tbuckley/cabot-search huggingface dataset:
Stable MRP4 knockdown via retroviral vector mediated short interfering RNA (siRNA) sensitizes neuroblastoma (NB) cell lines to camptothecin analogs in vitro.
Authors: P. Kellie Turner, Stacy L. Throm, Charles H. Fraga, John D. Schuetz, Clinton F. Stewart
Journal: Cancer Research (2006)

5436   Previously we have demonstrated that the NB cell line NB1691 is relatively resistant to topotecan (TPT), expresses the ATP-binding cassette transport proteins MRP4 and P-glycoprotein (Pgp), and accumulates less intracellular TPT than sensitive cell lines lacking MRP4 and Pgp expression (Turner, AACR Proceedings, 2003). In the current work, we have assessed the functional contribution of MRP4 expression to camptothecin resistance in NB by knocking down MRP4 expression. RNA interference (RNAi) is an evolutionarily conserved mechanism of gene silencing that targets mRNA degradation. Long-term MRP4 silencing is necessary to assess the functional contribution of MRP4 to camptothecin resistance in NB. Therefore, we have achieved stable MRP4 silencing using the MSCVGFP retroviral vector encoding MRP4 sequence-specific shRNA transcribed from the H1 promoter. GFP expression in this system permits rapid selection of single cell clones without antibiotics and tracking vector persistence. NB1691 cells were transduced with a retrovirus containing MRP4 shRNA and GFP or the GFP vector alone. Single cell clones expressing GFP were sorted by FACS and expanded for further analysis. MRP4 mRNA and protein expression levels were determined by quantitative RT-PCR (QRT-PCR) and western blot analysis. The NB1691 parental line, NB1691 GFP clone 1 expressing only the MSCV-GFP vector, and NB1691 GFP 4.7 and 4.9 expressing GFP and MRP4 shRNA were selected for further characterization. Knockdown of MRP4 function was determined by bis-POM-PMEA accumulation. IC 50  values were determined by MTT assay to quantify the sensitivity to irinotecan (CPT-11), SN-38, and TPT. GFP expression persists in these cell lines for at least 4 months after transduction. Moreover, QRT-PCR and western blot results demonstrate greater than 80% reduction in MRP4 expression in NB1691 GFP 4.7 and 4.9. PMEA accumulation was 1.5- and 2.4-fold higher in NB1691 GFP 4.7 and 4.9 compared to the parental or vector-only clones. Knocking down MRP4 resulted in a 2.5- and 1.8-fold increase in SN-38 sensitivity in NB1691 GFP 4.7 and 4.9, respectively, compared to NB1691 GFP1. In contrast, CPT-11 sensitivity was increased only 1.1-fold in NB1691 GFP 4.9 compared to NB1691 GFP1. TPT sensitivity increased 14- and 5.5- fold in NB1691 GFP 4.7 and 4.9. These results suggest that loss of MRP4 function may increase  in vitro  sensitivity to TPT and SN-38, the active metabolite of the prodrug CPT-11. We are currently utilizing xenograft models to determine the contribution of MRP4 expression to tumor response to camptothecin analogs  in vivo . Moreover, Pgp expression may also contribute to camptothecin analog resistance in NB1691, and we are investigating the effects of silencing Pgp expression.
331. Lentivirus-Mediated Ex Vivo Gene Therapy in ADA-Deficient SCID Mice
Authors: Alessandra Mortellaro, Raisa Jofra Hernández, Matteo Guerrini, Antonella Tabucchi, Filippo Carlucci, Antonia Follenzi, Luigi Naldini, Claudio Bordignon, Maria Grazia Roncarolo, Alessandro Aiuti
Journal: Molecular Therapy (2005)

Adenosine deaminase (ADA) deficiency is a severe combined immunodeficiency (SCID) characterized by systemic toxicity and profoundly impaired lymphoid cell development and functions due to the accumulation of purine metabolites. ADA-deficient (ADA KO) mice die within 3 weeks of age due to metabolic toxicity and can be rescued by enzyme replacement therapy with PEG-ADA. The aim of our study was to investigate the efficacy of gene therapy (GT) in comparison to bone marrow transplantation (BMT) in the ADA KO mouse model. A SIN HIV-1-based lentiviral vector encoding human ADA cDNA under the control of PGK promoter was constructed. ADA KO mice were maintained short-term on PEG-ADA and then transplanted, after non-myeloablative conditioning either with WT BM cells or with ADA KO BM cells transduced ex vivo. We first showed that BMT with donor WT cells rescued mice from lethality, restored T-cell and B-cell counts in the peripheral blood and led to normal proliferation after T or B cells specific stimulation. Similarly, GT with transduced BM cells rescued ADA KO mice from lethality and restored their growth to normal levels. Quantitative PCR for donor cells (Y chromosome in sex-mismatched transplant) and vector-positive cells showed the presence of ADA transduced cells in the peripheral circulation of transplanted ADA KO mice (30|[ndash]|40% 5 months post-GT). Two months after GT, ADA activity in red blood cells reached normal levels and dAXP toxic metabolites decreased to undetectable levels. GT resulted in normal lymphoid differentiation in primary and secondary lymphoid organs, as well as restoration of T-cell and B-cell in vitro proliferative responses after stimulation with anti-CD3/anti-CD28 and anti-IgM antibody, respectively. Finally, serum levels of IgM and IgG were comparable between GT and BMT mice. These studies demonstrate that lentiviral-mediated ADA gene transfer associated with non-myeloablative conditioning corrects both the metabolic and the immunological defects in the ADA KO animal model. We are currently evaluating the long-term safety related to the use of hematopoietic stem/progenitor cells transduced with lentiviral vectors.
Summary of Informal Discussions
Authors: Joseph W. Beard
Journal: Cancer Research (1960)

It was the purpose of this session to consider problems of the detection or demonstration of virus or virus-related substances associated with the induction and maintenance of the neoplastic state. No impediment to the progress of investi gations on virus-induced tumors or growths thought to be caused by viruses has been so great as the restriction of tumor-virus identifica tion to the classical transmission experiments so useful with many other infectious agents. Such investigations are almost always complex and, frequently, productive of highly variable and confusing results when applied to the tumor vi ruses. That investigators in this field have already experienced an almost inexpressible relief from the narrow limitations of the purely biologic ap proach was clearly revealed by the presentations of Dr. Bernhard and Dr. Gard and others pres ent, who extended the breadth of the discussions by their own contributions. It is evident, further, that what has already been accomplished has not only provided a new insight into previously bare ly conceivable relationships of the tumor viruses to their host cells, but, likewise, provided the basis for clarification of present perplexities and expansion of the area of the research to the most fundamental aspects of virus-cell reaction at the biochemical level. In his topic, Dr. Bernhard restricted himself to a discussion of the present status and expected potentialities of electron microscopy of ultrathin sections in the study of critical aspects of the tumor-virus problem. Likely directions for con tinued and new approaches were exemplified by recent progress in major fields: (a) recognition of the definitive aspects of the morphology of various viruses associated with known virusinduced tumors; ( b ) demonstration of character istic ultrastructural relationships of virus to host cell; (c) recognition of virus particles in latent infection of normal tissues; (d) demonstration of virus in growths not known to be caused by viruses; (e) applicability of the electron micro scopic technic to the study of the ultrafine struc ture of the virus particles themselves; and, finally (/), the search for electron-dense reagents suit able for demonstration at high resolution of virusspecific substance at the molecular level. In particular, there was emphasized adaptation of autoradiography at the electron microscopic level and the development of an ultramicro-Coons technic substituting an electron-dense material, such as ferritin, for the fluorescent material for marking antibody. The extraordinarily competent and comprehensive analysis clearly revealed the indispensability of this biophysical technic for the correlation in their physical and chemical aspects of viruses in their association with the disease process. Dr. Mellors' discussion of the results of studies
Abstract 1675: Effect of Rosiglitazone versus Placebo on Rapid Angiographic Progression of Non-Culprit Coronary Lesions in Patients with Type 2 DM
Authors: Aloke Finn, Jae S Oh, Michael Hendricks, Maureen Daher, Jeffrey Nadelson, Johanna Crimins, Adnan Kastrati, Albert Schomig, Olga Bruskina, Igor Palacios, Michael C John, Herman K Gold
Journal: Circulation (2007)

Background: We examined the effect of 4mg/day rosiglitazone (RSG) versus placebo (PLC) on rapid angiographic progression (RAP) of non-culprit coronary lesions (NCCL) in type 2 diabetes (DM 2). Methods: Using biomarkers and angiograms from 43 DM 2 enrolled in a randomized controlled double blind trial examining the effects of RSG or PLC on late loss after PCI, we investigated the effects of RSG on RAP of NCCL using logistic regression. All stenoses &gt;=30% of vessel diameter were identified at baseline and quantified by QCA. Patients had 8 month angiography and biomarkers (HOMA (insulin resistance index), insulin, MMP-9, adiponectin (ADI), fibrinogen, hs-CRP, A1C, and LDL and HDL cholesterol) drawn at baseline and 4 months. RAP was defined as &gt;=20% diameter reduction of pre-existing NCCL by QCA, or a new narrowing &gt;=30% arising in a segment angiographically normal at baseline. Results: There were 52 NCCL in the RSG versus 56 in the PLC. 14.8 % (16/108) of lesions had RAP with 7/52 (13.5%) lesions progressing in RSG versus 9/56 (16.1%) in PLC, p=ns. RSG was not a predictor of RAP. Of the biomarkers and angiographic variables examined, hsCRP was the only predictor of RAP. Patients with a 120 day hsCRP above the 75th percent had an OR of 7.35 [2.35,23] for RAP versus those below. Interestingly, although RSG treatment lowered hsCRP at 4 months (RSG 2.03Â±2.8 mg/dl vs. Placebo 3.37Â±4.25, p=0.06), it did not decrease the likelihood of plaque progression in either the low or high hsCRP groups (see graph). LDL levels at this time were not different (RSG 74Â±23 mg/dl vs. PLC 89Â±32, p=ns). Conclusion: 120 day hsCRP is a predictor of RAP. Despite lowering 120d hsCRP, RSG did not lower the frequency of RAP.
Antiproliferative cyclin dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.
Authors: Newell, CE Arris, FT Boyle, AH Calvert, NJ Curtin, P Dewsbury, JA Endicott, EF Garman, AE Gibson, BT Golding, RJ Griffin, LN Johnson, A Lawrie, Mem Noble, EA Sausville, R Schultz
Journal: Clinical Cancer Research (1999)
Abstract 1648: Chromosome 14 Plasma Plant Sterol Locus 14DKK Subcongenic Mice Show Decreased Sterol Absorption and Impaired Bile Acid Metabolism through a Mechanism that May Involve Fibroblast Growth Factor 15 (Fgf15) Signaling
Authors: Ephraim Sehayek, Yee-Yan Fung, Jan L Breslow
Journal: Circulation (2006)
Abstract 10131: Optimizing Timing of Defibrillation Guided by ECG Amplitude Spectrum Analysis Improves the Outcomes of CPR in a Rat Model of Prolonged Ventricular Fibrillation
Authors: Shijie Sun, Yinlun Weng, Xiaobo Wu, Sen Ye, Wei Chen, Katherine T Tang, Max H Weil, Wanchun Tang
Journal: Circulation (2011)

When VF is prolonged, defibrillation (DF) immediately causes myocardial injury and reduces the success of CPR. AHA guidelines recommend performing 2 minutes of CPR prior to DF. However, since there...
WPA guidance on the protection and promotion of mental health in children of persons with severe mental disorders
Authors: IAN BROCKINGTON, PRABHA CHANDRA, HOWARD DUBOWITZ, DAVID JONES, SUAAD MOUSSA, JULIET NAKKU, ISABEL QUADROS FERRE
Journal: World Psychiatry (2011)

This guidance details the needs of children, and the qualities of parenting that meet those needs. Parental mental disorders can damage the foetus during pregnancy through the action of drugs, prescribed or abused. Pregnancy and the puerperium can exacerbate or initiate mental illness in susceptible women. After their birth, the children may suffer from the social disadvantage associated with severe mental illness. The parents (depending on the disorder, its severity and its persistence) may have intermittent or prolonged difficulties with parenting, which may sometimes result in childhood psychological disturbance or child maltreatment. This guidance considers ways of preventing, minimizing and remedying these effects. Our recommendations include: education of psychiatrists and related professions about the effect of parental mental illness on children; revision of psychiatric training to increase awareness of patients as caregivers, and to incorporate relevant assessment and intervention into their treatment and rehabilitation; the optimum use of pharmacological treatment during pregnancy; pre-birth planning when women with severe mental illness become pregnant; development of specialist services for pregnant and puerperal women, with assessment of their efficacy; community support for parenting by mothers and fathers with severe mental disorders; standards of good practice for the management of child maltreatment when parents suffer from mental illness; the importance of multi-disciplinary teamwork when helping these families, supporting their children and ensuring child protection; the development of child and adolescent mental health services worldwide.
431. Selective Upregulation of TGFb1ACT in the Rat Heart To Induce Cardioprotection from Ischemia-Reperfusion Injury
Authors: Kui Chen, Yong Liu, Dayuan Li, Paul L. Hermonat, Jawahar L. Mehta
Journal: Molecular Therapy (2004)

Although there is upregulation of TGFb1 during ischemic injury to the heart, its conversion to active form (TGFb1 ACT) which is cardio-protective is lacking. To examine the modulation of cardiac function by TGFb1 ACT, we developed a model of selective upregulation of TGFb1 ACT in the rat myocardium. First, we cloned rat TGFb1 cDNA (position 413–1593, 1172 bp), with mutation of cysteine at position 223 and 225 into serine resulting in TGFb1 ACT. This mutated TGFb1ACT cDNA was ligated into the a basic AAV vector (dl6-95) to give AAV-TGFb1 ACT. Anesthetized Sprague Dawley rats were subjected to thoracotomy and administration of AAV/GFP or AAV/TGFb1ACT at 4 different sites in the left ventricular myocardium. GFP expression was identified in the myocardium at 2 as well as 6 weeks. TGFb1ACT expression (mRNA and protein) was not seen in the AAV/GFP-injected rat hearts, but was markedly increased in the TGFb1ACT-injected hearts at 2 weeks, with a further increase at 6 weeks post-injection. Plasma TGFb1ACT levels were similar in all animals, indicating selective TGFb1ACT expression in the heart. Most importantly, whereas the control rats showed a marked decline in ±dP/dt and a large infarct after left coronary artery occlusion and reperfusion, the rats overexpressing TGFb1ACT showed preservation of ±dP/dt and much smaller infarct despite the same duration of coronary artery occlusion and reperfusion. These data demonstrate the potential for selective upregulation of TGFb1ACT in the rat heart using rAAVvirus, and preservation of cardiac function from ischemic injury.
Ability of the α- and β anomers of chlorozotocin to kill rat 9L tumor cells in vitro
Authors: Ka-Ho Wong, Kenneth T. Wheeler
Journal: Cancer Research (1989)

Chlorozotocin (CLZ), a nitrosourea synthesized in the hope that it would have little bone marrow toxicity, has been shown to be effective against animal tumors and tumor cells in culture. However, the clinical results with CLZ have been disappointing. The original report on the synthesis of CLZ indicated that α and β anomers at the d-glucose moiety should be expected, particularly when CLZ is placed in aqueous solution. In this study, the α and β anomers have been separated by high-performance liquid chromatography and characterized by UV spectroscopy, mass spectroscopy, and nuclear magnetic resonance. The equilibration and decomposition of the anomers in various physiological solutions were determined as a function of temperature, pH, and serum concentration. In Eagle's basal medium (pH 7.2) held at 25°C, CLZ decomposed with a t ½ of ≈ 82 min; at 37°C with serum, CLZ decomposed with a t ½ of < 10 min. In these two cases, the β:α ratio reached 1 in ≈ 48 min and < 5 min, respectively. The maximum β:α ratio obtained in all cases ranged from 1.25 to 1.5. After holding CLZ in tissue culture medium and compensating for its decomposition, 9L rat brain tumor cells were treated in vitro with CLZ having different ratios of the α and β anomers. These experiments demonstrated that the β anomer has little, if any, ability to kill 9L cells. Thus, this anomerization phenomenon may have been responsible for the disappointing clinical results with CLZ. Our data suggest that appropriate preparation, handling, and drug delivery procedures might be devised to minimize this problem in both experimental and clinical situations.
Abstract 3109: Exaggerated Blood Pressure Response During Treadmill Test is Accompanied by a State of Pronounced Albuminuria, Hypoadiponectinemia and Increased Asymmetric Dimethylarginine Levels in Essential Hypertension
Authors: Kyriakos Dimitriadis, Costas Tsioufis, Dimitris Tsiachris, Costas Thomopoulos, Ioannis Skiadas, Andreas Michaelides, Christodoulos Stefanadis, Ioannis Kallikazaros
Journal: Circulation (2007)

Introduction: A hypertensive response to exercise (HRE) is associated with high cardiovascular risk, whereas the data regarding its relation to markers of atherosclerosis progression are currently scarce. Hypothesis: Urinary albumin excretion, expressed as the albumin to creatinine ratio (ACR), asymmetric dimethylarginine (ADMA) levels, and adiponectin may be correlated with HRE in essential hypertensives. Methods: Our population of 109 newly diagnosed untreated non-diabetics with stage I to II essential hypertension [76 men, mean age =52 years, office blood pressure (BP) = 146/94 mmHg] with a negative treadmill exercise test (Bruce protocol) were divided into those with HRE (n=34) (peak exercise systolic BP ≥ 210mmHg in men and ≥190 mmHg in women) and to those without HRE (n=75). In all subjects ACR values were determined as the mean of two non-consecutive morning spot urine samples and venous blood samples were drawn for estimation of adiponectin and ADMA concentrations. Results: Patients with HRE compared to those without HRE were older (55 ± 9 vs 51 ± 9 years, p&lt;0.05), had greater 24-h systolic BP (141 ± 13 vs 132 ± 12 mmHg, p&lt;0.05), while did not differ regarding metabolic profile and left ventricular mass index (p = NS). Patients with HRE compared to those without HRE exhibited greater levels of ADMA (0.62 ± 0.05 vs 0.54 ± 0.04 μ mol/l, p&lt;0.0001) and ACR (61.4 ± 12 vs 15.2 ± 2.2 mg/g, p&lt;0.0001), whereas had lower adiponectin values (6.1 ± 1.4 vs 9.3 ± 2.1 μg/ml, p&lt;0.0001), independently of confounders. In the total population, peak exercise systolic BP was related to 24-h systolic BP (r=0.239, p&lt;0.05), ACR (r=0.432, p&lt;0.0001), ADMA (r=0.260, p=0.007), and negatively associated with adiponectin (r = −0.216, p&lt;0.05). Multiple regression analysis revealed that 24-h systolic BP (b=0.232, p=0.023), male sex (b=0.240, p=0.029) and ACR (b=0.450, p&lt;0.0001) were independent predictors of peak exercise systolic BP. Conclusions: In essential hypertension, a HRE is associated with hypoadiponectinemia, augmented ADMA and ACR values, reflecting activation of diverse pro-atherosclerotic pathways. These findings suggest that treadmill exercise testing could be an additional tool to identify hypertensive patients with pronounced cardiorenal vascular dysfunction.
Chairman of NICE admits that its judgments are hard to defend
Authors: Gavin Yamey
Journal: BMJ (1999)

Professor Sir Michael Rawlins, chairman of the National Institute for Clinical Excellence (NICE), has admitted that its decisions are “questions of judgment, difficult to defend, difficult to teach.”

Speaking at a conference entitled “Medicine in the Millennium: confronting the issues,” jointly organised by the Royal College of Physicians, the Royal College of Surgeons, and the Royal Society of Medicine, Professor Rawlins discussed how the institute will have to balance clinical and cost effectiveness. “The most important criteria is the clinical need of patients,” he said, “but this must be considered in relation to the severity of the disease or condition, …
The preoperative level of physical activity is associated to the postoperative recovery after elective cholecystectomy – A cohort study
Authors: Aron Onerup, Ulf Angerås, David Bock, Mats Börjesson, Monika Fagevik Olsén, Martin Gellerstedt, Eva Haglind, Hanna Nilsson, Eva Angenete
Journal: International Journal of Surgery (2015)
Articulations of God
Authors: Laurie Rosenblatt
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Doctors should have a greater role in organising health services
Authors: Susan Mayor
Journal: BMJ (2004)

Doctors should be encouraged to engage in more open dialogue with the public and play a more active role in managing and designing health services, according to a UK report published last week that explored how doctors can maintain public confidence in their professionalism.

The report found that individual doctors were highly trusted by the public but that confidence in the profession as a whole had been undermined by recent scandals, including incompetence in paediatric heart surgery at Bristol ( BMJ 2001;323:181), mass retention of children's organs by a pathologist at Alder Hey hospital ( BMJ 2001;322:255), and the murder of more than 200 patients by a GP, Harold Shipman ( BMJ 2002;325:181).

Broader challenges, including greater public access to health information, higher …
Press: The great American mammography debate
Authors: F. Charatan
Journal: BMJ (2002)

It all started quite quietly. Tucked away on page 16 of the New York Times in the fourth week of January was a news item reporting that a committee of cancer experts—the Physician Data Query screening and prevention editorial board (known as the PDQ board)—had found that there was insufficient evidence to show that mammograms prevented breast cancer deaths.

The New York Times followed up its news story with a measured editorial, pointing out that a great deal of money was at stake. It predicted that it would not be easy to get an independent review of the benefits of mammography. “Mammography has been so strongly endorsed by the cancer establishment, and has become such a significant source of revenue … for many hospitals and doctors, that it may be difficult to excise …