tbuckley/cabot-search huggingface dataset:
MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells
Authors: Thales Papagiannakopoulos, Alice Shapiro, Kenneth S. Kosik
Journal: Cancer Research (2008)

MicroRNA dysregulation is observed in different types of cancer. MiR-21 up-regulation has been reported for the majority of cancers profiled to date; however, knowledge is limited on the mechanism of action of miR-21, including identification of functionally important targets that contribute to its proproliferative and antiapoptotic actions. In this study, we show for the first time that miR-21 targets multiple important components of the p53, transforming growth factor-beta (TGF-beta), and mitochondrial apoptosis tumor-suppressive pathways. Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest. These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63. These findings establish miR-21 as an important oncogene that targets a network of p53, TGF-beta, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells.
Synergistic Induction of HL60 Cell Differentiation by Ketoconazole and 1-Desoxy Analogues of Vitamin D3
Authors: Xuening Wang, Jeffrey P. Gardner, Ahmed Kheir, Milan R. Uskokovic, George P. Studzinski
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The goal of differentiation therapy is to induce cancer cells to stop proliferating and to express characteristics of normal cells. Vitamin D analogues, such as the deltanoids, are being evaluated as differentiation agents in the treatment of several human cancers (e.g., myeloid leukemias); however, these compounds have a tendency to produce hypercalcemia in patients receiving therapy. A combination of a differentiation-inducing deltanoid with a compound that blocks entry of calcium into cells (e.g., ketoconazole) may offer a new approach to differentiation therapy and address the problem of hypercalcemia. We investigated whether various ketoconazole—deltanoid combinations would alter cellular differentiation or intracellular calcium homeostasis in comparison with deltanoids used alone. Methods: Cultured human leukemia HL60 cells were treated with ketoconazole—deltanoid combinations. Markers of differentiation (expression of CD11b and CD14 antigens and of non-specific esterase) were measured by flow cytometry and cytochemistry; cell cycle distribution was measured by flow cytometry of propidium iodide-stained cells. Expression of differentiation-related genes was assessed by northern blotting and immunoblotting, and changes in intracellular calcium homeostasis were monitored by fluorescence analysis of fura-2-containing cells. Results: Ketoconazole strongly potentiated the differentiating activity of the deltanoids, which exhibited low potency when used alone. Ketoconazole—deltanoid combinations had little effect on HL60 cell-cycle distribution, although the cells did stop proliferating and they differentiated. Ketoconazole—deltanoid combinations produced only minor changes in intracellular calcium homeostasis compared with changes produced by 1,25-dihydroxyvitamin D3, either alone or in combination with ketoconazole. Conclusion: These results suggest that ketoconazole may be useful in combination with vitamin D analogues in the differentiation therapy for myeloid leukemias.
CD4+CD28null T cells in coronary artery disease: when helpers become killers
Authors: I. E. Dumitriu, E. T. Araguas, C. Baboonian, J. C. Kaski
Journal: Cardiovascular Research (2008)

The crucial role of T cells in atherosclerosis and coronary artery disease (CAD) has been highlighted by recent observations. Helper CD4+ T cells can both aggravate or attenuate the atherogenic process and the development of CAD. CD4+CD28null T cells are an unusual subset of helper cells which expand and have deleterious effects in CAD. In this review, we discuss the current issues on the generation of CD4+CD28null T cells and focus on their phenotypic and functional characteristics relevant to the development of cardiovascular events. The possible effects of the present day therapies for CAD on the CD4+CD28null T cells are also explored. Targeting the CD4+CD28null T cell subset in CAD could provide novel therapeutic strategies to prevent acute life-threatening coronary events.
Interferon β for rheumatoid arthritis: new clothes for an old kid on the block: Figure 1
Authors: Margriet J Vervoordeldonk, Caroline J Aalbers, Paul P Tak
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Pilot aim</h3> To explore how housing support workers (HSW) could support patients and carers as part of the hospice9s Clinical Nurse Specialist (CNS) team. CNS capacity was being reduced by undertaking important albeit non-clinical activities. Additionally the service received ineligible referrals that were nonetheless judged to be at risk of crisis where an assessment could be beneficial. The housing sector partner seconded a HSW into the hospice9s 9First Contact9 triage team. HSWs have valuable experience in supporting vulnerable clients and have knowledge of statutory and voluntary sector services, the hospice provided training on awareness of end of life care. The HSW makes contact with the patient and arranges a home visit to undertake a holistic assessment. The HSW supports the patient and their carers to access support including equipment, home adaptations, social care, benefit entitlements, in addition to liaising with healthcare professionals to organise GP reviews or District Nursing support where required. Other key areas of learning: HSW support is acceptable to patients when they are not ready to accept hospice support; anecdotal evidence suggests that some patients avoid all services whilst living in pain and/or on the edge of crisis.
Outcomes among Newborns with Total Serum Bilirubin Levels of 25 mg per Deciliter or More
Authors: Thomas B. Newman, Petra Liljestrand, Rita J. Jeremy, Donna M. Ferriero, Yvonne W. Wu, Esther S. Hudes, Gabriel J. Escobar
Journal: New England Journal of Medicine (2006)

