tbuckley/cabot-search huggingface dataset:
The Synthetic Triterpenoids, CDDO and CDDO-Imidazolide, Are Potent Inducers of Heme Oxygenase-1 and Nrf2/ARE Signaling
Authors: Karen Liby, Thomas Hock, Mark M. Yore, Nanjoo Suh, Andrew E. Place, Renee Risingsong, Charlotte R. Williams, Darlene B. Royce, Tadashi Honda, Yukiko Honda, Gordon W. Gribble, Nathalie Hill-Kapturczak, Anupam Agarwal, Michael B. Sporn
Journal: Cancer Research (2005)

Abstract The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.
Treating Multiple Myeloma: The Cause for Optimism
Authors: Marilyn P. Fenichel
Journal: JNCI Journal of the National Cancer Institute (2014)

process. “People in the top 5%–10% [for breast cancer risk] are identified, contacted by breast health specialists, and counseled about their options,” she said. To the extent that cost is a disincentive, the Affordable Care Act will, starting next year, require new health insurance plans to cover chemoprevention with no copayment or deductible in high-risk women. That typically means a 5-year breast cancer risk of 1.67% or higher, which includes nearly all American women older than 55 years. Meanwhile, European researchers are investigating reduced doses of tamoxifen to alleviate some side effects. Per Hall, M.D., Ph.D., of the Karolinska Institute in Stockholm, was among the researchers who showed that a change in breast density might be a useful surrogate for therapeutic effect. Now his group is about to launch another trial to learn whether women who take lower doses of tamoxifen can achieve the same benefit with fewer side effects. The group plans to randomize 1,000 Swedish women to receive placebo or one of four daily doses
Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors
Authors: Fadlo R. Khuri, Bonnie S. Glisson, Edward S. Kim, Paul Statkevich, Peter F. Thall, Michael L. Meyers, Roy S. Herbst, Reginald F. Munden, Craig Tendler, Yali Zhu, Sandra Bangert, Elizabeth Thompson, Charles Lu, Xue-Mei Wang, Dong M. Shin, Merrill S. Kies, Vali Papadimitrakopoulou, Frank V. Fossella, Paul Kirschmeier, W. Robert Bishop, Waun Ki Hong
Journal: Clinical Cancer Research (2004)

To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m(2) or 175 mg/m(2) administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m(2). Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m(2) of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.
The effect of an acute increase in renal perfusion pressure on sodium transport in the rat kidney.
Authors: R T Kunau, N H Lameire
Journal: Circulation Research (1976)

We used micropuncture techniques to examine the intrarenal response to an acute elevation of the renal perfusion pressure. In one series of studies (epinephrine, group I) the renal perfusion pressure was acutely increased by intravenous epinephrine infusion; in another series, by bilateral carotid occlusion and vagotomy. A third series of studies (epinephrine, group II) was performed identically to the epinephrine, group I, studies except that the renal perfusion pressure was held constant during the epinephrine infusion by suprarenal aortic constriction. After epinephrine infusion (group I) and following bilateral carotid occlusion and vagotomy the renal perfusion pressure increased, from 119 +/- 1.0 (SEM) to 166 +/- 1.85 mm Hg and from 122 +/- 5.9 to 168 +/- 3.1 mm Hg, respectively. Fractional sodium excretion rose from 2.31 +/- 0.34% to 5.09 +/- 0.58% (P less than 0.001) after epinephrine and from 1.80 +/- 0.71 to 6.40 +/- 1.0% (P less than 0.01) following carotid occlusion and vagotomy. In neither study, however, did we find that the increase in renal perfusion pressure changed the glomerular filtration rate (GFR) (both kidneys) or fractional sodium delivery from the superficial cortical late distal tubule. Furthermore, we found that epinephrine infusion at a constant renal perfusion pressure (epinephrine, group II) did not affect fractional sodium excretion, although a small, but significant, decrease in the GFR and sodium delivery from the superficial late distal tubule occurred. These data suggest that the natriuresis which follows an acute elevation of the renal perfusion pressure cannot be attributed to enhanced sodium delivery from superficial nephrons but must result from (1) inhibition of sodium reabsorption in inner cortical nephrons or (2) an effect on sodium transport in the collecting system.
Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure
Authors: Z. Makita, R. Bucala, E.J. Rayfield, H. Fuh, K.R. Manogue, A. Cerami, H. Viassara, E.A. Friedman, A.M. Kaufman, S.M. Korbet, R.H. Barth, J.A. Winston
Journal: The Lancet (1994)
A New Simple Method for the Measurement of Visceral Fat Accumulation by Bioelectrical Impedance
Authors: Miwa Ryo, Kazuhisa Maeda, Tomohiro Onda, Mitsuhiro Katashima, Akiko Okumiya, Makoto Nishida, Tohru Yamaguchi, Tohru Funahashi, Yuji Matsuzawa, Tadashi Nakamura, Iichiro Shimomura
Journal: Diabetes Care (2005)

