bluuebunny/crossref_metadata_2025 huggingface dataset:
Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis
Authors: Yokoyama Takashi , Kanno Yohei , Yamazaki Yukari , Takahara Tomoko , Miyata Satoshi , Nakamura Takuro
Published: July 2010

Trib1 is a myeloid oncogene that cooperates with Hoxa9 and Meis1. Although the MAPK pathway and C/EBP transcription factors are known to interact with Trib proteins, the mechanisms by which Trib1 contributes to myeloid leukemogenesis remains to be clarified. Here we report that interaction between Trib1 and MEK1 is required for Trib1-induced leukemogenesis. The C-terminal ILLHPWF motif that is well conserved among Trib family proteins is required for MEK1 binding, enhancement of ERK phosphorylation, enhanced self-renewal activity of bone marrow cells and leukemogenic activity by Trib1. The motif is also important for Trib1-induced C/EBPα degradation though interaction between Trib1 and C/EBPα is not necessary. Inhibition of ERK phosphorylation suppressed Trib1-induced C/EBPα degradation, indicating an important role for Trib1/MEK1 interaction. These results suggest that Trib1 may be a key mediator between the RTK-MAPK pathway and the C/EBP transcription factor in myeloid leukemogenesis.
The clinical application of monoclonal antibodies in chronic lymphocytic leukemia
Authors: Jaglowski Samantha M. , Alinari Lapo , Lapalombella Rosa , Muthusamy Natarajan , Byrd John C.
Published: July 2010

Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia. Treatment with chemotherapy over the past 3 decades has been palliative. The introduction of therapeutic antibodies has increased the number of treatment options for this disease. Despite this increase, our true understanding of the mechanism of action of antibody therapy in CLL remains limited. Rituximab, a CD20 antibody, is currently widely used in combination-based strategies for both previously untreated symptomatic CLL and as salvage therapy. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, including ofatumumab and GA-101, are coming forward. Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease but has less selectivity. Development of other therapeutic antibodies targeting alternative B-cell–specific antigens in CLL has been less successful, although many promising candidate antibodies and/or small modular immune pharmaceuticals (SMIPs) are coming forward. In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non–chemotherapy-based treatment approaches.
A recessive screen for genes regulating hematopoietic stem cells
Authors: Papathanasiou Peter , Tunningley Robert , Pattabiraman Diwakar R. , Ye Ping , Gonda Thomas J. , Whittle Belinda , Hamilton Adam E. , Cridland Simon O. , Lourie Rohan , Perkins Andrew C.
Published: July 2010

Identification of genes that regulate the development, self-renewal, and differentiation of stem cells is of vital importance for understanding normal organogenesis and cancer; such knowledge also underpins regenerative medicine. Here we demonstrate that chemical mutagenesis of mice combined with advances in hematopoietic stem cell reagents and genome resources can efficiently recover recessive mutations and identify genes essential for generation and proliferation of definitive hematopoietic stem cells and/or their progeny. We used high-throughput fluorescence-activated cell sorter to analyze 9 subsets of blood stem cells, progenitor cells, circulating red cells, and platelets in more than 1300 mouse embryos at embryonic day (E) 14.5. From 45 pedigrees, we recovered 6 strains with defects in definitive hematopoiesis. We demonstrate rapid identification of a novel mutation in the c-Myb transcription factor that results in thrombocythemia and myelofibrosis as proof of principal of the utility of our fluorescence-activated cell sorter–based screen. Such phenotype-driven approaches will provide new knowledge of the genes, protein interactions, and regulatory networks that underpin stem cell biology.
DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma
Authors: Shaknovich Rita , Geng Huimin , Johnson Nathalie A. , Tsikitas Lucas , Cerchietti Leandro , Greally John M. , Gascoyne Randy D. , Elemento Olivier , Melnick Ari
Published: July 2010

Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell–like (GCB) and activated B cell–like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50 000 CpG motifs distributed among more than 14 000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-α signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker.
Extended morphological processing: a practical method for automatic spot detection of biological markers from microscopic images
Authors: Kimori Yoshitaka , Baba Norio , Morone Nobuhiro
Published: July 2010

Background

A reliable extraction technique for resolving multiple spots in light or electron microscopic images is essential in investigations of the spatial distribution and dynamics of specific proteins inside cells and tissues. Currently, automatic spot extraction and characterization in complex microscopic images poses many challenges to conventional image processing methods.

Results

A new method to extract closely located, small target spots from biological images is proposed. This method starts with a simple but practical operation based on the extended morphological top-hat transformation to subtract an uneven background. The core of our novel approach is the following: first, the original image is rotated in an arbitrary direction and each rotated image is opened with a single straight line-segment structuring element. Second, the opened images are unified and then subtracted from the original image. To evaluate these procedures, model images of simulated spots with closely located targets were created and the efficacy of our method was compared to that of conventional morphological filtering methods. The results showed the better performance of our method. The spots of real microscope images can be quantified to confirm that the method is applicable in a given practice.

Conclusions

Our method achieved effective spot extraction under various image conditions, including aggregated target spots, poor signal-to-noise ratio, and large variations in the background intensity. Furthermore, it has no restrictions with respect to the shape of the extracted spots. The features of our method allow its broad application in biological and biomedical image information analysis.
The Pinus taeda genome is characterized by diverse and highly diverged repetitive sequences
Authors: Kovach Allen , Wegrzyn Jill L , Parra Genis , Holt Carson , Bruening George E , Loopstra Carol A , Hartigan James , Yandell Mark , Langley Charles H , Korf Ian , Neale David B
Published: July 2010

Background

In today's age of genomic discovery, no attempt has been made to comprehensively sequence a gymnosperm genome. The largest genus in the coniferous family Pinaceae is Pinus, whose 110-120 species have extremely large genomes (c. 20-40 Gb, 2N = 24). The size and complexity of these genomes have prompted much speculation as to the feasibility of completing a conifer genome sequence. Conifer genomes are reputed to be highly repetitive, but there is little information available on the nature and identity of repetitive units in gymnosperms. The pines have extensive genetic resources, with approximately 329000 ESTs from eleven species and genetic maps in eight species, including a dense genetic map of the twelve linkage groups in Pinus taeda.

Results

We present here the Sanger sequence and annotation of ten P. taeda BAC clones and Genome Analyzer II whole genome shotgun (WGS) sequences representing 7.5% of the genome. Computational annotation of ten BACs predicts three putative protein-coding genes and at least fifteen likely pseudogenes in nearly one megabase of sequence. We found three conifer-specific LTR retroelements in the BACs, and tentatively identified at least 15 others based on evidence from the distantly related angiosperms. Alignment of WGS sequences to the BACs indicates that 80% of BAC sequences have similar copies (≥ 75% nucleotide identity) elsewhere in the genome, but only 23% have identical copies (99% identity). The three most common repetitive elements in the genome were identified and, when combined, represent less than 5% of the genome.

Conclusions

This study indicates that the majority of repeats in the P. taeda genome are 'novel' and will therefore require additional BAC or genomic sequencing for accurate characterization. The pine genome contains a very large number of diverged and probably defunct repetitive elements. This study also provides new evidence that sequencing a pine genome using a WGS approach is a feasible goal.
Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse
Authors: Aulino Paola , Berardi Emanuele , Cardillo Veronica M , Rizzuto Emanuele , Perniconi Barbara , Ramina Carla , Padula Fabrizio , Spugnini Enrico P , Baldi Alfonso , Faiola Fabio , Adamo Sergio , Coletti Dario
Published: July 2010

Background

The majority of cancer patients experience dramatic weight loss, due to cachexia and consisting of skeletal muscle and fat tissue wasting. Cachexia is a negative prognostic factor, interferes with therapy and worsens the patients' quality of life by affecting muscle function. Mice bearing ectopically-implanted C26 colon carcinoma are widely used as an experimental model of cancer cachexia. As part of the search for novel clinical and basic research applications for this experimental model, we characterized novel cellular and molecular features of C26-bearing mice.

Methods

A fragment of C26 tumor was subcutaneously grafted in isogenic BALB/c mice. The mass growth and proliferation rate of the tumor were analyzed. Histological and cytofluorometric analyses were used to assess cell death, ploidy and differentiation of the tumor cells. The main features of skeletal muscle atrophy, which were highlighted by immunohistochemical and electron microscopy analyses, correlated with biochemical alterations. Muscle force and resistance to fatigue were measured and analyzed as major functional deficits of the cachectic musculature.

Results

We found that the C26 tumor, ectopically implanted in mice, is an undifferentiated carcinoma, which should be referred to as such and not as adenocarcinoma, a common misconception. The C26 tumor displays aneuploidy and histological features typical of transformed cells, incorporates BrdU and induces severe weight loss in the host, which is largely caused by muscle wasting. The latter appears to be due to proteasome-mediated protein degradation, which disrupts the sarcomeric structure and muscle fiber-extracellular matrix interactions. A pivotal functional deficit of cachectic muscle consists in increased fatigability, while the reported loss of tetanic force is not statistically significant following normalization for decreased muscle fiber size.

Conclusions

We conclude, on the basis of the definition of cachexia, that ectopically-implanted C26 carcinoma represents a well standardized experimental model for research on cancer cachexia. We wish to point out that scientists using the C26 model to study cancer and those using the same model to study cachexia may be unaware of each other's works because they use different keywords; we present strategies to eliminate this gap and discuss the benefits of such an exchange of knowledge.
Are health care professionals able to judge cancer patients' health care preferences correctly? A cross-sectional study
Authors: Wessels Hester , de Graeff Alexander , Wynia Klaske , de Heus Miriam , Kruitwagen Cas LJJ , Teunissen Saskia CCM , Voest Emile E
Published: July 2010

Background

Health care for cancer patients is primarily shaped by health care professionals. This raises the question to what extent health care professionals are aware of patients' preferences, needs and values.

The aim of this study was to explore to what extent there is concordance between patients' preferences in cancer care and patients' preferences as estimated by health care professionals. We also examined whether there were gender differences between health care professionals with regard to the degree in which they can estimate patients' preferences correctly.

Methods

To obtain unbiased insight into the specific preferences of cancer patients, we developed the 'Cancer patients' health care preferences' questionnaire'. With this questionnaire we assessed a large sample of cancer patients (n = 386). Next, we asked health care professionals (medical oncologists, nurses and policymakers, n = 60) to fill out this questionnaire and to indicate preferences they thought cancer patients would have. Mean scores between groups were compared using Mann-Whitney tests. Effect sizes (ESs) were calculated for statistically significant differences.

Results

We found significant differences (ESs 0.31 to 0.90) between patients and professionals for eight out of twenty-one scales and two out of eight single items. Patients valued care aspects related to expertise and attitude of health care providers and accessibility of services as more important than the professionals thought they would do. Health care professionals overestimated the value that patients set on particularly organisational and environmental aspects.

We found significant gender-related differences between the professionals (ESs 0.69 to 1.39 ) for eight out of twenty-one scales and two out of eight single items. When there were significant differences between male and female healthcare professionals in their estimation of patients health care preferences, female health care professionals invariably had higher scores. Generally, female health care professionals did not estimate patients' preferences and needs better than their male colleagues.

Conclusions

Health care professionals are reasonably well able to make a correct estimation of patients preferences, but they should be aware of their own bias and use additional resources to gain a better understanding of patients' specific preferences for each patient is different and ultimately the care needs and preferences will also be unique to the person.
Novel molecular imaging platform for monitoring oncological kinases
Authors: Nyati Shyam , Ross Brian D , Rehemtulla Alnawaz , Bhojani Mahaveer S
Published: July 2010

Recent advances in oncology have lead to identification of a plethora of alterations in signaling pathways that are critical to oncogenesis and propagation of malignancy. Among the biomarkers identified, dysregulated kinases and associated changes in signaling cascade received the lion's share of scientific attention and have been under extensive investigations with goal of targeting them for anti-cancer therapy. Discovery of new drugs is immensely facilitated by molecular imaging technology which enables non-invasive, real time, dynamic imaging and quantification of kinase activity. Here, we review recent development of novel kinase reporters based on conformation dependent complementation of firefly luciferase to monitor kinase activity. Such reporter system provides unique insights into the pharmacokinetics and pharmacodynamics of drugs that modulate kinase signaling and have a huge potential in drug discovery, validation, and drug-target interactions.
Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells
Authors: Debeb Bisrat G , Zhang Xiaomei , Krishnamurthy Savitri , Gao Hui , Cohen Evan , Li Li , Rodriguez Angel A , Landis Melissa D , Lucci Anthony , Ueno Naoto T , Robertson Fredika , Xu Wei , Lacerda Lara , Buchholz Thomas A , Cristofanilli Massimo , Reuben James M , Lewis Michael T , Woodward Wendy A
Published: July 2010

Background

Since the first suggestion of prospectively identifiable cancer stem cells in solid tumors, efforts have been made to characterize reported cancer stem cell surrogates in existing cancer cell lines, and cell lines rich with these surrogates have been used to screen for cancer stem cell targeted agents. Although 293T cells were derived from human embryonic kidney, transplantation of these cells into the mammary fat pad yields aggressive tumors that self-renew as evidenced by serial xenograft passages through transplantation. Herein we fully characterize cancer stem cell-like features in 293T human embryonic kidney cells.

Results

293T cells can be readily cultured and passaged as spheres in serum-free stem cell promoting culture conditions. Cells cultured in vitro as three-dimensional spheres (3D) were shown to contain higher ALDH1 and CD44+/CD24- population compared to monolayer cells. These cells were also resistant to radiation and upregulate stem cell survival signaling including β-catenin, Notch1 and Survivin in response to radiation. Moreover, 3D spheres generated from the 293T cells have increased expression of mesenchymal genes including vimentin, n-cadherin, zeb1, snail and slug as well as pro-metastatic genes RhoC, Tenascin C and MTA1. In addition, microRNAs implicated in self-renewal and metastases were markedly reduced in 3D spheres.

