bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α
Authors: Lim Sangbin , Liu Hao , da Silva Luciana Madeira , Arora Ritu , Liu Zixing , Phillips Joshua B. , Schmitt David C. , Vu Tung , McClellan Steven , Lin Yifeng , Lin Wensheng , Piazza Gary A. , Fodstad Oystein , Tan Ming 
Published: April 2016

Abstract
B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo. We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3–expressing cells. B7-H3 also increased the protein levels of HIF1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species–dependent stabilization of HIF1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression. Cancer Res; 76(8); 2231–42. ©2016 AACR.
Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth
Authors: Pathania Rajneesh , Ramachandran Sabarish , Mariappan Gurusamy , Thakur Priyanka , Shi Huidong , Choi Jeong-Hyeon , Manicassamy Santhakumar , Kolhe Ravindra , Prasad Puttur D. , Sharma Suash , Lokeshwar Bal L. , Ganapathy Vadivel , Thangaraju Muthusamy 
Published: April 2016

Abstract
Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSC), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Furthermore, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer. Cancer Res; 76(11); 3224–35. ©2016 AACR.
Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma
Authors: Rao Shuyun , Cai Kathy Q. , Stadanlick Jason E. , Greenberg-Kushnir Noa , Solanki-Patel Nehal , Lee Sang-Yun , Fahl Shawn P. , Testa Joseph R. , Wiest David L. 
Published: April 2016

Abstract
Mutations in ribosomal proteins cause bone marrow failure syndromes associated with increased cancer risk, but the basis by which they do so remains unclear. We reported previously that the ribosomal protein Rpl22 is a tumor suppressor in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), and that loss of just one Rpl22 allele accelerates T-cell lymphomagenesis by activating NF-κB and inducing the stem cell factor Lin28B. Here, we show that, paradoxically, loss of both alleles of Rpl22 restricts lymphoma progression through a distinct effect on migration of malignant cells out of the thymus. Lymphoma-prone AKT2-transgenic or PTEN-deficient mice on an Rpl22−/− background developed significantly larger and markedly more vascularized thymic tumors than those observed in Rpl22+/+ control mice. But, unlike Rpl22+/+ or Rpl22+/− tumors, Rpl22−/− lymphomas did not disseminate to the periphery and were retained in the thymus. We traced the defect in the Rpl22−/− lymphoma migratory capacity to downregulation of the KLF2 transcription factor and its targets, including the key migratory factor sphingosine 1-phosphate receptor 1 (S1PR1). Indeed, reexpression of S1PR1 in Rpl22-deficient tumor cells restores their migratory capacity in vitro. The regulation of KLF2 and S1PR1 by Rpl22 appears to be proximal as Rpl22 reexpression in Rpl22-deficient lymphoma cells restores expression of KLF2 and S1P1R, while Rpl22 knockdown in Rpl22-sufficient lymphomas attenuates their expression. Collectively, these data reveal that, while loss of one copy of Rpl22 promotes lymphomagenesis and disseminated disease, loss of both copies impairs responsiveness to migratory cues and restricts malignant cells to the thymus. Cancer Res; 76(11); 3387–96. ©2016 AACR.
A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice
Authors: Feng Jia-Hua , Nakagawa-Goto Kyoko , Lee Kuo-Hsiung , Shyur Lie-Fen 
Published: April 2016

Abstract
Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti–mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAFV600E mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163–76. ©2016 AACR.
Burden of Systolic and Diastolic Left Ventricular Dysfunction Among Hispanics in the United States
Authors: Mehta Hardik , Armstrong Anderson , Swett Katrina , Shah Sanjiv J. , Allison Matthew A. , Hurwitz Barry , Bangdiwala Shrikant , Dadhania Rupal , Kitzman Dalane W. , Arguelles William , Lima Joao , Youngblood Marston , Schneiderman Neil , Daviglus Martha L. , Spevack Daniel , Talavera Greg A. , Raisinghani Ajit , Kaplan Robert , Rodriguez Carlos J. 
Published: April 2016

Background—
Population-based estimates of cardiac dysfunction and clinical heart failure (HF) remain undefined among Hispanics/Latino adults.

Methods and Results—

Participants of Hispanic/Latino origin across the United States aged 45 to 74 years were enrolled into the Echocardiographic Study of Latinos (ECHO-SOL) and underwent a comprehensive echocardiography examination to define left ventricular systolic dysfunction (LVSD) and left ventricular diastolic dysfunction (LVDD). Clinical HF was defined according to self-report, and those with cardiac dysfunction but without clinical HF were characterized as having subclinical or unrecognized cardiac dysfunction. Of 1818 ECHO-SOL participants (mean age 56.4 years; 42.6% male), 49.7% had LVSD or LVDD or both. LVSD prevalence was 3.6%, whereas LVDD was detected in 50.3%. Participants with LVSD were more likely to be males and current smokers (all
P
<0.05). Female sex, hypertension, diabetes mellitus, higher body mass index, and renal dysfunction were more common among those with LVDD (all
P
<0.05). In age–sex adjusted models, individuals of Central American and Cuban backgrounds were almost 2-fold more likely to have LVDD compared with those of Mexican backgrounds. Prevalence of clinical HF with LVSD (HF with reduced EF) was 7.3%; prevalence of clinical HF with LVDD (HF with preserved EF) was 3.6%. 96.1% of the cardiac dysfunction seen was subclinical or unrecognized. Compared with those with clinical cardiac dysfunction, prevalent coronary heart disease was the only factor independently associated with subclinical or unrecognized cardiac dysfunction (odds ratio: 0.1; 95% confidence interval: 0.1–0.4).

Conclusions—
Among Hispanics/Latinos, most cardiac dysfunction is subclinical or unrecognized, with a high prevalence of diastolic dysfunction. This identifies a high-risk population for the development of clinical HF.
Outcomes After Vena Cava Filter Use in Noncancer Patients With Acute Venous Thromboembolism
Authors: White Richard H. , Brunson Ann , Romano Patrick S. , Li Zhongmin , Wun Ted 
Published: April 2016

Background—
Evidence that vena cava filters (VCFs) are beneficial is limited.

Methods and Results—
We retrospectively analyzed all noncancer patients admitted to nonfederal California hospitals for acute venous thromboembolism from 2005 to 2010. Analysis was stratified by the presence/absence of a contraindication to anticoagulation (active bleeding, major surgery). Outcomes were death within 30 or 90 days of admission and the 1-year incidence of recurrent venous thromboembolism manifested as pulmonary embolism or deep vein thrombosis. Propensity score methods were used to account for observed systematic differences in baseline characteristics between patients treated and those not treated with a VCF. Among 80 697 patients with no contraindication to anticoagulation, VCF use (n=7762, 9.6%) did not significantly reduce the 30-day risk of death (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.98–1.28). Among 3017 patients with active bleeding, VCF use (n=1095, 36.3%) reduced the 30-day risk of death by 32% (HR, 0.68; 95% CI, 0.52–0.88) and the 90-day risk by 27% (HR, 0.73; 95% CI, 0.59–0.90). VCF use (n=489, 33.8%) did not reduce mortality among 1445 patients who underwent major surgery (HR, 1.1; 95% CI, 0.71–1.77). In all subgroups, filter use did not reduce the risk of subsequent pulmonary embolism. However, the risk of subsequent deep vein thrombosis increased by 50% among VCF patients with no contraindication (HR, 1.53; 95% CI, 1.34–1.74) and by 135% among VCF patients with active bleeding (HR, 2.35; 95% CI, 1.56–3.52).

Conclusions—
VCF use significantly reduced the short-term risk of death only among patients with acute venous thromboembolism who had a contraindication to anticoagulation because of active bleeding. These results support the findings of a randomized clinical trial and current guidelines that recommend VCF use only in patients who cannot receive anticoagulation treatment.
Rnd3 as a Novel Target to Ameliorate Microvascular Leakage
Authors: Breslin Jerome W. , Daines Dayle A. , Doggett Travis M. , Kurtz Kristine H. , Souza‐Smith Flavia M. , Zhang Xun E. , Wu Mack H. , Yuan Sarah Y. 
Published: April 2016

Background

Microvascular leakage of plasma proteins is a hallmark of inflammation that leads to tissue dysfunction. There are no current therapeutic strategies to reduce microvascular permeability. The purpose of this study was to identify the role of Rnd3, an atypical Rho family
GTP
ase, in the control of endothelial barrier integrity. The potential therapeutic benefit of Rnd3 protein delivery to ameliorate microvascular leakage was also investigated.