The neurodevelopmental risks associated with high total serum bilirubin levels in newborns are not well defined.We identified 140 infants with neonatal total serum bilirubin levels of at least 25 mg per deciliter (428 micromol per liter) and 419 randomly selected controls from a cohort of 106,627 term and near-term infants born from 1995 through 1998 in Kaiser Permanente hospitals in northern California. Data on outcomes were obtained from electronic records, interviews, responses to questionnaires, and neurodevelopmental evaluations that had been performed in a blinded fashion.Peak bilirubin levels were between 25 and 29.9 mg per deciliter (511 micromol per liter) in 130 of the newborns with hyperbilirubinemia and 30 mg per deciliter (513 micromol per liter) or more in 10 newborns; treatment involved phototherapy in 136 cases and exchange transfusion in 5. Follow-up data to the age of at least two years were available for 132 of 140 children with a history of hyperbilirubinemia (94 percent) and 372 of 419 controls (89 percent) and included formal evaluation at a mean (+/-SD) age of 5.1+/-0.12 years for 82 children (59 percent) and 168 children (40 percent), respectively. There were no cases of kernicterus. Neither crude nor adjusted scores on cognitive tests differed significantly between the two groups; on most tests, 95 percent confidence intervals excluded a 3-point (0.2 SD) decrease in adjusted scores in the hyperbilirubinemia group. There was no significant difference between groups in the proportion of children with abnormal neurologic findings on physical examination or with documented diagnoses of neurologic abnormalities. Fourteen of the children with hyperbilirubinemia (17 percent) had "questionable" or abnormal findings on neurologic examination, as compared with 48 controls (29 percent; P=0.05; adjusted odds ratio, 0.47; 95 percent confidence interval, 0.23 to 0.98; P=0.04). The frequencies of parental concern and reported behavioral problems also were not significantly different between the two groups. Within the hyperbilirubinemia group, those with positive direct antiglobulin tests had lower scores on cognitive testing but not more neurologic or behavioral problems.When treated with phototherapy or exchange transfusion, total serum bilirubin levels in the range included in this study were not associated with adverse neurodevelopmental outcomes in infants born at or near term.
The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD
Authors: Akosua Vilaysane, Justin Chun, Mark E. Seamone, Wenjie Wang, Rick Chin, Simon Hirota, Yan Li, Sharon A. Clark, Jurg Tschopp, Kiril Trpkov, Brenda R. Hemmelgarn, Paul L. Beck, Daniel A. Muruve
Journal: Journal of the American Society of Nephrology (2010)

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3−/− mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.
BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease
Authors: Linda Chami, Frédéric Checler
Journal: Molecular Neurodegeneration (2012)

Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.
Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandin mediation.
Authors: G Staumont, J Fioramonti, J Frexinos, L Bueno
Journal: Gut (1988)

