Intense beam of metastable Muonium

Precision spectroscopy of the Muonium Lamb shift and fine structure requires a robust source of 2S Muonium. To date, the beam-foil technique is the only demonstrated method for creating such a beam in vacuum. Previous experiments using this technique were statistics limited, and new measurements would benefit tremendously from the efficient 2S production at a low energy muon ($<20$ keV) facility. Such a source of abundant low energy $\mathrm{\mu^+}$ has only become available in recent years, e.g. at the Low-Energy Muon beamline at the Paul Scherrer Institute. Using this source, we report on the successful creation of an intense, directed beam of metastable Muonium. We find that even though the theoretical Muonium fraction is maximal in the low energy range of $2-5$ keV, scattering by the foil and transport characteristics of the beamline favor slightly higher $\mathrm{\mu^+}$ energies of $7-10$ keV. We estimate that an event detection rate of a few events per second for a future Lamb shift measurement is feasible, enabling an increase in precision by two orders of magnitude over previous determinations

Naphthalenone polyketides produced by Neofusicoccum parvum , a fungus associated with grapevine Botriosphaeria dieback

A strain of Neofusicoccum parvum isolated from declining vines was pathogenic to grapevine cultivar Inzolia in Sicily. This strain produced some metabolites in liquid medium. Crude extract, through a bio-guided purification process, yielded four naphthalenone polyketides. They were identified by comparison with spectroscopic data and optical proprieties reported in literature as: (3S, 4S)-7-ethyl-3,4,8-trihydroxy-6-methoxy-3,4-dihydro-1-(2H)-naphthalenone, (3S*, 4S*)-3,4-dihydro-3,4,8-trihydroxy-7-(1-hydroxyethyl)-6-methoxy-1-(2H)-naphthalenone, (4S)-3,4-dihydro-4,8-dihydroxy-1-(2H)-naphthalenone, named botryosphaerones D and A, isosclerone, respectively, and (3S*,4S*)-3,4,5-trihydroxy-1-tetralone (1-4). Phytotoxic activity of the isolated compounds (1-4) was tested on grapevine leaves at using the leaf puncture assay. All tested compounds were phytotoxic, with botryosphaerone D showing the greatest activity. The phytotoxic effects decreased when treated leaves were exposed to light. All of the metabolites did not show in vitro antifungal activity against Diplodia seriata, Lasiodiplodia mediterranea, Neofusicoccum vitifusiforme, or Phytophthora citrophthora. This is the first report of in vitro production of botryosphaerones D and A, and 3,4,5-trihydroxy-1-tetralone by N. parvum

1472pimmunotherapy in elderly patients 75 yrs with advanced non small cell lung cancer nsclc a multicenter italian experience

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Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index

Background: Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score. Methods: We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012). Results: In the training cohort (n = 217), the median age was 69 years (range: 32–89), and the primary tumours were non–small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60–3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31–3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13–2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p &lt; 0.0001), PFS (p &lt; 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p &lt; 0.0001), PFS (p &lt; 0.0001) and ORR (p = 0.0006) within the external cohort. Conclusion: Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case–control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46–0.95], p = 0.0281), PFS (HR 0.65 [95% CI 0.48–0.89]; p = 0.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p = 0.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of ≥ 1 somatic DDR gene mutation was 20% and 24.5% (p = 0.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p = 0.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

Polymorphisms at codons 108 and 189 in murine PrP play distinct roles in the control of scrapie incubation time

Rona Barron - ORCID: 0000-0003-4512-9177 https://orcid.org/0000-0003-4512-9177Item not available from this repository.Susceptibility to transmissible spongiform encephalopathies (TSEs) is associated strongly with PrP polymorphisms in humans, sheep and rodents. In mice, scrapie incubation time is controlled by polymorphisms at PrP codons 108 (leucine or phenylalanine) and 189 (threonine or valine), but the precise role of each polymorphism in the control of disease is unknown. The L108F and T189V polymorphisms are present in distinct structural regions of PrP and thus provide an excellent model with which to investigate the role of PrP structure and gene variation in TSEs. Two unique lines of transgenic mice, in which 108F and 189V have been targeted separately into the endogenous murine Prnp a gene, have been produced. TSE inoculation of inbred lines of mice expressing all allelic combinations at codons 108 and 189 has revealed a complex relationship between PrP allele and incubation time. It has been established that both codons 108 and 189 control TSE incubation time, and that each polymorphism plays a distinct role in the disease process. Comparison of ME7 incubation times in mouse lines that are heterozygous at both codons has also identified a previously unrecognized intramolecular interaction between PrP codons 108 and 189.https://doi.org/10.1099/vir.0.80525-086pubpub

Regulating Factors of PrPres Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains

OBJECTIVE: The glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease. METHODS: PrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res). RESULTS: The regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD. INTERPRETATION: Regulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD