Impact of COVID-19 on 1-year survival outcomes in hepatocellular carcinoma: a multicenter cohort study

INTRODUCTION: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients' access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes. METHODS: A prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported. RESULTS: The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients. CONCLUSION: Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy

Quasiparticle spin susceptibility in heavy-fermion superconductors : An NMR study compared with specific heat results

Quasi-particle spin susceptibility ($\chi^{qp}$) for various heavy-fermion (HF) superconductors are discussed on the basis of the experimental results of electronic specific heat ($\gamma_{el}$), NMR Knight shift ($K$) and NMR relaxation rate ($1/T_1$) within the framework of the Fermi liquid model for a Kramers doublet crystal electric field (CEF) ground state. $\chi^{qp}_{\gamma}$ is calculated from the enhanced Sommerfeld coefficient $\gamma_{el}$ and $\chi^{qp}_{T_1}$ from the quasi-particle Korringa relation $T_1T(K^{qp}_{T_1})^2=const.$ via the relation of $\chi^{qp}_{T_1}=(N_A\mu_B/A_{hf})K^{qp}_{T_1}$ where $A_{hf}$ is the hyperfine coupling constant, $N_A$ the Abogadoro's number and $\mu_B$ the Bohr magneton. For the even-parity (spin-singlet) superconductors CeCu$_2$Si$_2$, CeCoIn$_5$ and UPd$_2$Al$_3$, the fractional decrease in the Knight shift, $\delta K^{obs}$, below the superconducting transition temperature ($T_c$) is due to the decrease of the spin susceptibility of heavy quasi-particle estimated consistently from $\chi^{qp}_{\gamma}$ and $\chi^{qp}_{T_1}$. This result allows us to conclude that the heavy quasi-particles form the spin-singlet Cooper pairs in CeCu$_2$Si$_2$, CeCoIn$_5$ and UPd$_2$Al$_3$. On the other hand, no reduction in the Knight shift is observed in UPt$_3$ and UNi$_2$Al$_3$, nevertheless the estimated values of $\chi^{qp}_{\gamma}$ and $\chi^{qp}_{T_1}$ are large enough to be probed experimentally. The odd-parity superconductivity is therefore concluded in these compounds. The NMR result provides a convincing way to classify the HF superconductors into either even- or odd- parity paring together with the identification for the gap structure, as long as the system has Kramers degeneracy.Comment: 11 pages, 3 tables, 5 figures, RevTex4(LaTex2e

Antiferromagnetic Domains and Superconductivity in UPt3

We explore the response of an unconventional superconductor to spatially inhomogeneous antiferromagnetism (SIAFM). Symmetry allows the superconducting order parameter in the E-representation models for UPt3 to couple directly to the AFM order parameter. The Ginzburg-Landau equations for coupled superconductivity and SIAFM are solved numerically for two possible SIAFM configurations: (I) abutting antiferromagnetic domains of uniform size, and (II) quenched random disorder of `nanodomains' in a uniform AFM background. We discuss the contributions to the free energy, specific heat, and order parameter for these models. Neither model provides a satisfactory account of experiment, but results from the two models differ significantly. Our results demonstrate that the response of an E_{2u} superconductor to SIAFM is strongly dependent on the spatial dependence of AFM order; no conclusion can be drawn regarding the compatibility of E_{2u} superconductivity with UPt3 that is independent of assumptions on the spatial dependence of AFMComment: 12 pages, 13 figures, to appear in Phys. Rev.