The effects of sennosides on colonic motility were investigated in eight conscious dogs chronically fitted with two strain gauge transducers in the proximal colon, an intracolonic silicone catheter and a polyethylene catheter implanted in a branch of the right colonic artery. Oral sennosides (30 mg/kg) inhibited colonic motility for 12 to 18 h after a three to six hours delay, and associated with giant contractions and diarrhoea. The minimal oral dose of sennosides to produce such changes varied from 5 to 15 mg/kg. Intracolonic sennosides at the minimal effective dose and at 30 mg/kg reproduced the effects of oral sennosides, but with a shorter latency (0.5-1.5 h). Intracolonic PGE2 (100 micrograms/kg) in viscous gel medium or intra-arterial PGE2 (10 micrograms/h) inhibited colonic motility and induced giant contractions often associated with defecation. The colonic motor changes induced by intracolonic sennosides at the minimal effective dose, but not those induced by intracolonic PGE2, were blocked by intra-arterial indomethacin (10 micrograms/h) or piroxicam (5 micrograms/h). These results suggest that colonic motor actions of sennosides are mediated through a local prostaglandins synthesis, as they were blocked by cyclooxygenase inhibitor and reproduced by PGE2.
Thyroid Carcinoma in Hiroshima and Nagasaki
Authors: Richard J. Sampson
Journal: JAMA (1969)

Carcinoma of the thyroid at autopsy was found to be far more frequent in Japan than in any recorded American series. In 3,067 consecutive autopsies from the fixed population sample of the Japanese National Institute of Health-Atomic Bomb Casualty Commission Life-Span Study in Hiroshima and Nagasaki, 536 primary thyroid carcinomas were found—97% were occult papillary. The prevalence was significantly higher in women and those exposed to 50 rads or more of direct atomic radiation. The prevalence rate in the 1,096 persons in this study with no radiation dose whose entire thyroid gland was examined was 17.9% compared to 1.0% to 4.0% in the American series. Radiation, method of examination, diagnostic criteria, and bias in autopsy selection did not appear to explain the observed high frequency of thyroid carcinoma at autopsy.
Lipid metabolism in the healthy and diseased heart: Edited by G. van der Vusse, H. Stam, 213 pp., 86.75 (hardback). Dordrecht: Kluwer Academic Publishers, 1992. ISBN 0792318501
Authors: H. S. Silverman, E. J. Griffiths
Journal: Cardiovascular Research (1995)

Lipid metabolism in the healthy and diseased heart: Edited by G. van der Vusse, H. Stam, 213 pp., £86.75 (hardback). Dordrecht: Kluwer Academic Publishers, 1992. ISBN 0792318501 Get access Howard S. Silverman, Howard S. Silverman Baltimore, MD, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Elinor J. Griffiths Elinor J. Griffiths Baltimore, MD, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 30, Issue 2, August 1995, Page 311, https://doi.org/10.1016/S0008-6363(95)90129-9 Published: 01 August 1995
A prospective study on treatment of hypercholesterolemia with lovastatin in renal transplant patients receiving cyclosporine.
Authors: A K Cheung, G A DeVault, M C Gregory
Journal: Journal of the American Society of Nephrology (1993)

Hypercholesterolemia occurs commonly in renal transplant recipients and may contribute to the high cardiovascular morbidity and mortality in these patients. Although an effective hypolipidemic agent, lovastatin has been associated with rhabdomyolysis and acute renal failure in patients on cyclosporin A (CsA). In this study, lovastatin was administered at 10 mg/day for 8 wk followed by 20 mg/day for 12 wk to six renal transplant recipients who were receiving CsA concomitantly. The 10-mg/day dose was effective, but an additional lipid-lowering effect was seen with the 20-mg/day dose. Both serum total cholesterol and low-density lipoprotein cholesterol levels decreased by 27% at the end of the 20 wk of lovastatin administration. Serum high-density lipoprotein cholesterol and triglyceride levels remained unchanged. No significant clinical or laboratory adverse effects were observed, including muscular symptoms, ophthalmologic abnormalities, or alterations in serum creatine kinase, urea nitrogen, creatinine, transaminases, and CsA levels. Peak and trough plasma concentrations of active lovastatin were comparable to those reported in normal subjects receiving a higher lovastatin dose without CsA. It was concluded that the administration of low-dose (10 to 20 mg/day) lovastatin to renal transplant recipients receiving concomitant CsA can be safe and effective in lowering serum cholesterol.
Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register
Authors: J B Galloway, K L Hyrich, L K Mercer, W G Dixon, A P Ustianowski, M Helbert, K D Watson, M Lunt, D P M Symmons
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. Methods Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological disease-modifying antirheumatic drug (nbDMARD)-treated patients. Results 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. Conclusions Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life-threatening complication.
Jejunal mucosal immunoglobulin-containing cells and jejunal fluid immunoglobulins in adult coeliac disease and dermatitis herpetiformis
Authors: M. Lancaster-Smith, P. Kumar, R. Marks, M. L. Clark, A. M. Dawson
Journal: Gut (1974)

