bluuebunny/crossref_metadata_2025 huggingface dataset:
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Authors: Doebele Robert C. , Davis Lara E. , Vaishnavi Aria , Le Anh T. , Estrada-Bernal Adriana , Keysar Stephen , Jimeno Antonio , Varella-Garcia Marileila , Aisner Dara L. , Li Yali , Stephens Philip J. , Morosini Deborah , Tuch Brian B. , Fernandes Michele , Nanda Nisha , Low Jennifer A.
Published: July 2015

Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion–bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA–NTRK1 gene fusion encoding a functional LMNA–TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.

Significance: TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA–NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions. Cancer Discov; 5(10); 1049–57. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1005
Complement Factor H Antibodies from Lung Cancer Patients Induce Complement-Dependent Lysis of Tumor Cells, Suggesting a Novel Immunotherapeutic Strategy
Authors: Campa Michael J. , Gottlin Elizabeth B. , Bushey Ryan T. , Patz Edward F.
Published: July 2015

Characterization of the humoral immune response in selected patients with cancer who uniformly do well may lead to the development of novel therapeutic strategies. We have previously shown an association between patients with early-stage nonmetastatic lung cancer and autoantibodies to complement factor H (CFH). CFH protects normal and tumor cells from destruction by the alternative complement pathway by inactivating C3b, a protein that is essential for formation of a lytic complex on the cell surface. Here, we show that CFH autoantibodies in lung cancer patients recognize a conformationally distinct form of CFH in vitro, are IgG3 subclass, and epitope map to a crucial functional domain of CFH known to interact with C3b. Purified CFH autoantibodies inhibited binding of CFH to A549 lung tumor cells, increased C3b deposition, and caused complement-dependent tumor cell lysis. This work demonstrates that CFH autoantibodies isolated from patients with lung cancer can kill tumor cells in vitro, suggesting that they may perform this function in vivo as well. Development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer. Cancer Immunol Res; 3(12); 1325–32. ©2015 AACR.
Andrographolide Exerts Pro-Osteogenic Effect by Activation of Wnt/β-Catenin Signaling Pathway in Vitro
Authors: Jiang Tongmeng , Zhou Bo , Huang Li , Wu Huayu , Huang Jiancheng , Liang Tihong , Liu Hui , Zheng Li , Zhao Jinmin
Published: July 2015

Background/Aims: Osteoporosis is a metabolic bone disorders that tortures about millions of people worldwide. Recent studies showed that Andrographolide (AP) is a promising natural compound for the treatment of osteoclast-related bone diseases. However, its potential in treatment of osteoporosis has not been fully explored. Methods: In this study, the effect of AP on osteoblasts metabolism was investigated via the detection of cell proliferation, cell viability, ALP activity, the expression of osteogenic specific genes including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), osteocalcin (OCN), Bone morphogenic protein-2 (BMP2) and Alkaline phosphatase(ALP) for 3, 5 and 7 days respectively. Further exploration of the association of AP with WNT/β-catenin signaling pathway was performed by examination of the expression of WNT related genes and proteins. Results: Results showed that AP of 4.46 and 8.92 µM, especially 8.92 µM was beneficial to osteogenic differentiation by upregulating ALP activity and expression of osteogenic related genes (P<0.05). Pathway analyses identify canonical WNT/β-catenin pathway as an important mediator in AP-induced osteogenesis. Conclusion: This study indicates that AP exerts its pro-osteogenic potential via activation of the WNT/β-catenin in osteoblasts and thus may represent a candidate of therapeutic agent for osteoporosis.
Virus-Induced Type I Interferon Deteriorates Control of Systemic Pseudomonas Aeruginosa Infection
Authors: Merches Katja , Khairnar Vishal , Knuschke Torben , Shaabani Namir , Honke Nadine , Duhan Vikas , Recher Mike , Navarini Alexander A. , Hardt Cornelia , Häussinger Dieter , Tümmler Burkhard , Gulbins Erich , Futerman Anthony H. , Hoffmann Daniel , Lang Florian , Lang Philipp A. , Westendorf Astrid M. , Lang Karl S.
Published: July 2015

Background: Type I interferon (IFN-I) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-α). IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-α-treatment occur independently of neutropenia. Methods: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocytic choriomeningitis virus (LCMV). Bacterial titers, numbers of neutrophils and the gene-expression of liver-lysozyme-2 were determined during a 24 hours systemic infection with P. aeruginosa in wild-type and Ifnar-/- mice under the influence of LCMV or poly(I:C). Results: Virus-induced IFN-I impaired the control of Pseudomonas aeruginosa. This was associated with neutropenia and loss of lysozyme-2-expression in the liver, which had captured P. aeruginosa. A lower release of IFN-I by poly(I:C)-injection also impaired the bacterial control in the liver and reduced the expression of liver-lysozyme-2. Low concentration of IFN-I after infection with a virulent strain of P. aeruginosa alone impaired the bacterial control and reduced lysozyme-2-expression in the liver as well. Conclusion: We found that during systemic infection with P. aeruginosa Kupffer cells quickly controlled the bacteria in cooperation with neutrophils. Upon LCMV-infection this cooperation was disturbed.
Circulating Hepatocellular Carcinoma Cells are Characterized by CXCR4 and MMP26
Authors: Yu Chang , Wang Zhiting , Xu Xiaomei , Xiang Wei , Huang Xiaoying
Published: July 2015

