tbuckley/cabot-search huggingface dataset:
648. In-Vivo Adenovirus Mediated RNA Interference of Multidrug Resistance Protein-2 (MRP-2/ABCC2/cMOAT)
Authors: Andrew W. Snowden, Lei Zhang, Fyodor Urnov, Carolyn Dent, Andrew R. McNamara, Yann Jouvenot, Steve H. Zhang, Edward J. Rebar, Andrew C. Jamieson, Casey C. Case, Philip D. Gregory
Journal: Molecular Therapy (2004)

Angiogenesis is of critical importance to tumor progression and therefore is an attractive target in the treatment of cancer. The pro-angiogenic Vascular Endothelial Growth Factor A (VEGF-A) a potent effector of angiogenesis, is over-expressed in a variety of human cancers, including highly invasive brain tumors. In this study, we have applied engineered zinc-finger protein transcription factors (ZFP TFs) to the regulation of VEGF-A expression in human cancer cell lines. We show that ZFP TFs containing either the ligand-binding domain of thyroid hormone receptor or its viral relative vErbA are potent transcriptional repressors of VEGF-A expression. The engineered ZFP chimera specifically binds its target site within the VEGF-A promoter in vitro and in vivo] and represses in a HDAC dependant manner via targeted deacetylation of promoter nucleosomes. The therapeutic relevance of ZFP-driven VEGF-A repression was addressed using the highly tumorigenic glioblastoma cell line U87MG. Despite the aberrant over-expression of VEGF-A in this cell line, engineered ZFP TFs were able to repress the expression of this gene by >20-fold. Furthermore, the levels of VEGF-A following ZFP TF-mediated repression were comparable to those of a non-angiogenic cancer line, U251MG, suggesting that this degree of repression may be sufficient to suppress tumor angiogenesis. The use of ZFP-mediated recruitment of alternative repression domains and activities which may confer long term, epigenetic repression; such as DNA methylation, histone H3 lysine 9 methylation and HP1 recruitment in the repression of VEGF-A transcription will also be discussed.
Diffusing capacity for carbon monoxide and mortality in patients with chronic thromboembolic pulmonary hypertension
Authors: Rika Suda, Nobuhiro Tanabe, Fumiaki Kato, Hajime Kasai, Takao Takeuchi, Takashi Urushibara, Ayumi Sekine, Rintaro Nishimura, Takayuki Jujo, Toshihiko Sugiura, Ayako Shigeta, Seiichiro Sakao, Yasunori Kasahara, Koichiro Tatsumi
Journal: European Respiratory Journal (2012)

Background: Diffusing capacity for carbon monoxide (DLCO) reflects the ability of gas exchange across the alveolar-capillary interface and is also used as a marker of pulmonary vascular disease. Recently, Chandra et al. reported that DLCO predicts mortality in patients with pulmonary arterial hypertension. However, there is little data about DLCO in chronic thromboembolic pulmonary artery hypertension (CTEPH).  Objectives: The aim of this study is to reveal the correlation between DLCO and other clinical markers and to evaluate DLCO as a predictor of mortality in CTEPH patients.  Methods and Results: We performed observational retrospective study of 202 consecutive patients with CTEPH (female 69.8%, age 54.6±12.8 yrs., 99:medial, 103:surgical) who underwent both pulmonary function test including DLCO and right heart catheterization from 1986 to 2011 in Chiba University Hospital. %DLCO showed correlation with age, NYHA, Hugh-Jones classification, oxygen delivery, PvO 2 , %VC, %FEV1 and 6 minutes walk distance. However, no correlation was shown between %DLCO and mean pulmonary artery pressure, pulmonary vascular resistance, PaO 2  and AaDO 2 . Among surgically treated patients, there is no difference about operative mortality between normal %DLCO (≥70%) group and decreased %DLCO group (  Conclusion: Decreased DLCO was associated with impaired quality of life, pulmonary function, oxygen delivery in CTEPH, and predicted the mortality in medically treated patients.
An ethnomedical perspective of Anglo-American psychiatry
Authors: H Fabrega
Journal: American Journal of Psychiatry (1989)

Although psychiatry is part of Western biomedicine and its roots in neurobiology are widely appreciated, Anglo-American psychiatry addresses social behavior that is deviant and potentially stigmatizing and is said to uniquely engage in social control. Moreover, its concerns overlap and compete with those of other regulatory institutions of the state. For these reasons, the manner in which psychiatry operates is subject to challenge, criticism, and controversy. The author proposes that a look at psychiatry from the vantage point of ethnomedicine--the comparative study of medical systems--can enhance an appreciation of the current controversies in psychiatry and psychiatry's role as a medical institution.
70. Stable packaging cell lines development for the production of lentiviral vectors
Authors: Sophie Broussau, Nadine Jabbour, Guillaume Lachapelle, Yan Xu, Alaka Mullick, Renald Gilbert, Bernard Massie
Journal: Molecular Therapy (2004)

Our ultimate goal is to develop an optimal lentivector (LV) backbone in a self-inactivated (SIN) configuration, in which the most efficient promoter controls transgene expression, flanked by adequate insulators. Although SIN vectors are ideal to minimize silencing and to insure proper control of regulated promoters, in this configuration, the production and recovery of LV are inefficient. We have worked towards the development of a new packaging cell line for the efficient production of regulated conditional SIN LV (cSIN). Our design involved the use of two gene-switches to independently regulate the packaging elements and the transgene. As the initial step we have established a stable 293SF (adapted to serum-free culture) cell line expressing both the cumate repressor (CymR) and the reverse tetracycline transctivator (rtTA). Our best 293SF-CymR/rtTA clones were shown to maintain optimal expression level of both CymR and rtTA without selective pressure for at least ten weeks in culture. The generation of LV packaging cell lines from 293SF-CymR/rtTA then proceeded in two steps. First, the selection of clones stably expressing the LV Gag-Pol and Rev. We demonstrated that for all the clones selected, the production of LV was improved by the addition of Rev, suggesting that the expression of Rev was rate limiting. We hypothesized that high-level stable expression of either Rev or the Gag-Pol was not well tolerated by the cells. At the second step, we therefore co-transfected the best clones with the VSV-G envelope along with a modified Rev vector (regulated with CymR) to finally yield the 293SF-PacLV packaging cell lines. The selection of the best packaging cell lines is currently underway and preliminary results indicate that the best clones produce LV at higher level that transient transfection. The approach of producing the packaging cells line by selecting first the best clone expressing Gag-Pol and Rev will open the possibility to generate a collection of packaging cell lines using various envelope genes to pseudotype the LV, which could ultimately be useful to produce LV with improved gene delivery efficiency in stem cells.
The Cardioprotective Effects of the Angiotensin-Converting Enzyme Inhibitor Perindopril in Patients With Stable Coronary Artery Disease Are Not Modified by Mild to Moderate Renal Insufficiency
Authors: Jasper J. Brugts, Eric Boersma, Michel Chonchol, Jaap W. Deckers, Michel Bertrand, Willem J. Remme, Roberto Ferrari, Kim Fox, Maarten L. Simoons
Journal: Journal of the American College of Cardiology (2007)
Abstract P039: Brachial-ankle Pulse Wave Velocity is Independently Associated with Presence of Coronary Calcification among 1131 Healthy Middle-aged Men. The ERA JUMP Study
Authors: Abhishek Vishnu, Akira Sekikawa, Bradley J Willcox, Jina Choo, Akira Fujiyoshi, Emma J Barinas-Mitchell, Todd B Seto, Takashi Hisamatsu, Daniel Edmundowicz, Sayuki Torii, Rhobert W Evans, Naoyuki Takashima, Marianne H Bertolet, Takashi Kadowaki, Tomonori Okamura, Katsuyuki Miura, Kamal H Masaki, Chol Shin, Lewis H Kuller, Hirotsugu Ueshima
Journal: Circulation (2014)

Objective: In an international population-based cross-sectional study among men aged 40-49 years, we examined the association between brachial-ankle pulse wave velocity (baPWV): a biomarker of combined arterial stiffness of central and peripheral arteries, and the presence of coronary artery calcification (CAC). Methods: Out of 1,335 men without clinical cardiovascular disease recruited during 2002-06, a total of 204 participants taking anti-hypertensive medications, or having missing data were excluded. Remaining participants were 281 Whites and 83 Blacks in Pittsburgh, 235 Japanese Americans in Honolulu, 280 Koreans in Ansan, South Korea, and 292 Japanese in Kusatsu, Japan. baPWV was measured using automated waveform analyzer (VP2000, Omron, Japan). Intra-class correlations of baPWV within and between technicians were 0.97 and 0.91 respectively. CAC was determined using electron-beam computed tomography (Imatron C-150) at all centers; all images were read at University of Pittsburgh by trained staff. Using logistic regression, presence of CAC (≥ 10 Agatston Units) was evaluated with increasing baPWV as a predictor variable (per 100 cm/s; per 1 SD change). Results: Prevalence of CAC among individual racial groups was Whites (25%), Blacks (16%), Japanese Americans (28%), Japanese (10%), and Koreans (10%). Overall, increased baPWV was significantly associated with presence of CAC in unadjusted model (Odds ratio=1.31, 95% CI 1.20, 1.44) as well as multivariable adjusted model (Odds ratio=1.19, 95% CI 1.06, 1.35). There was no effect-modification by race in the models. Similar odds ratios for presence of CAC with increasing baPWV were seen for individual races, but were statistically non-significant among Japanese American men and Japanese men in Japan, possibly due to inadequate power. Conclusion: Increasing baPWV is associated with presence of CAC, independent of other cardiovascular disease risk factors.
Abstract 782: Transmembrane 2-3 loop domain of the proton coupled folate transporter (PCFT) forms a novel “reentrant loop” structure and is functionally important
Authors: Michael R. Wilson, Zhanjun Hou, Larry H. Matherly
Journal: Cancer Research (2014)

Abstract The proton coupled folate transporter (PCFT) is a proton-folate symporter with a twelve transmembrane domain (TMD) structure. Human PCFT (hPCFT) is highly expressed in many solid tumors and has an acidic pH optimum, suggesting its high activity in the acidic tumor microenvironment. Our recent studies have focused on exploiting PCFT for targeting solid tumors with novel cytotoxic antifolates. Predicted topology models suggest that the loop domain between TMDs 2 and 3 resides in the cytosol. However, mutations in TMD2-3 loop residues Asp109 or Arg113 result in loss of PCFT activity, suggesting an important role in transport activity. Additionally, TMD2 may itself form a part of the substrate binding domain, suggesting functional importance for TMD2 residues. Using site-directed mutagenesis, we replaced each of the seven cysteine (cys) residues of hPCFT with serine, creating functional “cys-less” PCFT for use in substituted cys accessibility methods (SCAM). We then used site-directed mutagenesis to create 34 single cys mutants spanning TMD2 and the TMD 2-3 loop region (positions 85-118) in a cys-less PCFT background. These mutants were transfected into R1-11 HeLa cells, which express no endogenous folate transporters. We measured [3H]methotrexate uptake at pH 5.5 as a readout of PCFT activity and confirmed PCFT protein expression by western blotting. All 34 mutants were detected on westerns and 29 mutants were active, while W107C, D109C, G112C, R113C, and R114C were inactive. Using functionally active mutants, we performed pull-down assays with 2-aminoethyl methanethiosulfonate-biotin (MTSEA-biotin) and steptavidin beads, in order to determine the aqueous accessibility of each mutant. We found that mutants G93C, F94W, G105C, A106C, S110C, and L116C reacted with MTSEA-biotin, suggesting that these residues are aqueous-accessible. For G93C, F94C, and L116C, MTSEA-biotin labeling was inhibited by pemetrexed pretreatment, and MTSEA-biotin treatment inhibited transport activity of G93C and F94C. Our results suggest that the TMD 2-3 loop domain is aqueous accessible and must form a novel functionally important “reentrant loop” structure. Additionally, residues located in TMD2 (Gly93 and Phe94) appear to play a key role in substrate binding to PCFT. Better understanding of functional and structural determinants of PCFT membrane transport will be critical to the development of novel PCFT-selective antifolate drugs for targeting solid tumors. Citation Format: Michael R. Wilson, Zhanjun Hou, Larry H. Matherly. Transmembrane 2-3 loop domain of the proton coupled folate transporter (PCFT) forms a novel “reentrant loop” structure and is functionally important. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 782. doi:10.1158/1538-7445.AM2014-782
Abstract 3899: ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells
Authors: Brenda Auffinger, Alex L. Tobias, Yu Han, Maciej S. Lesniak, Atique U. Ahmed
Journal: Cancer Research (2014)

Abstract Only 3% of patients diagnosed each year with Glioblastoma Multiforme (GBM) survive longer than 5 years, making GBM one of the most lethal forms of human cancer. It has been proposed that GBMs are driven by a rare subset of tumor cells referred to as cancer stem cells (CSCs), which have the ability to resist conventional radio- and chemotherapy and initiate disease recurrence. Thus, the development of novel and effective therapeutic strategies targeting CSCs is required and should significantly improve the dismal prognosis for patients with GBM. A possible viable strategy to effectively target glioma stem cells (GSCs) is the use of bone morphogenetic proteins (BMPs) as differentiation inducers. Our results suggest that Rho-associated protein kinase (ROCK) could work as a pharmacological negative regulator of BMPs. Our preliminary data indicate that: i) Fasudil, a ROCK1 inhibitor, induces BMP2 and BMP4 expression both in vitro and in vivo in different human-derived glioma xenograft models; ii) Fasudil-induced BMPs can increase the expression of differentiation markers and decrease stemness in these glioma models; iii) temozolomide, a chemotherapeutic agent, converts glioma cells to a GSC phenotype, while Fasudil blocks this interconversion; iv) co-administration of Fasudil with temozolomide inhibits the invasive characteristics of GBM in an orthotropic glioma xenograft model; and v) the analysis of BMP expression in human-derived GBM samples from the Repository of Molecular Brain Neoplasia Database (REMBRABDT) reveals that patients with higher BMP2 expression survived four times longer than those with low or intermediate BMP2 expression (p&amp;lt;0.001). Based on this, we propose that, by blocking ROCK signaling with the FDA approved pharmacological inhibitor Fasudil, one can modulate BMP expression in human-derived gliomas. Fasudil, therefore, may redirect cellular signals regulating GSCs' stemness, fate, and initiate their differentiation. Such an agent will allow us to develop a more effective anti-glioma therapy through its combination with other conventional anti-cancer drugs. Citation Format: Brenda Auffinger, Alex L. Tobias, Yu Han, Maciej S. Lesniak, Atique U. Ahmed. ROCK inhibitor as a differentiation-inducing agent to target glioma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3899. doi:10.1158/1538-7445.AM2014-3899
84. Enhanced Detection Method for Retrovirus in Vaccine
Authors: Ji Young Yoo, Beom-Seok Suh, Sue Nie Park, Joo-Hang Kim, Chae-Ok Yun
Journal: Molecular Therapy (2004)

Detecting any presence of retroviruses in biological material is important to ensure safety and prevent retroviral infection, which has been associated with various disorders including malignancies, immunodeficiencies, and neurological disorders. Highly specific and sensitive PCR techniques are used to detect specifically the presence of a known retrovirus. In contrast, the presence of an unknown retrovirus can only be examined by non-specific methods such as transmission electron microscopy and growth of virus on susceptible cells. However, detection methodologies involving cell culture techniques may be ineffective because certain retroviruses are not cytopathic in vitro. Retroviruses possess RNA-dependent DNA polymerase known as reverse transcriptase (RT), which is inherent in all kinds of retrovirus. Taking advantage of its ubiquitous nature in retroviruses, enzymatic activity of RT may be measured to detect retroviral contamination in biological products. On the basis of the polymerase enhanced reverse transcriptase (PERT) assay, two different assay systems, PCR-based RT assay (PERT-PCR) and ELISA-based RT assay (PERT-ELISA), were developed. Respective optimum conditions were determined. Sensitivity, linearity and reproducibility of the methods were studied on purified RT. Both PERT-PCR and PERT-ELISA could detect as little as 10-10 unit/ml of RT. Nonetheless, no additional increase in sensitivity was observed by performing ELISA after PCR amplification. Treatment with RNase after cDNA synthesis increased sensitivity over 100 times, and the addition of synthetic DNA competitors, which suppress RT-like activities of cellular DNA-dependent DNA polymerases, greatly increased specificity of the assay. A modified form of PERT-PCR assay was used and subsequently RT activities were detected in vaccines and culture supernatant of retrovirus-producing cells. This enhanced form of PERT-PCR assay is easy to perform and is able to detect up to 10-10 unit/ml of purified RT, as well as RT in vaccines and cell culture supernatant. Thus, this study presents an enhanced assay, applicable to screening of all replication-competent retrovirus, quantification of the viral load, drug susceptibility testing of RT, and control of virus inactivation in biological products.
Erratum: Adult generation of glutamatergic olfactory bulb interneurons
Authors: Monika S Brill, Jovica Ninkovic, Eleanor Winpenny, Rebecca D Hodge, Ilknur Ozen, Roderick Yang, Alexandra Lepier, Sergio Gascón, Ferenc Erdelyi, Gabor Szabo, Carlos Parras, Francois Guillemot, Michael Frotscher, Benedikt Berninger, Robert F Hevner, Olivier Raineteau, Magdalena Götz
Journal: Nature Neuroscience (2010)
Studies on the Mouse Mammary Tumor Agent II. The Neutralization of the Agent by Placenta
Authors: Katharine P. Hummel, C. C. Little, Mary S. Eddy
Journal: Cancer Research (1949)

Blood, whole or separated into cells and plasma, and other tissues were inoculated into suitable test animals. The blood, except as it is from females with spontaneous mammary cancers, is a relatively poor source of the mammary tumor agent. The agent is present in very small amounts in plasma, as compared with the cell fraction. There is evidence that the spleen and liver contain the agent only by virtue of their contained blood, although the spleen is a better source when inoculated subcutaneously than is the liver. The agent was not recovered from clotted blood, fetal blood, or placenta. Either the agent is not present, or its activity is inhibited in blood during late pregnancy. Stomach milk from 4- to 11-day-old mice is shown to be a good source of the agent.
Abstract 15036: Role of miR-195 in Aneurysm Formation
Authors: Anna Zampetaki, Rizwab Attia, Ursula Mayr, Renata Gomes, Alkystis Phinikaridou, Xiaoke Yin, Sarah Lnagley, Peter Willeit, Bruce Fanshawe, Marika Fava, Javier Barallobre Barreiro, Po-Wah So, Abeera Abbas, Marjan Jahangiri, Matthew Waltham, Rene Botnar, Alberto Smith, Manuel Mayr
Journal: Circulation (2014)

Introduction: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta. Apart from the miR-29 family, miR-195 has been implicated in the regulation of the vascular extracellular matrix (ECM). Our aim was to assess the effect of the miR-15 family in aneurysm formation. Methods and Results: Expression of the miR-15 and miR-29 families was assessed in human aortic tissue. In human aneurysmal tissue, miR-195 expression was reduced to the same extent as miR-29b. In plasma, an inverse correlation of miR-195 was observed with the presence of AAA and aortic diameter. To evaluate the effect of miR-195 in ECM deposition, proteomics analysis was performed on the secretome of murine aortic smooth muscle cells (SMCs) following miRNA manipulation. MiR-195 targeted a cadre of ECM proteins, including collagens, proteoglycans, elastin and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect. Systemic administration of cholesterol bound antagomiRs revealed better targeting efficacy of miR-195 compared to miR-29b in the uninjured aorta. A significant increase in aortic elastin expression was observed in wildtype animals injected with antagomiR-195. Yet, in apolipoprotein E-deficient mice receiving angiotensin II, inhibition of miR-29b but not miR-195 led to a significant inhibition of aortic aneurysm formation. Conclusions: We provide the first evidence that miR-195 may contribute to the pathogenesis of aneurysmal disease. Levels of miR-195 were reduced in human aneurysmal tissue and in plasma of patients with AAA. Although, miR-195 emerged as a potent regulator of aortic ECM, its inhibition was less effective than miR-29b in preventing aneurysm formation in preclinical models.
Abstract 19955: When Should Statin Therapy in Patients with Early Coronary Artery Disease Begin?: Results from the CONFIRM (COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter) Registry
Authors: Yun-Kyeong Cho, Chang-Wook Nam, James K Min, Briain W.J. O’Hartaigh, Heidi Gransar
Journal: Circulation (2014)

Background:  The efficacy of statins for improving prognosis among individuals who vary depending on coronary artery calcium score (CAC) or non-obstructive coronary artery disease (CAD) by coronary computed tomographic angiography (CCTA) remains uncertain.   Objective:  To assess the usefulness of statins for lowering the all-cause mortality according to the degree of CAC, especially lower-to-intermediate scoring, and non-obstructive CAD by CCTA.   Methods:  Among 27,125 patients from the international multicenter CONFIRM registry, 9,229 patients (6396 without statin, 2833 with statin) without history of prior CAD or obstructive CAD (≥50% diameter stenosis) by CCTA for whom baseline statin use was available were included for analysis. Patients were followed for a 3 years for a primary endpoint of all-cause mortality and it was evaluated according to the degree of CAC or segment-involvement score (SIS).   Results:  Patients with statin therapy were older, had more cardiac risk factors except smoking and showed lesser trend of mortality (0.9% vs. 1.3%, p=0.08). Baseline statin use was associated with a decreased annual mortality for individuals with presence of CAC (0.9% without statin vs. 0.3% with statin in CAC 1-299, p   Conclusion:  In non-obstructive CAD, higher CAC or SIS showed increased risk of mortality and statin therapy reduced the risk of mortality in existing any grade of CAC or SIS.