tbuckley/cabot-search huggingface dataset:
Antisense treatment directed against mutated Ki-ras in human colorectal adenocarcinoma
Authors: H J N Andreyev
Journal: Gut (2001)

<h3>BACKGROUND</h3> Kirsten ras (Ki-ras) mutations are common in gastrointestinal cancer and one codon 12 mutation, glycine to valine, is particularly aggressive in colorectal cancer. <h3>AIMS</h3> To investigate if this valine point mutation could be targeted with antisense oligonucleotides and to determine the efficacy of any antisense/mRNA interaction. <h3>METHODS</h3> Twenty nine antisense oligonucleotides were screened against target and control Ki-ras RNA in a cell free system and against target and control cell lines in culture. <h3>RESULTS</h3> The activity and specificity of the oligonucleotides varied. Results for the individual oligonucleotides were consistent in a cell free model and in cell culture using two different uptake promoters. Only one oligonucleotide was specific in its cleavage of target Ki-ras mRNA in the cell free system and appeared specific in cell culture, although changes in Ki-ras mRNA and protein expression following a single treatment could not be detected. Experiments in the cell free system showed that the point mutation is relatively inaccessible to oligonucleotides. Other sites on the Ki-ras RNA molecule, away from the point mutation, can be targeted more effectively. <h3>CONCLUSIONS</h3> Successful targeting of the clinically relevant Ki-ras point mutation with antisense oligonucleotides is difficult because of RNA structure at the mutated site and is inefficient compared with other sites on the Ki-ras mRNA.
Overexpression of Protease-Activated Receptor-1 Contributes to Melanoma Metastasis via Regulation of Connexin 43
Authors: Gabriel J. Villares, Andrey S. Dobroff, Hua Wang, Maya Zigler, Vladislava O. Melnikova, Li Huang, Menashe Bar-Eli
Journal: Cancer Research (2009)

Abstract Protease-activated receptor-1 (PAR-1) is a key player in melanoma metastasis with higher expression seen in metastatic melanoma cell lines and tissue specimens. cDNA microarray and Western blot analyses reveal that the gap junctional intracellular communication molecule connexin 43 (Cx-43), known to be involved in tumor cell diapedesis and attachment to endothelial cells, is significantly decreased after PAR-1 silencing in metastatic melanoma cell lines. Furthermore, Cx-43 promoter activity was significantly inhibited in PAR-1–silenced cells, suggesting that PAR-1 regulates Cx-43 at the transcriptional level. Chromatin immunoprecipitation studies showed a reduction in the binding of SP-1 and AP-1 transcription factors to the promoter of Cx-43. Both transcription factors have been shown previously to be required for maximal Cx-43 promoter activity. These results were corroborated by mutating the AP-1 and SP-1 binding sites resulting in decreased Cx-43 promoter activity in PAR-1–positive cells. Moreover, as Cx-43 has been shown to facilitate arrest of circulating tumor cells at the vascular endothelium, melanoma cell attachment to endothelial cells was significantly decreased in PAR-1–silenced cells, with this effect being abrogated after PAR-1 rescue. Herein, we report that up-regulation of PAR-1 expression, seen in melanoma progression, mediates high levels of Cx-43 expression. As both SP-1 and AP-1 transcription factors act as positive regulators of Cx-43, our data provide a novel mechanism for the regulation of Cx-43 expression by PAR-1. Indeed, Cx-43 expression was restored following PAR-1 rescue in PAR-1–silenced cells. Taken together, our data support the tumor promoting function of Cx-43 in melanoma. [Cancer Res 2009;69(16):6730–7]
Detection of Neuroblastoma Cells in Bone Marrow and Peripheral Blood by Different Techniques
Authors: Maria Valeria Corrias, Lawrence B. Faulkner, Angela Pistorio, Cristina Rosanda, Francesco Callea, Maria Serena Lo Piccolo, Paola Scaruffi, Cinzia Marchi, Laura Lacitignola, Marzia Occhino, Claudio Gambini, Gian Paolo Tonini, Riccardo Haupt, Bruno De Bernardi, Vito Pistoia, Alberto Garaventa
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Detection of metastatic tumor cells in bone marrow (BM) and peripheral blood (PB) of children with neuroblastoma is crucial for prognosis and planning of therapy. Aims of this large descriptive repeated survey were to evaluate the diagnostic accuracy of different techniques in diagnostic samples obtained at several disease course time points and to correlate positive results with patient clinical features and outcome. Experimental Design: BM aspirates, trephine biopsies, PB, and peripheral blood stem cell (PBSC) samples from Italian children with neuroblastoma were analyzed by morphological and histologic techniques, as well as by immunocytochemistry (IC) for disialoganglioside GD2 and reverse transcription-PCRs (RT-PCRs) for tyrosine hydroxylase (TH) and pgp9.5 genes. The diagnostic odd ratio (DOR) was used to measure the accuracy of the different techniques. Results: A total of 2,247 evaluations were done on 561 BM, 265 PB, and 69 PBSC samples from 247 patients. IC showed the best accuracy. Whereas TH RT-PCR accuracy was satisfactory, that of pgp9.5 was very low. Positive results obtained by IC in BM and PB samples at diagnosis from stage 1, 2, and 3 patients correlated with unfavourable outcome. No correlation was found between positive results obtained by IC or TH RT-PCR in BM, PB, and PBSC samples from stage 4 patients and their outcome. Conclusions: Because of its elevated diagnostic accuracy, IC may represent a useful adjunct to conventional morphological techniques, especially in view of its potential prognostic role in patients with localized disease. Longitudinal multicenter studies are warranted to definitely establish the clinical usefulness of TH RT-PCR.
US universities get round regulations on stem cell research
Authors: Janice Hopkins Tanne
Journal: BMJ (2004)

Harvard University is the biggest, newest player to get around US government regulations saying that institutions that receive federal funding can carry out stem cell research only on 60 established stem cell lines. Harvard, together with other organisations, is circumventing the regulations by establishing institutions that use private funding for the research.

Harvard has established an institute involving 14 of its schools and hospitals and nearly 100 researchers and scientists. The university aims to raise $100m (£56m; €84m) for the institute.

Federal funding for stem cell research in the United States has been restricted since 2001, when President Bush said he was limiting research to 60 stem cell lines from embryos that had already been destroyed.

He said, “Embryonic stem cell research is at the leading edge of a series of moral hazards.” …
International Comparison of the Relationship of Chronic Kidney Disease Prevalence and ESRD Risk
Authors: Stein I. Hallan, Josef Coresh, Brad C. Astor, Arne A[Combining Ring Above]sberg, Neil R. Powe, Solfrid Romundstad, Hans A. Hallan, Stian Lydersen, Jostein Holmen
Journal: Journal of the American Society of Nephrology (2006)

ESRD incidence is much lower in Europe compared with the United States. This study investigated whether this reflects a difference in the prevalence of earlier stages of chronic kidney disease (CKD) or other mechanisms. CKD prevalence in Norway was estimated from the population-based Health Survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%). Data were analyzed using the same methods as two US National Health and Nutrition Examination Surveys in 1988 through 1994 (n = 15,488) and 1999 through 2000 (n = 4101). The primary analysis used gender-specific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. ESRD rates and other relevant data were extracted from national registries. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR >90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 to 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2), 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min per 1.73 m2), 0.2% (SE 0.01). This closely approximates reported US CKD prevalence (11.0% in 1988 through 1994 and 11.7% in 1999 through 2000). The relative risk for progression from CKD stages 3 or 4 to ESRD in US white patients compared with Norwegian patients was 2.5. This was only modestly modified by adjustment for age, gender, and diabetes. Age and GFR at start of dialysis were similar, hypertension and cardiovascular mortality in the populations were comparable, but US white patients were referred later to a nephrologist and had higher prevalence of obesity and diabetes. In conclusion, CKD prevalence in Norway was similar to that in the United States, suggesting that lower progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence of ESRD in Norway.
A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis) in Children with Refractory Solid Tumors. A Children's Oncology Group Study
Authors: Loretta Lau, Jeffery G. Supko, Susan Blaney, Linda Hershon, Nita Seibel, Mark Krailo, Wenchun Qu, David Malkin, Jose Jimeno, Mark Bernstein, Sylvain Baruchel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in children with refractory solid tumors, to establish the recommended dose for pediatric phase II trials, and to characterize the pharmacokinetics of ET-743 in children. Experimental Design: ET-743 was administered as a 3-hour i.v. infusion every 21 days. The starting dose was 1,100 μg/m2 with planned dose escalation of 200 μg/m2 increments. Pharmacokinetic sampling was done during the first treatment course. Results: Twelve evaluable patients received a total of 29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted at the first dose level. At the second dose level (1,300 μg/m2), there were two DLTs (reversible grade 4 elevations of hepatic transaminase); hence the maximum tolerated dose was defined as 1,100 μg/m2. Overall, reversible hepatic toxicity, manifested as grade 3 or 4 elevations in hepatic transaminase, occurred in more than 50% of the patients. No grade 3 or 4 thrombocytopenia was reported at either dose level and only one episode of isolated creatine phosphokinase grade 4 elevation was observed. One complete response was documented after six courses in a patient with metastatic Ewing sarcoma. The pharmacokinetics of ET-743 in 8 children was characterized by a terminal disposition phase with a mean half-life of 43.8 ± 18.4 hours, a total body clearance of 28.2 ± 10.5 L/h/m2, and a 959 ± 807 L/m2 steady-state apparent volume of distribution. Conclusion: ET-743 is safe. The phase II recommended dose of ET-743 administered as a 3-hour i.v. infusion following premedication with dexamethasone is 1,100 μg/m2.
Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer Reaction of relapsing fever.
Authors: Y Negussie, D G Remick, L E DeForge, S L Kunkel, A Eynon, G E Griffin
Journal: The Journal of Experimental Medicine (1992)

