Fund Fellowships Research Articles

Treasurer's Report November 2017

Treasurer's Report November 2017

883P - Synchronous vs metachronous metastatic disease: Impact of time to metastasis on outcome in metastatic renal cell carcinoma patients treated with targeted therapy

Background: Patients (pts) with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of timing of metastatic disease outbreak on outcomes from targeted therapy (TKI) is unclear. Methods: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to assess overall survival (OS) and time to treatment failure (TTF) on first line TKI, and performed Cox regression analyses comparing synchronous (metastases ≤ 3 mo of initial diagnosis of cancer) vs metachronous disease (metastasis diagnosed post initial diagnosis, evaluated by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, and >7yrs). Results: In 7386 pts with mRCC treated with first line TKI, 3906 pts (53%) had synchronous and 3480 pts (47%) had metachronous metastases. Synchronous vs metachronous disease by intervals >3-12 mo, >1-2 yrs, >2-7 yrs, >7yrs correlated with lower age at TKI initiation (mean 61 yrs vs 61, 62, 63, 66 yrs, respectively, p < 0.0001), higher rate of non-clear cell histology (14% vs 12%, 10%, 10%, 7%, respectively, p < 0.0001), and higher rate of IMDC risk features (mean 2.3 vs 1.6, 0.9, 0.9, 0.8, p < 0.0001). Compared with synchronous disease, the longer time to metastases was significantly associated with improved OS and TTF from TKI therapy initiation in multivariable Cox regression, adjusted for nephrectomy status, histology (cc vs ncc), IMDC risk factors (Hgb, Corrected calcium, Neutrophil, platelets, Karnofsky performance status), number of metastasis (1 vs > 1), age at TKI initiation and year of TKI initiation (2003-2007, 2008-2012, 2013-2016).Table883P Association of time to metastases with OS and TTF from TKI initiationOSTTFtime to metastasesTotalFailedMedian, months 95%CIAdjusted Hazard ratio (95%CI)Adjusted P-valueTotalFailedMedian, months 95%CIAdjusted Hazard ratio (95%CI)Adjusted P-value0-3mo3906(53%)285216.7(15.9-17.5)1.00(reference)–388034835.6(5.5-5.8)1.00(reference)–>3∼12mo1055(14%)72623.8(21.6-26.1)1.06(0.98-1.16)0.16210509417.3(6.6-8.0)1.02(0.95-1.1000.551>1∼2yrs638(9%)40130.2(26.7-32.5)0.84(0.76-0.94)0.0026355648.0(7.3-8.9)0.99(0.90-1.08)0.767>2∼7yrs1155(16%)72934.8(32.4-38.1)0.76(0.70-0.83)<.00011151101110.8(9.6-11.5)0.83(0.77-0.89)<.0001>7yrs632(9%)35941.7(36.3-46.0)0.65(0.58-0.73)<.000162752713.3(11.5-14.9)0.67(0.61-0.74)<.0001Total7386(100%)506773436526 Open table in a new tab Conclusions: Timing of metastases post initial RCC diagnosis impacts outcome with targeted therapy in mRCC. This may need to be taken into consideration in clinical trial designs. Legal entity responsible for the study: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Funding: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Disclosure: F. Donskov: Research funding (to institution) from Novartis, GSK and Pfizer. C. Porta: Consulting or advisory role: Novartis, Bristol-Myers Squib, Pfizer, Jannsen, Eisai, Pelefon, Ipsen, Speaker bureau: Novartis, Bristol-Myers Squib, Pfizer, Ipsen; Eisai Research funding: Pfizer. J.L. Lee: Honoraria from Pfizer and Astellas; consulting fees from Astellas; research funding from Pfizer, Bayer, Janssen, Novartis, and Exelixis. T. Yuasa: Honoraria from Astellas, Novartis, and Pfizer. I.D. Davis: Supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1102604) and research funding from Astellas and Exelixis. C. Pezaro: Honoraria from Janssen, Pfizer, Sanofi, Novartis, and Astellas; consulting fees from Novartis; and travel and accommodation funding from Pfizer and Sanofi. R. Kanesvaran: Honoraria from Pfizer, Novartis, Bayer, Astellas, Janssen, Mundipharma, and Sanofi; research funding from Sanofi; and travel and accommodation expenses from Pfizer and Astellas. N. Agarwal: Consulting fees from Pfizer, Exelixis, Cerulean, Argos, and Medivation. C.M. Canil: Advisory Boards for Janssen, Pfizer, Astellas and Amgen; speaking fees from Janseen and Astellas and travel grants from Novartis and Janssen. T.K. Choueiri: Consulting or advisory role for Bayer, Bristol-Myers Squib (institutional), GSK, Merck, Novartis, and Pfizer; and institutional research funding from AstraZeneca, Bristol-Myers Squib, Exelixis, GSK, Merck, Novartis, Peloton Therapeutics, Pfizer, Roche/Genentech, and TRACON Pharma. D.Y.C. Heng: Advisory boards Pfizer, Novartis, Bristol-Myers Squib, Exilexis. All other authors have declared no conflicts of interest.

