Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major ...histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy
. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB
, mutations that cause loss of MHC-I are rarely found
despite the frequent downregulation of MHC-I expression
. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8
T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
Abstract Availability of new rotavirus vaccines highlights the need to maintain and enhance rotavirus strain surveillance. We collected stool samples from children with gastroenteritis admitted to ...eight hospitals in South Korea from April 2005 to March 2007. Of the 6057 samples collected, 1337 (22%) were positive for rotavirus by one of several antigen detection assays. G and P genotypes were identified for 1299 (97%) of rotavirus-positive specimens. G1P8 (36%) was the most prevalent strain, followed by G3P8 (16%), G4P6 (8.9%) and G1P6 (8.2%). G1P8 was also the most prevalent strain in each hospital. Seasonal peaks of rotavirus infection were noted from November 2005 to April 2006 and January to March 2007. This large-scale surveillance study provides important insights into rotavirus genotype distribution and pattern changes in South Korea.
An albumin biosensor based on a potentiometric measurement using Biofield-effect-transistor (BioFET) has been designed and fabricated, and its characteristics were investigated. The BioFET was ...fabricated using semiconductor integrated circuit (IC) technology. The gate surface of the BioFET was chemically modified by newly developed self-assembled monolayer (SAM) synthesized by a thiazole benzo crown ether ethylamine (TBCEA)–thioctic acid to immobilize anti-albumin. SAM formation, antibody immobilization, and antigen–antibody interaction were verified using surface plasmon resonance (SPR). The output voltage changes of the BioFET with respect to various albumin concentrations were obtained. Quasi-reference electrode (QRE) and reference FET (ReFET) has been integrated with the BioFET, and its output characteristic was investigated. The results demonstrate the feasibility of the BioFET as the albumin sensor for diagnosing nephritis.
Summary
Background
Asthma in the elderly (aged ≥ 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late‐onset asthma. Recent studies ...suggest staphylococcal enterotoxin IgE (SE‐IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late‐onset elderly asthma.
Objective
We aimed to examine the associations of SE‐IgE sensitization with late‐onset asthma in the elderly, using a database of elderly asthma cohort study.
Methods
A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE‐IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12‐month follow‐up period.
Results
At baseline, serum SE‐IgE concentrations were significantly higher in patients with asthma than in controls median 0.16 (interquartile range 0.04–0.53) vs. 0.10 (0.01–0.19), P < 0.001. Elderly asthma patients with high SE‐IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE‐IgE levels. In multivariate logistic regression analyses, the associations between serum SE‐IgE concentrations and severe asthma were significant, independently of covariables SE‐IgE‐high (≥ 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86–30.03, P = 0.005. Multiple correspondence analyses also showed that high serum SE‐IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together.
Conclusions and Clinical Relevance
This is the first report on the significant associations of SE‐IgE sensitization with late‐onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late‐onset eosinophilic asthma in the elderly.
