A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1a hypoxic response in PDAC.

The usefulness of combined analysis using CIScore and VSRAD parameters for differentiating between dementia with Lewy body and Alzheimer's disease.

PURPOSE: The Cingulate Island score (CIScore) is useful index for differentiating between dementia with Lewy body (DLB) and Alzheimer's disease (AD) using regional cerebral blood flow (rCBF) SPECT. The Z score standing for medial temporal lobe (MTL) atrophy and the ratio of Z score between dorsal brain stem (DBS) to MTL are useful indices for differentiating between DLB and AD using MRI with VSRAD. The current study investigated the diagnostic ability by the combined use of rCBF SPECT and MRI in the differentiation between AD and DLB. MATERIALS AND METHODS: In cases with 42 AD and 28 DLB undertaken Tc-99m-ECD SPECT and MRI, we analyzed differential diagnostic ability between AD and DLB among following conditions by single or combined settings. Namely, they were (1) the CIScore as a parameter of rCBF SPECT (DLB â‰¦ 0.25), (2) Z score value of MTL atrophy (DLB â‰¦ 2.05), (3) the ratio of Z score of DBS to medial temporal gray matter as a parameter of brain atrophy using VSRAD (DLB â‰§ 0.38). Also, we analyzed them both including and omitting the elderly (over 75 years old). RESULTS: The accuracy of differential diagnosis in this condition was 74% for (1), 69% for (2), and 67% for (3). The accuracy by combination condition was 84% for (1) and (2), 81% for (1) and (3), and 67% for (2) and (3), respectively. The combination method by CIScore and the Z score of MTL showed the best accuracy. When we confined condition to ages younger than 75 years, the accuracy improved to 94% in the combination method. CONCLUSION: The combined use of CIScore and Z score of MTL was suggested to be useful in the differential diagnosis between DLB and AD particularly in younger than 75 years old.

Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics.

DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products. Mining the untapped chemical diversity encoded by soil microbiomes presents an opportunity to identify additional natural topoisomerase inhibitors. Here we couple metagenome mining, bioinformatic structure prediction algorithms, and chemical synthesis to produce the dual topoisomerase inhibitor tapcin. Tapcin is a mixed p-aminobenzoic acid (PABA)-thiazole with a rare tri-thiazole substructure and picomolar antiproliferative activity. Tapcin reduced colorectal adenocarcinoma HT-29 cell proliferation and tumor volume in mouse hollow fiber and xenograft models, respectively. In both studies it showed similar activity to the clinically used topoisomerase I inhibitor irinotecan. The study suggests that the interrogation of soil microbiomes using synthetic bioinformatic natural product methods has the potential to be a rewarding strategy for identifying potent, biomedically relevant, antiproliferative agents.

Characterization of Severe Uncontrolled Asthma in Japan: Analysis of Baseline Data from the PROSPECT Study.

Purpose: Treatment patterns and patient characteristics are not well elucidated among Japanese patients with severe uncontrolled asthma who currently have various treatment options, including biologics. We analyzed baseline characteristics of patients who did/did not initiate biologic treatment in PROSPECT, a 24-month observational study. Patients and Methods: Patients with severe uncontrolled asthma were prospectively enrolled at 34 sites in Japan from December 2019 to September 2021. The enrolled population was divided based on initiation/non-initiation of biologic treatment within 12 weeks after enrollment. Patient demographics, clinical characteristics, biomarker levels, and asthma-related treatment were assessed at enrollment. Results: Of 289 patients meeting the enrollment criteria, 127 patients initiated biologic treatment (BIO group: omalizumab, n = 16; mepolizumab, n = 10; benralizumab, n = 41; and dupilumab, n = 60) and 162 patients did not (non-BIO group). The proportion of patients with ≥2 asthma exacerbations was higher in the BIO group than the non-BIO group (65.0% vs 47.5%). Patients receiving omalizumab had the highest frequency of allergic rhinitis (87.5% vs other BIOs: 40.0%-53.3%). Patients receiving benralizumab and dupilumab had the highest incidence of nasal polyps (benralizumab: 19.5%, dupilumab: 23.3%, other BIOs: 0.0%). The proportion of patients with blood eosinophils ≥300 cells/µL was higher with benralizumab (75.6%) than other BIOs (26.7%-42.9%). Conclusion: This analysis of baseline data from the PROSPECT study is the first to clarify the characteristics of Japanese patients with severe uncontrolled asthma. BIOs were not necessarily prescribed to patients in whom they were indicated; however, for patients who received them, selection appeared to be made appropriately based on asthma phenotypes.

