tbuckley/cabot-search huggingface dataset:
CD8+ T Cells Regulate Bone Tumor Burden Independent of Osteoclast Resorption
Authors: Kaihua Zhang, Seokho Kim, Viviana Cremasco, Angela C. Hirbe, Deborah V. Novack, Katherine Weilbaecher, Roberta Faccio
Journal: Cancer Research (2011)

Abstract Blockade of osteoclast (OC) activity efficiently decreases tumor burden as well as associated bone erosion in immune-compromised animals bearing human osteolytic cancers. In this study, we showed that modulation of antitumor T-cell responses alters tumor growth in bone, regardless of OC status, by using genetic and pharmacologic models. PLCγ2−/− mice, with dysfunctional OCs and impaired dendritic cell (DC)–mediated T-cell activation, had increased bone tumor burden despite protection from bone loss. In contrast, Lyn−/− mice, with more numerous OCs and a hyperactive myeloid population leading to increased T-cell responses, had reduced tumor growth in bone despite enhanced osteolysis. The unexpected tumor/bone phenotype observed in PLCγ2−/− and Lyn−/− mice was transplantable, suggesting the involvement of an immune component. Consistent with this hypothesis, T-cell activation diminished skeletal metastasis whereas T-cell depletion enhanced it, even in the presence of zoledronic acid, a potent antiresorptive agent. Importantly, injection of antigen-specific wild-type cytotoxic CD8+ T cells in PLCγ2−/− mice or CD8+ T-cell depletion in Lyn−/− mice normalized tumor growth in bone. Our findings show the important contribution of CD8+ T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone. Cancer Res; 71(14); 4799–808. ©2011 AACR.
Costimulation Blockade with Belatacept in Renal Transplantation
Authors: Flavio Vincenti, Christian Larsen, Antoine Durrbach, Thomas Wekerle, Björn Nashan, Gilles Blancho, Philippe Lang, Josep Grinyo, Philip F. Halloran, Kim Solez, David Hagerty, Elliott Levy, Wenjiong Zhou, Kannan Natarajan, Bernard Charpentier
Journal: New England Journal of Medicine (2005)

Renal transplantation is the standard of care for patients with end-stage renal disease. Although maintenance immunosuppression with calcineurin inhibitors yields excellent one-year survival, it is associated over the long term with high rates of death and graft loss, owing in part to the adverse renal, cardiovascular, and metabolic effects of these agents. The use of potentially less toxic agents, such as belatacept, a selective blocker of T-cell activation, may improve outcomes.
Serial Diffusion MRI to Monitor and Model Treatment Response of the Targeted Nanotherapy CRLX101
Authors: Thomas S.C. Ng, David Wert, Hargun Sohi, Daniel Procissi, David Colcher, Andrew A. Raubitschek, Russell E. Jacobs
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation. Experimental Design: Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&amp;E) were conducted on tumor samples for correlation with imaging results. Results: CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = −5 ± 3%, −30 ± 4%, and −45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11–treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = −15 ± 5%, −22 ± 13%, and −26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02). Conclusions: Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics. Clin Cancer Res; 19(9); 2518–27. ©2013 AACR.
In Situ Carcinoma of the Breast
Authors: J L Connolly, J Boyages, S J Schnitt, A Recht, W Silen, N Sadowsky, J R Harris
Journal: Annual Review of Medicine (1989)

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is ...Read More
Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose
Authors: Peter C. Minneci, Katherine J. Deans, Steven M. Banks, Peter Q. Eichacker, Charles Natanson
Journal: Annals of Internal Medicine (2004)

Background: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied. Purpose: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials. Data Sources: Systematic MEDLINE search for studies published between 1988 and 2003. Study Selection: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements. Data Extraction: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes. Data Synthesis: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, [95% CI, 1.01 to 1.50]; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 [CI, 1.29 to 2.26]; P < 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 [CI, 0.82 to 0.97]; P = 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; P = 0.02), for longer courses (6 days vs. 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; P = 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02). Limitations: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results. Conclusions: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.
Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation
Authors: B. Vrugt, S. Wilson, A. Bron, J. Shute, S.T. Holgate, R. Djukanovic, R. Aalbers
Journal: European Respiratory Journal (2000)

