Notes

An incident report on making use of psychophysiological feedback for subconscious examination.
Autophagy is involved in various fungal morphogenetic processes. However, there are limited reports regarding the role of autophagy in mushroom fruiting body formation. The purpose of this study was to reveal the autophagy-related structures in mushroom-forming fungi. The edible mushroom Pleurotus ostreatus was used in this study. Transmission electron microscopy revealed double-membrane bounded structures containing cytoplasmic components in the fruiting bodies of this fungus. Some of these double-membrane structures were observed to interact with the vacuoles. Additionally, curved flat cisternae of various lengths were detected in the cytoplasm. The shape, size and thickness of the limiting membrane of the double-membrane structures and the flat cisternae corresponded well with those of the autophagosomes and the isolation membranes, respectively. Regarding autophagosome formation, a membrane-bound specific zone was detected near the isolation membrane, which appeared to expand along the novel membrane. This is the first detailed report showing autophagy-related structures in P. ostreatus and provides a possible model for autophagosome formation in these filamentous fungi.
Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC.

Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population.

Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI] 2.0-4.1) and 16.8 (95% CI 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%).

Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID NCT01086605).
Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID NCT01086605).
To assess cost-effectiveness of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in rheumatoid arthritis.

We conducted 3 analyses a lifetime analysis with a cohort model (study A) and 2 short-term analyses (studies B and C). Study A evaluated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained from costs of standard treatments. Study B evaluated yearly costs per person achieving American College of Rheumatology (ACR) response (ACR20, ACR50, and ACR70), and study C, costs per person achieving previously defined claims-based effectiveness (equivalent to 28-joint Disease Activity Score [DAS28] ≤ 3.2). The proportion of ACR responders to the drugs of interest were determined by mixed treatment comparisons. Studies B and C estimated costs using a claims database.

In study A, ICERs of all b/tsDMARDs were lower than 5.0 million JPY per QALY. In study B, yearly costs per person with ACR50 response were lower for subcutaneous tocilizumab (1.9 million JPY) and subcutaneous abatacept (2.3 million JPY). In study C, costs per person were lower for subcutaneous tocilizumab (1.3 million JPY) and intravenous tocilizumab (1.6 million JPY) and effectiveness rates were higher for intravenous tocilizumab (45.3%) and infliximab (43.0%).

The b/tsDMARDs with lower prices showed higher cost-effectiveness.
The b/tsDMARDs with lower prices showed higher cost-effectiveness.
To assess safety and pharmacokinetics (PK) of single-dose subcutaneous (SC) sarilumab or tocilizumab SC ± methotrexate; to assess pharmacodynamics (PD) of sarilumab SC or tocilizumab SC monotherapy in Japanese rheumatoid arthritis (RA) patients.

TDU13402 was a randomized, double-blind, placebo-controlled, single-ascending dose Phase 1 study (NCT01850680). Twenty-four patients (6 per treatment group) received sarilumab 50, 100, or 200 mg plus methotrexate or placebo (2 per cohort) on Day (D) 1; PK and safety were assessed through D57. PDY14191 was a randomized, open-label, single-dose study (NCT02404558). Thirty patients (15 per arm) received sarilumab 150 mg or tocilizumab 162 mg on D1; PK, PD and safety were assessed through D43.

TDU13402 mean serum sarilumab exposure increased in a greater than dose proportional manner from 50 to 200 mg dose with no clinically meaningful increase in treatment-emergent adverse events (TEAEs). PDY14191 PK profiles of single-dose sarilumab 150 mg or tocilizumab 162 mg were similar; some numerical differences in PD profiles and TEAEs were observed. Neutrophil count decreased/neutropenia was the most frequently reported TEAE with sarilumab treatment in both studies.

PK, PD and safety profiles of single-dose sarilumab SC with/without methotrexate were consistent with results anticipated in Japanese patients with RA.
PK, PD and safety profiles of single-dose sarilumab SC with/without methotrexate were consistent with results anticipated in Japanese patients with RA.
Lucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/β. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC).

