Characterization of perivascular alveolar epithelial stem cells and their niche in lung homeostasis and cancer.

Lung alveolar structure and function are maintained by subsets of alveolar type II stem cells (AT2s), but there is a need for characterization of these subsets and their associated niches. Here, we report a CD44high subpopulation of AT2s characterized by increased expression of genes that regulate immune signaling even during steady-state homeostasis. Disruption of one of these immune regulatory transcription factor STAT1 impaired the stem cell function of AT2s. CD44high cells were preferentially located near macro- blood vessels and a supportive niche constituted by LYVE1+ endothelial cells, adventitial fibroblasts, and accumulated hyaluronan. In this microenvironment, CD44high AT2 cells were more responsive to transformation by KRAS than general AT2 cells. Moreover, after bacterial lung injury, there was a significant increase of CD44high AT2s and niche components distributed throughout the lung parenchyma. Taken together, CD44high AT2 cells and their perivascular niche regulate tissue homeostasis and tumor formation.

Pan-cancer discovery of somatic mutations from RNA sequencing data.

Identification of somatic mutations (SMs) is essential for characterizing cancer genomes. While DNA-seq is the prevalent method for identifying SMs, RNA-seq provides an alternative strategy to discover tumor mutations in the transcribed genome. Here, we have developed a machine learning based pipeline to discover SMs based on RNA-seq data (designated as RNA-SMs). Subsequently, we have conducted a pan-cancer analysis to systematically identify RNA-SMs from over 8,000 tumors in The Cancer Genome Atlas (TCGA). In this way, we have identified over 105,000 novel SMs that had not been reported in previous TCGA studies. These novel SMs have significant clinical implications in designing targeted therapy for improved patient outcomes. Further, we have combined the SMs identified by both RNA-seq and DNA-seq analyses to depict an updated mutational landscape across 32 cancer types. This new online SM atlas, OncoDB ( https://oncodb.org ), offers a more complete view of gene mutations that underline the development and progression of various cancers.

Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10.

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

OncoDB: an interactive online database for analysis of gene expression and viral infection in cancer.

Large-scale multi-omics datasets, most prominently from the TCGA consortium, have been made available to the public for systematic characterization of human cancers. However, to date, there is a lack of corresponding online resources to utilize these valuable data to study gene expression dysregulation and viral infection, two major causes for cancer development and progression. To address these unmet needs, we established OncoDB, an online database resource to explore abnormal patterns in gene expression as well as viral infection that are correlated to clinical features in cancer. Specifically, OncoDB integrated RNA-seq, DNA methylation, and related clinical data from over 10 000 cancer patients in the TCGA study as well as from normal tissues in the GTEx study. Another unique aspect of OncoDB is its focus on oncoviruses. By mining TCGA RNA-seq data, we have identified six major oncoviruses across cancer types and further correlated viral infection to changes in host gene expression and clinical outcomes. All the analysis results are integratively presented in OncoDB with a flexible web interface to search for data related to RNA expression, DNA methylation, viral infection, and clinical features of the cancer patients. OncoDB is freely accessible at http://oncodb.org.

Uncertainty quantification of bioassay functions for the internal dosimetry of radioiodine.

Bioassay functions, which are provided by the International Commission on Radiological Protection, are used to estimate the intake activity of radionuclides; however, they include considerable uncertainties in terms of the internal dosimetry for a particular individual. During a practical internal dose assessment, the uncertainty in the bioassay function is generally not introduced because of the difficulty in quantification. Therefore, to clarify the existence of uncertainty in the bioassay function and provide dosimetrists with an insight into this uncertainty, this study attempted to quantify the uncertainty in the thyroid retention function used for radioiodine exposure. The uncertainty was quantified using a probabilistic estimation of the thyroid retention function through the propagation of the distribution of biokinetic parameters by the Monte Carlo simulation technique. The uncertainties in the thyroid retention function, expressed in terms of the scattering factor, were in the ranges of 1.55-1.60 and 1.40-1.50 for within 24 h and after 24 h, respectively. In addition, the thyroid retention function within 24 h was compared with actual measurement data to confirm the uncertainty due to the use of first-order kinetics in the biokinetic model calculation. Significantly higher thyroid uptakes (by a factor of 1.9) were observed in the actual measurements. This study indicates that consideration of the uncertainty in the thyroid retention function can avoid a significant over- and under-estimation of the internal dose, particularly when a high dose is predicted.