The Jarisch-Herxheimer Reaction (J-HR) is a clinical syndrome occurring soon after the first adequate dose of an antimicrobial drug to treat infectious diseases such as Lyme disease, syphilis, and relapsing fever. Previous attempts to identify factors mediating this reaction, that may cause death, have been unsuccessful. We conducted a prospective trial in Addis Ababa, Ethiopia on 17 patients treated with penicillin for proven louse-borne relapsing fever due to Borrelia recurrentis to evaluate the association of symptoms with plasma levels of tumor necrosis factor (TNF), interleukins 6, and 8 (IL-6 and -8). 14 of the 17 (82%) patients experienced a typical J-HR consisting of rigors, a rise in body temperature (1.06 +/- 0.2 degrees C) peaking at 2 h, leukopenia (7.4 +/- 0.6 x 10(-3) cells/mm3) at 4 h, a slight decrease, and then rise of mean arterial blood pressure. Spirochetes were cleared from blood in 5 +/- 1 h after penicillin. There were no fatalities, but constitutional symptoms were severe during J-HR. Plasma TNF, IL-6, and -8 were raised in several patients on admission, but a seven-, six-, and fourfold elevation of these plasma cytokine concentrations over admission levels was detected, respectively, occurring in transient form coincidental with observed pathophysiological changes of J-HR. Elevated plasma cytokine levels were not detected in the three patients who did not suffer J-HR. We conclude that the severe pathophysiological changes characterizing the J-HR occurring on penicillin treatment of louse-borne relapsing fever are closely associated with transient elevation of plasma TNF, IL-6, and -8 concentrations.
Prognostic Value of Skin Manifestations of Infective Endocarditis
Authors: Amandine Servy, Laurence Valeyrie-Allanore, François Alla, Catherine Lechiche, Pierre Nazeyrollas, Christian Chidiac, Bruno Hoen, Olivier Chosidow, Xavier Duval
Journal: JAMA Dermatology (2014)

<h3>Importance</h3> Infective endocarditis (IE) is a rare disease with poor prognosis. When IE is suspected, skin examination is mandatory to look for a portal of entry and classic skin lesions to help diagnose and manage the condition. <h3>Objectives</h3> To describe the prevalence of and factors associated with dermatological manifestations in patients with definite IE. <h3>Design</h3> Observational, prospective, population-based epidemiological study between January 1 and December 31, 2008. Subsequently, collected dermatological data were subjected to post hoc analysis. <h3>Setting and Participants</h3> Patients (n = 497) diagnosed in 7 French regions and hospitalized in France for definite IE satisfying modified Duke criteria. <h3>Main Outcomes and Measures</h3> Patient and disease epidemiological information was collected, focusing on the most classic dermatological manifestations of IE (Osler nodes, Janeway lesions, purpura, and conjunctival hemorrhages). Disease outcome was also recorded. <h3>Results</h3> Among 497 definite IE cases, 487 had known dermatological status. Of 487 cases, 58 (11.9%) had skin manifestations, including 39 (8.0%) with purpura, 13 (2.7%) with Osler nodes, 8 (1.6%) with Janeway lesions, and 3 (0.6%) with conjunctival hemorrhages (5 patients had 2 skin manifestations). Patients with skin manifestations had a higher rate of IE-related extracardiac complications than patients without skin manifestations, particularly cerebral emboli (32.8% vs 18.4%,<i>P</i> = .01), without increased mortality. Patients with purpura had larger cardiac vegetations (18.1 vs 13.7 mm,<i>P</i> = .01), and Janeway lesions were associated with more extracerebral emboli (75.0% vs 31.8%,<i>P</i> = .02). <h3>Conclusions and Relevance</h3> Specific skin manifestations of IE are associated with a higher risk of complications and should alert physicians to examine for extracardiac complications, notably with cerebral imaging.
Surgical Risk Factors in Primary Surgery for Localized Neuroblastoma: The LNESG1 Study of the European International Society of Pediatric Oncology Neuroblastoma Group
Authors: Giovanni Cecchetto, Veronique Mosseri, Bruno De Bernardi, Pierre Helardot, Tom Monclair, Elisa Costa, Ernst Horcher, Sylvia Neuenschwander, Paolo Tomà, Antonino Rizzo, Jean Michon, Keith Holmes
Journal: Journal of Clinical Oncology (2005)

Although tumor resection is the mainstay of treatment for localized neuroblastoma, there are no established guidelines indicating which patients should be operated on immediately and which should undergo surgery after tumor reduction with chemotherapy. In an effort to develop such guidelines, the LNESG1 study defined surgical risk factors (SRFs) based on the imaging characteristics.A total of 905 patients with suspected localized neuroblastoma were registered by 10 European countries between January 1995 and October 1999; 811 of 905 patients were eligible for this analysis.Information on SRFs was obtained for 719 of 811 patients; 367 without and 352 with SRFs. Of these 719 patients, 201 patients (four without and 197 with SRFs) underwent biopsy only. An attempt at tumor excision was made in 518 patients: 363 of 367 patients without and 155 of 352 patients with SRFs (98.9% v 44.0%). Complete excision was achieved in 271 of 363 patients without and in 72 of 155 patients with SRF (74.6% v 46.4%), near-complete excision was achieved in 81 and 61 patients (22.3% v 39.3%), and incomplete excision was achieved in 11 and 22 patients (3.0% v 14.2%), respectively. There were two surgery-related deaths. Nonfatal surgery-related complications occurred in 45 of 518 patients (8.7%) and were less frequent in patients without SRFs (5.0% v 17.4%). Associated surgical procedures were also less frequent in patients without SRFs (1.6% v 9.7%).The adoption of SRFs as predictors of adverse surgical outcome was validated because their presence was associated with lower complete resection rate and greater risk of surgery-related complications. Additional studies aiming to better define the surgical approach to localized neuroblastoma are warranted.
The pathology of human aortic valve homografts
Authors: J. C. Smith
Journal: Thorax (1967)

