bluuebunny/crossref_metadata_2025 huggingface dataset:
Very Large Database of Lipids: Rationale and Design
Authors: Martin Seth S. , Blaha Michael J. , Toth Peter P. , Joshi Parag H. , McEvoy John W. , Ahmed Haitham M. , Elshazly Mohamed B. , Swiger Kristopher J. , Michos Erin D. , Kwiterovich Peter O. , Kulkarni Krishnaji R. , Chimera Joseph , Cannon Christopher P. , Blumenthal Roger S. , Jones Steven R.
Published: October 2013

Blood lipids have major cardiovascular and public health implications. Lipid‐lowering drugs are prescribed based in part on categorization of patients into normal or abnormal lipid metabolism, yet relatively little emphasis has been placed on: (1) the accuracy of current lipid measures used in clinical practice, (2) the reliability of current categorizations of dyslipidemia states, and (3) the relationship of advanced lipid characterization to other cardiovascular disease biomarkers. To these ends, we developed the Very Large Database of Lipids (NCT01698489), an ongoing database protocol that harnesses deidentified data from the daily operations of a commercial lipid laboratory. The database includes individuals who were referred for clinical purposes for a Vertical Auto Profile (Atherotech Inc., Birmingham, AL), which directly measures cholesterol concentrations of low‐density lipoprotein, very low‐density lipoprotein, intermediate‐density lipoprotein, high‐density lipoprotein, their subclasses, and lipoprotein(a). Individual Very Large Database of Lipids studies, ranging from studies of measurement accuracy, to dyslipidemia categorization, to biomarker associations, to characterization of rare lipid disorders, are investigator‐initiated and utilize peer‐reviewed statistical analysis plans to address a priori hypotheses/aims. In the first database harvest (Very Large Database of Lipids 1.0) from 2009 to 2011, there were 1 340 614 adult and 10 294 pediatric patients; the adult sample had a median age of 59 years (interquartile range, 49–70 years) with even representation by sex. Lipid distributions closely matched those from the population‐representative National Health and Nutrition Examination Survey. The second harvest of the database (Very Large Database of Lipids 2.0) is underway. Overall, the Very Large Database of Lipids database provides an opportunity for collaboration and new knowledge generation through careful examination of granular lipid data on a large scale.
Lower Admission Hemoglobin Levels Are Associated With Longer Symptom Duration in Acute ST‐Elevation Myocardial Infarction
Authors: Shacham Yacov , Leshem‐Rubinow Eran , Ben‐Assa Eyal , Roth Arie , Steinvil Arie
Published: October 2013

Background

An acute‐phase response in patients with acute myocardial infarction could contribute to the development of anemia.

Hypothesis

An association may exist between symptom duration, hemoglobin (Hb) concentration and serum C‐reactive protein (CRP) values in patients presenting to an emergency department (ED) with acute ST‐segment elevation myocardial infarction (STEMI).

Methods

A retrospective analysis was conducted on consecutive male STEMI patients who were admitted to our medical center's ED from January 2008 to November 2012 and had presented within the first 12 hours after the onset of chest pain. Hemoglobin concentration and serum CRP levels were determined from blood samples taken prior to any drug or fluid administration. Analyses of variance were used to determine interactions between selected time‐to‐presentation cutoffs and admission Hb and CRP concentrations. Patients with other reasons known to cause elevation of inflammatory markers, anemia, or bleeding diathesis were excluded.

Results

The study population comprised 718 patients whose mean age was 61 ± 12 years (range, 27–96 years). Blood was drawn for Hb and CRP measurements directly upon admission. Patients who presented to the ED within 3 hours of symptom onset had higher Hb concentrations (P = 0.048) and lower serum CRP levels (P < 0.001) compared with those who presented after a longer interval from symptom onset.

Conclusions

Longer symptom duration is associated with a lower admission Hb level and an early rise in the CRP level of male patients with acute STEMI.
Safe‐Dose Thrombolysis Plus Rivaroxaban for Moderate and Severe Pulmonary Embolism: Drip, Drug, and Discharge
Authors: Sharifi Mohsen , Bay Curt , Schwartz Frederic , Skrocki Laura
Published: October 2013

Background

Thrombolysis, though very effective, has not been embraced as routine therapy for symptomatic pulmonary embolism (PE) except in very severe cases. Rivaroxaban recently has been approved for the treatment of venous thromboembolism (VTE). There are no data on the combined use of thrombolysis and rivaroxaban in PE.

Hypothesis

“Safe dose” thrombolysis (SDT) plus new oral anticoagulants are expected to become an appealing, safe and effective approach in the treatment of moderate and severe PE in the near future, thereby drastically reducing hospitalization time.

Methods

Over a 12‐month period, 98 consecutive patients with symptomatic PE were treated by a combination of SDT and rivaroxaban. The SDT was started in parallel with unfractionated heparin and given in 2 hours. Heparin was given for a total of 24 hours and rivaroxaban started at 15 or 20 mg daily 2 hours after termination of heparin infusion.

