The prehospital quick SOFA score is associated with in-hospital mortality in noninfected patients: A retrospective, cross-sectional study.

This study aimed to determine the accuracy of the quick Sequential Organ Failure Assessment (qSOFA) score in predicting mortality among prehospital patients with and without infection. This single-center, retrospective, cross-sectional study was conducted among patients who arrived via the emergency medical services (EMS). We calculated the qSOFA score and Modified Early Warning Score (MEWS) from prehospital records. We identified patients as infected if they received intravenous antibiotics at the emergency department or within the first 24 hours. Receiver operating characteristic analysis was used to evaluate and compare the performance of the qSOFA score, each physiological parameter, and the MEWS in predicting admission and in-hospital mortality in patients with and without infection. Multivariate analysis was used to evaluate the qSOFA score and other risk factors. Out of 1574 prehospital patients, 47.1% were admitted and 3.2% died in the hospital. The performance of the qSOFA score in predicting in-hospital mortality in noninfected patients was 0.70, higher than for each parameter and the MEWS. The areas under the curve for the qSOFA+ model vs. the qSOFA- model was 0.77 vs. 0.68 for noninfected patients (p <0.05) and 0.71 vs. 0.68 for infected patients (p = 0.41). The likelihood ratio test comparing the qSOFA- and qSOFA+ groups demonstrated significant improvement for noninfected patients (p <0.01). Multivariate regression analysis for in-hospital mortality demonstrated that the qSOFA score is an independent prognosticator for in-hospital mortality, especially among noninfected patients (odds ratio, 3.60; p <0.01). In conclusion, the prehospital qSOFA score was associated with in-hospital mortality in noninfected patients and may be a beneficial tool for identifying deteriorating patients in the prehospital setting.

Anti-angiogenic and anti-tumor effects of TAK-593, a potent and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase.

We recently reported that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase families. Moreover, TAK-593 exhibits a uniquely long-acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor ß (PDGFRß). In this study, we demonstrated that TAK-593 potently inhibits VEGF- and PDGF-stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells. TAK-593 also potently inhibits VEGF-induced tube formation of endothelial cells co-cultured with fibroblasts. Oral administration of TAK-593 exhibited strong anti-tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure. Even after the blood and tissue concentrations of TAK-593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK-593. Immunohistochemical staining indicated that TAK-593 showed anti-proliferative and pro-apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic contrast-enhanced magnetic resonance imaging revealed that TAK-593 reduced tumor vessel permeability prior to the onset of anti-tumor activity. In conclusion, TAK-593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti-angiogenic activity suggests therapeutic potential for the treatment of solid tumors.

Nucleobindin 1 controls the unfolded protein response by inhibiting ATF6 activation.

In response to endoplasmic reticulum (ER) stress, activating transcription factor 6 (ATF6), an ER membrane-anchored transcription factor, is transported to the Golgi apparatus and cleaved by site-1 protease (S1P) to activate the unfolded protein response (UPR). Here, we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. Overexpression of NUCB1 inhibits S1P-mediated ATF6 cleavage without affecting ER-to-Golgi transport of ATF6, whereas knock-down of NUCB1 by siRNA accelerates ATF6 cleavage during ER stress. NUCB1 protein localizes in the Golgi apparatus, and disruption of the Golgi localization results in loss of the ATF6-inhibitiory activity. Consistent with these observations, NUCB1 can suppress physical interaction of S1P-ATF6 during ER stress. Together, our results demonstrate that NUCB1 is the first-identified, Golgi-localized negative feedback regulator in the ATF6-mediated branch of the UPR.

A case of takotsubo-shaped hypokinesis of the left ventricle caused by a lightning strike.

A 62-year-old woman was struck by lightning while on a mountain and fortunately did not suffer burns or unconsciousness. She stayed at a mountain lodge overnight and was taken to our hospital by helicopter the next day. Upon admission, electrocardiography showed ST segment elevation indicating acute lateral myocardial infarction, and echocardiography showed takotsubo-shaped hypokinesis of the left ventricle indicating an apical aneurysm. Her serum escaped enzyme levels were increased, as is typical in cases of myocardial infarction, however, she did not complain of cardiac symptoms. Coronary arteriography performed 4 days after admission showed a normal coronary artery while left ventriculography showed apical akinesia. An echocardiogram obtained 2 days later showed resolution of the LV wall motion abnormality. This is the first reported case of takotsubo cardiomyopathy caused by lightning. Takotsubo-shaped hypokinesis is not described as a complication of lightning-induced cardiac injury and its pathogenesis remains controversial.

Combined protein C and protein S deficiency in a family with repetitive thromboembolism and segregated gene mutations.

A young man with repetitive deep venous thrombosis of the legs and the inferior vena cava, and his family were eventually diagnosed by means of molecular genetic analysis as having both hereditary protein C and protein S deficiency. There have been a few reports of families with combined protein C and protein S deficiency and only one report of such a family characterized at the DNA level. This was the first reported family in Japan with combined deficiency of protein C and protein S accompanied by segregation of gene lesions.

Prediction of chemosensitivity for patients with acute myeloid leukemia, according to expression levels of 28 genes selected by genome-wide complementary DNA microarray analysis.