Show me the money – funding opportunities for fellowships

SummaryIn a time when a fellowship can make a difference in a young ophthalmologist's curriculum, it is vital to know where to look for funding and plan ahead to be eligible for the opportunities.This talk will focus on potential sources for fellowship funding, providing links and information to attendees. It will cover both national and international funding sources, as well as an overview of specific funding for certain fields of Ophthalmology. Both research and clinical fellowships will be included in this overview.In the end, attendees are supposed to know where and when to look for funding opportunities.

Identification of Dietary Patterns Associated with Chronic Disease Risk Using Hybrid Dimension Reduction Techniques: Evidence from the Canadian National Nutrition Survey

Analysing dietary patterns is an important approach for characterizing the complex relationships between foods and nutrients in etiology of obesity and other chronic diseases. Several studies have used a priori and data‐driven dimension reduction techniques for evaluating dietary patterns in relation to chronic disease risks, even though methods for applying these techniques to complex nationally‐representative nutrition surveys are not yet developed. The objective of this study was to define a novel algorithm for using hybrid dimension reduction techniques for identifying dietary patterns of Canadians most strongly associated with obesity and other chronic diseases (diabetes, cancer, and cardiovascular diseases) at the national population level. Dietary data were collected using 24‐hour dietary recalls (second recall in sub‐sample). All analyses included 11,748 participants (≥18 y) in the cross‐sectional nationally‐representative Canadian Community Health Survey 2.2 (2004/5). To ensure nationally‐representative estimates, weighting algorithm was incorporated into the partial least squares analyses (PLS), to derive an energy‐dense (ED), high‐fat (HF) and low fiber density (LFD) dietary pattern using 38 food groups. PLS is the most flexible hybrid technique for deriving dietary patterns enabling discovery of important disease‐specific dietary exposures that have not been previously identified in etiology of chronic diseases. The association of dietary patterns with obesity and chronic diseases was ascertained using weighted multinominal logistic regression‐GLM adjusted for the following covariates in successive models: age, sex, dietary misreporting, energy intakes, physical activity and smoking. Using the weighted PLS algorithm, an ED,HF,LFD dietary pattern was derived with high positive loadings for fast foods, carbonated drinks, refined grains and negative loadings for whole fruits, and vegetables (≥|0.17|). Food groups with a “high” loading were summed to form a simplified dietary pattern score. Moving from the first (healthiest) to the fourth (least healthy) quartiles of the ED,HF,LFD and the simplified dietary pattern scores was associated with increasingly elevated odds ratios (OR) for “obesity with at least one chronic disease” (diabetes, cancer and cardiovascular diseases), with individuals in quartile 4 having an OR of 2.57 (95%CI:1.75,3.76) and 2.73 (1.88,3.98), respectively (p‐trend&lt;0.0001). The associations of dietary patterns with “healthy obesity” (obesity without having a chronic disease) and “being non‐obese with at least one chronic disease” were weaker, albeit significant (p&lt;0.05). Overall, consuming an ED,HF,LFD dietary pattern was associated with significantly higher risk of obesity with and without accompanying chronic diseases. Our findings demonstrated that novel techniques for deriving dietary patterns can be modified for successful use in nationally‐representative surveys. The weighted algorithm we defined in this research can be used for deriving dietary patterns associated with chronic diseases at the national population level, improving the applicability and use of novel dietary pattern techniques by governments and researchers.Support or Funding InformationThis research was supported by a grant from the Burroughs Wellcome Fund Innovation in Regulatory Science Award, and funds to the Canadian Research Data Centre Network (CRDCN) from the Social Science and Humanities research Council (SSHRC), the Canadian Institutes of Health Research (CIHR), the Canadian Foundation for Innovation (CFI) and Statistics Canada. M.J. was funded by a Burroughs Wellcome Fund Fellowship, the Canadian Institutes of Health Research (CIHR) Vanier Canada Graduate Scholarship, the CIHR/Cancer Care Ontario (CCO) Population Intervention for Chronic Disease Prevention (PICDP): A Pan‐Canadian Fellowship, Ontario Graduate Scholarship (OGS) and the Faculty of Medicine Hunter Fellowship (University of Toronto). M.L. is the Earle W. McHenry professor and is supported through chair endowed unrestricted research funds, University of Toronto. Funders had no role in the design, analysis or writing of this article.

Sex differences in the inflammatory response and inflammation-induced vascular dysfunction