Background/Aims: Primary hepatocellular carcinoma (HCC) is highly invasive, and often results in an early distal metastasis resulting in poor prognosis and therapeutic outcome. Cancer cells disseminating from the tumor and entering circulation are termed circulating tumor cells (CTCs). Although substantial progress has been made to identify those CTCs in HCC, no good marker (cocktail) has so far been identified. Methods: Since only tumorigenic CTCs form metastatic tumor in distal organs, we thus compared the HCC cells that form tumor spheres in culture to those that do not. We transduced HCC cells with a RFP reporter under MMP26 promoter and purified MMP26+CXCR4+ HCC cells. We examined tumor sphere formation in culture, presence of tumor cells in the circulation as well as capability of developing metastatic tumor after transplantation of MMP26+CXCR4+ HCC cells into nude mice, compared to other populations in HCC. Results: Sphere-forming HCC cells expressed high levels of MMP26 and CXCR4. MMP26+CXCR4+ HCC cells formed significantly more tumor spheres in culture, compared to MMP26-CXCR4-, MMP26-CXCR4+ or MMP26+CXCR4- HCC cells. Moreover, tumor cells were more frequently detected in the circulation when MMP26+CXCR4+ HCC cells were subcutaneously transplanted. Further, subcutaneous transplantation of MMP26+CXCR4+ HCC cells, but not transplantation of MMP26-CXCR4-, MMP26-CXCR4+ or MMP26+CXCR4-HCC cells significantly developed distal metastatic tumors. Conclusion: MMP26+CXCR4+ cells may be CTCs in HCC. Selective elimination of MMP26+CXCR4+ cells may substantially reduce HCC metastasis after primary tumor resection.
The Roles of p38 MAPK and ERK1/2 in Coplanar Polychlorinated Biphenyls-Induced Apoptosis of Human Extravillous Cytotrophoblast-Derived Transformed Cells
Authors: Liu Zhu , Ruan Hong-jie , Gu Ping-qing , Ding Wen-yan , Luo Xiao-hui , Huang Rong , Zhao Wei , Gao Ling-juan
Published: July 2015

Background/Aims: The purpose of this study was to investigate the relationships among exposure to coplanar polychlorinated biphenyls (Co-PCBs), the expression of gC1qR and the underlying intracellular apoptotic signaling pathways of human extravillous cytotrophoblast (EVCT)-derived transformed cells (HTR-8/SVneo and HPT-8). Methods: Apoptosis in HTR-8/SVneo and HPT-8 cells was assessed using flow cytometric analysis. gClqR expression was examined in the HTR-8/SVneo and HPT-8 cells using real-time qPCR and western blot analyses. The phosphorylations of p38 mitogen-activated protein kinase (p38 MAPK) (Thr180/Tyr182) and extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Thr204) were detected using western blot analyses. Results: The HTR-8/SVneo and HPT-8 cells treated with Co-PCBs exhibited significantly increased gClqR expression, p38 MAPK/ERK activation and an up-regulation of cellular apoptosis. These effects were abrogated by the application of gC1qR small interfering RNA (siRNA). Furthermore, apoptosis in HTR-8/SVneo and HPT-8 cells was observed upon treatment with Co-PCBs, and these effects were reversed by the p38 MAPK pathway inhibitor SB203580 or the ERK1/2 pathway inhibitor PD098059. Conclusion: These data support a mechanism wherein gC1qR plays a crucial p38 MAPK/ERK signaling pathway-dependent role in Co-PCBs-induced apoptosis of human EVCT-derived transformed cells.
Elderly-Onset Generalized Pustular Psoriasis without a Previous History of Psoriasis Vulgaris
Authors: Aizu Takayuki , Matsui Akinobu , Takiyoshi Noriko , Akasaka Eijiro , Kaneko Takahide , Nakano Hajime , Sugiura Kazumitsu , Akiyama Masashi , Sawamura Daisuke
Published: July 2015

