Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in ...gastric cancer are lacking. In this retrospective analysis, we use our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identify four molecular subtypes that are prognostic for survival. We then built a support vector machine with linear kernel to generate a risk score that is prognostic for five-year overall survival and validate the risk score using three independent datasets. We also find that the molecular subtypes predict response to adjuvant 5-fluorouracil and platinum therapy after gastrectomy and to immune checkpoint inhibitors in patients with metastatic or recurrent disease. In sum, we show that the 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated using large patient cohorts in a prospective manner.
Adjuvant chemotherapy after surgery improves survival of patients with stage II–III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, ...suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II–III gastric cancer.
In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II–III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival.
We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2–92·0), 74·8% (69·9–80·1), and 66·0% (60·1–72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% 95% CI 73·5–87·1 vs 64·5% 56·8–73·3; univariate hazard ratio 0·47 95% CI 0·30–0·75, p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% 66·5–79·9 in patients who received chemotherapy plus surgery vs 72·5% 65·8–79·9 in patients who only had surgery; 0·93 0·62–1·38, p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort.
The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II–III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted.
Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.
A flume test was conducted to evaluate the failure mechanism of a rainfall-induced landslide and to develop a physically based warning system. The test was performed at full scale to prevent scale ...effects, and the flume was a rectangular channel that was 20 m long, 4 m wide, and 2.5 m deep. The volumetric water content and the matric suction were measured at various depths to determine the rainfall infiltration into partially saturated soil. The displacement and tilt were measured at the slope surface, and a video camera was installed to record the slope failure. The results showed that the rainfall infiltration caused the volumetric water content to gradually increase and the matric suction to decrease. The resulting decrease in the soil strength caused soil deformation. Thus, the rainfall induced a landslide. The matric suction and the degree of saturation were used to calculate the generalized effective stress of the solid skeleton to develop a warning system. The stress paths were calculated using the effective mean stress and the deviatoric shear stress. The inflection point of the stress paths can be used to define a threshold for a rainfall-induced landslide warning system.
Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids ...remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.
Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (
= 12). Organoids were analyzed by whole-exome sequencing (
= 61) and RNA sequencing (
= 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.
PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an
exon 19 deletion and a
G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an
L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against
exon 20 insertions and pralsetinib against
fusions.
We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
A one-time password is a security system that uses a password that is only used once for authentication, and it is commonly used in multi-factor authentication systems. The process of generating an ...OTP is very similar to generating pseudorandom sequences in cryptography. However, since only a part of the bit string is used in OTP, an algorithm is needed to extract that part. In addition, the OTP process also includes converting the value of the bit string value into decimal form for human perception. This paper focuses on analyzing the extraction function, which is the step before the hexadecimal is reprocessed into the decimal form. We analyze a function family, which includes functions used in the process of extracting a bit string in terms of distinguishable security. As a result, we conclude that the OTP extraction function family is vulnerable in terms of distinguishable security compared to the random function family.
A mobile electrical impedance tomography (EIT) IC is proposed for early breast cancer detection personally at home. To assemble the entire system into a simple brassiere shape, EIT IC is integrated ...via a multi-layered fabric circuit board which includes 90 EIT electrodes and two reference electrodes for current stimulation and voltage sensing. The IC supports three operating modes; gain scanning, contact impedance monitoring, and EIT modes for the clear EIT image. A differential sinusoidal current stimulator (DSCS) is proposed for injection of low-distortion programmable current which has harmonics less than -59 dBc at a load impedance of 2 kΩ. To get high sensitivity, a 6-channel voltage sensing amplifier can adaptively control the gain up to a maximum of 60 dB, and has low input referred noise, 36 nV/ √Hz. The 2.5 × 5 mm chip is fabricated in a 0.18 μm 1P6M CMOS process and consumes 53.4 mW on average. As a result, a sensitivity of 4.9 mΩ is achieved which enables the detection of a 5 mm cancer mass within an agar test phantom.
•The forming condition independence of the forming limit criterion is validated.•The path insensitive formula of theoretical forming limit models are discussed.•The material property effect on the ...forming limit of the M–K model is discussed.•Physical implications of the maximum force and M–K models are compared.
