tbuckley/cabot-search huggingface dataset:
Gene delivery into malignant glioma by infectivity-enhanced adenovirus: In vivo versus in vitro models
Authors: Winan J. Van Houdt, Hongju Wu, Joel N. Glasgow, Martine L. Lamfers, Clemens M. Dirven, G. Yancey Gillespie, David T. Curiel, Yosef S. Haviv
Journal: Neuro-Oncology (2007)

Adenoviral (Ad) vectors demonstrate several attributes of potential utility for glioma gene therapy. Although Ad infection is limited in vitro by low expression levels of the coxsackie-adenoviral receptor (CAR), in vivo studies have shown the efficacy of Ad vectors as gene delivery vectors. To evaluate the in vivo utility of CAR-independent, infectivity-enhanced Ad vectors, we employed genetically modified Ad vectors in several experimental models of human gliomas. We used three capsid-modified Ad vectors: (1) a chimeric Ad vector with a human Ad backbone and a fiber knob of a canine Ad, (2) an Ad vector with a polylysine motif incorporated into the fiber gene, and (3) a double-modified Ad vector incorporating both an RGD4C peptide and the polylysine motif. These three modified Ad vectors target, respectively, the putative membrane receptor(s) of the canine Ad vector, heparan sulfate proteoglycans (HSPGs), and both integrins and HSPGs. Our in vitro studies indicated that these retargeting strategies all enhanced CAR-independent infectivity in both established and primary low-passage glioma cells. Enhancement of in vitro gene delivery by the capsid-modified vectors correlated inversely with the levels of cellular CAR expression. However, in vivo in orthotopic human glioma xenografts, the unmodified Ad vector was not inferior relative to the capsid-modified Ad vector. Although genetic strategies to circumvent CAR deficiency in glioma cells could reproducibly expand the cellular entry mechanisms of Ad vectors in cultured and primary glioma cells, these approaches were insufficient to confer in vivo significant infectivity enhancement over unmodified Ad vectors. Other factors, probably the extracellular matrix, stromal cells, and the three-dimensional tumor architecture, clearly play important roles in vivo and interfere with Ad-based gene delivery into glioma tumors.
Activation of Cdk4 and Cdk2 during rat liver regeneration is associated with intranuclear rearrangements of cyclin-Cdk complexes
Authors: Montserrat Jaumot, Josep-Maria Estanyol, Joan Serratosa, Neus Agell, Oriol Bachs
Journal: Hepatology (1999)

Partial hepatectomy (PH) triggers the entry of rat liver cells into the cell cycle. The signals leading to cell-cycle activation converge into a family of kinases named cyclin-dependent kinases (cdks). Specific cyclin-cdk complexes are sequentially activated during the cell cycle. Cyclin D-cdk4 and cyclin E-cdk2 are activated during the G1 phase, cyclin A-cdk2 is activated during the S phase, and cyclin B-cdk1 during mitosis. In the present study, we have examined the timing of the activation of cdk4 and cdk2, the intracellular location of G1/S cyclins and cdks, and the relationship between location and cdk4 and cdk2 activities during rat liver regeneration after a PH. Results showed that the activity of both kinases started at 13 hours and showed maximal levels at 24 hours after hepatectomy. In quiescent cells, cyclin D3 and cdk4 were cytoplasmatic, whereas cyclin D1 was nuclear. At 5 hours after hepatectomy, cyclin D3 and cdk4 began to move into the nucleus, and at 13 hours, they were mostly nuclear. During the first 13 hours after hepatectomy, significant amounts of cyclin D1-cdk4 and cyclin D3-cdk4 complexes were formed, but they were mostly inactive. At 24 hours, these complexes were maximally activated. This activation was associated with the accumulation of cyclin D1, cyclin D3, and cdk4 in a nuclear subfraction extractable with nucleases. At 28 hours, the activity of cdk4 in this nuclear subfraction decreased when cyclin D1 moved from this fraction to the nuclear matrix (NM) and the levels of cyclin D3 diminished. The maximal activation of cdk2 at 24 hours was also associated with the accumulation of cyclin E, cyclin A, and cdk2 in this nuclease-sensitive fraction. The inactivation of cdk2 at 28 hours was associated with a strong decrease in cdk2 in this nuclear subfraction. Thus, results reported here indicate that the activation of cdk4 and cdk2 observed in rat liver cells after a PH is associated with a specific intranuclear location of these cdks and their associated cyclins.
Activation of Peroxisome Proliferator-Activated Receptor γ Suppresses Telomerase Activity in Vascular Smooth Muscle Cells
Authors: Daisuke Ogawa, Takashi Nomiyama, Takafumi Nakamachi, Elizabeth B. Heywood, Jeffrey F. Stone, Joel P. Berger, Ronald E. Law, Dennis Bruemmer
Journal: Circulation Research (2006)