Generalized pustular psoriasis (GPP) is characterized by sudden fever and extensive erythema with pustules and occurs in patients with or without preceding psoriasis vulgaris. We report an 83-year-old man showing irregularly shaped erythema with pustules on the trunk and extremities. He initially had no fever and came to our clinic a few days after the onset of the skin lesions because of high fever and general malaise. We found an extension and new development of erythema and pustules on the whole body. The patient also manifested night delirium. Histological examination revealed neutrophil infiltration into the upper epidermis, which formed a spongiform pustule of Kogoj. Pustular fluid cultures were negative for bacteria. We diagnosed GPP without preceding psoriasis vulgaris. Mutation analysis revealed no significant mutations in IL36RN and CARD14. Previous reports indicated that onset of GPP at the age of 83 years is definitely rare. In older individuals, general disease characteristics include an atypical clinical course, an especially slow appearance and cure, and mental disorder. Our case also revealed such characteristics. Thus, it is necessary to be aware of the clinical course and mental problems in elderly patients with GPP.
Pediatric Acute Longitudinal Extensive Transverse Myelitis Secondary to Neuroborreliosis
Authors: Khan Sana , Singh Neeraj , Dow Amanda , Ramirez-Zamora Adolfo
Published: July 2015

Lyme neuroborreliosis has several different clinical manifestations in children, of which facial nerve palsies, meningitis and radiculopathies are the most common. Transverse myelitis (TM) secondary to Lyme disease has been reported in rare occasions, typically presenting with severe weakness, sensory abnormalities and autonomic dysfunction. We present the case of a 16-year-old male who developed acute left peripheral facial palsy and longitudinal extensive TM secondary to Lyme disease. Remarkably, the patient reported only mild symptoms with severe back pain in the absence of profound signs of myelopathy. We reviewed the medical literature and analyzed the clinical features of pediatric patients with Borrelia burgdorferi-related TM.
Asymptomatic Brugada Syndrome
Authors: Sieira Juan , Ciconte Giuseppe , Conte Giulio , Chierchia Gian-Battista , de Asmundis Carlo , Baltogiannis Giannis , Di Giovanni Giacomo , Saitoh Yukio , Irfan Ghazala , Casado-Arroyo Rubén , Julià Justo , La Meir Mark , Wellens Francis , Wauters Kristel , Pappaert Gudrun , Brugada Pedro
Published: July 2015

Background—

Among Brugada syndrome patients, asymptomatic individuals are considered to be at the lowest risk. Nevertheless, arrhythmic events and sudden cardiac death are not negligible. Literature focused on this specific group of patients is sparse. The purpose of this study is to investigate the clinical characteristics, management, and long-term prognosis of asymptomatic Brugada syndrome patients.

Methods and Results—

Patients presenting with spontaneous or drug-induced Brugada type I ECG and no symptoms at our institution were considered eligible. A total of 363 consecutive patients (200 men, 55.1%; mean age, 40.9±17.2 years; 41 [11.3%] with spontaneous type I ECG) were included. Electrophysiological study was performed in 321 (88.4%) patients, and ventricular arrhythmias were induced in 32 (10%) patients. An implantable cardioverter defibrillator was implanted in 61 (16.8%) patients. After a mean follow-up time of 73.2±58.9 months, 9 arrhythmic events occurred, accounting for an annual incidence rate of 0.5%. Event-free survival was 99.0% at 1 year, 96.2% at 5 years, and 95.4% at 10 and 15 years. Univariate analysis identified as risk factors: electrophysiological study inducibility (hazard ratio, 11.4;
P
<0.01), spontaneous type I (hazard ratio, 4.0;
P
=0.04), and previous sinus node dysfunction (hazard ratio, 8.0; 95% confidence interval, 1.0–63.9;
P
=0.05). At the multivariate analysis, only inducibility remained significant (hazard ratio, 9.1;
P
<0.01)

Conclusions—

Arrhythmic events in asymptomatic Brugada syndrome patients are not insignificant. Ventricular arrhythmia inducibility, spontaneous type I ECG, and presence of sinus node dysfunction might be considered as risk factors and used to drive long-term management.
Mouse Model of Human Congenital Heart Disease
Authors: Chowdhury Rajib , Ashraf Hassan , Melanson Michelle , Tanada Yohei , Nguyen Minh , Silberbach Michael , Wakimoto Hiroko , Benson D. Woodrow , Anderson Robert H. , Kasahara Hideko
Published: July 2015

Background—

Heterozygous human
NKX2-5
homeodomain (DNA-binding domain) missense mutations are highly penetrant for varied congenital heart defects, including progressive atrioventricular (AV) block requiring pacemaker implantation. We recently replicated this genetic defect in a murine knockin model, in which we demonstrated highly penetrant, pleiotropic cardiac anomalies. In this study, we examined postnatal AV conduction in the knockin mice.