Conclusions

293T cells exhibit a cancer stem cell-like phenotype when cultured as 3D spheres and represent an important research tool for studying the molecular and biological mechanisms of cancer stem cells and for testing and developing novel targets for cancer therapy.
Quality of reporting of trial abstracts needs to be improved: using the CONSORT for abstracts to assess the four leading Chinese medical journals of traditional Chinese medicine
Authors: Wang Ling , Li Yulin , Li Jing , Zhang Mingming , Xu Lin , Yuan Wenming , Wang Gang , Hopewell Sally
Published: July 2010

Background

Due to language limitations, the abstract of journal article may be the only way for people of non-Chinese speaking countries to know about trials in traditional Chinese medicine (TCM). However, little is known about the reporting quality of these trial abstracts. Our study is to assess the reporting quality of abstracts of randomized controlled trials (RCT) published in four leading Chinese medical journals of TCM, and to identify any differences in reporting between the Chinese and English version of the same abstract publication.

Method

Two reviewers hand-searched the Chinese Journal of Integrated Traditional and Western Medicine, the Chinese Journal of Integrative Medicine, the China Journal of Chinese Materia Medica and the Chinese Acupuncture & Moxibustion for all abstracts of RCTs published between 2006 and 2007. Two reviewers independently assessed the reporting quality of the Chinese and English version of all eligible abstracts based on a modified version of the CONSORT for reporting randomised trials in journal and conference abstracts (CONSORT for abstracts).

Results

We identified a total of 345 RCTs of TCM with both a Chinese and English abstract. More than half of Chinese abstracts reported details of the trial participants (68%; 234/345), control group intervention (52%; 179/345), the number of participants randomized (73%; 253/345) and benefits when interpreting the trial results (55%; 190/345). Reporting of methodological quality or key features of trial design and trial results were poor; only 2% (7/345) included details of the trial design, 3% (11/345) defined the primary outcome, 5% (17/345) described the methods of random sequence generation, and only 4% (13/345) reported the number of participants analyzed. No abstracts provided details on allocation concealment and trial registration. The percentage agreement in reporting (between the Chinese and English version of the same abstract) ranged from 84% to 100% across individual checklist item.

Conclusion

The reporting quality of abstracts of RCTs published in these four TCM journals needs to be improved. Since none of the four journals adopted CONSORT for Abstracts, we hope that the introduction and adoption of CONSORT for Abstracts by TCM journals will lead to an improvement in reporting quality.
A pragmatic cluster randomized trial evaluating the impact of a community pharmacy intervention on statin adherence: rationale and design of the Community Pharmacy Assisting in Total Cardiovascular Health (CPATCH) study
Authors: Evans Charity D , Eurich Dean T , Taylor Jeff G , Remillard Alfred J , Shevchuk Yvonne M , Blackburn David F
Published: July 2010

Background

Traditional randomized controlled trials are considered the gold standard for evaluating the efficacy of a treatment. However, in adherence research, limitations to this study design exist, especially when evaluating real-world applicability of an intervention. Although adherence interventions by community pharmacists have been tested, problems with internal and external validity have limited the usefulness of these studies, and further well-designed and well-conducted research is needed. We aimed to determine the real-world effectiveness of a community pharmacy adherence intervention using a robust study design. This novel design integrates cluster randomization and an outcome evaluation of medication adherence using a population-based administrative data source in the province of Saskatchewan, Canada.

Methods/Design

Community pharmacies from across the province of Saskatchewan, Canada were randomized to deliver an adherence intervention to their patients or usual care. Intervention pharmacies were trained to employ a practical adherence strategy targeted at new users of statin medications. While randomization and implementation of the intervention occurred at the community pharmacy level, the outcome analysis will occur at the level of the individual subjects. The primary outcome is the mean statin adherence among all eligible new users of statin medications. Secondary outcomes include the proportion of new statin users who exhibit adherence ≥80%, and persistence with statin use.

Discussion

This novel study design was developed to combine the rigor of a randomized trial with a pragmatic approach to implementing and capturing the results in a real-world fashion. We believe this approach can serve as an example for future study designs evaluating practice-based adherence interventions.

Trial Registration

ClinicalTrials.gov no. NCT00971412.
gp130 at the nexus of inflammation, autoimmunity, and cancer
Authors: Silver J S , Hunter C A
Published: July 2010

Review highlights the function of the cytokine receptor gp130, specifically the diverse roles it plays in inflammation, autoimmunity, and cancer.

Glycoprotein 130 (gp130) is a shared receptor utilized by several related cytokines, including IL-6, IL-11, IL-27, Leukemia Inhibitory Factor (LIF), Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNTF), Cardiotrophin 1 (CT-1) and Cardiotrophin-like Cytokine (CLC). Gp130 plays critical roles during development and gp130-deficient mice are embryonically lethal. However, the best characterized facet of this receptor and its associated cytokines is the ability to promote or suppress inflammation. The aim of this review is to discuss the role of gp130 in promoting or preventing the development of autoimmunity and cancer, two processes that are associated with aberrant inflammatory responses.
Inhibition of dynamin-dependent endocytosis interferes with type III IFN expression in bacteria-infected human monocyte-derived DCs
Authors: Pietilä Taija E , Latvala Sinikka , Österlund Pamela , Julkunen Ilkka
Published: July 2010

Induction of type III IFNs in bacteria-infected human moDCs requires bacterial phagocytosis in conjunction with signaling.

