The aims of the present study were to investigate the effects of fenofibrate and bezafibrate on the risk of develop-ment of diabetic retinopathy (DR) in patients with type 2 diabetes and ...dyslipidemia. Japanese working age patients with type 2 diabetes and dyslipidemia were extracted from the Nihon University School of Medicine Clinical Data Warehouse. These patients were divided into three groups: control group (n=2549), fenofibrate group (n=40), and bezafibrate group (n=135). Multivariate logistic regression analysis was performed to assess the association between fibrates and the development of DR. After adjustment for covariates, fenofibrate showed no association with the risk of DR adjusted odds ratio (OR), 0.160; 95% CI, 0.021-1.209; p=0.0758. Bezafibrate also showed no association with the risk of DR (adjusted OR, 0.731; 95% CI, 0.411-1.299; p=0.2855). However, poor control of hemoglobin A1c (HbA1c >= 8.0%; adjusted OR, 3.623; 95% CI, 2.649-4.956; p<0.0001) and high low-density lipoprotein cholesterol (LDL-C >= 140mg/dL; adjusted OR, 1.399; 95% CI, 1.013-1.932; p=0.0415) within the follow-up period of type 2 diabetes and dyslipidemia increased the risk of DR. Our results suggested that to prevent development of DR in patients with type 2 diabetes and dyslipidemia, controlling LDL-C levels as well as HbA1c levels under coexistence type 2 diabetes and dyslipidemia is more important than the selection of fibrate.
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Background: An association between improved responses to chemotherapy after exposure to vaccine-based immunotherapy has been previously reported in other cancers. However, it is ...unclear whether the chemotherapy response improves after exposure to immunotherapy, such as immune checkpoint inhibitors (ICIs). The objective of this retrospective study was to evaluate whether chemotherapy (4th-line) would yield improved efficacy when given after exposure to anti-PD-1 antibody in metastatic gastric cancer (mGC). Methods: We investigated retrospectively clinical characteristics at baseline of mGC patients who received chemotherapy after progression of anti-PD-1 antibody (Nivolumab) between February 2018 and July 2019. Anti-PD-1 antibody was adapted as third-line therapy. Inclusion criteria for the analysis reported herein: histologically proven adenocarcinoma; ECOG PS 0-2; adequate organ functions; and received chemotherapy including 5-fluoropyrimidines (5-FU), platinum, and taxane or irinotecan. We evaluated efficacy outcomes, including ORR, DCR by RECIST version 1.1, PFS, and OS. Results: Out of 27 treated with anti-PD-1 antibody, 10 patients were evaluable for responses and eligible to be included in this analysis. Patient characteristics were as follows: median age (range), 72 (50-88) years; male/female, 8/2; ECOG PS (0/1/2), 4/5/1; HER2 (+/-), 5/5; histology (differentiated/undifferentiated), 5/5; metastatic lesions (LN/peritoneum/liver/lung), 5/3/1/3; number of metastatic sites (1/≥2), 5/5; number of prior CTx regimens (3/4/5), 10/0/0; median period (range) from first line CTx, 18.8 (7.9-47.1) months; and CTx regimens (CPT-11/PTX/S-1+Oxaliplatin), 7/2/1; Among the 10 patients, 1 achieved a partial response, giving an ORR of 10.0%. Six patients had stable disease and three had progressive disease. The DCR was 70%. Median PFS and OS were 5.5M and 8.5M, respectively. These were no new irAEs appeared during CTx. Conclusions: In mGC patients, our study demonstrated that increased efficacy to cytotoxic agents chemotherapy given after exposure to ICI was higher as compared to our historical data from the pre-anti-PD1 era. Updated results will be presented.
We performed a caffeine (N-3-methyl-13C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included ...130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath samples were collected from the subjects. The subjects orally ingested 100 mg 13C-caffeine dissolved in distilled water. Subsequently, breath samples were collected in bags every 10 min for a total of 90 min. An analysis of 13CO2 in the expired breath was performed by infrared spectroscopy, and the sum of Δ13CO2 over 90 min (S90m) was calculated. DNA from saliva samples was genotyped using TaqMan® SNP Genotyping for the following genes: cytochrome P4501A2: rs762551, rs2472297, aryl-hydrocarbon receptor (rs4410790), and adenosine A2A receptor (rs5751876). All subjects had the genotype CC in rs2472297 alleles. No significant difference was observed in S90m among the genotypes of rs762551 and rs5751876; however, a significant difference was found in S90m among the genotypes of rs4410790 (C > T). Our findings suggest that the N-3 demethylation of caffeine is dependent on the rs4410790 allele and that CafeBT may be used to determine rs4410790 genotypes.
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Trade-offs in nature’s contributions to people (NCP), particularly in material NCP versus regulating and non-material NCP, continue to rise. Socio-ecological production landscapes and seascapes ...(SEPLS) represent harmonious human–nature interactions resulting in positive outcomes for both biodiversity and human well-being, thus implying synergies among multiple NCP are possible. In case studies of ten projects selected from biodiversity hotspots under the GEF-Satoyama Project, we investigated whether and how synergies in NCP exist within SEPLS and explored management interventions that enhanced these synergies. Using the responses to an online survey completed by project managers from each project and drawing on project reports, we identified a wide array of NCP deriving from various ecosystems within the project SEPLS. Habitat and food provisions, both attributed to multiple ecosystem types, were key components of the NCP bundles present in the project SEPLS. Among the management options that enhanced NCP in SEPLS were food-centred approaches entailing organic agriculture, eco-labelling, branding and improved agricultural practices. Habitat-centred approaches included participatory biodiversity monitoring, ecosystem restoration, co-management and conservation agreements with landowners. Synergies in NCP were generated by integrating these interventions with enabling governance structures and through community empowerment. If combined with mapping and modelling techniques, identifying NCP bundles in SEPLS from local people’s perspectives as we outlined in this study, would help to better contextualise the analysis of NCP bundles. Such contextualised NCP bundle analyses will help field practitioners understand how to enhance synergies between multiple NCP and the broader conservation community could access untapped NCP knowledge.