Methods and Results—

A murine knockin model (Arg52Gly,
Nkx2-5

+/R52G

) in a 129/Sv background was analyzed by histopathology, surface, and telemetry ECG, and in vivo electrophysiology studies, comparing with control
Nkx2-5
+/+
mice at diverse postnatal stages, ranging from postnatal day 1 (P1) to 17 months. PR prolongation (first degree AV block) was present at 4 weeks, 7 months, and 17 months of age, but not at P1 in the mutant mice. Advanced AV block was also occasionally demonstrated in the mutant mice. Electrophysiology studies showed that AV nodal function and right ventricular effective refractory period were impaired in the mutant mice, whereas sinus nodal function was not affected. AV nodal size was significantly smaller in the mutant mice than their controls at 4 weeks of age, corresponding to the presence of PR prolongation, but not P1, suggesting, at least in part, that the conduction abnormalities are the result of a morphologically atrophic AV node.

Conclusions—

The highly penetrant and progressive AV block phenotype seen in human heterozygous missense mutations in
NKX2-5
homeodomain was replicated in mice by knocking in a comparable missense mutation.
Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis
Authors: Hua Rui , MacLeod Sarah L. , Polina Iuliia , Moghtadaei Motahareh , Jansen Hailey J. , Bogachev Oleg , O’Blenes Stacy B. , Sapp John L. , Legare Jean-Francois , Rose Robert A.
Published: July 2015

Background—

Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the ANP gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation in people. The mechanism(s) through which mANP causes atrial fibrillation is unknown. Our objective was to compare the effects of wild-type ANP and mANP on atrial electrophysiology in mice and humans.

Methods and Results—

Action potentials (APs), L-type Ca
2+
currents (
I
Ca,L
), and Na
+
current were recorded in atrial myocytes from wild-type or natriuretic peptide receptor C knockout (NPR-C
−/−
) mice. In mice, ANP and mANP (10–100 nmol/L) had opposing effects on atrial myocyte AP morphology and
I
Ca,L
. ANP increased AP upstroke velocity (
V
max
), AP duration, and
I
Ca,L
similarly in wild-type and NPR-C
−/−
myocytes. In contrast, mANP decreased
V
max
, AP duration, and
I
Ca,L
, and these effects were completely absent in NPR-C
−/−
myocytes. ANP and mANP also had opposing effects on
I
Ca,L
in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on Na
+
current in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electric conduction in the atria, whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts, whereas treatment with ANP completely prevented the occurrence of arrhythmias.

Conclusions—

These findings provide mechanistic insight into how mANP causes atrial fibrillation and demonstrate that wild-type ANP is antiarrhythmic.
Left Atrial Appendage Occlusion Device and Novel Oral Anticoagulants Versus Warfarin for Stroke Prevention in Nonvalvular Atrial Fibrillation
Authors: Briceno David F. , Villablanca Pedro , Cyrille Nicole , Massera Daniele , Bader Eric , Manheimer Eric , Aagaard Philip , Ferrick Kevin , Gross Jay , Kim Soo Gyum , Krumerman Andrew , Palma Eugen , Guttenplan Nils , Romero Jorge , Fisher John , Garcia Mario , Natale Andrea , Di Biase Luigi
Published: July 2015

Background—

Nonvalvular atrial fibrillation is the most common arrhythmia. Patients with nonvalvular atrial fibrillation are at increased risk of stroke; therefore, we evaluated the efficacy and safety of different approaches to prevent this major complication.

Methods and Results—

We conducted electronic database searches of phase III randomized controlled trials. The groups were novel oral anticoagulants, Watchman left atrial appendage occlusion device (DEVICE), and warfarin. Efficacy outcomes were stroke or systemic embolism, and all-cause mortality. Safety outcome was major bleeding and procedure-related complications. A subgroup analysis of the elderly population was done. We used random-effects model to compare pooled outcomes and tested for heterogeneity. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each outcome. Seven randomized controlled trials (n=73 978) were included. There was a significant difference favoring novel oral anticoagulants for systemic embolism (OR, 0.84; 95% CI, 0.72–0.97;
P
=0.01), all-cause mortality (OR, 0.89; 95% CI, 0.84–0.94;
P
<0.001), and safety outcomes (OR, 0.79; 95% CI, 0.65–0.97;
P
=0.026) compared with warfarin. No difference was seen between DEVICE and warfarin for efficacy end points; however, DEVICE had more complications (OR, 1.85; 95% CI, 1.14–3.01;
P
=0.012). In the elderly (6 randomized controlled trials, n=30 699), systemic embolism was favored with novel oral anticoagulants over warfarin (OR, 0.77; 95% CI, 0.68–0.87;
P
≤0.001). No evidence of significant publication bias was found.

