bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B15: The pan-BCR-ABL inhibitor ponatinib inhibits viability of gatekeeper mutant BCR-ABLT315I cells with greater potency than a nilotinib/MEK inhibitor combination
Authors: Schrock Alexa B. , Gozgit Joseph M. , Rivera Victor
Published: March 2013

Introduction: The second generation BCR-ABL inhibitor nilotinib has recently been shown to have weak off-target activity against RAF and drive the paradoxical activation of BRAF and CRAF in cells with activated RAS. Importantly, this effect has been seen in cells expressing T315I mutant BCR-ABL, against which nilotinib is ineffective (Packer, Cancer Cell 20:715). Interestingly, nilotinib was shown to synergize with an inhibitor of MEK, a downstream effector of RAF, to inhibit the viability of cells expressing BCR-ABLT315I. Ponatinib is a pan-BCR-ABL inhibitor that potently kills cells expressing BCR-ABLT315I and is in a pivotal phase 2 trial in patients with CML. Here we examined the activity of ponatinib against RAF and compared the cellular potency of ponatinib against BCR-ABLT315I to that of a nilotinib/MEK inhibitor combination.

Results: Ponatinib potently inhibited the in vitro kinase activity of ARAF, BRAF, and CRAF with IC50s of 71, 33, and 17 nM, respectively, compared to IC50s of 4390, 235, and 188 for nilotinib. In 2 RAS mutant cell lines tested, nilotinib (1 to 10 μM) induced feedback activation of RAF/MEK/ERK signaling as reported previously; however ponatinib (0.01 to 10 μM) did not. Both ponatinib and nilotinib potently inhibited viability of Ba/F3 cells expressing native BCR-ABL, with IC50s of 1.5 and 10 nM, respectively. While nilotinib has no activity against cells expressing BCR-ABLT315I, when combined with a concentration of the MEK inhibitor AZD6244 that inhibits MEK signaling (2 μM), nilotinib inhibited viability with an IC50 of 550 nM. In contrast, ponatinib potently inhibited viability of cells expressing BCR-ABLT315I with an IC50 of 6 nM. Similarly, single agent ponatinib induced apoptosis in BCR-ABLT315I cells with 100-fold greater potency than the combination of nilotinib and AZD6244.

Conclusion: In contrast to nilotinib, ponatinib does not appear to induce the paradoxical activation of RAF/MEK/ERK signaling in RAS mutant cells, possibly due to its inhibition of all 3 RAF family members. Although nilotinib synergizes with a MEK inhibitor to kill BCR-ABLT315I mutant cells, this effect requires a concentration of nilotinib approximately 50-fold higher than that required to kill native BCR-ABL cells. Substantially greater potency, at clinically achievable drug concentrations, is achieved via the direct inhibition of BCR-ABLT315I by ponatinib.
Abstract B2: Supplementation of dietary fish oil induces apoptosis through activation of PPARγ and involves inhibition of angiogenesis in colon cancer
Authors: Kansal Shevali , Negi Anjana K. , Agnihotri Navneet
Published: March 2013

Introduction: Eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), the n-3 polyunsaturated fatty acids (PUFAs) enriched in fish oil, reduces proliferation and enhances apoptosis relative to n-6 PUFA treated cells. PPARγ, a member of retinoid X receptors (RXR) family, is implicated in the control of cell proliferation and apoptosis. One of the important components of Wnt pathway, β-catenin is also involved in cell proliferation. Hence, the present study was designed to understand the mechanism of action of different ratios of fish oil (FO) and corn oil (CO) in experimentally induced colon carcinoma by estimating the expression of PPARγ, apoptosis, β-catenin and VEGF.

Methods: Male wistar rats were divided into following groups-

Group I received purified diet while Group II and Group III received modified diet with FO:CO(1:1) and FO:CO(2.5:1) respectively for 4 weeks. After one week of purified diet, all the 3 groups were divided into two subgroups- one received the injection of ethylenediamine-tetra acetic acid intraperitoneally and another received dimethylhydrazine dihydrochloride (DMH) per week for 4 weeks (20mg/kg body weight). The animals which were killed 48 hours after the last injection constituted initiation phase whereas the remaining were kept on standard pellet diet and sacrificed on completion of 16 weeks constituted post initiation phase. The effect of different ratios of FO:CO was analyzed by estimating the expression of PPARγ in colonocytes; apoptotic/ necrotic cells by immunofluorescence; expression of β-catenin and VEGF by immunohistochemistry.

Results: DMH administered animals have shown:

No significant alteration in the expression of PPARγ in initiation phase whereas the expression was decreased significantly (p<0.001) in post-initiation phase.Apoptotic cells were increased significant (p<0.01) in the initiation phase whereas apoptotic cells were decreased significant in post-initiation phase (p<0.001).An increased expression of β-catenin and VEGF in both the phases.

In comparison to DMH treated animals, treatment with different ratios of FO and CO have shown:

A significant (p<0.001) increase in the expression of PPARγ in both the phases. However, the increase was more pronounced with FO+CO(2.5:1).A significant increase in apoptotic cells in both the phases. On treatment with FO+CO(2.5:1), cells undergoing necrosis were significantly increased as compared to FO+CO(1:1).The expression of β-catenin and VEGF were decreased in both the phases with both the ratios.

Conclusion: The dose and time dependent chemopreventive effect of FO and CO may be mediated by increasing the expression of PPARγ, apoptosis and by inhibiting β-catenin and VEGF.
Abstract B22: Re-expression of miR-200 by natural agents regulates the expression of PTEN and MT1-MMP in pancreatic cancer
Authors: Ali Shadan , Soubani Omar , Ali Azfur , Logna Farah , Philip Philip , Sarkar Fazlul
Published: March 2013

Purpose: Membrane type-1 matrix metalloproteinase (MT1-MMP) is often activated and expressed in tumor cells with significant invasive properties, and is associated with poor prognosis of patients. This could partly be due to deregulated expression of microRNAs (miRNAs) which regulates the expression of MT1-MMP and PTEN (Phosphatase and tensin homolog) contributing to tumor invasion and metastasis.

Experimental Procedure: We initially compared the expression profile of miR-200 family, PTEN and MT1-MMP expression in six pancreatic cancer (PC) cell lines by qRT-PCR and western blot analysis. Based on our initial findings, we chose BxPC-3, MIAPaCa-2, and MIAPaCa-2-GR cells for further mechanistic studies. We assessed the effect of two separate novel agents CDF, (a synthetic analogue of curcumin) and BR-DIM (a natural agent) on PC cells.

Results: We found loss of expression of miR-200a, b, and c in chemo-resistant PC cell lines, which was correlated with loss of PTEN and over-expression of MT1-MMP. The expression of miR-200 family and PTEN was significantly re-expressed whereas the expression of MT1-MMP was down-regulated by CDF and BR-DIM treatment. Forced over-expression or silencing of miR-200c, followed by either CDF or BR-DIM treatment of MIAPaCa-2 cells altered the morphology of cells, wound-healing capacity, colony formation, and the expression of MT1-MMP and PTEN.

Conclusion: These results provide strong experimental evidence showing that the loss of miR-200 family and PTEN expression, and increased level of MT1-MMP leads to aggressive behavior of PC cells, which could be attenuated through re-expression of miR-200c by CDF and/or BR-DIM treatment, suggesting that these agents could be useful for treatment.
Abstract B37: Monitoring kinome response to EGFR inhibition in triple negative breast cancer
Authors: Whittle Martin C. , Duncan James S. , Graves Lee M. , Johnson Gary L.
Published: March 2013

Triple negative breast cancers (TNBC) are resistant to hormone therapies and HER2-targeted therapies because of their ER-negative, PR-negative, and HER2-negative status. A further lack of molecularly targeted therapies for TNBC leaves conventional cytotoxic chemotherapy as the primary course of treatment for basal-like TNBC. While TNBCs are initially sensitive to chemotherapy, resistance can quickly develop, and tumors often recur with an aggressive metastatic phenotype and poorer patient prognosis. Expression of EGFR has been linked to basal-like TNBC, and EGFR expression is significantly associated with poorer prognosis in patients. However, clinical trials targeting EGFR in TNBC have been largely unsuccessful, possibly due to TNBC cell responses that bypass targeted inhibition of EGFR. Thus, EGFR inhibition in TNBC may cause a rewiring of kinase signaling, allowing TNBC cells to evade growth arrest and/or apoptosis. Rational design of combination therapies for treating cancer entails knowing how cancer cells rewire kinase growth signaling pathways to promote proliferation and survival in the presence of molecularly targeted therapies. In this study we applied a chemical proteomic approach to define kinome response to EGFR inhibitor treatment in TNBC and identify kinases upregulated in response to EGFR inhibition. We discovered compensatory upregulation of multiple receptor tyrosine kinases in response to EGFR inhibitors that may be mediating cell growth and survival following EGFR inhibition. Our methods show that kinome response to drug treatment can be monitored and proposes a new mode for designing effective small molecule inhibitor combinations for treating cancer.
Abstract B43: Alisertib (MLN8237), an Aurora Kinase A inhibitor, enhances Docetaxel-induced cell death in Upper Gastrointestinal Adenocarcinoma cells
Authors: Sehdev Vikas , Revetta Frank , Belkhiri Abbes , Ecsedy Jeffrey , Zaika Alexander , El-Rifai Wael
Published: March 2013

Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. We and others have previously reported frequent AURKA gene amplification and mRNA and protein overexpression in UGCs. It has been shown that AURKA can induce chemotherapeutic resistance and regulate several key signaling pathways in cancer cells, suggesting its role as a central node in cancer cell signaling. The DCF (docetaxel, cisplatin and 5-FU) regimen is the most promising chemotherapeutic regimen against UGC. However, AURKA overexpression can mediate resistance to both Taxol and cisplatin. These findings provide a credible rationale for targeting AURKA. In this study we have reported therapeutic response of the recently developed AURKA selective inhibitor MLN8237 as a single agent and in combination with docetaxel. Our findings provide a foundation for a promising new approach of future targeted therapy in UGCs. Using AGS, FLO-1 and OE33 UGC cell lines, with constitutive AURKA overexpression and variable-p53 status, we observed inhibition of cancer cell survival with 0.5μM MLN8237 (p<0.05) alone. This effect was significantly enhanced in combination with 1.0nM docetaxel (p<0.001). Cell cycle analyses after 48hr of treatment with MLN8237 demonstrated a significant increase in the percentage of polyploidy for AGS and OE33 UGC cells (p<0.01) which was further enhanced by docetaxel (p<0.001). Additionally, an increase in the percentage of cells in the sub-G1-phase at 24hrs and 48hrs was observed with MLN8237 in FLO-1 (p<0.01) cells which was significantly enhanced with MLN8237 and docetaxel combination (p<0.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 and cleaved PARP with the combined treatment, as compared to a single agent treatment. Using xenograft models, we demonstrated an enhanced anti-tumor role for the MLN8237 and docetaxel combination, as compared to single agent treatments (p<0.001). In conclusion, this study demonstrates that MLN8237, combined with docetaxel, can mediate a better therapeutic outcome in UGCs.
Abstract B45: Met-Dependent Positive and Negative Signaling Cascades in Gastric Cancer Cells
Authors: Lai Andrea Z. , Cory Sean , Zhao Hong , Bell Emily S. , Hallett Michael , Park Morag
Published: March 2013

Signaling by the Met, hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) activates multiple downstream signaling pathways that promote cell migration and invasive growth. Cells that overexpress and are “addicted” to Met also require Met signaling to sustain cell survival. Thus, a number of specific small-molecule inhibitors have been developed to target Met in the clinic. Although several successes of RTK-targeted therapies are acknowledged, several have limited long-term success clinically, due to development of drug resistance.

Initiation of RTK signaling cascades leads to the activation of a number of downstream signaling molecules, but prolonged activation also triggers negative feedback loops that function in part to abrogate this signaling. Hence, targeted inhibition of Met, in addition to suppressing Met-dependent signaling, may also release cells from negative feedback mechanisms and allow the reactivation of signaling pathways that may promote resistance to Met inhibition.

As MET amplification occurs in 20–40% of gastric cancers, to identify core Met dependent signaling pathways activated in Met dependent cancers we have used four different gastric cancer cell lines that exhibit amplification, overexpression, and constitutive activation of Met. Upon inhibition of Met with a small-molecule inhibitor, we observe abrogation of several downstream signaling pathways at both the protein phosphorylation and transcript level. Interestingly, as Met has been demonstrated to cross-talk with the EGF receptor family, we also observe a decrease in the phosphorylation of EGFR and HER3 upon treatment with Met inhibitor, and a decrease in expression of EGFR ligands. Conversely, Met inhibition results in an elevation in expression of HER3 transcript and protein in all 4 cell lines, implicating Met signaling in HER3 repression, and inhibition of Met may release HER3 from this negative regulation. As increases in HER3 phosphorylation and expression occur in other models (such as breast or lung cancer cell lines) upon treatment with EGFR, HER2, or AKT inhibitors, and high HER3 expression is strongly associated with tumor progression and poor prognosis in gastric cancer; hence, the loss of negative regulation of HER3, downstream from Met, may ultimately contribute to clinical efficacy, or lack thereof, of Met inhibitors.
Abstract B5: CpG-siRNA conjugates: Overcoming cancer immunoresistance
Authors: Nechaev Sergey , Zhang Qifang , Swiderski Piotr , Kortylewski Marcin
Published: March 2013

Small interfering RNA (siRNA) have been proved to be an effective tool for treating diseases caused by gene expression abnormalities. However, clinical relevance of siRNA technology is compromised by multiple obstacles, such as lack of cellular specificity, low efficiency of cellular uptake and/or poor cytoplasmic release. We have previously demonstrated that natural capability of certain immune cells to recognize non-methylated CpG motifs in DNA oligonucleotides can be harnessed for cell-specific siRNA delivery. The siRNA molecules conjugated to CpG oligonucleotides (CpG-siRNA) are efficiently internalized and bind to the intracellular Toll-like receptor 9 (TLR9) in human and mouse dendritic cells as well as in certain TLR9-positive tumor cells. We designed a CpG-siRNA targeting Stat3 (signal transducer and activator of transcription-3), a transcription factor, which is constitutively activated in majority of mouse and human cancers. Oncogenic Stat3 signaling regulates cancer cell proliferation, survival and promotes tumor immunoresistance. We have previously shown that CpG-Stat3 siRNA can eliminate Stat3 signaling in tumor-infiltrating myeloid cells, resulting in potent antitumor immunity. In the current study, we investigated the intracellular mechanism of action of CpG-siRNA conjugates. We have demonstrated that internalized CpG-siRNAs are recruited into endosomes by dynamin-dependent mechanism and bind to endosomal TLR9 receptor. Further events include uncoupling of siRNA from the CpG moiety by Dicer endonuclease, and rapid translocation of siRNA to endoplasmic reticulum for recruitment into functional RISC (RNA interference silencing complex). We confirmed the target gene silencing both in vitro and in vivo, and proved that it occurs through RNA interference mechanism. Our current results indicate that downstream effectors of TLR9 pathway may be involved in RISC assembly and/or activation. Overall, the CpG-siRNA strategy provides a novel opportunity for overcoming cancer immunoresistance with translational potential for therapy of various malignancies.
Abstract B53: Proteasome inhibitor MG132 induces NAG-1 expression through activation of p38 MAPK pathway
Authors: Shimizu Sachie , Kinyamu Harriet , Yoshioka Hiroki , Kadowaki Mitsutoshi , Watanabe Takashi , Eling Thomas
Published: March 2013

Glioblastoma multiforme (GBM) is the highly invasive primary tumors with a poor prognosis despite current surgical, radiation and chemotherapy approaches. Proteasome inhibitor, an approved drug for treatment of hematological cancer is currently being tested in clinical trials against various malignancies, including GBM. The pro-apoptotic and antitumorigenic protein NAG-1(nonsteroidal anti-inflammatory drug-activated gene-1) is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily. We showed that the proteasome inhibitor, MG132 induces NAG-1 protein and mRNA expression and apoptosis in a concentration-dependent manner in U87 cells. Studies with NAG-1 luciferase reporter constructs show that the −133 to +41 region of the NAG-1 promoter is activated by MG132 however activation does not require the Sp-/Egr-1 binding site. Using the selective pharmacologic p38 mitogen -activated protein kinase (MAPK) inhibitor, we showed that NAG-1 induction following MG132 is mediated by the p38 MAPK pathway. Pretreatment with MAPK inhibitor, SB203580 and SB202190, blocked the MG132-induced NAG-1 expression, whereas an inhibition of p53, JUNK, MEK, PKC, PKA activity had no effect on NAG-1 levels. In summary, our data indicate linkage between p38MAPK, NAG-1 and the proteasome inhibitor, MG132 and provides a new clue to the molecular mechanism of the antitumorigenic activity of NAG-1.
Abstract B8: FOXD3 enhances expression of ERBB3 and promotes resistance to vemurafenib
Authors: Basile Kevin J. , Abel Ethan V. , Aplin Andrew E.
Published: March 2013

Melanoma cells driven by mutant B-RAF are sensitive to vemurafenib (PLX4032), which selectively inhibits BRAF/MEK/ERK1/2 signaling. Despite initial tumor shrinkage, most responders in the trials experienced tumor relapse over time. Furthermore, approximately 5–15% of patients show tumor progression. These findings indicate that resistance mechanisms will hamper the clinical efficacy of vemurafenib. We have previously shown that a stemness factor, FOXD3, is upregulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that siRNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032 treatment in mutant B-RAF melanoma cell lines. Additionally, ectopic expression of FOXD3 in nonadherent cells significantly reduced cell death in response to PLX4720 treatment. Genome wide analyses revealed that FOXD3 significantly increased expression of ERBB3 through direct binding to a known enhancer region of the ERBB3 gene. Knockdown of endogenous FOXD3 reduced ERBB3 upregulation after treatment with PLX4032. Furthermore, activation of ERBB3 in the presence of ligand was enhanced by B-RAF inhibition in an ERBB2-dependent manner. Treatment with the EGFR/ERBB2 inhibitor, lapatinib, in combination with PLX4032/4720 significantly reduced viability in both in vitro and in vivo assays. These data indicate that upregulation of FOXD3 is an adaptive response to B-RAF inhibitors that enhances ERBB3 signaling and promotes a state of drug resistance.
Abstract IA14: Functional genomics to identify cancer targets and resistance
Authors: Hahn William C.
Published: March 2013

Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. While these approaches will yield critical information regarding the identity, number, and types of alterations found in human tumors, a complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. In pilot studies, we have identified several genes that act as synthetic lethal partners to known oncogenes or mediate resistance to targeted therapies. In recent work, we have expanded the scale of these experiments to genome scale in more than 100 cell lines, which has permitted greater expansion and deeper investigation into genes that program the malignant state. Together, these studies suggest that combining forward and reverse genetic approaches with information derived from the cancer genome characterization projects will yield a comprehensive list of cancer vulnerabilities and establish a general approach for the rational identification of oncogenic and codependent pathways in cancer.
Abstract IA2: Mechanisms of resistance to anti EGFR therapies in colorectal cancers
Authors: Bardelli Alberto
Published: March 2013

Personalized cancer medicine based on the genetic milieu of individual colorectal tumors has long been postulated but until recently this concept was not supported by clinical evidence. The advent of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab has paved the way to the individualized treatment of metastatic colorectal cancer (mCRC). There is clear evidence that mCRCs respond differently to EGFR-targeted agents and that the tumor specific response has a genetic basis. From the initial observation that cetuximab or panitumumab as monotherapy are effective only in 10–20%, of mCRCs, knowledge has being gained on the molecular mechanisms underlying primary resistance to these agents. The role of oncogenic activation of EGFR downstream effectors such as KRAS, BRAF, PIK3CA and PTEN on response to therapy will be discussed. The rapid and effective translation of these findings into predictive biomarkers to couple EGFR-targeted antibodies to the patients that benefit from them will be presented as a paradigm of modern clinical oncology. Unresolved questions such as understanding the molecular basis of response as well the mechanisms of secondary resistance will be discussed as the future fundamental goals in this research field.
Abstract IA8: BRAF and MEK resistance in melanoma
Authors: Herlyn Meenhard , Villanueva Jessie
Published: March 2013

The melanoma field has had a long history of frustrating experiences in clinical trials. Most of these were in immunotherapy, although all approaches in biotherapy, chemotherapy and radiation therapy have been similarly unsuccessful for the past 30 years with unchanged five-year survival rates of 15% for advanced disease. The therapy arena is dramatically changing with a new generation of BRAF inhibitors. Particularly those with high specificity for the mutant kinase are effective in killing cells carrying the BRAFV600E mutation. Two BRAF inhibitors have increased progression-free survival and overall survival from the disease. Considering the poor success rate from previous trials, the currently accumulated data are dramatic and exciting. However, there are no cures and all treated patients recur due to the development of resistance. In treated melanoma cells with BRAFV600E there are no new mutations, except the appearances of splice variants and mutations in NRAS in some tumors. Instead, cells learn to signal around inhibited BRAF through CRAF or ARAF to activate MEK and ERK. At the same time compensatory signaling activates receptor tyrosine kinases such as IGFR1 and PDGFR, leading to activation of the PI3K pathway. Potentially, additional pathways can be activated likely requiring an individual assessment of the mechanisms of resistance. Inhibition of the newly activated pathways can prevent progression in experimental systems but has not yet been validated in patients. In contrast to inhibitors of BRAF, inhibitors for MEK appear to induce mutations in either MEK 1 or MEK 2. It is not yet clear whether the mutations occur at multiple or unique sites. Likely, similar mutational events as in MEK will occur when inhibitors of ERK are given to cells over prolonged time periods. In summary, the MAPK pathway has emerged as a major driver for melanoma cells. However, when the malignant cells are treated with inhibitors for BRAF/MEK/ERK they develop secondary resistance. Why do some cells survive the drug insult? This question is particularly pertinent for inhibitors of mutant BRAF because all cells invariably contain the mutations. The reasons for this intrinsic or primary resistance are not clear and will require a major investigational effort in future years. Experimental studies in immunodeficient mice have shown that single melanoma cells are sufficient to induce a tumor, thus, the goal has to be the elimination of all cells and not just the majority of cells. Strategies to achieve this goal will in part depend on the mechanisms of survival of a sub-population of malignant cells. It is most likely that non-genetic events are responsible for the survival and they will be discussed.
Treatment of Exudative Age-Related Macular Degeneration with Intravitreal Ranibizumab in Clinical Practice: A 3-Year Follow-Up
Authors: Marques Inês P. , Fonseca Pedro , Luz Cachulo M. , Pires Isabel , Figueira João , Faria de Abreu J.R. , Silva Rufino
Published: March 2013

Purpose: To evaluate the 36-month efficacy of intravitreal ranibizumab injections for choroidal neovascularization secondary to age-related macular degeneration (AMD) in real world clinical practice. Methods: Retrospective study involving 84 eyes of 77 patients; 52 eyes completed 3 years of follow-up. Subjects were observed initially on a monthly basis and with extended follow-up intervals if signs of quiescence were detected, according to an established protocol. A comprehensive ophthalmologic examination was performed, including best-corrected visual acuity (BCVA) determined with Early Treatment Diabetic Retinopathy Study charts, stereoscopic macular biomicroscopy and optical coherence tomography (OCT) with fluorescein angiography and indocyanine green angiography if considered necessary. Treatment was given if signs of active lesions were present. Results: The mean baseline BCVA was 49.33 and 49.52 letters at the 36-month visit. The average of treatments was 8.6 at 3 years. At this time point, 77% of treated eyes stabilized or improved their vision (VA loss ≤5 letters). A predictive value for better VA was found for younger age, better baseline VA, good response on OCT and more frequent treatments. Conclusion: At 3 years, intravitreal ranibizumab is able to maintain baseline VA in exudative AMD patients, with a reduced number of injections, but not to show VA improvement, in clinical practice.
Very Low Protein Diet Reduces Indoxyl Sulfate Levels in Chronic Kidney Disease
Authors: Marzocco Stefania , Dal Piaz Fabrizio , Di Micco Lucia , Torraca Serena , Sirico Maria Luisa , Tartaglia Domenico , Autore Giuseppina , Di Iorio Biagio
Published: March 2013

Background and Objectives: High levels of indoxyl sulfate (IS) are associated with chronic kidney disease (CKD) progression and increased mortality in CKD patients. The aim of this pilot study was to assess whether a very low protein diet (VLPD; 0.3 g/kg bw/day), with a consequent low phosphorus intake, would reduce IS serum levels compared to a low protein diet (LPD; 0.6 g/kg bw/day) in CKD patients not yet on dialysis. Material and Methods: This is a post hoc analysis of a preceding cross-over study aimed to analyze FGF23 during VLPD. Here we performed a prospective randomized controlled crossover study in which 32 patients were randomized to receive either a VLPD (0.3 g/kg bw/day) supplemented with ketoanalogues during the first week and an LPD during the second week (group A, n = 16), or an LPD during the first week and a VLPD during the second week (group B, n = 16 patients). IS serum levels were measured at baseline and at the end of each study period. We compared them to 24 hemodialysis patients (HD) and 14 healthy subjects (control). Results: IS serum concentration was significantly higher in the HD (43.4 ± 12.3 µM) and CKD (11.1 ± 6.6 µM) groups compared to the control group (2.9 ± 1.1 µM; p < 0.001). IS levels also correlated with creatinine values in CKD patients (R2 = 0.42; p < 0.0001). After only 1 week of a VLPD, even preceded by an LPD, CKD patients showed a significant reduction of IS serum levels (37%). Conclusions: VLPD supplemented with ketoanalogues reduced IS serum levels in CKD patients not yet on dialysis.
Prevalence, Awareness, Treatment, and Control of Hypertension Among Residents in Guangdong Province, China, 2004 to 2007
Authors: Xu Bayi , Xu Zhixia , Xu Xiaojun , Cai Qiumao , Xu Yanjun
Published: March 2013

Background—

As a result of the large variation in geographic, demographic, and socioeconomic characteristics in different regions of China, the prevalence and treatment of hypertension in different regions differ widely. However, little is known about the recent trends of hypertension in Guangdong Province in southern China. We assessed the trends in prevalence, awareness, treatment, and control of hypertension in Guangdong Province between 2004 and 2007.

Methods and Results—

The Guangdong Provincial Chronic Disease Risk Factor Surveillance, modeled on the national Chronic Disease Risk Factor Surveillance, was conducted every 3 years beginning in 2004 with a representative sample of Guangdong Province residents ≥18 years of age. Data from the Guangdong Provincial Chronic Disease Risk Factor Surveillance I (2004; n=7633) and II (2007; n=6447) were used to describe the trends in the prevalence of hypertension among Guangdong Province adults. Hypertension outcomes were examined with interview and examination data. From 2004 to 2007, the age-standardized prevalence rate of hypertension in Guangdong Province residents increased from 12.2% to 15.4% (
P
<0.001), with the largest increases among rural women (from 9.3% to 19.1%;
P
<0.001). Among hypertensive people, there was no improvement in awareness and treatment between 2004 and 2007; the control rates decreased from 7.1% in 2004 to 4.5% in 2007 (
P
<0.01).

Conclusions—

One in 7 Guangdong Province adults is hypertensive, but only one quarter are aware of the condition. About 22% of hypertensive patients receive treatment, and few have their hypertension effectively controlled. Hypertension has become a major public health problem in southern China. Comprehensive public health measures need to be taken to decrease the incidence of hypertension and to prevent the progression of hypertension to cardiovascular disease.
Lost Childhoods in a New China: Child-Citizen-Workers at War, 1937–1945
Authors: Plum M. Colette
Published: March 2013

This article examines the emerging discourse of child-citizen-workers in wartime China and demonstrates how this concept of children’s citizenship was put into practice in work training programs within wartime children’s homes. This article argues that the idea of child-citizen-workers grew from three pre-war antecedents that converged and were greatly accelerated by China’s war with Japan: the new idea of an autonomous sphere of childhood articulated during the early Republican period; a progressive education movement to introduce labor training and experiential learning as essential elements of modern education; and Nationalist state-building and activist efforts at family reform, which viewed traditional parents with distrust and increasingly intervened in family life.

The second half of the article focuses particularly on orphans, who were considered potentially unstable social elements due to their position outside the control of families, and whose lack of parental protection made them available for appropriation. This article demonstrates that the war opened up a space in which Guomindang state-builders, working with educators and childcare workers, attempted to restructure orphans lives within wartime child welfare institutions to realize a vision for China’s future: the ideal of child-citizen-workers habituated toward sacrifice for the nation.
Scientising Relief: Nutritional Activism from Shanghai to the Southwest, 1937–1945
Authors: Fu Jia-Chen
Published: March 2013

The Shanghai Refugee Children Nutritional Aid Committee, formed in 1937, sought to improve refugee children’s nutritional health by making and distributing a scientifically tested soybean milk and soybean cakes. By 1942, the Committee had adopted a national platform and changed its moniker to the Chinese Nutritional Aid Council, with plans to open offices and nutrition clinics in Chongqing, Chengdu, Guiyang and Kunming. This paper argues that in linking biomedical understandings of nutrition with social change, this group of Western-trained physicians and young female social workers enacted a new kind of social activism, one which seized upon the food-as-fuel idea and staked the welfare of the nation upon the nutritional health of its citizenry. In contrast to earlier social relief projects promoted by the imperial state and the local philanthropic initiatives of gentry elites, the Chinese Nutritional Aid Committee articulated an image of professional and specialised expertise in the science of nutrition and care. Theirs was a project of modern refashioning in which science played a key and foundational role in crafting their understanding of both relief and the children they aimed to save.
Description of a new genus and species of Eucoilinae (Hymenoptera: Cynipoidea: Figitidae) from Colombia
Authors: PUJADE-VILLAR JULI , DÍAZ NORMA B. , GALLARDO FABIANA
Published: March 2013

Fontaliella, a new genus of Eucoilinae (Hymenoptera, Cynipoidea, Figitidae) and F. colombiensis sp. nov. from Colombia, are described and illustrated. This new genus belongs to the Ganaspini and morphologically resembles Zamischus Ashmead, 1903, Perischus Weld, 1931 and Steleucoela Kieffer, 1908. A key to differentiate these genera and species is given.
Integration of a Road Surface Model into NWS Operations
Authors: Rutz Jonathan J. , Gibson Chris V.
Published: March 2013

Today's winter weather headlines are based on the meteorological strength of an event with the assumption that stronger events produce larger public impacts. In reality, public impacts involve many factors, such as whether or not snow will accumulate on roads and affect traffic. Along with numerous environmental factors, decisions are further complicated by societal factors (e.g., timing of the commute).

The National Weather Service (NWS) Strategic Plan calls for increased emphasis on decision support services (DSS) to our partners, especially during high-impact events. However, determining when events will produce high-impact conditions often remains a challenge. While forecasters should be aware of the relevant societal factors, they also need objective tools capable of integrating over the wide range of environmental factors that intersect in producing high-impact weather. This is particularly true in the case of road surface conditions, where complex interactions between temperature, moisture, and the road surface play a key role in determining what hazards might develop during wintry weather.

Initial verification suggests that output from the Model of the Environment and Temperature of Roads (METRo) can provide useful information with regard to the timing and severity of hazardous road surface conditions, allowing NWS forecasters to more effectively highlight the impacts associated with impending meteorological events. This information enhances the DSS that the NWS is able to provide to government partners, local emergency management, and the public during high-impact winter weather events.
Analysis of WRF Model Wind Estimate Sensitivity to Physics Parameterization Choice and Terrain Representation in Andalusia (Southern Spain)
Authors: Santos-Alamillos F. J. , Pozo-Vázquez D. , Ruiz-Arias J. A. , Lara-Fanego V. , Tovar-Pescador J.
Published: March 2013

This paper reports on an evaluation of the relative roles of choice of parameterization scheme and terrain representation in the Weather Research and Forecasting (WRF) mesoscale model, in the context of a regional wind resource assessment. As a first step, 32 configurations using two different schemes for microphysics, cumulus, planetary boundary layer (PBL), or shortwave and longwave radiation were evaluated. In a second step, wind estimates that were obtained from various experiments with different spatial resolution (1, 3, and 9 km) were assessed. Estimates were tested against data from four stations, located in southern Spain, that provided hourly wind speed and direction data at 40 m above ground level. Results from the first analysis showed that wind speed standard deviation (STD) and bias values were mainly sensitive to the PBL parameterization selection, with STD differences up to 10% and bias differences between −15% and 10%. The second analysis showed a weak influence of spatial resolution on the STD values. On the other hand, the bias was found to be highly sensitive to model spatial resolution. The sign of the bias depended on terrain morphology and the spatial resolution, but absolute values tended to be much higher with coarser spatial resolution. Physical configuration was found to have little impact on wind direction distribution estimates. In addition, these estimates proved to be more sensitive to the ability of WRF to represent the terrain morphology around the station than to the model spatial resolution itself.
“Choose Your Classmates, Your GPA Is at Stake!”
Authors: Gašević Dragan , Zouaq Amal , Janzen Robert
Published: March 2013

This article presents results from an investigation of the association between student academic performance and social ties. Based on social capital and networked learning research, we hypothesized that (a) students’ social capital accumulated through their course progression is positively associated with their academic performance and (b) students with more social capital have significantly higher academic performance (operationalized as grade point average). Both hypotheses were supported by results of an empirical study that analyzed 10 years of student course enrolment records ( N = 505) in a master’s degree program offered through distance education at a Canadian university. These results are consistent with previous studies that looked at social networks built through student interaction in classrooms or computer-mediated communication environments. The significance of this research lies in the simplicity of the method used to establish student social networks from existing course registration records readily available through an institution’s student information system. Direct implications of this research are that (a) study plans for students should consider investment in building new social ties in each course during degree programs and (b) readily available data about cross-class networks can be used in software systems supporting study planning.
Informing Pedagogical Action
Authors: Lockyer Lori , Heathcote Elizabeth , Dawson Shane
Published: March 2013

This article considers the developing field of learning analytics and argues that to move from small-scale practice to broad scale applicability, there is a need to establish a contextual framework that helps teachers interpret the information that analytics provides. The article presents learning design as a form of documentation of pedagogical intent that can provide the context for making sense of diverse sets of analytic data. We investigate one example of learning design to explore how broad categories of analytics—which we call checkpoint and process analytics—can inform the interpretation of outcomes from a learning design and facilitate pedagogical action.
The reflexive subject: Towards a theory of reflexivity as practical intelligibility
Authors: Farrugia David
Published: March 2013

This article argues for a new perspective on the meaning and implications of reflexivity for understanding subjectivity. The two dominant perspectives on the genesis and consequences of reflexive subjectivities are discussed and critiqued in terms of the way they understand the relationship between reflexivity and the wider social world. Reflexive modernisation theory is critiqued for its empty and homogeneous view of reflexivity stemming ultimately from the absence of a theory of the subject. Critical realism is critiqued for its view of reflexivity as a disembodied rationality and its hostility to any connection between reflexivity and pre-reflexive foundations for identity. Drawing on the dialogue between these theories and practice theories, this article creates a new theory of reflexivity which overturns theoretical orthodoxies viewing reflexivity and social practice as opposed concepts. Based on insights from Bourdieu and other practice theorists, this article argues for a theory of reflexivity as actualising a practical intelligibility shaped by the dispositions of the habitus. Examples from empirical literature examining the relationship between reflexivity and class inequality support a theory of reflexive subjectivity based on principles of practice theory.
Professionalism: Value and ideology
Authors: Evetts Julia
Published: March 2013

Professionalism is a key concept in the sociologies of work, occupations, professions and organizations. But professionalism is changing and being changed. The article considers the different ways in which professionalism has been and is currently being interpreted. Beginning with a section on defining the field and clarifying concepts, the second section examines the concept of professionalism, its history and current developments. The third section considers the consequences of changes in work contexts and employment conditions for aspects of professionalism both as an occupational value and as an ideology in the global world.
Minority Performance on the Naglieri Nonverbal Ability Test, Second Edition, Versus the Cognitive Abilities Test, Form 6
Authors: Giessman Jacob A. , Gambrell James L. , Stebbins Molly S.
Published: March 2013

The Naglieri Nonverbal Ability Test, Second Edition (NNAT2), is used widely to screen students for possible inclusion in talent development programs. The NNAT2 claims to provide a more culturally neutral evaluation of general ability than tests such as Form 6 of the Cognitive Abilities Test (CogAT6), which has Verbal and Quantitative batteries in addition to a Nonverbal battery. This study compared the performance of 5,833 second graders who took the CogAT6 and 4,038 kindergartners, first graders, and second graders who took the NNAT2 between 2005 and 2011 as part of a grade-wide screening for a gifted program. Comparison between minorities and Whites on the CogAT6 and the NNAT2 found slightly larger gaps on the CogAT6 Composite for Hispanics and English-Language Learners (ELL) but the same gap for Black students. Considered alone, the Nonverbal battery of CogAT6 produced smaller gaps than the NNAT2 for Blacks, Hispanics, Asians, and ELL students. Fisher’s exact tests showed no significant differences between the CogAT6 Composite and the NNAT2 in subgroup identification rates at hypothetical cuts for gifted identification (top 20%, 10%, or 5%), except for Asian and ELL students. The CogAT6 Nonverbal score appeared to identify as many or more high-ability students from underrepresented groups as the NNAT2. Wechsler Intelligence Scale for Children, Fourth Edition, follow-up on the top 5% showed greater predictive validity for the CogAT6 Composite. These results suggest that gifted programs should not assume that using a figural screening test such as the NNAT2, without other adjustments to selection protocol, will address minority underrepresentation.
A recovery journey for people with personality disorder
Authors: Castillo Heather , Ramon Shulamit , Morant Nicola
Published: March 2013

Background:

The study investigates the process of recovery for people diagnosed with personality disorder, a client group that suffers significant social exclusion known to impact on demand for health and other public services. It aims to examine efforts that attempt to reverse this social exclusion as an aspect of the recovery process.

Aim and Method:

The following study aims to (1) explore what recovery means to people with personality disorder; (2) develop a conceptual model of recovery in personality disorder; and (3) evaluate the contribution of the setting (The Haven) to recovery practice. The study uses a Participatory Action Research (PAR) design. Data was collected from 66 participants by focus groups and individual interviews.

Findings:

A map based on thematic analysis of data collected during the study is proposed of the recovery journey for people with this diagnosis, shown as a pyramid that represents a hierarchy of progress, from building trust through stages of recovery to social inclusion.

Conclusion:

The findings offer contributions to knowledge in terms of the service design and propose a new model of recovery in personality disorder. This is defined as a journey of small steps highlighting recovery as a process rather than a goal, leading to the emergence of the new concept of transitional recovery.
Identification of moisture diffusion parameters in organic matrix composites
Authors: Dana Hossein Ramezani , Perronnet Annick , Fréour Sylvain , Casari Pascal , Jacquemin Frédéric
Published: March 2013

In this work, moisture penetration in glass fiber-reinforced polymers was systematically investigated through both experiments and theoretical approaches. The diffusivities of the neat resin and those of unidirectional composite plates containing various glass fiber volume fractions have been identified through the analysis of hygro-thermal aging tests. The main aim of the present paper consists in comparing the evolutions, as a function of the fiber volume fractions, of the moisture diffusion coefficients deduced from experiments to the corresponding values, predicted by the many traditional scale transition relations available in the literature.
Professor Thomas Lehner
Authors: Challacombe S.J.
Published: March 2013

Professor Thomas Lehner is one of the most distinguished oral and dental researchers to have come out of the UK. Over the past 40 years, he has made an astonishing number of discoveries which have had an impact on our understanding of the pathogenesis of a variety of mucosal diseases. He has consistently practiced both basic and clinical research and built an integrated group of clinical and non-clinical researchers, which allowed him easy transition from the laboratory to the clinic. Tom Lehner was among the early scientists studying mucosal immunology, initially exploring oral diseases, with special emphasis on the immunobiology of Streptococcus mutans, leading to active and passive vaccination against dental caries. He was the first to demonstrate cellular immunity as the immunopathological basis of periodontal diseases, recurrent aphthous stomatitis, and candidiasis. Over the past 20 years, his expertise in mucosal immunobiology has been applied to the immunology of HIV/SIV infections. His seminal contributions include regional innate mucosal immunity, prevention of SIV infection in macaques by secretory IgA antibodies, up-regulation of CC chemokines, and the first demonstration of protective CCR5 antibodies. Arguably, his leadership, his students, and the establishment of immunology applied to oral mucosal diseases will be his greatest legacy. His contributions continue unabated.