BackgroundPremenopausal women have a lower incidence of cardiovascular disease, although the exact mechanism underlying this protection is unclear. Both systemic and localised inflammation have a crucial role in the progression of cardiovascular disease, and much preclinical and observational data in human beings suggest that differences in inflammation between the sexes exist. We investigated whether inflammation, and which components of the inflammatory response, might be altered in women compared with men. MethodsWe performed two clinical studies with 24 and 32 healthy volunteers. In 12 men and 12 women (mean age 26·0 years [SD 5·7] and 24·7 [6·8], respectively), we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD) determined with ultrasound. Responses were assessed before administration of typhoid vaccine and then at 8 h and 32 h afterwards. In another study, in 16 male and 16 female volunteers (mean age 27·4 years [SD 1·1] and 26·8 [1·1], respectively), inflammatory exudate and cellular recruitment were measured at 24 h (acute) and 72 h (resolution) in skin blisters induced with cantharidin. Ethics approval was given by NRES: City Road and Hampstead Ethics Committee (11/LO/2038) for both studies. Both studies are registered with ClinicalTrials.gov, number NCT01582321. FindingsTyphoid vaccine caused a mild systemic inflammation, which was associated with a trend to decreased FMD in men and an increased response in women compared with baseline (p=0·006). By 24 h cantharidin induced a fluid-filled blister of a similar volume in both sexes; however, after 72 h blisters had resolved only in women (p=0·003). At 24 h there was a significant reduction in both monocyte (p=0·003) and lymphocyte count (p=0·011) in blisters in women compared with those in men. A generalised reduction in the activation state of all major leucocytes including neutrophils was evident in women. These differences in cell recruitment and activation were associated with higher proresolving mediators, including the D-resolvins, and a reduction in concentrations of the neutrophil chemoattractant leukotriene B4. InterpretationOur findings suggest that female sex protects against endothelial dysfunction induced by systemic inflammation. This effect is probably due to a rapid resolution of inflammation in women specifically targeting the neutrophil through elevation of the D-resolvin pathway. FundingKR receives doctoral research fellowship funding from the National Institute for Health Research. JD receives funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement 677542), and is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).

Using nationwide ‘big data’ from linked electronic health records to help improve outcomes in cardiovascular diseases: 33 studies using methods from epidemiology, informatics, economics and social science in the ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER) programme

BackgroundElectronic health records (EHRs), when linked across primary and secondary care and curated for research use, have the potential to improve our understanding of care quality and outcomes.ObjectiveTo evaluate new opportunities arising from linked EHRs for improving quality of care and outcomes for patients at risk of or with coronary disease across the patient journey.DesignEpidemiological cohort, health informatics, health economics and ethnographic approaches were used.Setting230 NHS hospitals and 226 general practices in England and Wales.ParticipantsUp to 2 million initially healthy adults, 100,000 people with stable coronary artery disease (SCAD) and up to 300,000 patients with acute coronary syndrome.Main outcome measuresQuality of care, fatal and non-fatal cardiovascular disease (CVD) events.Data platform and methodsWe created a novel research platform [ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER)] based on linkage of four major sources of EHR data in primary care and national registries. We carried out 33 complementary studies within the CALIBER framework. We developed a web-based clinical decision support system (CDSS) in hospital chest pain clinics. We established a novel consented prognostic clinical cohort of SCAD patients.ResultsCALIBER was successfully established as a valid research platform based on linked EHR data in nearly 2 million adults with &gt; 600 EHR phenotypes implemented on the web portal (seehttps://caliberresearch.org/portal). Despite national guidance, key opportunities for investigation and treatment were missed across the patient journey, resulting in a worse prognosis for patients in the UK compared with patients in health systems in other countries. Our novel, contemporary, high-resolution studies showed heterogeneous associations for CVD risk factors across CVDs. The CDSS did not alter the decision-making behaviour of clinicians in chest pain clinics. Prognostic models using real-world data validly discriminated risk of death and events, and were used in cost-effectiveness decision models.ConclusionsEmerging ‘big data’ opportunities arising from the linkage of records at different stages of a patient’s journey are vital to the generation of actionable insights into the diagnosis, risk stratification and cost-effective treatment of people at risk of, or with, CVD.Future workThe vast majority of NHS data remain inaccessible to research and this hampers efforts to improve efficiency and quality of care and to drive innovation. We propose three priority directions for further research. First, there is an urgent need to ‘unlock’ more detailed data within hospitals for the scale of the UK’s 65 million population. Second, there is a need for scaled approaches to using EHRs to design and carry out trials, and interpret the implementation of trial results. Third, large-scale, disease agnostic genetic and biological collections linked to such EHRs are required in order to deliver precision medicine and to innovate discovery.Study registrationCALIBER studies are registered as follows: study 2 – NCT01569139, study 4 – NCT02176174 and NCT01164371, study 5 – NCT01163513, studies 6 and 7 – NCT01804439, study 8 – NCT02285322, and studies 26–29 – NCT01162187. Optimising the Management of Angina is registered as Current Controlled Trials ISRCTN54381840.FundingThe National Institute for Health Research (NIHR) Programme Grants for Applied Research programme (RP-PG-0407-10314) (all 33 studies) and additional funding from the Wellcome Trust (study 1), Medical Research Council Partnership grant (study 3), Servier (study 16), NIHR Research Methods Fellowship funding (study 19) and NIHR Research for Patient Benefit (study 33).

On-field identification and management of concussion in amateur rugby union

James Brown would like to thank the BokSmart program and Chris Burger Petro Jackson Players’ Fund who provided his Post-Doctoral Fellowship funding.