Conclusions—

Novel oral anticoagulants is superior to warfarin for stroke prevention in nonvalvular atrial fibrillation. This benefit was also observed in the elderly population. DEVICE is a reasonable noninferior alternative to warfarin for stroke prevention, but cautious use is essential given safety concerns.
Effects of Evolocumab on Vitamin E and Steroid Hormone Levels
Authors: Blom Dirk J. , Djedjos C. Stephen , Monsalvo Maria Laura , Bridges Ian , Wasserman Scott M. , Scott Rob , Roth Eli
Published: July 2015

Rationale
:

Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels.

Objective:

To determine the effects of evolocumab on vitamin E and steroid hormone levels.

Methods and Results:

After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L.

Conclusions:

As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01516879.
Neuron-Specific Tumor Necrosis Factor Receptor–Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke
Authors: Gong Jun , Li Zuo-Zhi , Guo Sen , Zhang Xiao-Jing , Zhang Peng , Zhao Guang-Nian , Gao Lu , Zhang Yan , Zheng Ankang , Zhang Xiao-Fei , Xiang Mei , Li Hongliang
Published: July 2015

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor–associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase–, nuclear factor κB– and Rac-1–induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-β–activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3–TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3–TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.
Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia
Authors: Brownfoot Fiona C. , Tong Stephen , Hannan Natalie J. , Binder Natalie K. , Walker Susan P. , Cannon Ping , Hastie Roxanne , Onda Kenji , Kaitu’u-Lino Tu’uhevaha J.
Published: July 2015

Abstract—

Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12613000268741.
Defining Thresholds for Home Blood Pressure Monitoring in Octogenarians
Authors: Aparicio Lucas S. , Thijs Lutgarde , Boggia José , Jacobs Lotte , Barochiner Jessica , Odili Augustine N. , Alfie José , Asayama Kei , Cuffaro Paula E. , Nomura Kyoko , Ohkubo Takayoshi , Tsuji Ichiro , Stergiou George S. , Kikuya Masahiro , Imai Yutaka , Waisman Gabriel D. , Staessen Jan A.
Published: July 2015

To generate outcome-driven thresholds for home blood pressure (BP) in the elderly, we analyzed 375 octogenarians (60.3% women; 83.0 years [mean]) enrolled in the International Database on home BP in relation to cardiovascular outcome. Over 5.5 years (median), 155 participants died, 76 from cardiovascular causes, whereas 104, 55, 36, and 51 experienced a cardiovascular, cardiac, coronary, or cerebrovascular event, respectively. In 202 untreated participants, home diastolic in the lowest fifth of the distribution (≤65.1 mm Hg) compared with the multivariable-adjusted average risk was associated with increased risk of cardiovascular mortality and morbidity (hazard ratios [HRs], ≥1.96;
P
≤0.022), whereas the HR for cardiovascular mortality in the top fifth (≥82.0 mm Hg) was 0.37 (
P
=0.034). Among 173 participants treated for hypertension, the HR for total mortality in the lowest fifth of systolic home BP (<126.9 mm Hg) was 2.09 (
P
=0.020). In further analyses of home BP as continuous variable (per 1-SD increment), higher diastolic BP predicted lower cardiovascular mortality and morbidity and cardiac and coronary risk (HR≤0.65;
P
≤0.039) in untreated participants. In those treated, cardiovascular morbidity was curvilinearly associated with systolic home BP with nadir at 148.6 mm Hg and with a 1.45 HR (
P
=0.046) for a 1-SD decrease below this threshold. In conclusion, in untreated octogenarians, systolic home BP ≥152.4 and diastolic BP ≤65.1 mm Hg entails increased cardiovascular risk, whereas diastolic home BP ≥82 mm Hg minimizes risk. In those treated, systolic home BP <126.9 mm Hg was associated with increased total mortality with lowest risk at 148.6 mm Hg.
On the identity of Syntermes noiroti Krishna et al. 2013 (Isoptera: Termitidae: Syntermitinae)
Authors: CONSTANTINO REGINALDO
Published: July 2015

Syntermes emersoni Grassé & Noirot 1949 is an available name of uncertain taxonomic status. It was published in a paper about the nest and biology of the African termite Sphaerotermes sphaerothorax (Sjöstedt 1911), with a brief description and a few illustrations (Grassé & Noirot 1949). The description is limited to the following words: “les mandibles du Syntermes emersoni n. sp. resemblent passablement à celles d'un Sphaerotermes mais sont plus grandes” [the mandibles of Syntermes emersoni n. sp. resemble those of Sphaerotermes but are larger]. Specimens examined by the authors and the localities from which they were collected are not mentioned. Although brief and limited, this description satisfies the requirements of availability (ICZN 1999, articles 10–12). Besides the inadequate description, the name is a junior primary homonym of Syntermes emersoni Snyder 1924 and cannot be used as valid.
Taxonomic study on the leafhopper genus Cofana Melichar (Hemiptera: Cicadellidae: Cicadellinae) from China, with description of two new species
Authors: YANG MAO-FA , MENG ZE-HONG , LI ZI-ZHONG
Published: July 2015

