tbuckley/cabot-search huggingface dataset:
403. Selective Engraftment of Genetically Modified Hematopoietic Stem Cells by a Truncated Erythropoietin Receptor
Authors: Fabrizia Urbinati, Alexis Grande, Francesco Lotti, Giulia Facchini, Giuliana Ferrari, Fulvio Mavilio
Journal: Molecular Therapy (2004)

Genetic modification of hematopoietic stem cells (HSCs) has therapeutic potential for a variety of blood genetic disorders. Transplantation of HSCs, however, requires toxic myeloablation regimens which render this approach questionable for non life-threatening disorders. A potential alternative is the use of transgenes allowing positive selection of HSCs in vivo. We used MLV-derived retroviral vectors and HIV-derived lentiviral vectors to express a truncated form of the erythropoietin receptor (tEpoR) in murine and human hematopoietic cells. The tEpoR molecule carries a deletion of the 91 carboxy-terminal amino acids, which enhances its proliferative response due to the elimination of a negative regulatory domain. Murine HSCs expressing retrovirally-transferred tEpoR at different levels (1,500 to 13,000 receptors/cell) acquire a competitive repopulation capacity in vivo upon transplantation into co-isogenic mouse recipients. Human cord blood-derived CD34+ stem/progenitor cells transduced with a lentiviral vector expressing tEpoR significantly increase their marrow repopulation capacity upon xenotransplantation into sub-lethally irradiated NOD-SCID mice, with no alteration in their phenotype, survival and differentiation properties. Long-term analysis of serially transplanted mice showed that expression of tEpoR at physiological levels (i.e., comparable with, or slightly higher than, those of the wild-type EpoR in erythroblastic cells) has no effect on steady-state hematopoiesis, and induces no further expansion of transduced cells after the engraftment period. However, significant overexpression of tEpoR (>8-fold the physiological levels) causes mild anemia and erythrocyte morphological abnormalities. These data indicate that expression of tEpoR is a potential alternative for in vivo selection of murine and human repopulating HSCs.
Simple Collagen-Like Peptides Support Platelet Adhesion Under Static But Not Under Flow Conditions: Interaction Via α2β1 and von Willebrand Factor With Specific Sequences in Native Collagen Is a Requirement to Resist Shear Forces
Authors: Marilyn W. Verkleij, Laurence F. Morton, C. Graham Knight, Philip G. de Groot, Michael J. Barnes, Jan J. Sixma
Journal: Blood (1998)
Relationship of Gastroscopic Features to Histological Findings in Gastritis and<i>Helicobacter Pylori</i>Infection in a General Population Sample
Authors: S Redéen, F Petersson, K-A Jönsson, K Borch
Journal: Endoscopy (2003)

Background and Study Aim: Various gastroscopic features may be interpreted as signs of gastritis, but the significance of such features in relation to histomorphology is uncertain. The aim of this study was to determine how macroscopic findings were related to histomorphological changes and the presence of Helicobacter pylori in the gastric mucosa, in a sample of the general population. Subjects and Methods: 488 adult individuals, randomly selected from a general population, were screened with gastroscopy and biopsy. The macroscopic features recorded were erythema (diffuse, spotty, linear), erosions, absence of rugae in the gastric corpus, and presence of visible vessels. Gastritis was classified microscopically according to the Sydney system. The presence of H. pylori was determined histologically and using the urease test on fresh biopsy specimens. Results: The sensitivity and specificity of absence of rugae for moderate to severe atrophic gastritis in the gastric corpus were 67 % and 85 %, respectively. Corresponding values for severe atrophy were 90 % and 84 %. The sensitivity and specificity of the presence of visible vessels for moderate to severe atrophy in the corpus were 48 % and 87 %, and for severe atrophy the values were 80 % and 87 %, respectively. Considering the antrum, the sensitivity and specificity of the presence of visible vessels for moderate to severe atrophy was 14 % and 91 %, respectively. With regard to chronic inflammation (moderate to severe in the corpus or antrum), none of the features, alone or in combination, showed a sensitivity of more than 56 %. No endoscopic features (alone or in combination) showed a sensitivity of more than 57 % for H. pylori infection. Conclusions: Except for the absence of rugae and visible vessels in the gastric corpus, macroscopic features as observed during gastroscopy are of very limited value in the evaluation of whether or not gastritis or H. pylori infection are present. This is in accordance with most previous studies in patient populations, and it must be emphasized that the diagnosis of gastritis should be based on histological examination of the gastric mucosa.
Diagnosing suspected ectopic pregnancy
Authors: W. M Ankum
Journal: BMJ (2000)