Developing data-driven clinical pathways using electronic health records: The cases of total laparoscopic hysterectomy and rotator cuff tears.

OBJECTIVE: A clinical pathway is one of the tools used to support clinical decision making that provides a standardized care process in a specific context. The objective of this research was to develop a method for building data-driven clinical pathways using electronic health record data. MATERIALS AND METHODS: We proposed a matching rate-based clinical pathway mining algorithm that produces the optimal set of clinical orders for each clinical stage by employing matching rates. To validate the approach, we utilized two different datasets of deidentified inpatient records directly related to total laparoscopic hysterectomy (TLH) and rotator cuff tears (RCTs) from a hospital in South Korea. The derived data-driven clinical pathways were evaluated with knowledge-based models by health professionals using a delta analysis. RESULTS: Two different data-driven clinical pathways, i.e., TLH and RCTs, were produced by applying the matching rate-based clinical pathway mining algorithm. We identified that there were significant differences in clinical orders between the data-driven and knowledge-based models. Additionally, the data-driven clinical pathways based on our algorithm outperformed the models by clinical experts, with average matching rates of 82.02% and 79.66%, respectively. CONCLUSION: The proposed algorithm will be helpful for supporting clinical decisions and directly applicable in medical practices.

SUSTAINABLE MEDICAL PREPAREDNESS AND RESPONSE SYSTEM FOR RADIATION EMERGENCIES IN THE REPUBLIC OF KOREA.

This paper provides information about the medical preparedness and response system for radiation emergencies in Republic of Korea. The National Radiation Emergency Medical Center (NREMC) oversees medical affairs in the Korean radiological disaster prevention system since its establishment in 2002. It has dedicated itself to set up a nationwide radiation emergency medicine network with 24 designated radiation emergency hospitals. NREMC, as one division under the Korea Institute of Radiological And Medical Sciences (KIRAMS), provides efficient medical care to patients suspected with radiation exposure by collaborating with professional medical staffs in Korea Cancer Center Hospital (KCCH). For prompt response to radiation accidents, NREMC has offered specialized trainings for medical staffs and first responders. It has also operated the 24-h on-call system to consult public concerns of radiation exposure, which can be switched into an emergency mode upon receiving accident reports. In addition, NREMC has conducted dose assessments of radiation exposure with high level of accuracy and implemented R&D programs for radiation injury therapeutics and low-dose radiation risks evaluation in daily life. NREMC supports global initiatives for strengthening medical preparedness and response for radiation emergencies with international organizations.

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans.

The battle for iron between invading microorganisms and mammalian hosts is a pivotal determinant of the outcome of infection. The pathogenic fungus, Cryptococcus neoformans, employs multiple mechanisms to compete for iron during cryptococcosis, a disease primarily of immunocompromised hosts. In this study, we examined the role of endocytic trafficking in iron uptake by characterizing a mutant defective in the Sec1/Munc18 (SM) protein Vps45. This protein is known to regulate the machinery for vesicle trafficking and fusion via interactions with SNARE proteins. As expected, a vps45 deletion mutant was impaired in endocytosis and showed sensitivity to trafficking inhibitors. The mutant also showed poor growth on iron-limited media and a defect in transporting the Cfo1 ferroxidase of the high-affinity iron uptake system from the plasma membrane to the vacuole. Remarkably, we made the novel observation that Vps45 also contributes to mitochondrial function in that a Vps45-Gfp fusion protein associated with mitotracker, and a vps45 mutant showed enhanced sensitivity to inhibitors of electron transport complexes as well as changes in mitochondrial membrane potential. Consistent with mitochondrial function, the vps45 mutant was impaired in calcium homeostasis. To assess the relevance of these defects for virulence, we examined cell surface properties of the vps45 mutant and found increased sensitivity to agents that challenge cell wall integrity and to antifungal drugs. A change in cell wall properties was consistent with our observation of altered capsule polysaccharide attachment, and with attenuated virulence in a mouse model of cryptococcosis. Overall, our studies reveal a novel role for Vps45-mediated trafficking for iron uptake, mitochondrial function and virulence.