A systematic study was performed to understand the two major operation modes, valence change memory (VCM) and electrochemical memory (ECM), of tantalum oxide resistive memory, which were categorized ...by the type of conductive filament. The tantalum oxide insulator layer was predictably fabricated to modify the pristine oxygen-vacancy concentration in the insulator layer, where tantalum and copper top electrodes were used to achieve VCM and ECM modes. The distinguishable characteristics of the initial state and analog resistive switching operation revealed the prerequisites for switching capabilities and demonstrated the effects of oxygen vacancies in the two switching modes.
Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with ...the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt)-polyQ proteins in mammalian cells. Disruption of the CCT complex by RNAi-mediated knockdown enhanced Htt-polyQ aggregate formation and cellular toxicity. Analysis of the aggregation states of the Htt-polyQ proteins by fluorescence correlation spectroscopy revealed that CCT depletion results in the appearance of soluble Htt-polyQ aggregates. Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death. These results indicate that CCT has an essential role in protecting against the cytotoxicity of polyQ proteins by affecting the course of aggregation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
FIGHT‐102 was a phase 1, dose‐escalation, dose‐expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary ...efficacy of pemigatinib from FIGHT‐102.
Methods
Patients (≥20 years old) self‐administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy.
Results
Forty‐four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment‐emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95).
Conclusions
Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.
FIGHT‐102 (NCT03235570) was an open‐label, phase 1 study of pemigatinib, a potent and selective inhibitor of FGFR1‐3, in Japanese patients with advanced solid malignancies. The safety, pharmacokinetics, and pharmacodynamic profiles of pemigatinib in this study are consistent with those reported in the phase 1 FIGHT‐101 and phase 2 FIGHT‐202 studies. No new safety signals were reported, and promising efficacy was observed with responses across tumor types including cholangiocarcinoma with FGFR2 alterations.
Objectives
To simultaneously estimate how the risk of incident dementia nonlinearly varies with the administration period and cumulative dose of benzodiazepines, the duration of disorders with an ...indication for benzodiazepines, and other potential confounders, with the goal of settling the controversy over the role of benzodiazepines in the development of dementia.
Methods
The classical hazard model was extended using the techniques of multiple-kernel learning. Regularised maximum-likelihood estimation, including determination of hyperparameter values with 10-fold cross-validation, bootstrap goodness-of-fit test, and bootstrap estimation of confidence intervals, was applied to cohorts retrospectively extracted from electronic medical records of our university hospitals between 1 November 2004 and 31 July 2020. The analysis was mainly focused on 8160 patients aged 40 or older with new onset of insomnia, affective disorders, or anxiety disorders, who were followed up for
4.10
±
3.47
years.
Results
Besides previously reported risk associations, we detected significant nonlinear risk variations over 2–4 years attributable to the duration of insomnia and anxiety disorders, and to the administration period of short-acting benzodiazepines. After nonlinear adjustment for potential confounders, we observed no significant risk associations with long-term use of benzodiazepines.
Conclusions
The pattern of the detected nonlinear risk variations suggested reverse causation and confounding. Their putative bias effects over 2–4 years suggested similar biases in previously reported results. These results, together with the lack of significant risk associations with long-term use of benzodiazepines, suggested the need to reconsider previous results and methods for future analysis.
In Mott‐type resistive switching phenomena, which are based on the metal–insulator transition in strongly correlated materials, the presence of an abrupt temperature‐driven transition in the material ...is considered essential for achieving high‐speed and large‐resistance‐ratio switching. However, this means that the freedom of material/device design in applications is significantly reduced for this type of switching by the strict requirement of transition abruptness. Here, high‐speed, abrupt resistive switching with a switching time of 140 ns is demonstrated in epitaxial films of Ca2RuO4/LaAlO3 (001), which is a material with a nonthermal metal–insulator transition driven by current, despite the complete absence of an abrupt thermal transition in the resistivity–temperature characteristics. Highly smooth negative‐differential‐resistance behavior, very high cycling stability, and an endurance over 106 cycles are also demonstrated in the current–voltage and current–time characteristics, which confirm the nonstochastic nature of the abrupt switching. These results suggest that strict control of the resistivity–temperature characteristics is not necessarily required in a material with a nonthermal‐type metal–insulator transition to obtain high‐speed resistive switching because of the independence of the dynamics from those of the thermal transition, and this phenomenon potentially has important advantages in resistive switching applications.
High‐speed, abrupt resistance switching potentially attributable to the nonthermal metal–insulator transition is demonstrated in Ca2RuO4/LaAlO3 (001) epitaxial films independently of the presence of an abrupt thermal transition in the resistivity–temperature characteristics. A switching time of 140 ns, highly smooth negative‐differential‐resistance behavior, and an endurance over 106 cycles are observed in the switching phenomenon, indicating the intrinsic high reliability.
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