Ectopic pregnancy is an important cause of maternal deaths in early pregnancy. In the United Kingdom nine deaths were registered in 1991-3 and 12 in 1994-6. This raises the death rate from 0.3 to 0.4 per 1000 estimated ectopic pregnancies. Most fatal cases resulted from delayed diagnosis and inappropriate investigation and treatment despite the management of women with suspected ectopic pregnancy improving considerably during this period because of improved tools for diagnosis and management.1

The first step forward in the diagnostic management of ectopic pregnancy was the introduction of laparoscopy in the late 1960s. This procedure solved the dilemma of prolonged clinical observation and the risk of performing an unnecessary laparotomy in suspected cases.2 Laparoscopy remained the only reliable method for diagnosing and excluding ectopic pregnancy until well into the 1980s. Around this time, …
Abstract 4233: Mef2C enhances 1,25-dihydroxyvitamin D3-induced monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression
Authors: Ruifang Zheng, Xuening Wang, George P. Studzinski
Journal: Cancer Research (2014)

Abstract Myogenic enhancer factors 2 (Mef2) are members of the family of MADS (MCM1-agamous-deficiens-serum response factor)-box transcription factors known to have multiple roles in morphogenesis of skeletal, cardiac and smooth muscle cells. Recently, Mef2C was found to be also involved in hematopoiesis. Bone marrow cells isolated from Mef2C knockout mice demonstrated decreased monocytic differentiation in response to cytokine stimulation, whereas constitutive expression of Mef2C promoted monopoiesis. The above findings led us to examine the role of Mef2C in 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation. Human acute myeloid leukemia (AML) cell lines, HL60 and U937, were used in this study. We found that knockdown of Mef2C with small interfering RNA (siRNA) significantly decreased the expression of the monocytic marker CD14, as well as of nonspecific esterase (NSE), suggesting that Mef2C is required for 1,25D-induced monocytic differentiation in AML cells. Our laboratory has previously demonstrated that optimal monocytic differentiation induced by 1,25D requires ERK5, and that ERK5 expression shows positive correlation with Mef2C expression. Here we show that Mef2C knockdown demonstrates similar inhibition of CD14 expression as ERK5 knockdown. CCAAT-enhancer-binding proteins (C/EBPs) α and β are two major transcription factors that can directly regulate CD14 expression. Since 1,25D has been shown to increase both C/EBPα and β expression, and these two transcription factors form heterodimers to enhance CD14 expression, we used siRNA to knock down Mef2C and found decreased expression of 1,25D-induced C/EBPβ, but not C/EBPα. Similar results were obtained using an alternative method to titrate down Mef2C with dsDNA containing its DNA binding sequence. We conclude that Mef2C is a functional downstream target of ERK5, and that 1,25D-induced CD14 and NSE expression is mediated through ERK5/Mef2C activation. (Supported by T32 CA134268 training grant and R01 CA044722 both from the National Cancer Institute, NIH, and by the American Institute for Cancer Research grant 10A049) Citation Format: Ruifang Zheng, Xuening Wang, George P. Studzinski. Mef2C enhances 1,25-dihydroxyvitamin D3-induced monocytic differentiation of human myeloid leukemia cells by regulating C/EBPβ expression. [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 4233. doi:10.1158/1538-7445.AM2014-4233
Promotion of DNA strand breaks, interstrand cross links and apoptotic cell death in A2780 human ovarian cancer cells by transplatinum planar amine complexes.
Authors: Sheena Aris, David Gewirtz, John Ryan, Nicholas Farrell
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3207 

Cisplatin is one of the primary drugs utilized in the treatment of ovarian cancer. However, despite the initial effectiveness of chemotherapy in suppressing this disease, drug resistance almost invariably develops and cures are relatively rare. Consequently, the development of new therapeutic approaches is urgently needed.

While it is generally thought that only the cis isomeric form of transplatinum express antitumor activity, a number of transplatinum derivates have shown preclinical promise. The current work investigates the influence of transplanaramine (TPA) compounds of structure trans -[Pt (O2CR)2 (L) (L’)], (L=NH3, L’= pyridine, quinoline, isoquinoline; L = L ‘ = pyridine; R = H, CH3, CH2OH etc.) on growth and viability of A2780 human ovarian carcinoma cells as well as their putative mechanism(s) of cytotoxicity. A series of structural analogs were examined with a focus on the contribution of the carboxylate leaving group to drug action. The compounds, as a class, induce cell death through caspase-dependent apoptosis, with activation of both caspase 3 and caspase 9 and concomitant PARP cleavage. With some analogs, drug effects are clearly irreversible while others appear to allow proliferative recovery. The A2780 cells are most sensitive to trans -[Pt (O2CH)2(NH3)(pyr)], which may be related to its accelerated accumulation within the cell. The trans-platinum compounds tested show induction of p53 as well as time dependent γH2AX induction, consistent with the promotion of DNA lesions. trans -[Pt(O2CH)2(NH3)(pyr)] can be shown to promote significant DNA strand breaks as measured by alkaline unwinding and DNA interstrand cross linking as assessed by the alkaline comet assay. Thus these studies show that structural modification of the trans platinum geometry can lead to cellular responses similar to those induced by cisplatin. The enhanced cytotoxicity of trans -[Pt(O2CH)2(NH3)(pyr)] compared to its isostructural -O2CCH3 and -O2CCH2OH analogs may be a consequence of its increased hydrolytic activation ( determined in previous biophysical studies), enhanced cellular uptake, interstrand crosslinking and abortive efforts by the cell to repair the cross linked DNA.
Evidence based policy: proceed with care Commentary: research must be taken seriously
Authors: N. Black, A. Donald
Journal: BMJ (2001)

# Evidence based policy: proceed with care {#article-title-2}

The emergence of evidence based medicine in the early 1990s led to some clinicians challenging managers and policymakers to be equally evidence based in their policymaking. This demand was shared by some health policy analysts: “At a time when ministers are arguing that medicine should be evidence-based, is it not reasonable to suggest that this should also apply to health policy? If doctors are expected to base their decisions on the findings of research surely politicians should do the same … the case for evidence-based policymaking is difficult to refute.”1

The need to be seen to be making evidence based decisions has permeated all areas of British public policy. The government has proclaimed the need for evidence based policing, and the 1998 strategic defence review introduced evidence based defence.2 In the health sector, the concept of evidence based policy has gained ground, and a journal has been launched devoted to this challenge ( Journal of Evidence Based Health Policy and Management). 

Despite some groups using evidence based policy as a fig leaf, it seems difficult to argue with the idea that scientific research should drive policy. However, before accepting the argument we need to understand the implied model of policymaking.

#### Summary points

Evidence based policy is being encouraged in all areas of public service, including health care

Research currently has little direct influence on health services policy or governance policies

The implicit assumption of a linear relation between research evidence and policy needs to be replaced with a more interactive model

Researchers need a better understanding of the policy process, funding bodies must change their conception of how research influences policy, and policy makers should become more involved in the conceptualisation and conduct of research

Until then, researchers should be cautious about uncritically accepting the notion of evidence based policy

In …
In vitro and in vivo characterization of SCH727965 a novel potent cyclin dependent kinase inhibitor
Authors: David Parry, Timothy Guzi, Wolfgang Seghezzi, Kamil Paruch, Ronald Doll, Amin Nomeir, Yaolin Wang, Martin Oft, Paul Kirschmeier, Taiying Chen, Emma Lees
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4371 

Dysregulation of cell cycle control is a hallmark of human cancer. The cyclin-dependent kinases (CDKs) are key positive regulators of cell cycle progression and are attractive oncology targets. SCH 727965 is a potent inhibitor of CDK1, CDK2 and CDK9, inhibiting each kinase in vitro with IC50 values of 1, 4 and 1 nM, respectively. In cellular assays, SCH 727965 induced complete suppression of Rb phosphorylation, which was correlated with total inhibition of BrdU incorporation and onset of apoptosis in over 100 tumor cell lines of diverse origin and background. Mean/median IC50 values in a variety of cell based assays were in the 10-to-20 nM range. SCH 727965 was selected on the basis of an in vivo functional screen that integrated both efficacy and safety parameters. SCH 727965 was subsequently effective in a range of murine tumor models, inducing regressions of established solid tumors following intermittent scheduling, at doses below the maximally tolerated level. Exposures predicted to be efficacious were achieved without dose-limiting toxicity in mice and dogs. Moreover, these plasma levels were associated with modulation of pharmacodynamic biomarkers in skin punch biopsies. Analyses of the in vitro and in vivo effects of SCH 727965 suggest that this potent and selective CDK inhibitor has great potential as a tumor-specific apoptotic agent.
The national service framework: a scaffold for mental health
Authors: P. Tyrer
Journal: BMJ (1999)

The National Service Framework for Mental Health, part of the programme to establish better quality and reduce unacceptable variations in the NHS,1 has just been published.2 This, an accompaniment to the introduction of the National Institute of Clinical Excellence (NICE), sets new standards for the delivery and monitoring of mental health services. In his introduction Frank Dobson, the secretary of state for health, claims that these national standards are founded on “a solid base of evidence” provided by the external reference group (chaired by Professor Graham Thornicroft of the Institute of Psychiatry). Mental health services have always had difficulties in setting standards, because of uncertainty over whether subjective patient oriented 3 4 or external “service” outcomes of mental illness 5 are preferable, so the framework has set itself ambitious objectives.

Has it succeeded? The answer is the same as the response to asking whether it is wiseto plant a tree in a desert. It seems churlish to give …
Use of Diuretics and Risk of Incident Gout: A Population‐Based Case–Control Study
Authors: Saskia Bruderer, Michael Bodmer, Susan S. Jick, Christoph R. Meier
Journal: Arthritis & Rheumatology (2013)

Use of diuretics has been associated with an increased risk of gout. Data on different types of diuretics are scarce. We undertook this study to investigate the association between use of loop diuretics, thiazide or thiazide-like diuretics, and potassium-sparing agents and the risk of developing incident gout.We conducted a retrospective population-based case-control analysis using the General Practice Research Database established in the UK. We identified case patients who were diagnosed as having incident gout between 1990 and 2010. One control patient was matched to each case patient for age, sex, general practice, calendar time, and years of active history in the database. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs), and we adjusted for potential confounders.We identified 91,530 incident cases of gout and the same number of matched controls. Compared to past use of diuretics from each respective drug class, adjusted ORs for current use of loop diuretics, thiazide diuretics, thiazide-like diuretics, and potassium-sparing diuretics were 2.64 (95% CI 2.47-2.83), 1.70 (95% CI 1.62-1.79), 2.30 (95% CI 1.95-2.70), and 1.06 (95% CI 0.91-1.23), respectively. Combined use of loop diuretics and thiazide diuretics was associated with the highest relative risk estimates of gout (adjusted OR 4.65 [95% CI 3.51-6.16]). Current use of calcium channel blockers or losartan slightly attenuated the risk of gout in patients who took diuretics.Use of loop diuretics, thiazide diuretics, and thiazide-like diuretics was associated with an increased risk of incident gout, although use of potassium-sparing agents was not.
Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator
Authors: Simon D. Bamforth, José Bragança, Jyrki J. Eloranta, Jennifer N. Murdoch, Fatima I.R. Marques, Kamil R. Kranc, Hend Farza, Deborah J. Henderson, Helen C. Hurst, Shoumo Bhattacharya
Journal: Nature Genetics (2001)
On Your Own Terms
Authors: Ronald Wallace
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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Factors associated with survival in a contemporary adult sickle cell disease cohort
Authors: Hany Elmariah, Melanie E. Garrett, Laura M. De Castro, Jude C. Jonassaint, Kenneth I. Ataga, James R. Eckman, Allison E. Ashley‐Koch, Marilyn J. Telen
Journal: American Journal of Hematology (2014)

In this study, the relationship of clinical differences among patients with sickle cell disease (SCD) was examined to understand the major contributors to early mortality in a contemporary cohort. Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed up for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis. Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sβ 0 was 58 years and for Hb SC and Sβ + was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM‐1, and short‐acting narcotics use were significantly associated with decreased survival. Forty‐two percent of subjects were on hydroxyurea therapy, which was not associated with survival. SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ 0 and SS. Not only were comorbidities individually associated with decreased survival but also an additive effect was observed, thus, those with a greater number of negative endpoints had worse survival ( P &lt; 0.0001). The association of higher sVCAM‐1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial. Am. J. Hematol. 89:530–535, 2014. © 2014 Wiley Periodicals, Inc.
Epitopes, avidity and IgG subclasses of tyrosine hydroxylase autoantibodies in vitiligo and alopecia areata patients
Authors: S.F.E. Rahoma, H.K. Sandhu, A.J.G. McDonagh, D.J. Gawkrodger, A.P. Weetman, E.H. Kemp
Journal: British Journal of Dermatology (2012)

We previously detected antibodies against tyrosine hydroxylase (TH) in 23% of patients with nonsegmental vitiligo and in 19% of patients with alopecia areata (AA).To identify TH epitopes recognized by TH antibodies in patients with vitiligo and AA.Recombinant plasmids containing defined fragments of TH cDNA were constructed. The cloned TH cDNA fragments were subsequently translated in vitro to produce a series of [(35) S]-labelled TH protein fragments which were then used in radioimmunoassays to analyse the immunoreactivity of sera from 18 TH antibody-positive patients with vitiligo and so initially define TH epitope domains. Further localization of TH epitopes was investigated by antibody absorption experiments using synthetic TH peptides and nonradiolabelled, in vitro-expressed TH protein fragments. Antibody binding to identified epitopes was confirmed in TH peptide enzyme-linked immunosorbent assays.Analysis of the results obtained indicated the presence of two major antibody-binding sites on TH between amino acids 1 and 14 (epitope 1-14) and between amino acids 61 and 80 (epitope 61-80). Of 18 patients with vitiligo and six with AA, 17 (94%) and five (83%), respectively, had antibodies against epitope 1-14. In addition, 11/18 (61%) vitiligo and 2/6 (33%) AA patient sera displayed immunoreactivity against epitope 61-80.Two major binding sites for human TH antibodies are located at the N-terminus of the protein. The humoral immune response to TH in vitiligo and AA is heterogeneous in nature in that patients may have antibodies to more than one TH epitope. TH antibodies from patients with vitiligo or AA can recognize identical epitopes.