4,649 research outputs found

    Image_2_Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial.jpeg

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    BackgroundRetreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening.MethodsPatients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing.ResultsA total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAFV600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS, NRAS, and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRASQ61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (p = 0.12). Among the 133 patients with RAS/BRAFV600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA, FBXW7, GNAS, MAP2K, ERBB2, BRAF (class I and II non-BRAFV600E), SMAD, EGFR, AKT1, and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients.ConclusionsThis is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.</p

    S2 File -

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    The administration of painful primes has been shown to influence the perception of successively presented semantic stimuli. Painful primes lead to more negative valence ratings of pain-related, negative, and positive words than no prime. This effect was greater for pain-related than negative words. The identities of this effect’s neural correlates remain unknown. In this EEG experiment, 48 healthy subjects received noxious electrical stimuli of moderate intensity. During this priming, they were presented with adjectives of variable valence (pain-related, negative, positive, and neutral). The triggered event-related potentials were analyzed during N1 (120–180 ms), P2 (170–260 ms), P3 (300–350 ms), N400 (370–550 ms), and two late positive complex components (LPC1 [650–750 ms] and LPC2 [750–1000 ms]). Larger event-related potentials were found for negative and pain-related words compared to positive words in later components (N400, LPC1, and LPC2), mainly in the frontal regions. Early components (N1, P2) were less affected by the word category but were by the prime condition (N1 amplitude was smaller with than without painful stimulation, P2 amplitude was larger with than without painful stimulation). Later components (LPC1, LPC2) were not affected by the prime condition. An interaction effect involving prime and word category was found on the behavioral level but not the electrophysiological level. This finding indicates that the interaction effect does not directly translate from the behavioral to the electrophysiological level. Possible reasons for this discrepancy are discussed.</div

    Grand averages and topographic maps for late potentials.

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    Left: Grand average ERPs from the right frontal electrode F4 for all word categories. Right: Topographic maps of the time intervals of N400, LPC1, and LPC2 for trials with pain-related words. Note the activity shift from left to right frontal regions between LPC1 and LPC2.</p

    Neural correlates of word processing influenced by painful primes.

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    The administration of painful primes has been shown to influence the perception of successively presented semantic stimuli. Painful primes lead to more negative valence ratings of pain-related, negative, and positive words than no prime. This effect was greater for pain-related than negative words. The identities of this effect's neural correlates remain unknown. In this EEG experiment, 48 healthy subjects received noxious electrical stimuli of moderate intensity. During this priming, they were presented with adjectives of variable valence (pain-related, negative, positive, and neutral). The triggered event-related potentials were analyzed during N1 (120-180 ms), P2 (170-260 ms), P3 (300-350 ms), N400 (370-550 ms), and two late positive complex components (LPC1 [650-750 ms] and LPC2 [750-1000 ms]). Larger event-related potentials were found for negative and pain-related words compared to positive words in later components (N400, LPC1, and LPC2), mainly in the frontal regions. Early components (N1, P2) were less affected by the word category but were by the prime condition (N1 amplitude was smaller with than without painful stimulation, P2 amplitude was larger with than without painful stimulation). Later components (LPC1, LPC2) were not affected by the prime condition. An interaction effect involving prime and word category was found on the behavioral level but not the electrophysiological level. This finding indicates that the interaction effect does not directly translate from the behavioral to the electrophysiological level. Possible reasons for this discrepancy are discussed

    Valence ratings for the factors prime and category.

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    Data are shown as mean (SE); ***: p < 0.001, **: p < 0.01.</p

    Fig 5 -

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    ERPs for different regions (top: N1, bottom: P2). Data are shown as mean ÎĽV (SE); ***: p < 0.001, **: p < 0.01, *: p < 0.05.</p

    S1 File -

    No full text
    The administration of painful primes has been shown to influence the perception of successively presented semantic stimuli. Painful primes lead to more negative valence ratings of pain-related, negative, and positive words than no prime. This effect was greater for pain-related than negative words. The identities of this effect’s neural correlates remain unknown. In this EEG experiment, 48 healthy subjects received noxious electrical stimuli of moderate intensity. During this priming, they were presented with adjectives of variable valence (pain-related, negative, positive, and neutral). The triggered event-related potentials were analyzed during N1 (120–180 ms), P2 (170–260 ms), P3 (300–350 ms), N400 (370–550 ms), and two late positive complex components (LPC1 [650–750 ms] and LPC2 [750–1000 ms]). Larger event-related potentials were found for negative and pain-related words compared to positive words in later components (N400, LPC1, and LPC2), mainly in the frontal regions. Early components (N1, P2) were less affected by the word category but were by the prime condition (N1 amplitude was smaller with than without painful stimulation, P2 amplitude was larger with than without painful stimulation). Later components (LPC1, LPC2) were not affected by the prime condition. An interaction effect involving prime and word category was found on the behavioral level but not the electrophysiological level. This finding indicates that the interaction effect does not directly translate from the behavioral to the electrophysiological level. Possible reasons for this discrepancy are discussed.</div

    Design of the experimental trials with painful stimulation.

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    The adjective used in the figure and the scale were translated from German to English for illustration. In control trials, the timing was the same but without painful stimulation.</p

    Image_4_Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial.jpeg

    No full text
    BackgroundRetreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening.MethodsPatients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing.ResultsA total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAFV600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS, NRAS, and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRASQ61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (p = 0.12). Among the 133 patients with RAS/BRAFV600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA, FBXW7, GNAS, MAP2K, ERBB2, BRAF (class I and II non-BRAFV600E), SMAD, EGFR, AKT1, and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients.ConclusionsThis is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.</p

    Progetto di un ADC SAR di tipo loop unrolled per impiego in reti neurali fotoniche

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    Progetto di un ADC SAR di tipo loop unrolled per impiego in reti neurali fotoniche. Viene sviluppato un convertitore analogico digitale su ambiente Cadence Virtuoso con non linearità integrata direttamente nel componente. Nello specifico il tipo di funzione non lineare scelta è una tangente iperbolica. Il sistema funziona ad frequenza di 200Mhz ed è dotato di una risoluzione di 6 bit
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