Activation of the peroxisome proliferator-activated receptor (PPAR) gamma, the molecular target for insulin sensitizing thiazolidinediones used in patients with type 2 diabetes, inhibits vascular smooth muscle cell (VSMC) proliferation and prevents atherosclerosis and neointima formation. Emerging evidence indicates that telomerase controls key cellular functions including replicative lifespan, differentiation, and cell proliferation. In the present study, we demonstrate that ligand-induced and constitutive PPARgamma activation inhibits telomerase activity in VSMCs. Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPARgamma ligands inhibit TERT expression through a receptor-dependent suppression of the TERT promoter. 5'-deletion analysis, site-directed mutagenesis, and transactivation studies using overexpression of Ets-1 revealed that suppression of TERT transcription by PPARgamma is mediated through negative cross-talk with Ets-1-dependent transactivation of the TERT promoter. Chromatin immunoprecipitation assays further demonstrated that PPARgamma ligands inhibit Ets-1 binding to the TERT promoter, which is mediated at least in part through an inhibition of Ets-1 expression by PPARgamma ligands. In VSMCs overexpressing TERT, the efficacy of PPARgamma ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPARgamma ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPARgamma ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPARgamma ligands and support the concept that PPARgamma ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.
Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell Growth
Authors: Ada Girnita, Leonard Girnita, Fabrizio del Prete, Armando Bartolazzi, Olle Larsson, Magnus Axelson
Journal: Cancer Research (2004)

Abstract The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of malignant cells, and has emerged as a general and promising target for cancer treatment. However, no fully selective IGF-1R inhibitors have thus far been found. This is explained by the fact that IGF-1R is highly homologous to the insulin receptor, coinhibition of which may cause diabetic response. The receptors are both tyrosine kinases, and their ATP binding sites are identical, implying that ATP inhibitors cannot discriminate between them. Therefore, the current strategy has been to identify compounds interfering with receptor autophosphorylation at the substrate level. In this study we investigated the effects of cyclolignans and related molecules on IGF-1R activity. We report that certain cyclolignans are potent and selective inhibitors of tyrosine phosphorylation of the IGF-1R. Of particular interest was picropodophyllin (PPP), which is almost nontoxic (LD50 &amp;gt;500 mg/kg in rodents). PPP efficiently blocked IGF-1R activity, reduced pAkt and phosphorylated extracellular signal regulated kinase 1 and 2 (pErk1/2), induced apoptosis in cultured IGF-1R-positive tumor cells, and caused complete tumor regression in xenografted and allografted mice. PPP did not affect the insulin receptor or compete with ATP in an in vitro kinase assay, suggesting that it may inhibit IGF-1R autophosphorylation at the substrate level. This is also in agreement with our molecular model of how the cyclolignans may act on the IGF-1R kinase. Our results open the possibility to use PPP or related compounds with inhibitory effects on IGF-1R as lead compounds in development of anticancer agents.
Abstract 3804: Transcriptional repression of androgen receptor in human prostate cancer cells by plant flavone apigenin
Authors: Sanjeev Shukla, Sanjay Gupta
Journal: Cancer Research (2010)

Abstract Accumulating evidence suggest that androgen receptor (AR)-mediated signaling plays an important role in the development and progression of prostate cancer. Although Prostate Cancer Prevention Trial (PCPT) showed controversial results however manipulation of AR signaling pathway reduced the incidence of prostate cancer. Safer agents are needed that can modulate AR signaling pathways with effective suppression of prostate cancer. Plant flavonoids have been shown to possess weak oestrogenic and anti-androgen activity. Apigenin, a naturally occurring plant flavone, has shown promising anticancer activity by modulating several signaling pathways that have relevance to prostate cancer. However, the effect of apigenin on AR signaling has not been fully investigated. Using androgen-responsive human prostate cancer LNCaP and 22Rv1cells, we determine the effect of apigenin on androgen receptor signaling. Exposure of these cells with 5-40μM apigenin suppressed cell proliferation and arrested cells in sub G0-G1 phase of the cell cycle after 5nM dihydrotestosterone (DHT) stimulation. Apigenin inhibited endogenous prostate-specific antigen (PSA) transcription and reduced intracellular and secreted PSA protein levels induced by DHT in these cells. In LNCaP cells apigenin inhibited AR expression in a concentration-dependent manner by restricting its translocation into the nucleus. Co-transfection of PC-3 cells with wild-type AR-GFP-tag plasmid demonstrated that apigenin has ability to inhibit DHT-induced AR translocation into the nucleus. Additionally, receptor binding assays indicated that apigenin is a strong competitive inhibitor of DHT binding to the AR. These observations matched with the results of structural modeling studies exhibiting that apigenin is remarkably similar in conformational geometry and surface charge distribution to synthetic AR antagonist, flutamide, although the atomic compositions of the two substances were quite different. Taken together, our results indicate that apigenin exhibits potent anti-proliferative and anti-androgenic properties and may be developed as useful and safer agent for prevention/therapy of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3804.
Abstract 3560: Evaluation of RNA-stress granules formation as an indicator of response to Darinaparsin in cancer cell lines
Authors: Elena Kolobova, M. Cecilia Larocca, James R. Goldenring
Journal: Cancer Research (2010)

Abstract Darinaparsin (ZIO101) is a novel organic arsenic compound demonstrating clinical efficacy and a favorable safety profile in hematological cancers and solid tumors. Its mechanism of action includes disruption of mitochondrial functions and induction of apoptosis. We studied the ability of darinaparsin to induce RNA stress granules, a critical survival adaptation mechanism for cells under stress. Darinaparsin caused a stress granule response similar to sodium arsenite, but at lower concentrations. Treatment of cells with darinaparsin induced the formation of granules containing a number of proteins specifically associated with stress granules, including G3BP (the Ras-GAP SH3 domain binding protein), CCAR1 (Cell Cycle and Apoptosis Regulatory Protein-1), caprin-1 (Cytoplasmic Activation/Proliferation-associated protein1) and AKAP350A (AKAP9). However, darinaparsin led to development of a greater number of smaller granules compared to sodium arsenite-induced stress. We evaluated the effect of 0.5 mM arsenite or 0.05 mM darinaparsin on poorly differentiated uterine sarcoma (MES-SA) and the multiple drug resistant cell line MES-SA/Dx5 that was established from MES-SA cells. MES-SA/Dx5 cells express high levels of mdr-1 mRNA and P-glycoprotein. Both sodium arsenite and darinaparsin led to stress granule formation in both cell lines. However, MES-SA/Dx5 cells were extremely sensitive to darinaparsin treatment and exhibited a prominent loss of cell contact. The amount of cleaved PARP (a marker of apoptosis) determined at 48h and 72h after darinaparsin treatment was consistent with the immunofluorescence findings in that cleaved PARP was significantly elevated in MES-SA/Dx5 cells compared to MES-SA cells. This indicates enhanced cytotoxic effects of darinaparsin on this otherwise chemotherapeutic resistant cell line. We also evaluated the effect of darinaparsin and sodium arsenite on different leukemia cell lines including Jurkat (T-cell lymphoblastic leukemia derived), Oci and THP1 (acute myeloid leukemia derived). THP1 cells express wild type nucleophosmin (NPM), while Oci cells are heterozygous for its mutant form NPMc+. Interestingly, we found that Jurkat cells did not developed stress granules in response to darinaparsin treatment and this cell line showed accelerated toxicity compared with THP1 and Oci cells, which did form stress granules. These studies demonstrate that darinaparsin has a different spectrum of activity than sodium arsenite and can elicit differential toxicity on specific classes of tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3560.
Diagnostic Clues in Pulmonary Thrombo-embolism Evaluated by Angiographic and Ventilation-Blood Flow Studies
Authors: R. Llamas, E. W. Swenson
Journal: Thorax (1965)

Abraham, Salzberg, and Balter (1954) have called pulmonary thrombo-embolism the commonest chest disease of adult patients in hospital.Routine necropsy series indicate its incidence to be as high as 25% (T'owbin, 1954).To the chagrin of clinicians its ubiquity is matched by the difficulties encountered in its antemortem diagnosis.The classical syndrome of chest pain, haemoptysis, friction rub, and ill-defined consolidation of the lung is often incomplete, vague, or obscured by such predisposing conditions as left ventricular failure (Parker and Smith, 1958).This applies not only to symptoms and signs but also to the electro- cardiogram and conventional radiographic studies (Dexter, Dock, McGuire, Hyland, and Haynes, 1960).In an effort to gain further understanding of this condition and to determine, if possible, what clinical manifestations might give us the most help in its diagnosis, we have studied 10 patients with symptoms and signs of localized pulmonary thrombo-embolism.The methods we used included the measurement of ventilatory function and lung volume subdivisions, haemo- dynamics, respiratory gas exchange,-and pul- monary angiography.Since only two of our patients came to necropsy (M.U. and E. H.) where pulmonary emboli and infarction were found, we have used the positive findings at angiography as the principal criterion for the diagnosis.CLINICAL DATA AND METHODS Our 10 patients ranged in age from 38 to 73 years; nine were men, as expected in a veterans' hospital from which we received most of our referrals.Two had electrocardiographic evidence of left- sided cardiac disease (P.L. and F. B.S.).Eight had experienced one or more clear-cut episodes of chest pain, haemoptysis, dyspnoea, and pulmonary
Turbulent future for school nursing and health visiting
Authors: K. Billingham, D. Hall
Journal: BMJ (1998)

The government is attempting to reduce inequalities in health by public health measures rather than by a fundamental redistribution of wealth.1 Primary prevention and health promotion will be encouraged and health action zones will “provide more integrated care … better housing, healthy schools, and healthy workplaces.”2 In the light of this, the recent proposal by Cambridge and Huntingdon Health Authority to move resources from health visiting and school nursing into acute care may seem perverse. Of course, health authorities must consider cost effectiveness, but it seems shortsighted to sacrifice primary prevention and health promotion to pay for technology and acute services.

What do health visitors and school nurses do, and how effective is it? The health visitor's first task is to identify health care needs. Together with general practitioners, they provide the child health surveillance programme of immunisations, screening, and advice. They aim to identify those important conditions that parents might overlook and, for the rest, to …
Atlas of Technetium Bone Scans
Authors: Manuel L. Brown
Journal: JAMA (1980)

Although there have been atlases of various nuclear medicine procedures, this one is the first that specifically addresses bone scanning. Bone scintigraphy is important, because it is becoming increasingly useful in the diagnosis and management of both benign and malignant disease. The authors have well-developed chapters on the major divisions of bone scanning, including technical aspects and the normal bone scan findings, as well as sections on metastatic bone disease, the arthritides, trauma, and metabolic bone disease. The text is readable and is supplemented with extensive references but at times becomes unnecessarily anecdotal and opinionated. Numerous illustrations of bone scans provide good accompaniment to the text, although reproduction is less than optimal. The roentgenograms are so poorly reproduced as to be almost worthless. The book as a whole would be of value to the trainee, but the experienced practitioner in nuclear medicine will find little new. It would also be
Abstract P2-10-05: Lymphatic and pro-inflammatory candidate gene variations and breast-cancer related lymphedema
Authors: MR Fu, D Axelrod, AA Guth, J Goldberg, X Li, F Cartwright, J Haber, Y Conley
Journal: Cancer Research (2013)