The authors have investigated whether the steroid-sparing effect of methotrexate (MTX) in severe orally glucocorticoid-insensitive asthmatics may be accounted for by the ability of this drug to increase the T-cell responsiveness sensitivity to dexamethasone in vitro. In addition the authors have investigated whether low-dose MTX treatment is associated with anti-inflammatory effects in peripheral blood and the bronchial mucosa. In eight patients with severe atopic asthma, using > or =15 mg x day(-1) prednisolone, the inhibitory effect of dexamethasone on mitogen stimulated peripheral blood mononuclear cells (PBMC) in vitro was tested before and after 8 weeks of uncontrolled treatment with MTX. Endobronchial biopsies were taken before and after MTX therapy in seven subsequent patients, and analysed using immunohistochemistry. In eight patients, serum was drawn for measuring levels of free interleukin (IL)-8. The in vitro sensitivity of PBMC to dexamethasone (at 1.6 x 10(-9) and 3.2 x 10(-10) mol x L(-1)) was significantly lower in the asthmatics before treatment when compared with the control subjects (p=0.03 and =0.001) but increased significantly after MTX treatment (p=0.04 and =0.02) to normal responsiveness. This was not associated with a decrease in peripheral blood T-cell numbers or activation. Except for a significant increase in the numbers of CD3+ (p=0.04), no significant numerical changes in activated T-cells, eosinophils, or mast cells were found (p>0.05). However, MTX treatment was associated with a significant fall in serum levels of free IL-8 (p=0.03). It is hypothesized that the steroid-sparing effect of methotrexate originates from increased sensitivity of lymphocytes to the inhibitory effects of glucocorticoids. The absence of an inhibitory effect on inflammatory cells in blood and mucosa suggests that this effect is achieved by modulating cell function rather than cell number.
Concatenation and Concordance in the Reconstruction of Mouse Lemur Phylogeny: An Empirical Demonstration of the Effect of Allele Sampling in Phylogenetics
Authors: David W. Weisrock, Stacey D. Smith, Lauren M. Chan, Karla Biebouw, Peter M. Kappeler, Anne D. Yoder
Journal: Molecular Biology and Evolution (2012)

The systematics and speciation literature is rich with discussion relating to the potential for gene tree/species tree discordance. Numerous mechanisms have been proposed to generate discordance, including differential selection, long-branch attraction, gene duplication, genetic introgression, and/or incomplete lineage sorting. For speciose clades in which divergence has occurred recently and rapidly, recovering the true species tree can be particularly problematic due to incomplete lineage sorting. Unfortunately, the availability of multilocus or "phylogenomic" data sets does not simply solve the problem, particularly when the data are analyzed with standard concatenation techniques. In our study, we conduct a phylogenetic study for a nearly complete species sample of the dwarf and mouse lemur clade, Cheirogaleidae. Mouse lemurs (genus, Microcebus) have been intensively studied over the past decade for reasons relating to their high level of cryptic species diversity, and although there has been emerging consensus regarding the evolutionary diversity contained within the genus, there is no agreement as to the inter-specific relationships within the group. We attempt to resolve cheirogaleid phylogeny, focusing especially on the mouse lemurs, by employing a large multilocus data set. We compare the results of Bayesian concordance methods with those of standard gene concatenation, finding that though concatenation yields the strongest results as measured by statistical support, these results are found to be highly misleading. By employing an approach where individual alleles are treated as operational taxonomic units, we show that phylogenetic results are substantially influenced by the selection of alleles in the concatenation process.
PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma
Authors: Yu-Jen Chen, Hamish G. Campbell, Anna K. Wiles, Michael R. Eccles, Roger R. Reddel, Antony W. Braithwaite, Janice A. Royds
Journal: Cancer Research (2008)