Next Generation Sequencing Reveals Potentially Actionable Alterations in the Majority of Patients with Lymphoid Malignancies

Introduction: The rapid technological advances in next generation sequencing (NGS) have allowed oncologists to sequence tumorexomesin a clinically meaningful period of time. NGS allows for identification of alterations that may be potentially targetable by already available Food and Drug Administration (FDA) approved drugs, providing a biologic rational for consideration of therapies and/or experimental treatments (clinical trials) that would not have otherwise been contemplated. Here we report our experience using NGS in a cohort of 60 patients with various lymphoid malignancies.Methods: We retrospectively reviewed the medical charts of 60 patients with various lymphoid malignancies who had undergone NGS. Patients were seen at the UCSD Moores Cancer Center (La Jolla, CA) from October 2012 until March 2016. We collected tumor samples from tissue (Table 1) or peripheral blood from 60 patients that were submitted for testing to Foundation Medicine, a clinical laboratory improvement amendments (CLIA)-certified lab. Hybrid capture based NGS (405 gene panel) was performed (http://www.foundationone.com/). The methods used in this assay have been described in detail in a previous report (He, J. et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016. 127:3004-3014.).Results: Sixty patients including 35 men (58%) and 25 women (42%), were identified with lymphoid malignancies (Table 1). A total of 224 alterations were found by NGS in the entire cohort of 60 individuals. Types of alterations identified included substitutions, indels, copy number alterations (CNAs), and gene fusions. Figure 1 demonstrates the 15 most frequent alterations among the cohort: TP53 mutations (10 patients), IGH rearrangements (9 patients), loss of CDKN2A/B (8 patients), and BCL2 mutations (8 patients). The median number of alterations detected per patient was 3 (range, 0 to 14). Shown in Figure 2, 7 patients (12%) had no reportable alterations, 10 patients (17%) had 1 alteration, and 43 (71%) patients had 2 or more alterations. The maximum number of alterations identified was 14, which occurred in two patients (3%), one with chronic lymphocytic leukemia (CLL) and the other with diffuse large B-cell lymphoma (DLBCL). A total of 49 patients (82%) had potentially actionable alterations using FDA approved drugs and/or experimental therapies (clinical trials) while 11 patients (18%) had no theoretically actionable alterations. Only 3 patientshad an alteration for which an approved drug in the disease is available (on-label) while 45 patients (75%) had an alteration for which an approved drug is available in another disease (off-label). Twenty-three patients (38%), 12 patients (20%), and 10 patients (17%) had 1, 2 and³ 3 FDA targetable alterations, respectively. The median number of theoretical FDA actionable alterations was 1.Conclusions:Most patients with lymphoid malignancies will have alterations that are potentially pharmacologically identified by NGS; however, only a minority of patients will have alterations for which an approved drug in the disease is available (on-label). Patients with lymphoid malignancies who have exhausted standard therapy or who are unable to tolerate chemotherapy may be excellent candidates for matched targeted therapies, ideally administered in the context of a clinical trial. [Display omitted] [Display omitted] [Display omitted] DisclosuresGoodman:Pfizer: Other: Fellowship funding. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurzrock:Serono: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Actuate Therapeutics: Research Funding; Sequenom: Research Funding; X Biotech: Research Funding; Genentech: Research Funding; Curematch: Equity Ownership; Novena: Equity Ownership.

38P - MYD88 mutations are associated with a high tumor mutational burden

Aim/Background: MYD88 is a universal adaptor protein used by almost all toll-like receptors (TLRs) and is critical for IL1 receptor innate immunity signaling. Activating mutations in MYD88 have been described in the majority of patients with lymphoplasmocytic lymphoma. MYD88 mutations have not been characterized in solid tumors. Methods: Whole-genome somatic tumor mutation data were downloaded from the resource project TCGA (Broad GDAC website (https://gdac.broadinstitute.org/)). 8,495 samples corresponding to unique patients (32 tumor types) were curated. Lists of significant variants were generated using the MutSig2CV algorithm (http://www.broadinstitute.org/cancer/cga/mutsig). All non-synonymous missense, nonsense, del/insertions, frameshift or splicing site mutations within MYD88 were kept. Association between MYD88 non-silent mutations and the overall tumor mutational burden (TMB) was assessed by univariate analysis using the Mann-Whitney’s test. Results: Of the 8,475 samples curated, 22 were mutated for MYD88. Tumor histologies included 7 diffuse large B-cell lymphoma (DLBCL) (32%), as well as 15 solid tumors (68%): stomach (18% of 22), colorectal (14%), endometrial (9%) and others (30%). Tumors with mutated versus wild-type MYD88 demonstrated a median of 811 vs 66 mutations (p = <0.0001). Solid tumors, excluding hematologic malignancies, mutated for MYD88 (n = 15) harbored a median of 1,528 mutations (range, 50-12,312) vs 68 (range, 1-23,950) for wild-type MYD88 (p = <0.0001) (Table). Table Open table in a new tab Conclusions: MYD88 non-silent alterations are rare in solid tumors. However, solid tumors with MYD88 non-silent alterations are associated with very high overall TMB compared to tumors with no MYD88 mutation. Signaling through MYD88 can induce NFKB expression, which may result in high TMB via aberrant expression of activation-induced cytidine deaminase. The relationship between MYD88 alterations and high TMB merits further exploration. Legal entity responsible for the study: Aaron Goodman Funding: No funding Disclosure: A.M. Goodman: Fellowship Funding from Pfizer. R. Kurzrock: Genentech, Merck, Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant fees from Sequenom, X Biotech, and Actuate Therapeutics and an ownership interest in Novena, Inc. and Curematch Inc. All other authors have declared no conflicts of interest.

Controlled unknown quantum operations on hybrid systems**Project supported by the National Natural Science Foundation of China (Grant Nos. 61303039 and 61201253), Chunying Fellowship, and Fundamental Research Funds for the Central Universities, China (Grant No. 2682014CX095).

Any unknown unitary operations conditioned on a control system can be deterministically performed if ancillary subspaces are available for the target systems [Zhou X Q, et al. 2011 Nat. Commun. 2 413]. In this paper, we show that previous optical schemes may be extended to general hybrid systems if unknown operations are provided by optical instruments. Moreover, a probabilistic scheme is proposed when the unknown operation may be performed on the subspaces of ancillary high-dimensional systems. Furthermore, the unknown operations conditioned on the multi-control system may be reduced to the case with a control system using additional linear circuit complexity. The new schemes may be more flexible for different systems or hybrid systems.

Abstract 3712: The relationship of Procollagen alpha 1 type 1 (Col1A1) / DDR2 signaling in malignant glioma and sensitivity to STAT 3/5 inhibitor

Abstract We have previously shown that Procollagen alpha 1 type 1 (Col1A1) is found in low and intermediate grade glioma and in less aggressive glioblastoma multiforme (GBM) (Cancer Invest. 23:577, 2005). However, these tumor cells are more prone to ER stress -inducing agents such as Befeldine (BFA) which block the transport of Procollagen to the cell surface. We also found that GBM cells which possess Col1A1 also express DDR2. The role of Col1A1/ DDR2 signaling in glioma is not known. We have used three GBM cell lines: Glioma1 established in our laboratory from a patient who progressed from grade 3 to grade 4, U-118, A-172 and U-373 to study this signaling pathway. Both Glioma1 and U-118 express Col1A1 and DDR1 and 2. A-172 and U-373 do not express Col1A1 but express both DDR2. U-373 does not express HSP47 which is an essential protein to fold collagen. In order to define the function of DDR2/ Col1A1 in GBM, we have used knock down COL1A1 and DDR2. Silencing Col1A1 leads to a significant increase in invasiveness by Matrigel assay which indicated that Col1A1 is important in preventing invasion in GBM and hence is found more in low and intermediate grade glioma. However, it has minimal effect on cell cycle or cell proliferation. Next, we have silenced DDR2 in all 4 cell lines and studied the biochemical changes. We found that silencing DDR2 does not affect cell proliferation, cell death or cell cycle. However, it does affect the sensitivity to BFA. In cell lines which possess Col1A1, the cell viability increased by 20 -30% (p &amp;lt;0.05). In contrast, cell lines which do not express Col1A1, the cell viability decreased by 25-30% (p&amp;lt;0.01). However, there is no difference in sensitivity to the DNA damaging agent cisplatin. Thus, DDR2 may function differently depending on the presence of Col1A1. To explore this further, we have performed a limited phoshoprotein kinase array in Glioma 1 with siCol1A1 or siDDR2. We found increase in STAT3, 5 and STAT6 upon silencing either Col1A1 or DDR2 which is further confirmed by immunoblot in Glioma 1 for pSTAT 3 and 5. We then tested the antitumor effect of STAT3/5 inhibitor (SH4-54) a benzoic acid based inhibitor (provided by Dr. James Turkson) which interferes with the SH2 and DNA binding domains as well as tyr705 phosphorylation in Glioma1 and U-118 w/wo SiCol1A1. At 0.5 uM the cell viability in Glioma 1 is 55.65 + 1.35 and 74.2 + 4.6 in U-118 while SiCol1A1 it decreased to 44.5 + 3.53% in Glioma 1 and 58.2+ 1.9, respectively, with minimal activity in A-172 which does not possess Col1A1. In contrast, there is no effect with another commercially available STAT 3 inhibitor S31-201 which only interferes with DNA binding domain. Overall, our data suggest that Col1A1/DDR2/ STAT signaling may be important in certain GBM cell lines and can be exploited for future treatment in brain tumor (Supported by Wanfang Hospital-Taipei Medical University Fellowship and VA Research Fund). Citation Format: Shumei Chen, Chunjing Wu, Ying-Ying Li, Medhi Wangpaichitr, Ronald J. Benveniste, James Turkson, Niramol Savaraj, Lynn G. Feun. The relationship of Procollagen alpha 1 type 1 (Col1A1) / DDR2 signaling in malignant glioma and sensitivity to STAT 3/5 inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3712.

Training the scientific workforce: Does funding mechanism matter?

A National Institutes of Health (NIH) taskforce recently recommended decreasing the number of graduate students supported on research assistantships, and instead favoring traineeship and fellowship funding mechanisms. Using instrumental variables estimation with survey data collected from U.S. PhD-granting biomedical sciences departments and their newly-minted PhDs, we find that increases in these programs’ NIH-funded traineeships and fellowships do significantly increase programs’ total graduate enrollments, particularly of female students. However, PhDs who were funded primarily as research assistants are significantly more likely to take research-focused jobs in the U.S. scientific workforce after they graduate, as compared to PhDs who were primarily supported as trainees or fellows. The suggested policy changes thus may have unintended, negative consequences for scientific workforce participation.

Loss of Cdk5 Function May Mediate Age‐Related Decline in Voluntary Physical Activity

Increases in age are associated with declining levels of physical activity in multiple species, including humans, which in turn promotes the development of numerous chronic diseases. However, the neuro‐molecular mechanisms that regulate physical activity motivation at various ages are poorly understood. Our lab has previously observed that, in female Wistar rats, lifetime voluntary wheel running behavior is greatest at 8 wks of age.ObjectiveWe aimed to assess differences in the nucleus accumbens (NAc), a specific brain nucleus postulated to influence rewarding behavior, of wheel running and sedentary female Wistar rats at 8 and 14 weeks (wks) of age (n= 5–8).MethodsWheel running rats were introduced to wheels at 5 wks of age. RNA‐seq, qRT‐PCR and Western blotting were used to assess molecular changes between 8‐ and 14‐wk‐old wheel running and sedentary rats.ResultsVoluntary wheel running was greatest at 8 wks (17.7± 1.0 km/d) and had significantly decreased by 14 wks (11.1± 1.2 km/d). From 619 differentially expressed genes, bioinformatics suggested that cAMP‐mediated signaling, DARPP‐32 feedback, PKA signaling, and synaptic plasticity were increased at 8‐ compared to 14‐wk in wheel running rats. While analyzing transcripts specific to these functions, we observed significant (~20–30%; p&lt; 0.05) decreases in Cadm4, Cdk5, and p39 (Cdk5 activator) mRNAs and proteins from 8 to 14 wks of age in voluntary running rats. Further, Cadm4 (r= 0.84), Cdk5 (r= 0.57), and p39 (r= 0.71) mRNAs were significantly correlated with voluntary running distance during the week of sacrifice. Follow‐up analysis of sedentary 8‐ and 14‐wk‐old rats (n= 5–8) by qRT‐PCR found similar decreases in Cadm4 and p39 mRNAs and proteins from 8 to 14 wks of age (p&lt; 0.05), suggesting an age‐dependent reduction in synaptic function and Cdk5 activity may mediate decreases in wheel running. In light of these transcriptomic and protein changes, we assessed wheel‐running distance following NAc injection of the Cdk5 inhibitor roscovitine (ROS) (80 nmol/0.5μg) (n= 7) or vehicle (n= 5). Compared to vehicle, ROS significantly decreased wheel running distance 0–30 and 30–60 min post‐injection (p&lt; 0.001), and 60–90 min post‐injection (p&lt; 0.01). These effects were present after both 1 day and 5 days of daily injections.ConclusionCollectively, these experiments suggest that an age‐dependent loss in synaptic function and Cdk5/p39 activity in the NAc may mediate the age‐related decline in voluntary running behavior.SignificanceGiven the epidemic levels of physical inactivity and its associated consequences, these data may foster the development of therapies targeted to reduce age‐dependent increases sedentary behavior.Support or Funding InformationResearch was supported by an MU Life Sciences pre‐doctoral fellowship (GNR) and MU development funds (FWB).

Proximal‐tubule‐select dual knockout of insulin and insulin‐like‐growth factor (type I) receptors in mice alters responses to dietary fructose

The monosaccharide, fructose is a common dietary constituent, but metabolized quite differently from glucose. One site of fructose metabolism is the renal proximal tubule (PT). How and whether insulin or the related hormone, insulin‐like‐growth‐factor, type 1 (IGF1), modulate fructose metabolism at this site is not known. To address this, we bred mice with dual knockout (KO) of the insulin receptor (IR) and the IGF1 receptor (IGF1R) from PT by Cre‐lox recombination using a γ‐glutamyltransferase promoter. Male (M) and female (F) wild‐type (WT) and KO mice were fed control (C) or high fructose (Fr) diet (60%) for 4 weeks (n = 10–12/group). KO mice had marginally lower body and/or kidney weights. Fructose feeding did not affect final body weight. Glucose tolerance was significantly impaired by fructose feeding, but only in the WT mice. KO mice also had a phenotype suggesting renal tubular acidosis, i.e., with significantly elevated blood chloride levels, and decreased blood total CO2 levels. Plasma sodium was also reduced in male KO by fructose, but not in the WT or females. Western blotting of cortex homogenates revealed significantly reduced (2‐way ANOVA) band densities for IR, IGF1R, and NaPi‐2 (sodium phosphate cotransporter) in the KO mice. However, no genotype differences were found for band densities of the fructose transporter (GLUT5) and ketohexokinase (KHK), the first enzyme in fructose metabolism, although the abundances of these two proteins were significantly increased in males and in fructose‐fed animals. The sodium bicarbonate cotransporter (NBC) was reduced in KO, but not WT males by fructose‐feeding. Females, overall, had significantly lower levels of NBC. Overall, genotype differences in the metabolic responses to fructose suggest a role for PT IR/IGF1R expression as a modulator of PT metabolism and/or acid‐base homeostasis.Support or Funding InformationMarriott Cardiovascular Fellowship and Georgetown Internal funding

Investigating Env9's Mechanism of Membrane Insertion in Saccharomyces cerevisiae

Tail‐anchored proteins have vital roles within the cell such as vesicular transport and apoptosis, and often times their specific membrane localization is crucial to their function. These proteins have hydrophobic regions near their C‐terminus, making them identifiable to protein insertion machinery. One pathway which targets C‐tail anchored proteins is the well‐characterized Guided Entry of Tail‐Anchored Protein (GET) complex, consisting of Get1‐5 and Sgt2. Interestingly, a second mechanism has been proposed named the SRP‐independent (SND) pathway which similarly targets tail‐anchored proteins. Our protein of interest, Env9, is one of four novel endosome to vacuole interface (ENV) gene products and our data suggests it possesses a hydrophobic region near its C‐terminus. Env9 localizes to lipid droplet membranes however, its insertion mechanism is unknown. We hypothesize Env9 is targeted to membranes by either GET or SND pathways because of both its c‐terminal hydrophobic domain and its interactions with components of both complexes. Negative genetic interactions with both ENV8 (GET4) and with ENV10 (SND2) have been reported in systematic studies and have been observed in our laboratory. In order to investigate these interactions, we used both microscopic and biochemical approaches. Env9 was tagged with either GFP (green fluorescent protein) under an inducible galactose promoter or HA (hemagglutinin) under a constitutive PGK promoter to analyze localization in GET and SND mutants via confocal microscopy and western blot analysis, respectively. Preliminary microscopy results show slight disruption in GET mutants whereas SND mutants appear to have wild‐type Env9 localization patterns. In preliminary western blot analysis, tagged double mutants Δget4/env9 and Δsnd2/env9 continue to localize Env9‐HA to the P13 pellet that includes lipid droplets, but also vacuoles and aggregated protein complexes. These results suggest Env9 may be targeted to membranes via the GET complex and specifically implicate the GET complex in the process of insertion of Env9 into the ER membrane. These moderate phenotypes may also suggest compensation by one complex in the absence of the other in order to accurately target vital C‐tail anchored proteins. Additionally, the compensatory effect may be further stimulated by the highly overexpressed constructs used in these studies. We are currently exploring the insertion of Env9 expressed at native levels. Additionally, we are examining Env9 localization in GET double and triple mutants, as well as determining protein‐protein interactions via other biochemical approaches such as co‐immunoprecipitation.Support or Funding InformationAcknowledgements: This project was supported by NIH AREA #R‐15 GM85794‐02, NSF‐MRI grant #DBI0722757 for confocal microscopy, and NIH 2R25GM071638‐09A1 for the Research Initiative for Scientific Advancement Fellowship funding. We'd like to thank Dr. Maya Schuldiner at the Weizmann Institute of Science for her donations of the GET and SND mutants.

Announcing the Raelyn Cole Editorial Fellowship Fund

Announcing the Raelyn Cole Editorial Fellowship Fund

We need to know more about providing effective support for communication partners of children who use augmentative and alternative communication

This review provides a summary and appraisal commentary on the treatment review by Shire, S. Y., & Jones, N. (2015). Communication partners supporting children with complex communication needs who use AAC: A systematic review. Communication Disorders Quarterly, 37, 3–15. doi: 10.1177/1525740114558254Source of funding and declaration of interests: The first author received fellowship funds from the Canadian Institutes of Health Research (Doctoral Foreign Study Award) and Autism Speaks (Weatherstone Pre-Doctoral Fellowship). The authors reported no potential conflicts of interest.

Architectural History’s Futures

> You throw a stone into a deep pond. Splash. The sound is big, and it reverberates throughout the surrounding area. What comes out of the pond after that? All we can do is stare at the pond, holding our breath. > > — Haruki Murakami , 1Q84 What is the future of architectural history? The very question embodies an inherent contradiction, since historians are particularly skilled at studying the past; our aptitudes for predicting the future are far less honed. Nevertheless, important anniversaries invite introspection, reflection on our past, and speculation about our future. What pressures are coming to bear on our field that are most likely to cause significant change? Who will be our audiences in the decades to come? How will they find our work, and what will be the forms of our scholarship? In what follows, I examine three aspects of the architectural historian’s practice, casting stones into the pond of our field to see, as Murakami writes, what might come out of it after that. Until very recently, architectural historians generally conducted research in mostly the same manner as their colleagues across the humanities, which is to say, they did so largely working alone in libraries, museums, archives, and special collections. The single factor differentiating our work from that of scholars studying largely text-based or pictorially based subjects was our need for on-site investigation. Examining architectural, urban, and landscape spaces themselves has always been—and will no doubt continue to be—a crucial distinguishing aspect of our research culture, and there is little doubt that we will continue to perform solitary investigations with a range of primary and secondary sources. However much our methods of inquiry may remain constant, the archive, the library, and even the museum have changed. What does “the archive” now mean? In our current era of increasingly massive amounts of digitized …

Antidepressants May Help Improve Heart Health

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAntidepressants May Help Improve Heart HealthNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:14 Apr 2015https://doi.org/10.1176/appi.pn.2015.4b20AbstractA preliminary study in mice shows the biological effect of paroxetine in treating heart failure. Another recent analysis in humans with heart problems and depression provides some corroboration.When people think about the secondary effects of drugs, they naturally focus on adverse reactions like nausea or rashes. Sometimes, though, drugs can provide some extra benefits that may make them even more attractive as therapies.In the case of the antidepressant paroxetine, sometimes sold under the brand name Paxil, new research suggests that it may help reverse heart failure.These studies have been carried out only in animal models, but lead author Walter Koch, Ph.D., the William Wikoff Smith Endowed Chair in Cardiovascular Medicine at Temple University, believes the discovery heralds an intriguing new therapeutic path for a disease now considered irreversible.“Heart failure is a pretty serious and terminal condition,” he noted in an interview with Psychiatric News. “And right now we don’t have a lot of treatment options; beta blockers have gotten some buzz, but they pose their own risks as they slow your heart rate down.”“We still have a long way to go before we can have a therapy ready,” Koch continued. “But we have a molecule to serve as a template, and we have a target, and that’s a great start.”Paroxetine’s heart benefits stem from its action on an enzyme called GRK2, so it’s separate from the drug’s antidepressant properties. GRK2 levels are elevated following a heart attack, and the enzyme tries to repair the damage caused. Unfortunately, the efforts result in heart tissue that is larger, thicker, and less efficient at pumping blood; over time, these problems progress until the heart eventually fails.In their study, published in Science Translation Medicine, Koch and his team tested paroxetine against both another antidepressant (fluoxetine) and the beta blocker metroprolol in mice that had developed heart failure following a heart attack. After four weeks of paroxetine therapy, the mice’s hearts returned to a more normal size and showed better pumping ability. Fluoxetine, which is a similar class of drug but has a different chemical structure, had no effect, confirming that the results were not related to actions against the serotonin receptor.In another promising sign, paroxetine also proved more adept at restoring heart function than did metroprolol.These mice were given doses that were about five to 10 times higher than a person would take for depression, so it may be difficult to extrapolate what sort of benefits someone with heart failure taking paroxetine for comorbid depression would experience. Koch, though, thinks it is something clinicians should consider. “I’ve received numerous emails from patients with depression and heart problems asking whether they should tell their doctor they want to switch to Paxil. I personally think, why not at least give it a try?”Given the large numbers of people with both illnesses, supporting data may already be out there, and Koch is gathering information from antidepressant clinical studies to see if there might be ways to analyze how different drug classes might affect heart health. Some evidence in humans was scheduled to be presented at the American College of Cardiology Scientific Sessions in San Diego in March. Researchers from the Intermountain Medical Center Heart Institute in Utah found that in patients with moderate to severe depression, antidepressant therapy was more effective at reducing the risk of heart disease than statins were.This analysis, which looked at the records of more than 26,000 patients, found that antidepressant medications reduced the risk of heart disease, stroke, or death by about 53 percent compared with patients taking no medications; this reduction was not as strong in patients taking statins or—somewhat surprisingly—statins and antidepressants.“We thought we’d see an additive effect,” noted lead author Heidi May, Ph.D. “But we found that in the more depressed people, the antidepressant really was what made the biggest difference.”May thinks that improvements in mood contributed a lot to the improved heart health, but she did not rule out that there might be biological effects from these medications, and more work into the relationship between depression and cardiovascular health is worthwhile.Koch’s work was supported by grants from the National Heart, Lung, and Blood Institute and a Brody Family Medical Trust Fund Fellowship. ■An abstract of “Paroxetine-Mediated GRK2 Inhibition Reverses Cardiac Dysfunction and Remodeling After Myocardial Infarction” can be accessed here. ISSUES NewArchived

Spaceflight-relevant stem education and outreach: Social goals and priorities

This paper is based on a presentation and conference proceedings paper given at the 65th International Astronautical Congress. The paper addresses concerns in education and public outreach (EPO) in science, technology, engineering and mathematics (STEM). The author serves as a Director of a US statewide NASA-funded Space Grant Consortium, with responsibilities to coordinate funding for undergraduate scholarships, graduate fellowships, and program awards. Space Grant is a national NASA network of STEM EPO programs including over 1000 higher education, outreach center, science museum, local government, and corporate partners. As a Space Grant Director, the author interacts with a variety of levels of STEM literacy and sophistication among members of the public. A number of interactions highlight the need for STEM EPO leaders to speak directly to a variety of social goals and priorities. Spaceflight is largely seen as an appealing and potentially desirable STEM application. However, members of the public are often unclear and ill-informed regarding relative expense, relative benefit, and relative breadth of domains of expertise that are relevant to the spaceflight enterprise. In response (and resulting in further disconnects between STEM specialists and the public), focused STEM professionals frequently over-emphasize their own technical specialty and its priority in general because of its importance to that professional. These potential divides in the attempt to share and connect STEM related goals and priorities are discussed as an elaboration of invitations to discuss spacefaring in “futures forum” contexts. Spaceflight can be seen as addressing a combination of “actualization” and “aspirational” goals at social and societal levels. Maslow׳s hierarchy of needs distinguishes between “basic needs” and “actualization” as a higher–order need. Another aspect of spaceflight is aspirational—it speaks to hopes and desires for levels of flexibility and capability at the societal level. One analogy is the marketing of premium brand luxury items, at lower cost and larger volumes, to larger segments of the population. STEM EPO activities should not be directed solely at the “rocket science” applications of technology and engineering capabilities. Additional effort is needed to connect spaceflight experiences and examples to broader STEM needs, social priorities, and local contexts.