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma

Background and Aims Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. Methods 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. Results The elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65–2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54–1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. Conclusions Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC

Stabilization of Enzyme Structures by Inhibitors: A Nuclear Magnetic Resonance Study of the Effect of Phosphate on the Acid Unfolding of Ribonuclease A

The acid denaturation of bovine pancreatic ribonuclease A in the presence of 0.2 M sodium dihydrogen phosphate has been studied by n.m.r spectroscopy. Phenylalanine, tyrosine and methionine resonances serve as monitors of the unfolding process. It is shown that the inhibitor shifts the equilibrium towards the native structure at acid pH. Exchange broadening of the C-2 resonances of the active site histidines, 12 and 119, occurs in the presence of phosphate, suggesting an equilibrium between native and unfolded structures. Stabilization of the partially unfolded protein is observed at pH 1.5, as evidenced by the lack of the histidine resonance due to random coil protein. A scheme of the equilibria relating the various states of protein is proposed

Stabilisation of enzyme structures by inhibitors: a nuclear magnetic resonance study of the effect of phosphate on the acid unfolding of ribonuclease a

The acid denaturation of bovine pancreatic ribonuclease A in the presence of 0.2 M sodium dihydrogen phosphate has been studied by n.m.r. spectroscopy. Phenylalanine, tyrosine and methionine resonances serve as monitors of the unfolding process. It is shown that the inhibitor shifts the equilibrium towards the native structure at acid pH. Exchange broadening of the C-2 resonances of the active site histidines, 12 and 119, occurs in the presence of phosphate, suggesting an equilibrium between native and unfolded structures. Stabilisation of the partially unfolded protein is observed at pH 1.5, as evidenced by the lack of the histidine resonance due to random coil protein. A scheme of the equilibria relating the various states of the protein is proposed

The Tertiary Structure at 1.59 \AA Resolution and the Proposed Amino Acid Sequence of a Family-11 Xylanase from the Thermophilic Fungus Paecilomyces varioti Bainier

We report the crystal structure at 1.59 \AA and the proposed amino acid sequence of an endo-1,4-$\beta$-xylanase (PVX) from the thermophilic fungus Paecilomyces varioti Bainier (PvB), stable up to $75^o C$. This fungus is attracting clinical attention as a pathogen causing post-surgical infections. Its xylanase, known as a skin-contact allergen, is the first protein from this fungus whose three-dimensional structure has been elucidated. The crystals of PVX conform to the space group $P2_12_12_1$ with $a = 38.76 \AA$, $b = 54.06 \AA$ and $c = 90.06 \AA$. The structure was solved by molecular replacement techniques using polyalanine coordinates of the Thermomyces lanuginosus xylanase (PDB code 1YNA) and a careful model building based on the amino acid sequence known for two trypsin-digested peptide fragments (17 residues), the sequence and structural alignment of family-11 xylanases and electron density maps. The final refined model has 194 amino acid residues and 128 water molecules, with a crystallographic R-factor of 19.07 % and a free R-factor of 21.94%. The structure belongs to an all-$\beta$ fold, with two curved $\beta$-sheets, forming the cylindrical active-site cleft, and a lone $\alpha$-helix, as present in other family-11 xylanases. We have carried out a quantitative comparison of the structure and sequence of the present thermophilic xylanase (PVX) with other available native structures of mesophiles and thermophiles, the first such detailed analysis to be carried out on family-11 xylanases. The analysis provides a basis for the rationalisation of the idea that the “hinge” region is made more compact in thermophiles by the addition of a disulphide bridge between Cys110 and Cys154 and a N-H···O hydrogen bond between Trp159 near the extremity of the lone α-helix and Trp138 on $\beta$-strand B8. This work brings out explicitly the presence of the C-H···O and the C-H···$\pi$ type interactions in these enzymes. A complete description of structural stability of these enzymes needs to take account of these weaker interactions

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Recent developments in the modification of methionine and other thioether-containing residues in peptides, polypeptides, and proteins are reviewed. Properties and potential applications of the resulting functionalized products are also discussed. While much of this work is focused on natural Met residues, modifications at other side-chain residues have also emerged as new thioether-containing amino acids have been incorporated into peptidic materials. Functional modification of thioether-containing amino acids has many advantages and is a complementary methodology to the widely utilized methods for modification at cysteine residues