tbuckley/cabot-search huggingface dataset:
Advances in Ewing's Sarcoma Research: Where Are We Now and What Lies Ahead?
Authors: José Luis Ordóñez, Daniel Osuna, David Herrero, Enrique de Álava, Juan Madoz-Gúrpide
Journal: Cancer Research (2009)

Ewing's sarcoma family tumors (EFT) are characterized by specific chromosomal translocations, which lead to EWS/ETS transcription factors. Elucidation of EWS/ETS target gene networks within the context of other signaling pathways, together with the identification of the initiating cell, and the development of genetically engineered mice will hopefully lead to biology-based therapeutic strategies for these tumors.
The Health Care Workforce: Will It Be Ready as the Boomers Age? A Review of How We Can Know (or Not Know) the Answer
Authors: Thomas C. Ricketts
Journal: Annual Review of Public Health (2011)

The baby-boom generation will reach the age of eligibility for Medicare starting in 2011. This large group of Americans will require more health care, and more health care workers will be needed to meet those needs. Understanding the needs as well as the size of the workforce needed requires substantial analysis and extensive data. Two major approaches can be used to make these estimates, and the choice of both methods and assumptions can affect the outcomes of any analysis. For the United States to make workforce policy decisions with the best information, we must invest in systems and resources to generate those data and support policy-making bodies that can interpret and make recommendations consistent with the analyses.
Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives
Authors: M. Joossens, G. Huys, M. Cnockaert, V. De Preter, K. Verbeke, P. Rutgeerts, P. Vandamme, S. Vermeire
Journal: Gut (2011)

<h3>Background and aims</h3> A general dysbiosis of the intestinal microbiota has been established in patients with Crohn9s disease (CD), but a systematic characterisation of this dysbiosis is lacking. Therefore the composition of the predominant faecal microbiota of patients with CD was studied in comparison with the predominant composition in unaffected controls. Whether dysbiosis is present in relatives of patients CD was also examined. <h3>Methods</h3> Focusing on families with at least three members affected with CD, faecal samples of 68 patients with CD, 84 of their unaffected relatives and 55 matched controls were subjected to community fingerprinting of the predominant microbiota using denaturing gradient gel electrophoresis (DGGE). To analyse the DGGE profiles, BioNumerics software and non-parametric statistical analyses (SPSS V.17.0) were used. Observed differences in the predominant microbiota were subsequently confirmed and quantified with real-time PCR. <h3>Results</h3> Five bacterial species characterised dysbiosis in CD, namely a decrease in <i>Dialister invisus</i> (p=0.04), an uncharacterised species of <i>Clostridium</i> cluster XIVa (p=0.03), <i>Faecalibacterium prausnitzii</i> (p&lt;1.3×10<sup>−5</sup>) and <i>Bifidobacterium adolescentis</i> (p=5.4×10<sup>−6</sup>), and an increase in <i>Ruminococcus gnavus</i> (p=2.1×10<sup>−7</sup>). Unaffected relatives of patients with CD had less <i>Collinsella aerofaciens</i> (p=0.004) and a member of the <i>Escherichia coli–Shigella</i> group (p=0.01) and more <i>Ruminococcus torques</i> (p=0.02) in their predominant microbiota as compared with healthy subjects. <h3>Conclusion</h3> Unaffected relatives of patients with CD have a different composition of their microbiota compared with healthy controls. This dysbiosis is not characterised by lack of butyrate producing-bacteria as observed in CD but suggests a role for microorganisms with mucin degradation capacity.
Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans
Authors: Stefano Romeo, Wu Yin, Julia Kozlitina, Len A. Pennacchio, Eric Boerwinkle, Helen H. Hobbs, Jonathan C. Cohen
Journal: Journal of Clinical Investigation (2008)

The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat storage (adipose tissue) and oxidation (heart and skeletal muscle). Here we used a reverse genetic strategy to test the hypothesis that 4 angiopoietin-like proteins (ANGPTL3, -4, -5, and -6) play key roles in triglyceride (TG) metabolism in humans. We re-sequenced the coding regions of the genes encoding these proteins and identified multiple rare nonsynonymous (NS) sequence variations that were associated with low plasma TG levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL3 and ANGPTL4 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL protein to inhibit LPL. A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma TG in the lowest quartile had a rare loss-of-function mutation in ANGPTL3, ANGPTL4, or ANGPTL5. Thus, ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in TG metabolism, and multiple alleles at these loci cumulatively contribute to variability in plasma TG levels in humans.
The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis
Authors: Yolanta Kruszynska, Nicholas Williams, Michael Perry, Philip Home
Journal: Hepatology (1988)

