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Giuseppe Palermo

Bio: Giuseppe Palermo is an academic researcher from Hoffmann-La Roche. The author has contributed to research in topics: Chronic lymphocytic leukemia & Leukemia. The author has an hindex of 7, co-authored 13 publications receiving 219 citations.

Papers
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Journal ArticleDOI
TL;DR: In blood and cerebrospinal fluid, mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations correlated with disease severity in HD patients and showed that alterations in circulating NfL and mHTT concentrations may be among the earliest detectable changes in HD.
Abstract: Huntington’s disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

127 citations

Journal ArticleDOI
TL;DR: No SNPs associated with treatment response to TNF&agr; inhibitors are found in a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis of available studies.
Abstract: OBJECTIVE Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. METHODS TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. RESULTS After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. CONCLUSION In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

68 citations

Journal ArticleDOI
TL;DR: D dose-escalation designs that incorporate both the dose-limiting events and dose- Limiting toxicities (DLTs) and indicative responses of efficacy into the procedure are introduced.
Abstract: The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

17 citations


Cited by
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Journal ArticleDOI
TL;DR: The therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.

645 citations

Journal ArticleDOI
TL;DR: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events and dose-dependent reductions in concentrations of mutant huntingtin were observed.
Abstract: Background Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTR...

378 citations

Journal ArticleDOI
TL;DR: New insights are discussed into the molecular pathogenesis of Huntington disease and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself are discussed.
Abstract: Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.

193 citations