Methods and Results

Using immunofluorescence microscopy, Rnd3 was observed primarily in cytoplasmic areas around the nuclei of human umbilical vein endothelial cells. Permeability to fluorescein isothiocyanate–albumin and transendothelial electrical resistance of human umbilical vein endothelial cell monolayers served as indices of barrier function, and RhoA, Rac1, and Cdc42 activities were determined using G‐
LISA
assays. Overexpression of Rnd3 significantly reduced the magnitude of thrombin‐induced barrier dysfunction, and abolished thrombin‐induced Rac1 inactivation. Depleting Rnd3 expression with si
RNA
significantly extended the time course of thrombin‐induced barrier dysfunction and Rac1 inactivation. Time‐lapse microscopy of human umbilical vein endothelial cells expressing
GFP
‐actin showed that co‐expression of
mC
herry‐Rnd3 attenuated thrombin‐induced reductions in local lamellipodia that accompany endothelial barrier dysfunction. Lastly, a novel Rnd3 protein delivery method reduced microvascular leakage in a rat model of hemorrhagic shock and resuscitation, assessed by both intravital microscopic observation of extravasation of fluorescein isothiocyanate–albumin from the mesenteric microcirculation, and direct determination of solute permeability in intact isolated venules.

Conclusions
The data suggest that Rnd3 can shift the balance of RhoA and Rac1 signaling in endothelial cells. In addition, our findings suggest the therapeutic, anti‐inflammatory potential of delivering Rnd3 to promote endothelial barrier recovery during inflammatory challenge.
Features and Determinants of Lacune Shape
Authors: Gesierich Benno , Duchesnay Edouard , Jouvent Eric , Chabriat Hugues , Schmidt Reinhold , Mangin Jean-Francois , Duering Marco , Dichgans Martin 
Published: April 2016

Background and Purpose—
Lacunes are a major manifestation of cerebral small vessel disease. Although still debated, the morphological features of lacunes may offer mechanistic insights. We systematically analyzed the shape of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetically defined small vessel disease.

Methods—
A total of 88 incident lacunes from 57 patients were segmented from 3-dimensional T1 magnetic resonance images and 3 dimensionally reconstructed. Anatomic location, diameter, volume, surface area, and compactness of lacunes were assessed. The shape was analyzed using a size, orientation, and position invariant spectral shape descriptor. We further investigated the relationship with perforating arteries and fiber tracts.

Results—
Lacunes were most abundant in the centrum semiovale and the basal ganglia. Diameter, volume, and surface area of lacunes in the basal ganglia and centrum semiovale were larger than in other brain regions. The spectral shape descriptor revealed a continuum of shapes with no evidence for distinct classes of lacunes. Shapes varied mostly in elongation and planarity. The main axis and plane of lacunes were found to align with the orientation of perforating arteries but not with fiber tracts.

Conclusions—
Elongation and planarity are the primary shape principles of lacunes. Their main axis and plane align with perforating arteries. Our findings add to current concepts on the mechanisms of lacunes.
Utility of Global Ensemble Forecast System (GEFS) Reforecast for Medium-Range Drought Prediction in India
Authors: Shah Reepal D. , Mishra Vimal 
Published: April 2016

Abstract
Medium-range (~7 days) forecasts of agricultural and hydrologic droughts can help in decision-making in agriculture and water resources management. India has witnessed severe losses due to extreme weather events during recent years and medium-range forecasts of precipitation, air temperatures (maximum and minimum), and hydrologic variables (root-zone soil moisture and runoff) can be valuable. Here, the skill of the Global Ensemble Forecast System (GEFS) reforecast of precipitation and air temperatures is evaluated using retrospective data for the period of 1985–2010. It is found that the GEFS forecast shows better skill in the nonmonsoon season than in the monsoon season in India. Moreover, skill in temperature forecast is higher than that of precipitation in both the monsoon and nonmonsoon seasons. The lower skill in forecasting precipitation during the monsoon season can be attributed to representation of intraseasonal variability in precipitation from the GEFS. Among the selected regions, the northern, northeastern, and core monsoon region showed relatively lower skill in the GEFS forecast. Temperature and precipitation forecasts were corrected from the GEFS using quantile–quantile (Q–Q) mapping and linear scaling, respectively. Bias-corrected forecasts for precipitation and air temperatures were improved over the raw forecasts. The influence of corrected and raw forcings on medium-range soil moisture, drought, and runoff forecasts was evaluated. The results showed that because of high persistence, medium-range soil moisture forecasts are largely determined by the initial hydrologic conditions. Bias correction of precipitation and temperature forecasts does not lead to significant improvement in the medium-range hydrologic forecasting of soil moisture and drought. However, bias correcting raw GEFS forecasts can provide better predictions of the forecasts of precipitation and temperature anomalies over India.
Observation-Dependent Posterior Inflation for the Ensemble Kalman Filter
Authors: Hodyss Daniel , Campbell William F. , Whitaker Jeffrey S. 
Published: April 2016

AbstractEnsemble-based Kalman filter (EBKF) algorithms are known to produce posterior ensembles whose variance is incorrect for a variety of reasons (e.g., nonlinearity and sampling error). It is shown here that the presence of sampling error implies that the true posterior error variance is a function of the latest observation, as opposed to the standard EBKF, whose posterior variance is independent of observations. In addition, it is shown that the traditional ensemble validation tool known as the “binned spread-skill” diagram does not correctly identify this issue in the ensemble generation step of the EBKF, leading to an overly optimistic impression of the relationship between posterior variance and squared error. An updated ensemble validation tool is described that reveals the incorrect relationship between mean squared error (MSE) and ensemble variance, and gives an unbiased evaluation of the posterior variances from EBKF algorithms. Last, a new inflation method is derived that accounts for sampling error and correctly yields posterior error variances that depend on the latest observation. The new method has very little computational overhead, does not require access to the observations, and is simple to use in any serial or global EBKF.
Prognostic Factors in Myoepithelial Carcinoma of the Major Salivary Glands
Authors: Xiao Christopher C. , Baker Andrew B. , White‐Gilbertson Shai J. , Day Terry A. 
Published: April 2016

Objectives(1) Identify all cases of myoepithelial carcinoma of the major salivary glands from the National Cancer Data Base (NCDB). (2) Analyze the effect of grade, stage, and regional nodal metastasis on survival in myoepithelial carcinoma of the major salivary glands.Study DesignRetrospective review of NCDB.SettingMulticenter data pooled from 1998 to 2012 in the NCDB.MethodsWe identified all reported cases of myoepithelial carcinomas of the major salivary glands from the United States from 1998 to 2012 in the NCDB. Clinical parameters were then examined and analyzed for predictors of survival.ResultsA total of 473 cases of myoepithelial carcinoma were identified. Of the reported cases, 38.1% were low grade; 26.7%, intermediate grade; and 35.2%, high grade. When presenting stage was examined, 24.4% were stage I; 30.6%, stage II; 22.5%, stage III; 12.2%, stage IVa; 3.0%, stage IVb; and 4.1%, stage IVc. At presentation, 18.7% of patients had regional nodal disease, and 4.5% had distant metastases. The 3‐ and 5‐year survival rates were 73% and 64%, respectively. The presence of nodal disease significantly reduced mean survival time versus those without (64 vs 108 months, P <. 001), as did high‐grade disease compared with low grade (67 vs 114 months, P <. 001) and stage III/IV compared with stage I/II disease (61 vs 118 months, P <. 001).ConclusionsThe presence of regional nodal disease, high‐grade disease, and advanced stage are predictors of lower survival in myoepithelial carcinoma. Further studies based on types of treatment are warranted.
Impact of effect-site concentration of propofol on cardiac systolic function assessed by tissue Doppler imaging
Authors: Oh Chung-Sik , Lee Yungu , Kang Woon-Seok , Kim Seong-Hyop 
Published: April 2016

Objective To evaluate the relationship between effect-site concentration (CE) of propofol during total intravenous anaesthesia (TIVA) and cardiac systolic function using tissue Doppler imaging (TDI) in patients undergoing cardiovascular procedures. Methods Stepwise increments of CE of propofol of 1.0, 2.0, 3.0 and 4.0 µg/ml (modified Marsh model) were achieved using a target-controlled infusion device. Transthoracic echocardiographic assessments using TDI were performed for each CE of propofol and corresponding systolic myocardial velocity (s′), mean arterial blood pressure (MAP), heart rate (HR) and bispectral index (BIS) were evaluated. Results Data from 31 patients were analysed in this prospective study. The s′ velocity decreased with increasing propofol CE and values recorded at propofol CE 3.0 and 4.0 µg/ml were near or below 8 cm/s indicating abnormal cardiac systolic function. MAP, HR and BIS also decreased with each propofol CE increment. Conclusion Although the recommended dosage for propofol is up to 4.0 µg/ml, caution should be taken when using propofol concentrations above 2.0 µg/ml during TIVA in patients with underlying cardiovascular diseases.