We and others (1–9) have shown that the accumulation of visceral fat is associated with multiple risk factor syndrome more closely than with the BMI itself or the amount of subcutaneous fat. In these studies, computed tomography (CT) scan at the umbilical level (10) was used for the assessment of visceral fat area (VFA). However, the method is not cost-effective and/or radiation exposure is problematic; thus, it is often unsuitable for screening large groups of individuals. There is a need for a simple and noninvasive method to assess visceral fat accumulation. The bioelectrical impedance analysis (BIA) method, which is based on the electric resistance difference between the fat and components of other organs (11–14), should meet this need. Conventional BIA approaches have estimated total fat content but not regional fat distribution (11–13). Recently, attempts to assess the amount of abdominal subcutaneous fat by the local BIA method were reported (14). Here, we developed a new technique to specifically evaluate VFA by using the abdominal BIA method.

The study subjects were 59 healthy volunteers and 32 inpatients with suspected cardiovascular disease at Osaka University Hospital. Waist circumference (Wc) at the umbilical level was measured in the late exhalation phase while standing. All subjects underwent the abdominal BIA method to estimate VFA. The voltage occurring at the flank to the flow of current between the umbilicus and the back correlates significantly …
T lymphocyte engineering with cytokine nanogels for enhanced cancer immunotherapy
Authors: Li Tang, Yiran Zheng, Llian Mabardi, Darrell J Irvine
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Adoptive cell transfer (ACT) with autologous tumor-reactive T cells is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable antigen-specific
Microsatellite DNA Alterations of Gastrointestinal Stromal Tumors Are Predictive for Outcome
Authors: Paulus Schurr, Stefan Wolter, Jussuf Kaifi, Uta Reichelt, Helge Kleinhans, Robin Wachowiak, Emre Yekebas, Tim Strate, Viacheslav Kalinin, Ronald Simon, Guido Sauter, Hansjoerg Schaefer, Jakob Izbicki
Journal: Clinical Cancer Research (2006)

Abstract Purpose: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear. Experimental Design: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots. Results: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P = 0.005, χ2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P &amp;lt; 0.001, log-rank test). Likewise, LOH significantly predicted survival (P = 0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P &amp;lt; 0.001). Conclusions: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.
A Successful Institutional Strategy to Increase the Number of Therapeutic Operations Among Patients With Lung Lesions
Authors: Amelia W. Maiga, Stephen A. Deppen, Rhonda Pinkerman, Eric L. Grogan
Journal: JAMA Surgery (2015)

Pulmonary resection is a diagnostic and therapeutic strategy for patients with known or suspected lung cancer.Surgeons must strike a balance between resecting early-stage cancer and improving survival, while minimizing the removal of benign lesions and the low but finite risk of resection.Overall rates of nontherapeutic resections of benign lesions (ie, benign rates) have surpassed 20% in recent large cooperative trials but may vary among institutions depending on the underlying population risk, referral patterns, and the level of aversion to risk among clinicians. 1,2Institutional strategies that include multidisciplinary conferences with participation from specialists in the fields of surgery, pulmonology, radiology, pathology, and oncology participation may minimize benign rates and increase the number of therapeutic resections.
The Emerging Role of microRNAs and Nutrition in Modulating Health and Disease
Authors: Sharon A. Ross, Cindy D. Davis
Journal: Annual Review of Nutrition (2014)