Intraductal oncocytic papillary neoplasm of the pancreas: clinical and radiological features compared to those of intraductal papillary mucinous neoplasm.

PURPOSE: This study aimed to characterize the clinical and imaging findings of intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) compared to those of intraductal papillary mucinous adenoma/carcinoma (IPMA/IPMC). METHODS: This multi-institutional retrospective study reviewed the clinical, imaging, and pathological findings of 21 patients with pathologically proven IOPN-P. Twenty-one computed tomography (CT) and magnetic resonance imaging, and seven 18F-fluorodeoxyglucose (FDG)-positron emission tomography were performed before surgery. The following findings were evaluated: preoperative blood test results, lesion size and location, pancreatic duct diameter, contrast-enhancement effect, bile duct and peripancreatic invasion, maximum standardized uptake (SUVmax) value, and pathological stromal invasion. RESULTS: Serum carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) levels were significantly higher in the IPMN/IPMC group than in the IOPN-P group. Except in one patient, IOPN-P showed multifocal cystic lesions with solid components or a tumor in the main pancreatic duct (MPD) with dilatation. IOPN-P had a higher frequency of solid parts and a lower frequency of downstream MPD dilatation than IPMA. IPMC showed smaller overall cyst size, more radiological peripancreatic invasion, and worse recurrence-free and overall survival than IOPN-P. The average SUVmax value of IOPN-P was 7.5. Pathologically, 17 of the 21 IOPN-Ps had a malignant component, and six showed stromal invasion. CONCLUSION: IOPN-P shows cystic-solid lesions similar to IPMC but has lower serum CEA and CA19-9 levels, larger overall cyst size, lower frequency of peripancreatic invasion, and more favorable prognosis than IPMC. Moreover, the high FDG uptake by IOPN-Ps may be a characteristic finding of this study.

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration-resistant prostate cancer in real-world clinical practice: The multi-institutional observational ZENSHIN study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC. METHODS: This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS). RESULTS: Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations. CONCLUSIONS: In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

Immune profile analysis of peripheral blood and tumors of lung cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have become central to lung cancer drug therapy, and establishing biomarkers that can predict effects and adverse events (AEs) is awaited. We prospectively analyzed the association between the immune-related molecular expression in peripheral blood mononuclear cells (PBMCs) and lung cancer tissues, and the effects of ICI monotherapy. Methods: Twenty-one patients with advanced non-small cell lung cancer (NSCLC) who received ICI monotherapy were included. Changes in the expression of immune-related molecules in PBMCs before and after the administration of ICI were analyzed by flow cytometry. The major histocompatibility complex (MHC) class I and programmed cell death-ligand 1 (PD-L1) expression of cancer cells, and the PD-L1, CD8 and CD103 expression of tumor infiltrating immune cells in lung cancer tissue before the administration of ICI were confirmed by immunohistochemistry (IHC). Results: Twenty-one patients were investigated, including 11 adenocarcinoma and 10 squamous cell carcinoma cases. Anti-programmed cell death protein-1 (PD-1) antibody (n=18) and anti-PD-L1 antibody (n=3) were administered. The clinical responses were graded as follows: complete response (CR) (n=1), partial response (PR) (n=7), stable disease (SD) (n=10) and progressive disease (PD) (n=3). Among immune-related molecules expressed in PBMCs, the CD103+ CD39+ CD8+ T cell change after administration closely correlated with the clinical response. In the univariate analyses of the factors associated with progression-free survival (PFS), CD103+ CD39+ CD8+ cell change after administration was identified as a significant prognostic factor, while the CD103+ CD39+ CD8+ cell change after administration and Brinkman index were independent prognostic factors in a multivariate analysis of the factors associated with PFS. Conclusions: The CD103+ CD39+ CD8+ cell change after administration may predict the efficacy of ICIs.

Quality of Life Analysis of HPV-Positive Oropharyngeal Cancer Patients in a Randomized Trial of Reduced-Dose Versus Standard Chemoradiotherapy: 5-Year Follow-Up.

Background: Human papillomavirus-positive oropharyngeal carcinoma (HPVOPC) portends a more favorable prognosis compared to environmentally related oropharynx cancer (EROPC). Patients with HPVOPC may be overtreated and endure unnecessary long-term toxicities. Methods: Patients with untreated locally advanced HPVOPC received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and were randomized to standard chemoradiotherapy (sdCRT) (70 Gy) or reduced-dose chemoradiotherapy (rdCRT) (56 Gy) with weekly carboplatin. Patients were followed for changes in five validated quality of life (QoL) surveys: MD Anderson Dysphagia Inventory and Symptom Inventory for head and neck cancer (MDADI, MDASI-HN), Xerostomia Questionnaire (XQ), and European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). The secondary endpoints of this study were 5-year progression-free survival (PFS) and overall survival (OS). Results: Twenty patients were enrolled and randomized to rdCRT (n = 12) or sdCRT (n = 8). Median follow-up was 88 months. At 5 years, difference in QoL changes all favored the rdCRT arm and two QoL scales reached statistical significance (EORTC global health score: 11.49 vs. -23.94, P = 0.014; EORTC symptom scale: -7.76 vs. 15.19, P = 0.015). The 5-year PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively. Conclusions: Therefore, rdCRT after TPF in HPVOPC is feasible in accordance with the earlier results of the Quarterback Trial and long-term follow-up. These limited results are more favorable in specific QoL domains compared to those of sdCRT and demonstrate equivalent long-term survival. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01706939, The Quarterback Trial [NCT01706939].

The Association of Timing of Tracheostomy and Survival of Patients with COVID-19.

Tracheostomy is performed for critically ill patients with prolonged endotracheal intubation including COVID-19 to mitigate the risk of airway complications. We analyzed the difference in mortality of COVID-19 patients undergoing early tracheostomy within 14 days of intubation compared to later tracheostomy than 14 days after intubation. The mortality was not significantly higher in early tracheostomy compared to later tracheostomy.

Prediction of in-hospital mortality with machine learning for COVID-19 patients treated with steroid and remdesivir.

We aimed to create the prediction model of in-hospital mortality using machine learning methods for patients with coronavirus disease 2019 (COVID-19) treated with steroid and remdesivir. We reviewed 1571 hospitalized patients with laboratory confirmed COVID-19 from the Mount Sinai Health System treated with both steroids and remdesivir. The important variables associated with in-hospital mortality were identified using LASSO (least absolute shrinkage and selection operator) and SHAP (SHapley Additive exPlanations) through the light gradient boosting model (GBM). The data before February 17th, 2021 (N = 769) was randomly split into training and testing datasets; 80% versus 20%, respectively. Light GBM models were created with train data and area under the curves (AUCs) were calculated. Additionally, we calculated AUC with the data between February 17th, 2021 and March 30th, 2021 (N = 802). Of the 1571 patients admitted due to COVID-19, 331 (21.1%) died during hospitalization. Through LASSO and SHAP, we selected six important variables; age, hypertension, oxygen saturation, blood urea nitrogen, intensive care unit admission, and endotracheal intubation. AUCs using training and testing datasets derived from the data before February 17th, 2021 were 0.871/0.911. Additionally, the light GBM model has high predictability for the latest data (AUC: 0.881) (https://risk-model.herokuapp.com/covid). A high-value prediction model was created to estimate in-hospital mortality for COVID-19 patients treated with steroid and remdesivir.

The association of remdesivir and in-hospital outcomes for COVID-19 patients treated with steroids.

BACKGROUND: Remdesivir has been shown to decrease SARS-CoV-2 viral loads and the duration of COVID-19 symptoms. However, current evidence regarding the association between remdesivir and in-hospital mortality for patients with COVID-19 steroid treatments is limited. We aimed to investigate whether remdesivir reduces in-hospital mortality among patients with COVID-19 treated with steroids. METHODS: In this retrospective multicentre study, we reviewed the medical records of 3372 patients discharged between 1 March 2020 and 30 March 2021, with laboratory confirmed COVID-19 in the Mount Sinai Health System and treated with steroids. We evaluated the effect of remdesivir on the outcomes using propensity score analyses. Subgroup analyses were conducted by stratification of patients by endotracheal intubation and COVID-19 antibody status. Acute kidney injury (AKI) was defined as an absolute serum creatinine increase of 0.3 mg/dL or a relative increase of 50%. RESULTS: Of the 3372 eligible patients, 1336 (39.6%) received remdesivir. After 1:1 propensity score matching (N = 999 pairs), in-hospital mortality was similar between those with and without remdesivir (21.4% versus 21.6%, respectively, P = 0.96). Remdesivir was not significantly associated with in-hospital mortality regardless of endotracheal intubation or COVID-19 antibody status. However, there was a signal that remdesivir was associated with a reduced risk of AKI in the propensity matched analysis (17.5% versus 23.4%, respectively, P = 0.001). CONCLUSIONS: Remdesivir was not associated with reduced risk of in-hospital mortality in patients with COVID-19 treated with steroids but potentially associated with decreased risk of AKI. These findings should be confirmed in prospective studies focusing on COVID-19 patients treated with steroids.