Abstract Paired box (PAX) developmental genes are frequently expressed in cancers and confer survival advantages on cancer cells. We have previously found that PAX genes are deregulated in glioma. We have now investigated the expression of PAX genes in glioma and their role in telomere maintenance. The mRNA level of PAX8 showed a positive correlation with telomerase activity in glioma biopsies (r2 = 0.75, P &amp;lt; 0.001) and in established glioma cell lines (r2 = 0.97, P = 0.0025). We found that PAX8 is able to coordinately transactivate the promoter for both the telomerase catalytic subunit (hTERT) and the telomerase RNA component (hTR) genes. By electrophoretic mobility shift assay, quantitative PCR, and a telomerase activity assay, we show that PAX8 binds directly to the hTERT and hTR promoters, up-regulating hTERT and hTR mRNA, as well as telomerase activity. Additionally, PAX8 small interfering RNA down-regulated hTERT and hTR. Collectively, these results show that PAX8 may have a role in telomerase regulation. [Cancer Res 2008;68(14):5724–32]
Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico
Authors: Jochen Profit, Diana Lee, John A. Zupancic, LuAnn Papile, Cristina Gutierrez, Sue J. Goldie, Eduardo Gonzalez-Pier, Joshua A. Salomon
Journal: PLoS Medicine (2010)

Joshua Salomon and colleagues performed a cost-effectiveness analysis using health and economic outcomes following preterm birth in Mexico and showed that neonatal intensive care provided high value for the money in this setting.
Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis
Authors: R N Maini, P C Taylor, E Paleolog, P Charles, S Ballara, F M Brennan, M Feldmann
Journal: Annals of the Rheumatic Diseases (1999)

Preclinical studies based on in vitro cell systems and in vivo models had established a position for tumour necrosis factor (TNF) α as a pivotal molecule regulating cellular activation and interactions in rheumatoid inflammation by 1992. That neutralisation of TNFα has a profound impact on the biology of inflammation is reflected by the rapid reduction in the concentration of C reactive protein (CRP), an acute phase protein, associated with a fall in the level of its well known inducer, interleukin (IL) 6. This supports the hypothesis that TNFα is a critical part of a regulatory cytokine network.

The reduction in clinical signs of inflammation were soon shown by arthroscopic examination and synovial biopsies of knee joints to be a consequence of reduction in the density of infiltrating lymphocytes and macrophages. Circulating numbers of lymphocytes increased transiently after infliximab in a dose dependent fashion, associated with a reduction in soluble adhesion molecules E selectin, ICAM-1, and density of cells staining for these and VCAM-1 in synovial biopsies. The dynamics of cell trafficking have been examined by tracking the fate of the indium111 labelled polymorphonuclear cells injected intravenously in rheumatoid arthritis (RA) patients. These experiments show a reduction in uptake of radioactivity in joints after anti-TNF treatment indicating reduced adhesiveness and retention of the leucocytes in joints.

The results of anti-TNF treatment on the progression of damage to cartilage, bone and other connective tissue components is not yet established in RA, although in collagen induced arthritis in DBA/1 mice, joint protection was reported. Measurement of circulating matrix metalloproteinases, MMP-1 and MMP-3, in their inactive form, has been noted following infliximab in patients. Recently we have documented a reduction in raised concentrations of serum VEGF, an important angiogenic factor after infliximab treatment. More direct evidence of a reduction in angiogenesis has been …
Challenges and Opportunities in Measuring Cancer Recurrence in the United States
Authors: J. L. Warren, K. R. Yabroff
Journal: JNCI Journal of the National Cancer Institute (2015)