Type I IFNs (IFN-α/βs) and type III IFNs (IFN-λ1–3) play an important role in host defense against viral infections. The induction of type I IFNs has recently been found to take place also in bacterial infections, and therefore, this study focuses on analyzing the regulation of type III IFNs in response to bacterial stimulation. We found by quantitative RT-PCR that the expression of IFN-λ1 and IFN-λ2/3 mRNAs, as well as that of IFN-β, was similarly up-regulated in response to stimulation with live Salmonella typhimurium or TLR4 agonist LPS in human moDCs. The induction of IFN-λ mRNAs did not require ongoing protein synthesis, and only IFN-λ1 was detected at the protein level. The induction of IFN-λ mRNAs was sensitive to SB202190, Ly294002, and PDTC, which inhibit p38 MAPK, PI3K, and NF-κB activation, respectively. Furthermore, we observed that blocking dynamin-dependent endocytosis pathways with dynasore led to decreased cell surface expression of CD86 and HLA class II molecules and reduced production of IFN-λ1, CXCL10, and IL-6 when the cells were infected with S. typhimurium. Cytokine production was also impaired in dynasore-treated, Streptococcus thermophilus-stimulated cells. Further, inhibition of dynamin prevented S. typhimurium-induced phosphorylation of IRF3 and the internalization of the bacteria. In summary, induction of type III IFNs in bacteria-infected human moDCs requires multiple signaling pathways and involves bacterial phagocytosis.
PDGF β-Receptor Kinase Activity and ERK1/2 Mediate Glycosaminoglycan Elongation on Biglycan and Increases Binding to LDL
Authors: Getachew Robel , Ballinger Mandy L. , Burch Micah L. , Reid Julianne J. , Khachigian Levon M. , Wight Thomas N. , Little Peter J. , Osman Narin
Published: July 2010

The initiation of atherosclerosis involves the subendothelial retention of lipoproteins by proteoglycans (PGs). Structural characteristics of glycosaminoglycan (GAG) chains on PGs influence lipoprotein binding and are altered adversely by platelet-derived growth factor (PDGF). The signaling pathway for PDGF-mediated GAG elongation via the PDGF receptor (PDGFR) was investigated. In human vascular smooth muscle cells, PDGF significantly increased 35S-sulfate incorporation into PGs and GAG chain size. PGs from PDGF-stimulated cells showed increased binding low-density lipoprotein (P < 0.001) in gel mobility shift assays. Knockdown of PDGFRβ using small interfering RNA demonstrated that PDGF mediated changes in PGs via PDGFRβ. GAG synthesis and hyperelongation was blocked by inhibition of receptor tyrosine kinase autophosphorylation site Tyr857 activity using Ki11502 or imatinib. Downstream signaling to GAG hyperelongation was mediated through ERK MAPK and not phosphatidylinositol-3 kinase or phospholipase Cγ. In high-fat-fed apolipoprotein E−/− mice, inhibition of PDGFRβ activity by imatinib reduced aortic total lipid staining area by 35% (P < 0.05). Inhibition of PDGFRβ tyrosine kinase activity leads to inhibition of GAG synthesis on vascular PGs and aortic lipid area in vivo. PDGFRβ and its signaling pathways are potential targets for novel therapeutic agents to prevent the earliest stages atherosclerosis.
Insulin Receptor (IR) Pathway Hyperactivity in IGF-IR Null Cells and Suppression of Downstream Growth Signaling Using the Dual IGF-IR/IR Inhibitor, BMS-754807
Authors: Dinchuk Joseph E. , Cao Carolyn , Huang Fei , Reeves Karen A. , Wang Jeanne , Myers Fanny , Cantor Glenn H. , Zhou Xiadi , Attar Ricardo M. , Gottardis Marco , Carboni Joan M.
Published: July 2010

The biology of IGF-IR/IR signaling was studied in normal mouse embryonic fibroblasts (MEFs) that were either wild type (wt), heterozygous (het), or null for the IGF-IR. The ability of IGF-I, IGF-II, or insulin to stimulate serum-starved MEFs was characterized by gene expression profiling and biochemical analyses for activation of downstream signals. Each genotypic group of MEFs exhibited distinct patterns of expression both while resting and in response to stimulation. The insulin receptor (IR) pathway in IGF-IR null MEFs was hypersensitive to insulin ligand stimulation resulting in greater AKT phosphorylation than in wt or het MEFs stimulated with the same ligand. Interestingly, the IR pathway hypersensitivity in IGF-IR null MEFs occurred with no observed changes in the levels of IR isoforms A or B. A new small molecule IGF-IR inhibitor (BMS-754807), having equipotent activity against both IGF-IR and IR, proved effective in suppressing both AKT and ERK phosphorylation from both the IGF-IR and IR pathways by all three ligands tested in wt, het, and null MEFs. The use of a dual IGF-IR/IR inhibitor addresses concerns about the use of growth inhibiting therapies directed against the IGF-IR receptor in certain cancers. Lastly, comparison of the antiproliferative effects (IC50s) of various compounds in wt vs. null MEFs demonstrates that genetically characterized MEFs provide a simple and inexpensive tool with which to define compounds as having mostly on-target or off-target IGF-IR activities because off-target compounds affect both wt and null MEFs equally.
Interleukin-6 Is an Essential Determinant of On-Time Parturition in the Mouse
Authors: Robertson Sarah A. , Christiaens Inge , Dorian Camilla L. , Zaragoza Dean B. , Care Alison S. , Banks Anke M. , Olson David M.
Published: July 2010

IL-6 abundance in amniotic fluid and uterine tissues increases in late gestation or with infection-associated preterm labor. A role in regulation of labor onset is suggested by observations that IL-6 increases expression of genes controlling prostaglandin synthesis and signaling in isolated uterine cells, but whether IL-6 is essential for normal parturition is unknown. To evaluate the physiological role of IL-6 in parturition in mice, we investigated the effect of Il6 null mutation on the timing of parturition and expression of genes associated with uterine activation. Il6 null mutant mice delivered 24 h later than wild-type mice, although circulating progesterone fell similarly in both genotypes during the prepartal period. Il6 null mutant mice were also refractory to low doses of lipopolysaccharide sufficient to induce preterm delivery in wild-type mice. The characteristic late-gestation elevation in uterine expression of Oxtr mRNA encoding oxytocin receptor, and peripartal increases in Ptgfr and Ptgs2 mRNAs regulating prostaglandin synthesis and signaling were delayed by 24 h in Il6 null mutant mice. Conversely, Ptger4 mRNA encoding the prostaglandin E receptor-4 was abnormally elevated in late-gestation in Il6 null mutant mice. Administration of recombinant IL-6 from d 11.5 postcoitum until term restored the normal timing of delivery and normalized Ptger4 mRNA expression in late gestation. We conclude that IL-6 has a key role in controlling the progression of events culminating in parturition and that it acts downstream of luteolysis in the uterus to regulate genes involved in the prostaglandin-mediated uterine activation cascade.
Circulating C-Type Natriuretic Peptide (CNP) Rescues Chondrodysplastic CNP Knockout Mice from Their Impaired Skeletal Growth and Early Death
Authors: Fujii Toshihito , Komatsu Yasato , Yasoda Akihiro , Kondo Eri , Yoshioka Tetsuro , Nambu Takuo , Kanamoto Naotestu , Miura Masako , Tamura Naohisa , Arai Hiroshi , Mukoyama Masashi , Nakao Kazuwa
Published: July 2010

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.
Central Injection of the Stable Somatostatin Analog ODT8-SST Induces a Somatostatin2 Receptor-Mediated Orexigenic Effect: Role of Neuropeptide Y and Opioid Signaling Pathways in Rats
Authors: Stengel Andreas , Coskun Tamer , Goebel Miriam , Wang Lixin , Craft Libbey , Alsina-Fernandez Jorge , Rivier Jean , Taché Yvette
Published: July 2010

Somatostatin and octreotide injected into the brain have been reported to modulate food intake. However, little is known regarding the underlying mechanisms. The stable oligosomatostatin analog, des-AA1,2,4,5,12,13-[DTrp8]-somatostatin (ODT8-SST), like somatostatin, binds to all five somatostatin receptors (sst1–5). We characterized the effects of ODT8-SST injected intracerebroventricularly (icv) on food consumption and related mechanisms of action in freely fed rats. ODT8-SST (0.3 and 1 μg per rat, icv) injected during the light or dark phase induced an early onset (within 1 h) and long-lasting (4 h) increase in food intake in nonfasted rats. By contrast, ip injection (0.3–3 mg/kg) or icv injection of selective sst1 or sst4 agonists (1 μg per rat) had no effect. The 2 h food intake response during the light phase was blocked by icv injection of a sst2 antagonist, the neuropeptide Y (NPY) Y1 receptor antagonist, BIBP-3226, and ip injection of the μ-opioid receptor antagonist, naloxone, and not associated with changes in plasma ghrelin levels. ODT8-SST (1 μg per rat, icv) stimulated gastric emptying of a solid meal which was also blocked by naloxone. The increased food intake was accompanied by a sustained increase in respiratory quotient, energy expenditure, and drinking as well as μ-opioid receptor-independent grooming behavior and hyperthermia, while ambulatory movements were not altered after ODT8-SST (1 μg per rat, icv). These data show that ODT8-SST acts primarily through brain sst2 receptors to induce a long-lasting orexigenic effect that involves the activation of Y1 and opiate-receptors, accompanied by enhanced gastric transit and energy expenditure suggesting a modulation of NPYergic and opioidergic orexigenic systems by brain sst2 receptors.
A New Oxytocin-Saporin Cytotoxin for Lesioning Oxytocin-Receptive Neurons in the Rat Hindbrain
Authors: Baskin Denis G. , Kim Francis , Gelling Richard W. , Russell Brian J. , Schwartz Michael W. , Morton Gregory J. , Simhan Hyagriv N. , Moralejo Daniel H. , Blevins James E.
Published: July 2010

Evidence suggests that release of oxytocin in the nucleus tractus solitarius (NTS) of the hindbrain from descending projections that originate in the paraventricular nucleus can inhibit food intake by amplifying the satiety response to cholecystokinin (CCK). To further evaluate this mechanism in rats, we used a novel cytotoxin, saporin conjugated to oxytocin (OXY-SAP), a compound designed to destroy cells that express oxytocin receptors (OXYr). OXY-SAP was injected directly into the NTS to lesion neurons that express OXYr and that are implicated in potentiating CCK’s satiety effects. The control consisted of injection of saporin conjugated to a nonsense peptide. We found that OXY-SAP was cytotoxic to human uterine smooth muscle cells in vitro, demonstrating that OXY-SAP can lesion cells that express OXYr. Using laser capture microdissection and real-time quantitative PCR, we demonstrated that OXYr mRNA levels were reduced in the NTS after OXY-SAP administration. Moreover, we found that OXY-SAP attenuated the efficacy of CCK-8 to reduce food intake and blocked the actions of an OXYr antagonist to stimulate food intake. The findings suggest that OXY-SAP is an effective neurotoxin for in vivo elimination of cells that express OXYr and is potentially useful for studies to analyze central nervous system mechanisms that involve the action of oxytocin on food intake and other physiological processes.
Serum Insulin-Like Growth Factor I (IGF-I), IGF-Binding Proteins 2 and 3, and the Risk for Development of Malignancies in Adults with Growth Hormone (GH) Deficiency Treated with GH: Data from KIMS (Pfizer International Metabolic Database)
Authors: Popovic Vera , Mattsson Anders F. , Gaillard Rolf C. , Wilton Patrick , Kołtowska-Häggström Maria , Ranke Michael B.
Published: July 2010

Context: The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation.

Objective: The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 sd scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies.

Design: Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions.

Setting: The setting included the KIMS (the Pfizer International Metabolic Database).

Patients: One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy.

Intervention(s): Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS.

Main Outcome Measures: Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry.

Results: No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7–30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2–26%; P = 0.01)].

Conclusions: IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.
Acromegaly without Imaging Evidence of Pituitary Adenoma
Authors: Lonser Russell R. , Kindzelski Bogdan A. , Mehta Gautam U. , Jane John A. , Oldfield Edward H.
Published: July 2010

Context: GH-secreting pituitary adenomas are nearly always visible on conventional magnetic resonance (MR) imaging. However, management and outcome of acromegalic patients lacking imaging evidence of GH-secreting pituitary adenomas are undefined.

Objective: The aim was to evaluate surgical exploration for MR-invisible GH-secreting pituitary adenomas.

Design and Setting: We conducted a retrospective review at two tertiary care centers.

Patients or Other Participants: Consecutive acromegalic patients without imaging evidence of a pituitary adenoma on pre- and postcontrast, spin echo T1-weighted MR imaging and who lacked evidence of an ectopic (nonpituitary) source causing GH excess were included.

Interventions: Surgical exploration with identification and resection of a pituitary adenoma was performed.

Main Outcome Measures: Laboratory values (GH, IGF-I), surgical findings, and clinical outcome were analyzed.

Results: Six patients (three males, three females; 3% of all patients) with suspected GH-secreting adenomas did not demonstrate imaging evidence of pituitary adenoma on conventional MR imaging. Three patients underwent a postcontrast, volumetric interpolated breath-hold examination MR-imaging sequence (1.2-mm slice thickness), which revealed a 4-mm pituitary adenoma not seen on the spin echo T1-weighted MR imaging in one patient. A pituitary adenoma was identified and removed in all patients (mean diameter, 5.6 mm; range, 5 to 6.7 mm). Histological analysis confirmed that the lesions were GH-secreting adenomas. All patients achieved biochemical remission after surgical resection.