Beta-propiolactone sterilized, freeze-dried aortic valve homografts offer a dead framework which is accepted by the host and is capable of immediate and full function. The survival time of such grafts as fully functional units may be limited by physical and chemical alterations produced in the tissues by sterilization and freeze-drying. The organizing reaction of the host in covering the grafts or using them as a scaffolding may also be affected by these processes. It is possible that better long-term results may be achieved by using fresh grafts. There is no difference in host cellular response to fresh and sterilized and/or freeze-dried grafts. There is a possibility that heterogeneous reactions to polypeptides in the graft may occur in some individuals. Organization and covering of the graft by host tissue occurs from host tissues contiguous to the graft. Cells circulating in the bloodstream play no part in this by seeding on the surface. Thrombosis, in the absence of infection, is a rare complication. (Anticoagulants were not used in these patients.) Calcification occurs as only a late complication in persisting `dead9 tissue. Unsuspected, and often extensive, myocardial ischaemia occurs frequently under bypass conditions with coronary artery perfusion and substantially contributes to immediate post-operative mortality and morbidity.
MDM2 Promoter Polymorphism and Pancreatic Cancer Risk and Prognosis
Authors: Kofi Asomaning, Amy E. Reid, Wei Zhou, Rebecca S. Heist, Rihong Zhai, Li Su, Eunice L. Kwak, Lawrence Blaszkowsky, Andrew X. Zhu, David P. Ryan, David C. Christiani, Geoffrey Liu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The mouse double minute 2 homologue (MDM2) -309T/G promoter polymorphism has been associated recently with the development and prognosis of a variety of tumors. The G allele is associated with increased affinity for Sp1 binding and higher MDM2 mRNA and protein levels, leading to diminished tumor suppressor activity of the p53 pathway. We hypothesized that the G allele is also associated with increased risk and worse outcome in pancreatic cancer. Experimental Design: We evaluated the association between MDM2 309T/G and the risk of histologically confirmed pancreatic adenocarcinoma at Massachusetts General Hospital using unconditional logistic regression (123 cases and 372 controls). Complete overall survival and progression-free survival data were also available for 109 newly diagnosed patients. Results: The adjusted odds ratios (95% confidence intervals) of pancreatic cancer associated with the MDM2 T/G and G/G genotypes compared with TT were 1.89 (1.20-2.99) and 2.07 (1.03-4.16), respectively (adjusting for age, gender, smoking status, and pack-years of smoking). In Cox proportional hazards model with the wild-type T/T genotype as the reference category and adjusting for stage, treatment, and performance status, both the heterozygous T/G and the homozygous G/G genotypes were associated with decreased progression-free survival [adjusted hazard ratio (95% confidence interval), 1.67 (0.98-2.84) for T/G and 2.28 (1.11-4.71) for G/G] and overall survival [2.64 (1.23-5.67) for T/G and 3.12 (1.22-7.91) for G/G]. Conclusions: The G allele of the MDM2 -309T/G polymorphism is associated with 2- to 3-fold increase risk and progression of pancreatic adenocarcinoma and a corresponding decrease in survival.
The use of opioids for palliative care in refractory dyspnoea
Authors: G P Currie
Journal: Thorax (2003)

▴ Abernethy AP, Currow DC, Frith P, et al . Randomised, double blind, placebo controlled crossover trial of sustained releases morphine for the management of refractory dyspnoea. BMJ2003;327:523–6 [OpenUrl][1][Abstract/FREE Full Text][2] Dyspnoea is a disabling and distressing problem for many patients and carers. Clinicians are often reluctant to prescribe opioids for such patients because of concerns of adverse effects—particularly respiratory depression and sedation—and paucity of evidence of clinical benefit. Abernethy and colleagues conducted a small (n = 48) double blind, placebo controlled, crossover study. Patients, most … [1]: {openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DAbernethy%26rft.auinit1%253DA.%2BP%26rft.volume%253D327%26rft.issue%253D7414%26rft.spage%253D523%26rft.epage%253D528%26rft.atitle%253DRandomised%252C%2Bdouble%2Bblind%252C%2Bplacebo%2Bcontrolled%2Bcrossover%2Btrial%2Bof%2Bsustained%2Brelease%2Bmorphine%2Bfor%2Bthe%2Bmanagement%2Bof%2Brefractory%2Bdyspnoea%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.327.7414.523%26rft_id%253Dinfo%253Apmid%252F12958109%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=bmj&resid=327/7414/523&atom=%2Fthoraxjnl%2F59%2F1%2F7.atom
Extended haplotype studies in South African and Dutch variegate porphyria families carrying the recurrent p.R59W mutation confirm a common ancestry
Authors: A.M. van Tuyll van Serooskerken, B.I. Drögemöller, K. te Velde, R.S. Bladergroen, P.M. Steijlen, P. Poblete-Gutiérrez, M. van Geel, C.J. van Heerden, L. Warnich, J. Frank
Journal: British Journal of Dermatology (2011)

Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century.To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation.Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene.A core haplotype cosegregated in all families studied.Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor.