tbuckley/cabot-search huggingface dataset:
Abstract #5518: Bortezomib targets FANCD2 and enhances melphalan response in myeloma cells
Authors: Danielle Yarde, Lori Hazlehurst, Vasco Oliveira, Linda Mathews, David Boulware, Dung-Tsa Chen, Qing Chen, William Dalton
Journal: Cancer Research (2009)

We recently reported that Fanconi Anemia (FA)/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan (Chen et al.,  Blood  2005). Furthermore, others have found that proteasome function is required for FA/BRCA pathway activation (Jacquemont et al.,  Cancer Res  2007). In this study, we show that the enhanced sensitivity to melphalan seen when cells are first treated with bortezomib is linked to reduced expression and function of FA/BRCA pathway genes. We found that treatment of melphalan sensitive (8226/S and U266/S) and melphalan resistant (8226/LR5 and U266/LR6) MM cell lines with the proteasome inhibitor bortezomib causes a temporal decrease of FA/BRCA pathway gene expression, with maximal decreases seen 24 hours post-bortezomib treatment. Additionally, analysis of two drug resistant MM cell lines, the 8226/LR5 and U266/LR6 cell lines, revealed that FANCD2 gene and protein expression were decreased following treatment with low-dose (3nM) bortezomib, and remain attenuated with the combination of bortezomib plus melphalan. Bortezomib blocked melphalan-induced activation of FANCD2 in both melphalan resistant cell lines, as indicated by inhibition of monoubiquitination of FANCD2 protein. Using confocal microscopy, we found that melphalan-induced FANCD2 foci formation was also inhibited by bortezomib. Analysis of DNA damage and DNA damage repair, using the alkaline comet assay following treatment with low-dose bortezomib and melphalan, showed that bortezomib enhanced DNA damage following melphalan treatment at levels comparable to DNA damage seen when cells were depleted of FANCD2 using siRNA techniques. Collectively, these data show that bortezomib enhances melphalan response by reducing global FA/BRCA gene expression, blocking FANCD2 monoubiquitination and activation, and enhancing DNA damage, secondary to diminished DNA damage repair capacity mediated by the FA/BRCA pathway. Our findings provide evidence for targeting the FA/BRCA pathway to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma patients.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5518.
Exosomes and microvesicles derived from activated platelets increase the metastatic potential of lung cancer cells
Authors: Anna Janowska-Wieczorek, Leah A. Marquez, Janina Ratajczak, Mariusz Z. Ratajczak
Journal: Cancer Research (2004)

1764   It has been recognized that platelets exacerbate tumor progression and metastasis but the possible role of circular fragments shed from the surface membranes of activated platelets (microvesicles) and of exosomes that are secreted as smaller fragments during degranulation of platelet α-granules has not been sufficiently investigated. As the level of platelet-derived microvesicles (PMV) increases in the peripheral blood of cancer patients during inflammation, thrombosis or platelet activation by tumor cells, we hypothesized that PMV could contribute to tumor progression/metastasis. We used five human lung cancer cell lines (CRL 2066, CRL 2062, A549, HTB 183, HTB 177), together with the murine Lewis Lung Carcinoma (LLC) cell line as an in vivo model of metastasis, and found that PMV not only transferred platelet-derived receptors to the surface of lung cancer cells but also stimulated them directly, modulating various aspects of their biology. These included stimulation of cell proliferation, chemotaxis, chemoinvasion across Matrigel and adhesion to fibrinogen and human endothelial cells, activation of phosphorylation of MAPK p42/44 and serine/threonine kinase AKT, as well as upregulation of mRNA expression for cyclin D2. Further, PMV upregulated secretion and expression of angiogenic factors such as VEGF, IL-8, HGF and matrix metalloproteinases (MMP-9 and MT1-MMP) in lung cancer A549 cells. Moreover, syngeneic animals injected with LLC cells covered with murine PMV had enhanced metastasis compared to animals injected with non-covered LLC cells. Based on these observations we conclude that PMV and exosomes take part in intercellular crosstalk and play a prominent role in modulating the metastatic potential of lung cancer cells. We have already obtained evidence that PMV operate similarly in other types of tumors including breast cancer.
Soundings
Authors: G Dunea
Journal: BMJ (1991)

velope: invi- tation to lecture abroad.Pleasure tinged with disbelief-really necessary fly me all that way for just 45 minutes plus \ questions?And shouldn't they be asking someone older?Accept with alacrity before they change minds.If Hon Sec's head on platter afterwards, his problem not mine.Months pass, then last minute dash to medical photography.Cynical cartoons on wall, including picture of hysterical photographers saying "You want it wHEN?"Receptionist tries to keep straight face at yet another supplicant with impossible deadline.Slides completed, minutes to spare.Photo- grapher much better than desktop slidemaker: computer doesn't frown and click tongue to discourage lecturer from producing overcomplicated slides.Essential that slides are simple, even if they make lecturer look simple too.Slide- making twentieth century skill: fun to imagine great minds of history distilling wisdom into two by twos.If projectors around in first century AD, might have had St Paul's slides to the Corinthians: 3 CHARITY * suffereth long * is kind
Enhanced Shear-Induced Platelet Aggregation in Patients Who Experience Subacute Stent Thrombosis
Authors: Nadine Ajzenberg, Pierre Aubry, Marie-Genevieve Huisse, Agnés Cachier, Walid El Amara, Laurent J. Feldman, Dominique Himbert, Dominique Baruch, Marie-Claude Guillin, Ph. Gabriel Steg
Journal: Journal of the American College of Cardiology (2005)
Elderly people need "high tech" services too
Authors: K. Stewart, M. Gill
Journal: BMJ (1994)

EDITOR,—Jackie Morris is rightly concerned that the health needs of vulnerable elderly patients may be overlooked by local authority assessment for community care.1 We disagree, however, with the assertion that the creation of community geriatricians would solve the problem.

Successful rehabilitation and placement of elderly patients depend on the patients' acute medical problems being assessed and treated, …
CD34+ Cells in the Blood of Patients With Multiple Myeloma Express CD19 and IgH mRNA and Have Patient-Specific IgH VDJ Gene Rearrangements
Authors: Agnieszka J. Szczepek, P.L. Bergsagel, Linus Axelsson, Christopher B. Brown, Andrew R. Belch, Linda M. Pilarski
Journal: Blood (1997)
Mitral valve prolapse and oral contraceptive therapy [letter]
Authors: Brenner Pr
Journal: JAMA (1982)

Contraindications to the use of combination oral contraceptives (OCs) include vascular disease hypertension hyperlipidemia diabetes heart disease cancer of the breast or endometrium pregnancy and active liver disease.  The medical indications for the prevention of pregnancy may equal or exceed the social reasons for the woman with substantial cardiac disease.  The selection of a family planning method is a compromise for all persons.  The heart disease patient should balance her need for a highly effective method of contraception against the potential of that method to cause a deterioration in her cardiac function.  Some of the rare but serious side effects associated with the use of birth control pills include an increased risk of thromboembolic disease hypertension fluid retention and hyperlipidemia.  These effects are particularly deleterious for persons with heart disease and if possible they should avoid the use of combination OCs.  Women with mitral valve prolapse are particularly at increased risk for thromboembolic disease.  The choice of a family planning method is always made on an individual basis.  In general OCs are contraindicated for women with heart disease but this may be the only alternative for a specific individual.  In that case I would use a combination OC with 30 or 35 mcg of synthetic estrogen.  There is 1 group of women with heart disease that I recommend for the use of birth control pills.  Women with valvular disease who receive anticoagulants are known to have an increased incidence of hemoperitoneum at the time of ovulation.  The use of anticoagulants reduces their risk for thromboembolic disease and the OC is a highly effective method of contraception that acts by inhibiting ovulation and reduces the risk of an intraperitoneal hemorrhage in these women.  (full text)
Abstract 2301: Frail Elderly Patients at Increased Risk for Mortality and Prolonged Institutional Care After Cardiac Surgery
Authors: Dana H Lee, Billie Jean Martin, Alexandra M Yip, Karen J Buth, Gregory M Hirsch
Journal: Circulation (2008)

Patients referred for cardiac surgery are increasingly older, but chronological age does not always capture biological age. This study assessed frailty, as a functional parameter of biological age, as a predictor of mortality or prolonged institutional care. Functional measures of frailty and clinical preoperative data were collected for all cardiac surgery patients at a single center (2004 –2007). Based on the Katz Index of Activities of Daily Living, frailty was defined as any impairment in feeding, bathing, dressing, transferring, toileting, continence, or ambulation, or dementia. The impact of frailty on in-hospital mortality or institutional discharge (other hospital or nursing facility) was assessed with multivariate logistic regression. The interaction of frailty and age was examined, with non-frail patients age&lt;70 as the referent group. Results: Of 3096 patients, 133 (4.3%) were frail. Frail patients were older, more likely to be female, have COPD, CHF, EF&lt;40%, recent MI, pre-operative renal failure, cerebrovascular disease, greater acuity, and more complex operations (p&lt;0.05). Frail patients experienced higher rates of mortality, sepsis, delirium, post-operative renal failure, and transfusion (p&lt;0.001). A greater proportion of frail patients than non-frail patients (49% vs. 9%) were discharged to a setting other than home. In the risk-adjusted models, frailty was an independent predictor of mortality (OR 1.8, 95% CI 1.0 –3.2) or institutional discharge (OR 6.4, 95% CI 4.1–9.9). Furthermore, frail elderly (age≥70) patients had greater risk of institutional discharge (OR 22.7, CI 12.4 – 41.7) than frail younger patients (OR 6.5, CI 3.4 –12.5) or non-frail elderly patients (OR 3.5, CI 2.6 – 4.6). Similarly, frail elderly patients had greater risk of mortality (OR 4.0, CI 1.9 – 8.1) than frail younger patients (OR 1.9, CI 0.8 – 4.7) or non-frail elderly patients (OR 2.4, CI 1.7–3.5). Frailty was an independent predictor of in-hospital mortality and prolonged institutional care. Frailty combined with older age further discriminated those at highest risk. Special consideration should be given to the management of frail elderly patients who have surgical cardiac disease.
Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines
Authors: Ayse L. Mindikoglu, Thomas C. Dowling, Laurence S. Magder, Robert H. Christenson, Matthew R. Weir, Stephen L. Seliger, William R. Hutson, Charles D. Howell
Journal: Clinical Gastroenterology and Hepatology (2015)
Abstract 199: Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation
Authors: Hui-Huang Lai, Yu-Jhen Lyu, Jie-Ning Li, Jen-Liang Su, Pai-Sheng Chen
Journal: Cancer Research (2015)

Abstract MicroRNAs (miRNAs) are generated by a multiple steps process that post-transcriptionally regulate the expression of target genes. Dysregulation of miRNAs is linked to human diseases including the development of human cancer. Abrogation of cellular global miRNAs maturation has been proposed to promote tumorigenesis and cancer metastasis. Hypoxia stress is the major cause of dysregulation of miRNAs and promotes tumor angiogenesis, metastasis and tumorigenesis which is a pivotal factor to switch on the cellular oncogenic features during tumor progression. Although hypoxia stress regulates expression of a subset of miRNAs, the upstream regulators controlling miRNAs regulation under hypoxia remain unclear. This study demonstrates the molecular mechanism of post-translational regulation of Dicer under hypoxia. Our results show that knockdown of hypoxia inducible factor 1 alpha (HIF-1α) up-regulates Dicer expression in colorectal cancer (CRC) cells. Overexpression of HIF-1α enhances ubiquitination of Dicer and subsequently promotes it recognition by autophagic receptor for autophagy-lysosomal degradation. We also find that HIF-1α enhances cancer cell migration by regulating Dicer-regulated miRNAs. In conclusion, we demonstrated that HIF-1α down-regulated Dicer and abolishes miRNA biogenesis to enhance cancer cell migration. This study may provide a potential therapeutic direction that targets the dysregulated miRNAs in tumor hypoxia for patients with poor prognosis and metastatic CRC. Citation Format: Hui-Huang Lai, Yu-Jhen Lyu, Jie-Ning Li, Jen-Liang Su, Pai-Sheng Chen. Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 199. doi:10.1158/1538-7445.AM2015-199
Screening of newborn infants for cholestatic hepatobiliary disease
Authors: E. Linnane, A. Paul, R. Parry, P. T Clayton, S. Logan
Journal: BMJ (1999)