Results

There was no bleeding due to SDT. Recurrent VTE occurred in 3 patients who had been switched to warfarin. No patient on rivaroxaban developed VTE. Two patients died of cancer at a mean follow‐up of 12 ± 2 months. The pulmonary artery systolic pressure dropped from 52.8 ± 3.9 mm Hg before to 32 ± 4.4 mm Hg within 36 hours of SDT (P < 0.001). The duration of hospitalization for patients presenting primarily for PE was 1.9 ± 0.2 days.

Conclusions

“Safe dose” thrombolysis plus rivaroxaban is highly safe and effective in the treatment of moderate and severe PE, leading to favorable early and intermediate‐term outcomes and early discharge.
Development of Remote Sensing Based Models for Surface Water Quality
Authors: Akbar Tahir Ali , Hassan Quazi K. , Achari Gopal
Published: October 2013

The objectives of this paper were to develop, evaluate, and apply the remote sensing based models for Canadian Water Quality Index (CWQI) and turbidity for the Bow River of Alberta. We used 31 scenes of Landsat‐5 TM satellite data to establish the relationship between the planetary reflectance and the monthly ground measured data for the period of 5 years (i.e. 2006–2010). The four spectral bands (i.e. blue, green, red, and near infrared) were used to obtain the most suitable models from 26 different band combinations. The co‐efficients of determination on the basis of red band were 0.91 for the CWQI model and 0.82 for the turbidity model. The best‐fit models were validated with ground measured data and found that: 72% of the data showed 100% matching for the CWQI model and 83% of the data for the turbidity model. The Landsat‐5 TM based CWQI and turbidity models were applied on all the scenes to obtain five CWQI classes (i.e. excellent, good, fair, marginal and poor), and six classes of turbidity (i.e. 0–10 NTU, 10–20 NTU, 20–30 NTU, 30–40 NTU, 40–50 NTU, >50 NTU). On the basis of percentages obtained for CWQI and turbidity classes, the ranks of years in terms of water quality from best to worst were: 2009, 2006, 2008, 2010, and 2007 respectively. The variation of river water quality in different years of interest was associated with the climatic changes. The most deteriorated water quality noted in two natural sub‐regions included mixed grass and dry mixed grass, which could be related to irrigation‐based farming.
Defining Reference Nutrient Concentrations in Southeast Eco‐Region Lakes, China
Authors: Huo Shouliang , Ma Chunzi , Xi Beidou , Su Jing , Zan Fengyu , Jiang Tiantian
Published: October 2013

Establishing nutrient reference conditions of lakes in eco‐region is beneficial to set realistic restoration targets and guide regulation of water bodies, and aid in the analysis of economic losses derived from eutrophication. In this paper, total phosphorus (TP), total nitrogen (TN), Secchi depth (SD), and planktonic chlorophyll a (Chl‐a) reference conditions in Southeast eco‐region lakes were calculated using lake population distribution method and trisection method. The results indicated that the two methods provided consistently similar values to our predicted baselines of TP, TN, SD, and Chl‐a. Furthermore, multiple linear regression model prediction and a novel extrapolation approach by combining optimal map recognition with pattern recognition inverse mapping were developed for estimating reference nutrient concentrations. Although there is no clear recommendation about the best method for determining nutrient reference values, reference values determined by these methods were nearly consistent for all parameters. The values and ranges considered as nutrients reference conditions for Southeast eco‐region lakes were given as follows: 0.020–0.025 mg/L TP, 0.55–0.65 mg/L TN, 1.6–2.50 mg/m3 Chl‐a, 2.00–2.50 m SD. Overall, the results suggest that multiple linear regression and extrapolation approach can be used to define reference conditions, and the reference condition corresponds to mesotrophic status in Southeast eco‐region lakes.
Ecological Footprint Analysis Applied to a Coal‐Consumption County in China
Authors: Wang Yan , Wang Li , Shao Hongbo
Published: October 2013

Sustainable development is a critical issue in developing countries, especially for some regions whose economy depends greatly on non‐renewable resources. The ecological footprint is a measured area‐based indicator to analyze the sustainable use of natural resources. It has been widely used to evaluate whether the natural ecosystem's carrying capacity in a region could support its development. In this study, the method was utilized to determine the per capita ecological footprint, biocapacity and related indices for Shenmu County. Results showed that the ecological deficit was 20.075 ha/capita (cap) in 2009, indicating that Shenmu County was practicing unsustainable development, both socially and economically, and was over‐exploiting its natural resources and the environment. The ecological deficit worsened between 2004, when it was “overloading” (1.978 ha/cap), and 2009, when it was “seriously overloading” (20.075 ha/cap); this was linked to increases in the ecological footprint. The main reason for the ecological deficits was the large energy consumption of industrial production. Most coal consumption was used to produce coke, and coke output thus had that greatest impact on deficits as indicated by stepwise multiple linear regression. In order to decrease ecological deficits, attention should focus on the development of alternative energy sources or technology. Improving and changing land use and energy‐consumption patterns to create a resource‐saving approach would result in steady increases in resource conservation leading to sustainable consumption that will improve the future ecological environment of Shenmu County.
Purification of tropomyosin Br‐3 and 5NM1 and characterization of their interactions with actin
Authors: Kis‐Bicskei Nikolett , Vig Andrea , Nyitrai Miklós , Bugyi Beáta , Talián Gábor C.
Published: October 2013

Tropomyosins were first identified in neuronal systems in 1973. Although numerous isoforms were found and described since then, many aspects of their function and interactions remained unknown. Tropomyosin isoforms show different sorting pattern in neurogenesis. As one example, TM5NM1/2 is present in developing axons, but it is replaced by TMBr‐3 in mature neurons, suggesting that these tropomyosin isoforms contribute differently to the establishment of the functional features of the neuronal actin networks. We developed a method for the efficient purification of TMBr‐3 and TM5NM1 as recombinant proteins using bacterial expression system and investigated their interactions with actin. We found that both isoforms bind actin filaments, however, the binding of TM5NM1 was much stronger than that of TMBr‐3. TMBr‐3 and TM5NM1 modestly affected actin assembly kinetics, in an opposite manner. Consistently with the higher affinity of TM5NM1 it inhibited actin filament disassembly more efficiently than TMBr‐3. Similarly to other previously studied tropomyosins TM5NM1 inhibited the Arp2/3 complex‐mediated actin assembly. Notably, TMBr‐3 did not influence the Arp2/3 complex‐mediated polymerization. This is a unique feature of TMBr‐3, since so far it is the only known tropomyosin supporting the activity of the Arp2/3 complex, indicating that TMBr‐3 may colocalize and work simultaneously with Arp2/3 complex in neuronal cells. © 2013 Wiley Periodicals, Inc.
IQGAP1 interactome analysis by in vitro reconstitution and live cell 3‐color FRET microscopy
Authors: Wallrabe Horst , Cai Ying , Sun Yuansheng , Periasamy Ammasi , Luzes Rafael , Fang Xiaolan , Kan Ho‐Man , Cameron Luiz‐Claudio , Schafer Dorothy A. , Bloom George S.
Published: October 2013

IQGAP1 stimulates branched actin filament nucleation by activating N‐WASP, which then activates the Arp2/3 complex. N‐WASP can be activated by other factors, including GTP‐bound Cdc42 or Rac1, which also bind IQGAP1. Here we report the use of purified proteins for in vitro binding and actin polymerization assays, and Förster (or fluorescence) resonance energy transfer (FRET) microscopy of cultured cells to illuminate functional interactions among IQGAP1, N‐WASP, actin, and either Cdc42 or Rac1. In pyrene‐actin assembly assays containing N‐WASP and Arp2/3 complex, IQGAP1 plus either small G protein cooperatively stimulated actin filament nucleation by reducing the lag time before 50% maximum actin polymerization was reached. Similarly, Cdc42 and Rac1 modulated the binding of IQGAP1 to N‐WASP in a dose‐dependent manner, with Cdc42 enhancing the interaction and Rac1 reducing the interaction. These in vitro reconstitution results suggested that IQGAP1 interacts by similar, yet distinct mechanisms with Cdc42 versus Rac1 to regulate actin filament assembly through N‐WASP in vivo. The physiological relevance of these multi‐protein interactions was substantiated by 3‐color FRET microscopy of live MDCK cells expressing various combinations of fluorescent N‐WASP, IQGAP1, Cdc42, Rac1, and actin. This study also establishes 3‐color FRET microscopy as a powerful tool for studying dynamic intermolecular interactions in live cells. © 2013 Wiley Periodicals, Inc.
Actin and microtubules play distinct roles in governing the anisotropic deformation of cell nuclei in response to substrate strain
Authors: Tremblay Dominique , Andrzejewski Lukasz , Leclerc Alexandre , Pelling Andrew E.
Published: October 2013

Physical forces arising in the cellular microenvironment have been hypothesized to play a major role in governing cell function. Moreover, it is thought that gene regulation may be sensitive to nuclear deformations taking place in response to extracellular forces over short and long timescales. Although nuclear responses to mechanical stimuli over long timescales are relatively well studied, the short‐term responses are poorly understood. Therefore, to characterize the short‐term instantaneous deformation of the nucleus in a mechanically dynamic environment, we exposed MDCK epithelial monolayers to varying mechanical strain fields. The results reveal that nuclei deform anisotropically in response to substrate strain, specifically, the minor nuclear axis is significantly more deformable than the major axis. We show that upon microtubule depolymerization, nuclear deformation anisotropy completely disappears. Moreover, the removal of actin causes a significant increase in nuclear deformation along the minor axis and a corresponding increase in mechanical anisotropy. The results demonstrate that the nucleus deforms in a manner that is very much dependent on the direction of strain and the characteristics of the strain field. Actin and microtubules also appear to play distinct roles in controlling the anisotropic deformation of the nucleus in response to mechanical forces that arise in the cellular microenvironment. © 2013 Wiley Periodicals, Inc.
Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors
Authors: Leese Mathew P. , Jourdan Fabrice L. , Major Meriel R. , Dohle Wolfgang , Hamel Ernest , Ferrandis Eric , Fiore Ann , Kasprzyk Philip G. , Potter Barry V. L.
Published: October 2013

