Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been ...limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
The skin is an external organ that is most frequently exposed to radiation. High-dose radiation initiates and promotes skin cancer and acute radiation injury. It is important to investigate the ...influence of high-dose radiation exposure on the skin at the molecular level to understand acute radiation injury. To identify genes that are associated with injury caused by high-dose radiation exposure of the skin, we used microarray technology to examine the effect of irradiation on approximately 1000 genes in normal human epidermal keratinocytes at 3 h postirradiation with a cytotoxic dose of X-ray (5 Gy). We found that 16 and 59 genes were up- and down-regulated respectively in the keratinocytes. Several apoptosis-related genes, for example, BAK and TSC-22, and anti-proliferative genes, for example, BTG-1 and BTG-3, were upregulated. We focused on ATF3 because ATF3 is induced most strongly by X-irradiation, and its function in keratinocytes is unknown. The induction of the ATF3 mRNA and protein in keratinocytes following X-ray was confirmed by RT-PCR and western blot analysis. ATF3 was also induced and accumulated within the nuclei of keratinocytes after X-ray irradiation in vivo and in vitro. Exogenous EYFP-ATF3 also accumulated within the nuclei of keratinocytes. In the transient expression assay, EYFP-ATF3, but not EYFP, induced apoptosis in keratinocytes. Taken together, these results suggest that ATF3 plays a role in apoptosis in keratinocytes and is associated with skin injury caused by ionizing radiation.
Abstract
Objectives
We studied the prevalence and prognostic significance of mismatch repair deficient (MMRD) and p53 aberrant ovarian clear cell carcinoma (CCO) and their association with other ...prognostic and theranostic biomarkers (p16, HER2, PD-L1). We also aimed to identify morphologic features to serve as screening tools for immunohistochemical testing for these biomarkers.
Methods
Tissue microarrays with 3-mm cores from 71 pure CCOs were immunostained with PMS2, MSH6, p53, p16, HER2, and PD-L1. Expression status was correlated with tumor recurrence/disease progression and survival. It was also correlated with morphologic features (tumor size, nuclear grade, tumor architecture, mitotic activity, presence of endometriosis, tumor budding, and tumor inflammation).
Results
p53 aberrant tumors were associated with shorter overall and recurrence-free survivals (P = .002 and P = .01, respectively). In multivariate analysis, p53 aberrant status and tumor stage were independently associated with recurrence/disease progression (hazard ratio HR = 3.31, P = .037 and HR = 1.465, P = .004, respectively). p53 aberrant status was associated with tumor budding (P = .037). MMRD, p16, HER2, and PD-L1 expression had no prognostic significance. HER2 and PD-L1 were expressed in 56% and 35% of tumors, respectively. MMRD was associated with tumor expression of PD-L1 (P > .05) but not with tumor inflammation.
Conclusions
Aberrant p53 in CCO is infrequent but associated with poor prognosis independent of stage. Presence of tumor budding could be a screening tool for p53 testing. High prevalence of HER2 and PD-L1 expression indicates the eligibility of patients with CCO for ongoing clinical trials using these therapeutic targets.
With the development of genomic technologies, the isolation of genomic DNA (gDNA) from clinical samples is increasingly required for clinical diagnostics and research studies. In this study, we ...explored the potential of utilizing various leftover blood samples obtained from routine clinical tests as a viable source of gDNA. Using an automated method with optimized pre-treatments, we obtained gDNA from seven types of clinical leftover blood, with average yields of gDNA ranging from 3.11 ± 0.45 to 22.45 ± 4.83 μg. Additionally, we investigated the impact of storage conditions on gDNA recovery, resulting in yields of 8.62-68.08 μg when extracting gDNA from EDTA leftover blood samples stored at 4 °C for up to 13 weeks or -80 °C for up to 78 weeks. Furthermore, we successfully obtained sequenceable gDNA from both Serum Separator Tube and EDTA Tube using a 96-well format extraction, with yields ranging from 0.61 to 71.29 μg and 3.94-215.98 μg, respectively. Our findings demonstrate the feasibility of using automated high-throughput platforms for gDNA extraction from various clinical leftover blood samples with the proper pre-treatments.
Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human ...psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.
This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer ...(31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
The present study aims to establish the Japanese Cancer Genome Atlas (JCGA) by analyzing fresh frozen tumor tissues obtained from 5143 Japanese cancer patients. Somatic driver and druggable alterations were detected in 72.2% and 11.3% of samples, respectively, and germline pathogenic mutations in hereditary cancer genes were identified in 9.2% of samples. The JCGA dataset and analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
Serial Dictatorship Mechanism with Grouping Shiomi, Taisei; Entani, Tomoe
2021 60th Annual Conference of the Society of Instrument and Control Engineers of Japan (SICE),
2021-Sept.-8
Conference Proceeding
Every year, the local governments in Japan assign children to nursery schools before a new school year starts. The assignment should be fair in social welfare as well as should be acceptable for the ...parents. We solve the matching problem of children and nursery schools based on a serial dictatorship mechanism. It is reasonable that a parent requests the siblings be assigned to the same nursery school. On the other hand, since two or more children of a parent are often dealt with independently based on the children's priority ordering, the siblings may be assigned to different nursery schools. To tackle this problem, we assume a group of agents who are children of a parent and a group of objects which belong to the same nursery school. We present a serial dictatorship mechanism under the conditions that there are groups of agents and objects. Using the given independent children's priority ordering, we reorder children from the viewpoint of parents' needs. The priority orderings of the siblings become equal, and they are assigned to the vacancies in the same group, a nursery school. The assignment is feasible, i.e., parents do not decline it. The proposed approach is practical in real situations, as well as easily explainable for fairness.
Aloe extract product is an extract from the leaves of Aloe arborescens Mill., which is used as a natural thickening stabilizer in Japan. In order to establish the identification method of aloe ...extract product, we investigated the characteristic low molecular constituents such as anthrone, chromone and phenyl pyrone derivatives by LC/MS and TLC. We confirmed that aloe extract was different in the constituents from JP grade aloe and reagent grade aloin. Aloenin was detected only in aloe extract from A. arborescens. The detection of aloenin made it possible to distinguish aloe extract from JP grade aloe and reagent grade aloin. The amounts of aloenin, barbaloin, and isobarbaloin in the aloe extract were determined by using the absolute calibration method, and their contents were 2.0%, 0.8%, and 0.7%, respectively. The correction factor (CF) was derived from the calibration curves of barbaloin and aloenin, and it was confirmed that the content of aloenin was also calculated from the calibration curve of barbaloin and the correction factor (CF) even if aloenin standard could not be found in reagent markets.
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