Iron-Dependent Mitochondrial Dysfunction Contributes to the Pathogenesis of Pulmonary Fibrosis.

Although the pathogenesis of pulmonary fibrosis remains unclear, it is known to involve epithelial injury and epithelial-mesenchymal transformation (EMT) as a consequence of cigarette smoke (CS) exposure. Moreover, smoking deposits iron in the mitochondria of alveolar epithelial cells. Iron overload in mitochondria causes the Fenton reaction, leading to reactive oxygen species (ROS) production, and ROS leakage from the mitochondria induces cell injury and inflammation in the lungs. Nevertheless, the mechanisms underlying iron metabolism and pulmonary fibrosis are yet to be elucidated. In this study, we aimed to determine whether iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. We demonstrated that administration of the iron chelator deferoxamine (DFO) reduced CS-induced pulmonary epithelial cell death, mitochondrial ROS production, and mitochondrial DNA release. Notably, CS-induced cell death was reduced by the administration of an inhibitor targeting ferroptosis, a unique iron-dependent form of non-apoptotic cell death. Transforming growth factor-ß-induced EMT of pulmonary epithelial cells was also reduced by DFO. The preservation of mitochondrial function reduced Transforming growth factor-ß-induced EMT. Furthermore, transbronchial iron chelation ameliorated bleomycin-induced pulmonary fibrosis and leukocyte migration in a murine model. Our findings indicate that iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. Thus, they may be leveraged as new therapeutic targets for pulmonary fibrosis.

Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane.

Small-cell lung cancer (SCLC) is a highly aggressive cancer with poor prognosis, due to a lack of therapeutic targets. Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables and has shown anticancer effects against numerous types of cancer. However, its anticancer effect against SCLC remains unclear. The present study aimed to demonstrate the anticancer effects of SFN in SCLC cells by investigating cell death (ferroptosis, necroptosis and caspase inhibition). The human SCLC cell lines NCI-H69, NCI-H69AR (H69AR) and NCI-H82 and the normal bronchial epithelial cell line, 16HBE14o- were used to determine cell growth and cytotoxicity, evaluate the levels of iron and glutathione, and quantify lipid peroxidation following treatment with SFN. mRNA expression levels of cystine/glutamate antiporter xCT (SLC7A11), a key component of the cysteine/glutamate antiporter, were measured using reverse transcription-quantitative PCR, while the levels of SLC7A11 protein were measured using western blot analysis. Following the addition of SFN to the cell culture, cell growth was significantly inhibited, and cell death was shown in SCLC and multidrug-resistant H69AR cells. The ferroptotic effects of SFN were confirmed following culture with the ferroptosis inhibitor, ferrostatin-1, and deferoxamine; iron levels were elevated, which resulted in the accumulation of lipid reactive oxygen species. The mRNA and protein expression levels of SLC7A11 were significantly lower in SFN-treated cells compared with that in the control cells (P<0.0001 and P=0.0006, respectively). These results indicated that the anticancer effects of SFN may be caused by ferroptosis in the SCLC cells, which was hypothesized to be triggered from the inhibition of mRNA and protein expression levels of SLC7A11. In conclusion, the present study demonstrated that SFN-induced cell death was mediated via ferroptosis and inhibition of the mRNA and protein expression levels of SLC7A11 in SCLC cells. The anticancer effects of SFN may provide novel options for SCLC treatment.

GATA2 and PU.1 Collaborate To Activate the Expression of the Mouse Ms4a2 Gene, Encoding FcεRIß, through Distinct Mechanisms.

GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the ß chain of the high-affinity IgE receptor (FcεRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal -60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and -60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FcεRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.

Increased extracellular vesicle miRNA-466 family in the bronchoalveolar lavage fluid as a precipitating factor of ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. METHODS: Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. RESULTS: Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1ß) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1ß expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. CONCLUSIONS: These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

Clinicopathological characteristics of thyroid transcription factor 1-negative small cell lung cancers.