A structure–activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)‐based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B‐ring‐mimicking THIQ core was connected to methoxyaryl D‐ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7‐methoxy‐2‐(3‐ methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (20 c) GI50=2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ‐based A,B‐mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7‐methoxy‐6‐sulfamoyloxy‐2‐(3,4,5‐trimethoxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis‐ sulfamate in an in vivo model of multiple myeloma.
De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl‐1
Authors: Ding Xiao , Li Yan , Lv Li , Zhou Mi , Han Li , Zhang Zhengxi , Ba Qian , Li Jingquan , Wang Hui , Liu Hong , Wang Renxiao
Published: October 2013

Considerable efforts have been made to the development of small‐molecule inhibitors of antiapoptotic B‐cell lymphoma 2 (Bcl‐2) family proteins (such as Bcl‐2, Bcl‐xL, and Mcl‐1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl‐2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl‐2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl‐2, Bcl‐xL, and Mcl‐1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (Ki<20 μM) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl‐1 with no detectable binding to Bcl‐2 or Bcl‐xL, among which the most potent one has a Ki value of 0.18 μM for Mcl‐1. Binding modes of four selected compounds to Mcl‐1 and Bcl‐xL were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl‐1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl‐1 inhibitors with potential pharmaceutical applications.
Intermittent versus continuous erlotinib with concomitant modified “XELOX” (q3W) in first‐line treatment of metastatic colorectal cancer
Authors: Ma Brigette B. Y. , Chan Stephen L. , Ho Wing M. , Lau Wilson , Mo Frankie , Hui Edwin P. , Chan Charles , Poon Annette , Dattatray Rasalkar D. , Wong S. C. Cesar , To Ka F. , King Ann D. , Ahuja Anil , Chan Anthony T. C.
Published: October 2013

BACKGROUND

This study evaluated the activity of 2 schedules of erlotinib in combination with chemotherapy, and the prognostic significance of serum amphiregulin (AREG) and transforming growth factor alpha (TGFa) in metastatic colorectal cancer.

METHODS

A total of 60 untreated patients were randomized to a “continuous” (CON; erlotinib 100 mg daily) or an “intermittent” (INT; erlotinib 150 mg on alternate day on day 2 to 14, then 150 mg daily on days 15 to 21) schedule of erlotinib with a modified XELOX (capecitabine plus oxaliplatin) regimen. Serum levels of AREG and TGFa were determined serially.

RESULTS

Baseline characteristics were similar between the 2 arms. Of the 58 patients evaluated for response, there was a nonsignificant trend toward a slightly higher overall response rate in the INT arm (66.7%) versus the CON arm (56.7%). At a median follow‐up of 2.8 years, the median overall survival was 18.8 months (95% confidence interval = 11.3‐22.9 months) and 20.7 months (95% confidence interval = 12.5‐31 months, P = .19) for the CON and INT arm, respectively. KRAS mutation did not predict drug response. The 2 arms did not differ significantly in toxicity. Baseline serum TGFa was an independent predictor of progression‐free survival, whereas a drop in serum TGFa and AREG levels following 3 to 4 cycles of treatment were associated with shorter progression‐free survival and overall survival, respectively.

CONCLUSIONS

The intermittent erlotinib schedule was associated with a higher response rate, although this is not statistically significant. Serum TGFa and AREG levels have prognostic significance in erlotinib‐treated patients with colorectal cancer, and further studies are warranted. Cancer 2013;119:4145–4153. © 2013 American Cancer Society.
TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first‐line treatment of metastatic colorectal cancer
Authors: Fuchs Charles S. , Fakih Marwan , Schwartzberg Lee , Cohn Allen L. , Yee Lorrin , Dreisbach Luke , Kozloff Mark F. , Hei Yong‐jiang , Galimi Francesco , Pan Yang , Haddad Vincent , Hsu Cheng‐Pang , Sabin Antony , Saltz Leonard
Published: October 2013

BACKGROUND

In patients with previously untreated metastatic colorectal cancer (mCRC), we conducted a phase 1b/randomized phase 2 trial to define the safety, tolerability, and efficacy of mFOLFOX6 plus bevacizumab (mFOLFOX6/bev) with conatumumab, an investigational, fully human monoclonal IgG1 antibody that specifically activates death receptor 5 (DR5).

METHODS

Twelve patients were enrolled in a phase 1b open‐label dose‐escalation trial of conatumumab with mFOLFOX6/bev; thereafter, 190 patients were randomized 1:1:1 to receive mFOLFOX6/bev in combination with 2 mg/kg conatumumab, 10 mg/kg conatumumab, or placebo. Therapy cycles were repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity.

RESULTS

In phase 1b, conatumumab with mFOLFOX6/bev was tolerated without apparent added toxicity over mFOLFOX6/bev alone. In phase 2, conatumumab with mFOLFOX6/bev did not confer a benefit in progression‐free survival when compared with placebo with mFOLFOX6/bev. Toxicity was similar in all treatment arms. Following treatment, similar increases in circulating caspase‐3 levels were observed in all arms.

CONCLUSIONS

Conatumumab with mFOLFOX6/bev did not offer improved efficacy over the same chemotherapy with placebo in first‐line treatment of patients with mCRC. These data do not support further development of conatumumab in advanced CRC. Cancer 2013;119:4290–4298. © 2013 American Cancer Society.
Associations among prognostic understanding, quality of life, and mood in patients with advanced cancer
Authors: El‐Jawahri Areej , Traeger Lara , Park Elyse R. , Greer Joseph A. , Pirl William F. , Lennes Inga T. , Jackson Vicki A. , Gallagher Emily R. , Temel Jennifer S.
Published: October 2013

BACKGROUND

Patients' perception of their prognosis has an impact on their decisions about medical care. However, the relations between prognostic understanding and quality of life (QoL) and mood are unknown. The objectives of this study were to assess perceptions of prognosis and preferences for prognostic information among patients with advanced cancer and to explore the associations of prognostic understanding with QoL and mood.

METHODS

Fifty patients were assessed within 6 to 12 weeks of initiating chemotherapy for advanced gastrointestinal cancers. A 13‐item questionnaire was used to assess patients' information preferences, perceptions of their prognosis and goal of therapy, and communication about end‐of‐life care. The Functional Assessment of Cancer Therapy‐General and the Hospital Anxiety and Depression Scale were used to assess QoL and mood, respectively.

RESULTS

Fifty of 62 (80%) consecutive, eligible patients were enrolled. Thirty‐eight of 50 patients (75%) wanted to know as many details as possible about their cancer diagnosis and treatment. However, 25 of 50 patients (50%) stated that the goal of therapy was to “cure their cancer,” and only 10 of 49 patients (22%) reported having a discussion about end‐of‐life preferences with their oncologist. Patients who acknowledged their illness as terminal reported lower QoL (P = .005) and higher anxiety (P = .003) compared with those who did not perceive themselves as being terminally ill.

CONCLUSIONS

Although patients desired detailed information about their illness, half incorrectly perceived their cancer as curable. Accurate prognostic understanding was associated with lower QoL and worse anxiety. Interventions to improve patients' prognostic understanding while providing adequate psychosocial support are warranted. Cancer 2014;120:278–285. © 2013 American Cancer Society.
The cross‐talk between estrogen receptor and peroxisome proliferator‐activated receptor gamma in thyroid cancer
Authors: Chu Ryan , van Hasselt Andrew , Vlantis Alexander C. , Ng Enders K. W. , Liu Shirley Y. W. , Fan Michael Dahua , Ng Siu Kwan , Chan Amy B. W. , Liu Zhimin , Li Xin‐ying , Chen George G.
Published: October 2013

BACKGROUND

Estrogen receptor (ER) and peroxisome proliferator‐activated receptor gamma (PPARγ) are associated with thyroid tumorigenesis and treatment. However, the interaction between them has not been studied.

METHODS

The impact of ER over‐expression or down‐expression by DNA/small interfering RNA (siRNA) transfection, ERα agonists, and the ERβ agonist diarylpropiolnitrile (DPN) on PPARγ expression/activity was examined in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) cells. The effects of PPARγ modulation by rosiglitazone (RTZ), a PPARγ ligand, and of PPARγ siRNA on ER expression were determined. Cellular functions reflected by cell proliferation and migration were assayed. Apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick‐end labeling, and apoptotic‐related proteins were evaluated by Western blot analysis.

RESULTS

PPARγ protein and activity were reduced by the over‐expression of either ERα or ERβ, whereas repression of ERα or ERβ increased PPARγ expression. The administration of RTZ counteracted the effects of ER and also reduced their expression, particularly in PTC cells. Moreover, knockdown of PPARγ increased ER expression and activity. Functionally, ERα activation offset the inhibitory effect of PPARγ on cellular functions, but ERβ activation aggregated it and induced apoptosis, particularly in PTC cells. Finally, the interaction between ERβ and PPARγ enhanced the expression of proapoptotic molecules, such as caspase‐3 and apoptosis‐inducing factor.

CONCLUSIONS

This study provides evidence supporting a cross‐talk between ER and PPARγ. The reciprocal interaction between PPARγ and ERβ significantly inhibits the proliferation and migration of thyroid cancer cells, providing a new therapeutic strategy against thyroid cancer. Cancer 2014;120:142–153. © 2013 American Cancer Society.
Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma
Authors: Tsuchiya Kaoru , Asahina Yasuhiro , Matsuda Shuya , Muraoka Masaru , Nakata Toru , Suzuki Yuichiro , Tamaki Nobuharu , Yasui Yutaka , Suzuki Shoko , Hosokawa Takanori , Nishimura Takashi , Ueda Ken , Kuzuya Teiji , Nakanishi Hiroyuki , Itakura Jun , Takahashi Yuka , Kurosaki Masayuki , Enomoto Nobuyuki , Izumi Namiki
Published: October 2013

BACKGROUND

A new predictive biomarker for determining prognosis in patients with hepatocellular carcinoma (HCC) who receive sorafenib is required, because achieving a reduction in tumor size with sorafenib is rare, even in patients who have a favorable prognosis. Vascular endothelial growth factor (VEGF) receptor is a sorafenib target. In the current study, the authors examined changes in plasma VEGF concentrations during sorafenib treatment and determined the clinical significance of VEGF as a prognostic indicator in patients with HCC.

METHODS

Plasma VEGF concentrations were serially measured in 63 patients with advanced HCC before and during sorafenib treatment. A plasma VEGF concentration that decreased >5% from the pretreatment level at 8 weeks was defined as a “VEGF decrease.” An objective tumor response was determined using modified Response Evaluation Criteria in Solid Tumors 1 month after the initiation of therapy and every 3 months thereafter.

RESULTS

Patients who had a VEGF decrease at week 8 (n = 14) had a longer median survival than those who did not have a VEGF decrease (n = 49; 30.9 months vs 14.4 months; P = .038). All patients who had a VEGF decrease survived for >6 months, and the patients who had both a VEGF decrease and an α‐fetoprotein response (n = 6) survived during the observation period (median, 19.7 months; range, 6.5‐31.0 months). In univariate analyses, a VEGF decrease, radiologic findings classified as progressive disease, and major vascular invasion were associated significantly with 1‐year survival; and, in multivariate analysis, a VEGF decrease was identified as an independent factor associated significantly with survival.

CONCLUSIONS

A plasma VEGF concentration decrease at 8 weeks after starting sorafenib treatment may predict favorable overall survival in patients with advanced HCC. Cancer 2014;120:229–237. © 2013 American Cancer Society.
Suicide ideation and associated mortality in adult survivors of childhood cancer
Authors: Brinkman Tara M. , Zhang Nan , Recklitis Christopher J. , Kimberg Cara , Zeltzer Lonnie K. , Muriel Anna C. , Stovall Marilyn , Srivastava Deo Kumar , Sklar Charles A. , Robison Leslie L. , Krull Kevin R.
Published: October 2013

BACKGROUND

Adult survivors of childhood cancer are at risk for suicide ideation, although longitudinal patterns and rates of recurrent suicide ideation are unknown. This study investigated the prevalence of late report (ie, after initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality.

METHODS

Participants included 9128 adult survivors of childhood cancer and 3082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory‐18 instrument. Mortality data was ascertained from the National Death Index.

RESULTS

Survivors were more likely to report late (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.5‐2.5) and recurrent suicide ideation (OR = 2.6, 95% CI = 1.8‐3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR = 1.9, 95% CI = 1.3‐2.7; recurrent: OR = 1.9, 95% CI = 1.2‐2.9). Suicide ideation was associated with increased risk for all‐cause mortality (hazard ratio = 1.3, 95% CI = 1.03‐1.6) and death by external causes (hazard ratio = 2.4, 95% CI = 1.4‐4.1).

CONCLUSIONS

Adult survivors of childhood cancer are at risk for late‐report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions. Cancer 2014;120:271–277. © 2013 American Cancer Society.
Underutilization of radiation therapy in patients with glioblastoma
Authors: Aizer Ayal A. , Ancukiewicz Marek , Nguyen Paul L. , Shih Helen A. , Loeffler Jay S. , Oh Kevin S.
Published: October 2013

BACKGROUND

Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients.

METHODS

The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all‐cause mortality.

RESULTS

Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR = 1.048 per year increase, 95% CI = 1.046‐1.051, P < .001), lower annual income (OR = 0.93 per $10,000 increase, 95% CI = 0.90‐0.96, P < .001), African American race (reference = white, OR = 1.19, 95% CI = 1.03‐1.37, P = .02), Hispanic race (OR = 1.34, 95% CI = 1.19‐1.50, P < .001), Asian American race (OR = 1.24, 95% CI = 1.04‐1.48, P < .001), unmarried status (OR = 1.71, 95% CI = 1.60‐1.83, P < .001), and subtotal resection/biopsy (OR = 1.82, 95% CI = 1.69‐1.96, P < .001). The use of radiation was significantly associated with improved overall survival (2‐year survival: 14.6% versus 4.2%, P < .001; adjusted HR = 2.09, 95% CI = 2.02‐2.16, P < .001). When the population was restricted to patients < 50 years old, these findings remained largely unchanged.

CONCLUSIONS

Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research. Cancer 2014;120:238–243. © 2013 American Cancer Society.
Combined lenalidomide, low‐dose dexamethasone, and rituximab achieves durable responses in rituximab‐resistant indolent and mantle cell lymphomas
Authors: Ahmadi Tahamtan , Chong Elise A. , Gordon Amanda , Aqui Nicole A. , Nasta Sunita D. , Svoboda Jakub , Mato Anthony R. , Schuster Stephen J.
Published: October 2013

BACKGROUND

Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody‐dependent cell‐mediated cytotoxicity and reverse tumor‐induced immune suppression. Furthermore, single‐agent lenalidomide has therapeutic activity in relapsed/refractory B‐cell lymphomas. These immunologic effects potentially may enhance the action of rituximab.

METHODS

To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low‐dose dexamethasone, and rituximab in patients who had rituximab‐resistant, relapsed/refractory, indolent B‐cell or mantle cell lymphomas. Patients received two 28‐day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide‐dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide‐dexamethasone.

RESULTS

Twenty‐seven patients with follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow‐up of 12.2 months, the median progression‐free survival was 23.7 months.

CONCLUSIONS

The combination of lenalidomide, low‐dose dexamethasone, and rituximab achieved high response rates with durable responses in patients with rituximab‐resistant, indolent B‐cell and mantle cell lymphomas. Overall response rate increased from 29% after two 28‐day cycles of lenalidomide and low‐dose dexamethasone to 58% after the addition of rituximab, suggesting that lenalidomide can overcome resistance to rituximab. Cancer 2014;120:222–228. © 2013 American Cancer Society.
Conditional prerequisites for microchannel cytologic analysis on wet mount (fluid‐based) biopsies
Authors: Mojica Wilfrido , Bassey Rosemary , Chen Frank , Hannahoe Brigid , Sauer Paul , Hard Robert , Furlani Edward P.
Published: October 2013

BACKGROUND

Advanced capabilities in genomic sequencing developed in the research sector will soon enter the clinical arena. Issues such as the proportioning of patient specimen material for traditional bright‐field microscopic evaluation or dedication for molecular analysis will intensify, particularly in situations of small core biopsies. Microfluidics appears aptly suited as a platform capable of allowing traditional cytologic diagnostics and downstream molecular analysis from the same specimen. However, clarification is needed to determine that forces which act on cells in a fluidic environment do not drastically alter their cytologic features.

METHODS

Cells were processed for flow‐through in a microfluidic channel and evaluated qualitatively and quantitatively for alterations due to fluid‐shear stress or anoikis.

RESULTS

Processing caused separation of cells from cohesive clusters to smaller groups and individual cells, leading to greater variation in parameters associated with the nucleus in nontumor cells but no significant change in tumor cells. These differences were most readily apparent by quantitative measures, and to a lesser extent, qualitative evaluation. Time‐dependent processing played a larger role in cytologic alteration than fluid‐shear stress for nontumor cells.

CONCLUSIONS

Passage of cells through a microfluidic channel is a feasible approach that can be integrated into future platforms intent on integrating cytologic assessment of cells with recovery of the same cells for downstream assays. Cancer (Cancer Cytopathol) 2014;122:59–69. © 2013 American Cancer Society.
Physical (in)activity‐dependent structural plasticity in bulbospinal catecholaminergic neurons of rat rostral ventrolateral medulla
Authors: Mischel Nicholas A. , Llewellyn‐Smith Ida J. , Mueller Patrick J.
Published: October 2013

Increased activity of the sympathetic nervous system is thought to play a role in the development and progression of cardiovascular disease. Recent work has shown that physical inactivity versus activity alters neuronal structure in brain regions associated with cardiovascular regulation. Our physiological studies suggest that neurons in the rostral ventrolateral medulla (RVLM) are more responsive to excitation in sedentary versus physically active animals. We hypothesized that enhanced functional responses in the RVLM may be due, in part, to changes in the structure of RVLM neurons that control sympathetic activity. We used retrograde tracing and immunohistochemistry for tyrosine hydroxylase (TH) to identify bulbospinal catecholaminergic (C1) neurons in sedentary and active rats after chronic voluntary wheel‐running exercise. We then digitally reconstructed their cell bodies and dendrites at different rostrocaudal levels. The dendritic arbors of spinally projecting TH neurons from sedentary rats were more branched than those of physically active rats (P < 0.05). In sedentary rats, dendritic branching was greater in more rostral versus more caudal bulbospinal C1 neurons, whereas, in physically active rats, dendritic branching was consistent throughout the RVLM. In contrast, cell body size and the number of primary dendrites did not differ between active and inactive animals. We suggest that these structural changes provide an anatomical underpinning for the functional differences observed in our in vivo studies. These inactivity‐related structural and functional changes may enhance the overall sensitivity of RVLM neurons to excitatory stimuli and contribute to an increased risk of cardiovascular disease in sedentary individuals. J. Comp. Neurol. 522:499–513, 2014. © 2013 Wiley Periodicals, Inc.
Differences in the morphology of spinal V2a neurons reflect their recruitment order during swimming in larval zebrafish
Authors: Menelaou Evdokia , VanDunk Cassandra , McLean David L.
Published: October 2013

Networks of neurons in spinal cord generate locomotion. However, little is known about potential differences in network architecture that underlie the production of varying speeds of movement. In larval zebrafish, as swimming speed increases, Chx10‐positive V2a excitatory premotor interneurons are activated from ventral to dorsal in a topographic pattern that parallels axial motoneuron recruitment. Here, we examined whether differences in the morphology and synaptic output of V2a neurons reflect their recruitment order during swimming. To do so, we used in vivo single‐cell labeling approaches to quantify the dorsoventral distribution of V2a axonal projections and synapses. Two different classes of V2a neurons are described, cells with ascending and descending axons and cells that are only descending. Among the purely descending V2a cells, more dorsal cells project longer distances than ventral ones. Proximally, all V2a neurons have axonal distributions that suggest potential connections to cells at and below their own soma positions. At more distal locations, V2a axons project dorsally, which creates a cumulative intersegmental bias to dorsally located spinal neurons. Assessments of the synapse distribution of V2a cells, reported by synaptophysin expression, support the morphological observations and also demonstrate that dorsal V2a cells have higher synapse densities proximally. Our results suggest that V2a cells with more potential output to spinal neurons are systematically engaged during increases in swimming frequency. The findings help explain patterns of axial motoneuron recruitment and set up clear predictions for future physiological studies examining the nature of spinal excitatory network connectivity as it relates to movement intensity. J. Comp. Neurol. 522:1232–1248, 2014. © 2013 Wiley Periodicals, Inc.
Comparative analysis of the dendritic organization of principal neurons in the lateral and central nuclei of the rhesus macaque and rat amygdala
Authors: Morgan John T. , Amaral David G.
Published: October 2013