Understanding the molecular mechanisms that inform how diet and dietary supplements influence health and disease is an active research area. One such mechanism concerns the role of diet in modulating the activity and function of microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that are involved in posttranscriptional gene silencing and have been shown to control gene expression in diverse biological processes including development, differentiation, cell proliferation, metabolism, and inflammation as well as in human diseases. Recent evidence described in this review highlights how dietary factors may influence cancer, cardiovascular disease, type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease through modulation of miRNA expression. Additionally, circulating miRNAs are emerging as putative biomarkers of disease, susceptibility, and perhaps dietary exposure. Research needs to move beyond associations in cells and animals to understanding the direct effects of diet and dietary supplements on miRNA expression and function in human health and disease.
Lyn Kinase Activity Is the Predominant Cellular Src Kinase Activity in Glioblastoma Tumor Cells
Authors: Michelle R. Stettner, Wenquan Wang, L. Burton Nabors, Suman Bharara, Daniel C. Flynn, J. Robert Grammer, G. Yancey Gillespie, Candece L. Gladson
Journal: Cancer Research (2005)

Abstract Cellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. As we have found that Lyn, but not Fyn, activity promotes migration of glioblastoma cells in response to the cooperative signal generated by platelet-derived growth factor receptor β and integrin αvβ3, we compared the activity and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy samples with that in anaplastic astrocytoma (grade III) tumors, nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity was significantly elevated in glioblastoma tumor samples. Notably, the Lyn kinase activity accounted for &amp;gt;90% of pan-Src kinase activity in glioblastoma samples but only ≈30% of pan-Src kinase activity in the other groups. The levels of phosphorylation of the autophosphorylation site were consistent with significantly higher Lyn activity in glioblastoma tumor tissue than nonneoplastic brain. Although the normalized levels of Lyn protein and the relative levels of Lyn message were significantly higher in glioblastoma samples than nonneoplastic brain, the normalized levels of Lyn protein did not correlate with Lyn activity in the glioblastoma samples. There was no significant difference in the normalized levels of c-Src and Fyn protein and message in the glioblastoma and nonneoplastic brain. Immunostaining revealed that Lyn is located primarily in the glioblastoma cells in the tumor biopsies. These data indicate that Lyn kinase activity is significantly elevated in glioblastoma tumors and suggest that it is the Lyn activity that promotes the malignant phenotype in these tumors.
Low back pain in primary care
Authors: R. A. Deyo, J. G. Jarvik, R. Chou
Journal: BMJ (2014)

#### Key points

A woman aged 71 with smoking related lung disease and frequent use of corticosteroids presented to clinic with acute severe low back pain. The pain began yesterday after she moved furniture in her apartment, is centrally located in the upper lumbar region without radiation to the legs, and is worse with movement. On examination, she has tenderness to palpation over the upper lumbar spine.

Many observers argue that lumbar spine imaging is overused in developed countries because of a low yield of clinically useful findings, a high yield of misleading findings, radiation exposure (especially to the gonads), and costs. This is a particular concern in the United States, where imaging capacity is high, and spine specialists commonly have their own imaging facilities. These concerns are valid, despite the broad differential diagnosis of back pain, which includes not only degenerative changes but deformity, fracture, and underlying systemic diseases such as malignancy, infection, or ankylosing spondylitis. Though metastatic cancer might be the most common of these systemic conditions, its prevalence in …
Ewing Sarcoma: Current Management and Future Approaches Through Collaboration
Authors: Nathalie Gaspar, Douglas S. Hawkins, Uta Dirksen, Ian J. Lewis, Stefano Ferrari, Marie-Cecile Le Deley, Heinrich Kovar, Robert Grimer, Jeremy Whelan, Line Claude, Olivier Delattre, Michael Paulussen, Piero Picci, Kirsten Sundby Hall, Hendrik van den Berg, Ruth Ladenstein, Jean Michon, Lars Hjorth, Ian Judson, Roberto Luksch, Mark L. Bernstein, Perrine Marec-Bérard, Bernadette Brennan, Alan W. Craft, Richard B. Womer, Heribert Juergens, Odile Oberlin
Journal: Journal of Clinical Oncology (2015)