Consecutive results of blood cell count and retrospective biodosimetry: useful tools of health protection regulation for radiation workers.

BACKGROUND: Industrial radiography is known to be one of the most vulnerable lines of work among the range of different radiation work. According to the relevant law in Korea, every worker registered in this work should check their blood cell counts every year in addition to their thermoluminescent dosimeter (TLD) doses. Since the law was enacted, however, few follow-up studies have been carried out based on the obtained results. OBJECTIVES: To ascertain the clinical usefulness of complete blood cell count (CBC) results and suggest a proper protocol of health protection for radiation workers. METHODS: After reviewing all the consecutive results of CBC and TLD doses from radiation workers registered nationwide, we selected two groups of high-risk radiation workers, CBC-high risk (CBC-HR) and TLD-high risk (TLD-HR) groups. A control group of unexposed healthy adults was also included. We compared the absorbed doses calculated by cytogenetic biodosimetry among those three groups, and examined possible confounding factors for each group. RESULTS: Both groups of high-risk radiation workers, CBC-HR and TLD-HR, showed higher chromosome aberrations than the control group. In the control group, previous medical history of a CT scan increased the frequency of chromosome aberrations. In contrast, the frequency of chromosome aberrations in the high-risk radiation workers was affected not by the previous CT history but only by the duration of their work. CONCLUSIONS: We ascertain that reviewing consecutive results of blood cell counts and cytogenetic biodosimetry are useful complementary tools to TLD doses for health protection regulation. Several confounding factors including work duration and previous medical history need to be considered for the interpretation of biodosimetry results.

Volume-controlled versus pressure-controlled ventilation-volume guaranteed mode during one-lung ventilation.

BACKGROUND: The purpose of this study was to investigate the changes in airway pressure and arterial oxygenation between ventilation modes during one-lung ventilation (OLV) in patients undergoing thoracic surgery. METHODS: We enrolled 27 patients for thoracic surgery with OLV in the lateral decubitus position. The subjects received various modes of ventilation in random sequences during surgery, including volume-controlled ventilation (VCV) and pressure-controlled ventilation-volume guaranteed (PCV-VG) with a tidal volume (TV) of 8 ml/kg of actual body weight. Target-controlled infusion (TCI) with propofol and remifentanil was used for anesthesia induction and maintenance. After double-lumen endobronchial tube (DLT) insertion, the proper positioning of the DLT was assessed using a fiberoptic bronchoscope. Peak inspiratory pressure (Ppeak), exhaled TV, and arterial blood gas were measured 30 min after each ventilation mode. RESULTS: Ppeak was significantly reduced with the PCV-VG mode (19.6 ± 2.5 cmH2O) compared with the VCV mode (23.2 ± 3.1 cmH2O) (P < 0.000). However, no difference in arterial oxygen tension was noted between the groups (PCV-VG, 375.8 ± 145.1 mmHg; VCV, 328.1 ± 123.7 mmHg) (P = 0.063). The exhaled TV was also significantly increased in PCV-VG compared with VCV (451.4 ± 85.4 vs. 443.9 ± 85.9 ml; P = 0.035). CONCLUSIONS: During OLV in patients with normal lung function, although PCV-VG did not provide significantly improved arterial oxygen tension compared with VCV, PCV-VG provided significantly attenuated airway pressure despite significantly increased exhaled TV compared with VCV.