Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Beyond Progressive Disease: A Retrospective Analysis for Japanese Patients with Activating EGFR Mutations

IntroductionIt is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug.MethodsWe retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non–small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0–1/ 2–4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second).ResultsA total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42–86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21–0.83, p = 0.013) was associated with improved survival.ConclusionContinuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results

Fundamental electron-transfer and proton-coupled electron-transfer properties of Ru(iv)-oxo complexes

Isolation and characterisation of Ru-IV(O) complexes were accomplished to investigate their fundamental electron transfer (ET) and proton-coupled ET (PCET) properties. Reorganisation energies (lambda) in electron transfer (ET) and proton-coupled ET (PCET) from electron donors to the isolated Ru-IV(O) complexes have been determined for the first time to be in the range of 1.70-1.88 eV (ET) and 1.20-1.26 eV (PCET). It was suggested that the reduction of the lambda values of PCET in comparison with those of ET should be due to the smaller structural change in PCET than that in ET on the basis of DFT calculations on 1 and 1e(-)-reduced 1 in the absence and presence of TFA, respectively. In addition, the smaller lambda values for the Ru-IV(O) complexes than those reported for Fe-IV(O) and Mn-IV(O) complexes should be due to the lack of participation of d(sigma) orbitals in the ET and PCET reactions. This is the first example to evaluate fundamental ET and PCET properties of Ru-IV(O) complexes leading to further understanding of their reactivity in oxidation reactions

Change in brain plasmalogen composition by exposure to prenatal undernutrition leads to behavioral impairment of rats.

Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the prefrontal cortex (PFC), but not in the nucleus accumbens or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area was observed in the offspring exposed to prenatal undernutrition and was mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the nucleus accumbens or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior and its injection using liposome is a potential therapeutic approach for cognitive impairment.Significance Statement:Maternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the prefrontal cortex (PFC). Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and was circumscribed to the center area for a long time period, in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Self-Assembly of Fine Particles on Patterned Wettability in Dip Coating and Its Scale Extension with Contact Printing

This study demonstrates the application of dip coating to self-assembly of fine particles on a substrate that is covered with line-and-space pattern of hydrophilic (SiO_2) and hydrophobic materials (OTS). The pattern was fabricated on a substrate by lithography first. The substrates were drawn up from the water-based suspension in which particles were dispersed and the particles self-assembled on the hydrophilic region only forming the packed-structure. Then, contact printing was applied for the patterning to extend the scale. The scale was extended up to 10mm x 10mm while keeping the self-assemble performance

DTI consultation on implementation of the Directive on Electronic Commerce (2000/31/EC) Summary of responses

SIGLEAvailable from British Library Document Supply Centre-DSC:m02/21806 / BLDSC - British Library Document Supply CentreGBUnited Kingdo