. The decision-making process requires a close collaboration between transplant hematologists and neurologists and a full discussion of risk-benefit of AHSCT and alternative treatments. In this context, we propose a standardized protocol for decision-making and informed consent process.
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http://dx.doi.org/10.1007/s40120-020-00200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606396PMC
December 2020

LC-MS/MS analyses of bile and histological analyses of thymus as diagnostic tools to detect low dose dexamethasone illicit treatment in beef cattle at slaughterhouse.

Steroids 2020 08 25;160:108671. Epub 2020 May 25.

Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche "Togo Rosati", 06126 - Perugia, Italy. Electronic address:

Dexamethasone (DXM) is a synthetic adrenal corticosteroid with anti-inflammatory properties used for therapeutic purposes in a wide range of pathologies and of the most common corticosteroids used for anabolic purposes in beef cattle. It is proven that DXM induces histological changes, traceable as increasing fatty infiltration of the thymus associated with a concurrent decrease of the cortex-medulla ratio, so the histological examination of the thymus gland has been established as an indirect morphological biomarker. The aim of the present study is to compare thymus histology and DXM concentrations in biological fluids collected at slaughterhouse after 1 month of DXM treatment. Our findings demonstrate that a low dosage of DXM administered to 12 months-old-Chianina beef cattle induces severe thymic atrophy with concurrent reduction of the cortex/medulla ratio, demonstrable even when DXM residues are not found in serum and urine samples. It is worth to note that, at the slaughterhouse, DXM residues are detectable in bile samples, indicating the ability of this biological fluid to bio-concentrate the administered drug if compared to serum and urine. Therefore, bile could be candidates as new liquid matrix for the screening programs planned to contrast the illegal use of anabolic substances.
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http://dx.doi.org/10.1016/j.steroids.2020.108671DOI Listing
August 2020

Detection of a gE-deleted Pseudorabies virus strain in an Italian red fox.

Vet Microbiol 2020 May 11;244:108666. Epub 2020 Apr 11.

Diagnostic Laboratory of Fermo, Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche, Contrada San Martino, 6/A, 63023 Fermo, Italy.

This study describes an Aujeszky's disease case in an adult male red fox found in an urban area in Central Italy, that exhibited a fatal infection with neurological lesions, but neither itching nor skin lesions. Diagnostic examinations included histology, and parasitological, bacteriological and virological analyses. Detection of parasitic enteric pathogens, bacteria, E. coli, Leptospira spp., rabies, canine distemper virus, parvovirus, hepatitis E virus and pseudorabies virus (PrV) was performed. Results showed the presence of a gE-deleted PrVthat was closely related to the NIA-3 strain but differed from the PrV strains currently circulating in wild boars and domestic pigs in Italy. All the results led to the conclusion that the fox suffered from Aujeszky's disease caused by a gE-deleted PrV strain closely related to a vaccine strain. The epidemiological link between the PrV vaccine strain and fox infection remains unclear. It could involve vaccinated pigs as a primary source of infection by direct or indirect contact with the red fox or less likely it could be related to improper use of the vaccine in the fox.
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http://dx.doi.org/10.1016/j.vetmic.2020.108666DOI Listing
May 2020

Prognostic relevance of a blastic plasmacytoid dendritic cell neoplasm-like immunophenotype in cytogenetically normal acute myeloid leukemia patients.

Leuk Lymphoma 2020 07 18;61(7):1695-1701. Epub 2020 Mar 18.

Department of Oncology and Hematology, Ospedale Policlinico San Martino, Genoa, Italy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a poor prognosis myeloid malignancy characterized by an atypical phenotype (CD123+, CD56+, and CD4+). We reported that BPDCN-like phenotype (CD123+ and either CD56+ or CD4+ or both) confers poor prognosis to acute myeloblastic leukemia (AML) patients with mutated NPM1. Here, we evaluated the incidence and the prognostic relevance of BPDCN-like phenotype in cytogenetically normal AML (CN-AML) patients. From 2006 to 2016, 83 young (age <60 yrs), consecutive, CN-AML patients underwent intensive treatment. Fifteen patients (18%) showed a BPDCN-like phenotype with no difference between -mutated (mut) and -wt patients. It did not significantly affect survival neither in the whole cohort, nor in -wt patients. However, as reported, it conferred a dismal prognosis in -mut AML ( < 0.001), irrespectively of the mutational status for FLT3-ITD. In conclusion we show that BPDCN-like phenotype displays a negative prognostic relevance only in -mutated AML.
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http://dx.doi.org/10.1080/10428194.2020.1737685DOI Listing
July 2020

Highly Sensitive Detection of Mutations in Acute Myeloid Leukemia.

J Clin Med 2020 Jan 19;9(1). Epub 2020 Jan 19.

Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano (Turin), Italy.

Background: Acute myeloid leukemia is a heterogeneous hematological disease, characterized by karyotypic and molecular alterations. Mutations in have a role in diagnosis and as a minimal residue disease marker. Often the variant allele frequency during follow up is less than 20%, which represents the limit of detection of Sanger sequencing. Therefore, the development of sensitive methodologies to identify mutations might help to monitor patients' response to therapy. We compared three different methods to identify and monitor mutations in patients' specimens.

Methods: Performances of PNA-PCR clamping, droplet digital PCR and Sanger for status identification were evaluated and compared in 96 DNA patients' specimens.

Results: In contrast with Sanger sequencing, our results highlighted the concordance between PNA clamping and digital PCR. Furthermore, PNA-PCR clamping was able to detect more mutated DNA with respect to Sanger sequencing that showed several false negatives independently from the allelic frequency.

Conclusions: We found that PNA-PCR clamping and digital PCR identified mutations in DNA samples with comparable results in a percentage significantly higher compared to Sanger sequencing. PNA-PCR clamping can be used even in laboratories not equipped for sophisticated analyses, decreasing cost and time for characterization.
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http://dx.doi.org/10.3390/jcm9010271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019902PMC
January 2020

Efficacy of Cholesterol Nose-to-Brain Delivery for Brain Targeting in Huntington's Disease.

ACS Chem Neurosci 2020 02 7;11(3):367-372. Epub 2020 Jan 7.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milan , Italy.

The current pharmacological treatment of Huntington's disease (HD) is palliative, and therapies to restore functions in patients are needed. One of the pathways affected in HD involves brain cholesterol (Chol) synthesis, which is essential for optimal synaptic transmission. Recently, it was reported that in a HD mouse model, the delivery of exogenous Chol to the brain with brain-permeable nanoparticles protected animals from cognitive decline and rescued synaptic communication, indicating Chol as a therapeutic candidate. We examined whether nose-to-brain delivery, already used in human therapy, could be an alternative, noninvasive strategy to deliver Chol to the adult brain and, in the future, replenish Chol in the HD brain. We gave wild-type (WT) mice a single intranasal (IN) dose of liposomes loaded with deuterium-labeled cholesterol (Chol-D6, to distinguish and quantify the exogenous cholesterol from the native one) (200 μg Chol-D6/dose). After different intervals, Chol-D6 levels, determined by LC-MS in plasma, striatum, cortex, and cerebellum, reached a steady-state concentration of 0.400 ng/mg between 24 and 72 h. A subsequent acute study confirmed the kinetic profiles of Chol-D6 in all tissues, indicating correspondence between the dose (two doses of 200 μg Chol-D6/dose) and the calculated brain area concentration (0.660 ng/mg). Finally, in WT mice given repeated IN doses, the average Chol-D6 level after 24 h was about 1.5 ng/mg in all brain areas. Our data indicate the effectiveness of IN Chol-loaded liposomes to deliver Chol in different brain regions, opening the way to future investigations in HD mice.
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http://dx.doi.org/10.1021/acschemneuro.9b00581DOI Listing
February 2020

Rhino-Orbital-Cerebral Mucormycosis after Allogeneic Hematopoietic Stem Cell Transplantation and Isavuconazole Therapeutic Drug Monitoring during Intestinal Graft versus Host Disease.

Mediterr J Hematol Infect Dis 2019 1;11(1):e2019061. Epub 2019 Nov 1.

Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.

A diagnosis of rhino-orbital-cerebral mucormycosis was made in a 59-year-old man with a secondary acute myeloid leukemia a few days after hematopoietic stem cell transplantation. Prompt treatment with combined antifungal therapy (liposomal amphotericin B and isavuconazole) followed by a procedure of endoscopic sinus surgery resulted in the resolution of the infection. Therapeutic drug monitoring of isavuconazole was performed during the year of treatment showing an increment of plasma concentrations in correspondence with the improvement of intestinal GvHD, thus suggesting that in this or similar conditions TDM for isavuconazole can be of value. A literature review of cases of rhino-orbital-cerebral and rhino-cerebral mucormycosis in allogeneic hematopoietic stem cell transplant recipients was carried out.
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http://dx.doi.org/10.4084/MJHID.2019.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827600PMC
November 2019