Cancer recurrence and disease-free survival are key outcomes for measuring the burden of illness, assessing the quality of cancer care, and informing decisions about increasingly costly cancer therapies. Yet information about recurrence is not collected in cancer registries or other population-based data sources. To address the lack of population-based recurrence information, researchers are increasingly using algorithms applied to health claims to infer recurrence. However, the validity of these approaches has not been comprehensively evaluated. In this commentary, we review existing studies and discuss options for improving the availability of recurrence data. We found that the validity of claims-based approaches appears promising in small, single institution studies, but larger population-based studies have identified substantial limitations with using claims to identify recurrence. With the increasing availability of health data, there are potential options that can be implemented to enhance information about recurrence. These options include design of software for the electronic medical record that enables rapid and standardized reporting of recurrence, use of electronic pathology reports to facilitate streamlined collection of recurrence by cancer registries, and mandates by insurers to require reporting of recurrence on health claims submitted by physicians. All of these options will require that governmental agencies, health insurers, professional societies, and other groups recognize the importance of population-based recurrence data and determine that this information is a priority for assessing cancer outcomes and costs.
Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation
Authors: Vanderson Rocha, Rendrik F. Franco, Raphaël Porcher, Henrique Bittencourt, Wilson A. Silva, Aurelien Latouche, Agnès Devergie, Hélène Espérou, Patricia Ribaud, Gérard Socié, Marco Antonio Zago, Eliane Gluckman
Journal: Blood (2002)
Hepatic damage associated with mineral oil deposits.
Authors: R W Blewitt, K Bradbury, M J Greenall, H Burrow
Journal: Gut (1977)

The case of a 33 year old male is reported. Hepatic inflammation and scarring were associated with deposits of mineral oil in portal triads. This is believed to be the first reported case of hepatic damage resulting from mineral oil accumulation. Possible sources of the oil are considered.
Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure
Authors: S. Kääb, J. Dixon, J. Duc, D. Ashen, M. Näbauer, D. J. Beuckelmann, G. Steinbeck, D. McKinnon, G. F. Tomaselli
Journal: Circulation (1998)

Background —Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K + currents—prominently, the Ca 2+ -independent transient outward current ( I to ). The mechanism for the reduction of I to in heart failure is unknown. The K + channel α-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I to in humans. Methods and Results —We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I to in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak I to density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied ( HERG , Kv1.4, Kir2.1, Kvβ1.3, and the α1C subunit of the Ca 2+ channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle. Conclusions —These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac I to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.
Is Skeletal Myoblast Transplantation Clinically Relevant in the Era of Angiotensin-Converting Enzyme Inhibitors?
Authors: Bruno Pouzet, Saïd Ghostine, Jean-Thomas Vilquin, Isabelle Garcin, Marcio Scorsin, Albert A. Hagège, Denis Duboc, Ketty Schwartz, Philippe Menasché
Journal: Circulation (2001)

There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors.A myocardial infarction was created in 99 rats by coronary artery ligation. They were divided into 4 groups. Two groups did not receive any drug and were intramyocardially injected 7 days after the infarct with either culture medium alone (control rats, n=16) or autologous SM cells (2.3x10(6) myoblasts) previously expanded ex vivo for 7 days (myoblasts, n=24). Two other groups received the ACE inhibitor perindoprilat (1 mg. kg(-1). d(-1)), started the day of the infarct and continued uninterruptedly thereafter, and underwent time-matched procedures, that is, they were intramyocardially injected at 7 days after infarction with either culture medium alone (ACE inhibitors, n=22) or autologous SM cells (2.5x10(6) myoblasts) previously expanded ex vivo for 7 days (ACE inhibitors+myoblasts, n=37). Left ventricular function was assessed by 2D echocardiography. At the end of the 2-month study, left ventricular ejection fraction (%, mean+/-SEM) was increased in all groups (myoblasts, 37.4+/-1.2; ACE inhibitors, 31.6+/-1.7; ACE inhibitors+myoblasts, 43.9+/-1.4) compared with that in control rats (19.8+/-0.7) (P<0.0001). The improvement in ejection fraction was similar in the ACE inhibitor and the myoblast groups (31.6+/-1.7 versus 37.4+/-1.2, P=0.0636). However, in the ACE inhibitor+myoblast group, this improvement was greater than that seen in hearts receiving either treatment alone (43.9+/-1.4 versus 31.6+/-1.7 in the ACE inhibitor group and 43.9+/-1.4. versus 37.4+/-1.2 in the myoblast group, P<0.0001 and P=0.0084, respectively).These data provide further support for the clinical relevance of autologous SM cell transplantation in that its cardioprotective effects are additive to those observed with ACE inhibitors.