The amygdala plays a critical role in emotional processing and has been implicated in the etiology of numerous psychiatric disorders. It is an evolutionarily ancient structure that is enlarged in primates relative to rodents. Certain amygdala nuclei, such as the lateral nucleus, show relatively greater phylogenetic expansion than other nuclei. However, it is unknown whether there is also differential alteration in neuronal features. To address this question, we examined the dendritic arbors of principal neurons, visualized by using the Golgi method, in the lateral and central nuclei of young adult rhesus macaques and rats. Total dendritic length is greater in the macaque than in the rat. Dendritic trees are increased by 250% in length in the lateral nucleus of the monkey compared with the rat (6,009 μm vs. 2,473 μm); dendritic tree length in the central nucleus is increased by 50% (1,786 μm vs. 1,232 μm). Somal volume is increased 62% between species in the lateral nucleus and 48% in the central nucleus. Spine density is lower on macaque lateral nucleus dendrites compared with rat (−22%) but equivalent in the central nucleus. Spines are equally long in the lateral nucleus of rat and macaque, but spines are longer by about 20% in the central nucleus of the macaque. The alterations in dendritic structure that we observed between the two species suggest differences in the number and spacing of inputs into these nuclei that undoubtedly influence amygdala function. J. Comp. Neurol. 522:689–716, 2014. © 2013 Wiley Periodicals, Inc.
Characterization of the hypothalamus of Xenopus laevis during development. II. The basal regions
Authors: Domínguez Laura , González Agustín , Moreno Nerea
Published: October 2013

The expression patterns of conserved developmental regulatory transcription factors and neuronal markers were analyzed in the basal hypothalamus of Xenopus laevis throughout development by means of combined immunohistochemical and in situ hybridization techniques. The connectivity of the main subdivisions was investigated by in vitro tracing techniques with dextran amines. The basal hypothalamic region is topologically rostral to the basal diencephalon and is composed of the tuberal (rostral) and mammillary (caudal) subdivisions, according to the prosomeric model. It is dorsally bounded by the optic chiasm and the alar hypothalamus, and caudally by the diencephalic prosomere p3. The tuberal hypothalamus is defined by the expression of Nkx2.1, xShh, and Isl1, and rostral and caudal portions can be distinguished by the distinct expression of Otp rostrally and Nkx2.2 caudally. In the mammillary region the xShh/Nkx2.1 combination defined the rostral mammillary area, expressing Nkx2.1, and the caudal retromammillary area, expressing xShh. The expression of xLhx1, xDll4, and Otp in the mammillary area and Isl1 in the tuberal region highlights the boundary between the two basal hypothalamic territories. Both regions are strongly connected with subpallial regions, especially those conveying olfactory/vomeronasal information, and also possess abundant intrahypothalamic connections. They show reciprocal connections with the diencephalon (mainly the thalamus), project to the midbrain tectum, and are bidirectionally related to the rhombencephalon. These results illustrate that the basal hypothalamus of anurans shares many features of specification, regionalization, and hodology with amniotes, reinforcing the idea of a basic bauplan in the organization of this prosencephalic region in all tetrapods. J. Comp. Neurol. 522:1102–1131, 2014. © 2013 Wiley Periodicals, Inc.
Sex‐ and region‐specific pubertal maturation of the corticotropin‐releasing factor receptor system in the rat
Authors: Weathington Jill M. , Hamki Ali , Cooke Bradley M.
Published: October 2013

One of the most reliable findings in psychiatry is in the incidence of anxiety and depression. Beginning at puberty, women develop mood disorders twice as often as men. Because corticotropin‐releasing factor (CRF) receptors are implicated, we compared CRF receptor binding in pre‐ and postpubertal rats. In each brain area, CRF receptor binding was sexually dimorphic, but no two areas were alike in the way the sexes differed. In the nucleus accumbens and olfactory tubercle, CRF1 binding was initially the same in juveniles, but became greater in adult females. In piriform cortex, CRF1 binding increased in females and decreased in males, again becoming sexually dimorphic. CRF1 binding in the anterior cingulate was greater in females than in males at both ages. In CA3, CRF1 binding was greater in males before puberty but decreased during puberty, abolishing the sex difference. CRF2 binding in the posterior bed nucleus of the stria terminalis was greater in males irrespective of age. In contrast, in each of three subdivisions of the lateral septum, females had greater CRF2 binding than males as juveniles, or, as juveniles and as adults. CRF2 binding in the ventromedial hypothalamus was the same in juveniles, but binding levels increased in males, leading to an adult sex difference. Thus, eight CRF receptor‐expressing areas displayed eight distinct sex differences. These results show that sex differences pervade the CRF receptor system in juvenile and adult rats, and the mechanisms that control them are likely to be sex‐, region‐, and subtype‐specific. J. Comp. Neurol. 522:1284–1298, 2014. © 2013 Wiley Periodicals, Inc.