tbuckley/cabot-search huggingface dataset:
Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion
Authors: Tammy L. Sirich, Benjamin A. Funk, Natalie S. Plummer, Thomas H. Hostetter, Timothy W. Meyer
Journal: Journal of the American Society of Nephrology (2013)

Dialytic clearance of urea is efficient, but other small solutes normally secreted by the kidney may be cleared less efficiently. This study tested whether the high concentrations of these solutes in hemodialysis patients reflect a failure of passive diffusion methods to duplicate the efficacy of clearance by tubular secretion. We compared the plasma concentrations and clearance rates of four solutes normally cleared by tubular secretion with the plasma concentrations and clearance rates of urea and creatinine in patients receiving maintenance hemodialysis and normal subjects. The predialysis concentrations (relative to normal subjects) of unbound phenylacetylglutamine (122-fold), hippurate (108-fold), indoxyl sulfate (116-fold), and p-cresol sulfate (41-fold) were much greater than the concentrations of urea (5-fold) and creatinine (13-fold). The dialytic clearance rates (relative to normal subjects) of unbound phenylacetylglutamine (0.37-fold), hippurate (0.16-fold), indoxyl sulfate (0.21-fold), and p-cresol sulfate (0.39-fold) were much lower than the rates of urea (4.2-fold) and creatinine (1.3-fold). Mathematical modeling showed that prominent accumulation of the normally secreted solutes in hemodialysis patients could be accounted for by lower dialytic clearance relative to physiologic clearance combined with the intermittency of treatment. Whether or not more efficient removal of normally secreted solutes improves outcomes in dialysis patients remains to be tested.
HEREDITARY BRACHYDACTYLIA AND ALLIED ABNORMALITIES IN THE RABBIT
Authors: Harry S. N. Greene, John A. Saxton
Journal: The Journal of Experimental Medicine (1939)

A series of deformities in the rabbit ranging from brachydactylia to acheiropodia have been described. Experimental breeding demonstrated that the occurrence of the deformities was determined by simple recessive hereditary factors and that the various types were genetically related and were not distinct hereditary entities. Embryological investigation showed the first abnormal change was a dilatation of blood vessels in affected buds. This was followed by hemorrhage and necrosis of the parts involved. Sloughing subsequently occurred, and the deformity was completely expressed by the 25th day of fetal life.
Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non–Small-Cell Lung Cancer
Authors: Ibrahim S. Aljada, Nithya Ramnath, Kathleen Donohue, Shashi Harvey, John J. Brooks, Sam M. Wiseman, Thaer Khoury, Gregory Loewen, Harry K. Slocum, Timothy M. Anderson, Gerold Bepler, Dongfeng Tan
Journal: Journal of Clinical Oncology (2004)

Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been shown that TIMP-1 may be a multifunctional protein. Little is known about the role of TIMP-1 in progression and metastasis of human lung cancer (tumor inhibiting or tumor promoting), although studies using a variety of techniques have analyzed the expression of TIMP-1 mRNA and/or protein in human cancers.We examined the expression of TIMP-1 protein by immunohistochemistry in patients (n = 160) with primary respectable (stage I to IIIA) non-small-cell lung cancer (NSCLC).Twenty-seven percent of the tumors (43 of 160) demonstrated elevated expression of this protein. We demonstrate that overexpression of TIMP-1 protein is associated with an adverse outcome. In addition, disease stage, patient's age, and performance status were all significantly related to survival. In multivariate analyses, patients with high TIMP-1 expression had a 90% increased risk of death when compared with those with low expression (relative risk, 1.92; 95% CI, 1.19 to 3.09; P =.008). TIMP-1 expression did not correlate with expression of MMP-2 and MMP-9.These results suggest that TIMP-1, independent of its inhibiting activity of MMPs, may have other function(s) critical for NSCLCs. The significance of our results is two-fold. The adverse outcome in patients with overexpression of TIMP-1 indicates its potential prognostic value in NSCLC. Thus, TIMP-1 overexpression may serve to help identify patients with particularly aggressive disease for adjuvant treatments. In addition, the TIMP-1 molecule may represent a novel therapeutic target for treatment of some NSCLCs.
G2A Deficiency in Mice Promotes Macrophage Activation and Atherosclerosis
Authors: David T. Bolick, Marcus D. Skaflen, Laura E. Johnson, Seong-Chun Kwon, Deborah Howatt, Alan Daugherty, Kodi S. Ravichandran, Catherine C. Hedrick
Journal: Circulation Research (2008)

G2A is a stress-inducible G protein-coupled receptor that is expressed on several cell types within atherosclerotic lesions. We demonstrated previously that G2A deficiency in mice increased aortic monocyte recruitment and increased monocyte:endothelial interactions. To investigate the impact of G2A deficiency in macrophages, we isolated peritoneal macrophages from G2A(+/+)ApoE(-/-) and G2A(-/-)ApoE(-/-) mice. G2A(-/-)ApoE(-/-) macrophages had significantly lower apoptosis than control macrophages. The prosurvival genes BCL-2, BCL-xL, and cFLIP were increased in G2A(-/-)ApoE(-/-) macrophages. Macrophages from G2A(-/-)ApoE(-/-) mice also had increased proinflammatory status that was indicative of a M1 macrophage phenotype. This was indicated by significantly increased nuclear translocation of nuclear factor kappaB, as well as production of interleukin-12p40, tumor necrosis factor alpha, and interleukin-6, and reduced expression of arginase-I. Moreover, G2A(-/-)ApoE(-/-) macrophages had reduced ability to engulf apoptotic cells in vitro. We examined atherosclerosis in mice fed a Western diet for 10 weeks and found that G2A deficiency increased lesion size in the aortic root by 50%. Plasma lipid levels were not changed in G2A(-/-)ApoE(-/-) mice. However, we found that absence of G2A increased the number of aortic macrophages and attenuated apoptosis in this cell type. Moreover, bone marrow transplantation studies indicated that deficiency of G2A in marrow-derived cells significantly contributed to atherosclerosis development. In the absence of G2A, increased macrophage activation and decreased apoptosis is associated with accumulation of macrophages in the aorta and increased atherosclerosis.
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update
Authors: Josef S Smolen, Robert Landewé, Johannes Bijlsma, Gerd Burmester, Katerina Chatzidionysiou, Maxime Dougados, Jackie Nam, Sofia Ramiro, Marieke Voshaar, Ronald van Vollenhoven, Daniel Aletaha, Martin Aringer, Maarten Boers, Chris D Buckley, Frank Buttgereit, Vivian Bykerk, Mario Cardiel, Bernard Combe, Maurizio Cutolo, Yvonne van Eijk-Hustings, Paul Emery, Axel Finckh, Cem Gabay, Juan Gomez-Reino, Laure Gossec, Jacques-Eric Gottenberg, Johanna M W Hazes, Tom Huizinga, Meghna Jani, Dmitry Karateev, Marios Kouloumas, Tore Kvien, Zhanguo Li, Xavier Mariette, Iain McInnes, Eduardo Mysler, Peter Nash, Karel Pavelka, Gyula Poór, Christophe Richez, Piet van Riel, Andrea Rubbert-Roth, Kenneth Saag, Jose da Silva, Tanja Stamm, Tsutomu Takeuchi, René Westhovens, Maarten de Wit, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at &gt;50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR9s most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
Reg4 protects against acinar cell necrosis in experimental pancreatitis
Authors: G. Hu, J. Shen, L. Cheng, C. Guo, X. Xu, F. Wang, L. Huang, L. Yang, M. He, D. Xiang, S. Zhu, M. Wu, Y. Yu, W. Han, X. Wang
Journal: Gut (2010)

<h3>Background and aims</h3> Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental pancreatitis. <h3>Methods</h3> AP was induced in C57BL/6 mice by administration of either l-arginine or caerulein, and Reg4 expression was assessed by immunofluorescence, reverse transcriptase (RT)-PCR and western blot analyses. Recombinant human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by subcutaneous injection. The severity of AP was determined by measuring amylase and lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with l-arginine. <h3>Results</h3> Reg4 mRNA and protein were markedly upregulated during arginine-induced pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against arginine-induced necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the caerulein-induced murine model of AP. It was shown that arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell necrosis in isolated pancreatic acinar cells. <h3>Conclusions</h3> The data suggest that Reg4 may protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.
<i>NF2</i> Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition
Authors: Maria E.R. Garcia-Rendueles, Julio C. Ricarte-Filho, Brian R. Untch, Iňigo Landa, Jeffrey A. Knauf, Francesca Voza, Vicki E. Smith, Ian Ganly, Barry S. Taylor, Yogindra Persaud, Gisele Oler, Yuqiang Fang, Suresh C. Jhanwar, Agnes Viale, Adriana Heguy, Kety H. Huberman, Filippo Giancotti, Ronald Ghossein, James A. Fagin
Journal: Cancer Discovery (2015)

Abstract Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP–TEAD transcriptional program. We find that the three RAS genes are themselves YAP–TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP–TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. Significance: Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors. Cancer Discov; 5(11); 1178–93. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1111
New Insights Into BDNF Signaling: Relevance to Major Depression and Antidepressant Action
Authors: Ilan A. Kerman
Journal: American Journal of Psychiatry (2012)

AlaMajor depressive disorder is a serious multifactorial mental illness that is characterized by disruptions in multiple symptom domains, including affect, reward, suicidality, cognition, and homeostasis (1).According to the National Institute of Mental Health, it is the leading cause of disability for individuals 15-44 years old, affecting 18.4 million Americans (or 6.7% of the adult population) each year (2).Its prevalence is higher in women, who often report more severe symptoms and longer illness duration.Only 36.8% of patients achieve remission in response to first-line treatment, and a cumulative total of 67% achieve remission following multiple treatment trials that may take several months or years (3).Given its burden of disease, it is imperative that we improve our understanding of the pathophysiology of major depression, with the hope of developing more efficacious treatments.
High-dose mitoxantrone–vinblastine–cyclophosphamide and autologous stem cell transplantation for stage III breast cancer: final results of a prospective multicentre study
Authors: D.A. Stewart, A.H.G. Paterson, J.D. Ruether, J. Russell, P. Craighead, M. Smylie, J. Mackey
Journal: Annals of Oncology (2005)
Antiviral Therapy of HIV Infection
Authors: Douglas D. Richman
Journal: Annual Review of Medicine (1991)

In only five years, antiretroviral therapy progressed from promising in vitro results with a newly recognized virus (HIV) to the standard practice of primary care applicable to hundreds of thousands of patients. With AZT (zidovudine) we have learned that we can prolong survival, reduce morbidity, and delay the progression of asymptomatic infection to disease. We have also learned that doses of AZT lower than those used in the original studies are as effective but less toxic. Additional compounds are under evaluation and more are needed to provide regimens, probably as combinations of drugs, that can be administered chronically with more efficacy, less toxicity, and diminished likelihood to select for drug-resistant virus.
Pancreatic Steatosis and Its Relationship to β-Cell Dysfunction in Humans
Authors: Lidia S. Szczepaniak, Ronald G. Victor, Ruchi Mathur, Michael D. Nelson, Edward W. Szczepaniak, Nicole Tyer, Ida Chen, Roger H. Unger, Richard N. Bergman, Ildiko Lingvay
Journal: Diabetes Care (2012)

To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans.We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels.Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R(2) = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R(2) = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R(2) = 0.32).In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population.
Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS): Table 1
Authors: David Couper, Lisa M LaVange, MeiLan Han, R Graham Barr, Eugene Bleecker, Eric A Hoffman, Richard Kanner, Eric Kleerup, Fernando J Martinez, Prescott G Woodruff, Stephen Rennard
Journal: Thorax (2013)

Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) is a multicentre observational study of chronic obstructive pulmonary disease (COPD) designed to guide future development of therapies for COPD by providing robust criteria for subclassifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, and identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials. The goal is to enrol 3200 participants in four strata. Participants undergo a baseline visit and three annual follow-up examinations, with quarterly telephone calls. Adjudication of exacerbations and mortality will be undertaken.
A prospective study of injuries and training amongst the England 2003 Rugby World Cup squad
Authors: J H M Brooks, C W Fuller, S P T Kemp, D B Reddin
Journal: British Journal of Sports Medicine (2005)

Objectives: To assess the aetiology, incidence, severity, and causes of injuries to England rugby union players during preparation for and participation in the 2003 Rugby World Cup. Method: A 63 week prospective design was employed to study the training practices and injuries of England rugby players. The team physician reported all training and match injuries and provided details of the location, diagnosis, severity, and mechanism of each injury. The team fitness coach reported details of the number and duration of training sessions and the time dedicated to rugby and conditioning training. Players’ stature, body mass, and skinfolds were measured at the beginning and end of the study period. Results: The overall incidence of injury was 17 injuries/1000 h of exposure (match: 218 injuries/1000 h; training: 6.1 injuries/1000 h). The major locations of injuries were the lower (60%) and upper (17%) limbs and the most common diagnoses were muscle and tendon (50%) and joint (non-bone) and ligament (41%) injuries. The highest incidences of match injuries occurred whilst being tackled (50 injuries/1000 h) and in a ruck or maul (35 injuries/1000 h), whilst the greatest incidences of training injuries occurred during endurance running (24 injuries/1000 h) and contact activities (20 injuries/1000 h). Players’ average body mass increased and skinfold measurement decreased significantly over the study period. Conclusions: The incidence of match injuries at international level was found to be higher than previously reported. The tackle, ruck, and maul elements of match play and the endurance running and contact elements of training presented the highest risk of injury for all players.
Hemochromatosis: Genetics and Pathophysiology
Authors: Ernest Beutler
Journal: Annual Review of Medicine (2005)

A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.
Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial
Authors: Kathy S Albain, William E Barlow, Peter M Ravdin, William B Farrar, Gary V Burton, Steven J Ketchel, Charles D Cobau, Ellis G Levine, James N Ingle, Kathleen I Pritchard, Allen S Lichter, Daniel J Schneider, Martin D Abeloff, I Craig Henderson, Hyman B Muss, Stephanie J Green, Danika Lew, Robert B Livingston, Silvana Martino, C Kent Osborne
Journal: The Lancet (2009)