A review of the genus Cofana Melichar from China is presented. Ten species are recorded, of which two species are new: C. cheni sp. nov. and C. nii sp. nov. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). In this paper, C. bidentata Krishnankutty & Viraktamath, 2008 is placed as junior synonym of C. yasumatsui Young, 1979. A key of all Chinese species of the genus is provided.
A new record of Larnaca Walker, 1869 (Orthoptera: Gryllacrididae: Gryllacridinae) from China with description of a new species
Authors: BIAN XUN , GUO LI-YING , SHI FU-MING
Published: July 2015

In the paper, Larnaca is recorded from the Chinese fauna for the first time. A single new species, Larnaca (Larnaca) emarginata Bian, Guo & Shi, sp. nov., is described. This extends the distribution of the genus Larnaca from Lao Cai prov., Vietnam to Yunnan prov. in southwestern China.
Znaczenie dwujęzycznych korpusów w polsko‑litewskich badaniach konfrontatywnych
Authors: Roszko Roman
Published: July 2015

The meaning of bilingual corpora in the Polish-Lithuanian comparative studiesIn his article, the author compares and contrasts the results of his own research on the hypothetical modality in Polish and Lithuanian: a) carried out together with Danuta Roszko, using the traditional method (without use of bilingual corpora in the 90s); b) with use of parallel Polish-Lithuanian corpora resources. As for the contrast of the two methods, special attention has been drawn to the lexical exponents singled out. The use of the corpora resources resulted in the fact that the number of exponents of hipothetical modality singled out in the two languages has slightly risen. Moreover, the borders between the corresponding groups of exponents have become more distinct and obvious. There has been confirmed a possibility of using the corresponding groups of exponents to express the meanings of the adjacent groups. The conclusion has been drawn that this phenomenon is as obvious now as it was earlier expected (in studies without use of bilingual corpora). The separate analysis of corpora resources with the division into the material being a) mutual Polish-Lithuanian translations (i.e. from Polish into Lithuanian and vice versa) and b) translations into Polish and Lithuanian from third languages (here: from German, English or Russian) does not significantly influence the number and diversity of the lexical exponents applied in the two languages. This fact proves a high competence of the translators. The formal resemblance of some of the Polish and Lithuanian exponents does not have a significant influence on which form to choose in the target language. In the translations from Polish into Lithuanian, part of the lexical exponents are conveyed with morphological exponents (lack of such in Polish). The hypothetical modality understated in Polish is sometimes clarified in translations into Lithuanian with the help of morphological forms. In some translations from Lithuanian into Polish the total omission of meanings (also the hypothetical) can be noticed, which results from applying the Lithuanian modus relativus forms. In several cases where some Lithuanian-Polish divergences in translations from Lithuanian into Polish have been noticed, a preliminary comparison of a Lithuanian original material and its translation into Russian can suggest that despite the confirmed direction of translation (from Lithuanian into Polish), it can indeed be a translation from Russian into Polish. However, proving this hypothesis requires the establishing of a trilingual Polish-Lithuanian-Russian corpora for the selected material to allow systematic and consistent studies in this direction. The author gives statistical data for the Polish-Lithuanian lexical exponents of hypothetical modality to distinguish between the mutual translations (Polish-Lithuanian) and those of third languages.
The USArray Transportable Array as a Platform for Weather Observation and Research
Authors: Tytell Jonathan , Vernon Frank , Hedlin Michael , de Groot Hedlin Catherine , Reyes Juan , Busby Bob , Hafner Katrin , Eakins Jennifer
Published: July 2015

The USArray Transportable Array (TA), a component of the National Science Foundation’s EarthScope Initiative, has proven to be a successful model for large-scale real-time monitoring networks. Approximately 400 stations are deployed simultaneously in the continental United States on a nominal Cartesian grid across an area of approximately 2,000,000 km2. Each station was originally designed to operate autonomously as a seismic observing platform capable of recording and transmitting data at 1 and 40 samples per second in real time. The expansion of onboard instrumentation to include surface atmospheric pressure sensors improved the USArray’s real-time capability in monitoring the atmosphere and weather phenomena at the same sample rates. Though not a traditional weather monitoring station, the combination of these seismic and pressure sensors at each TA station can contribute to the observation of surface weather phenomena and has facilitated broader-scale observational applications. Twenty-five TA stations have a Vaisala WXT520 weather station installed in order to create an observational array of “full meteorological” (full-met) stations. Meteorological phenomena have been recorded in high detail, including a data quality comparison between a pair of TA and National Weather Service (NWS) stations, a gust-front passage, rainfall measurements following a squall-line passage, and a near pass of a tornado by one station. Additional products have been constructed from the TA data for visualization and research purposes. The large spatial extent and station configuration of the TA network increases the probability for making high-resolution recordings of data from rare encounters with atmospheric events.
Parameterization of the Spatial Variability of Rain for Large-Scale Models and Remote Sensing
Authors: Lebo Z. J. , Williams C. R. , Feingold G. , Larson V. E.
Published: July 2015

The spatial variability of rain rate R is evaluated by using both radar observations and cloud-resolving model output, focusing on the Tropical Warm Pool–International Cloud Experiment (TWP-ICE) period. In general, the model-predicted rain-rate probability distributions agree well with those estimated from the radar data across a wide range of spatial scales. The spatial variability in R, which is defined according to the standard deviation of R (for R greater than a predefined threshold Rmin) σ(R), is found to vary according to both the average of R over a given footprint μ(R) and the footprint size or averaging scale Δ. There is good agreement between area-averaged model output and radar data at a height of 2.5 km. The model output at the surface is used to construct a scale-dependent parameterization of σ(R) as a function of μ(R) and Δ that can be readily implemented into large-scale numerical models. The variability in both the rainwater mixing ratio qr and R as a function of height is also explored. From the statistical analysis, a scale- and height-dependent formulation for the spatial variability of both qr and R is provided for the analyzed tropical scenario. Last, it is shown how this parameterization can be used to assist in constraining parameters that are often used to describe the surface rain-rate distribution.
Drop Size Distributions and Radar Observations of Convective and Stratiform Rain over the Equatorial Indian and West Pacific Oceans
Authors: Thompson Elizabeth J. , Rutledge Steven A. , Dolan Brenda , Thurai Merhala
Published: July 2015

Two-dimensional video disdrometer (2DVD) data were analyzed from two equatorial Indian (Gan) and west Pacific Ocean (Manus) islands where precipitation is primarily organized by the intertropical convergence zone and the Madden–Julian oscillation (MJO). The 18 (3.5) months of 2DVD data from Manus (Gan) Island show that 1) the two sites have similar drop size distribution (DSD) spectra of liquid water content, median diameter, rain rate R, radar reflectivity z, normalized gamma number concentration Nw, and other integral rain parameters; 2) there is a robust Nw-based separation between convective (C) and stratiform (S) DSDs at both sites that produces consistent separation in other parameter spaces.

The 2DVD data indicate an equatorial, maritime average C/S rainfall accumulation fraction (frequency) of 81/19 (41/59) at these locations. It is hypothesized that convective fraction and frequency estimates are slightly higher than previous radar-based studies, because the ubiquitous weak, shallow convection (<10 mm h−1) characteristic of the tropical warm pool is properly resolved by this high-resolution DSD dataset and identification method. This type of convection accounted for about 30% of all rain events and 15% of total rain volume. These rain statistics were reproduced when newly derived C/S R(z) equations were applied to 2DVD-simulated reflectivity. However, the benefits of using separate C/S R(z) equations are only realizable when C/S partitioning properly classifies each rain type. A single R(z) relationship fit to all 2DVD data yielded accurate total rainfall amounts but overestimated (underestimated) the stratiform (convective) rain fraction by ±10% and overestimated (underestimated) stratiform (convective) rain accumulation by +50% (−15%).
Evaluation of a Regional Climate Modeling Effort for the Western United States Using a Superensemble from Weather@home*
Authors: Li Sihan , Mote Philip W. , Rupp David E. , Vickers Dean , Mera Roberto , Allen Myles
Published: July 2015

Simulations from a regional climate model (RCM) as part of a superensemble experiment were compared with observations of surface meteorological variables over the western United States. The RCM is the Hadley Centre Regional Climate Model, version 3, with improved physics parameterizations (HadRM3P) run at 25-km resolution and nested within the Hadley Centre Atmosphere Model, version 3 (HadAM3P). Overall, the means of seasonal temperature were well represented in the simulations; 95% of grid points were within 2.7°, 2.4°, and 3.6°C of observations in winter, spring, and summer, respectively. The model was too warm over most of the domain in summer except central California and southern Nevada. HadRM3P produced more extreme temperatures than observed. The overall magnitude and spatial pattern of precipitation were well characterized, though HadRM3P exaggerated the orographic enhancement along the coastal mountains, Cascade Range, and Sierra Nevada. HadRM3P produced warm/dry northwest, cool/wet southwest U.S. patterns associated with El Niño. However, there were notable differences, including the locations of the transition from warm (dry) to cool (wet) in the anomaly fields when compared with observations, though there was disagreement among observations. HadRM3P simulated the observed spatial pattern of mean annual temperature more faithfully than any of the RCM–GCM pairings in the North American Regional Climate Change Assessment Program (NARCCAP). Errors in mean annual precipitation from HadRM3P fell within the range of errors of the NARCCAP models. Last, this paper provided examples of the size of an ensemble required to detect changes at the local level and demonstrated the effect of parameter perturbation on regional precipitation.
Cloud Object Analysis of CERES Aqua Observations of Tropical and Subtropical Cloud Regimes: Four-Year Climatology
Authors: Xu Kuan-Man , Wong Takmeng , Dong Shengtao , Chen Feng , Kato Seiji , Taylor Patrick C.
Published: July 2015

Four distinct types of cloud objects—tropical deep convection, boundary layer cumulus, stratocumulus, and overcast stratus—were previously identified from CERES Tropical Rainfall Measuring Mission (TRMM) data. Six additional types of cloud objects—cirrus, cirrocumulus, cirrostratus, altocumulus, transitional altocumulus, and solid altocumulus—are identified from CERES Aqua satellite data in this study. The selection criteria for the 10 cloud object types are based on CERES footprint cloud fraction and cloud-top pressure, as well as cloud optical depth for the high-cloud types. The cloud object is a contiguous region of the earth with a single dominant cloud-system type. The data are analyzed according to cloud object types, sizes, regions, and associated environmental conditions. The frequency of occurrence and probability density functions (PDFs) of selected physical properties are produced for the July 2006–June 2010 period. It is found that deep convective and boundary layer types dominate the total population while the six new types other than cirrostratus do not contribute much in the tropics and subtropics. There are pronounced differences in the size spectrum between the types, with the largest ones being of deep convective type and with stratocumulus and overcast types over the ocean basins off west coasts. The summary PDFs of radiative and cloud physical properties differ greatly among the size categories. For boundary layer cloud types, the differences come primarily from the locations of cloud objects: for example, coasts versus open oceans. They can be explained by considerable variations in large-scale environmental conditions with cloud object size, which will be further qualified in future studies.
Estimation of Time-Averaged Surface Divergence and Vorticity from Satellite Ocean Vector Winds
Authors: O’Neill Larry W. , Haack Tracy , Durland Theodore
Published: July 2015

Two methods of computing the time-mean divergence and vorticity from satellite vector winds in rain-free (RF) and all-weather (AW) conditions are investigated. Consequences of removing rain-contaminated winds on the mean divergence and vorticity depend strongly on the order in which the time-average and spatial derivative operations are applied. Taking derivatives first and averages second (DFAS_RF) incorporates only those RF winds measured at the same time into the spatial derivatives. While preferable mathematically, this produces mean fields biased relative to their AW counterparts because of the exclusion of convergence and cyclonic vorticity often associated with rain. Conversely, taking averages first and derivatives second (AFDS_RF) incorporates all RF winds into the time-mean spatial derivatives, even those not measured coincidentally. While questionable, the AFDS_RF divergence and vorticity surprisingly appears qualitatively consistent with the AW means, despite using only RF winds. The analysis addresses whether the AFDS_RF method accurately estimates the AW mean divergence and vorticity.

Model simulations indicate that the critical distinction between these two methods is the inclusion of typically convergent and cyclonic winds bordering rain patches in the AFDS_RF method. While this additional information removes some of the sampling bias in the DFAS_RF method, it is shown that the AFDS_RF method nonetheless provides only marginal estimates of the mean AW divergence and vorticity given sufficient time averaging and spatial smoothing. Use of the AFDS_RF method is thus not recommended.
Evaluation of the Global Land Data Assimilation System (GLDAS) Air Temperature Data Products
Authors: Ji Lei , Senay Gabriel B. , Verdin James P.
Published: July 2015

There is a high demand for agrohydrologic models to use gridded near-surface air temperature data as the model input for estimating regional and global water budgets and cycles. The Global Land Data Assimilation System (GLDAS) developed by combining simulation models with observations provides a long-term gridded meteorological dataset at the global scale. However, the GLDAS air temperature products have not been comprehensively evaluated, although the accuracy of the products was assessed in limited areas. In this study, the daily 0.25° resolution GLDAS air temperature data are compared with two reference datasets: 1) 1-km-resolution gridded Daymet data (2002 and 2010) for the conterminous United States and 2) global meteorological observations (2000–11) archived from the Global Historical Climatology Network (GHCN). The comparison of the GLDAS datasets with the GHCN datasets, including 13 511 weather stations, indicates a fairly high accuracy of the GLDAS data for daily temperature. The quality of the GLDAS air temperature data, however, is not always consistent in different regions of the world; for example, some areas in Africa and South America show relatively low accuracy. Spatial and temporal analyses reveal a high agreement between GLDAS and Daymet daily air temperature datasets, although spatial details in high mountainous areas are not sufficiently estimated by the GLDAS data. The evaluation of the GLDAS data demonstrates that the air temperature estimates are generally accurate, but caution should be taken when the data are used in mountainous areas or places with sparse weather stations.