Editor-Bero's editorial on commercial sponsorship for research is important 1 because commercial interests can bias the conduct and reporting of research. 2It may, however, leave the impression that pressure on research is an issue only in relation to commercial sponsorship.I used to believe that public sponsors would allow the independent conduct of research, but experiences have taught me otherwise.Recent stories in the Norwegian mass media indicate that public sponsors may also breach ethical codes for research sponsorship.Newspapers have told their readers that the ministry of education tried to influence research into the effects of an educational reform, 3 while a trade union tried to keep secret a report on privatisation of municipal services. 4 The National Council of Tobacco and Health asked a research team to change its methods for analysing the economic consequences of smoking: the methods had been agreed on before the project started, but the council later asked the team to switch to a method that would make smoking seem more "costly" to society. 5 In the end, the funding was stopped.For all three cases, the sponsors denied any unethical conduct.Industry's motive for influencing research is obvious (profit), but the motives of public sponsors may be obscure.The perceived benefits from getting the "right" results are probably related more to organisations or interest groups than to individuals.Conceivably, civil servants or other parties see themselves as agents for public interests that entitle them to influence research.In the commercial sector agents are more used to criticism for biased research and may be better aware of the ethical rules.Interestingly, some researchers say they feel less pressure when undertaking research for the pharmaceutical industry than for government.
Acute Myocardial Infarction With Hyperoxemic Therapy (AMIHOT)
Authors: William W. O’Neill, Jack L. Martin, Simon R. Dixon, Antonio L. Bartorelli, Daniela Trabattoni, Pranobe V. Oemrawsingh, Douwe E. Atsma, Michael Chang, William Marquardt, Jae K. Oh, Mitchell W. Krucoff, Raymond J. Gibbons, J. Richard Spears
Journal: Journal of the American College of Cardiology (2007)
Therapeutic potential of MDM2 inhibitors in testicular germ cell tumors
Authors: Sebastian Bauer, Thomas Muhlenberg, Ruud van Gurp, Fadime Aksakal, Oliver Konstanty, Martin Schuler, Leendert Looijenga
Journal: Cancer Research (2008)

2381   Introduction:  Inadequate response to or relapse following cisplatin-based chemotherapies is associated with poor prognosis of patients with advanced testicular germ cell tumors (TGCT). Novel chemotherapeutic agents have so far failed to substantially improve the outcome of these patients. The majority of TGCT express low levels of p53 and p53 mutations are rarely observed. This is attributed to alternative mechanisms of p53 inactivation, such as specific microRNAs and MDM2 amplification. MDM2 inhibitors increase levels of endogenous p53 and enhance apoptosis in tumors harbouring wild type (wt) p53. We therefore sought to investigate the potential therapeutic value of MDM2 in TGCT.  Materials and Methods:  The MDM2 inhibitor nutlin-3 was evaluated alone and in combination with cisplatin in a panel of TGCT-derived cell lines (embryonal carcinomas). While the cell lines NT2 and 2102EP have wt p53 status, NCCIT has no functional p53 (allelic loss and nonsense mutation with premature stop codon). Biological consequences of MDM2 inhibition were determined by analysis of the p53 pathway, cell proliferation and apoptosis.  Results:  Nutlin-3 exhibited significant activity (IC50 2.8 µM) in NT2 and 2102EP (wt p53), but not in p53-mutated NCCIT cells (
Abstract 2846: Prevention of Contrast-Induced Nephropathy with Sodium Bicarbonate in Patients Undergoing an Emergent Coronary Procedure: A Prospective Randomized Controlled Trial
Authors: Masaharu Masuda, Takahisa Yamada, Takanao Mine, Takashi Morita, Shunsuke Tamaki, Yasumasa Tsukamoto, Keiji Okuda, Yuusuke Iwasaki, Masatake Fukunami
Journal: Circulation (2006)

Background:  Contrast-Induced Nephropathy (CIN) remains a common complication of radiographic procedure. CIN is postulated to occur from free radical injury, which may be reduced by alkalizing renal tubular fluid with bicarbonate. However, there is no information available on the efficacy of sodium bicarbonate for the prophylaxis against CIN in patients undergoing an emergent coronary procedure.   Methods:  We enrolled 56 patients who had renal dysfunction (serum creatinine > 1.1mg/dl or glomerular filtration rate    Results:  There were no significant group differences in age, sex, incidence of diabetes mellitus (sodium bicarbonate, 32% vs. sodium chloride, 36%), contrast volume (110±89 vs. 119±69ml), left ventricular ejection fraction (58±12% vs. 55±13%) or baseline serum creatinine. In patients infused with sodium bicarbonate, there was no significant change in the serum creatinine after the contrast administration (1.26±0.49 to 1.29±0.60mg/dl), while it significantly increased in those with sodium chloride (1.24±0.44 to 1.37±0.71mg, p   Conclusion:  In patients undergoing emergent cardiac catheterization, hydration with sodium bicarbonate is more effective than hydration with sodium chloride for the prevention of CIN.
Anterior Segment Imaging Predicts Incident Gonioscopic Angle Closure
Authors: Mani Baskaran, Jayant V. Iyer, Arun K. Narayanaswamy, Yingke He, Lisandro M. Sakata, Renyi Wu, Dianna Liu, Monisha E. Nongpiur, David S. Friedman, Tin Aung
Journal: Ophthalmology (2015)
Existing children are treated differently from embryos
Authors: T. G Stammers
Journal: BMJ (1995)

in better paediatric care, education, or social environment, which are more likely than in vitro fertilisation to maximise utility.When resources for health care are scarce we need to consider the opportunity costs of any investment.While infertility can cause psychological distress, a better use of resources may be to offer counselling to allow couples to accept their condition, or to attempt to alter the expectations of relatives and friends.
Abstract 196: DDAH1 Knockout Exacerbates Hypoxia-induced Pulmonary Arterial Hypertension In Mice
Authors: Dongmin Kwak, Dachun Xu, Dorothee Atzler, Xinli Hu, Xin Xu, Huan Wang, John Fassett, Hailing Li, Shuo Yan, Haipeng Guo, Yingjie Chen
Journal: Circulation Research (2014)

Pulmonary arterial hypertension (PAH) is a progressive disease with a very poor prognosis. Recent studies have demonstrated that PAH is associated with diminished nitric oxide bioavailability, increased levels of endogenous nitric oxide synthase (NOS) inhibitor ADMA, and decreased lung dimethylarginine dimethylaminohydrolase (DDAH) activity. We have demonstrated that DDAH1 is essential for degradation of endogenous NOS inhibitor ADMA, and is important for optimal vascular endothelial NO production. However, it is not clear whether decreased DDAH activity and ADMA accumulation exacerbates development or progression of PAH and right ventricular hypertrophy. In addition, the impact of cardiomyocyte specific DDAH1 dysfunction on right ventricular hypertrophy is unknown. Using global DDAH1 gene deficient mice, we demonstrate that chronic ADMA accumulation by global DDAH1 gene deletion did not cause spontaneous PAH under control conditions, but significantly exacerbated chronic hypoxia-induced PAH, as indicated by significantly increased right ventricular (RV) pressure, more RV hypertrophy, and enhanced pulmonary vascular remodeling in DDAH1 deficient mice as compared to wild type mice. Chronic hypoxia resulted in reduced lung DDAH activity and increased circulating ADMA content in wild type mice. Cardiomyocyte specific DDAH1 gene deletion did not exacerbate hypoxia-induced increases in RV pressure or lung vascular remodeling, but significantly exacerbated hypoxia-induced RV hypertrophy in comparison to wild type littermates, indicating DDAH1 distributed in cardiomyocytes protect the heart against RV hypertrophy independent to pressure overload. Collectively, our data indicate that lung DDAH1 plays a critical role in protection against hypoxia-induced PAH and right ventricular hypertrophy.