Lab Funding Research Articles

Targeted SNP Interrogation to Determine if Select Polymorphisms are Associated with Skeletal Muscle Hypertrophy Following 12 Weeks of Resistance Training

IntroductionWe aimed to determine if candidate genetic polymorphisms were associated with resistance training‐induced changes in skeletal muscle hypertrophy variables.MethodsTwo cohorts of predominantly Caucasian college‐aged male participants (N=109; n=66: Auburn, AL, USA; n=43: Hamilton, Ontario, Canada) performed 12 weeks of progressive full‐body resistance training (3–4 days/week). Vastus lateralis muscle biopsies and dual x‐ray absorptiometry (DXA) scans were performed prior to the intervention (Pre), and 72 hours following the last training bout (Post). Immunohistochemistry was performed to assess mean fiber cross sectional area (fCSA), DXA scans were analyzed to assess whole‐body (fat‐ and bone‐free) lean soft tissue mass (LSTM), and over 800,000 genetic polymorphisms were interrogated from muscle tissue using DNA microarrays. Select polymorphisms from a systematic literature review were examined in relation to Pre‐to‐Post changes in mean fCSA as well as changes in DXA LSTM.ResultsThere were no genotype*time interactions for ACTN3 (rs1815739), ACE (rs4343), ADRB2 (rs1042714), FTO (rs9939609, rs1421085, rs8050136), IL15RA (rs2296135), VDR (rs1544410), LEPR (rs113710182), FST (rs7229102), IGF1 (rs5742692), or MSTN (rs72909336) with regard to training‐induced changes in DXA LSTM or mean fCSA. Interestingly, when participants were clustered in tertiles according to percent changes in mean fCSA and DXA LSTM, Pre mean fCSA and Pre DXA LSTM were inversely correlated. Pre mean fCSA values were greater in the lower (5607±1195 μm2) versus middle (4673±1154 μm2, p=0.007) and upper tertiles (4558±895 μm2, p<0.001), while Pre DXA LSTM values were greater in the lower (63.3±7.0 kg) versus middle (59.6±6.9 kg, p=0.043) upper tertiles (57.5±5.8 kg, p<0.001). Stepwise linear regression was performed using baseline DXA LSTM and mean fCSA along with gene scores from the candidate polymorphisms to predict percent changes in DXA LSTM as well as mean fCSA with training, respectively. The only significant predictor of percent DXA LSTM change to training was Pre DXA LSTM (β=−0.327, model r2=0.11, p=0.001). Likewise, the only significant predictor of percent mean fCSA change to training was Pre mean fCSA (β=−0.310, model r2=0.09, p=0.001).ConclusionsCollectively, our data suggest that pre‐training DXA LSTM or fCSA values (rather than the genetic influence of select polymorphisms) are better predictors of change scores in these variables with resistance training.Support or Funding InformationFunding for this project on the Auburn Campus was provided by Hilmar Ingredients, Bionutritional Research Group, and discretionary lab funds by M.D.R. Funding for the McMaster Campus project was provided through an operating grant provided to S.M.P through the Natural Science and Engineering Research Council of Canada.Figure 1

Strategies and Tactics of Academics in the Context of Transition toward the Entrepreneurial University

A new form of the university has been emerging since the 1980s. Open, closely connected to the state and businesses, and internalizing the market logic of decision making, the university is becoming entrepreneurial. In Russia, changes occur with a certain lag, but present-day Russian universities already feature the new forms of activities characteristic of the global trend, such as patents, academic incubators, science parks, and startups. Formally, Russian universities have already become entrepreneurial, but they still remain traditionally overregulated institutions. In addition to collisions between the traditional logic of academia and the new one of the market that are typical of Western universities, Russia also features conflicts with the logic of bureaucracy.A study based on 30 in-depth interviews with university researchers of virtual and augmented reality and five expert interviews with representatives of other market actors was conducted with a view to find out how everyday practices and strategies of academics change in the context of transition toward the entrepreneurial university. Referring to James C. Scott’s concept of “mētis”, we describe the most widespread situations of conflict between different logics: procuring and allocating lab funding, choosing problems for research and development, launching new education programs, and assigning statuses to institutional departments. Completing our theoretical framework with Robert K. Merton’s anomie theory, we demonstrate possible versions of strategy design and possible reasons for choosing a specific course of action. The strategies of innovation and rebellion manifest themselves most saliently in the laboratories analyzed, while conformity, retreatism and ritualism are expressed mildly and blend into one another. However, regardless of the choices they make, academics still have enough freedom and creativity to avoid being determined completely of partially by any undesired logic.

LBA23 - MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC)

LBA23 - MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC)

Determining Accuracy of oAb as a Mechanistic Biomarker for Alzheimer's Disease in Human Plasma

Alzheimer's disease (AD) is a fatal neurodegenerative disease that is the 6th leading cause of death in the United States with no cure and few palliative treatments. Currently, there is no preventative treatment, and even if such a therapeutic could be identified, without a predictive biomarker, a target population for treatment could not be determined. Although the mechanism remains unclear, AD is caused by increased levels of the amyloid‐b peptide (Ab), which aggregates to form both amyloid plaques and soluble oligomeric Ab (oAb), the latter considered a proximal neurotoxin. We believe that levels of oAb in human plasma are a prognostic biomarker, and have developed and licensed a method for their detection (LOD <5pMol). While age is the greatest risk factor for AD, APOE4 is the greatest genetic risk factor, increasing risk up to 15‐fold compared to the more common APOE3. Importantly, female (♀) APOE4 carriers have an increased risk for AD compared to male (♂) APOE4 carriers. Key to the success of this project has been the stratification of both control and AD subjects by sex within APOE genotype, with the results that plasma oAb levels are: ♀APOE4> ♂APOE4> ♀APOE3> ♂APOE3. This response was observed in two large human post‐mortem cohorts. However, stratification, the principle of personalized medicine, is simply not applied to AD populations. We now seek to threshold oAb levels using longitudinal and human AD trial data to establish prognostic potential, with the goal of partnering with the private sector for commercialization.Support or Funding InformationLaDu lab funding includes an Anonymous Donor, the University of Illinois College of Medicine, and UIC Honors College Grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The effects of sex and APOE genotype on the gut microbiome in EFAD transgenic mice

While the gut microbiome (GM), the collective genome of bacteria in the gastrointestinal tract, is primarily studied in metabolism and immune defense, the GM may also serve as a diagnostic tool and therapeutic target in neurological disorders, including Alzheimer's disease (AD). While age is the greatest risk factor for AD, the e4allele of APOE is the greatest genetic risk factor, increasing risk up to 15‐fold compared to APOE3, the common genotype. APOE4 is associated with the accelerated accumulation of the peptide amyloid‐b(Ab), which can aggregate to form both amyloid plaques and small soluble aggregates or oligomeric Ab (oAb), the latter considered a proximal neurotoxin. Importantly, among APOE4 carriers, females have an increased AD risk, rate of cognitive loss and accumulation of Ab42 compared to males. Although the GM of individuals with AD exhibit specific microbial differences compared to healthy controls, a greater understanding of how age, APOE genotype and sex contribute to the altered GM in AD may help determine the diagnostic potential of the GM composition. To study the interactions among these AD risk factors, we developed the EFAD‐transgenic mice, which express the human APOE genotypes and over‐express human Ab42. Thus, our hypothesis is that APOE genotype and sex interact to modulate the GM composition in EFAD mice. Fecal samples from 4 month (M) ♂ and ♀ E3FAD and E4FAD mice were sequenced and compared. The Shannon H index, a measure of species richness and diversity, identified a negative correlation between diversity and severity of AD pathology in the 4M EFAD cohorts of mice: ♂E4FAD > ♀E4FAD and ♀E3FAD > ♀E4FAD. Analysis of similarities (ANOSIM) demonstrated significant differences in the GM in E3FAD vs E4FAD across different taxonomic levels (operational taxonomic unit/OTU, Genus, and Family). Comparison across sex within APOE genotype revealed a significant difference between ♂E3FAD vs ♂E4FAD and ♀E3FAD vs ♀E4FAD at all taxonomic levels. Additionally, there is a significant effect for ♂E4FAD vs ♀E4FAD, though only at the OTU level. Further, heatmap analysis demonstrates clustering of ♀E4FAD samples based on 29 OTUs. Therefore, the synergistic effect of APOE4 and female sex on AD risk is exhibited by the GM, observed by the stratification of the EFAD cohorts. This study is the first step in defining the composition of the GM as a function APOE genotype and sex modulation of AD pathology.Support or Funding InformationLaDu lab funding includes institutional funds from the University of Illinois College of Medicine, the Bridge to the Doctorate Fellowship, and the Honor's College Undergraduate Research Award at the University of Illinois at Chicago.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Portrayal of EMT Like Process in Human Glioma and Its Impediment by Rabeprazole to Combat Glioma Growth and Temozolomide Resistance

Background: Epithelial to mesenchymal transition (EMT) is a well-documented process in other cancers; its recognition in glioma is relatively new and lacking clinical and therapeutic significance. Methods: To characterize the EMT like process in glioma we investigated the expression profile of EMT associated proteins in clinical biopsies through western and immunohistochemistry and correlated with various clinicopathological features and the cancer genome atlas (TCGA) dataset. Further, we explored the anticancer efficacy of rabeprazole by in-vitro and in-vivo and its therapeutic relevance to EMT and temozolomide chemosensitization through multiple cell-based assays, western blotting, and confocal imaging. Findings: The expression analysis of EMT associated proteins and TCGA dataset revealed non-canonical expression of E-cadherin or N-cadherin and upregulation of GFAP, vimentin, and β-catenin in human glioma. The increased EMT proteins may attribute to glioma malignancy and poor prognosis. The in-vitro study unveils rabeprazole treatment attenuated glioma cell growth, cell migration, and induced apoptosis. Rabeprazole exposure suppressed EMT by repressing NF-κB signaling and/or inhibiting Akt/GSK3β phosphorylation. Further, the in-vivo studies confer restricted tumor growth in the confluence of EMT inhibition. We also showed temozolomide sensitizing effect of rabeprazole on temozolomide resistant cell line. Interpretation: We evidenced the clinical association of EMT like process in glioma malignancy and poor prognosis and its therapeutic relevance to rabeprazole along with rabeprazole anticancer and chemosensitization efficacy. Funding Statement: Authors acknowledged financial assistance of Department of Science and technology (DST- India) (Grant no: SB/EMEQ-257/2013, SR/CSRI/196/2016) and Department of Biotechnology (DBT-India) (Grant No. BT/PR18168/MED/29/1064/2016, BT/PR13111/MED/29/149/2009) for lab funding. D.B. thanks, Department of Biotechnology (DBT-India) for student fellowship (Award no: DBT/2013/UOH/79). Declaration of Interests: Written informed consent was obtained from all participants included in the study. Ethics Approval Statement: Institutional Ethics Committee (IEC) (reference number UH/IEC/2016/180) and Institutional Animal Ethics Committee (IAEC) (reference number UH/IAEC/PPB/2017-I/P7), University of Hyderabad, Hyderabad (500 046) approved all procedures involving human tissue and animal related experiments.

The effect of sex on APOE‐modulated AD pathology in EFAD mice

APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) and is associated with accelerated accumulation of both amyloid plaques and and soluble oligomeric forms of the amyloid‐β peptide (oAβ), likely a proximal neurotoxin. Importantly, female APOE4 carriers have a greater lifetime risk for developing AD, an increased rate of cognitive decline and accelerated accumulation of Aβ compared to male APOE4 carriers. In vivo progress has been limited by the lack of a tractable familial AD‐transgenic (FAD‐Tg) mouse model expressing human (h)‐ rather than mouse (m)‐APOE. To study the interactions among sex, h‐APOE and AD pathology, we developed the EFAD‐Tg mice by introducing the h‐APOE genotypes into the 5×FAD‐Tg mice. We previously demonstrated that in the EFAD mice, confirmed in human control and AD samples of CSF and brain, that apoE lipidation is lower and soluble Aβ levels are higher with APOE4 vs. APOE3. Thus, we have developed the mechanistic hypothesis that AD pathology and APOE4 cause a reduction in apoE lipidation, resulting in inefficient clearance of soluble A β synaptic loss, memory/cognitive deficits, and dementia. Novel preliminary data demonstrate that the differences in female vs. male E4FAD mice mimic these established APOE4 vs. APOE3 differences in Aβ aggregation/accumulation, and apoE levels/lipidation. In addition, amyloid deposition, neuroinflammation and tau pathology is significantly greater in the EFAD females compared to males. These data suggest that sex profoundly influences APOE genotype‐specific effects on AD pathology, with apoE lipidation and oAβ levels possibly at the intersection between these two AD risk factors. Together, these data will help to address the critical need for treatment options for women at high risk for AD from the APOE4 allele.Support or Funding InformationCurrent LaDu lab funding includes NIH (NIA) P01AG044682, R21AG030128, R21AG048498, R21AG051233, CCTS (UL1RR029879)

High Temperature (225 °C) SiC – Based Wireless Power Demonstrator

A high temperature, SiC-based wireless power demonstrator has been demonstrated by APEI engineers under Air Force Research Lab (AFRL) funding. The system consists of high temperature (> 225 °C) assembly processes and materials, including the ceramic substrate, die attach, and components. The wireless power transfer is demonstrated at different distances with respect to temperature. This system has significant implications for extreme environment applications which would benefit from condition-based monitoring.

Development and Repurposing of Small-Molecule Kinase Inhibitors to Target Novel Leukemogenic TNK2 Mutations

Development and Repurposing of Small-Molecule Kinase Inhibitors to Target Novel Leukemogenic TNK2 Mutations

Activating Mutations Observed in De Novo Acute Myeloid Leukemia Are Also Present in a Subset of Philadelphia Chromosome (Ph)-Positive Leukemia Patients with BCR-ABL1-Independent Resistance to ABL1 Kinase Inhibitors

Activating Mutations Observed in De Novo Acute Myeloid Leukemia Are Also Present in a Subset of Philadelphia Chromosome (Ph)-Positive Leukemia Patients with BCR-ABL1-Independent Resistance to ABL1 Kinase Inhibitors

Dasatinib Shows Therapeutic Potential in the Murine Xenograft Model for TCF3 rearranged Acute Lymphoblastic Leukemia

Transcription Factor 3 (TCF3) rearrangements are a recurring chromosomal abnormality in B-cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) occurring in approximately five percent of pediatric ALL. Historically, the majority of these patients carried a poor prognosis, but advances with more intensive cytotoxic chemotherapy have improved the survival rate while exposing patients to increased short and long-term toxicities. Two genetic rearrangements produce the chimeric transcription factors, TCF3-PBX1 t(1;19)(q23;p13) and a much rarer TCF3-HLF t(17;19)(q22;p13). Sadly, TCF3-HLF remains an extremely difficult disease to treat with few, if any known survivors. Although it is unknown how these translocations lead directly to disease, it is established that they do result in diseases arrested in a later stage of B-cell differentiation and pre-B cell receptor (pre-BCR) dependence. Recently, we highlighted the concept of targeting the pre-BCR pathway for therapeutic potential using dasatinib (Sprycel). Here, we further examine dasatinib effectiveness in the murine xenograft model for TCF3-rearranged ALL. Methods: Primary patient samples were obtained with written informed consent approved by the Institutional Review Board of Oregon Health and Science University and processed. Mononuclear cells were separated by Ficoll and exposed to increasing concentrations of dasatinib. Inhibitory Concentration of fifty-percent viability (IC50) was calculated for each sample. The median IC50 for over four hundred acute leukemic samples interrogated by this assay was calculated to approximately 100nM. Samples with IC50 values below 30nM were deemed hypersensitive to dasatinib. For xenografts, frozen viable primary patient samples were thawed and grafted via tail-vein into NOD/SCID/IL-2rgnull(NSG) mice 24 hours after sub-lethal irradiation with 200 cGy. Upon engraftment, and in vivo expansion, animals were euthanized and leukemic cells recovered from the spleen were then injected in secondary recipients. One week after injection the mice were divided into two groups and treated by oral gavage with dasatinib at 50mg/kg/dose daily or citrate control for 5 days per week. Treatment continued until the day of sacrifice (4-20 weeks). Peripheral blood engraftment was monitored weekly starting on week 3 by flow cytometry analysis using anti-human CD19 and CD45 (hCD19-APC, hCD45-FITC) versus anti-murine CD45 (mCD45-PerCP-Cy5.5). Flow cytometric data was analyzed using FACS/AriaIII. Results: Screening over one hundred BCP-ALL samples identified that approximately ten percent of these samples show hypersensitivity to dasatinib. TCF3-rearranged ALL and BCR-ABL1 ALL had a majority of samples with IC50’s less than 10nM. Throughout all known subsets of ALL except ETV6-RUNX1, there also appeared to be individual samples that have IC50 values less than 30nM, suggesting significant sensitivity to this drug. Of these, three individual TCF3-rearranged ALL samples were identified and xenografted into NSG mice, expanded and injected into secondary recipients. All dasatinib treated cohorts showed significantly less leukemic peripheral blood chimerisms as compared to their vehicle control counterparts. Further, in vitro treatment of xenografted cells with dasatinib indicated inhibition of the pre-BCR by decrease in pan-phospho-SRC. Intriguingly, dasatinib did not completely abolish disease in all TCF3-rearranged ALL, suggesting other important mechanisms for cell viability. Conclusions: These studies show in vivo therapeutic benefits of dasatinib as treatment for TCF3-rearranged ALL, and open the possibility of adding this drug to their treatment. Further studies are underway to address the mechanisms of dasatinib sensitivity of other subsets of ALL identified in our screen in hopes of adding targeted therapies to their treatment. [Display omitted] DisclosuresDruker:Molecular MD: Consultancy, Equity Ownership, Scientific Founder. Some clinical trials on which I participate as PI or co-investigator utilize MolecularMD for molecular testing. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU. Other; Bristol-Myers Squibb: Clinical trial funding: PI and co-investigator on ARIAD clinical trials. OHSU has contracts with ARIAD to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Clinical trial funding: PI and co-investigator on ARIAD clinical trials. OHSU has contracts with ARIAD to pay for patient costs, nurse and data manager salaries, and institutional overhead. I do not derive salary, or lab funds from these contracts. Other. Off Label Use: Dasatinib use as potential therapy in ALL.

Overhaul or Overload for French Science?

Far-reaching government reforms are being implemented to overhaul France's national research organizations in the life and health sciences, but researchers are anxious about what lies ahead. Karen Dente reports.

Further development of a graduate program in nuclear and radiochemistry at the University of Texas

Over the last three years we have developed a very robust nuclear and radiochemistry program at The University of Texas at Austin. The cornerstone of support was the DOE Radiochemistry Educational Award Program (REAP) that was awarded from 2002–2005. A second award for the period of 2005–2008 was just received. This award has enabled us to support many educational activities from vanguard classroom instruction, to laboratory enhancements, to research activities at the graduate and undergraduate levels. Both traditional radiochemistry and advanced topics in nuclear instrumentation have been supported. Various DOE university programs, national lab funding and IAEA fellowship grants, have allowed the Nuclear and Radiation Engineering Program at the University of Texas to be at the forefront of nuclear and radiochemistry educational and research activities and help secure the next generation of needed expertise.

Research lab funding debated

A bill aimed at rebuilding and modernizing scientific research facilities at colleges and universities has received mixed reviews in the academic community. While university administrators seem to agree that research buildings and laboratories desperately need revitalization, some officials differ with the funding mechanism set forth in the proposed legislation.