bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute renal response to rapid onset respiratory acidosis
Authors: Ramadoss Jayanth , Stewart Randolph H. , Cudd Timothy A. 
Published: March 2011

Renal strong ion compensation to chronic respiratory acidosis has been established, but the nature of the response to acute respiratory acidosis is not well defined. We hypothesized that the response to acute respiratory acidosis in sheep is a rapid increase in the difference in renal fractional excretions of chloride and sodium (FeCl – FeNa). Inspired CO2 concentrations were increased for 1 h to significantly alter PaCO2 and pHa from 32 ± 1 mm Hg and 7.52 ± 0.02 to 74 ± 2 mm Hg and 7.22 ± 0.02, respectively. FeCl – FeNa increased significantly from 0.372 ± 0.206 to 1.240 ± 0.217% and returned to baseline at 2 h when PaCO2 and pHa were 37 ± 0.6 mm Hg and 7.49 ± 0.01, respectively. Arterial pH and FeCl – FeNa were significantly correlated. We conclude that the kidney responds rapidly to acute respiratory acidosis, within 30 min of onset, by differential reabsorption of sodium and chloride.
A fingernail clam (Sphaerium sp.) shows higher reproductive success in hypoxic waters
Authors: Joyner-Matos J. , Richardson H. , Sammeli T. , Chapman L. J. 
Published: March 2011

Low dissolved O2, or hypoxia, is becoming increasingly prevalent in aquatic habitats and is considered to be stressful for aerobic organisms. However, hypoxia also can be beneficial by decreasing cellular stress, particularly that related to free radicals. Therefore, an animal’s ideal habitat may have the minimum O2necessary to sustain aerobic metabolism, with excess O2increasing the need to scavenge free radicals and repair free radical damage. Here we show that a natural population of small (<9 mm shell length) freshwater clams (genus Sphaerium Scopoli, 1777) lives along a dissolved O2gradient from extreme hypoxia to moderate hypoxia. We tested the hypothesis that clams living in extreme hypoxia would have higher reproductive success than clams that live in moderate hypoxia. Clam abundance was highest in water with very low dissolved O2, conditions previously demonstrated to decrease cellular stress. The internally brooding clams reproduced year-round and had higher reproductive output in extreme hypoxia than in moderate hypoxia. The findings demonstrate that the apparent cellular-level benefits of hypoxia may translate into increased fitness, especially for small organisms.
Spatial organization of Molina’s hog-nosed skunk (Conepatus chinga) in two landscapes of the Pampas grassland of Argentina
Authors: Castillo D. F. , Lucherini M. , Luengos Vidal E. M. , Manfredi C. , Casanave E. B. 
Published: March 2011

We radio-tracked 16 individuals (6 males, 10 females) of the little known Molina’s hog-nosed skunk ( Conepatus chinga (Molina, 1782)) and compared home-range dynamics, movement rates, and densities between a protected area and a landscape fragmented by agriculture. The mean home-range size (95% fixed kernel) was 166.7 ha (SD = 107.5 ha), without significant differences between areas. Home-range size varied significantly between males (mean = 243.7 ha, SD = 76.5 ha) and females (mean = 120.4 ha, SD =77.6 ha). Overlap between home range and core area was extensive between and within sexes in the protected area and more limited in the cropland area. Mean distance traveled between two consecutive resting sites was 269.5 m (SD = 365 m) and did not differ between areas, although movements were greater for males than females. Distance moved was influenced by seasons, being greater during the cold period. Finally, density estimates were consistently greater at the protected area. We argue that home-range size in Molina’s hog-nosed skunks is an inherent species property, whereas population density and territoriality are more flexible parameters that could reflect how the ecosystem state was affected. In our study, the greater dispersion of food patches in the cropland area than in the protected area may be the major factor influencing these parameters.
Sperm morphology, ATP content, and analysis of motility in Atlantic halibut (Hippoglossus hippoglossus)
Authors: Alavi Sayyed Mohammad Hadi , Butts Ian A.E. , Hatef Azadeh , Mommens Maren , Trippel Edward A. , Litvak Matthew K. , Babiak Igor 
Published: March 2011

Spermatozoon of Atlantic halibut ( Hippoglossus hippoglossus (L., 1758)) is uniflagellated, lacks an acrosome, and is differentiated into a head, midpiece, and flagellum. There are two to five mitochondria in the midpiece, as well as proximal and distal centrioles. The flagellum consisted of 9 + 2 microtubules surrounded by plasma membrane, which is extended at the proximal part of the flagellum owing to the presence of vacuoles. After sperm activation in seawater, sperm motility and velocity decreased from 98.4% ± 3.4% and 170.3 ± 8.9 µm·s–1at 15 s after sperm activation to 4.8% ± 4.7% and 9.2 ± 8.9 µm·s–1at 120 s after sperm activation, respectively. ATP content (nmol·L–1ATP per 108spermatozoa) significantly decreased at 60 s after sperm activation (5.9 ± 1.5) compared with at 0 and 30 s after sperm activation (14.9 ± 1.5 and 14.5 ± 1.5, respectively). Beating waves propagated along the full length of the flagellum after sperm activation, whereas waves were restricted to the proximal section during the latter motility period. Wave amplitude significantly decreased at 45 s after sperm activation, but wavelength did not differ. The present study showed associations among sperm morphology, ATP content, flagellar wave parameters, and sperm velocity, which could be used in comparative spermatology.
Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors
Authors: Lou Yuanmei , McDonald Paul C. , Oloumi Arusha , Chia Stephen , Ostlund Christina , Ahmadi Ardalan , Kyle Alastair , auf dem Keller Ulrich , Leung Samuel , Huntsman David , Clarke Blaise , Sutherland Brent W. , Waterhouse Dawn , Bally Marcel , Roskelley Calvin , Overall Christopher M. , Minchinton Andrew , Pacchiano Fabio , Carta Fabrizio , Scozzafava Andrea , Touisni Nadia , Winum Jean-Yves , Supuran Claudiu T. , Dedhar Shoukat 
Published: March 2011

Abstract
Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1–inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4Luc+ cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis. Cancer Res; 71(9); 3364–76. ©2011 AACR.
Ribonucleotide Reductase Small Subunit M2B Prognoses Better Survival in Colorectal Cancer
Authors: Liu Xiyong , Lai Lily , Wang Xiaochen , Xue Lijun , Leora Sofia , Wu Jun , Hu Shuya , Zhang Keqiang , Kuo Mei-Ling , Zhou Lun , Zhang Hang , Wang Yafan , Wang Yan , Zhou Bingsen , Nelson Rebecca A. , Zheng Shu , Zhang Suzhan , Chu Peiguo , Yen Yun 
Published: March 2011

Abstract
Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here, we report that high levels of RRM2B expression are correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in nonmetastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to carry out immunohistochemistry for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan–Meier and multivariate Cox analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (HR = 0.40; 95% CI = 0.18–0.86, P = 0.016). In the validation set, RRM2B was negatively related to tumor invasion (OR = 0.45, 95% CI = 0.19–0.99, P = 0.040) and lymph node involvement (OR = 0.48, 95% CI = 0.25–0.92, P = 0.026). Furthermore, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR = 0.48, 95% CI = 0.26–0.91, P = 0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III and IV tumors rather than earlier stage I and II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients. Cancer Res; 71(9); 3202–13. ©2011 AACR.
Dual mTORC2/mTORC1 Targeting Results in Potent Suppressive Effects on Acute Myeloid Leukemia (AML) Progenitors
Authors: Altman Jessica K. , Sassano Antonella , Kaur Surinder , Glaser Heather , Kroczynska Barbara , Redig Amanda J. , Russo Suzanne , Barr Sharon , Platanias Leonidas C. 
Published: March 2011

Abstract
Purpose: To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors.
Experimental Design: Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.
Results: mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro.
Conclusions: Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin. Clin Cancer Res; 17(13); 4378–88. ©2011 AACR.
Persistence of Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients Predicts Increased Risk for Relapse—A European Pooled Analysis
Authors: Janni Wolfgang , Vogl Florian D. , Wiedswang Gro , Synnestvedt Marit , Fehm Tanja , Jückstock Julia , Borgen Elin , Rack Brigitte , Braun Stephan , Sommer Harald , Solomayer Erich , Pantel Klaus , Nesland Jahn , Friese Klaus , Naume Bjørn 
Published: March 2011

