109 research outputs found
VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases
No full textVEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described pathological entity. It is an acquired monogenic autoinflammatory disease caused by somatic mutations of the UBA1 gene in blood cells precursors; the gene encodes one of the two E1 enzyme isoforms that initiates ubiquitylation in cell's cytoplasm. VEXAS syndrome leads to systemic inflammation, with all organs and tissues potentially involved. The clinical picture may be extremely heterogenous, mimicking different other systemic rheumatologic entities coexisting with haematological disorders, especially myelodysplastic syndrome. This new disease represents a very intriguing clinical condition in several respects: it accounts for the paradigm of adult-onset monogenic autoinflammatory diseases determined by a genetic mosaicism resulting in the development of a challenging multiorgan inflammatory condition. Moreover, VEXAS syndrome is perhaps not an exceptionally rare condition and represents an example of a systemic genetic autoinflammatory disease drawing its origin in bone marrow disorders. VEXAS syndrome should be strongly considered in each adult patient with an unexplained systemic inflammatory condition, especially when recurrent fevers, neutrophilic dermatosis, relapsing polychondritis, ocular inflammation and other systemic inflammatory symptoms accompanying myelodysplastic syndrome or other haematological disorders. The syndrome deserves a multidisciplinary approach to reach the diagnosis and ensure the best management of a potentially very challenging condition. To quickly describe the clinical course, long-term outcomes, and the optimal management of this new syndrome it is essential to join forces internationally. To this end, the international AutoInflammatory Disease Alliance (AIDA) registry dedicated to VEXAS syndrome has been developed and is already active. © 2023, The Author(s)
Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder
No full textGenetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable
Corrigendum: Spondyloocular syndrome: A novel XYLT2 variant with description of the neonatal phenotype
No full textPharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: two years experience in routine clinical practice
No full textOBJECTIVES: To assess the inter-individual and intra-individual plasma
concentration variabilities of non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to
investigate their relationships with virological failure.
METHODS: We retrospectively enrolled HIV-infected patients undergoing therapeutic
drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma
drug concentrations were measured by HPLC-UV and were considered therapeutic if
above the proposed minimum efficacy trough concentration. Inter-individual and
intra-individual variabilities were evaluated through the coefficient of
variation (CV).
RESULTS: A total of 457 PI and 172 NNRTI plasma concentrations were measured from
363 patients (HIV-RNA <50 copies/mL in 70.8%, median CD4 count 434 cells/mm(3)).
NNRTIs showed less inter-individual (CV(inter) 54.8% versus 84.3%) and
intra-individual (CV(intra) 19.0% versus 38.1%) pharmacokinetic variabilitie
Private somatic mutations identified with liquid biopsy lead tumor progression in solid cancers
No full textAim: Primary tumors can be divided into oncogene-addicted (e.g., lung) and non-oncogene addicted (e.g., breast). Only the former group has an Achilles-heel single gene for successful target therapy, whereas the latter has mutations of multiple causative genes. Currently, tissue biopsy used for genetic surveys do not give a complete picture of the molecular profile and clonal evolution, but only provide static information over time.Methods: A series of 133 patients with 16 different solid tumors were enrolled. Blood samples were collected and cell-free DNA (cfDNA) was extracted. cfDNA libraries were analyzed using AVENIO circulating tumor DNA (ctDNA) Expanded Kit and Illumina NextSeq 550 for sequencing was used. In order to evaluate the clinical evolution over time, a second cfDNA analysis was performed after a mean interval of 2 months.Results: Through the cfDNA liquid biopsy, we found 89 pathogenic variants in 54 genes. Breast, lung, and prostate cancers showed the largest number of mutated genes. TP53, PIK3CA, FGFR3, KRAS, and ERBB2 were the most frequently mutated genes among 16 different tumors. Gene distribution didn’t show any type of prevalence. In particular, every patient with disease progression seems to have a “private” combination of gene pair mutations, with TP53 as the most frequently mutated gene.Conclusion: We showed that the clonal evolution of tumors includes a private combination of genes, regardless of tumor type. In the future, the cancer treatment can be the targeted therapy against specific tumor mutation(s). The present approach seems promising to both identify key cancer genes and follow clonal evolution over time
High prevalence of Hepatic Steatosis in a cohort of People Living With HIV: exploring the role of metabolic and HIV-related factors
No full textThe Case of Formic Acid on Anatase TiO2(101): Where is the Acid Proton?
No full textCover graphics by Andrea Stangonifor the CommunicationThe case of formic acid on (101) anatase TiO2: where is the acid proton? Angew. Chem. Int. Ed. 2019, 58, 12431.By:Gloria Tabacchi, Marco Fabbiani, Lorenzo Mino, Gianmario Martra, Ettore Foisrdcu.be/bNMqYhttps://doi.org/10.1002/anie.201906709Short summary:https://link.growkudos.com/1l0q0u5e8lcSubmitted author version:https://figshare.com/articles/The_case_of_formic_acid_on_101_anatase_TiO2_where_is_the_acid_proton_/9206555Preprint on chemrXiv:https://chemrxiv.org/articles/Quantum_vs_Thermal_Effects_in_Formic_Acid_Adsorption_on_101_TiO2_Anatase_Surfaces/7797719</div
3-Year efficacy and durability of simplification to single tablet regimens: a comparison between co-formulated efavirenz/emtricitabine/tenofovir and rilpivirine/emtricitabine/tenofovir
No full textBACKGROUND:
Few data are available about efficacy and durability of simplification from multi-tablet antiretroviral regimens to co-formulated efavirenz (EFV)/emtricitabine (FTC)/tenofovir (TDF) versus rilpivirine (RPV)/FTC/TDF in virologically suppressed HIV-1-infected patients.
METHODS:
We retrospectively analysed HIV-infected patients with HIV RNA 50 copies/ml or a single determination >1,000 copies/ml) and their predictors were investigated.
RESULTS:
1,560 patients were reviewed of which 1,097 (70%) switched to EFV/FTC/TDF and 463 (30%) to RPV/FTC/TDF. During follow-up, VF and TD occurred in 44 (4%) and 242 (22%) patients in EFV/FTC/TDF and in 29 (6%) and 50 (11%) patients in RPV/FTC/TDF, respectively. The 3-year estimated probability of remaining free from VF was 96.2% with EFV/FTC/TDF versus 92.7% with RPV/FTC/TDF (P=0.003). At multivariate analysis, regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 0.24; P=0.004) and time of virological suppression (aHR 0.85; P=0.048) were the only independent predictors of VF. The estimated 3-year probability of remaining free from TD was 77.4% with EFV/FTC/TDF versus 88.4% with RPV/FTC/TDF (P=0.001). Predictors of TD were female sex, switching from PI-based regimens, older age, shorter time of virological suppression and regimen type (EFV/FTC/TDF versus RPV/FTC/TDF aHR 2.48; P<0.001). RPV/FTC/TDF showed a safer lipid profile and a greater increase in creatinine.
CONCLUSIONS:
Both regimens showed good safety and efficacy in this real-life setting, although switch to RPV/FTC/TDF seemed better tolerated while EFV/FTC/TDF was associated with a lower probability of VF
Evolution of blood-associated HIV-1 DNA levels after 48 weeks of switching to atazanavir/ritonavir+lamivudine dual therapy versus continuing triple therapy in the randomized AtLaS-M trial
No full textAbstract
OBJECTIVES:
The AtLaS-M randomized trial showed that in patients with HIV-1 RNA <50 copies/mL on atazanavir/ritonavir + two NRTIs, switching to a dual therapy with atazanavir/ritonavir+lamivudine had superior efficacy as compared with continuing the previous triple therapy. This substudy was designed to evaluate at 48 weeks the impact of the dual therapy versus the three-drug atazanavir/ritonavir-based therapy on the HIV-1 cellular reservoir as reflected by the quantification of blood-associated HIV-1 DNA levels.
METHODS:
In a representative subset of 201 of 266 randomized patients (104 in the dual-therapy arm and 97 in the triple-therapy arm) total HIV-1 DNA levels in whole blood at baseline and after 48 weeks and factors associated with the HIV-1 DNA levels were evaluated.
RESULTS:
The mean baseline HIV-1 DNA levels (2.47 log 10 copies/10 6 leucocytes) were comparable between arms. A significant mean decrease between baseline and week 48 was observed: -0.069 log 10 copies/10 6 leucocytes in the dual-therapy arm ( P = 0.046) and -0.078 in the triple-therapy arm ( P = 0.011); the mean difference between arms was -0.009 ( P = 0.842). Nadir CD4 count was inversely correlated with baseline HIV-1 DNA ( P = 0.009); longer duration of ART and lower nadir CD4 correlated with a less prominent HIV-1 DNA decrease (both P < 0.005). Higher baseline HIV-1 DNA was associated with residual viraemia at week 48 ( P = 0.031).
CONCLUSIONS:
When compared with continuing three-drug therapy, atazanavir/ritonavir+lamivudine dual therapy resulted in a similar decline in HIV-1 DNA levels in patients with sustained virological suppression. These data support the safety of this simplified treatment strategy in terms of its effect on the cellular HIV-1 reservoi
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