We have examined the hypothesis that insulin insensitivity in hepatic cirrhosis is related to abnormalities of glycogen deposition and skeletal muscle enzyme activities. Otherwise well patients with biopsy-proven hepatic cirrhosis secondary to previous excess alcohol intake were studied. Prior to study, in basal state, patients had identical blood glucose concentrations but raised serum insulin concentrations (cirrhotic: 8.5 +/- 0.8 mU per liter; matched control subjects: 5.7 +/- 0.5 mU per liter, p less than 0.01). Muscle glycogen content, glycogen synthase activity and pyruvate dehydrogenase activity were normal in the basal state. The cirrhotic patients required less glucose to maintain the clamp in response to 0.1 unit per kg per hr insulin (6.7 +/- 0.5 vs. control 8.3 +/- 0.4 mg per kg per min, p less than 0.05) and deposited less glycogen in muscle during the clamp (8.6 +/- 0.5 vs. 12.0 +/- 1.4 mg per gm protein, p less than 0.05). Glycogen deposition correlated with clamp glucose requirement in the cirrhotic patients (r = 0.78, p less than 0.05). The expressed activity of glycogen synthase activity was significantly lower in cirrhotic patients at the end of the clamp (26.5 +/- 1.1% vs. 30.9 +/- 1.6%) and again correlated with clamp glucose requirement (r = 0.82, p less than 0.05). Skeletal muscle pyruvate dehydrogenase activity was not different in patients and control subjects. Insulin insensitivity in hepatic cirrhosis appears to be related to abnormalities of glucose deposition as glycogen in skeletal muscle.
Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types
Authors: Paolo A. Ascierto, Michael Kalos, David A. Schaer, Margaret K. Callahan, Jedd D. Wolchok
Journal: Clinical Cancer Research (2013)

Abstract Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising new approach of immunotherapy for cancer. The recent approval of the CTLA-4–blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IV melanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti-GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success. Clin Cancer Res; 19(5); 1009–20. ©2013 AACR.
Can studies of tolerance ever lead to therapy?
Authors: H von Boehmer
Journal: Annals of the Rheumatic Diseases (2006)

Studies in murine models have suggested that regulatory T (Treg) cells can be generated by any antigen and such antigen specific Treg cells not only prevent but also reverse unwanted immunity. Another key finding of these experimental studies is that Treg cells could possibly be used therapeutically to ameliorate disease because of their ability to interfere with the execution of effector programmes of fully differentiated T effector cells. However, more work is needed before these findings can be safely translated into better targeted therapy and prevention of unwanted immune responses in clinical settings.
Twenty Years' Work in the Samaritan Hospital, 1857-1877
Authors: T. S. Wells
Journal: BMJ (1877)

GENTLEMEN,-The operation I have just performed is the last I shall undertake in this Hospital, unless I do another next Wednesday, the 1gth.There have been a few parietal and omental adhesions; but you have seen that a very few minutes-hardly more than a quarter of an hour-have been enough to complete the whole process, in com- plete silence, and without any hurry.Dr. Tweedie, one of our oldest physicians, but as young and active, apparently, as ever, has watched this proceeding with as much interest as a boy.The two cases I did last week you will see presently; one done the week before, two others by Dr. Bantock and Mr. Thornton, and a patient in process of recovery after draining a renal cyst--all encouraging results of less than a month's work.
From extreme emotions to extreme actions: Explaining non-normative collective action and reconciliation
Authors: Allard R. Feddes, Liesbeth Mann, Bertjan Doosje
Journal: Behavioral and Brain Sciences (2012)

Abstract A key argument of Dixon et al. in the target article is that prejudice reduction through intergroup contact and collective action work in opposite ways. We argue for a complementary approach focusing on extreme emotions to understand why people turn to non-normative collective action and to understand when and under what conditions extreme emotions may influence positive effects of contact on reconciliation.
INHIBITION OF NITRIC OXIDE SYNTHASE AS A POTENTIAL THERAPEUTIC TARGET
Authors: Adrian J. Hobbs, Annie Higgs, Salvador Moncada
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract Nitric oxide (NO) regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states. This provides the rationale for the design of therapies that modulate NO concentrations selectively. A well-characterized family of compounds are the inhibitors of NO synthase, the enzyme responsible for the generation of NO; such agents are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including septic shock, neurodegenerative disorders, and inflammation. This article provides an overview of NO synthase inhibitors, focusing on agents that prevent binding of substrate l-arginine.
Engagement of Transferrin Receptor by Polymeric IgA1
Authors: Ivan C. Moura, Michelle Arcos-Fajardo, Abdelaziz Gdoura, Vale[Combining Acute Accent]rie Leroy, Charlotte Sadaka, Nizar Mahlaoui, Yves Lepelletier, Franc[COMBINING CEDILLA]ois Vrtovsnik, Elie Haddad, Marc Benhamou, Renato C. Monteiro
Journal: Journal of the American Society of Nephrology (2005)

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.
Spiral computed tomography of pulmonary embolism
Authors: C.J. Herold
Journal: European Respiratory Journal (2002)

Within the last several years, spiral computed tomography angiography (SCTA) of the pulmonary arteries has emerged as a noninvasive angiographic modality for the evaluation of patients with suspected pulmonary embolism (PE). SCTA is based on continuous computed tomography (CT) data acquisition during patient transport through the rotating X-ray tube and detector system, where scanning is performed in the time period in which the injected contrast material passes through the pulmonary arteries. Single detector spiral CT has a sensitivity of approximately 85-90% and a specificity between 88-95%. Sensitivity and specificity are very likely to increase with the use of multidetector spiral CT scanners that allow scanning of large lung volumes with a scan collimation as narrow as 1 mm. Currently, SCTA is most commonly used as a primary imaging method in patients with suspected PE, and as a second-line method in cases with inconclusive ventilation/ perfusion scintigraphy results. SCTA has proven to be cost-effective, especially in combination with ultrasound of the lower extremities. Limitations of the method include a decreased sensitivity for the detection of small isolated clots in the peripheral pulmonary arterial bed, and a potentially reduced image quality in patients with coexistent cardiopulmonary disorders. Despite these limitations, several studies have now documented that, in patients with suspected pulmonary embolism, it is safe to withhold anticoagulation therapy if a spiral computed tomography exam of the pulmonary arteries is negative and no lower extremity venous thrombosis is present. In the future, multislice computed tomography scanning of the pulmonary arteries with multiplanar reformation and one-stop shopping, i.e. scanning of the pulmonary arteries and the lower extremity veins in a single session, will further enhance the role of computed tomography angiography in the examination of patients with suspected pulmonary embolism.
Prediction of Doxorubicin Resistance In Vitro in Myeloma, Lymphoma, and Breast Cancer by P-Glycoprotein Staining
Authors: S. E. Salmon, T. M. Grogan, T. Miller, R. Scheper, W. S. Dalton
Journal: JNCI Journal of the National Cancer Institute (1989)

Prior studies have shown that the p-glycoprotein is ac cell membrane efflux pump that is quantitavely increased in expression in multidrug-resistant tumor cell lines. In this study, fresh tumor tissues from patients with multiple myeloma, malignant lymphoma, or metastatic breast cancer were studied immunohistochemically for P-glycoprotein expression and for in vitro sensitivity to doxourbicin. Twenty-six patients who were either previously untreated or in relapse after chemotherapy had tumor specimens submitted that could be evaluated in both assays. The testing was done independently and blindly in separate laboratories instead of our being provided relevant clinical data on the patients. Tumor cells from 12 of the 26 patients (46%) stained positively for P-glycoprotein. Fifteen of the 26 specimens (58%) exhibited drug resistance in vitro. Although only three (21%) of the 14 p-glycoprotein-negative tumors exhibited in vitro resistance to doxourbicin, all 12 fresh tumors that stained positively for P-glycoprotein were resistant to doxourbicin. The difference in frequency of intrinsic doxourbicin resistance between P-glycoprotein-negative and-positive tumors was highly significant (P<.001).Similar trends were observed in each of the individual tumor categories and were statistically significant in myeloma and breast cancer. Four of he biopsy specimens that stained positively for P-glycoprotein and exhibited doxorubicin resistance were from patients who had not received prior cytotoxic chemotherapy. Similar conclusions were reached when results of drug sensitivity tests were ranked in relation to the median infective dose rather than by criteria based on correlations with clinical drug resistance. Our findings indicate that positive staining for P-glucoprotein associated with multidrug resistance predicts intrinsic cellular resistance of human cancers to doxourbicin. We anticipate that immunohistochemical staining for P-glucoprotein will prove useful in clinical oncology. [J Natl Cancer Inst 81:696–701, 1989]
CD8+ T cells respond clonally to Mls-1a-encoded determinants.
Authors: H R MacDonald, R K Lees, Y Chvatchko
Journal: The Journal of Experimental Medicine (1990)

T cell responses to the product of the minor lymphocyte stimulatory locus Mls-1a involve the selective use of TCR V beta domains (especially V beta 6 and V beta 8.1) and are generally considered to be restricted to the CD4+ mature subset. We show here that CD8+ (presumably MHC class I-restricted) T cells bearing V beta 6 or V beta 8.1 also respond preferentially to Mls-1a determinants either in vitro (in mixed leukocyte cultures) or in vivo (in an adoptive transfer system). In vitro responses of both CD4+ V beta 6+ and CD8+ V beta 6+ cells to Mls-1a were dependent upon the MHC haplotype of the stimulator cells, with I-E+ (H-2d or H-2k) alleles being much more stimulatory than I-E- (H-2q). These data strengthen the analogy between Mls gene products and other MHC class II-dependent superantigens such as the bacterial enterotoxins.
Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation
Authors: Tohru Morisada, Yuichi Oike, Yoshihiro Yamada, Takashi Urano, Masaki Akao, Yoshiaki Kubota, Hiromitsu Maekawa, Yoshishige Kimura, Masako Ohmura, Takeshi Miyamoto, Shiro Nozawa, Gou Young Koh, Kari Alitalo, Toshio Suda
Journal: Blood (2005)
Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data
Authors: N.M. van den Boogaard, A.J. Bensdorp, K. Oude Rengerink, K. Barnhart, S. Bhattacharya, I.M. Custers, C. Coutifaris, A.J. Goverde, D.S. Guzick, E.C. Hughes, P. Factor-Litvak, P. Steures, P.G.A. Hompes, F. van der Veen, B.W.J. Mol, P. Bossuyt
Journal: Human Reproduction Update (2013)

At present, it is unclear which treatment strategy is best for couples with unexplained or mild male subfertility. We hypothesized that the prognostic profile influences the effectiveness of assisted conception. We addressed this issue by analysing individual patient data (IPD) from randomized controlled trials (RCTs).We performed an IPD analysis of published RCTs on treatment strategies for subfertile couples. Eligible studies were identified from Cochrane systematic reviews and we also searched Medline and EMBASE. The authors of RCTs that compared expectant management (EM), intracervical insemination (ICI), intrauterine insemination (IUI), all three with or without controlled ovarian stimulation (COS) and IVF in couples with unexplained or male subfertility, and had reported live birth or ongoing pregnancy as an outcome measure, were invited to share their data. For each individual patient the chance of natural conception was calculated with a validated prognostic model. We constructed prognosis-by-treatment curves and tested whether there was a significant interaction between treatment and prognosis.We acquired data from 8 RCTs, including 2550 couples. In three studies (n = 954) the more invasive treatment strategies tended to be less effective in couples with a high chance of natural conception but this difference did not reach statistical significance (P-value for interaction between prognosis and treatment outcome were 0.71, 0.31 and 0.19). In one study (n = 932 couples) the strategies with COS (ICI and IUI) led to higher pregnancy rates than unstimulated strategies (ICI 8% versus 15%, IUI 13% versus 22%), regardless of prognosis (P-value for interaction in all comparisons >0.5), but at the expense of a high twin rate in the COS strategies (ICI 6% versus 23% and IUI 3% versus 30%, respectively). In two studies (n = 373 couples), the more invasive treatment strategies tended to be more effective in couples with a good prognosis but this difference did not reach statistical significance (P-value for interaction: 0.38 and 0.68). In one study (n = 253 couples) the differential effect of prognosis on treatment effect was limited (P-value for interaction 0.52), perhaps because prognosis was incorporated in the inclusion criteria. The only study that compared EM with IVF included 38 couples, too small for a precise estimate.In this IPD analysis of couples with unexplained or male subfertility, we did not find a large differential effect of prognosis on the effectiveness of fertility treatment with IUI, COS or IVF.
671 SERPINB3 INCREASES RESISTANCE TO CISPLATIN- OR DOXORUBICIN-INDUCED CELL DEATH IN HEPATOMA CELLS THROUGH DEREGULATION OF PERMEABILITY TRANSITION PORE
Authors: F. Ciscato, M. Sciacovelli, M. Ruvoletto, S. Çmarta, P. Bernardi, A. Rasola, A. Gatta, P. Pontisso
Journal: Journal of Hepatology (2011)