Abstract
Background: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death.
Patients and Methods: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I–III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS).
Results: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P &lt; 0.001 values for all investigated endpoints).
Conclusion: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials. Clin Cancer Res; 17(9); 2967–76. ©2011 AACR.
New Strategies in Muscle-Invasive Bladder Cancer: On the Road to Personalized Medicine
Authors: Shah Jay B. , McConkey David J. , Dinney Colin P.N. 
Published: March 2011

Abstract
Bladder cancer remains one of the most deadly and expensive diseases affecting modern society. The options currently available to patients with muscle-invasive bladder cancer have remained essentially unchanged for the last generation. As the roles for surgery and chemotherapy in the management of this lethal disease have become better defined, so too have the limitations of these two treatment modalities. Despite the lack of groundbreaking clinical advances over the past two decades, recent years have witnessed a notable increase in the amount of promising preclinical and early translational research that will greatly improve our understanding of the molecular underpinnings of bladder cancer. If this momentum in bladder cancer research continues to build, it is likely that in the next 5 to 10 years we will be able to achieve our goal of bringing bladder cancer treatment into the age of personalized medicine. Clin Cancer Res; 17(9); 2608–12. ©2011 AACR.
PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53
Authors: Zandi Roza , Selivanova Galina , Christensen Camilla Laulund , Gerds Thomas Alexander , Willumsen Berthe Marie , Poulsen Hans Skovgaard 
Published: March 2011

Abstract
Purpose: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1Met (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1Met to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.
Experimental Design: The therapeutic effect of PRIMA-1Met/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1Met/APR-246 was further evaluated in two different SCLC xenograft models.
Results: PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1Met/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1Met/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1Met after i.v. injection in SCLC mouse models with no apparent toxicity.
Conclusion: This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1Met/APR-246 for the treatment of SCLC. Clin Cancer Res; 17(9); 2830–41. ©2011 AACR.
C-Reactive Protein Polarizes Human Macrophages to an M1 Phenotype and Inhibits Transformation to the M2 Phenotype
Authors: Devaraj Sridevi , Jialal Ishwarlal 
Published: March 2011

Objective—
Inflammation is pivotal in atherosclerosis. Monocyte-macrophages are crucial in atherosclerosis. Monocytes can develop into subsets: classically (M1) or alternatively (M2) activated cells. Several studies point to a proinflammatory role for C-reactive protein (CRP). Because there is a paucity of data on the effects of CRP on macrophage phenotype, we tested effects of CRP on macrophage polarization.

Methods and Results—
Monocytes were incubated with CRP (0 to 50 μg/mL) and differentiated into macrophages for 7 days. Phenotypic characterization of M1 and M2 macrophages was performed using flow cytometry. CRP treatment resulted in increased population of M1 macrophages (tumor necrosis factor [TNF]/interleukin [IL]-12/C-C chemokine receptor 2, TNF/IL-12/monocyte chemotactic protein-1, or TNF/IL-1/IL-12). These effects were not abrogated by polymixin B or small interfering RNA to Toll-like receptor-4, but they were abrogated by boiled CRP. Administration of human CRP to rats in vivo increased polarization of macrophages to M1 phenotype compared with human serum albumin. When macrophages were primed to the M2 phenotype with IL-4, addition of CRP resulted in significantly increased secretion of TNF-α, MCP-1, and IL-1 and conversion of macrophages from the M2 to the M1 phenotype. CRP failed to prime macrophages to the M1 phenotype in presence of CD32/CD64 small interfering RNA or dominant-negative nuclear factor kappa B.

Conclusion—
Collectively, these results further support a role for CRP in promoting differentiation of human monocytes toward a proinflammatory M1 phenotype.
Late Gadolinium Enhancement Magnetic Resonance Imaging in the Diagnosis and Prognosis of Endomyocardial Fibrosis Patients
Authors: Salemi Vera M.C. , Rochitte Carlos E. , Shiozaki Afonso A. , Andrade Joalbo M. , Parga José R. , de Ávila Luiz F. , Benvenuti Luiz A. , Cestari Ismar N. , Picard Michael H. , Kim Raymond J. , Mady Charles 
Published: March 2011

Background—
Endocardial fibrous tissue (FT) deposition is a hallmark of endomyocardial fibrosis (EMF). Echocardiography is a first-line and the standard technique for the diagnosis of this disease. Although late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) allows FT characterization, its role in the diagnosis and prognosis of EMF has not been investigated.

Methods and Results—

Thirty-six patients (29 women; age, 54±12 years) with EMF diagnosis after clinical evaluation and comprehensive 2-dimensional Doppler echocardiography underwent cine-CMR for assessing ventricular volumes, ejection fraction and mass, and LGE-CMR for FT characterization and quantification. Indexed FT volume (FT/body surface area) was calculated after planimetry of the 8 to 12 slices obtained in the short-axis view at end-diastole (mL/m
2
). Surgical resection of FT was performed in 16 patients. In all patients, areas of LGE were confined to the endocardium, frequently as a continuous streak from the inflow tract extending to the apex, where it was usually most prominent. There was a relation between increased FT/body surface area and worse New York Heart Association functional class and with increased probability of surgery (
P
<0.05). The histopathologic examination of resected FT showed typical features of EMF with extensive endocardial fibrous thickening, proliferation of small vessels, and scarce inflammatory infiltrate. In multivariate analysis, the patients with FT/body surface area >19 mL/m
2
had an increased mortality rate, with a relative risk of 10.8.

Conclusions—
Our study provides evidence that LGE-CMR is useful in the diagnosis and prognosis of EMF through quantification of the typical pattern of FT deposition.
Feasibility of Contrast-Enhanced and Nonenhanced MRI for Intraprocedural and Postprocedural Lesion Visualization in Interventional Electrophysiology
Authors: Nordbeck Peter , Hiller Karl-Heinz , Fidler Florian , Warmuth Marcus , Burkard Natalie , Nahrendorf Matthias , Jakob Peter M. , Quick Harald H. , Ertl Georg , Bauer Wolfgang R. , Ritter Oliver 
Published: March 2011

Background—
Imaging of myocardial ablation lesions during electrophysiology procedures would enable superior guidance of interventions and immediate identification of potential complications. The aim of this study was to establish clinically suitable MRI-based imaging techniques for intraprocedural lesion visualization in interventional electrophysiology.

Methods and Results—

Interventional electrophysiology was performed under magnetic resonance guidance in an animal model, using a custom setup including magnetic resonance–conditional catheters. Various pulse sequences were explored for intraprocedural lesion visualization after radiofrequency ablation. The developed visualization techniques were then used to investigate lesion formation in patients immediately after ablation of atrial flutter. The animal studies in 9 minipigs showed that gadolinium-DTPA–enhanced T1-weighted and nonenhanced T2-weighted pulse sequences are particularly suitable for lesion visualization immediately after radiofrequency ablation. MRI-derived lesion size correlated well with autopsy (
R
2
=0.799/0.709 for contrast-enhanced/nonenhanced imaging). Non–contrast agent–enhanced techniques were suitable for repetitive lesion visualization during electrophysiological interventions, thus allowing for intraprocedural monitoring of ablation success. The patient studies in 24 patients with typical atrial flutter several minutes to hours after cavotricuspid isthmus ablation confirmed the results from the animal experiments. Therapeutic lesions could be visualized in all patients using contrast-enhanced and also nonenhanced MRI with high contrast-to-noise ratio (94.6±35.2/111.1±32.6 versus 48.0±29.0/68.0±37.3 for ventricular/atrial lesions and contrast-enhanced versus nonenhanced imaging).

Conclusions—
MRI allows for precise lesion visualization in electrophysiological interventions just minutes after radiofrequency ablation. Nonenhanced T2-weighted MRI is particularly feasible for intraprocedural delineation of lesion formation as lesions are detectable within minutes after radiofrequency delivery and imaging can be repeated during interventions.