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.
The "Murmur on Top of the Head" in Acquired Mitral Insufficiency
Authors: K. Alvin Merendino
Journal: JAMA (1967)

A "murmur on top of the head" has been documented in seven patients with mitral insufficiency. Five patients revealed ruptured chordae tendineae of anterior leaflets secondary to rheumatic fever or subacute bacterial endocarditis. Two remaining patients exhibited rheumatic valvulitis and annular dilatation. The regurgitation was readily corrected by excising or plicating the flail area or posteromedial annuloplasty, or both. Survivors are asymptomatic without embolization or infection. Whether due to ruptured chordae of the aortic leaflet (usual) or valvulitis and annular dilatation (and in the absence of valvular calcification by fluoroscopy), the problem has been correctable by iow-risk reconstructive procedures without need for prosthetic valve replacement. Therefore, when this murmur is present, valuable inferences regarding etiology, pathology, surgical therapy, and prognosis can be made.
Clinical and cost-effectiveness of cognitive behaviour therapy for health anxiety in medical patients: a multicentre randomised controlled trial
Authors: Peter Tyrer, Sylvia Cooper, Paul Salkovskis, Helen Tyrer, Michael Crawford, Sarah Byford, Simon Dupont, Sarah Finnis, John Green, Elenor McLaren, David Murphy, Steven Reid, Georgina Smith, Duolao Wang, Hilary Warwick, Hristina Petkova, Barbara Barrett
Journal: The Lancet (2013)
Non–Mannose-capped Lipoarabinomannan Induces Lung Inflammation via Toll-like Receptor 2
Authors: Catharina W. Wieland, Sylvia Knapp, Sandrine Florquin, Alex F. de Vos, Kiyoshi Takeda, Shizuo Akira, Douglas T. Golenbock, Annelies Verbon, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Non-mannose-capped lipoarabinomannan (AraLAM) is part of the cell membrane of atypical mycobacteria. To determine the capacity of AraLAM to induce lung inflammation in vivo and to determine the signaling receptors involved herein, wild-type (WT) mice, lipopolysaccharide binding protein knockout mice, CD14-deficient (CD14 KO) mice, Toll-like receptor (TLR) 4 mutant mice, or TLR2 KO mice were intranasally inoculated with purified AraLAM. AraLAM induced high lung levels of tumor necrosis factor, interleukin-1beta, interleukin-6, and cytokine-induced neutrophil chemoattractant (KC) and an influx of neutrophils into the pulmonary compartment of WT mice. Lipopolysaccharide binding protein knockout, CD14 KO, and TLR4 mutant mice displayed similar inflammatory responses as WT mice, whereas in TLR2 KO mice, AraLAM-induced lung inflammation was strongly diminished. In addition, TLR2 KO mice, but not CD14 KO or TLR4 mutant mice, displayed a delayed clearance of pulmonary infection with the atypical AraLAM expressing Mycobacterium smegmatis. These data indicate that TLR2 is the signaling receptor for purified AraLAM in the lung in vivo and that this receptor contributes to an effective clearance of M. smegmatis from the pulmonary compartment.
Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study
Authors: Alex Iranzo, Francesc Valldeoriola, Francisco Lomeña, José Luis Molinuevo, Mónica Serradell, Manel Salamero, Albert Cot, Domènec Ros, Javier Pavía, Joan Santamaria, Eduardo Tolosa
Journal: The Lancet Neurology (2011)
Muscular Dystrophy
Authors: S. GAILANI, T. S. DANOWSKI, D. S. FISHER
Journal: Circulation (1958)

In an attempt to explain the electrocardiographic and other cardiac abnormalities in patients with muscular dystrophy, hemodynamic studies by right heart catheterization were done on 12 patients with muscular dystrophy. The study indicated the presence of latent congestive failure in some patients. An attempt to explain the abnormal QRS complexes and leads from the right side of the precordium in some of those patients is also made.