Immunoglobulin-containing plasma cell densities in the jejunal mucosa and serum and jejunal fluid immunoglobulins have been measured in patients with adult coeliac disease and dermatitis herpetiformis with and without jejunal mucosal abnormality. Studies were performed in patients before and after treatment of the jejunal lesion.Total immunofluorescent plasma cells were increased in untreated adult coeliac disease and dermatitis herpetiformis patients with jejunal lesions, but in general the normal predominance of IgA > IgM > IgG was found. There was no difference from controls in IgA-containing cells in the two conditions before or after treatment. The numbers of IgM-containing cells were significantly increased both before and after treatment in groups of patients with adult coeliac disease and dermatitis herpetiformis who had jejunal lesions. IgG-containing cells were significantly raised in only the before-treatment groups. Patients with dermatitis herpetiformis without jejunal lesions, even whilst on gluten-containing diets, had normal numbers of immunoglobulin-containing cells. IgA and IgM jejunal fluid immunoglobulins were significantly raised in dermatitis herpetiformis and adult coeliac disease.It is concluded that patients with dermatitis herpetiformis with jejunal morphological abnormality have a comparable immunological disturbance of the jejunal mucosa to that found in adult coeliac disease.
Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804
Authors: N.L. Bartlett, D. Niedzwiecki, J.L. Johnson, J.W. Friedberg, K.B. Johnson, K. van Besien, A.D. Zelenetz, B.D. Cheson, G.P. Canellos
Journal: Annals of Oncology (2007)
Microtubule-Based Transport Systems in Neurons: The Roles of Kinesins and Dyneins
Authors: Lawrence S. B. Goldstein, Zhaohuai Yang
Journal: Annual Review of Neuroscience (2000)

The large size and extreme polarization of neurons is crucial to their ability to communicate at long distances and to form the complex cellular networks of the nervous system. The size, shape, and compartmentalization of these specialized cells must be generated and supported by the cytoskeletal systems of intracellular transport. One of the major systems is the microtubule-based transport system along which kinesin and dynein motor proteins generate force and drive the traffic of many cellular components. This review describes our current understanding of the functions of kinesins and dyneins and how these motor proteins may be harnessed to generate some of the unique properties of neuronal cells.
Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer
Authors: Stephen Chan, Max E. Scheulen, Stephen Johnston, Klaus Mross, Fatima Cardoso, Christian Dittrich, Wolfgang Eiermann, Dagmar Hess, Rudolph Morant, Vladimir Semiglazov, Markus Borner, Marc Salzberg, Valerijus Ostapenko, Hans-Joachim Illiger, Dirk Behringer, Nathalie Bardy-Bouxin, Joseph Boni, Steven Kong, Maria Cincotta, Laurence Moore
Journal: Journal of Clinical Oncology (2005)

In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated.Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus.Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%).In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.
Doctors' suicides: economic considerations and beyond
Authors: C. L. Manning, D. Peters, G. Lewith
Journal: BMJ (2015)

Hawton states that “doctors have long been known to be at risk of suicide.”1 Each such suicide, aside from all the human suffering and pain, costs about £2m (€2.8m; $1.5m).2 Against this, the General Medical Council’s recommendation …
HOW IS THE EARLY DIAGNOSIS OF PULMONARY TUBERCULOSIS TO BE MADE?
Authors: J. C. Mackwood
Journal: BMJ (1918)

C m lmJoU 741 for them free of charge under those Acts; h-lowever, such cases can be multiplied indefinitely wlhere people consider it more desirable to employ a handy-woman wlho remains in residence during the lying-in, period, and washes and liouselieeps for the household, wllile the unremunerated disiensary doctor is compelled to take over the work, and also the opprobritum of the untrained midwives' too- frequently-fatal mistakes.Where in the bill are we empowered to expel untrained women from the charge of a " Poor Law emnergency case " and substitute our trained lnurse?No suclh provision is made.Is the Local Government Board prepared to