The Nucleon's Virtual Meson Cloud and Deep Inelastic Lepton Scattering

We address the question whether the nucleon's antiquark sea can be attributed entirely to its virtual meson cloud and, in essence, whether there exists a smooth transition between hadronic and quark-gluon degrees of freedom. We take into account contributions from $\pi$ and $K$ mesons and compare with the nucleon's antiquark distributions which serve as a non-perturbative input to the QCD evolution equations. We elucidate the different behavior in the flavor singlet and non-singlet channels and study the dependence of our results on the scale $Q^2$. The meson-nucleon cut-offs that we determine give not only an indication on the size of the region within which quarks are confined in a nucleon, but we find that the scale of these form factors is closely related to the four-momentum transfer, $Q^2$, where gluons are resolved by a high energy probe, and that large meson loop momenta, $|{\bf k}| \approx 0.8$ GeV, contribute significantly to the sea quark distributions. While the agreement of our calculations with data-based parametrizations is satisfactory and scale independent for the flavor breaking share of the nucleon's antiquark sea, the flavor singlet component is quite poorly described. This hints the importance of gluon degrees of freedom.Comment: 34 pages, RevTeX, 6 figures optionally included using epsfig.st

Mapping of the variegate porphyria (VP) gene: Contradictory evidence for linkage between VP and microsatellite markers at chromosome 14q32

The gene for variegate porphyria (VP), an autosomal dominant disease with a high prevalence in South Africa, evidently due to a founder effect, was previously mapped to chromosome 14q32. In the current study this localization was evaluated by linkage and haplotype analyses using microsatellite markers spanning a region of more than 20 cM on chromosome 14q32. In many recent studies linkage disequilibrium between disease and marker loci has been utilized to map genes in founder populations, but we could not find any association between VP and the markers used in this study. Our data suggest that the allocation of VP to chromosome 14q32 may be incorrect.Articl

NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment. © 2021, The Author(s)