bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homing of Human B Cells to Lymphoid Organs and B-Cell Lymphoma Engraftment Are Controlled by Cell Adhesion Molecule JAM-C
Authors: Doñate Carmen , Ody Christiane , McKee Thomas , Ruault-Jungblut Sylvie , Fischer Nicolas , Ropraz Patricia , Imhof Beat A. , Matthes Thomas 
Published: December 2012

Abstract
Junctional adhesion molecule C (JAM-C) is expressed by vascular endothelium and human but not mouse B lymphocytes. The level of JAM-C expression defines B-cell differentiation stages and allows the classification of marginal zone–derived (JAM-C–positive) and germinal center–derived (JAM-C–negative) B-cell lymphomas. In the present study, we investigated the role of JAM-C in homing of human B cells, using a xenogeneic nonobese diabetic/severe combined immunodeficient mouse model. Treatment with anti-JAM-C antibodies in short-term experiments reduced migration of normal and malignant JAM-C–expressing B cells to bone marrow, lymph nodes, and spleen. Blocking homing to the spleen is remarkable, as most other antiadhesion antibodies reduce homing of B cells only to bone marrow and lymph nodes. Long-term administration of anti-JAM-C antibodies prevented engraftment of JAM-Cpos lymphoma cells in bone marrow, spleen, and lymph nodes of mice. Plasmon resonance studies identified JAM-B as the major ligand for JAM-C, whereas homotypic JAM-C interactions remained at background levels. Accordingly, anti-JAM-C antibodies blocked adhesion of JAM-C–expressing B cells to their ligand JAM-B, and immunofluorescence analysis showed the expression of JAM-B on murine and human lymphatic endothelial cells. Targeting JAM-C could thus constitute a new therapeutic strategy to prevent lymphoma cells from reaching supportive microenvironments not only in the bone marrow and lymph nodes but also in the spleen. Cancer Res; 73(2); 640–51. ©2012 AACR.
Therapeutic Effects of Deleting Cancer-Associated Fibroblasts in Cholangiocarcinoma
Authors: Mertens Joachim C. , Fingas Christian D. , Christensen John D. , Smoot Rory L. , Bronk Steven F. , Werneburg Nathan W. , Gustafson Michael P. , Dietz Allan B. , Roberts Lewis R. , Sirica Alphonse E. , Gores Gregory J. 
Published: December 2012

Abstract
Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are “activated” and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors. Cancer Res; 73(2); 897–907. ©2012 AACR.
CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8
Authors: Goetz Matthew P. , Suman Vera J. , Hoskin Tanya L. , Gnant Michael , Filipits Martin , Safgren Stephanie L. , Kuffel Mary , Jakesz Raimund , Rudas Margaretha , Greil Richard , Dietze Otto , Lang Alois , Offner Felix , Reynolds Carol A. , Weinshilboum Richard M. , Ames Matthew M. , Ingle James N. 
Published: December 2012

Abstract
Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy.
Experimental Design: A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism.
Results: The common CYP2D6*4 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95–2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30).
Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole. Clin Cancer Res; 19(2); 500–7. ©2012 AACR.
BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies
Authors: Kuhne Michelle R. , Mulvey Tanya , Belanger Blake , Chen Sharline , Pan Chin , Chong Colin , Cao Fei , Niekro Wafa , Kempe Tom , Henning Karla A. , Cohen Lewis J. , Korman Alan J. , Cardarelli Pina M. 
Published: December 2012

Abstract
Purpose: CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non–Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma.
Experimental Design: Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice.
Results: BMS-936564/MDX-1338 is a fully human IgG4 monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC50 values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition.
Conclusions: BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma. Clin Cancer Res; 19(2); 357–66. ©2012 AACR.
SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival
Authors: Hassanein Mohamed , Hoeksema Megan D. , Shiota Masakazu , Qian Jun , Harris Bradford K. , Chen Heidi , Clark Jonathan E. , Alborn William E. , Eisenberg Rosana , Massion Pierre P. 
Published: December 2012

Abstract
Purpose: We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non–small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival.
Experimental Design: To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines.
Results: Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na+-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling.
Conclusions: These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival. Clin Cancer Res; 19(3); 560–70. ©2012 AACR.
Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma: A Review of the Current Understanding of Epidemiology, Biology, Risk Stratification, and Management of Myeloma Precursor Disease
Authors: Agarwal Amit , Ghobrial Irene M. 
Published: December 2012

Abstract
The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even “cure” a person at this premalignant stage. Clin Cancer Res; 19(5); 985–94. ©2012 AACR.
A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma
Authors: Puntoni Matteo , Branchi Daniela , Argusti Alessandra , Zanardi Silvia , Crosta Cristiano , Meroni Emanuele , Munizzi Francesco , Michetti Paolo , Coccia Gianni , De Roberto Giuseppe , Bandelloni Roberto , Turbino Laura , Minetti Egle , Mori Marco , Salvi Sandra , Boccardo Simona , Gatteschi Beatrice , Benelli Roberto , Sonzogni Angelica , DeCensi Andrea 
Published: December 2012

Abstract
Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis.
After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue.
Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of −10.6%, 95% confidence interval (CI), −20.5 to −0.7, and −8.1%, 95% CI, −22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (−16.4%; 95% CI, −29.0 to −3.8). No dose–response relationship was noted, except for NF-κB expression in normal tissue.
Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity. Cancer Prev Res; 6(2); 74–81. ©2012 AACR.
Metrical Structure and Production of English Rhythm
Authors: Erickson Donna , Suemitsu Atsuo , Shibuya Yoshiho , Tiede Mark 
Published: December 2012

Abstract
This paper examines kinematic patterns of jaw opening and associated F1 values of 4 American English speakers in productions of the sentence ‘I saw five bright highlights in the sky’. Results show strong-weak jaw opening alternations during the production of the utterance, and significant correlation of F1 with jaw opening for 3 of the 4 speakers. The observed jaw opening patterns correspond to metrically generated syllable stress levels for productions of the sentence by these 4 speakers.
Preterm Heart in Adult Life
Authors: Lewandowski Adam J. , Augustine Daniel , Lamata Pablo , Davis Esther F. , Lazdam Merzaka , Francis Jane , McCormick Kenny , Wilkinson Andrew R. , Singhal Atul , Lucas Alan , Smith Nic P. , Neubauer Stefan , Leeson Paul 
Published: December 2012

Background—
Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development. In animal studies, this results in an adversely remodeled left ventricle. We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans.

Methods and Results—

A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance. One hundred two had been followed prospectively since preterm birth (gestational age=30.3±2.5 week; birth weight=1.3±0.3 kg), and 132 were born at term to uncomplicated pregnancies. Longitudinal and short-axis cine images were used to quantify left ventricular mass, 3-dimensional geometric variation by creation of a unique computational cardiac atlas, and myocardial function. We then determined whether perinatal factors modify these left ventricular parameters. Individuals born preterm had increased left ventricular mass (66.5±10.9 versus 55.4±11.4 g/m
2
;
P
<0.001) with greater prematurity associated with greater mass (
r
= −0.22,
P
=0.03). Preterm-born individuals had short left ventricles with small internal diameters and a displaced apex. Ejection fraction was preserved (
P
>0.99), but both longitudinal systolic (peak strain, strain rate, and velocity,
P
<0.001) and diastolic (peak strain rate and velocity,
P
<0.001) function and rotational (apical and basal peak systolic rotation rate,
P
=0.05 and
P
=0.006; net twist angle,
P
=0.02) movement were significantly reduced. A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring (
P
=0.02, n=29).

Conclusions—
Individuals born preterm have increased left ventricular mass in adult life. Furthermore, they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01487824.
The Brewer–Dobson Circulation in a Changing Climate: Impact of the Model Configuration
Authors: Bunzel Felix , Schmidt Hauke 
Published: December 2012

Abstract
Most climate models simulate a strengthening of the Brewer–Dobson circulation (BDC) under a changing climate. However, the magnitude of the trend as well as the underlying mechanisms varies significantly among the models. In this work the impact of both vertical resolution and vertical extent of a model on the simulated BDC change is investigated by analyzing sensitivity simulations performed with the general circulation model ECHAM6 in three different model configurations for three different climate states. Tropical upwelling velocities and age of stratospheric air are used as measures for the strength of the BDC. Both consistently show a BDC strengthening from the preindustrial to the future climate state for all configurations of the model. However, the amplitude and origin of this change vary between the different setups. Analyses of the tropical upward mass flux indicate that in the model with a lid at 10 hPa the BDC strengthening at 70 hPa is primarily produced by resolved wave drag, while in the model with a higher lid (0.01 hPa) the parameterized wave drag yields the main contribution to the BDC increase. This implies that consistent changes in the BDC originate from different causes when the stratosphere is not sufficiently resolved in a model. Furthermore, the effect of enhancing the horizontal diffusion in the upper model layers to avoid resolved wave reflection at the model lid is quantified, and a possible link to the different behavior of the low-top model with regard to the origin of the BDC change is identified.
Characteristics Associated with the Madden–Julian Oscillation at Manus Island
Authors: Deng Liping , McFarlane Sally A. , Flaherty Julia E. 
Published: December 2012

Abstract
Ground-based high temporal and vertical resolution datasets from observations during 2002–07 at the Atmospheric Radiation Measurement (ARM) tropical western Pacific (TWP) site on Manus Island are used to examine the characteristics of clouds and rainfall associated with the active phase of the Madden–Julian oscillation (MJO) passing over Manus. A composite MJO event at Manus is developed based on the NOAA MJO index 4 and precipitation using 13 events. The cloud characteristics associated with the active phase of the MJO at Manus show a two-phase structure as the wave passes over Manus. During the development phase, congestus plays an important role, and the enhanced convection is located between surface westerly and easterly wind anomalies (type-I structure). During the mature phase, deep convection is the dominant cloud type, and the enhanced convection is collocated with the westerly wind anomalies (type-II structure). Consistent with this two-phase structure, the heavy rainfall frequency also shows a two-peak structure during the MJO disturbance, while light rainfall does not show a clear relation to the intraseasonal disturbance associated with the MJO. In addition, a positive relationship between the precipitation rate and precipitable water vapor exists at Manus, and the atmospheric column is less moist after the passing of the MJO convection center than before.
Changes in the Relationship between ENSO and Asia–Pacific Midlatitude Winter Atmospheric Circulation
Authors: He Shengping , Wang Huijun , Liu Jiping 
Published: December 2012

Abstract
Interdecadal changes in the relationship between El Niño–Southern Oscillation (ENSO) and midlatitude atmospheric circulation are investigated in this study. Comparison of associations between ENSO and midlatitude atmospheric circulation anomalies between 1958–76 and 1977–2010 suggest that during 1958–76, ENSO exerted a strong impact on the East Asian winter monsoon (EAWM) and the associated atmospheric circulation pattern was similar to the positive North Pacific Oscillation (NPO). In contrast, during 1977–2010, the NPO-like atmospheric pattern disappeared. Instead, ENSO exerted a strong impact on the eastern North Pacific Ocean (NP) and North America, and the associated atmospheric circulation pattern resembled the Pacific–North America (PNA) teleconnection. Also, significant correlations between ENSO and sea surface temperature anomalies (SSTAs) over the western subtropical NP during 1958–76 became insignificant during 1977–2010, whereas negative correlations between ENSO and SSTAs in the central and northeastern subtropical NP became more significant since the mid-1970s. Further analyses suggest that the interdecadal shift of the Aleutian low, which occurred around the mid-1970s, might be responsible for the identified changes. Before the mid-1970s, warm ENSO events generated an anomalous anticyclone over the western NP, which is a key system bridging ENSO and EAWM-related atmospheric circulation. After the mid-1970s, the Aleutian low intensified and shifted eastward, leading to the impact of ENSO prevailing over the eastern NP. In addition, the weakened (strengthened) ENSO–NPO/EAWM (ENSO–PNA) relationship likely contributed to the weakened (strengthened) relationship between ENSO and SSTAs over the western (central and eastern) subtropical NP.
Comparison of Mobile-Radar Measurements of Tornado Intensity with Corresponding WSR-88D Measurements
Authors: Toth M. , Trapp R. J. , Wurman J. , Kosiba K. A. 
Published: December 2012

Abstract
In the United States, visual observations of tornadoes and/or the existence of tornado damage currently provide the sole evidence of tornadogenesis in association with a mesocyclone or other radar-detected storm-scale vortex. The severity of the tornado damage is currently the only means of estimating the intensity of tornadoes, radar detected or otherwise. The limitations of the damage-based record of tornado occurrence and intensity are well known and motivated this research. Weather Surveillance Radar-1988 Doppler (WSR-88D) measurements of the translating tornadic flow were compared with (semi-) coordinated measurements obtained near the surface with mobile radar. On the basis of a small yet fairly broad sample of tornadoes, high linear correlation was found between the vortex intensity (rotation plus translation) quantified using WSR-88D data and that quantified using Doppler on Wheels data. The possible effects of Doppler radar sampling on these results were explored through experiments with a simple vortex model. These experiments argued that the likelihood is high that a tornado would be sampled in a favorable way during at least one radar scan. Hence, the suggestion from this work is that WSR-88Ds (or similar operational radars) can potentially be used in isolation to estimate low-level tornado intensity. The proposed estimation is by way of a linear regression model, and application of this model is relevant only once a tornado is already confirmed.