The Role of Type I Insulin-Like Growth Factor Receptor Signaling in Breast Cancer Brain Metastasis

Brain metastasis is a common cause of mortality in cancer patients. Approximately 20-30% of breast cancer patients acquire brain metastasis, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF- IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that the IGF-IR signaling axis is constitutively active in brain-seeking sublines of breast cancer cells, driving an increase in in vitro metastatic properties. We demonstrate that IGF-IR signaling is activated in an autocrine manner as a result of IGFBP3 overexpression in brain-seeking cells. Transient and stable knockdown of IGF-IR results in a downregulation of IGF-IR downstream signaling through phospho-AKT, as well as decreased in vitro migration and invasion of MDA- MB-231Br brain-seeking cells. Using an in vivo experimental brain metastasis model, we show that IGF-IR ablation attenuates the establishment of brain metastases and prolongs survival. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo.

Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.

Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts.

The mechanisms by which insulin-like growth factors (IGFs) can be both mitogenic and differentiation-promoting in skeletal myoblasts are unclear because these two processes are believed to be mutually exclusive in this tissue. The phosphorylation state of the ubiquitous nuclear retinoblastoma protein (Rb) plays an important role in determining whether myoblasts proliferate or differentiate: Phosphorylated Rb promotes mitogenesis, whereas un- (or hypo-) phosphorylated Rb promotes cell cycle exit and differentiation. We hypothesized that IGFs might affect the fate of myoblasts by regulating the phosphorylation of Rb. Although long-term IGF treatment is known to stimulate differentiation, we find that IGFs act initially to inhibit differentiation and are exclusively mitogenic. These early effects of IGFs are associated with maintenance of Rb phosphorylation typical of proliferating cells; upregulation of the gene expression of cyclin-dependent kinase 4 and cyclin D1, components of a holoenzyme that plays a principal role in mediating Rb phosphorylation; and marked inhibition of the gene expression of myogenin, a member of the MyoD family of skeletal muscle-specific transcription factors that is essential in muscle differentiation. We also find that IGF-induced inhibition of differentiation occurs through a process that is independent of its mitogenic effects. We demonstrate, thus, that IGFs regulate Rb phosphorylation and cyclin D1 and cyclin-dependent kinase 4 gene expression; together with their biphasic effects on myogenin expression, these results suggest a mechanism by which IGFs are initially mitogenic and subsequently differentiation-promoting in skeletal muscle.

A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, lGF-I production and body weight gain in normal mice

Diabetic retinopathy and acromegaly are diseases associated with excess action of GH and its effector IGF-1, and there is a need for improved therapies. We have designed all optimised 2'-O-(2-methoxyethyl)-modified phosphorothioate oligodeoxynucleotide, ATL 227446, and demonstrated its ability to Suppress GH receptor mRNA in vitro. Subcutaneous injections of ATL 227446 reduced GH receptor mRNA levels, GH binding activity and serum IGF-1 levels in mice after seven days of closing. The reduction in serum IGF-1 could be sustained for over tell weeks of dosing at therapeutically relevant levels, during which there was also a significant decrease in body weight gain in antisense-treated mice relative to saline and mismatch control-treated mice. The findings indicate that administration of an antisense oligonucleotide to the GH receptor may be applicable to human diseases in which suppression of GH action provides therapeutic benefit.

i-Cobb - An innovative technique in spinal radiographic measurement

The measurement of Cobb angles from radiographs is routine practice in spinal clinics. The technique relies on the use and availability of specialist equipment such as a goniometer, cobbometer or protractor. The aim of this study was to validate the use of i-Phone (Apple Inc) combined with Tilt Meter Pro software as compared to a protractor in the measurement of Cobb angles. Between November 2008 and December 2008 20 patients were selected at random from the Paediatric Spine Research Groups Database. A power calculation was performed which indicated if n=240 measurements the study had a 96% chance of detecting a 5 degree difference between groups. All patients had idiopathic scoliosis with a range of curve types and severities. The study found the i-Phone combined with Tilt Meter Pro software offers a faster alternative to the traditional method of Cobb angle measurement. The use of i-Phone offers a more convenient way of measuring Cobb angles in the outpatient setting. The intra-observer repeatability of the iPhone is equivalent to the protractor in the measurement of Cobb angles.

Low-complexity estimation of CFO and frequency independent I/Q mismatch for OFDM systems

CFO and I/Q mismatch could cause significant performance degradation to OFDM systems. Their estimation and compensation are generally difficult as they are entangled in the received signal. In this paper, we propose some low-complexity estimation and compensation schemes in the receiver, which are robust to various CFO and I/Q mismatch values although the performance is slightly degraded for very small CFO. These schemes consist of three steps: forming a cosine estimator free of I/Q mismatch interference, estimating I/Q mismatch using the estimated cosine value, and forming a sine estimator using samples after I/Q mismatch compensation. These estimators are based on the perception that an estimate of cosine serves much better as the basis for I/Q mismatch estimation than the estimate of CFO derived from the cosine function. Simulation results show that the proposed schemes can improve system performance significantly, and they are robust to CFO and I/Q mismatch.

"Well, now I'm upset": Moral and social orders in the playground

There is much still to learn about how young children’s membership with peers shapes their constructions of moral and social obligations within everyday activities in the school playground. This paper investigates how a small group of girls, aged four to six years, account for their everyday social interactions in the playground. They were video-recorded as they participated in a pretend game of school. Several days later, a video-recorded excerpt of the interaction was shown to them and invited to comment on what was happening in the video. This conversation was audio-recorded. Drawing on a conversation analysis approach, this chapter shows that, despite their discontent and complaining about playing the game of school, the girls’ actions showed their continued orientation to the particular codes of the game, of ‘no going away’ and ‘no telling’. By making relevant these codes, jointly constructed by the girls during the interview, they managed each other’s continued participation within two arenas of action: the pretend, as a player in a pretend game of school; and the real, as a classroom member of a peer group. Through inferences to explicit and implicit codes of conduct, moral obligations were invoked as the girls attempted to socially exclude or build alliances with others, and enforce their own social position. As well, a shared history that the girls re-constructed has moral implications for present and future relationships. The girls oriented to the history as an interactional resource for accounting for their actions in the pretend game. This paper uncovers how children both participate in, and shape, their everyday social worlds through talk and interaction and the consequences a taken-for-granted activity such as playing school has for their moral and social positions in the peer group.

Concurrent multi-scale modeling of civil infrastructures for analyses on structural deterioration—Part I : Modeling methodology and strategy

This paper aims to develop the methodology and strategy for concurrent finite element modeling of civil infrastructures at the different scale levels for the purposes of analyses of structural deteriorating. The modeling strategy and method were investigated to develop the concurrent multi-scale model of structural behavior (CMSM-of-SB) in which the global structural behavior and nonlinear damage features of local details in a large complicated structure could be concurrently analyzed in order to meet the needs of structural-state evaluation as well as structural deteriorating. In the proposed method, the “large-scale” modeling is adopted for the global structure with linear responses between stress and strain and the “small-scale” modeling is available for nonlinear damage analyses of the local welded details. A longitudinal truss in steel bridge decks was selected as a case to study how a CMSM-of-SB was developed. The reduced-scale specimen of the longitudinal truss was studied in the laboratory to measure its dynamic and static behavior in global truss and local welded details, while the multi-scale models using constraint equations and substructuring were developed for numerical simulation. The comparison of dynamic and static response between the calculated results by different models indicated that the proposed multi-scale model was found to be the most efficient and accurate. The verification of the model with results from the tested truss under the specific loading showed that, responses at the material scale in the vicinity of local details as well as structural global behaviors could be obtained and fit well with the measured results. The proposed concurrent multi-scale modeling strategy and implementation procedures were applied to Runyang cable-stayed bridge (RYCB) and the CMSM-of-SB of the bridge deck system was accordingly constructed as a practical application.

I-cobb - An innovative technique in spinal radiographic measurement

The measurement of Cobb angles on radiographs of patients with spinal deformities is routine practice in spinal clinics. The technique relies on the use and availability of specialist equipment such as a goniometer, cobbometer or protractor. The aim of this study was to validate the use of i-Phone (Apple Inc) combined with Tilt Meter Pro software as compared to a protractor in the measurement of Cobb angles. The i-Phone combined with Tilt Meter Pro software offers a faster alternative to the traditional method of Cobb angle measurement. The use of i-Phone offers a more convenient way of measuring Cobb angles in the outpatient setting. The intra-observer repeatability of the iPhone is equivalent to the protractor in the measurement of Cobb angles.

“I am a secondary teacher and I teach history and SOSE” : negotiating pre-service teacher identities in times of curriculum change

Secondary social education in Australia is set to change with the new national history curriculum but integrated social education will continue in the middle years of schooling. Competing discourses of disciplinary and integrated social education approaches create new challenges for pre-service teachers as identification with a teaching area is an important aspect of developing a broader teacher identity. Feedback on a compulsory, final year curriculum studies unit revealed the majority of secondary pre-service teachers identified with at least one social science discipline. However, only a small number listed the integrated social education curriculum of Studies of Society and Environment (SOSE), even though SOSE was an essential part of their brief. More complex identities were revealed in post-teaching practice interviews. In times of curriculum change, attention to pre-service teachers’ disciplinary knowledge is critical in developing a stable subject identity.