Limitations in obtaining surgically resected or biopsy samples of small cell lung cancer (SCLC) tumors make comprehensive biological analyses difficult. The loss of thyroid transcription factor 1 (TTF-1) has been associated with the aggressive behavior of non-small cell lung cancer; however, clinicopathological features of TTF-1-negative SCLC remain unclear. This study aimed to elucidate the characteristics of TTF-1-negative SCLC. We studied the associations between the expression of TTF-1 and the clinicopathological factors associated with SCLC, including survival and expression of neuroendocrine markers (synaptophysin, chromogranin A, and CD56), neuroendocrine cell-specific transcription factors (ASCL1, BRN2), a proliferation marker (Ki-67 labeling index), and an oncogene (NF1B). Formalin-fixed and paraffin-embedded sections of SCLC tumors were subjected to immunohistochemistry and quantitative reverse-transcription polymerase chain reaction analyses. In a case-control cohort matched for basic clinical factors, expression of ProGRP, synaptophysin, chromogranin A, and ASCL1 was significantly decreased in TTF-1-negative SCLC samples. In contrast, there was no significant correlation between Ki-67 labeling index and TTF-1. In a larger serial case cohort, TTF-1-negative SCLC cases were older at diagnosis, but there was no significant difference in the overall survival of patients with TTF-1-negative and TTF-1-positive SCLC. In conclusion, TTF-1-negative SCLC showed decreased neuroendocrine differentiation, and significantly worse clinical outcomes were not observed.

Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7.

PURPOSE: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis. METHODS: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. RESULTS: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (ß = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (ß = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (ß = -2.16 and -2.82 µm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (ß = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (ß = 0.03 mm3, P = 4.60E-02) and mean cup depth (ß = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (ß = -0.87 dB, P = 2.44E-02; dominant model). CONCLUSION: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

Reclassification of Flexibacter tractuosus NBRC 15981T as Marivirga harenae sp. nov. in the family Flammeovirgaceae.

Flexibacter tractuosa [Lewin, 1969] was reclassified as Marivirga tractuosa. Flexibacter tractuosus NBRC 15981T was reclassified herein by using a polyphasic taxonomic approach. Cells of the strain were strictly aerobic, Gram-stain-negative, slender rods, which were motile by gliding. The major respiratory quinone was menaquinone-7 and the predominant (>5 %) cellular fatty acids were iso-C15 : 0, iso-G-C15 : 1, C16 : 1ω7c and iso-C17 : 0 3-OH. The polar lipid pattern indicated the presence of a phosphatidylethanolamine, several unidentified aminolipids, glycolipids and five unidentified polar lipids. The G+C content of the genomic DNA was 35.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain NBRC 15981T clustered with members of the genus Marivirga in the family Flammeovirgaceae of the phylum Bacteroidetes. Levels of DNA-DNA relatedness were less than 16 % between strain NBRC 15981T and the two closely related species, Marivirga sericea NBRC 15983T and Marivirga tractuosa NBRC 15989T. Strain NBRC 15981T could be differentiated from these type strains in the genus Marivirga based on the polar lipid pattern and the activity of α-chymotrypsin, as well as by α-glucosidase and ß-glucosidase activity. On the basis of these results, NBRC 15981T is proposed as representing a novel species of the genus Marivirga, named Marivirga harenae sp. nov. The type strain is JK11T (=NBRC 15981T=NCIMB 1429T).

Evaluation of airway resistance in primary small cell carcinoma of the trachea by MostGraph: a case study.

The case subject was a 58-year-old woman who presented to our hospital with a chief complaint of respiratory discomfort. Wheezing could be heard in both lungs; treatment was initiated with inhaled steroids for suspected bronchial asthma. However, 1 week later, the respiratory discomfort had not improved and the wheezing sound had progressed to the neck area. Upper airway obstruction was suspected; therefore, chest computed tomography (CT) was performed, revealing tracheal stenosis caused by a tumor in the upper airway. Because of the high risk of airway obstruction, tracheotomy and tracheal tumor resection were performed. Histopathological examination of the resected tumor revealed small cell lung cancer (SCLC); the stage was determined to be clinical stage IIIB (cT4N2M0), for which chemotherapy with two cycles of cisplatin plus etoposide followed by radiation therapy were administered. Pulmonary function testing revealed no change in the forced expiratory volume in 1 sec and flow volume (FV) curve before and after tumor resection, whereas airway resistance measured by MostGraph-01 showed a marked decrease following treatment. We believe that MostGraph-01 may be useful for measuring airway resistance and evaluating a tracheal tumor, and report a case using MostGraph-01.