This paper focuses on the tectonic and sedimentary evolution of the Cretaceous volcanic rocks and nonmarine successions in the southeastern part of the Korean peninsula, which constitute an ancient ...continental arc system. The arc system (Gyeongsang Arc System), comprising an arc platform (Gyeongsang Volcanic Arc) and a backarc basin (Gyeongsang Backarc Basin), was a southwestward extension of the Japanese Arc formed by oblique northward subduction of the proto-Pacific (Izanagi) plate under the Asian continent. The backarc basin was initiated in the southeastern part of the Korean peninsula in the Early Cretaceous as a narrow NS-trending trough. The basin was bounded by a major fault in the northern part of the basin from which sediments largely emanated. Sediments were deposited in streamflow-dominated alluvial fans adjacent to the fault-bounded basin margin in the north and low-gradient fluvial systems of braided channels that extended southward and southeastward for tens of kilometers. Sediments were also derived from the western highland margin, draining Precambrian to Jurassic basement rocks. The initially narrow trough progressively expanded toward the east, resulting in eastward migration of depocenters that eventually generated a broad fluvio-lacustrine plain fringing the volcanic arc platform. The arc platform played an important role for the derivation of volcanogenic materials and accreted sediments into the backarc basin via extensive fluvial network. Pyroclastic density currents and landslides, which originated from the arc platform, also entered the basin. In addition, extrusion of basaltic volcanic rocks was continual within the basin during basin expansion. The resultant succession of mixed sedimentary and volcanogenic rocks is generally indicative of a temporal increase in volcanic activity in the arc platform and in subsidence rate of the basin. In the Late Cretaceous, andesitic to rhyolitic volcanism became climactic in the arc platform, producing a number of calderas or volcanotectonic depressions. Volcaniclastic aprons fringing the arc platform encroached upon the basin fill. Intraarc basins, produced by sinistral shearing of the arc platform, received sediments from active volcanoes and footwalls of contemporaneous faults, forming small-scale streamflow-dominated alluvial fans and floodplains with later development of a deep lake. Overall, the Gyeongsang Arc System formed under an extensional or transtensional (sinistral strike–slip) stress regime, suggesting that the subducting and the overriding plates were not strongly coupled. Both the volcanic arc and the backarc basin ceased to develop as volcanic activities shifted progressively eastward in the Paleogene accompanied with rollback of the subduction of the Izanagi plate.
Zusammenfassung
Hintergrund
Seit einiger Zeit stehen 2 operative Verfahren zum intrauterinen „repair“ offener spinaler Dysraphien am Fetus zur Verfügung, die zunehmend eingesetzt werden.
Material und ...Methoden
Die Literatur wurde bezüglich beider chirurgischer Verfahren verglichen. Es wird über acht nach unterschiedlichen Verfahren intrauterin operierte Patienten bezüglich Frühergebnis und Komplikationen berichtet.
Ergebnisse
Im Vergleich zur konventionellen postpartalen Korrektur war das Outcome der Patienten bezüglich neurologischer Ausfälle distal der Läsion und Ausprägung der Chiari 2-Malformation und der Liquorabflussstörung besser. Insbesondere kam es seltener zum behandlungsbedürftigen Hydrozephalus. Die Ergebnisse bestätigen die Daten aus der Literatur.
Schlussfolgerung
Systematische, standardisierte Langzeitbeobachtungen stehen als weiterer Schritt an, v. a. im Hinblick auf Sekundärkomplikationen (Re-Tethering, Hirndruck, Stammhirnaffektion) und die kognitive Entwicklung mit und ohne therapiepflichtigen Hydrozephalus.
•We propose an approach to the optimal location of bicycle-sharing stations that can replace short car trips.•We extracted taxi trajectories similar to bicycle riding patterns asan applicable ...dataset.•We applied the proposed framework to Gangnam-gu, Seoul, Korea as an illustration.
Substantial motor vehicle exhaust, a primary cause of air pollution, is emitted on short car trips of three miles or less. Bicycles have been considered an optimum means of completing these short trips because the bicycle is an environmentally friendly, economical, and convenient vehicle. Accordingly, many countries have adopted public bicycle-sharing systems to reduce the use of private vehicles for short trips in central downtown areas. In this paper, we propose a new framework, based on taxi trajectory data, for locating bicycle-sharing stations most efficiently to replace short automobile trips. The proposed framework is applied to Gangnam-gu, a district within the city of Seoul, Korea. Results using two different location-allocation models are demonstrated. As expected, when the p-median model was implemented, the selected stations were more scattered over the whole district, whereas when the MCLP model was implemented, the stations were more concentrated on central areas. Our approach is applicable to any city considering a bicycle-sharing system and can contribute to the system’s efficiency in improving environmental conditions in a central downtown area.
An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to ...progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval CI, 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
We demonstrate a tunable filter with a wide tunable wavelength range (>300 nm) based on coupling between a side-polished fiber and a tapered planar waveguide (PWG). The thickness variation, due to ...sliding of the upper block, of taper PWG on the side-polished fiber region shifted the resonance wavelength of the coupler. Design and fabrication technique are presented.
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