In the common industrial thin sheet metal forming process at room temperature, in which in-homogenous deformation under the plane stress condition is typically the case, sheets are so ductile that sheet forming more often fails after abruptly severe strain localization, especially in the thinning mode. In such a case, measuring the fracture property might be impractical and an alternative criterion to measure sheet proneness to abruptly severe strain localization according to deformation modes, often dubbed as the forming limit criterion, replaces the fracture criterion to account for formability of the sheet, assuming that the criterion is applicable as a material property. However, severe strain localization is a mathematical consequence (of the boundary value problem) of the principle of linear momentum and the constitutive law; therefore not a part of material properties in principle, regardless of its sensitivity to deformation path. Nonetheless, the assumed applicability of the forming limit criterion as a material property in approximation for room temperature forming under the plane stress condition was partially validated in Part II in view of regular and modified hemispherical dome stretching and circular cup drawing tests, while its deformation path insensitive formulae were theoretically justified in Part I by examining the isotropic hardening formulation of rigid-plasticity and also theoretical forming limit models including the Considère (1885), Dorn and Thomsen (1947) and Hill (1952) models as well as the M–K (1967) model.
Single-cell transcriptomic profiles analysis has proposed new insights for understanding the behavior of human gastric cancer (GC). GC offers a unique model of intratumoral heterogeneity. However, ...the specific classes of cells involved in carcinogenetic passage, and the tumor microenvironment of stromal cells was poorly understood. We characterized the heterogeneous cell population of precancerous lesions and gastric cancer at the single-cell resolution by RNA sequencing. We identified 10 gastric cell subtypes and showed the intestinal and diffuse-type cancer were characterized by different cell population. We found that the intestinal and diffuse-type cancer cells have the differential metaplastic cell lineages: intestinal-type cancer cells differentiated along the intestinal metaplasia lineage while diffuse-type cancer cells resemble de novo pathway. We observed an enriched CCND1 mutation in premalignant disease state and discovered cancer-associated fibroblast cells harboring pro-stemness properties. In particular, tumor cells could be categorized into previously proposed molecular subtypes and harbored specific subtype of malignant cell with high expression level of epithelial-myofibroblast transition which was correlated with poor clinical prognosis. In addition to intratumoral heterogeneity, the analysis revealed different cellular lineages were responsible for potential carcinogenetic pathways. Single-cell transcriptomes analysis of gastric pre-cancerous lesions and cancer may provide insights for understanding GC cell behavior, suggesting potential targets for the diagnosis and treatment of GC.
Functional polymers with sulfobetaine or phosphorylcholine zwitterions as pendent groups are demonstrated as both ligands and host matrices for CsPbBr3 perovskite nanoparticles (PNPs). These polymers ...produce nanocomposite films with excellent NP dispersion, optical transparency, and impressive resistance to NP degradation upon exposure to water. Multidentate interactions of the zwitterion‐containing copolymers with the PNPs induce dispersed or weakly aggregated nanocomposite morphologies, depending on the extent of zwitterionic functionality in the polymer. Incorporating additional functionality into the polymers, such as benzophenone pendent groups, yields lithographically patternable films, while time‐resolved photoluminescence measurements provide insight into the electronic impact of PNPs in zwitterionic polymer matrices.
Functional polymer zwitterions are demonstrated as both ligands and host matrices for CsPbBr3 perovskite nanoparticles. These polymers produce nanocomposite films with excellent nanoparticle dispersion and optical transparency, and impressive resistance to degradation upon exposure to water. Incorporating additional functionality into the polymers, such as benzophenone groups, yields lithographically patternable films.
In this work, the onset of failure induced by severe strain at elevated temperature was numerically estimated with cross-formed empirical hardening law describing material softening. The hardening ...law can replicate the rate-sensitive behavior of aluminum alloy 7075 sheets (thickness of 2.0 mm) with initial hardening and progressive material deterioration caused by dynamic recrystallization, dynamic recovery, and micro-void development. The characterized material was applied to the two-step hybrid forming process consisting of a drawing at 400 °C followed by a pneumatic forming at 470 °C to produce a shock absorber housing with an extremely complex shape. The user-defined subroutine codes, VUMAT (ABAQUS/Explicit) and UMAT (ABAQUS/Standard), were sequentially utilized for the drawing and the pneumatic forming, respectively. The identified hardening parameters based on uniaxial tensile tests were validated by simulating the two-step hybrid forming process and compared with the conventional Voce type law (converging function) and the combined Swift-Voce type law (ever-increasing function) since they play a key role in accurately predicting the onset of failure induced by severe strain localization. Finally, simulation results are reasonably well matched with experiments in terms of the moment of failure occurrence, failure location, final blank shape, and thickness distribution.
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