Patients with pretreated RM-NPC were randomly divided into two treatment arms continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).

One hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years.

Lucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. NSC16168 Lucitanib is now being evaluated in phase II/III studies.

NCT03260179.
NCT03260179.
Early graft failure (EGF) is a devastating postoperative complication following heart transplant. Institutional studies have modelled donor and recipient risk factors predictive of graft failure. To date, no studies have assessed specific recipient profiles associated with mortality after recipients suffer from EGF. The objective of this study was to identify this recipient profile.

We performed a retrospective review of patients in the United Network for Organ Sharing database undergoing heart transplant from August 2000 to September 2019. EGF was defined as graft dysfunction at 24 hours post-heart transplant. The primary outcome was 90-day mortality. To isolate recipient characteristics associated with mortality, we performed the univariate analysis on 24 recipient characteristics adjusted for high-risk donor characteristics (ischaemic time, donor age, race mismatch, BUN/creatinine ratio) predictive of 1-year mortality (P < 0.2). We then performed backward stepwise multivariable regression adjusted fical during preoperative planning in these recipients.
Obstructive sleep apnea (OSA), sleep fragmentation, and short sleep duration (SD) have been associated with chronic kidney disease (CKD). However, these potential mechanisms for CKD have not been compared in the same cohort. This study investigated the independent and combined impact of OSA and insomnia with short sleep duration on the risk of CKD progression in a sleep clinic population.

In a cross-sectional study design, adults with suspected OSA completed an overnight sleep study and a questionnaire that included the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI). They also provided blood and urine samples for measurement of the glomerular filtration rate and urine albumincreatinine ratio, from which the risk of CKD progression was determined.

Participants (n = 732, 41% female, 55 ± 13 years) were categorized into four groups no/mild OSA without insomnia (NM-OSA, n = 203), insomnia with SD without OSA (Insomnia-SD, n = 104), moderate-to-severe OSA without insomnia (MS-OSA, n OSA.In eukaryotes, three-dimensional (3D) chromatin architecture maintains genome stability and is important in regulating gene transcription. However, little is known about the mechanisms by which diverse ATP-dependent chromatin remodeling complexes regulate the 3D chromatin structure in plants. We examined the 3D chromatin structure within the ATPase subunit of the SWI/SNF, ISWI, INO80, and CHD remodeling complexes in wild-type (WT) and mutant Arabidopsis thaliana plants by combining high-throughput sequencing with in situ Hi-C, the enrichment of histone marks, nucleosome density, and gene expression. We found that compartment regions switched and compartmental strength was significantly weakened in all four enzyme mutants. Chromatin remodeling complexes differentially regulated the nucleosome distribution pattern and density within the switching compartments. Alterations of nucleosome distribution pattern and density were associated with a reduction in H3K27me3 levels in the chromatin remodeling enzyme mutants and led to compartment switching. Our data show that chromatin remodeling complexes regulate the linear nucleosome distribution pattern and density to promote H3K27me3 deposition, which in turn regulates 3D chromatin structure.Asians are underrepresented across many omics databases, thereby limiting the potential of precision medicine in nearly 60% of the global population. As such, there is a pressing need for multi-omics derived quantitative trait loci (QTLs) to fill the knowledge gap of complex traits in populations of Asian ancestry. Here, we provide the first blood-based multi-omics analysis of Asian pregnant women, constituting high-resolution genotyping (N = 1079), DNA methylation (N = 915) and transcriptome profiling (N = 238). Integrative omics analysis identified 219 154 CpGs associated with cis-DNA methylation QTLs (meQTLs) and 3703 RNAs associated with cis-RNA expression QTLs (eQTLs). Ethnicity was the largest contributor of inter-individual variation across all omics datasets, with 2561 genes identified as hotspots of this variation; 395 of these hotspot genes also contained both ethnicity-specific eQTLs and meQTLs. Gene set enrichment analysis of these ethnicity QTL hotspots showed pathways involved in lipid metabolism, adaptive immune system and carbohydrate metabolism.
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