Conclusion: Acromegaly can be caused by GH-secreting pituitary adenomas that are not evident on conventional MR imaging. Adenomas in some of these patients become evident using volumetric interpolated breath-hold examination MR imaging. Surgical exploration of the pituitary gland in acromegalic patients with endocrine findings consistent with a GH-secreting adenoma but negative MR imaging can lead to identification and removal of an adenoma.
Research Resource: The Androgen Receptor Modulates Expression of Genes with Critical Roles in Muscle Development and Function
Authors: Wyce Anastasia , Bai Yuchen , Nagpal Sunil , Thompson Catherine C.
Published: July 2010

Androgen signaling through the androgen receptor (AR), a ligand-dependent transcription factor within the steroid receptor superfamily, plays an important role in the development and maintenance of many tissues. In muscle, androgens act as anabolic agents that increase both muscle mass and strength; however, a key unanswered question is the mechanism through which AR-mediated gene expression leads to these effects. To gain further insight into the mechanism of AR action in muscle, we identified AR-binding sites in primary human muscle cells using ChIP-on-Chip (chromatin immunoprecipitation coupled with tiling microarray detection of genomic fragments). Through this analysis, we identified 32,518 potential AR-binding sites throughout the genome that were enriched upon androgen treatment. Sequence analysis of these regions indicated that approximately 90% possess a consensus androgen response element or half-site. Among the identified AR-binding sites are genes known to be directly regulated by AR, confirming the validity of our methodology. Additionally, we identified a number of novel AR targets, including genes and micro-RNAs implicated in muscle differentiation and function, suggesting a direct role for AR-mediated transcription in muscle development. Intriguingly, binding sequences for the Mef2 family of transcription factors were enriched in the AR-bound regions, and we show that several Mef2c-dependent genes are direct targets of AR, suggesting a functional interaction between Mef2c and AR in skeletal muscle. Our results provide new insights into the mechanisms by which androgens promote muscle growth and validate AR as a potential therapeutic target for sarcopenia, muscle wasting, and other androgen-related muscle disorders.
Does Wage Persistence Matter for Employment Fluctuations? Evidence from Displaced Workers
Authors: Schmieder Johannes F , von Wachter Till
Published: July 2010

Previous literature has found that tight labor market conditions during a job raise wages. Using the Displaced Worker Survey from 1984 to 2006, we show that wage gains associated with good labor market conditions disappear at job loss. We also find that workers with higher wages due to tight past labor market conditions face higher risk of layoff. These findings suggest an important role of persistent rigidities in the wage setting process that are related to layoff decisions. This supports the notion that downward rigid employment contracts help explain the Shimer (2005) “puzzle” of low wage relative to employment fluctuations. (JEL J31, J41, J63)
Information, Direct Access to Farmers, and Rural Market Performance in Central India
Authors: Goyal Aparajita
Published: July 2010

This paper estimates the impact of a change in procurement strategy of a private buyer in the central Indian state of Madhya Pradesh. Beginning in October 2000, Internet kiosks and warehouses were established that provide wholesale price information and an alternative marketing channel to soy farmers in the state. Using a new market-level dataset, the estimates suggest a significant increase in soy price after the introduction of kiosks, supporting the predictions of the theoretical model. Moreover, there is a robust increase in area under soy cultivation. The results point toward an improvement in the functioning of rural agricultural markets. (JEL O13, O18, Q12, Q13)
Dynamics of the Gender Gap for Young Professionals in the Financial and Corporate Sectors
Authors: Bertrand Marianne , Goldin Claudia , Katz Lawrence F
Published: July 2010

The careers of MBAs from a top US business school are studied to understand how career dynamics differ by gender. Although male and female MBAs have nearly identical earnings at the outset of their careers, their earnings soon diverge, with the male earnings advantage reaching almost 60 log points a decade after MBA completion. Three proximate factors account for the large and rising gender gap in earnings: differences in training prior to MBA graduation, differences in career interruptions, and differences in weekly hours. The greater career discontinuity and shorter work hours for female MBAs are largely associated with motherhood. (JEL J16, J22, J31, J44)
Confucianism and the East Asian Miracle
Authors: Liang Ming-Yih
Published: July 2010

We examine two behavioral traits essential to Confucianism, and put forward hypotheses as to whether these behavioral traits impede or are conducive to “leading” or “follower” mode growth. A dynamic leader-follower general equilibrium model with appropriately specified “Confucian” parameters is shown to generate results that correspond to some of the main features of East Asian economies: their miracle growths, subsequent slowdowns, trade surpluses, and persistent accumulations of foreign exchange reserves. We calibrate the model to assess the quantitative importance of these cultural effects and examine their implications for future evolution of these economies. (JEL E23, O17, O41, O47, P24, Z12, Z13)
Central Bank Communication and Expectations Stabilization
Authors: Eusepi Stefano , Preston Bruce
Published: July 2010

The value of communication is analyzed in a model in which agents' expectations need not be consistent with central bank policy. Without communication, the Taylor principle is not sufficient for macroeconomic stability: divergent learning dynamics are possible. Three communication strategies are contemplated to ensure consistency between private forecasts and monetary policy strategy: communicating the precise details of policy; communicating only the variables on which policy decisions are conditioned; and communicating the inflation target. The former strategies restore the Taylor principle as a sufficient condition for anchoring expectations. The latter strategy, in general, fails to protect against expectations-driven fluctuations. (JEL E32, E43, E52, E58)