To identify genes involved in the sensitivity of acute myeloid leukemia (AML) cells to chemotherapy, we monitored gene-expression profiles of cancer cells from 76 AML patients using a cDNA microarray consisting of 23,040 genes. We identified 63 genes that were commonly overexpressed and 372 genes suppressed in AML. Because these genes represent key molecules for disclosing the molecular mechanisms of AML, they may be potential targets for drug development. We also found 28 that revealed different expression levels between good and poor responders to chemotherapy and appeared to be associated with chemosensitivity. On that basis, we developed a "Drug Response Scoring" system that was correlated well with individual sensitivity to an anticancer drug regimen. Among the 44 cases with positive drug-response scores by our definition, 40 achieved complete remission after treatment, whereas the only 3 of the 20 cases with negative scores responded well to the treatment. An ability to predict chemosensitivity should eventually lead to achievement of our goal of "personalized therapy."

Involvement of FKHR-dependent TRADD expression in chemotherapeutic drug-induced apoptosis.

Chemotherapeutic drugs exhibit their cytotoxic effect by inducing apoptosis in tumor cells. Because the serine/threonine kinase Akt is involved in apoptosis suppression, we investigated the relationship between Akt activity and drug sensitivity. We discovered that certain chemotherapeutic drugs induced apoptosis with caspase activation only when Akt was inactivated after drug treatment, while inactivation of Akt was not observed when tumor cells showed resistance to the drug-induced caspase activation. So, turn-off of the Akt-mediated survival signal is correlated with the sensitivity of the cells to chemotherapy. With a cDNA microarray, we revealed that tumor necrosis factor receptor-associated death domain (tradd) gene expression was elevated in response to Akt inactivation. Reportedly, Forkhead family transcription factors are phosphorylated by Akt, which results in their nuclear exit and inactivation. Analysis of the tradd promoter revealed that it contains at least one potential Forkhead family transcription factor-responsive element, and we confirmed that this element was involved in chemotherapeutic drug-induced TRADD expression. Overexpression of mutant TRADD proteins to block its apoptosis-inducing capability attenuated chemotherapeutic drug-induced apoptosis. Thus, chemotherapeutic drugs exhibited their cytotoxic effects in part by down-regulating Akt signaling following TRADD expression. These results indicate that Akt kinase activity after drug treatment is a hallmark of sensitivity of the cells to chemotherapeutic drugs.

Classification of sensitivity or resistance of cervical cancers to ionizing radiation according to expression profiles of 62 genes selected by cDNA microarray analysis.

To identify a set of genes related to radiosensitivity of cervical squamous cell carcinomas and to establish a predictive method, we compared expression profiles of 9 radiosensitive and 10 radioresistant tumors obtained by biopsy before treatment, on a cDNA microarray consisting of 23,040 human genes. We identified 121 genes whose expression was significantly greater in radiosensitive cells than in radioresistant cells, and 50 genes that showed higher levels of expression in radioresistant cells than in radiosensitive cells. Some of these genes had already known to be associated with the radiation response, such as aldehyde dehydrogenase 1 (ALDH1) and X-ray repair cross-complementing 5 (XRCC5) (P<.05, Mann-Whitney test). The validity of the total of 171 genes as radiosensitivity related genes were certified by permutation test (P<.05). Furthermore, we selected 62 genes on the basis of a clustering analysis, and confirmed the validity of these genes with cross-validation test. The cross-validation test also indicates the possibility of making prediction of radiosensitivity for discriminating radiation-sensitive from radiation resistant biopsy samples by predicting score (PS) values calculated from expression values of 62 genes in 19 samples, because the prediction successfully and unequivocally discriminated the radiosensitive phenotype from the radioresistant phenotype in our test panel of 19 cervical carcinomas. The extensive list of genes identified in these experiments provides a large body of potentially valuable information for studying the mechanism(s) of radiosensitivity, and selected 62 genes opens the possibility of providing appropriate and effective radiotherapy to cancer patients.

An integrated database of chemosensitivity to 55 anticancer drugs and gene expression profiles of 39 human cancer cell lines.

To explore genes that determine the sensitivity of cancer cells to anticancer drugs, we investigated using cDNA microarrays the expression of 9216 genes in 39 human cancer cell lines pharmacologically characterized on treatment with various anticancer drugs. A bioinformatical approach was then exploited to identify genes related to anticancer drug sensitivity. An integrated database of gene expression and drug sensitivity profiles was constructed and used to identify genes with expression patterns that showed significant correlation to patterns of drug responsiveness. As a result, sets of genes were extracted for each of the 55 anticancer drugs examined. Whereas some genes commonly correlated with various classes of anticancer drugs, other genes correlated only with specific drugs with similar mechanisms of action. This latter group of genes may reflect the efficacy of each class of drugs. Therefore, the integrated database approach of gene expression and chemosensitivity profiles may be useful in the development of systems to predict drug efficacies of cancer cells by examining the expression levels of particular genes.

Genome-wide cDNA microarray screening to correlate gene expression profiles with sensitivity of 85 human cancer xenografts to anticancer drugs.

One of the most critical issues to be solved in regard to cancer chemotherapy is the need to establish a method for predicting efficacy or toxicity of anticancer drugs for individual patients. To identify genes that might be associated with chemosensitivity, we used a cDNA microarray representing 23,040 genes to analyze expression profiles in a panel of 85 cancer xenografts derived from nine human organs. The xenografts, implanted into nude mice, were examined for sensitivity to nine anticancer drugs (5-fluorouracil, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine). Comparison of the gene expression profiles of the tumors with sensitivities to each drug identified 1,578 genes whose expression levels correlated significantly with chemosensitivity; 333 of those genes showed significant correlation with two or more drugs, and 32 correlated with six or seven drugs. These data should contribute useful information for identifying predictive markers for drug sensitivity that may eventually provide "personalized chemotherapy" for individual patients, as well as for development of novel drugs to overcome acquired resistance of tumor cells to chemical agents.