Abstract Background Traditionally, breast cancer-related lymphedema is considered to be mainly due to the mechanical injury from cancer surgery. Recent research identified that inflammation-infection may be one of the important predictors for breast cancer-related lymphedema. This pilot study aimed to explore the associations between lymphatic and pro-inflammatory candidate gene variations and lymphedema following breast cancer treatment. Methods A prospective, longitudinal, repeated-measure, and comparative design was used to recruit a sample of 178 breast cancer survivors. To ensure the accuracy of lymphedema phenotype, lymphedema was classified into two phenotypes: lymphedema of arm and breast. Arm lymphedema refers to swelling in the affected arm that must have been validated by infra-red perometer-S350 and a bioimpedance device. Breast lymphedema refers to swelling in the affected breast validated by self-report and an observational scale since no objective measure is available. Saliva samples were collected for DNA extraction from all the 178 participants. Candidate Gene Association Research Method was used to examine the eight genes known for inflammation and lymphatic specific growth factors, including candidate genes for inflammation, cytokines (IL1A, IL6, IL8, IL10, IL13) and PTGS2 (COX2), and lymphatic specific growth factors [VEGF-C &amp; D]. Descriptive statistics, Chi-Squared tests for contingency tables and one-way analysis of variance for continuous variables were used to compare the genotypes for each of these genes in patients with and without lymphedema. Odds ratios of developing lymphedema are estimated. Results Among 178 survivors, 39 women were confirmed to have arm lymphedema by infra-red perometer-S350 and a bioimpedance device and 43 women had breast lymphedema. Five genes were significantly associated with breast cancer-related lymphedema. Specific single nucleic polymorphisms (SNPs) for lymphatic specific growth factors VEGF-C (rs4604006) and cytokine IL13 (rs1800925) were related to arm lymphedema. Specific SNPs of cytokine IL1A (rs1800587) and PTGS2 (COX2) (rs20417) were associated with breast lymphedema. Conclusion Our findings provided preliminary data on genetic susceptibility as a risk factor for breast cancer-related lymphedema. Findings of our study may serve as a preliminary foundation for a priori recognition of genetic risk that may facilitate lymphedema risk prediction prior to surgery and raises the potential for early intervention for a high-risk group. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-05.
Health Care Under Social Security
Authors: Hubert H. Humphrey
Journal: JAMA (1961)

Senator Humphrey asked for an opportunity to present inThe Journalhis views on health care under social security. The AMA disagrees with Senator Humphrey in principle, and specifically with many of the statements which appear in this communication. In deference to him, however, his manuscript is reproduced without critical comment or annotation. A summary of the testimony on the King Bill, H. R. 4222, by Dr. L. W. Larson was published in the Aug. 12, 1961, issue ofThe Journal.—Ed.
Horizon: The Atkins Diet
Authors: N. Koralage
Journal: BMJ (2004)

BBC 2, 22 January at 9 pm Rating:![Graphic][1]</img>![Graphic][2]</img> It is January again. People make and break their new year's resolution of getting in shape, while the Commons health select committee talks of introducing a “fat tax” on junk food. Cue Horizon: The Atkins Diet . Fish and cheese have replaced the national institution of fish and chips, as we ditch the carbs and head for the protein and fat. Horizon said that last year bread sales slumped because of what has been “the most controversial diet in history.” This documentary was shown in the week that saw the latest twist in Dr Robert Atkins' 30 year story, when the company that he founded, Atkins Nutritionals, was reported to have revised its earlier advice and recommended a lower fat diet. The company later issued a denial. A … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif