The semipermeability arising from filtration effects on ionic species at the pore spaces in clay minerals has been recognized as a fundamental transport property of argillites. However, little is ...known about the dependence of the semipermeability on the confining stress that controls the pore sizes. Thus, we investigated the evolution of the semipermeability during cyclic loading by performing chemical osmosis experiments on siliceous mudstones. Results show that the semipermeability irreversibly increases with increasing confining stress, but once the stress exceeds the past maximum effective burial stress, it reversibly changes in accordance with the change in the stress. The net increase in the semipermeability from the first loading cycle to the last unloading cycle implies the irreversible shrinking of pores that should have expanded owing to stress relief before testing. The reversible change in the semipermeability probably reflects the reversible pore deformation due to the elasticity of argillites in the overconsolidated state.
Plain Language Summary
In this manuscript, we show experimental results that clarify for the first time the stress dependence of argillite semipermeability during loading and unloading. The experimental results show that the semipermeability irreversibly increases with increasing confining stress, but once the stress exceeds the past maximum effective burial stress, it reversibly changes in accordance with the change in the stress. The observed net increase in the semipermeability from the first loading cycle to the last unloading cycle is probably caused by the irreversible shrinking of pores that should have expanded owing to stress relief before testing. The reversible change in the semipermeability after the application of the past maximum effective burial stress probably reflects the elastic deformation of the test samples in overconsolidated states. The experimental results have significant implications for identifying geologic membrane behaviors of argillaceous formations because the rocks to be tested for semipermeability can be exposed to stress relief before testing in both the laboratory and field. Moreover, argillites in geologic formations can be in stress relief conditions owing to the denudation of surface geologic strata.
Key Points
The evolution of the semipermeability during cyclic loading and unloading was investigated for the Wakkanai mudstones
The semipermeability reversibly changed with the confining stress after the past maximum effective burial stress was applied
Consideration of the stresses to which the test samples have been exposed is crucial for estimating the argillite semipermeability
The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. ...Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.
Background
Analysis of the errors in the Raven's Coloured Progressive Matrices (RCPM) has been previously performed for children with intellectual disabilities but has not been investigated for those ...with cerebral palsy (CP). This study aimed to investigate whether the types and positions of errors made by individuals with CP differed from those made by typically developing (TD) controls.
Methods
Forty‐five participants with CP aged 4–18 years and 30 TD children aged 3–9 years underwent RCPM testing. We first compared the RCPM performance and error characteristics between the groups and then examined the association between RCPM and the severity of CP and receptive vocabulary in the CP group.
Results
The results showed that while mean total scores in the two groups were comparable, the types and positions of errors made by individuals with CP differed from those of TD controls. The development of non‐verbal intelligence in children with CP increased with age; when controlling for age, non‐verbal intelligence was significantly correlated with all three functional levels of CP severity and receptive vocabulary.
Conclusions
This study provides valuable insights into the problem‐solving strategies employed by children with CP.
Summary
Background
We previously reported that a humanized anti‐factor IXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive ...hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation.
Objectives
To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use.
Methods
A non‐human primate model of acquired hemophilia A was established by injecting anti‐primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed‐inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple‐dosing simulations of ACE910 were also performed.
Results
A single bolus of 1 or 3 mg kg−1 ACE910 showed hemostatic activity comparable to that of 10 U kg−1 (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half‐life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once‐weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis.
Conclusions
ACE910 may offer an alternative on‐demand treatment option for patients with hemophilia A, as well as user‐friendly and aggressive routine supplementation.
Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 ...that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
The aim of this study was to evaluate the levels of semi‐volatile compounds (SVOCs) in residential detached houses in Sapporo, Japan, and whether exposure to these SVOCs was associated with the ...development of building‐related symptoms named ‘sick house syndrome’ (SHS). The definition of SHS is fundamentally the same as that of the sick building syndrome (SBS). The presence of symptoms of SHS was evaluated using a validated self‐administered questionnaire. Surveys and samplings of air and house dust in 41 dwellings were performed from October 2006 to January 2007, and 134 occupants responded to questionnaires. Samples were analyzed to quantify the concentrations of eight plasticizers, eleven phosphate triester flame retardants, two alkyl phenols used as anti‐oxidants, and one organochlorine synergist called s‐421, by gas chromatography–mass spectrometry and gas chromatography–flame photometry. The compounds frequently detected were di‐n‐butylphthalate, di(2‐ethylhexyl)phthalate (DEHP), and dibutylhydroxytoluene in air, and DEHP and tris(2‐butoxyethyl)phosphate (TBEP) in dust. Tributylphosphate was strongly and directly associated with mucosal symptoms of SHS; s‐421 was also directly associated with mucosal symptoms of SHS. On the contrary, some chemicals such as diethylphthalate and TBEP were inversely associated with SHS. In future studies, we plan to assess these associations in a larger population.
Practical Implications
This study suggests that it may be possible to reduce building‐related symptoms by altering exposure to certain SVOCs, such as tributylphosphate commonly found in ceiling and wall coverings and s‐421 used as a synergist for pyrethroids. The association between SHS and s‐421 suggested that use of pyrethroid insecticides could elicit symptoms of SHS. However, further studies are necessary to test the associations observed in the present study and to examine whether the SVOCs associated with symptoms are causative agents or simply surrogates for some other factor that is causing the symptoms.
A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the ...European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection.
•The PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib recently received regulatory approval.•Such tumour-agnostic regulatory approvals, based on tumour biomarker status, represent a paradigm shift in cancer therapy.•These recommendations provide guidance on which patients should be selected and tested for tumour MSI and NTRK gene fusions.
This paper provides a comparative account of the essential oil chemical composition and biological activities of five Brazilian species of
(Asteraceae), namely
,
,
,
, and
. The chemical compositions ...of three species (
,
, and
) are reported for the first time. Analyses by GC/MS showed notable differences in the essential oil compositions of the five species. α-Pinene was observed in the highest concentration (24.50%) in
. Other major compounds included α-bisabolol (23.63%) in
, spathulenol (24.74%) and kongol (22.22%) in
, β-pinene (18.33%) and limonene (18.77%) in
, and β-pinene (15.24%), limonene (14.33%), and spathulenol (13.15%) in
. In vitro analyses for antimalarial, antitrypanosomal, and insecticidal activities were conducted for all of the species.
and
showed good antitrypanosomal activities;
showed insecticidal activities in fumigation bioassay against bed bugs; and
,
, and
exhibited moderate antimalarial activities.
and
showed cytotoxicity. The leaves and stems of all five species showed glandular trichomes and ducts as secretory structures. DNA barcoding successfully determined the main DNA sequences of the investigated species and enabled authenticating them.
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